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Does Buspirone and Bacitracin interact?

•Drug A: Buspirone •Drug B: Bacitracin •Severity: MINOR •Description: Bacitracin may decrease the excretion rate of Buspirone which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Bacitracin is indicated in topical formulations for acute and chronic localized skin infections. Occasionally, it is also used intramuscularly for infantile streptococcal pneumonia and empyema. Bacitracin is also formulated as an ointment with neomycin and polymyxin B for over the counter use. A bacitracin ointment formulated with neomycin and polymyxin B along with hydrocortisone is indicated for the treatment of corticosteroid responsive dermatoses with secondary infection. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bacitracin is a mixture of polypeptides that prevent the formation of the bacterial cell wall and oxidatively cleave DNA. It has a short duration of action as it must be given every 3 to 4 hours topically. Bacitracin is nephrotoxic when given intramuscularly and may lead to renal failure. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Bacitracin binds to a divalent metal ion such as Mn(II), Co(II), Ni(II), Cu(II), or Zn(II). These complexes bind C 55 -isoprenyl pyrophosphate, preventing the hydrolysis of a lipid dolichol pyrophosphate, which finally inhibits cell wall synthesis. Bacitracin metal complexes also bind and oxidatively cleave DNA. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Topical, ophthalmic, and oral formulations of bacitracin are poorly absorbed systemically. Intramuscular bacitracin is readily and completely absorbed. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): Data regarding the volume of distribution of bacitracin in humans is not readily available. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Data regarding the protein binding of bacitracin in humans is not readily available. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Data regarding the metabolism of bacitracin in humans is not readily available. Because bacitracin is a protein it is expected to be metabolized into smaller polypeptides and amino acids. However, the structure of bacitracin may afford it some protection from the action of proteases. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Bacitracin is mainly excreted renally with 87% of and intramuscular dose being recovered in the urine after 6 hours. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Data regarding the half life of bacitracin in humans is not readily available. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): Data regarding the clearance of bacitracin in humans has not been well studied. A study of 9 subjects in 1947 shows a renal clearance of 105-283mL/min with an average renal clearance of 159mL/min. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The oral LD 50 of bacitracin in rats is >2000mg/kg. Specific data regarding bacitracin overdoses is not readily available. An overdose of bacitracin may lead to nephrotoxicity and patients should be treated with supportive measures. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Baciguent, Baciject, Cortisporin, Diosporin, Diphen, Neo-polycin, Neo-polycin HC, Neosporin Ointment, Neosporin Plus Maximum Strength, Neosporin Solution, Polycin-B, Polysporin, Procomycin, Rash Relief Antibacterial, Triple Antibiotic •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bacitracin is a cyclic polypeptide antibiotic used to prevent wound infections, treat pneumonia and empyema in infants, and to treat skin and eye infections.

The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Question: Does Buspirone and Bacitracin interact? Information: •Drug A: Buspirone •Drug B: Bacitracin •Severity: MINOR •Description: Bacitracin may decrease the excretion rate of Buspirone which could result in a higher serum level. •Extended Description: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Bacitracin is indicated in topical formulations for acute and chronic localized skin infections. Occasionally, it is also used intramuscularly for infantile streptococcal pneumonia and empyema. Bacitracin is also formulated as an ointment with neomycin and polymyxin B for over the counter use. A bacitracin ointment formulated with neomycin and polymyxin B along with hydrocortisone is indicated for the treatment of corticosteroid responsive dermatoses with secondary infection. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bacitracin is a mixture of polypeptides that prevent the formation of the bacterial cell wall and oxidatively cleave DNA. It has a short duration of action as it must be given every 3 to 4 hours topically. Bacitracin is nephrotoxic when given intramuscularly and may lead to renal failure. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Bacitracin binds to a divalent metal ion such as Mn(II), Co(II), Ni(II), Cu(II), or Zn(II). These complexes bind C 55 -isoprenyl pyrophosphate, preventing the hydrolysis of a lipid dolichol pyrophosphate, which finally inhibits cell wall synthesis. Bacitracin metal complexes also bind and oxidatively cleave DNA. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Topical, ophthalmic, and oral formulations of bacitracin are poorly absorbed systemically. Intramuscular bacitracin is readily and completely absorbed. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): Data regarding the volume of distribution of bacitracin in humans is not readily available. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Data regarding the protein binding of bacitracin in humans is not readily available. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Data regarding the metabolism of bacitracin in humans is not readily available. Because bacitracin is a protein it is expected to be metabolized into smaller polypeptides and amino acids. However, the structure of bacitracin may afford it some protection from the action of proteases. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Bacitracin is mainly excreted renally with 87% of and intramuscular dose being recovered in the urine after 6 hours. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Data regarding the half life of bacitracin in humans is not readily available. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): Data regarding the clearance of bacitracin in humans has not been well studied. A study of 9 subjects in 1947 shows a renal clearance of 105-283mL/min with an average renal clearance of 159mL/min. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The oral LD 50 of bacitracin in rats is >2000mg/kg. Specific data regarding bacitracin overdoses is not readily available. An overdose of bacitracin may lead to nephrotoxicity and patients should be treated with supportive measures. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Baciguent, Baciject, Cortisporin, Diosporin, Diphen, Neo-polycin, Neo-polycin HC, Neosporin Ointment, Neosporin Plus Maximum Strength, Neosporin Solution, Polycin-B, Polysporin, Procomycin, Rash Relief Antibacterial, Triple Antibiotic •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bacitracin is a cyclic polypeptide antibiotic used to prevent wound infections, treat pneumonia and empyema in infants, and to treat skin and eye infections. Output: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. The severity of the interaction is minor.

Does Buspirone and Baclofen interact?

•Drug A: Buspirone •Drug B: Baclofen •Severity: MINOR •Description: Baclofen may increase the central nervous system depressant (CNS depressant) activities of Buspirone. •Extended Description: Baclofen possesses CNS depressant effects and can cause drowsiness and sedation, which may be an additive when used concomitantly with other CNS depressants. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Oral baclofen is indicated for the treatment of spasticity resulting from multiple sclerosis and is particularly useful for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity. It may also be used to treat patients with spinal cord injuries and other spinal cord diseases. Baclofen should not be used to treat skeletal muscle spasms resulting from rheumatic disorders. Intrathecal baclofen is also indicated for the management of severe spasticity of the cerebral or spinal original in patients 4 years of age and older. It is reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerable central nervous system side effects at effective doses. For use in spasticity due to traumatic brain injury, baclofen should be considered after at least one year of injury. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Baclofen is an antispasmodic agent that induces muscle relaxation. It reduces the release of excitatory neurotransmitters in the pre-synaptic neurons and stimulates inhibitory neuronal signals in the post-synaptic neurons. Oral formulations of baclofen are the most commonly used form of the drug. In one cross-section study, intrathecal baclofen was more effective than oral baclofen in relieving spasticity directly at the level of the spinal cord. Baclofen has CNS depression properties and can cause sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression. Baclofen also mediates some antinociceptive effects and stimulates gastric acid secretion. Baclofen exhibits anti-inflammatory and neuroprotective activities: it inhibits the release of pro-inflammatory cytokines from microglia and astrocytes, and decreases oxidative stress in rats. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): The exact mechanism of action of baclofen is unclear. Baclofen is an agonist at the beta subunit of gamma-aminobutyric acid (GABA) receptors expressed on pre- and post-synaptic neurons. Upon binding to GABA B receptors, baclofen causes an influx of potassium into the neuron, leading to hyperpolarization of the neuronal membrane and decreased calcium influx at presynaptic nerve terminals. This results in a decreased rate of action potential threshold being reached by presynaptic neurons and reduced action potential of postsynaptic motor neurons that innervate the muscle spindles. Baclofen thereby inhibits the transmission of both mono- and polysynaptic reflexes at the spinal cord, relaxing spasticity. Baclofen may act on some voltage-gated calcium channels; however, the clinical significance of this is unclear. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Baclofen has an oral bioavailability of 70% to 85%. Following oral administration, it is rapidly absorbed through the gastrointestinal tract with peak plasma concentrations being reached two to three hours after ingestion. Peak effect is observed about four hours after intrathecal administration. The absorption is dose-dependent and increases with higher doses. There is intersubject variation in absorption. Administration of oral baclofen suspension with a high-fat meal resulted in 9% decrease in AUC and 33% decrease in C max compared to the fasted state. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The volume of distribution of baclofen is 0.7 L/kg. As baclofen is mainly water-soluble, it does not readily cross the blood-brain barrier. Drug concentrations of baclofen in the cerebrospinal fluid are approximately 8.5 times lower than in the plasma. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): The protein binding is approximately 30%. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Approximately 15% of the oral dose is metabolized in the liver, mainly by deamination. Deamination yields the main metabolite, β-(p-chlorophenyl)-4-hydroxybutyric acid, which is pharmacologically inactive. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): About 70-80% of baclofen is eliminated in an unchanged form by renal excretion within 72 hours of administration. About 5% of the dose is excreted via the kidneys as metabolites. There is intersubject variation in elimination. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The half-life is 2-6 hours after oral administration and 1-5 hours following intrathecal administration. The apparent elimination half-life of baclofen oral suspension or granules is about 5.6 hours. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): The systemic clearance (CL/F) was 180 mL/min and the renal clearance was 103 mL/min following oral administration. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The oral LD 50 in rats is 145 mg/kg. Baclofen withdrawal symptoms typically occur within hours to days following interruption of either oral or intrathecal drug formulations. Abrupt discontinuation of baclofen is not advised. Clinical manifestations of baclofen overdose may include altered mental status, somnolence, seizure, hypothermia, respiratory depression, and coma. Overdose from baclofen oral tablets resulted in vomiting, lightheadedness, drowsiness, muscular hypotonia, accommodation disorders, coma, respiratory depression, and seizures. Most overdose symptoms are neurological but uncommon cardiovascular effects such as hypertension, bradycardia, and tachycardia may be observed. In case of overdose, symptomatic treatment and gastric decontamination should be initiated. When the patient is alert, gastric emptying should be performed by inducing emesis and then performing lavage while maintaining an adequate airway and respiration. Emesis should not be induced in unconscious patients. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Fleqsuvy, Gablofen, Kemstro, Lioresal, Lyvispah, Ozobax •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Baclofen Baclofène Baclofeno Baclofenum DL-Baclofen •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Baclofen is a GABA-ergic agonist used to manage severe spasticity of cerebral or spinal origin in adult and pediatric patients.

Baclofen possesses CNS depressant effects and can cause drowsiness and sedation, which may be an additive when used concomitantly with other CNS depressants. The severity of the interaction is minor.

Question: Does Buspirone and Baclofen interact? Information: •Drug A: Buspirone •Drug B: Baclofen •Severity: MINOR •Description: Baclofen may increase the central nervous system depressant (CNS depressant) activities of Buspirone. •Extended Description: Baclofen possesses CNS depressant effects and can cause drowsiness and sedation, which may be an additive when used concomitantly with other CNS depressants. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Oral baclofen is indicated for the treatment of spasticity resulting from multiple sclerosis and is particularly useful for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity. It may also be used to treat patients with spinal cord injuries and other spinal cord diseases. Baclofen should not be used to treat skeletal muscle spasms resulting from rheumatic disorders. Intrathecal baclofen is also indicated for the management of severe spasticity of the cerebral or spinal original in patients 4 years of age and older. It is reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerable central nervous system side effects at effective doses. For use in spasticity due to traumatic brain injury, baclofen should be considered after at least one year of injury. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Baclofen is an antispasmodic agent that induces muscle relaxation. It reduces the release of excitatory neurotransmitters in the pre-synaptic neurons and stimulates inhibitory neuronal signals in the post-synaptic neurons. Oral formulations of baclofen are the most commonly used form of the drug. In one cross-section study, intrathecal baclofen was more effective than oral baclofen in relieving spasticity directly at the level of the spinal cord. Baclofen has CNS depression properties and can cause sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression. Baclofen also mediates some antinociceptive effects and stimulates gastric acid secretion. Baclofen exhibits anti-inflammatory and neuroprotective activities: it inhibits the release of pro-inflammatory cytokines from microglia and astrocytes, and decreases oxidative stress in rats. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): The exact mechanism of action of baclofen is unclear. Baclofen is an agonist at the beta subunit of gamma-aminobutyric acid (GABA) receptors expressed on pre- and post-synaptic neurons. Upon binding to GABA B receptors, baclofen causes an influx of potassium into the neuron, leading to hyperpolarization of the neuronal membrane and decreased calcium influx at presynaptic nerve terminals. This results in a decreased rate of action potential threshold being reached by presynaptic neurons and reduced action potential of postsynaptic motor neurons that innervate the muscle spindles. Baclofen thereby inhibits the transmission of both mono- and polysynaptic reflexes at the spinal cord, relaxing spasticity. Baclofen may act on some voltage-gated calcium channels; however, the clinical significance of this is unclear. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Baclofen has an oral bioavailability of 70% to 85%. Following oral administration, it is rapidly absorbed through the gastrointestinal tract with peak plasma concentrations being reached two to three hours after ingestion. Peak effect is observed about four hours after intrathecal administration. The absorption is dose-dependent and increases with higher doses. There is intersubject variation in absorption. Administration of oral baclofen suspension with a high-fat meal resulted in 9% decrease in AUC and 33% decrease in C max compared to the fasted state. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The volume of distribution of baclofen is 0.7 L/kg. As baclofen is mainly water-soluble, it does not readily cross the blood-brain barrier. Drug concentrations of baclofen in the cerebrospinal fluid are approximately 8.5 times lower than in the plasma. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): The protein binding is approximately 30%. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Approximately 15% of the oral dose is metabolized in the liver, mainly by deamination. Deamination yields the main metabolite, β-(p-chlorophenyl)-4-hydroxybutyric acid, which is pharmacologically inactive. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): About 70-80% of baclofen is eliminated in an unchanged form by renal excretion within 72 hours of administration. About 5% of the dose is excreted via the kidneys as metabolites. There is intersubject variation in elimination. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The half-life is 2-6 hours after oral administration and 1-5 hours following intrathecal administration. The apparent elimination half-life of baclofen oral suspension or granules is about 5.6 hours. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): The systemic clearance (CL/F) was 180 mL/min and the renal clearance was 103 mL/min following oral administration. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The oral LD 50 in rats is 145 mg/kg. Baclofen withdrawal symptoms typically occur within hours to days following interruption of either oral or intrathecal drug formulations. Abrupt discontinuation of baclofen is not advised. Clinical manifestations of baclofen overdose may include altered mental status, somnolence, seizure, hypothermia, respiratory depression, and coma. Overdose from baclofen oral tablets resulted in vomiting, lightheadedness, drowsiness, muscular hypotonia, accommodation disorders, coma, respiratory depression, and seizures. Most overdose symptoms are neurological but uncommon cardiovascular effects such as hypertension, bradycardia, and tachycardia may be observed. In case of overdose, symptomatic treatment and gastric decontamination should be initiated. When the patient is alert, gastric emptying should be performed by inducing emesis and then performing lavage while maintaining an adequate airway and respiration. Emesis should not be induced in unconscious patients. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Fleqsuvy, Gablofen, Kemstro, Lioresal, Lyvispah, Ozobax •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Baclofen Baclofène Baclofeno Baclofenum DL-Baclofen •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Baclofen is a GABA-ergic agonist used to manage severe spasticity of cerebral or spinal origin in adult and pediatric patients. Output: Baclofen possesses CNS depressant effects and can cause drowsiness and sedation, which may be an additive when used concomitantly with other CNS depressants. The severity of the interaction is minor.

Does Buspirone and Balsalazide interact?

•Drug A: Buspirone •Drug B: Balsalazide •Severity: MINOR •Description: The risk or severity of hypertension can be increased when Buspirone is combined with Balsalazide. •Extended Description: Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For the treatment of mildly to moderately active ulcerative colitis. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Balsalazide is a prodrug that has little or no pharmacologic activity until it is enzymatically cleaved in the colon to produce mesalamine (5-aminosalicylic acid), an anti inflammatory drug indicated for the treatment of mildly to moderately active ulcerative colitis. Balsalazide disodium is delivered intact to the colon where it is cleaved by bacterial azoreduction to release equimolar quantities of mesalamine, which is the therapeutically active portion of the molecule, and the intert 4-aminobenzoyl-(beta)-alanine. As a result, the spectrum of pharmacologic activity of balsalazide is similar to that of mesalamine. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): The mechanism of action of 5-aminosalicylic acid is unknown, but appears exert its anti-inflammatory effects locally (in the GI tract) rather than systemically. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways (catalyzes the formation of prostaglandin precursors from arachidonic acid), and through the lipoxygenase pathways (catalyzes the formation of leukotrienes and hydroxyeicosatetraenoic acids from arachidonic acid and its metabolites), is increased in patients with chronic inflammatory bowel disease. Therefore, it is possible that 5-aminosalicylic acid diminishes inflammation by blocking production of arachidonic acid metabolites in the colon through both the inhibition of cyclooxygenase and lipoxygenase. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Low and variable, intact balsalazide is poorly absorbed systemically. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): ≥99% •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Cleaved in the colon via bacterial azoreduction to 5–aminosalicylic acid (5–ASA) and 4–aminobenzoyl-beta-alanine, the inactive carrier moiety. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): The products of the azoreduction of this compound, 5-ASA and 4-aminobenzoyl-ß-alanine, and their N-acetylated metabolites have been identified in plasma, urine and feces. Following single-dose administration of 2.25 g COLAZAL (three 750 mg capsules) under fasting conditions in healthy subjects, mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.20%, 0.22% and 10.2%, respectively. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Half-life could not be determined. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): A single oral dose of balsalazide disodium at 5 grams/kg or 4-aminobenzoyl-(beta)-alanine, a metabolite of balsalazide disodium, at 1 gram/kg was non-lethal in mice and rats. No symptoms of acute toxicity were seen at these doses. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Colazal •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Balsalazida Balsalazide Balsalazidum •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Balsalazide is an aminosalicylate used to treat ulcerative colitis.

Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity. The severity of the interaction is minor.

Question: Does Buspirone and Balsalazide interact? Information: •Drug A: Buspirone •Drug B: Balsalazide •Severity: MINOR •Description: The risk or severity of hypertension can be increased when Buspirone is combined with Balsalazide. •Extended Description: Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For the treatment of mildly to moderately active ulcerative colitis. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Balsalazide is a prodrug that has little or no pharmacologic activity until it is enzymatically cleaved in the colon to produce mesalamine (5-aminosalicylic acid), an anti inflammatory drug indicated for the treatment of mildly to moderately active ulcerative colitis. Balsalazide disodium is delivered intact to the colon where it is cleaved by bacterial azoreduction to release equimolar quantities of mesalamine, which is the therapeutically active portion of the molecule, and the intert 4-aminobenzoyl-(beta)-alanine. As a result, the spectrum of pharmacologic activity of balsalazide is similar to that of mesalamine. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): The mechanism of action of 5-aminosalicylic acid is unknown, but appears exert its anti-inflammatory effects locally (in the GI tract) rather than systemically. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways (catalyzes the formation of prostaglandin precursors from arachidonic acid), and through the lipoxygenase pathways (catalyzes the formation of leukotrienes and hydroxyeicosatetraenoic acids from arachidonic acid and its metabolites), is increased in patients with chronic inflammatory bowel disease. Therefore, it is possible that 5-aminosalicylic acid diminishes inflammation by blocking production of arachidonic acid metabolites in the colon through both the inhibition of cyclooxygenase and lipoxygenase. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Low and variable, intact balsalazide is poorly absorbed systemically. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): ≥99% •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Cleaved in the colon via bacterial azoreduction to 5–aminosalicylic acid (5–ASA) and 4–aminobenzoyl-beta-alanine, the inactive carrier moiety. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): The products of the azoreduction of this compound, 5-ASA and 4-aminobenzoyl-ß-alanine, and their N-acetylated metabolites have been identified in plasma, urine and feces. Following single-dose administration of 2.25 g COLAZAL (three 750 mg capsules) under fasting conditions in healthy subjects, mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.20%, 0.22% and 10.2%, respectively. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Half-life could not be determined. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): A single oral dose of balsalazide disodium at 5 grams/kg or 4-aminobenzoyl-(beta)-alanine, a metabolite of balsalazide disodium, at 1 gram/kg was non-lethal in mice and rats. No symptoms of acute toxicity were seen at these doses. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Colazal •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Balsalazida Balsalazide Balsalazidum •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Balsalazide is an aminosalicylate used to treat ulcerative colitis. Output: Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity. The severity of the interaction is minor.

Does Buspirone and Baricitinib interact?

•Drug A: Buspirone •Drug B: Baricitinib •Severity: MINOR •Description: Buspirone may decrease the excretion rate of Baricitinib which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): In the US and Europe, baricitinib is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF blockers. Baricitinib may be used as monotherapy or in combination with methotrexate or other DMARDs. In Europe, baricitinib is indicated for the treatment of moderate to severe atopic dermatitis in adult patients who are candidates for systemic therapy. In the US, baricitinib is also indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation. Recently, it is also approved as the treatment for severe alopecia areata in adults. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Baricitinib is a disease-modifying antirheumatic drug (DMARD) used to ameliorate symptoms and slow down the progression of rheumatoid arthritis. In animal models of inflammatory arthritis, baricitinib was shown to have significant anti-inflammatory effects but also led to the preservation of cartilage and bone, with no detectable suppression of humoral immunity or adverse hematologic effects. Baricitinib decreased the levels of immunoglobulins and serum C-reactive protein in patients with rheumatoid arthritis. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): As members of the tyrosine kinase family, Janus kinases (JAKs) are intracellular enzymes that modulate signals from cytokines and growth factor receptors involved in hematopoiesis, inflammation, and immune cell function. Upon binding of extracellular cytokines and growth factors, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs). STATs modulate intracellular activity, including gene transcription of inflammatory mediators that promote an autoimmune response, such as IL-2, IL-6, IL-12, IL-15, IL-23, IFN-γ, GM-CSF, and interferons. The JAK-STAT pathway has been implicated in the pathophysiology of rheumatoid arthritis, as it is associated with an overproduction of inflammatory mediators. There are four JAK proteins: JAK 1, JAK 2, JAK 3 and TYK2. JAKs form homodimers or heterodimers and pair differently in different cell receptors to transmit cytokine signaling. Baricitinib is a selective and reversible inhibitor of JAK1 and JAK2 with less affinity for JAK3 and TYK2; however, the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. Baricitinib inhibits the activity of JAK proteins and modulates the signaling pathway of various interleukins, interferons, and growth factors. It was also shown to decrease the proliferation of JAK1/JAK2 expression in mutated cells and induce cell apoptosis. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): The absolute bioavailability of baricitinib is approximately 80%. The C max was reached after one hour of oral drug administration. A high-fat meal decreased the mean AUC and C max of baricitinib by approximately 11% and 18%, respectively, and delayed T max by 0.5 hours. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): Following intravenous administration, the volume of distribution was 76 L, indicating distribution into tissues. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Baricitinib is approximately 50% bound to plasma proteins and 45% bound to serum proteins. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Baricitinib is metabolized by CYP3A4. Approximately 6% of the orally administered dose was identified as metabolites in urine and feces; however, no metabolites of baricitinib were quantifiable in plasma. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Baricitinib is predominantly excreted via renal elimination. It is cleared via filtration and active secretion. Approximately 75% of the administered dose was eliminated in the urine, with 20% of that dose being the unchanged drug. About 20% of the dose was eliminated in the feces, with 15% of that dose being an unchanged drug. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The elimination half-life in patients with rheumatoid arthritis is approximately 12 hours. The elimination half-life was 10.8 hours in intubated patients with COVID-19 who received baricitinib via nasogastric (NG) or orogastric (OG) tube. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): The total body clearance of baricitinib was 8.9 L/h in patients with rheumatoid arthritis. The total body clearance and half-life of baricitinib was 14.2 L/h in intubated patients with COVID-19 who received baricitinib via nasogastric (NG) or orogastric (OG) tube. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The oral lowest published toxic dose (TDLo) is 1820 g/kg in mice and 5096 g/kg in rats. In clinical trials, single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days did not result in any dose-limiting toxicity. Pharmacokinetic data of a single dose of 40 mg in healthy volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 24 hours. In case of an overdose, it is recommended that patients are monitored for signs and symptoms of drug-related adverse reactions, which should be responded with appropriate treatment. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Olumiant •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Baricitinib is a Janus kinase inhibitor used to treat moderate to severe rheumatoid arthritis that has responded poorly to at least one TNF antagonist.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Buspirone and Baricitinib interact? Information: •Drug A: Buspirone •Drug B: Baricitinib •Severity: MINOR •Description: Buspirone may decrease the excretion rate of Baricitinib which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): In the US and Europe, baricitinib is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF blockers. Baricitinib may be used as monotherapy or in combination with methotrexate or other DMARDs. In Europe, baricitinib is indicated for the treatment of moderate to severe atopic dermatitis in adult patients who are candidates for systemic therapy. In the US, baricitinib is also indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation. Recently, it is also approved as the treatment for severe alopecia areata in adults. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Baricitinib is a disease-modifying antirheumatic drug (DMARD) used to ameliorate symptoms and slow down the progression of rheumatoid arthritis. In animal models of inflammatory arthritis, baricitinib was shown to have significant anti-inflammatory effects but also led to the preservation of cartilage and bone, with no detectable suppression of humoral immunity or adverse hematologic effects. Baricitinib decreased the levels of immunoglobulins and serum C-reactive protein in patients with rheumatoid arthritis. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): As members of the tyrosine kinase family, Janus kinases (JAKs) are intracellular enzymes that modulate signals from cytokines and growth factor receptors involved in hematopoiesis, inflammation, and immune cell function. Upon binding of extracellular cytokines and growth factors, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs). STATs modulate intracellular activity, including gene transcription of inflammatory mediators that promote an autoimmune response, such as IL-2, IL-6, IL-12, IL-15, IL-23, IFN-γ, GM-CSF, and interferons. The JAK-STAT pathway has been implicated in the pathophysiology of rheumatoid arthritis, as it is associated with an overproduction of inflammatory mediators. There are four JAK proteins: JAK 1, JAK 2, JAK 3 and TYK2. JAKs form homodimers or heterodimers and pair differently in different cell receptors to transmit cytokine signaling. Baricitinib is a selective and reversible inhibitor of JAK1 and JAK2 with less affinity for JAK3 and TYK2; however, the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. Baricitinib inhibits the activity of JAK proteins and modulates the signaling pathway of various interleukins, interferons, and growth factors. It was also shown to decrease the proliferation of JAK1/JAK2 expression in mutated cells and induce cell apoptosis. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): The absolute bioavailability of baricitinib is approximately 80%. The C max was reached after one hour of oral drug administration. A high-fat meal decreased the mean AUC and C max of baricitinib by approximately 11% and 18%, respectively, and delayed T max by 0.5 hours. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): Following intravenous administration, the volume of distribution was 76 L, indicating distribution into tissues. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Baricitinib is approximately 50% bound to plasma proteins and 45% bound to serum proteins. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Baricitinib is metabolized by CYP3A4. Approximately 6% of the orally administered dose was identified as metabolites in urine and feces; however, no metabolites of baricitinib were quantifiable in plasma. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Baricitinib is predominantly excreted via renal elimination. It is cleared via filtration and active secretion. Approximately 75% of the administered dose was eliminated in the urine, with 20% of that dose being the unchanged drug. About 20% of the dose was eliminated in the feces, with 15% of that dose being an unchanged drug. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The elimination half-life in patients with rheumatoid arthritis is approximately 12 hours. The elimination half-life was 10.8 hours in intubated patients with COVID-19 who received baricitinib via nasogastric (NG) or orogastric (OG) tube. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): The total body clearance of baricitinib was 8.9 L/h in patients with rheumatoid arthritis. The total body clearance and half-life of baricitinib was 14.2 L/h in intubated patients with COVID-19 who received baricitinib via nasogastric (NG) or orogastric (OG) tube. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The oral lowest published toxic dose (TDLo) is 1820 g/kg in mice and 5096 g/kg in rats. In clinical trials, single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days did not result in any dose-limiting toxicity. Pharmacokinetic data of a single dose of 40 mg in healthy volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 24 hours. In case of an overdose, it is recommended that patients are monitored for signs and symptoms of drug-related adverse reactions, which should be responded with appropriate treatment. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Olumiant •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Baricitinib is a Janus kinase inhibitor used to treat moderate to severe rheumatoid arthritis that has responded poorly to at least one TNF antagonist. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Buspirone and Beclomethasone dipropionate interact?

•Drug A: Buspirone •Drug B: Beclomethasone dipropionate •Severity: MODERATE •Description: The metabolism of Buspirone can be increased when combined with Beclomethasone dipropionate. •Extended Description: The subject is an inducer of the CYP3A5 enzyme, and the affected drug is a substrate of the CYP3A5 enzyme. When these drugs are administered concomitantly, the metabolism of the affected drug is increased, leading to decreased serum concentrations and lower efficacy. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Indicated for oral inhalation use in the maintenance treatment of asthma as prophylactic therapy in patients 5 years of age and older. The aerosol form of beclomethasone diproprionate is not indicated for the relief of acute bronchospasm. Indicated for intranasal use to relieve the symptoms of seasonal or perennial allergic and nonallergic (vasomotor) rhinitis and prevent the recurrence of nasal polyps following surgical removal. Indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 13 years of age and older. Corticosteroid-responsive dermatoses include psoriasis, contact dermatitis (dermatitis venenata), atopic dermatitis (infantile eczema, allergic dermatitis), neurodermatitis (lichen simplex chronicus, lichen planus, eczema, eczematous dermatitis), intertrigo, dyshidroses (pompholyx), seborrheic dermatitis, exfoliative dermatitis, solar dermatitis, stasis dermatitis, and anogenital and senile pruritus. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Inflammatory conditions, including asthma, dermatoses, and allergic rhinitis, involve the activation of cascades by inflammatory mediators. Inflammation is a primary defense mechanism and the homeostatic response of the immune system; however, a prolonged inflammatory response in certain disorders may lead to tissue damage, pain, and swelling. Beclomethasone dipropionate works by attenuating the inflammatory responses associated with asthma, allergic rhinitis, nasal polyps, and corticosteroid-responsive dermatoses. It suppresses the actions of inflammatory cells, such as mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils. It also inhibits the release of inflammatory mediators, such as histamine, eicosanoids, leukotrienes, and cytokines. Beclomethasone dipropionate is reported to exhibit potent topical activity while possessing low systemic effects. Beclomethasone dipropionate is a corticosteroid drug with anti-inflammatory and vasoconstrictive effects used to treat chronic inflammatory processes such as asthma, allergic rhinitis, corticosteroid-responsive dermatoses. When inhaled, it improves lung function, decreases airway hyper-reactivity, and reduces the severity of asthmatic symptoms. Although inhaled corticosteroids, including beclomethasone dipropionate, are reported to mainly act locally in the lungs, systemic effects such as disruption of hypothalamic-pituitary-adrenal (HPA) axis function, bone turnover, osteoporosis, and growth suppression may still be observed with chronic use or high dose administration. There were varying findings from clinical studies examining the effect of beclomethasone dipropionate on growth suppression in pediatric patients. It was shown to suppress the hypothalamo-pituitary-adrenal (HPA) axis in a dose-dependent manner. HPA axis is a central hormonal response system to stress and activation of HPA axis leads to the production of endogenous steroid hormone production. Long-term use of high-dose systemic corticosteroids, including those inhaled, was often associated with signs and symptoms of adrenal insufficiency when exposed to stress conditions, such as trauma, surgery, or infections. As corticosteroids work by suppressing the immune system, there may be an increased risk for developing infections. Cases of Candida albicans infection of the mouth and throat have been reported with inhaled beclomethasone dipropionate therapy. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Beclomethasone dipropionate is a corticosteroid and prodrug that is rapidly activated by hydrolysis to the active monoester, 17 monopropionate (17-BMP), which mediates anti-inflammatory actions. 17-BMP has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 13 times that of dexamethasone and 25 times that of beclomethasone dipropionate. Upon binding of the ligand, the glucocorticoid receptors dimerize and translocate into the nucleus, where they subsequently bind to glucocorticoid response elements (GRE) on glucocorticoid-responsive genes, leading to changes in transcription. There are several proposed mechanisms for the anti-inflammatory action of corticosteroids. Corticosteroids may work by increasing the transcription of genes coding for anti-inflammatory proteins, including lipocortin-1 and interleukin-10. Corticosteroids were also shown to inhibit the expression of multiple genes that encode pro-inflammatory factors, such as cytokines, chemokines, and adhesion molecules, that are activated during the chronic inflammatory process. This is thought to be due to the direct inhibitory interaction between activated glucocorticoid receptors and activated pro-inflammatory transcription factors, such as nuclear factor-kappa B and activator protein-1. Chronic inflammation is often characterized by enhanced expression of these transcription factors that bind to and activate coactivator molecules, which then acetylate core histones to switch on gene transcription to further amplify the inflammatory process. Corticosteroids suppress the multiple inflammatory gene expression by promoting histone deacetylation, resulting in tighter coiling of DNA and reduced access of transcription factors to their binding sites. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Following oral inhalation of 320 mcg of beclomethasone dipropionate (BDP), the Cmax was 88 pg/mL and it was reached after 0.5 at post-administration. The mean Cmax of the major and most active metabolite, beclomethasone-17-monopropionate (17-BMP), was 1419 pg/mL at 0.7 hour post-dosing. In another pharmacokinetic study, the AUC of BDP and 17-BMP were 6660 and 6185 pgxh/mL, respectively. The Cmax was 35356 pg/mL for BDP and 2633 pg/mL for 17-BMP, and and the median time to reach these concentrations (Tmax) was 0.2 hours. In the same study, the AUC of 17-BMP following oral and intranasal administration were 10158 and 3660 pgxh/mL, respectively. The Cmax of 17-BMP following oral and intranasal administration were 703 and 310 pg/mL, respectively, and the Tmax was 4 hours. The total bioavailability of 17-BMP following oral and intranasal administration were 41% and 44%, respectively. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): Following intravenous administration, the steady-state volume of distribution was 20 L for beclomethasone dipropionate and 424 L for the active metabolite, beclomethasone-17-monopropionate. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Based on the findings of in vitro studies, the protein binding of the main active metabolite, beclomethasone-17-monopropionate (17-BMP), was 94-96% over the concentration range of 1000 to 5000 pg/mL. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): During absorption, beclomethasone dipropionate is undergoes rapid and extensive hydrolysis mediated by esterases CYP3A to form beclomethasone-17-monopropionate (17-BMP), beclomethasone-21-monopropionate (21-BMP), and beclomethasone (BOH). 17-BMP is the major active metabolite with the most potent anti-inflammatory activity. About 95% of the total beclomethasone dipropionate administered via oral inhalation undergoes presystemic conversion to form 17-BMP in the lung. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Regardless of the route of administration, beclomethasone dipropionate and its metabolites are predominantly excreted in the feces, with less than 10% of the drug and its metabolites being excreted in the urine. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Following intravenous administration, the half life of beclomethasone dipropionate was 0.5 hours while the half life of the active metabolite 17-BMP was 2.7 hours. Following oral and intranasal administration, the half life of 17-BMP was 8.8 and 5.7 hours, respectively. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): Following intravenous administration, the clearance of beclomethasone dipropionate and 17-BMP were 150 L/h and 120 L/h, respectively. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The oral LD 50 in rats is >3750 mg/kg. The acute toxicity of beclometasone dipropionate is low. The only harmful effect that follows inhalation of large amounts of the drug over a short period of time is suppression of hypothalamic-pituitary-adrenal (HPA) function. Chronic: The excessive use of beclometasone dipropionate over a long period could lead to adrenal suppression. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Alanase, Beconase, Propaderm, Qnasl, Qvar, Rivanase AQ •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Beclometasone dipropionate Beclometasone dipropionato Beclomethasone dipropionate •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Beclomethasone dipropionate is an inhaled corticosteroid used as maintenance treatment in the prophylaxis of asthma attacks.

The subject is an inducer of the CYP3A5 enzyme, and the affected drug is a substrate of the CYP3A5 enzyme. When these drugs are administered concomitantly, the metabolism of the affected drug is increased, leading to decreased serum concentrations and lower efficacy. The severity of the interaction is moderate.

Question: Does Buspirone and Beclomethasone dipropionate interact? Information: •Drug A: Buspirone •Drug B: Beclomethasone dipropionate •Severity: MODERATE •Description: The metabolism of Buspirone can be increased when combined with Beclomethasone dipropionate. •Extended Description: The subject is an inducer of the CYP3A5 enzyme, and the affected drug is a substrate of the CYP3A5 enzyme. When these drugs are administered concomitantly, the metabolism of the affected drug is increased, leading to decreased serum concentrations and lower efficacy. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Indicated for oral inhalation use in the maintenance treatment of asthma as prophylactic therapy in patients 5 years of age and older. The aerosol form of beclomethasone diproprionate is not indicated for the relief of acute bronchospasm. Indicated for intranasal use to relieve the symptoms of seasonal or perennial allergic and nonallergic (vasomotor) rhinitis and prevent the recurrence of nasal polyps following surgical removal. Indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 13 years of age and older. Corticosteroid-responsive dermatoses include psoriasis, contact dermatitis (dermatitis venenata), atopic dermatitis (infantile eczema, allergic dermatitis), neurodermatitis (lichen simplex chronicus, lichen planus, eczema, eczematous dermatitis), intertrigo, dyshidroses (pompholyx), seborrheic dermatitis, exfoliative dermatitis, solar dermatitis, stasis dermatitis, and anogenital and senile pruritus. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Inflammatory conditions, including asthma, dermatoses, and allergic rhinitis, involve the activation of cascades by inflammatory mediators. Inflammation is a primary defense mechanism and the homeostatic response of the immune system; however, a prolonged inflammatory response in certain disorders may lead to tissue damage, pain, and swelling. Beclomethasone dipropionate works by attenuating the inflammatory responses associated with asthma, allergic rhinitis, nasal polyps, and corticosteroid-responsive dermatoses. It suppresses the actions of inflammatory cells, such as mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils. It also inhibits the release of inflammatory mediators, such as histamine, eicosanoids, leukotrienes, and cytokines. Beclomethasone dipropionate is reported to exhibit potent topical activity while possessing low systemic effects. Beclomethasone dipropionate is a corticosteroid drug with anti-inflammatory and vasoconstrictive effects used to treat chronic inflammatory processes such as asthma, allergic rhinitis, corticosteroid-responsive dermatoses. When inhaled, it improves lung function, decreases airway hyper-reactivity, and reduces the severity of asthmatic symptoms. Although inhaled corticosteroids, including beclomethasone dipropionate, are reported to mainly act locally in the lungs, systemic effects such as disruption of hypothalamic-pituitary-adrenal (HPA) axis function, bone turnover, osteoporosis, and growth suppression may still be observed with chronic use or high dose administration. There were varying findings from clinical studies examining the effect of beclomethasone dipropionate on growth suppression in pediatric patients. It was shown to suppress the hypothalamo-pituitary-adrenal (HPA) axis in a dose-dependent manner. HPA axis is a central hormonal response system to stress and activation of HPA axis leads to the production of endogenous steroid hormone production. Long-term use of high-dose systemic corticosteroids, including those inhaled, was often associated with signs and symptoms of adrenal insufficiency when exposed to stress conditions, such as trauma, surgery, or infections. As corticosteroids work by suppressing the immune system, there may be an increased risk for developing infections. Cases of Candida albicans infection of the mouth and throat have been reported with inhaled beclomethasone dipropionate therapy. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Beclomethasone dipropionate is a corticosteroid and prodrug that is rapidly activated by hydrolysis to the active monoester, 17 monopropionate (17-BMP), which mediates anti-inflammatory actions. 17-BMP has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 13 times that of dexamethasone and 25 times that of beclomethasone dipropionate. Upon binding of the ligand, the glucocorticoid receptors dimerize and translocate into the nucleus, where they subsequently bind to glucocorticoid response elements (GRE) on glucocorticoid-responsive genes, leading to changes in transcription. There are several proposed mechanisms for the anti-inflammatory action of corticosteroids. Corticosteroids may work by increasing the transcription of genes coding for anti-inflammatory proteins, including lipocortin-1 and interleukin-10. Corticosteroids were also shown to inhibit the expression of multiple genes that encode pro-inflammatory factors, such as cytokines, chemokines, and adhesion molecules, that are activated during the chronic inflammatory process. This is thought to be due to the direct inhibitory interaction between activated glucocorticoid receptors and activated pro-inflammatory transcription factors, such as nuclear factor-kappa B and activator protein-1. Chronic inflammation is often characterized by enhanced expression of these transcription factors that bind to and activate coactivator molecules, which then acetylate core histones to switch on gene transcription to further amplify the inflammatory process. Corticosteroids suppress the multiple inflammatory gene expression by promoting histone deacetylation, resulting in tighter coiling of DNA and reduced access of transcription factors to their binding sites. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Following oral inhalation of 320 mcg of beclomethasone dipropionate (BDP), the Cmax was 88 pg/mL and it was reached after 0.5 at post-administration. The mean Cmax of the major and most active metabolite, beclomethasone-17-monopropionate (17-BMP), was 1419 pg/mL at 0.7 hour post-dosing. In another pharmacokinetic study, the AUC of BDP and 17-BMP were 6660 and 6185 pgxh/mL, respectively. The Cmax was 35356 pg/mL for BDP and 2633 pg/mL for 17-BMP, and and the median time to reach these concentrations (Tmax) was 0.2 hours. In the same study, the AUC of 17-BMP following oral and intranasal administration were 10158 and 3660 pgxh/mL, respectively. The Cmax of 17-BMP following oral and intranasal administration were 703 and 310 pg/mL, respectively, and the Tmax was 4 hours. The total bioavailability of 17-BMP following oral and intranasal administration were 41% and 44%, respectively. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): Following intravenous administration, the steady-state volume of distribution was 20 L for beclomethasone dipropionate and 424 L for the active metabolite, beclomethasone-17-monopropionate. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Based on the findings of in vitro studies, the protein binding of the main active metabolite, beclomethasone-17-monopropionate (17-BMP), was 94-96% over the concentration range of 1000 to 5000 pg/mL. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): During absorption, beclomethasone dipropionate is undergoes rapid and extensive hydrolysis mediated by esterases CYP3A to form beclomethasone-17-monopropionate (17-BMP), beclomethasone-21-monopropionate (21-BMP), and beclomethasone (BOH). 17-BMP is the major active metabolite with the most potent anti-inflammatory activity. About 95% of the total beclomethasone dipropionate administered via oral inhalation undergoes presystemic conversion to form 17-BMP in the lung. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Regardless of the route of administration, beclomethasone dipropionate and its metabolites are predominantly excreted in the feces, with less than 10% of the drug and its metabolites being excreted in the urine. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Following intravenous administration, the half life of beclomethasone dipropionate was 0.5 hours while the half life of the active metabolite 17-BMP was 2.7 hours. Following oral and intranasal administration, the half life of 17-BMP was 8.8 and 5.7 hours, respectively. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): Following intravenous administration, the clearance of beclomethasone dipropionate and 17-BMP were 150 L/h and 120 L/h, respectively. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The oral LD 50 in rats is >3750 mg/kg. The acute toxicity of beclometasone dipropionate is low. The only harmful effect that follows inhalation of large amounts of the drug over a short period of time is suppression of hypothalamic-pituitary-adrenal (HPA) function. Chronic: The excessive use of beclometasone dipropionate over a long period could lead to adrenal suppression. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Alanase, Beconase, Propaderm, Qnasl, Qvar, Rivanase AQ •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Beclometasone dipropionate Beclometasone dipropionato Beclomethasone dipropionate •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Beclomethasone dipropionate is an inhaled corticosteroid used as maintenance treatment in the prophylaxis of asthma attacks. Output: The subject is an inducer of the CYP3A5 enzyme, and the affected drug is a substrate of the CYP3A5 enzyme. When these drugs are administered concomitantly, the metabolism of the affected drug is increased, leading to decreased serum concentrations and lower efficacy. The severity of the interaction is moderate.

Does Buspirone and Benazepril interact?

•Drug A: Buspirone •Drug B: Benazepril •Severity: MINOR •Description: Buspirone may decrease the antihypertensive activities of Benazepril. •Extended Description: The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Benazepril is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Benazepril, an angiotensin-converting enzyme (ACE) inhibitor, is a prodrug which, when hydrolyzed by esterases to its active Benazeprilat, is used to treat hypertension and heart failure, to reduce proteinuria and renal disease in patients with nephropathies, and to prevent stroke, myocardial infarction, and cardiac death in high-risk patients. Benazepril and Benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Benazeprilat, the active metabolite of Benazepril, competes with angiotensin I for binding at the angiotensin-converting enzyme, blocking the conversion of angiotensin I to angiotensin II. Inhibition of ACE results in decreased plasma angiotensin II. As angiotensin II is a vasoconstrictor and a negative-feedback mediator for renin activity, lower concentrations result in a decrease in blood pressure and stimulation of baroreceptor reflex mechanisms, which leads to decreased vasopressor activity and to decreased aldosterone secretion. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Bioavailability of oral dosing is 3% to 4% in horses. In humans at least 37% of oral benazepril is absorbed and reaches peak plasma concentration in 0.5 hours to 1 hour. Other studies have shown a peak plasma concentration at a median of 1.5 hours. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The final population pharmacokinetic model in one study estimated the volume of distribution to be 203±69.9L. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Benazepril is 96.7% protein bound while benazeprilat is 95.3% protein bound. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat. Benazepril and benazeprilat are conjugated to glucuronic acid prior to urinary excretion. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of benazeprilat excretion in healthy subjects. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The half life of the prodrug benazepril is 2.7±8.5h. The half life of the active metabolite benazeprilat is 22.3±9.2h The accumulation half life of benazepril is 10 to 11 hours. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): The final population pharmacokinetic model of one study estimates the clearance to be 129±30.0L. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The most common adverse effects include headache, dizziness, fatigue, somnolence, postural dizziness, nausea, and cough. The most likely symptom of overdosage is severe hypotension. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Amlobenz, Lotensin, Lotensin Hct, Lotrel •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benazepril is an ACE inhibitor prodrug used to treat hypertension.

The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. The severity of the interaction is minor.

Question: Does Buspirone and Benazepril interact? Information: •Drug A: Buspirone •Drug B: Benazepril •Severity: MINOR •Description: Buspirone may decrease the antihypertensive activities of Benazepril. •Extended Description: The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Benazepril is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Benazepril, an angiotensin-converting enzyme (ACE) inhibitor, is a prodrug which, when hydrolyzed by esterases to its active Benazeprilat, is used to treat hypertension and heart failure, to reduce proteinuria and renal disease in patients with nephropathies, and to prevent stroke, myocardial infarction, and cardiac death in high-risk patients. Benazepril and Benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Benazeprilat, the active metabolite of Benazepril, competes with angiotensin I for binding at the angiotensin-converting enzyme, blocking the conversion of angiotensin I to angiotensin II. Inhibition of ACE results in decreased plasma angiotensin II. As angiotensin II is a vasoconstrictor and a negative-feedback mediator for renin activity, lower concentrations result in a decrease in blood pressure and stimulation of baroreceptor reflex mechanisms, which leads to decreased vasopressor activity and to decreased aldosterone secretion. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Bioavailability of oral dosing is 3% to 4% in horses. In humans at least 37% of oral benazepril is absorbed and reaches peak plasma concentration in 0.5 hours to 1 hour. Other studies have shown a peak plasma concentration at a median of 1.5 hours. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The final population pharmacokinetic model in one study estimated the volume of distribution to be 203±69.9L. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Benazepril is 96.7% protein bound while benazeprilat is 95.3% protein bound. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat. Benazepril and benazeprilat are conjugated to glucuronic acid prior to urinary excretion. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of benazeprilat excretion in healthy subjects. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The half life of the prodrug benazepril is 2.7±8.5h. The half life of the active metabolite benazeprilat is 22.3±9.2h The accumulation half life of benazepril is 10 to 11 hours. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): The final population pharmacokinetic model of one study estimates the clearance to be 129±30.0L. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The most common adverse effects include headache, dizziness, fatigue, somnolence, postural dizziness, nausea, and cough. The most likely symptom of overdosage is severe hypotension. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Amlobenz, Lotensin, Lotensin Hct, Lotrel •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benazepril is an ACE inhibitor prodrug used to treat hypertension. Output: The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. The severity of the interaction is minor.

Does Buspirone and Benperidol interact?

•Drug A: Buspirone •Drug B: Benperidol •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Buspirone is combined with Benperidol. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): No half-life available •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benperidol is a neuroleptic butyrophenone derivative indicated in the treatment of psychoses, manic episodes, and psychomotor agitation.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Buspirone and Benperidol interact? Information: •Drug A: Buspirone •Drug B: Benperidol •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Buspirone is combined with Benperidol. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): No half-life available •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benperidol is a neuroleptic butyrophenone derivative indicated in the treatment of psychoses, manic episodes, and psychomotor agitation. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Buspirone and Benzatropine interact?

•Drug A: Buspirone •Drug B: Benzatropine •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Buspirone is combined with Benzatropine. •Extended Description: Reports have indicated that concomitant administration of benzatropine and inhibitors of dopamine activity can increase gastrointestinal adverse effects, fever, and heat intolerance. The effects could be caused by the reversal of dopamine antagonism or a neurotransmitter imbalance. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Benztropine is indicated to be used as an adjunct in the therapy of all forms of parkinsonism. It can also be used for the control of extrapyramidal disorders due to neuroleptic drugs. The extrapyramidal symptoms are defined as drug-induced disorders that include symptoms of dystonia, akathisia, parkinsonism, bradykinesia, tremors, and dyskinesia. Parkinsonism is a general term that refers to the group of neurological disorders that produce symptoms similar to Parkinson's disease such as tremors, slow movement, and stiffness. The parkinsonism includes a large number of disorders and some of them have not been clearly defined. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): The inhibition of dopamine reuptake by benztropine produces a dose-dependent increase of dopamine in the nerve terminal of the dopaminergic system. Clinically the activity of benztropine is observed after 1-2 hours of oral administration and after a few minutes of intramuscular administration with a last-longing effect of about 24 hours. Reports have indicated that benztropine has a very large sedative effect. The antihistaminic effect of benztropine is very similar to the effect found in pyrilamine and the anticholinergic activity was found to be equal to atropine ex vivo and of about 50% activity in vivo. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Benztropine is an agent with anti-muscarinic and antihistaminic effects. Its main mechanism of action is presented by the selective inhibition of dopamine transporters but it also presents affinity for histamine and muscarine receptors. It is widely known that benztropine is a potent inhibitor of presynaptic carrier-mediated dopamine transport. As well, it is known to be an analog of atropine and hence, it has a large affinity for muscarinic receptors M1 in the human brain. Once bound, benztropine blocks the activity of the muscarinic receptors mainly in the striatum. The increased advantage of benztropine lays on the antagonism of acetylcholine activity which corrects the imbalance between dopamine and acetylcholine in Parkinson patients. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Oral administration of 1.5 mg of benztropine is slowly absorbed in the gastrointestinal tract and it reaches a peak concentration of 2.5 ng/ml in about 7 hours. It has an approximate oral bioavailability of 29%. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): Benztropine is expected to present a large volume of distribution between 12-30 L/kg. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): About 95% of the administered dose of benztropine is found bound to plasma proteins. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Benztropine has been shown to undergo metabolism mainly marked by N-oxidation, N-dealkylation and ring hydroxylation. The extensive metabolism of benztropine produces eight phase-I metabolites plus four glucuronide conjugates. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Benztropine is mainly excreted in the urine but it is also found in the feces unchanged. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The elimination half-life of benztropine is very variable and it is reported to be of around 36 hours. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): Extensive pharmacodynamic or pharmacokinetic studies have not been performed. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The oral LD50 of benztropine is reported to be of 940 mg/kg in rats. In the presence of overdose with benztropine, it has been observed symptoms of circulatory collapse, cardiac arrest, respiratory depression, respiratory arrest, psychosis, shock, coma, seizure, ataxia, combativeness, anhidrosis, hyperthermia, fever, dysphagia, decreased bowel sounds and sluggish pupils. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Cogentin •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Benzatropina Benzatropine Benzatropinum Benztropine Tropine benzohydryl ether •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benzatropine is an anticholinergic drug used to treat Parkinson's disease (PD) and extrapyramidal symptoms, except tardive dyskinesia.

Reports have indicated that concomitant administration of benzatropine and inhibitors of dopamine activity can increase gastrointestinal adverse effects, fever, and heat intolerance. The effects could be caused by the reversal of dopamine antagonism or a neurotransmitter imbalance. The severity of the interaction is moderate.

Question: Does Buspirone and Benzatropine interact? Information: •Drug A: Buspirone •Drug B: Benzatropine •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Buspirone is combined with Benzatropine. •Extended Description: Reports have indicated that concomitant administration of benzatropine and inhibitors of dopamine activity can increase gastrointestinal adverse effects, fever, and heat intolerance. The effects could be caused by the reversal of dopamine antagonism or a neurotransmitter imbalance. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Benztropine is indicated to be used as an adjunct in the therapy of all forms of parkinsonism. It can also be used for the control of extrapyramidal disorders due to neuroleptic drugs. The extrapyramidal symptoms are defined as drug-induced disorders that include symptoms of dystonia, akathisia, parkinsonism, bradykinesia, tremors, and dyskinesia. Parkinsonism is a general term that refers to the group of neurological disorders that produce symptoms similar to Parkinson's disease such as tremors, slow movement, and stiffness. The parkinsonism includes a large number of disorders and some of them have not been clearly defined. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): The inhibition of dopamine reuptake by benztropine produces a dose-dependent increase of dopamine in the nerve terminal of the dopaminergic system. Clinically the activity of benztropine is observed after 1-2 hours of oral administration and after a few minutes of intramuscular administration with a last-longing effect of about 24 hours. Reports have indicated that benztropine has a very large sedative effect. The antihistaminic effect of benztropine is very similar to the effect found in pyrilamine and the anticholinergic activity was found to be equal to atropine ex vivo and of about 50% activity in vivo. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Benztropine is an agent with anti-muscarinic and antihistaminic effects. Its main mechanism of action is presented by the selective inhibition of dopamine transporters but it also presents affinity for histamine and muscarine receptors. It is widely known that benztropine is a potent inhibitor of presynaptic carrier-mediated dopamine transport. As well, it is known to be an analog of atropine and hence, it has a large affinity for muscarinic receptors M1 in the human brain. Once bound, benztropine blocks the activity of the muscarinic receptors mainly in the striatum. The increased advantage of benztropine lays on the antagonism of acetylcholine activity which corrects the imbalance between dopamine and acetylcholine in Parkinson patients. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Oral administration of 1.5 mg of benztropine is slowly absorbed in the gastrointestinal tract and it reaches a peak concentration of 2.5 ng/ml in about 7 hours. It has an approximate oral bioavailability of 29%. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): Benztropine is expected to present a large volume of distribution between 12-30 L/kg. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): About 95% of the administered dose of benztropine is found bound to plasma proteins. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Benztropine has been shown to undergo metabolism mainly marked by N-oxidation, N-dealkylation and ring hydroxylation. The extensive metabolism of benztropine produces eight phase-I metabolites plus four glucuronide conjugates. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Benztropine is mainly excreted in the urine but it is also found in the feces unchanged. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The elimination half-life of benztropine is very variable and it is reported to be of around 36 hours. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): Extensive pharmacodynamic or pharmacokinetic studies have not been performed. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The oral LD50 of benztropine is reported to be of 940 mg/kg in rats. In the presence of overdose with benztropine, it has been observed symptoms of circulatory collapse, cardiac arrest, respiratory depression, respiratory arrest, psychosis, shock, coma, seizure, ataxia, combativeness, anhidrosis, hyperthermia, fever, dysphagia, decreased bowel sounds and sluggish pupils. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Cogentin •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Benzatropina Benzatropine Benzatropinum Benztropine Tropine benzohydryl ether •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benzatropine is an anticholinergic drug used to treat Parkinson's disease (PD) and extrapyramidal symptoms, except tardive dyskinesia. Output: Reports have indicated that concomitant administration of benzatropine and inhibitors of dopamine activity can increase gastrointestinal adverse effects, fever, and heat intolerance. The effects could be caused by the reversal of dopamine antagonism or a neurotransmitter imbalance. The severity of the interaction is moderate.

Does Buspirone and Benznidazole interact?

•Drug A: Buspirone •Drug B: Benznidazole •Severity: MINOR •Description: Buspirone may decrease the excretion rate of Benznidazole which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For use in the treatment of Chagas disease in children 2-12 years of age. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Benznidazole is a trypanocidal agent which kills the causative organism in Chagas disease, Trypanosoma cruzi. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Benznidazole is thought to be reduced to various electrophilic metabolites by nitroreductases present in Trypanosoma cruzi. These metabolites likely bind to proteins, lipids, DNA, and RNA resulting in damage to these macromolecules. Benznidazole has been found to increase trypanosomal death through interferon-γ which is likely present in increased amounts due to inflammation caused by macromolecule damage. DNA in parasites affected by benznidazole has been found to undergo extensive unpacking with overexpression of DNA repair proteins supporting the idea of DNA damage contributing to the mechanism of the drug. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Benznidazole has a bioavailability of 91.7% and a Tmax of 2.93 h. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The apparent volume of distribution is 39.19 L. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Benznidazole is metabolized by nitroreductases in Trypanosoma cruzi and by cytochrome P450 enzymes. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): The metabolites of benznidazole appear to be primarily exreted in the urine. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The half life of elimination is 13.27 h. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): The apparent oral clearance is 2.04 L/h. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): At clinically relevant dosages, benznidazole can produce hepatotoxicity, peripheral neuropathy, and angioedema. •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benznidazole is a trypanocidal agent used to treat Chagas disease.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Buspirone and Benznidazole interact? Information: •Drug A: Buspirone •Drug B: Benznidazole •Severity: MINOR •Description: Buspirone may decrease the excretion rate of Benznidazole which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For use in the treatment of Chagas disease in children 2-12 years of age. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Benznidazole is a trypanocidal agent which kills the causative organism in Chagas disease, Trypanosoma cruzi. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Benznidazole is thought to be reduced to various electrophilic metabolites by nitroreductases present in Trypanosoma cruzi. These metabolites likely bind to proteins, lipids, DNA, and RNA resulting in damage to these macromolecules. Benznidazole has been found to increase trypanosomal death through interferon-γ which is likely present in increased amounts due to inflammation caused by macromolecule damage. DNA in parasites affected by benznidazole has been found to undergo extensive unpacking with overexpression of DNA repair proteins supporting the idea of DNA damage contributing to the mechanism of the drug. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Benznidazole has a bioavailability of 91.7% and a Tmax of 2.93 h. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The apparent volume of distribution is 39.19 L. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Benznidazole is metabolized by nitroreductases in Trypanosoma cruzi and by cytochrome P450 enzymes. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): The metabolites of benznidazole appear to be primarily exreted in the urine. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The half life of elimination is 13.27 h. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): The apparent oral clearance is 2.04 L/h. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): At clinically relevant dosages, benznidazole can produce hepatotoxicity, peripheral neuropathy, and angioedema. •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benznidazole is a trypanocidal agent used to treat Chagas disease. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Buspirone and Benzocaine interact?

•Drug A: Buspirone •Drug B: Benzocaine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Buspirone is combined with Benzocaine. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Benzocaine is indicated for local anesthesia in dentistry, minor trauma, and as preparation for infiltrative anesthesia. Benzocaine products are indicated for topical anesthesia in a wide variety of conditions including skin irritation, oral pain, and hemorrhoids. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Benzocaine is indicated for use as a topical anesthetic. It has a duration of action of approximately 10 minutes and a wide therapeutic window. Patients should be counselled regarding the risks of methemoglobinemia. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Benzocaine diffuses into nerve cells where it binds to sodium channels, preventing the channels from opening, and blocking the influx of sodium ions. Nerve cells unable to allow sodium into cells cannot depolarize and conduct nerve impulses. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Benzocaine binds to both serum albumin and alpha-1-acid glycoprotein. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Benzocaine undergoes ester hydrolysis to form 4-aminobenzoic acid, acetylation to form acetylbenzocaine, or N-hydroxylation to form benzocaine hydroxide. 4-aminobenzoic acid can be acetylated or acetylbenzocaine can undergo ester hydrolysis to form 4-acetaminobenzoic acid. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): No half-life available •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Patients experiencing an overdose may present with local anesthetic systemic toxicity syndrome, decreased cardiovascular function, decreased central nervous system function, cardiac arrest, bradycardia, hypotension, cardiac arrhythmias, syncope, and seizures. Patients should be treated with symptomatic and supportive measures which include airway maintenance, controlling seizures, and hemodynamic stabilization. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Anbesol Cold Sore Therapy, Cepacol Sore Throat Plus Cough, Cetacaine, Chloraseptic Sore Throat, Chloraseptic Sore Throat + Cough, Diphen, Docusol Plus, Enemeez Plus, Medicaine Sting and Bite, One Touch Reformulated Apr 2009, Orasep Reformulated Dec 2013, Rectogel, Salinocaine, Topex, Vagisil Original Formula, Zap, Zilactin-B •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Amben ethyl ester Benzocaina Benzocaine Benzocainum Ethyl aminobenzoate Ethyl p-aminobenzoate Ethyl p-aminophenylcarboxylate p-(Ethoxycarbonyl)aniline p-Carbethoxyaniline p-Ethoxycarboxylic aniline •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benzocaine is a topical local anesthetic used for the temporary relief of pain and itching associated with minor burns, sunburn, scrapes and insect bites or minor skin irritations.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Buspirone and Benzocaine interact? Information: •Drug A: Buspirone •Drug B: Benzocaine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Buspirone is combined with Benzocaine. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Benzocaine is indicated for local anesthesia in dentistry, minor trauma, and as preparation for infiltrative anesthesia. Benzocaine products are indicated for topical anesthesia in a wide variety of conditions including skin irritation, oral pain, and hemorrhoids. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Benzocaine is indicated for use as a topical anesthetic. It has a duration of action of approximately 10 minutes and a wide therapeutic window. Patients should be counselled regarding the risks of methemoglobinemia. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Benzocaine diffuses into nerve cells where it binds to sodium channels, preventing the channels from opening, and blocking the influx of sodium ions. Nerve cells unable to allow sodium into cells cannot depolarize and conduct nerve impulses. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Benzocaine binds to both serum albumin and alpha-1-acid glycoprotein. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Benzocaine undergoes ester hydrolysis to form 4-aminobenzoic acid, acetylation to form acetylbenzocaine, or N-hydroxylation to form benzocaine hydroxide. 4-aminobenzoic acid can be acetylated or acetylbenzocaine can undergo ester hydrolysis to form 4-acetaminobenzoic acid. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): No half-life available •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Patients experiencing an overdose may present with local anesthetic systemic toxicity syndrome, decreased cardiovascular function, decreased central nervous system function, cardiac arrest, bradycardia, hypotension, cardiac arrhythmias, syncope, and seizures. Patients should be treated with symptomatic and supportive measures which include airway maintenance, controlling seizures, and hemodynamic stabilization. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Anbesol Cold Sore Therapy, Cepacol Sore Throat Plus Cough, Cetacaine, Chloraseptic Sore Throat, Chloraseptic Sore Throat + Cough, Diphen, Docusol Plus, Enemeez Plus, Medicaine Sting and Bite, One Touch Reformulated Apr 2009, Orasep Reformulated Dec 2013, Rectogel, Salinocaine, Topex, Vagisil Original Formula, Zap, Zilactin-B •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Amben ethyl ester Benzocaina Benzocaine Benzocainum Ethyl aminobenzoate Ethyl p-aminobenzoate Ethyl p-aminophenylcarboxylate p-(Ethoxycarbonyl)aniline p-Carbethoxyaniline p-Ethoxycarboxylic aniline •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benzocaine is a topical local anesthetic used for the temporary relief of pain and itching associated with minor burns, sunburn, scrapes and insect bites or minor skin irritations. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Buspirone and Benzphetamine interact?

•Drug A: Buspirone •Drug B: Benzphetamine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Buspirone is combined with Benzphetamine. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For the management of exogenous obesity as a short term adjunct (a few weeks) in a regimen of weight reduction based on caloric restriction •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Benzphetamine, a phenylalkylamin, is related to amphetamine both chemically and pharmacologically. It is an anorectic agent indicated in the management of exogenous obesity as a short term adjunct (a few weeks) in a regimen of weight reduction based on caloric restriction. Benzphetamine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, the amphetamines. Actions include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): The mechanism of action of these drugs is not fully understood, however it may be similar to that of amphetamines. Amphetamines stimulate noepinephrine and dopamine release in nerve endings in the lateral hypothalamic feeding centre, decreasing appetite. This release is mediated by the binding of benzphetamine to centrally located adrenergic receptors. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Readily absorbed from the gastro-intestinal tract and buccal mucosa. It Is resistant to metabolism by monoamine oxidase. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): 75-99% •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Hepatic. Benzphetamine's metabolites include amphetamine and methamphetamine. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): 16 to 31 hours •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): LD 50 =160 mg/kg (orally in rats). Acute overdosage may result in restlessness, tremor, tachypnea, confusion, assaultiveness, and panic states. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Didrex •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): (S)-benzphetamine Benzaphetamine Benzfetamina Benzfetamine Benzfetaminum Benzphetamine Benzylamphetamine •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benzphetamine is a sympathomimetic used to manage exogenous obesity short term.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Buspirone and Benzphetamine interact? Information: •Drug A: Buspirone •Drug B: Benzphetamine •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Buspirone is combined with Benzphetamine. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For the management of exogenous obesity as a short term adjunct (a few weeks) in a regimen of weight reduction based on caloric restriction •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Benzphetamine, a phenylalkylamin, is related to amphetamine both chemically and pharmacologically. It is an anorectic agent indicated in the management of exogenous obesity as a short term adjunct (a few weeks) in a regimen of weight reduction based on caloric restriction. Benzphetamine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, the amphetamines. Actions include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): The mechanism of action of these drugs is not fully understood, however it may be similar to that of amphetamines. Amphetamines stimulate noepinephrine and dopamine release in nerve endings in the lateral hypothalamic feeding centre, decreasing appetite. This release is mediated by the binding of benzphetamine to centrally located adrenergic receptors. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Readily absorbed from the gastro-intestinal tract and buccal mucosa. It Is resistant to metabolism by monoamine oxidase. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): 75-99% •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Hepatic. Benzphetamine's metabolites include amphetamine and methamphetamine. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): 16 to 31 hours •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): LD 50 =160 mg/kg (orally in rats). Acute overdosage may result in restlessness, tremor, tachypnea, confusion, assaultiveness, and panic states. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Didrex •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): (S)-benzphetamine Benzaphetamine Benzfetamina Benzfetamine Benzfetaminum Benzphetamine Benzylamphetamine •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benzphetamine is a sympathomimetic used to manage exogenous obesity short term. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Buspirone and Benzydamine interact?

•Drug A: Buspirone •Drug B: Benzydamine •Severity: MINOR •Description: The risk or severity of hypertension can be increased when Buspirone is combined with Benzydamine. •Extended Description: Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Available predominantly as a liquid mouthwash, oromucosal spray, or topical cream, benzydamine is most frequently employed as a locally acting analgesic and anti-inflammatory treatment for the relief of painful inflammatory conditions. When formulated as a mouthwash or spray, benzydamine may be used to treat traumatic conditions like pharyngitis following tonsillectomy or the use of a naso-gastric tube, inflammatory conditions like pharyngitis, aphthous ulcers and oral ulceration due to radiation therapy, dentistry operations and procedures, or more general conditions like sore throat, sore tongue, sore gums, mouth ulcers, or discomfort caused by dentures. When used as a topical cream, benzydamine may be employed to relieve symptoms associated with painful inflammatory conditions of the muscolo-skeletal system including acute inflammatory disorders such as myalgia and bursitis or traumatic conditions like sprains, strains, bruises, sore muscles, stiff joints, or even the after-effects of fractures. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Benzydamine is a non-steroidal anti-inflammatory drug (NSAID) designed to elicit local anesthetic and analgesic effects mainly for the mouth and throat. It specifically acts on the local mechanisms of inflammation such as pain, oedema, or granuloma. Typically applied topically, the drug demonstrates anti-inflammatory activity reducing oedema as well as exudate and granuloma formation. Moreover, benzydamine exhibits analgesic properties and local anaesthetic activity if pain is caused by an inflammatory condition. Benzydamine can be absorbed into the oral mucosa and intact skin. Once absorbed in the local area of pain or inflammation, benzydamine binds selectively to local inflamed tissues, usually allowing it to act with few adverse systemic effects. On average a period of 2 to 4 hours is necessary for the substance to reach peak plasma concentration. Benzydamine can be synthesized with the reaction of the N-benzyl derivative from methyl anthranilate with nitrous acid to give N-nitoso derivative. This is next reduced by sodium thiosulfate to give transient hydrazine. This hydrazine can then undergo spontaneous internal hydrazide formation. Treating this resultant enolate with 3-chloro-1-dimethylamkino propane ultimately yields benzydamine. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Despite being categorized as a non-steroidal anti-inflammatory drug (NSAID), benzydamine demonstrates various mechanisms of action that differ from those of traditional aspirin-like NSAIDs. In particular, benzydamine predominantly acts by inhibiting the synthesis of pro inflammatory cytokines like tumour necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) without largely affecting other pro inflammatory cytokines (ie. such as IL-6 and IL-8) or anti-inflammatory cytokines (ie. like IL-10 or IL-1 receptor antagonist). Moreover, benzydamine is largely a weak inhibitor of prostaglandin synthesis as it has been shown to effectively inhibit cyclooxygenase (COX) and lipoxygenase enzyme activity only at concentrations of 1mM or greater. Considering most contemporary usages of benzydamine are topical applications that are generally not well absorbed through the skin and/or non-specialized mucosae, benzydamine does not often achieve the kind of absorption or blood concentrations necessary to cause any extraneous distant systemic effects or COX inhibition, allowing it to localize its action. Additionally, it is also hypothesized that benzydamine is capable of inhibiting the oxidative burst of neutrophils and membrane stabilization. These actions are exhibited by the substance’s ability to inhibit the release of granules from neutrophils and to stabilize lysosomes. Furthermore, benzydamine is capable of a local anaesthetic effect that may be related to its capability for inhibiting the release of inflammatory mediators like substance P and calcitonin gene related peptide from sensory nerve endings. Since substance P is capable of causing the release of histamine from mast cells, benzydamine’s prevention of substance P release further contributes to an anti-inflammatory effect. Benzydamine also demonstrates a non-specific antibacterial activity against various bacterial strains that are resistant to broad-spectrum antibiotics such as ampicillin, chloramphenicol, and tetracycline at concentrations of about 3 mmol/L. Combinatorial use of benzydamine and other antibiotics like tetracycline and chloramphenicol are also synergistic against antibiotic resistant strains of Staphylococcus aureus and Pseudomonas aeruginosa. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Oral doses of benzydamine are well absorbed and plasma drug concentrations reach a peak fairly rapidly and then decline with a half-life of approximately 13 hours. When applied topically, although the local drug concentrations are relatively large, the systemic absorption of topically applied benzydamine is relatively low compared to oral doses. This low topical absorption contributes to a decreased potential for any systemic drug side-effects when benzydamine is administered in this way. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The volume of distribution of benzydamine is 10 L. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Benzydamine exhibits < 20% plasma protein binding after oral administration. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Benzydamine is primarily metabolized by oxidation, dealkylation, and conjugation into hydroxy, dealkylated, and N-oxide metabolites. In general, however, when used at the recommended doses the levels at which benzydamine is absorbed or exposed into the body are usually not sufficient to produce systemic pharmacological effects [L •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): The relatively high lipid solubility of the weak base benzydamine is thought to be associated with considerable passive resorption within the renal tubule, which suggests that only approximately 5% of benzydamine is excreted unchanged in the urine. At the same time however, other studies have suggested that considerably larger amounts (50-65%) of the drug is excreted unchanged in urine. While several inactive oxidized metabolites of benzydamine are excreted in urine, the benzydamine N-oxide metabolite can remain in plasma and demonstrate a half-life that is longer than the parent benzydamine compound. Nevertheless, it is generally believed that excretion occurs mainly through urine and is mostly in the form of inactive metabolites or conjugation products. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Approximately 13 h after oral administration, with a terminal half life of about 7.7 h. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): Benzydamine demonstrateas a systemic clearance of 170 ml/min. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): A possible adverse reaction associated with the use of the mouthwash or oromucosal spray formulations of benzymadine is potential numbness and/or stinging in the mouth and/or throat. Some possible adverse reactions that tend to be associated more with topical cream formulations of benzymadine include increased sensitivity to sunlight, and localized itching, skin rash, redness, or swelling. The prescribing information for all formulations of benzymadine however, warn against the possibility of severe allergic reaction (anaphylaxis) associated with swelling of the throat and mouth, difficulty in swallowing, speaking, and breathing, or wheezing. As benzydamine is a non-steroidal anti-inflammatory drug (NSAID), it is necessary to determine if a patient is allergic to NSAIDs before considering its use. Intoxication is expected as a consequence of accidental ingestion of large quantities of benzydamine (over 300 mg ingestion). Other symptoms associated with overdose of ingested benzydamine include gastrointestinal and central nervous system symptoms like nausea, vomiting, abdominal pain, oesophageal irritation, dizziness, hallucinations, agitation, anxiety, and irritability. The official prescribing information for benzydamine generally suggest that benzydamine mouthwashes and sprays should not be used in pregnancy. Similarly, the official prescribing information for benzydamine also generally suggest that benzydamine mouthwashes and sprays should not be used during lactation unless considered essential by a physician. The prescribing information for topical cream formulations of benzydamine note that benzydamine cream should not be used in pregnancy or lactation unless considered necessary by the physician. Overall, non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeated toxicity, genotoxicity, cardiogenic potential, and toxicity to reproduction. Additionally, there is no evidence of teratogenic effects in animal studies. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Pharixia, Tantum •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benzydamine is a locally-acting NSAID indicated for the symptomatic relief of pain in acute sore throat and for the symptomatic relief of oropharyngeal mucositis caused by radiation therapy.

Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity. The severity of the interaction is minor.

Question: Does Buspirone and Benzydamine interact? Information: •Drug A: Buspirone •Drug B: Benzydamine •Severity: MINOR •Description: The risk or severity of hypertension can be increased when Buspirone is combined with Benzydamine. •Extended Description: Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Available predominantly as a liquid mouthwash, oromucosal spray, or topical cream, benzydamine is most frequently employed as a locally acting analgesic and anti-inflammatory treatment for the relief of painful inflammatory conditions. When formulated as a mouthwash or spray, benzydamine may be used to treat traumatic conditions like pharyngitis following tonsillectomy or the use of a naso-gastric tube, inflammatory conditions like pharyngitis, aphthous ulcers and oral ulceration due to radiation therapy, dentistry operations and procedures, or more general conditions like sore throat, sore tongue, sore gums, mouth ulcers, or discomfort caused by dentures. When used as a topical cream, benzydamine may be employed to relieve symptoms associated with painful inflammatory conditions of the muscolo-skeletal system including acute inflammatory disorders such as myalgia and bursitis or traumatic conditions like sprains, strains, bruises, sore muscles, stiff joints, or even the after-effects of fractures. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Benzydamine is a non-steroidal anti-inflammatory drug (NSAID) designed to elicit local anesthetic and analgesic effects mainly for the mouth and throat. It specifically acts on the local mechanisms of inflammation such as pain, oedema, or granuloma. Typically applied topically, the drug demonstrates anti-inflammatory activity reducing oedema as well as exudate and granuloma formation. Moreover, benzydamine exhibits analgesic properties and local anaesthetic activity if pain is caused by an inflammatory condition. Benzydamine can be absorbed into the oral mucosa and intact skin. Once absorbed in the local area of pain or inflammation, benzydamine binds selectively to local inflamed tissues, usually allowing it to act with few adverse systemic effects. On average a period of 2 to 4 hours is necessary for the substance to reach peak plasma concentration. Benzydamine can be synthesized with the reaction of the N-benzyl derivative from methyl anthranilate with nitrous acid to give N-nitoso derivative. This is next reduced by sodium thiosulfate to give transient hydrazine. This hydrazine can then undergo spontaneous internal hydrazide formation. Treating this resultant enolate with 3-chloro-1-dimethylamkino propane ultimately yields benzydamine. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Despite being categorized as a non-steroidal anti-inflammatory drug (NSAID), benzydamine demonstrates various mechanisms of action that differ from those of traditional aspirin-like NSAIDs. In particular, benzydamine predominantly acts by inhibiting the synthesis of pro inflammatory cytokines like tumour necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) without largely affecting other pro inflammatory cytokines (ie. such as IL-6 and IL-8) or anti-inflammatory cytokines (ie. like IL-10 or IL-1 receptor antagonist). Moreover, benzydamine is largely a weak inhibitor of prostaglandin synthesis as it has been shown to effectively inhibit cyclooxygenase (COX) and lipoxygenase enzyme activity only at concentrations of 1mM or greater. Considering most contemporary usages of benzydamine are topical applications that are generally not well absorbed through the skin and/or non-specialized mucosae, benzydamine does not often achieve the kind of absorption or blood concentrations necessary to cause any extraneous distant systemic effects or COX inhibition, allowing it to localize its action. Additionally, it is also hypothesized that benzydamine is capable of inhibiting the oxidative burst of neutrophils and membrane stabilization. These actions are exhibited by the substance’s ability to inhibit the release of granules from neutrophils and to stabilize lysosomes. Furthermore, benzydamine is capable of a local anaesthetic effect that may be related to its capability for inhibiting the release of inflammatory mediators like substance P and calcitonin gene related peptide from sensory nerve endings. Since substance P is capable of causing the release of histamine from mast cells, benzydamine’s prevention of substance P release further contributes to an anti-inflammatory effect. Benzydamine also demonstrates a non-specific antibacterial activity against various bacterial strains that are resistant to broad-spectrum antibiotics such as ampicillin, chloramphenicol, and tetracycline at concentrations of about 3 mmol/L. Combinatorial use of benzydamine and other antibiotics like tetracycline and chloramphenicol are also synergistic against antibiotic resistant strains of Staphylococcus aureus and Pseudomonas aeruginosa. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Oral doses of benzydamine are well absorbed and plasma drug concentrations reach a peak fairly rapidly and then decline with a half-life of approximately 13 hours. When applied topically, although the local drug concentrations are relatively large, the systemic absorption of topically applied benzydamine is relatively low compared to oral doses. This low topical absorption contributes to a decreased potential for any systemic drug side-effects when benzydamine is administered in this way. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The volume of distribution of benzydamine is 10 L. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Benzydamine exhibits < 20% plasma protein binding after oral administration. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Benzydamine is primarily metabolized by oxidation, dealkylation, and conjugation into hydroxy, dealkylated, and N-oxide metabolites. In general, however, when used at the recommended doses the levels at which benzydamine is absorbed or exposed into the body are usually not sufficient to produce systemic pharmacological effects [L •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): The relatively high lipid solubility of the weak base benzydamine is thought to be associated with considerable passive resorption within the renal tubule, which suggests that only approximately 5% of benzydamine is excreted unchanged in the urine. At the same time however, other studies have suggested that considerably larger amounts (50-65%) of the drug is excreted unchanged in urine. While several inactive oxidized metabolites of benzydamine are excreted in urine, the benzydamine N-oxide metabolite can remain in plasma and demonstrate a half-life that is longer than the parent benzydamine compound. Nevertheless, it is generally believed that excretion occurs mainly through urine and is mostly in the form of inactive metabolites or conjugation products. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Approximately 13 h after oral administration, with a terminal half life of about 7.7 h. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): Benzydamine demonstrateas a systemic clearance of 170 ml/min. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): A possible adverse reaction associated with the use of the mouthwash or oromucosal spray formulations of benzymadine is potential numbness and/or stinging in the mouth and/or throat. Some possible adverse reactions that tend to be associated more with topical cream formulations of benzymadine include increased sensitivity to sunlight, and localized itching, skin rash, redness, or swelling. The prescribing information for all formulations of benzymadine however, warn against the possibility of severe allergic reaction (anaphylaxis) associated with swelling of the throat and mouth, difficulty in swallowing, speaking, and breathing, or wheezing. As benzydamine is a non-steroidal anti-inflammatory drug (NSAID), it is necessary to determine if a patient is allergic to NSAIDs before considering its use. Intoxication is expected as a consequence of accidental ingestion of large quantities of benzydamine (over 300 mg ingestion). Other symptoms associated with overdose of ingested benzydamine include gastrointestinal and central nervous system symptoms like nausea, vomiting, abdominal pain, oesophageal irritation, dizziness, hallucinations, agitation, anxiety, and irritability. The official prescribing information for benzydamine generally suggest that benzydamine mouthwashes and sprays should not be used in pregnancy. Similarly, the official prescribing information for benzydamine also generally suggest that benzydamine mouthwashes and sprays should not be used during lactation unless considered essential by a physician. The prescribing information for topical cream formulations of benzydamine note that benzydamine cream should not be used in pregnancy or lactation unless considered necessary by the physician. Overall, non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeated toxicity, genotoxicity, cardiogenic potential, and toxicity to reproduction. Additionally, there is no evidence of teratogenic effects in animal studies. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Pharixia, Tantum •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benzydamine is a locally-acting NSAID indicated for the symptomatic relief of pain in acute sore throat and for the symptomatic relief of oropharyngeal mucositis caused by radiation therapy. Output: Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity. The severity of the interaction is minor.

Does Buspirone and Benzyl alcohol interact?

•Drug A: Buspirone •Drug B: Benzyl alcohol •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Buspirone is combined with Benzyl alcohol. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Ulesfia (benzyl alcohol) lotion is indicated for the topical treatment of head lice infestation in patients 6 months of age and older. Ulesfia Lotion does not have ovicidal activity. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Benzyl alcohol inhibits lice from closing their respiratory spiracles, allowing the vehicle to obstruct the spiracles and causing the lice to asphyxiate. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): No half-life available •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): 1250 mg/kg (rat, oral) LD50 400 mg/kg IPR-RAT LD50 2000 mg/kg SKN-RBT LD50 53 mg/kg IVN-RAT LD50 2500 mg/kg ORL-GPG LD50 •Brand Names (Drug A): Buspar •Brand Names (Drug B): Cipro, Cipro HC, Itch-X, Ivy-dry Cream, Ulesfia, Zilactin Cold Sore •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): (hydroxymethyl)benzene Alcoholum benzylicum Alcool benzylique Alcoolbenzylique alpha-Hydroxytoluene Aromatic alcohol Bentalol Benzalalcohol Benzalcohol Benzenecarbinol Benzenemethanol Benzoyl alcohol Benzyl alcohol Benzylalkohol Benzylic alcohol Hydroxymethylbenzene Phenylcarbinol Phenylmethanol Phenylmethyl alcohol •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benzyl alcohol is an antiparasitic agent used for the topical treatment of head lice infestation in patients 6 months of age and older.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Buspirone and Benzyl alcohol interact? Information: •Drug A: Buspirone •Drug B: Benzyl alcohol •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Buspirone is combined with Benzyl alcohol. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Ulesfia (benzyl alcohol) lotion is indicated for the topical treatment of head lice infestation in patients 6 months of age and older. Ulesfia Lotion does not have ovicidal activity. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Benzyl alcohol inhibits lice from closing their respiratory spiracles, allowing the vehicle to obstruct the spiracles and causing the lice to asphyxiate. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): No half-life available •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): 1250 mg/kg (rat, oral) LD50 400 mg/kg IPR-RAT LD50 2000 mg/kg SKN-RBT LD50 53 mg/kg IVN-RAT LD50 2500 mg/kg ORL-GPG LD50 •Brand Names (Drug A): Buspar •Brand Names (Drug B): Cipro, Cipro HC, Itch-X, Ivy-dry Cream, Ulesfia, Zilactin Cold Sore •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): (hydroxymethyl)benzene Alcoholum benzylicum Alcool benzylique Alcoolbenzylique alpha-Hydroxytoluene Aromatic alcohol Bentalol Benzalalcohol Benzalcohol Benzenecarbinol Benzenemethanol Benzoyl alcohol Benzyl alcohol Benzylalkohol Benzylic alcohol Hydroxymethylbenzene Phenylcarbinol Phenylmethanol Phenylmethyl alcohol •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Benzyl alcohol is an antiparasitic agent used for the topical treatment of head lice infestation in patients 6 months of age and older. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Buspirone and Bepotastine interact?

•Drug A: Buspirone •Drug B: Bepotastine •Severity: MINOR •Description: Buspirone may decrease the excretion rate of Bepotastine which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For the symptomatic treatment of itchy eyes (caused by IgE-induced mast cell degranulation) due to allergic conjunctivitis. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bepotastine is a non-sedating, selective antagonist of the histamine 1 (H1) receptor. It belongs to the second-generation piperidine chemical class. It is a mast cell stabilizer and suppresses the migration of eosinophils into inflamed tissues. Furthermore, bepotastine does not interact with serotonin, muscarinic, benzodiazepine, and beta-adrenergic receptor that would otherwise result in adverse reactions such as dry mouth or sonmolence. Onset of action = 0.25 hours; Duration of action = 12-24 hours; •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Because of a type 1 hypersensitivity reaction cascade that is triggered by antigen exposure, allergic conjunctivitis occurs. Allergen exposure is followed by conjunctival mast cell degranulation and histamine released as a result of the formation of complementary IgE cross-links on the conjunctiva. Due to the release of histamine, symptoms such as itching can be observed. Bepotastine works to relieve itchy eyes by three primary mechanisms of action. It is a non-sedating, selective antagonist of the histamine 1 (H1) receptor, a mast cell stabilizer, and it suppresses the migration of eosinophils into inflamed tissues to prevent tissue damage and worsening of allergic inflammation of the conjunctiva. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Tmax, after single dose, opthalmic = 1.2 hours; Cmax, 1.5%, opthalmic dose = 7.3 ±1.9 ng/mL; After 24 hours post-installation, levels of bepotastine are below quantifiable limit of 2 ng/mL. Minimal systemic absorption with opthalmic dosage form. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): 55.4% mean plasma protein binding with 10 mg oral dose. Extent of protein binding is independent of plasma drug concentration. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Minimal metabolism via CYP enzymes •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): When a oral dose of 2.5 - 40 mg bepotastine is given, 75%-90% of the dose was excreted unchanged in the urine by 24 hours. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Elimination half life = 2.5 hours •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Buspar •Brand Names (Drug B): Bepreve •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bepotastine is an ophthalmic H1 antagonist used to treat itchiness associated with allergic conjunctivitis.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Buspirone and Bepotastine interact? Information: •Drug A: Buspirone •Drug B: Bepotastine •Severity: MINOR •Description: Buspirone may decrease the excretion rate of Bepotastine which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For the symptomatic treatment of itchy eyes (caused by IgE-induced mast cell degranulation) due to allergic conjunctivitis. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bepotastine is a non-sedating, selective antagonist of the histamine 1 (H1) receptor. It belongs to the second-generation piperidine chemical class. It is a mast cell stabilizer and suppresses the migration of eosinophils into inflamed tissues. Furthermore, bepotastine does not interact with serotonin, muscarinic, benzodiazepine, and beta-adrenergic receptor that would otherwise result in adverse reactions such as dry mouth or sonmolence. Onset of action = 0.25 hours; Duration of action = 12-24 hours; •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Because of a type 1 hypersensitivity reaction cascade that is triggered by antigen exposure, allergic conjunctivitis occurs. Allergen exposure is followed by conjunctival mast cell degranulation and histamine released as a result of the formation of complementary IgE cross-links on the conjunctiva. Due to the release of histamine, symptoms such as itching can be observed. Bepotastine works to relieve itchy eyes by three primary mechanisms of action. It is a non-sedating, selective antagonist of the histamine 1 (H1) receptor, a mast cell stabilizer, and it suppresses the migration of eosinophils into inflamed tissues to prevent tissue damage and worsening of allergic inflammation of the conjunctiva. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Tmax, after single dose, opthalmic = 1.2 hours; Cmax, 1.5%, opthalmic dose = 7.3 ±1.9 ng/mL; After 24 hours post-installation, levels of bepotastine are below quantifiable limit of 2 ng/mL. Minimal systemic absorption with opthalmic dosage form. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): 55.4% mean plasma protein binding with 10 mg oral dose. Extent of protein binding is independent of plasma drug concentration. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Minimal metabolism via CYP enzymes •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): When a oral dose of 2.5 - 40 mg bepotastine is given, 75%-90% of the dose was excreted unchanged in the urine by 24 hours. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Elimination half life = 2.5 hours •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Buspar •Brand Names (Drug B): Bepreve •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bepotastine is an ophthalmic H1 antagonist used to treat itchiness associated with allergic conjunctivitis. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Buspirone and Berotralstat interact?

•Drug A: Buspirone •Drug B: Berotralstat •Severity: MODERATE •Description: The metabolism of Buspirone can be decreased when combined with Berotralstat. •Extended Description: The subject drug is a moderate CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, leading to increased serum concentrations as well as increased risk and severity of adverse effects. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Berotralstat is indicated for prophylaxis of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years and older. It is not used for the treatment of acute HAE attacks. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Berotralstat prevents angioedema attacks by inhibiting plasma kallikrein, thereby regulating excess bradykinin generation in patients with hereditary angioedema (HAE). It had a fast onset of action, long duration of action, and acceptable tolerance in clinical trials. Berotralstat inhibits plasma kallikrein in a concentration-dependent. In clinical trials, berotralstat reduced HAE attack rates at 24 weeks, and its effects sustained through 48 weeks. In clinical trials, doses of berotralstat higher than 150 mg once daily led to QT Prolongation in a concentration-dependent manner. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Hereditary angioedema (HAE) is a rare genetic disorder associated with severe swelling of the skin and upper airway. It is caused by mutations in the regulatory or coding regions of the gene that encodes C1 inhibitor (SERPING1), which result in either a deficiency (type I) or dysfunction (type II) of C1 inhibitor (C1 esterase inhibitor, C1-INH). C1 inhibitor is a serine protease inhibitor that normally regulates bradykinin production by covalently binding to and inactivating plasma kallikrein. Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK). During HAE attacks, the levels of plasma kallikrein fall, leading to the cleavage of high-molecular-weight-kininogen and the release of bradykinin, a potent vasodilator that increases vascular permeability. Bradykinin plays a major role in promoting edema and pain associated with HAE. Patients with HAE cannot properly regulate plasma kallikrein activity due to the deficiency or dysfunction of a serum inhibitor of C1 inhibitor, leading to uncontrolled increases in plasma kallikrein activity and recurrent angioedema attacks. Berotralstat is a potent inhibitor of plasma kallikrein that works by binding to plasma kallikrein and blocking its proteolytic activity, thereby controlling excess bradykinin generation. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): The steady-state of berotralstat is reached within 6 to 12 days following initial administration. After once-daily administration, the Cmax and AUC of berotralstat at steady-state is approximately five times that of the drug after a single dose. Following oral administration of berotralstat once-daily, the steady-state Cmax was 158 ng/mL (range: 110 to 234 ng/mL) at the dose of 150 mg and 97.8 ng/mL (range: 63 to 235 ng/mL) at the dose of 110 mg. The area under the curve over the dosing interval (AUCtau) was 2770 ng hr/mL (range: 1880 to 3790 ng hr/mL) and 1600 ng hr/mL (range: 950 to 4170 ng hr/mL) at the dose of 110 mg. The median Tmax is 2 hours in a fasted state and a high-fat meal delays the Tmax to 5 hours. The Tmax can range from 1 to 8 hours. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The blood to plasma ratio was approximately 0.92 following a single 300 mg dose administration of radiolabeled berotralstat. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Plasma protein binding is approximately 99%. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Berotralstat is metabolized by CYP2D6 and CYP3A4. The metabolic pathway and the metabolites of berotralstat have not yet been characterized. Following a single oral dose administration of 300 mg radiolabeled berotralstat, about 34% of the total plasma radioactivity accounted for the unchanged drug while about eight detectable metabolites accounted for 1.8 to 7.8% of the total radioactivity. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Following a single oral dose administration of 300 mg radiolabeled berotralstat, approximately 9% of the drug was excreted in the urine, where 1.8 to 4.7% of the total radiolabeled compound accounted for the unchanged parent drug. About 79% of the drug was excreted in feces. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Following a single oral dose administration of 300 mg radiolabeled berotralstat, the median elimination half-life of berotralstat was approximately 93 hours, ranging from 39 to 152 hours. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): There is no information on the clearance rate. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): There is no information on the LD 50 or overdose of berotralstat. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Orladeyo •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Berotralstat is an inhibitor of plasma kallikrein used for prophylaxis of angioedema attacks in patients with hereditary angioedema.

The subject drug is a moderate CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, leading to increased serum concentrations as well as increased risk and severity of adverse effects. The severity of the interaction is moderate.

Question: Does Buspirone and Berotralstat interact? Information: •Drug A: Buspirone •Drug B: Berotralstat •Severity: MODERATE •Description: The metabolism of Buspirone can be decreased when combined with Berotralstat. •Extended Description: The subject drug is a moderate CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, leading to increased serum concentrations as well as increased risk and severity of adverse effects. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Berotralstat is indicated for prophylaxis of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years and older. It is not used for the treatment of acute HAE attacks. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Berotralstat prevents angioedema attacks by inhibiting plasma kallikrein, thereby regulating excess bradykinin generation in patients with hereditary angioedema (HAE). It had a fast onset of action, long duration of action, and acceptable tolerance in clinical trials. Berotralstat inhibits plasma kallikrein in a concentration-dependent. In clinical trials, berotralstat reduced HAE attack rates at 24 weeks, and its effects sustained through 48 weeks. In clinical trials, doses of berotralstat higher than 150 mg once daily led to QT Prolongation in a concentration-dependent manner. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Hereditary angioedema (HAE) is a rare genetic disorder associated with severe swelling of the skin and upper airway. It is caused by mutations in the regulatory or coding regions of the gene that encodes C1 inhibitor (SERPING1), which result in either a deficiency (type I) or dysfunction (type II) of C1 inhibitor (C1 esterase inhibitor, C1-INH). C1 inhibitor is a serine protease inhibitor that normally regulates bradykinin production by covalently binding to and inactivating plasma kallikrein. Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK). During HAE attacks, the levels of plasma kallikrein fall, leading to the cleavage of high-molecular-weight-kininogen and the release of bradykinin, a potent vasodilator that increases vascular permeability. Bradykinin plays a major role in promoting edema and pain associated with HAE. Patients with HAE cannot properly regulate plasma kallikrein activity due to the deficiency or dysfunction of a serum inhibitor of C1 inhibitor, leading to uncontrolled increases in plasma kallikrein activity and recurrent angioedema attacks. Berotralstat is a potent inhibitor of plasma kallikrein that works by binding to plasma kallikrein and blocking its proteolytic activity, thereby controlling excess bradykinin generation. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): The steady-state of berotralstat is reached within 6 to 12 days following initial administration. After once-daily administration, the Cmax and AUC of berotralstat at steady-state is approximately five times that of the drug after a single dose. Following oral administration of berotralstat once-daily, the steady-state Cmax was 158 ng/mL (range: 110 to 234 ng/mL) at the dose of 150 mg and 97.8 ng/mL (range: 63 to 235 ng/mL) at the dose of 110 mg. The area under the curve over the dosing interval (AUCtau) was 2770 ng hr/mL (range: 1880 to 3790 ng hr/mL) and 1600 ng hr/mL (range: 950 to 4170 ng hr/mL) at the dose of 110 mg. The median Tmax is 2 hours in a fasted state and a high-fat meal delays the Tmax to 5 hours. The Tmax can range from 1 to 8 hours. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The blood to plasma ratio was approximately 0.92 following a single 300 mg dose administration of radiolabeled berotralstat. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Plasma protein binding is approximately 99%. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Berotralstat is metabolized by CYP2D6 and CYP3A4. The metabolic pathway and the metabolites of berotralstat have not yet been characterized. Following a single oral dose administration of 300 mg radiolabeled berotralstat, about 34% of the total plasma radioactivity accounted for the unchanged drug while about eight detectable metabolites accounted for 1.8 to 7.8% of the total radioactivity. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Following a single oral dose administration of 300 mg radiolabeled berotralstat, approximately 9% of the drug was excreted in the urine, where 1.8 to 4.7% of the total radiolabeled compound accounted for the unchanged parent drug. About 79% of the drug was excreted in feces. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Following a single oral dose administration of 300 mg radiolabeled berotralstat, the median elimination half-life of berotralstat was approximately 93 hours, ranging from 39 to 152 hours. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): There is no information on the clearance rate. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): There is no information on the LD 50 or overdose of berotralstat. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Orladeyo •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Berotralstat is an inhibitor of plasma kallikrein used for prophylaxis of angioedema attacks in patients with hereditary angioedema. Output: The subject drug is a moderate CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, leading to increased serum concentrations as well as increased risk and severity of adverse effects. The severity of the interaction is moderate.

Does Buspirone and Betamethasone interact?

•Drug A: Buspirone •Drug B: Betamethasone •Severity: MINOR •Description: The metabolism of Buspirone can be increased when combined with Betamethasone. •Extended Description: The subject is a weak inducer of the CYP3A5 enzyme, and the affected drug is a substrate of the CYP3A5 enzyme. When these drugs are administered concomitantly, the metabolism of the affected drug is increased, leading to decreased serum concentrations and lower efficacy. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): As a member of the corticosteroid family, betamethasone is indicated for the treatment of several inflammatory conditions. As topical monotherapy, betamethasone is indicated to relieve pruritic and inflammatory symptoms of corticosteroid-responsive-dermatoses. Betamethasone can be used topically in combination with a vitamin D analog such as calcipotriene to treat plaque psoriasis. The corticosteroid is also available as an injectable suspension and can be used to manage a range of inflammatory conditions including endocrine disorders, gastrointestinal disorders, and rheumatic disorders among other conditions. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Corticosteroids bind to the glucocorticoid receptor inhibiting pro-inflammatory signals, while promoting anti-inflammatory signals. Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces. Patients who require long-term treatment with a corticosteroid should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Glucocorticoids inhibit neutrophil apoptosis and demargination, and inhibit NF-Kappa B and other inflammatory transcription factors. They also inhibit phospholipase A2, leading to decreased formation of arachidonic acid derivatives. In addition, glucocorticoids promote anti-inflammatory genes like interleukin-10. Corticosteroids like betamethasone can act through nongenomic and genomic pathways. The genomic pathway is slower and occurs when glucocorticoids activate glucocorticoid receptors and initiate downstream effects that promote transcription of anti-inflammatory genes including phosphoenolpyruvate carboxykinase (PEPCK), IL-1-receptor antagonist, and tyrosine amino transferase (TAT). On the other hand, the nongenomic pathway is able to elicit a quicker response by modulating T-cell, platelet and monocyte activity through the use of existing membrane-bound receptors and second messengers. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): The absorption and potency of any topical corticosteroid including betamethasone depends on the vehicle in which the steroid is delivered. For example, betamethasone dipropionate 0.05% ointment is classified as a highly potent topical steroid, while betamethasone dipropionate 0.05% cream or lotion is considered to be moderately potent. There are several structural modifications that can determine the potency of a topical corticosteroid. For example, corticosteroids containing a halogen at specific carbons, or that contain esters are more potent due to enhanced lipophilicity. As such, there is a marked difference between topical products containing betamethasone dipropionate vs. betamethasone valerate. Betamethasone dipropionate contains 2 esters which enhances its potency, while betamethasone valerate has only one ester and is less potent. It should be noted that the use of occlusive dressings with topical steroids significantly increases the absorption, increasing the risk for adverse effects. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): In a study that included Indian women of reproductive age, the volume of distribution following a single intramuscular dose of betamethasone phosphate was 94,584±23,539 mL(s). •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Betamethasone valerate binds to serum albumin and corticosteroid-binding globulin. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): The metabolism of betamethasone yields 6 metabolites. The metabolic processes include 6β hydroxylation, 11β-hydroxyl oxidation, and reduction of the C-20 carbonyl group followed by removal of the side chain. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Corticosteroids are eliminated predominantly in the urine. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): In a study that included Indian women of reproductive age, the half-life following a single intramuscular dose of betamethasone phosphate was 10.2 ± 2.5 hours. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): In a study that included Indian women of reproductive age, the CL/F following a single intramuscular dose of betamethasone phosphate was 6,466 ± 805 mL/hour. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Chronic high doses of glucocorticoids can lead to the development of cataracts, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency. Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Betaderm, Betaloan Suik, Beteflam, Celestoderm, Celestone Soluspan, Dermacinrx Therazole Pak, Diprolene, Diprosalic, Diprosone, Dovobet, Enstilar, Fucibet, Lotriderm, Lotrisone, Luxiq, Marbeta, Rivasone, Rolene, Rosone, Sernivo, Taclonex, Valisone-G, Wynzora •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): beta-Methasone alcohol Betadexamethasone Betametasona Betamethasone Bétaméthasone Betamethasonum •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Betamethasone is a systemic corticosteroid used to relieve inflammation in various conditions, including but not limited to allergic states, dermatologic disorders, gastrointestinal diseases, and hematological disorders.

The subject is a weak inducer of the CYP3A5 enzyme, and the affected drug is a substrate of the CYP3A5 enzyme. When these drugs are administered concomitantly, the metabolism of the affected drug is increased, leading to decreased serum concentrations and lower efficacy. The severity of the interaction is minor.

Question: Does Buspirone and Betamethasone interact? Information: •Drug A: Buspirone •Drug B: Betamethasone •Severity: MINOR •Description: The metabolism of Buspirone can be increased when combined with Betamethasone. •Extended Description: The subject is a weak inducer of the CYP3A5 enzyme, and the affected drug is a substrate of the CYP3A5 enzyme. When these drugs are administered concomitantly, the metabolism of the affected drug is increased, leading to decreased serum concentrations and lower efficacy. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): As a member of the corticosteroid family, betamethasone is indicated for the treatment of several inflammatory conditions. As topical monotherapy, betamethasone is indicated to relieve pruritic and inflammatory symptoms of corticosteroid-responsive-dermatoses. Betamethasone can be used topically in combination with a vitamin D analog such as calcipotriene to treat plaque psoriasis. The corticosteroid is also available as an injectable suspension and can be used to manage a range of inflammatory conditions including endocrine disorders, gastrointestinal disorders, and rheumatic disorders among other conditions. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Corticosteroids bind to the glucocorticoid receptor inhibiting pro-inflammatory signals, while promoting anti-inflammatory signals. Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces. Patients who require long-term treatment with a corticosteroid should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Glucocorticoids inhibit neutrophil apoptosis and demargination, and inhibit NF-Kappa B and other inflammatory transcription factors. They also inhibit phospholipase A2, leading to decreased formation of arachidonic acid derivatives. In addition, glucocorticoids promote anti-inflammatory genes like interleukin-10. Corticosteroids like betamethasone can act through nongenomic and genomic pathways. The genomic pathway is slower and occurs when glucocorticoids activate glucocorticoid receptors and initiate downstream effects that promote transcription of anti-inflammatory genes including phosphoenolpyruvate carboxykinase (PEPCK), IL-1-receptor antagonist, and tyrosine amino transferase (TAT). On the other hand, the nongenomic pathway is able to elicit a quicker response by modulating T-cell, platelet and monocyte activity through the use of existing membrane-bound receptors and second messengers. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): The absorption and potency of any topical corticosteroid including betamethasone depends on the vehicle in which the steroid is delivered. For example, betamethasone dipropionate 0.05% ointment is classified as a highly potent topical steroid, while betamethasone dipropionate 0.05% cream or lotion is considered to be moderately potent. There are several structural modifications that can determine the potency of a topical corticosteroid. For example, corticosteroids containing a halogen at specific carbons, or that contain esters are more potent due to enhanced lipophilicity. As such, there is a marked difference between topical products containing betamethasone dipropionate vs. betamethasone valerate. Betamethasone dipropionate contains 2 esters which enhances its potency, while betamethasone valerate has only one ester and is less potent. It should be noted that the use of occlusive dressings with topical steroids significantly increases the absorption, increasing the risk for adverse effects. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): In a study that included Indian women of reproductive age, the volume of distribution following a single intramuscular dose of betamethasone phosphate was 94,584±23,539 mL(s). •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Betamethasone valerate binds to serum albumin and corticosteroid-binding globulin. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): The metabolism of betamethasone yields 6 metabolites. The metabolic processes include 6β hydroxylation, 11β-hydroxyl oxidation, and reduction of the C-20 carbonyl group followed by removal of the side chain. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Corticosteroids are eliminated predominantly in the urine. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): In a study that included Indian women of reproductive age, the half-life following a single intramuscular dose of betamethasone phosphate was 10.2 ± 2.5 hours. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): In a study that included Indian women of reproductive age, the CL/F following a single intramuscular dose of betamethasone phosphate was 6,466 ± 805 mL/hour. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Chronic high doses of glucocorticoids can lead to the development of cataracts, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency. Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Betaderm, Betaloan Suik, Beteflam, Celestoderm, Celestone Soluspan, Dermacinrx Therazole Pak, Diprolene, Diprosalic, Diprosone, Dovobet, Enstilar, Fucibet, Lotriderm, Lotrisone, Luxiq, Marbeta, Rivasone, Rolene, Rosone, Sernivo, Taclonex, Valisone-G, Wynzora •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): beta-Methasone alcohol Betadexamethasone Betametasona Betamethasone Bétaméthasone Betamethasonum •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Betamethasone is a systemic corticosteroid used to relieve inflammation in various conditions, including but not limited to allergic states, dermatologic disorders, gastrointestinal diseases, and hematological disorders. Output: The subject is a weak inducer of the CYP3A5 enzyme, and the affected drug is a substrate of the CYP3A5 enzyme. When these drugs are administered concomitantly, the metabolism of the affected drug is increased, leading to decreased serum concentrations and lower efficacy. The severity of the interaction is minor.

Does Buspirone and Betaxolol interact?

•Drug A: Buspirone •Drug B: Betaxolol •Severity: MINOR •Description: Buspirone may decrease the antihypertensive activities of Betaxolol. •Extended Description: The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For the management of hypertension. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Betaxolol is a competitive, beta(1)-selective (cardioselective) adrenergic antagonist. Betaxolol is used to treat hypertension, arrhythmias, coronary heart disease, glaucoma, and is also used to reduce non-fatal cardiac events in patients with heart failure. Activation of beta(1)-receptors (located mainly in the heart) by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Drugs such as betaxolol that block these receptors therefore have the reverse effect: they lower the heart rate and blood pressure and hence are used in conditions when the heart itself is deprived of oxygen. They are routinely prescribed in patients with ischemic heart disease. In addition, beta(1)-selective blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. Betaxolol is lipophilic and exhibits no intrinsic sympathomimetic activity (ISA) or membrane stabilizing activity. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Betaxolol selectively blocks catecholamine stimulation of beta(1)-adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension. Betaxolol can also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles, causing bronchospasm. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Absorption of an oral dose is complete. There is a small and consistent first-pass effect resulting in an absolute bioavailability of 89% ± 5% that is unaffected by the concomitant ingestion of food or alcohol. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): 50% •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Primarily hepatic. Approximately 15% of the dose administered is excreted as unchanged drug, the remainder being metabolites whose contribution to the clinical effect is negligible. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): 14-22 hours •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Oral LD 50 s are 350 to 400 mg betaxolol/kg in mice and 860 to 980 mg/kg in rats. Predicted symptoms of overdose include bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Betoptic, Betoptic Pilo, Betoptic S •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Betaxolol Bétaxolol Betaxololum •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Betaxolol is a cardioselective beta blocking agent commonly used to treat hypertension and elevated intraocular pressure (when administered ophthalmically).

The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. The severity of the interaction is minor.

Question: Does Buspirone and Betaxolol interact? Information: •Drug A: Buspirone •Drug B: Betaxolol •Severity: MINOR •Description: Buspirone may decrease the antihypertensive activities of Betaxolol. •Extended Description: The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For the management of hypertension. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Betaxolol is a competitive, beta(1)-selective (cardioselective) adrenergic antagonist. Betaxolol is used to treat hypertension, arrhythmias, coronary heart disease, glaucoma, and is also used to reduce non-fatal cardiac events in patients with heart failure. Activation of beta(1)-receptors (located mainly in the heart) by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Drugs such as betaxolol that block these receptors therefore have the reverse effect: they lower the heart rate and blood pressure and hence are used in conditions when the heart itself is deprived of oxygen. They are routinely prescribed in patients with ischemic heart disease. In addition, beta(1)-selective blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. Betaxolol is lipophilic and exhibits no intrinsic sympathomimetic activity (ISA) or membrane stabilizing activity. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Betaxolol selectively blocks catecholamine stimulation of beta(1)-adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension. Betaxolol can also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles, causing bronchospasm. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Absorption of an oral dose is complete. There is a small and consistent first-pass effect resulting in an absolute bioavailability of 89% ± 5% that is unaffected by the concomitant ingestion of food or alcohol. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): 50% •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Primarily hepatic. Approximately 15% of the dose administered is excreted as unchanged drug, the remainder being metabolites whose contribution to the clinical effect is negligible. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): 14-22 hours •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Oral LD 50 s are 350 to 400 mg betaxolol/kg in mice and 860 to 980 mg/kg in rats. Predicted symptoms of overdose include bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Betoptic, Betoptic Pilo, Betoptic S •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Betaxolol Bétaxolol Betaxololum •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Betaxolol is a cardioselective beta blocking agent commonly used to treat hypertension and elevated intraocular pressure (when administered ophthalmically). Output: The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. The severity of the interaction is minor.

Does Buspirone and Bicisate interact?

•Drug A: Buspirone •Drug B: Bicisate •Severity: MINOR •Description: Buspirone may decrease the excretion rate of Bicisate which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Bicisate as a complex with technetium Tc-99m is used in single photon emission computerized tomography (SPECT) as an adjunct to conventional CT or MRI in the localization of stroke in patients whom the presence of a stroke has already been diagnosed. It is not indicated to assess the functional viability of brain tissue or to distinguish between a stroke and other brain lesions. A stroke is defined as a condition in which the blood stops flowing to any part of the brain causing a damage to brain cells. The potential effect of a stroke depends on the part of the brain that was affected by it as well as the extension of the damage. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): The neutral and lipophilic nature of bicisate provides it with high stability. This property is given by its N2S2 core. This characteristic has been proven to allow bicisate to be used even several hours after preparation and to present an easy passage through the blood-brain barrier. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Bicisate is rapidly uptaken by the brain. The retention of bicisate in the brain is associated with stereospecific de-esterification to hydrophilic acid derivatives. Even though both DD and LL isomers demonstrate brain uptake, only the LL presents brain retention. Bicisate brain localization is performed by passive diffusion and the presence of slow hydrolysis in the blood and rapid hydrolysis in the brain. The hydrolysis of bicisate forms the monoacid and diacid bicisate derivatives. The formation of these derivatives results in high brain uptake and retention. The uptake of bicisate depends on the blood flow directed to the brain and thus the presence of a stroke will be translated into specific zones in the brain that would not include the complex of bicisate and technetium Tc-99m. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): After intravenous administration, bicisate presents a very large brain extraction. About 5% of the administered dose remains in the blood one hour after administration. The highest concentration of radioactivity in blood was attained 0.5 minutes after intravenous injection and it represented 13.9% of the injected dose. After intravenous administration of bicisate, the permeability surface area was 0.48 ml.g/min. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): After intravenous administration of bicisate, the distribution volume was 0.74 L. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Bicisate and its major metabolites are not protein-bound. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Bicisate is metabolized to form mono- and di-acids by the action of esterases. The exact metabolic transformation has not been elucidated. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Bicisate is primarily excreted by the kidneys. It has been reported that 50% of the dose is excreted in urine two hours after initial administration and even 74% of the administered dose is excreted in urine after 24 hours. Fecal excretion just accounts for 12.5% of the administered dose 48 hours after initial administration. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The stability of bicisate is superior when compared to other brain radiopharmaceuticals. Thus, the reported half-life of bicisate is of 6.02 hours. When broadly studied in clinical trials, the pharmacokinetic profile fits a three-compartment model with half-lives of 43 seconds, 49.5 minutes and 533 minutes. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): The clearance of bicisate from 1 to 24 hours, studied as a loss of hydrophilic tracer, is of approximate 3.5% per hour. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): In vitro, the complex of bicisate and technetium Tc-99m has been shown to cause unscheduled DNA synthesis and caused an increased frequency of chromatid exchange. Bicisate as a unique compound increased the apparent rate of gene mutation but it did not demonstrate clastogenic activity. Studies related to clastogenic potential or effects in fertility have not been performed. •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bicisate is a compound complexed with technetium 99 used in single photon emission computerized tomography to localize a stroke.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Buspirone and Bicisate interact? Information: •Drug A: Buspirone •Drug B: Bicisate •Severity: MINOR •Description: Buspirone may decrease the excretion rate of Bicisate which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Bicisate as a complex with technetium Tc-99m is used in single photon emission computerized tomography (SPECT) as an adjunct to conventional CT or MRI in the localization of stroke in patients whom the presence of a stroke has already been diagnosed. It is not indicated to assess the functional viability of brain tissue or to distinguish between a stroke and other brain lesions. A stroke is defined as a condition in which the blood stops flowing to any part of the brain causing a damage to brain cells. The potential effect of a stroke depends on the part of the brain that was affected by it as well as the extension of the damage. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): The neutral and lipophilic nature of bicisate provides it with high stability. This property is given by its N2S2 core. This characteristic has been proven to allow bicisate to be used even several hours after preparation and to present an easy passage through the blood-brain barrier. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Bicisate is rapidly uptaken by the brain. The retention of bicisate in the brain is associated with stereospecific de-esterification to hydrophilic acid derivatives. Even though both DD and LL isomers demonstrate brain uptake, only the LL presents brain retention. Bicisate brain localization is performed by passive diffusion and the presence of slow hydrolysis in the blood and rapid hydrolysis in the brain. The hydrolysis of bicisate forms the monoacid and diacid bicisate derivatives. The formation of these derivatives results in high brain uptake and retention. The uptake of bicisate depends on the blood flow directed to the brain and thus the presence of a stroke will be translated into specific zones in the brain that would not include the complex of bicisate and technetium Tc-99m. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): After intravenous administration, bicisate presents a very large brain extraction. About 5% of the administered dose remains in the blood one hour after administration. The highest concentration of radioactivity in blood was attained 0.5 minutes after intravenous injection and it represented 13.9% of the injected dose. After intravenous administration of bicisate, the permeability surface area was 0.48 ml.g/min. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): After intravenous administration of bicisate, the distribution volume was 0.74 L. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Bicisate and its major metabolites are not protein-bound. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Bicisate is metabolized to form mono- and di-acids by the action of esterases. The exact metabolic transformation has not been elucidated. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Bicisate is primarily excreted by the kidneys. It has been reported that 50% of the dose is excreted in urine two hours after initial administration and even 74% of the administered dose is excreted in urine after 24 hours. Fecal excretion just accounts for 12.5% of the administered dose 48 hours after initial administration. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The stability of bicisate is superior when compared to other brain radiopharmaceuticals. Thus, the reported half-life of bicisate is of 6.02 hours. When broadly studied in clinical trials, the pharmacokinetic profile fits a three-compartment model with half-lives of 43 seconds, 49.5 minutes and 533 minutes. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): The clearance of bicisate from 1 to 24 hours, studied as a loss of hydrophilic tracer, is of approximate 3.5% per hour. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): In vitro, the complex of bicisate and technetium Tc-99m has been shown to cause unscheduled DNA synthesis and caused an increased frequency of chromatid exchange. Bicisate as a unique compound increased the apparent rate of gene mutation but it did not demonstrate clastogenic activity. Studies related to clastogenic potential or effects in fertility have not been performed. •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bicisate is a compound complexed with technetium 99 used in single photon emission computerized tomography to localize a stroke. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Buspirone and Bimekizumab interact?

•Drug A: Buspirone •Drug B: Bimekizumab •Severity: MODERATE •Description: The metabolism of Buspirone can be increased when combined with Bimekizumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Bimekizumab is indicated for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bimekizumab exerts its pharmacologic effects by binding to and inhibiting one of the pro-inflammatory cytokines involved in psoriasis pathogenesis. It is administered once-monthly as a subcutaneous injection. Bimekizumab may increased the risk of infection, including upper respiratory tract infections and oral candidiasis. Any clinically important active infections should be resolved prior to therapy. In addition, the use of live vaccines during bimekizumab therapy is not recommended - ensure patients beginning therapy have completed all age appropriate immunizations prior to initiation. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): The pathophysiology of psoriasis involves a dysregulation of the immune system and is facilitated by a variety of cytokines released by dendritic cells and T-helper cells. Plaque psoriasis, the most common subtype of psoriasis, is driven primarily by tumor necrosis factor-alpha (TNF-α) and interleukins 17 and 23 (IL-17 and IL-23), with the axis between these three cytokines integral to the maintenance phase of psoriasis. IL-17 acts through two separate mechanisms: the first, dependent on the cytoplasmic adaptor protein ACT1, involves the activation of NF-κB and the transcription of inflammatory genes. The second, independent of ACT1, involves the activation of the JAK/STAT signaling cascade, which leads to further transcription of pro-inflammatory proteins and continued psoriasis pathogenicity. Bimekizumab is a monoclonal antibody targeted against IL-17A, IL-17F, and a heterodimer of the two called IL-17AF. It blocks the interaction of these interleukins with their respective receptors, thus reducing psoriatic inflammation. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): In healthy volunteers, the absolute bioavailability of bimekizumab following subcutaneous injection was 70.1%. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): In patients with plaque psoriasis, the median volume of distribution at steady-state was 11.2 L. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): As a monoclonal antibody, bimekizumab is likely degraded into smaller peptides and amino acids via catabolic processes. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The mean terminal elimination half-life of bimekizumab in patients with plaque psoriasis was 23 days. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): The median apparent clearance of bimekuzmab in patients with plaque psoriasis was 0.337 L/day. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Single doses of up to 640mg given both intravenously and subcutaneously have been administered in clinical studies without evidence of dose-limiting toxicities. If overdosage of bimekizumab is suspected, monitor the patient for adverse reactions and institute symptomatic treatment as clinically indicated. •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bimekizumab is an anti-IL-17A, IL-17F, and IL-17AF monoclonal antibody used in the treatment plaque psoriasis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Buspirone and Bimekizumab interact? Information: •Drug A: Buspirone •Drug B: Bimekizumab •Severity: MODERATE •Description: The metabolism of Buspirone can be increased when combined with Bimekizumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Bimekizumab is indicated for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bimekizumab exerts its pharmacologic effects by binding to and inhibiting one of the pro-inflammatory cytokines involved in psoriasis pathogenesis. It is administered once-monthly as a subcutaneous injection. Bimekizumab may increased the risk of infection, including upper respiratory tract infections and oral candidiasis. Any clinically important active infections should be resolved prior to therapy. In addition, the use of live vaccines during bimekizumab therapy is not recommended - ensure patients beginning therapy have completed all age appropriate immunizations prior to initiation. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): The pathophysiology of psoriasis involves a dysregulation of the immune system and is facilitated by a variety of cytokines released by dendritic cells and T-helper cells. Plaque psoriasis, the most common subtype of psoriasis, is driven primarily by tumor necrosis factor-alpha (TNF-α) and interleukins 17 and 23 (IL-17 and IL-23), with the axis between these three cytokines integral to the maintenance phase of psoriasis. IL-17 acts through two separate mechanisms: the first, dependent on the cytoplasmic adaptor protein ACT1, involves the activation of NF-κB and the transcription of inflammatory genes. The second, independent of ACT1, involves the activation of the JAK/STAT signaling cascade, which leads to further transcription of pro-inflammatory proteins and continued psoriasis pathogenicity. Bimekizumab is a monoclonal antibody targeted against IL-17A, IL-17F, and a heterodimer of the two called IL-17AF. It blocks the interaction of these interleukins with their respective receptors, thus reducing psoriatic inflammation. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): In healthy volunteers, the absolute bioavailability of bimekizumab following subcutaneous injection was 70.1%. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): In patients with plaque psoriasis, the median volume of distribution at steady-state was 11.2 L. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): As a monoclonal antibody, bimekizumab is likely degraded into smaller peptides and amino acids via catabolic processes. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The mean terminal elimination half-life of bimekizumab in patients with plaque psoriasis was 23 days. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): The median apparent clearance of bimekuzmab in patients with plaque psoriasis was 0.337 L/day. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Single doses of up to 640mg given both intravenously and subcutaneously have been administered in clinical studies without evidence of dose-limiting toxicities. If overdosage of bimekizumab is suspected, monitor the patient for adverse reactions and institute symptomatic treatment as clinically indicated. •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bimekizumab is an anti-IL-17A, IL-17F, and IL-17AF monoclonal antibody used in the treatment plaque psoriasis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Buspirone and Biperiden interact?

•Drug A: Buspirone •Drug B: Biperiden •Severity: MODERATE •Description: The metabolism of Buspirone can be decreased when combined with Biperiden. •Extended Description: The subject drug is known to be an inhibitor of CYP2D6 while the affected drug is reported to be metabolized by CYP2D6. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to a decrease in metabolism by CYP2D6, which may result in increased incidence and/or severity of adverse effects related to the affected drug. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For use as an adjunct in the therapy of all forms of parkinsonism and control of extrapyramidal disorders secondary to neuroleptic drug therapy. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Biperiden is a weak peripheral anticholinergic agent. It has, therefore, some antisecretory, antispasmodic and mydriatic effects. In addition, biperiden possesses nicotinolytic activity. The parenteral form of biperiden is an effective and reliable agent for the treatment of acute episodes of extrapyramidal disturbances sometimes seen during treatment with neuroleptic agents. Akathisia, akinesia, dyskinetic tremors, rigor, oculogyric crisis, spasmodic torticollis, and profuse sweating are markedly reduced or eliminated. With parenteral biperiden, these drug-induced disturbances are rapidly brought under control. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Parkinsonism is thought to result from an imbalance between the excitatory (cholinergic) and inhibitory (dopaminergic) systems in the corpus striatum. The mechanism of action of centrally active anticholinergic drugs such as biperiden is considered to relate to competitive antagonism of acetylcholine at cholinergic receptors in the corpus striatum, which then restores the balance. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): 87% bioavailability •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): 60% •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): The metabolism of biperiden is not completely understood, but does involve hydroxylation. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): No half-life available •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): LD 50 =760 mg/kg (Orally in rats). Signs of overdose include dilated and sluggish pupils, warm, dry skin, facial flushing, decreased secretions of the mouth, pharynx, nose, and bronchi, foul-smelling breath, elevated temperature, tachycardia, cardiac arrhythmias, decreased bowel sounds, urinary retention, delirium, disorientation, anxiety, hallucinations, illusions, confusion, incoherence, agitation, hyperactivity, ataxia, loss of memory, paranoia, combativeness, and seizures. •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Biperiden Biperidene Biperideno Biperidenum •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Biperiden is a muscarinic receptor antagonist used to treat parkinsonism and control extrapyramidal side effects of neuroleptic drugs.

The subject drug is known to be an inhibitor of CYP2D6 while the affected drug is reported to be metabolized by CYP2D6. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to a decrease in metabolism by CYP2D6, which may result in increased incidence and/or severity of adverse effects related to the affected drug. The severity of the interaction is moderate.

Question: Does Buspirone and Biperiden interact? Information: •Drug A: Buspirone •Drug B: Biperiden •Severity: MODERATE •Description: The metabolism of Buspirone can be decreased when combined with Biperiden. •Extended Description: The subject drug is known to be an inhibitor of CYP2D6 while the affected drug is reported to be metabolized by CYP2D6. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to a decrease in metabolism by CYP2D6, which may result in increased incidence and/or severity of adverse effects related to the affected drug. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For use as an adjunct in the therapy of all forms of parkinsonism and control of extrapyramidal disorders secondary to neuroleptic drug therapy. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Biperiden is a weak peripheral anticholinergic agent. It has, therefore, some antisecretory, antispasmodic and mydriatic effects. In addition, biperiden possesses nicotinolytic activity. The parenteral form of biperiden is an effective and reliable agent for the treatment of acute episodes of extrapyramidal disturbances sometimes seen during treatment with neuroleptic agents. Akathisia, akinesia, dyskinetic tremors, rigor, oculogyric crisis, spasmodic torticollis, and profuse sweating are markedly reduced or eliminated. With parenteral biperiden, these drug-induced disturbances are rapidly brought under control. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Parkinsonism is thought to result from an imbalance between the excitatory (cholinergic) and inhibitory (dopaminergic) systems in the corpus striatum. The mechanism of action of centrally active anticholinergic drugs such as biperiden is considered to relate to competitive antagonism of acetylcholine at cholinergic receptors in the corpus striatum, which then restores the balance. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): 87% bioavailability •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): 60% •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): The metabolism of biperiden is not completely understood, but does involve hydroxylation. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): No half-life available •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): LD 50 =760 mg/kg (Orally in rats). Signs of overdose include dilated and sluggish pupils, warm, dry skin, facial flushing, decreased secretions of the mouth, pharynx, nose, and bronchi, foul-smelling breath, elevated temperature, tachycardia, cardiac arrhythmias, decreased bowel sounds, urinary retention, delirium, disorientation, anxiety, hallucinations, illusions, confusion, incoherence, agitation, hyperactivity, ataxia, loss of memory, paranoia, combativeness, and seizures. •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Biperiden Biperidene Biperideno Biperidenum •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Biperiden is a muscarinic receptor antagonist used to treat parkinsonism and control extrapyramidal side effects of neuroleptic drugs. Output: The subject drug is known to be an inhibitor of CYP2D6 while the affected drug is reported to be metabolized by CYP2D6. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to a decrease in metabolism by CYP2D6, which may result in increased incidence and/or severity of adverse effects related to the affected drug. The severity of the interaction is moderate.

Does Buspirone and Bismuth subgallate interact?

•Drug A: Buspirone •Drug B: Bismuth subgallate •Severity: MINOR •Description: Buspirone may decrease the excretion rate of Bismuth subgallate which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): The most common medical purpose for which bismuth subgallate is currently and formally indicated for is the use as a non-prescription internal deodorant product for the purpose of deodorizing flatulence and stools. Additionally, there are also various non-prescription (over the counter) bismuth subgallate based wound healing products as well as ongoing studies into whether or not the substance can be utilized as a legitimate hemostatic agent - usually for soft tissue surgery in otorhinolaryngology and/or dermatologic settings. Moreover, in the past bismuth subgallate may have seen some use as a treatment for Helicobacter pylori infection. In contrast, contemporary first-line therapies generally involve proton pump inhibitor and antibiotic combination therapies that generally achieve high rates of pathogen eradication, ease of administration, and patient compliance. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bismuth subgallate is a heavy metal salt that is relatively insoluble and poorly absorbed. As a result, systemic absorption is not necessary or possibly even desired when the agent is administered orally or onto specific otorhinolaryngology and/or dermatologic wound sites where it can execute its pharmacologic action directly within the gastrointestinal lumen to deodorize flatulence and stools or potentially elicit a hemostatic effect on wounds. Additionally, like other bismuth agents, one of the most common side effects associated with bismuth subgallate is its propensity to cause a black discoloration of the tongue and stools when the agent combines with trace amounts of sulfur in the saliva and/or gastrointestinal tract. This discoloration is temporary and harmless, gradually dissipating over a number of days and eventually disappearing after the discontinuation of the bismuth agent. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Bismuth salts exert their action largely in the upper gastrointestinal tract by way of local activity from luminal bismuth in the stomach and duodenum. In terms of bismuth subgallate's ability to deodorize flatulence and stools as an internal deodorant - although not fully elucidated - it is believed that when the substance is administered orally, its relative insolubility and poor absorption allows it to remain within the gastrointestinal lumen and inhibit colonic bacteria from acting on fermentable food residues in the GI tract. Moreover, when bismuth subgallate is taken orally, various salts like bismuth citrate, bismuth oxychloride, and others are formed. These salts are then taken up into surrounding gastric mucus as well as bound to protein within the base of any ulcers that may be present after coming into contact with gastric juice. Additionally, bismuth compounds like bismuth subgallate are also believed to have the capacity to trigger the secretion of prostaglandins, epithelial growth factor (EGF), and mucosal bicarbonate as a means to inhibit the action of pepsin in gastric juice. These actions subsequently protect gastric mucous from peptic luminal degradation as well as enhance the properties of mucous to assist in the healing of both duodenal and gastric ulcers. In this way, bismuth subgallate works to absorb extra water and/or toxins in the large intestine, allowing it to form a protective coat on the intestinal mucosa and over ulcers that may or may not be associated with infections like those of Helicobacter pylori. Furthermore, studies have shown that bismuth compounds like bismuth subgallate are capable of demonstrating antimicrobial effects against various gastrointestinal tract pathogens like E. coli, Salmonella, Shigella, Vibrio cholera, Campylobacter jejuni, H. pylori, and some enteric viruses like Rotaviruses. Although the exact mechanism(s) of action by which bismuth compounds are able to elicit such antimicrobial effects remains unclear, a number of experimental observations suggest that bismuth has been able to complex with the bacterial wall and periplasmic membrane; inhibit bacterial enzymes like urease, catalase, and lipase; inhibit bacterial protein and ATP synthesis; and also inhibit or decrease the adherence of bacteria like H. pylori to epithelial cells. In essence, ultrastructural studies have shown evidence of the binding of bismuth complexes to the bacterial wall and periplasmic space between the inner and outer bacterial membrane of H.pylori with subsequent ballooning and disintegration of the pathogen. To various extents, these antimicrobial actions may also illustrate how bismuth subgallate is capable of neutralizing colonic bacteria from acting on fermentable foods as well. Numerous studies have and continue to study the possible hemostatic action that bismuth subgallate may have. As the bismuth salt of gallic acid, bismuth subgallate's chemical structure shares similarities to ellagic acid, another gallic acid derivative. Ellagic acid itself is a clot-promoting agent that initiates thrombin formation by way of the intrinsic pathway via an action on Hageman factor (clotting factor XII). It is believed that bismuth subgallate's ability to activate factor XII is associated with the chemical's negatively charged moieties - whose contact with factor XII would theoretically initiate the intrinsic pathway to blood clotting. Other studies have also suggested that bismuth subgallate is capable of inducing macrophages to secrete growth factors to facilitate wound healing, decreasing lesion area, enhancing granulation tissue formation and re-epithelialization, the initiation of the proliferation of collagen via the activation of fibroblasts, the accelerated re-establishment of blood vessels, and also the restriction of nitric oxide formation. Given such studies regarding bismuth subgallate's potential hemostatic abilities, there has been and continues to be interest in indicating the agent for use in otolaryngology as in tonsillectomies or adenotonsillectomies to achieve reduced bleeding and surgery times; topical treatment in various open wound surgeries to facilitate faster and earlier clotting between tissues; ileostomy; dental surgeries; epistaxis management; among others. Nevertheless, study results are conflicting; where there may be experimental results suggesting some improvements in reduced operation time and operative blood loss when bismuth subgallate is used as a hemostatic agent in tonsillectomies there are also study results that observed bismuth subgallate having a negative influence on the healing processes of wounds inflicted in animal models, in which the use of the agent actually delayed the rate of new vessel formation and optimal wound healing. Finally, bismuth subgallate also demonstrates a strong astringent ability - an action that can facilitate both its deodorant and hemostatic effects and assists in its indication as an active ingredient in a number of non-prescription products for hemorrhoid suppositories or topical applications, diarrhea, etc. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Bismuth subgallate is only slightly, if at all, absorbed after oral ingestion. The general human oral bioavailability of bismuth subgallate has been reported as low as 0.04%. Any absorption that does occur is likely to happen from the upper small intestine. The gastrointestinal absorption of bismuth from bismuth compounds demonstrates a large interindividual variation. Factors affecting the absorption involve the formulation of the bismuth subgallate compound as well as the dietary factors of the individuals themselves. Nevertheless, absorption can be enhanced with the concomitant intake of citrate and sulfhydryl-group-containing compounds. Conversely, the simultaneous administration of antacids or a diet that is high in thiol content can lower absorption of bismuth subgallate. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): In general, oral administration is one of the most common routes of administration for non-prescription bismuth subgallate products and gastrointestinal and systemic absorption is usually very low. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): In general, any systemic absorption of bismuth subgallate is expected to be low but any bismuth that is absorbed is also expected to bind to plasma proteins and be distributed throughout all tissues, with the highest concentration found in the kidney and lower levels in the lung, spleen, liver, brain, bone, and muscle. The bismuth component itself is generally known to demonstrate a high percentage binding to plasma proteins of >90%. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): No specific metabolism of bismuth is known. In the kidney it induces the de novo synthesis of a bismuth-metal-binding protein, which is a kind of methallothionein. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Ingested bismuth is primarily eliminated unabsorbed by way of the faeces. Any absorbed bismuth is eliminated from the body by both the urinary and faecal (including bile) routes. Excretion of absorbed bismuth in the urine is rapid, with most of the metal excreted within 24 hours. About 10% of the absorbed bismuth is detected in faeces, presumably owing to biliary secretion. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The bismuth component of bismuth subgallate is known to have a terminal half-life of 21-72 days. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): On average, the blood clearance of the bismuth component of a bismuth salt like bismuth subgallate is within the range of 50 to 95 ml/min. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Depending on the level of severity of a patient's renal impairment, administration of bismuth compounds may not be appropriate as the reduced renal clearance can lead to undesirably elevated blood levels of bismuth. Similarly, because of the biliary excretion of bismuth, severe liver disease may theoretically result in accumulation of bismuth as well. Bismuth toxicity seemingly develops only from excessive dosage (perhaps from ingestion of bismuth over a prolonged time or intramuscular injections) and is characterized by nephrotoxicity, osteoarthropathy, encephalopathy, hepatotoxicity, stomatitis, and gingivitis. However, the insoluble inorganic bismuth compounds are reported to be mainly associated with reversible encephalopathy. In fact a number of studies have discussed how patients may experience a syndrome of subacute, progressive encephalopathy involving potential aphasia, myoclonous, and/or gait instability after taking bismuth subgallate in large quantities well over the usual recommended dosages. This kind of encephalopathy is usually reversible with the discontinuation of the bismuth subgallate usage however. •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): basisches Wismutgallat Bismuth subgallate Bismuto subgalato gallic acid bismuth basic salt Wismutgallathydroxid •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bismuth subgallate is a medication used to deodorize flatulence and stools as well as hemostasis in soft tissue surgery.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Buspirone and Bismuth subgallate interact? Information: •Drug A: Buspirone •Drug B: Bismuth subgallate •Severity: MINOR •Description: Buspirone may decrease the excretion rate of Bismuth subgallate which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): The most common medical purpose for which bismuth subgallate is currently and formally indicated for is the use as a non-prescription internal deodorant product for the purpose of deodorizing flatulence and stools. Additionally, there are also various non-prescription (over the counter) bismuth subgallate based wound healing products as well as ongoing studies into whether or not the substance can be utilized as a legitimate hemostatic agent - usually for soft tissue surgery in otorhinolaryngology and/or dermatologic settings. Moreover, in the past bismuth subgallate may have seen some use as a treatment for Helicobacter pylori infection. In contrast, contemporary first-line therapies generally involve proton pump inhibitor and antibiotic combination therapies that generally achieve high rates of pathogen eradication, ease of administration, and patient compliance. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bismuth subgallate is a heavy metal salt that is relatively insoluble and poorly absorbed. As a result, systemic absorption is not necessary or possibly even desired when the agent is administered orally or onto specific otorhinolaryngology and/or dermatologic wound sites where it can execute its pharmacologic action directly within the gastrointestinal lumen to deodorize flatulence and stools or potentially elicit a hemostatic effect on wounds. Additionally, like other bismuth agents, one of the most common side effects associated with bismuth subgallate is its propensity to cause a black discoloration of the tongue and stools when the agent combines with trace amounts of sulfur in the saliva and/or gastrointestinal tract. This discoloration is temporary and harmless, gradually dissipating over a number of days and eventually disappearing after the discontinuation of the bismuth agent. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Bismuth salts exert their action largely in the upper gastrointestinal tract by way of local activity from luminal bismuth in the stomach and duodenum. In terms of bismuth subgallate's ability to deodorize flatulence and stools as an internal deodorant - although not fully elucidated - it is believed that when the substance is administered orally, its relative insolubility and poor absorption allows it to remain within the gastrointestinal lumen and inhibit colonic bacteria from acting on fermentable food residues in the GI tract. Moreover, when bismuth subgallate is taken orally, various salts like bismuth citrate, bismuth oxychloride, and others are formed. These salts are then taken up into surrounding gastric mucus as well as bound to protein within the base of any ulcers that may be present after coming into contact with gastric juice. Additionally, bismuth compounds like bismuth subgallate are also believed to have the capacity to trigger the secretion of prostaglandins, epithelial growth factor (EGF), and mucosal bicarbonate as a means to inhibit the action of pepsin in gastric juice. These actions subsequently protect gastric mucous from peptic luminal degradation as well as enhance the properties of mucous to assist in the healing of both duodenal and gastric ulcers. In this way, bismuth subgallate works to absorb extra water and/or toxins in the large intestine, allowing it to form a protective coat on the intestinal mucosa and over ulcers that may or may not be associated with infections like those of Helicobacter pylori. Furthermore, studies have shown that bismuth compounds like bismuth subgallate are capable of demonstrating antimicrobial effects against various gastrointestinal tract pathogens like E. coli, Salmonella, Shigella, Vibrio cholera, Campylobacter jejuni, H. pylori, and some enteric viruses like Rotaviruses. Although the exact mechanism(s) of action by which bismuth compounds are able to elicit such antimicrobial effects remains unclear, a number of experimental observations suggest that bismuth has been able to complex with the bacterial wall and periplasmic membrane; inhibit bacterial enzymes like urease, catalase, and lipase; inhibit bacterial protein and ATP synthesis; and also inhibit or decrease the adherence of bacteria like H. pylori to epithelial cells. In essence, ultrastructural studies have shown evidence of the binding of bismuth complexes to the bacterial wall and periplasmic space between the inner and outer bacterial membrane of H.pylori with subsequent ballooning and disintegration of the pathogen. To various extents, these antimicrobial actions may also illustrate how bismuth subgallate is capable of neutralizing colonic bacteria from acting on fermentable foods as well. Numerous studies have and continue to study the possible hemostatic action that bismuth subgallate may have. As the bismuth salt of gallic acid, bismuth subgallate's chemical structure shares similarities to ellagic acid, another gallic acid derivative. Ellagic acid itself is a clot-promoting agent that initiates thrombin formation by way of the intrinsic pathway via an action on Hageman factor (clotting factor XII). It is believed that bismuth subgallate's ability to activate factor XII is associated with the chemical's negatively charged moieties - whose contact with factor XII would theoretically initiate the intrinsic pathway to blood clotting. Other studies have also suggested that bismuth subgallate is capable of inducing macrophages to secrete growth factors to facilitate wound healing, decreasing lesion area, enhancing granulation tissue formation and re-epithelialization, the initiation of the proliferation of collagen via the activation of fibroblasts, the accelerated re-establishment of blood vessels, and also the restriction of nitric oxide formation. Given such studies regarding bismuth subgallate's potential hemostatic abilities, there has been and continues to be interest in indicating the agent for use in otolaryngology as in tonsillectomies or adenotonsillectomies to achieve reduced bleeding and surgery times; topical treatment in various open wound surgeries to facilitate faster and earlier clotting between tissues; ileostomy; dental surgeries; epistaxis management; among others. Nevertheless, study results are conflicting; where there may be experimental results suggesting some improvements in reduced operation time and operative blood loss when bismuth subgallate is used as a hemostatic agent in tonsillectomies there are also study results that observed bismuth subgallate having a negative influence on the healing processes of wounds inflicted in animal models, in which the use of the agent actually delayed the rate of new vessel formation and optimal wound healing. Finally, bismuth subgallate also demonstrates a strong astringent ability - an action that can facilitate both its deodorant and hemostatic effects and assists in its indication as an active ingredient in a number of non-prescription products for hemorrhoid suppositories or topical applications, diarrhea, etc. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Bismuth subgallate is only slightly, if at all, absorbed after oral ingestion. The general human oral bioavailability of bismuth subgallate has been reported as low as 0.04%. Any absorption that does occur is likely to happen from the upper small intestine. The gastrointestinal absorption of bismuth from bismuth compounds demonstrates a large interindividual variation. Factors affecting the absorption involve the formulation of the bismuth subgallate compound as well as the dietary factors of the individuals themselves. Nevertheless, absorption can be enhanced with the concomitant intake of citrate and sulfhydryl-group-containing compounds. Conversely, the simultaneous administration of antacids or a diet that is high in thiol content can lower absorption of bismuth subgallate. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): In general, oral administration is one of the most common routes of administration for non-prescription bismuth subgallate products and gastrointestinal and systemic absorption is usually very low. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): In general, any systemic absorption of bismuth subgallate is expected to be low but any bismuth that is absorbed is also expected to bind to plasma proteins and be distributed throughout all tissues, with the highest concentration found in the kidney and lower levels in the lung, spleen, liver, brain, bone, and muscle. The bismuth component itself is generally known to demonstrate a high percentage binding to plasma proteins of >90%. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): No specific metabolism of bismuth is known. In the kidney it induces the de novo synthesis of a bismuth-metal-binding protein, which is a kind of methallothionein. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Ingested bismuth is primarily eliminated unabsorbed by way of the faeces. Any absorbed bismuth is eliminated from the body by both the urinary and faecal (including bile) routes. Excretion of absorbed bismuth in the urine is rapid, with most of the metal excreted within 24 hours. About 10% of the absorbed bismuth is detected in faeces, presumably owing to biliary secretion. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The bismuth component of bismuth subgallate is known to have a terminal half-life of 21-72 days. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): On average, the blood clearance of the bismuth component of a bismuth salt like bismuth subgallate is within the range of 50 to 95 ml/min. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Depending on the level of severity of a patient's renal impairment, administration of bismuth compounds may not be appropriate as the reduced renal clearance can lead to undesirably elevated blood levels of bismuth. Similarly, because of the biliary excretion of bismuth, severe liver disease may theoretically result in accumulation of bismuth as well. Bismuth toxicity seemingly develops only from excessive dosage (perhaps from ingestion of bismuth over a prolonged time or intramuscular injections) and is characterized by nephrotoxicity, osteoarthropathy, encephalopathy, hepatotoxicity, stomatitis, and gingivitis. However, the insoluble inorganic bismuth compounds are reported to be mainly associated with reversible encephalopathy. In fact a number of studies have discussed how patients may experience a syndrome of subacute, progressive encephalopathy involving potential aphasia, myoclonous, and/or gait instability after taking bismuth subgallate in large quantities well over the usual recommended dosages. This kind of encephalopathy is usually reversible with the discontinuation of the bismuth subgallate usage however. •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): basisches Wismutgallat Bismuth subgallate Bismuto subgalato gallic acid bismuth basic salt Wismutgallathydroxid •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bismuth subgallate is a medication used to deodorize flatulence and stools as well as hemostasis in soft tissue surgery. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Buspirone and Bisoprolol interact?

•Drug A: Buspirone •Drug B: Bisoprolol •Severity: MINOR •Description: Buspirone may decrease the antihypertensive activities of Bisoprolol. •Extended Description: The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Bisoprolol is indicated for the treatment of mild to moderate hypertension. It may be used off-label to treat heart failure, atrial fibrillation, and angina pectoris. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bisoprolol decreases heart rate (chronotropy), decreases contractility (inotropy), and reduces blood pressure. The results of various clinical studies indicate that bisoprolol reduces cardiovascular mortality and all-cause mortality in patients with heart failure and decreased cardiac ejection fraction (EF). •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Though the mechanism of action of bisoprolol has not been fully elucidated in hypertension, it is thought that therapeutic effects are achieved through the antagonism of β-1adrenoceptors to result in lower cardiac output. Bisoprolol is a competitive, cardioselective β1-adrenergic antagonist. When β1-receptors (located mainly in the heart) are activated by adrenergic neurotransmitters such as epinephrine, both the blood pressure and heart rate increase, leading to greater cardiovascular work, increasing the demand for oxygen. Bisoprolol reduces cardiac workload by decreasing contractility and the need for oxygen through competitive inhibition of β1-adrenergic receptors. Bisoprolol is also thought to reduce the output of renin in the kidneys, which normally increases blood pressure. Additionally, some central nervous system effects of bisoprolol may include diminishing sympathetic nervous system output from the brain, decreasing blood pressure and heart rate. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Bisoprolol is well absorbed in the gastrointestinal tract. The AUC is 642.87 g.hr/mL and bioavailability of bisoprolol is about 90% due to the minimal first pass effects. Absorption is unaffected by food intake. Peak plasma concentrations of bisoprolol are attained within 2-4 hours and steady-state concentrations are achieved within 5 days of administration. In a pharmacokinetic study, the mean peak concentration of bisoprolol was 52 micrograms/L. Cmax at steady state concentrations of bisoprolol is 64±21 ng/ml administered at 10 mg daily. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The volume of distribution of bisoprolol is 3.5 L/kg. The mean volume of distribution was found to be 230 L/kg in heart failure patients, which was similar to the volume of distribution in healthy patients. Bisoprolol is known to cross the placenta. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Binding to serum proteins is approximately 30%. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Approximately 50% of the bisoprolol dose is eliminated by non-renal pathways. Bisoprolol is metabolized through oxidative metabolic pathways with no subsequent conjugation. Bisoprolol metabolites are polar and, therefore, really eliminated. Major metabolites found in plasma and urine are inactive. Bisoprolol is mainly metabolized by CYP3A4 (95%), whereas CYP2D6 plays a minor role. The CYP3A4-mediated metabolism of bisoprolol appears to be non-stereoselective. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Bisoprolol is eliminated equally by both renal and hepatic pathways. About 50% of an oral dose is excreted unchanged in the urine with the remainder of the dose excreted as inactive bisoprolol metabolites. Under 2% of the ingested dose is found to be excreted in the feces. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): A pharmacokinetic study in 12 healthy individuals determined the mean plasma half-life of bisoprolol to be 10-12 hours. Another study comprised of healthy patients determined the elimination half-life to be approximately 10 hours. Renal impairment increased the half-life to 18.5 hours. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): Total body clearance in healthy patients was determined to be 14.2 L/h. In patients with renal impairment, clearance was reduced to 7.8 L/h. Hepatic dysfunction also reduced the clearance of bisoprolol. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): LD50 information Oral LD50 of bisoprolol in the mouse was 730 mg/kg. Overdose information Signs of a β-blocker overdose include cardiovascular symptoms such as hypotension, congestive heart failure, and bradycardia. Other symptoms such as bronchospasm, and hypoglycemia may occur. If an overdose occurs with bisoprolol, supportive treatment should be initiated. Glucagon has been shown to be beneficial in bradycardia and hypotension associated with beta-blocker overdosage. Hypoglycemia may be managed by administering IV glucose. Monitor the patient and administer atropine in cases of bradycardia, pressors and fluids in the case of hypotension, and conventional heart failure therapy if heart failure occurs. If heart block occurs, the patient must be closely monitored and isoproterenol infusion or transvenous cardiac pacemaker insertion should take place. For the management of overdose-related bronchospasm, administer bronchodilators with or without IV aminophylline. Limited research suggests that bisoprolol fumarate is not removed adequately by hemodialysis sessions. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Ziac •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Bisoprolol Bisoprololum •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bisoprolol is a beta-1 adrenergic blocking agent used to prevent myocardial infarction and heart failure and to treat mild to moderate hypertension.

The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. The severity of the interaction is minor.

Question: Does Buspirone and Bisoprolol interact? Information: •Drug A: Buspirone •Drug B: Bisoprolol •Severity: MINOR •Description: Buspirone may decrease the antihypertensive activities of Bisoprolol. •Extended Description: The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Bisoprolol is indicated for the treatment of mild to moderate hypertension. It may be used off-label to treat heart failure, atrial fibrillation, and angina pectoris. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bisoprolol decreases heart rate (chronotropy), decreases contractility (inotropy), and reduces blood pressure. The results of various clinical studies indicate that bisoprolol reduces cardiovascular mortality and all-cause mortality in patients with heart failure and decreased cardiac ejection fraction (EF). •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Though the mechanism of action of bisoprolol has not been fully elucidated in hypertension, it is thought that therapeutic effects are achieved through the antagonism of β-1adrenoceptors to result in lower cardiac output. Bisoprolol is a competitive, cardioselective β1-adrenergic antagonist. When β1-receptors (located mainly in the heart) are activated by adrenergic neurotransmitters such as epinephrine, both the blood pressure and heart rate increase, leading to greater cardiovascular work, increasing the demand for oxygen. Bisoprolol reduces cardiac workload by decreasing contractility and the need for oxygen through competitive inhibition of β1-adrenergic receptors. Bisoprolol is also thought to reduce the output of renin in the kidneys, which normally increases blood pressure. Additionally, some central nervous system effects of bisoprolol may include diminishing sympathetic nervous system output from the brain, decreasing blood pressure and heart rate. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Bisoprolol is well absorbed in the gastrointestinal tract. The AUC is 642.87 g.hr/mL and bioavailability of bisoprolol is about 90% due to the minimal first pass effects. Absorption is unaffected by food intake. Peak plasma concentrations of bisoprolol are attained within 2-4 hours and steady-state concentrations are achieved within 5 days of administration. In a pharmacokinetic study, the mean peak concentration of bisoprolol was 52 micrograms/L. Cmax at steady state concentrations of bisoprolol is 64±21 ng/ml administered at 10 mg daily. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The volume of distribution of bisoprolol is 3.5 L/kg. The mean volume of distribution was found to be 230 L/kg in heart failure patients, which was similar to the volume of distribution in healthy patients. Bisoprolol is known to cross the placenta. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Binding to serum proteins is approximately 30%. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Approximately 50% of the bisoprolol dose is eliminated by non-renal pathways. Bisoprolol is metabolized through oxidative metabolic pathways with no subsequent conjugation. Bisoprolol metabolites are polar and, therefore, really eliminated. Major metabolites found in plasma and urine are inactive. Bisoprolol is mainly metabolized by CYP3A4 (95%), whereas CYP2D6 plays a minor role. The CYP3A4-mediated metabolism of bisoprolol appears to be non-stereoselective. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Bisoprolol is eliminated equally by both renal and hepatic pathways. About 50% of an oral dose is excreted unchanged in the urine with the remainder of the dose excreted as inactive bisoprolol metabolites. Under 2% of the ingested dose is found to be excreted in the feces. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): A pharmacokinetic study in 12 healthy individuals determined the mean plasma half-life of bisoprolol to be 10-12 hours. Another study comprised of healthy patients determined the elimination half-life to be approximately 10 hours. Renal impairment increased the half-life to 18.5 hours. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): Total body clearance in healthy patients was determined to be 14.2 L/h. In patients with renal impairment, clearance was reduced to 7.8 L/h. Hepatic dysfunction also reduced the clearance of bisoprolol. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): LD50 information Oral LD50 of bisoprolol in the mouse was 730 mg/kg. Overdose information Signs of a β-blocker overdose include cardiovascular symptoms such as hypotension, congestive heart failure, and bradycardia. Other symptoms such as bronchospasm, and hypoglycemia may occur. If an overdose occurs with bisoprolol, supportive treatment should be initiated. Glucagon has been shown to be beneficial in bradycardia and hypotension associated with beta-blocker overdosage. Hypoglycemia may be managed by administering IV glucose. Monitor the patient and administer atropine in cases of bradycardia, pressors and fluids in the case of hypotension, and conventional heart failure therapy if heart failure occurs. If heart block occurs, the patient must be closely monitored and isoproterenol infusion or transvenous cardiac pacemaker insertion should take place. For the management of overdose-related bronchospasm, administer bronchodilators with or without IV aminophylline. Limited research suggests that bisoprolol fumarate is not removed adequately by hemodialysis sessions. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Ziac •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Bisoprolol Bisoprololum •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bisoprolol is a beta-1 adrenergic blocking agent used to prevent myocardial infarction and heart failure and to treat mild to moderate hypertension. Output: The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. The severity of the interaction is minor.

Does Buspirone and Bleomycin interact?

•Drug A: Buspirone •Drug B: Bleomycin •Severity: MINOR •Description: Bleomycin may decrease the excretion rate of Buspirone which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For palliative treatment in the management malignant neoplasm (trachea, bronchus, lung), squamous cell carcinoma, and lymphomas. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bleomycin is an antibiotic which has been shown to have antitumor activity. Bleomycin selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of mitomycin-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed. Bleomycin has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFa, and IL-2. The antibiotic antitumor drugs are cell cycle-nonspecific except for Bleomycin (which has major effects in G2 and M phases). •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Although the exact mechanism of action of bleomycin is unknown, available evidence would seem to indicate that the main mode of action is the inhibition of DNA synthesis with some evidence of lesser inhibition of RNA and protein synthesis. As evident in in vitro studies, the DNA-cleaving actions of bleomycin is dependent on oxygen and metal ions. It is believed that bleomycin chelates metal ions (primarily iron) producing a pseudoenzyme that reacts with oxygen to produce superoxide and hydroxide free radicals that cleave DNA. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Systemic absorption is approximately 45%. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): 1% •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): It was reported that patients with moderately severe renal failure excreted less than 20% of the dose in the urine. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): 115 minutes •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Excessive exposure may cause fever, chills, nausea, vomiting, mental, confusion, and wheezing. Bleomycin may cause irritation to eyes, skin and respiratory tract. It may also cause a darkening or thickening of the skin. It may cause an allergic reaction. •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bleomycin is a chemotherapy agent used to treat various malignancies, including head and neck malignancy, lymphoma, and testicular tumors, among others.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Buspirone and Bleomycin interact? Information: •Drug A: Buspirone •Drug B: Bleomycin •Severity: MINOR •Description: Bleomycin may decrease the excretion rate of Buspirone which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): For palliative treatment in the management malignant neoplasm (trachea, bronchus, lung), squamous cell carcinoma, and lymphomas. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bleomycin is an antibiotic which has been shown to have antitumor activity. Bleomycin selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of mitomycin-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed. Bleomycin has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFa, and IL-2. The antibiotic antitumor drugs are cell cycle-nonspecific except for Bleomycin (which has major effects in G2 and M phases). •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Although the exact mechanism of action of bleomycin is unknown, available evidence would seem to indicate that the main mode of action is the inhibition of DNA synthesis with some evidence of lesser inhibition of RNA and protein synthesis. As evident in in vitro studies, the DNA-cleaving actions of bleomycin is dependent on oxygen and metal ions. It is believed that bleomycin chelates metal ions (primarily iron) producing a pseudoenzyme that reacts with oxygen to produce superoxide and hydroxide free radicals that cleave DNA. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Systemic absorption is approximately 45%. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): 1% •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): It was reported that patients with moderately severe renal failure excreted less than 20% of the dose in the urine. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): 115 minutes •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Excessive exposure may cause fever, chills, nausea, vomiting, mental, confusion, and wheezing. Bleomycin may cause irritation to eyes, skin and respiratory tract. It may also cause a darkening or thickening of the skin. It may cause an allergic reaction. •Brand Names (Drug A): Buspar •Brand Names (Drug B): No brand names available •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bleomycin is a chemotherapy agent used to treat various malignancies, including head and neck malignancy, lymphoma, and testicular tumors, among others. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Buspirone and Bortezomib interact?

•Drug A: Buspirone •Drug B: Bortezomib •Severity: MINOR •Description: The metabolism of Buspirone can be decreased when combined with Bortezomib. •Extended Description: Both of these drugs are metabolized by CYP2D6. Concomitant administration of these agents may produce a decrease in the metabolic rate of one or both drugs as they compete for metabolism by CYP2D6 enzymes. This may result in elevated serum concentrations of one or both medications and may, therefore, increase the incidence or severity of associated adverse effects. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Bortezomib is indicated for the treatment of adults with multiple myeloma or mantle cell lymphoma. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bortezomib works to target the ubiquitin-proteasome pathway, an essential molecular pathway that regulates intracellular concentrations of proteins and promotes protein degradation. The ubiquitin-proteasome pathway is often dysregulated in pathological conditions, leading to aberrant pathway signalling and the formation of malignant cells. In one study, patient-derived chronic lymphocytic leukemia (CLL) cells contained 3-fold higher levels of chymotrypsin-like proteasome activity than normal lymphocytes. By reversibly inhibiting proteasome, bortezomib prevents proteasome-mediated proteolysis. Bortezomib exerts a cytotoxic effect on various cancer cell types in vitro and delays tumour growth in vivo in nonclinical tumour models. Bortezomib inhibits the proteasome activity in a dose-dependent manner. In one pharmacodynamic study, more than 75% of proteasome inhibition was observed in whole blood samples within one hour after dosing of bortezomib. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): The ubiquitin-proteasome pathway is a homeostatic proteolytic pathway for intracellular protein degradation: proteins marked with a poly-ubiquitin chain are degraded to small peptides and free ubiquitin by the proteasome, which is a large multimeric protease. Aberrant proteasome-dependent proteolysis, as seen in some malignancies, can lead to uncontrolled cell division, leading to tumorigenesis, cancer growth, and spread. Bortezomib is a reversible inhibitor of the 26S proteasome, which is made up of a 20S core complexed with a 19S regulatory complex. Individual β-subunits allow specific catalytic action of the 20S core. In mammalian cells, bortezomib is a potent inhibitor of the proteasome’s chymotryptic-like activity, which is attributed to the β5-subunit of the 20S core particle. Bortezomib binds to the active site of the threonine hydroxyl group in the β5-subunit. A probing study showed bortezomib also binding to and inhibiting the β1-subunit, which mediates the caspase-like activity of the proteasome, and β1i-subunit, which is an altered subunit that is expressed to form immunoproteasomes in response to cell stress or inflammation. By inhibiting the proteasome-mediated degradation of key proteins that promote cell apoptosis, bortezomib induces a cell cycle arrest during the G2-M phase. It is believed that multiple mechanisms, other than proteasome inhibition, may be involved in the anticancer activity of bortezomib. The anticancer activity of bortezomib was largely associated with suppression of the NF-κB signalling pathway, resulting in the downregulation of anti-apoptotic target genes and expression of anti-apoptic proteins. This may be explained by bortezomib preventing uncontrolled degradation of IκB, which is an inhibitory protein of NF-κB. NOXA, which is a pro-apoptotic factor, induced by bortezomib selectively in cancer cells; thus, it is suggested to be another key mechanism of bortezomib. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Following intravenous administration of 1 mg/m and 1.3 mg/m doses, the mean C max of bortezomib were 57 and 112 ng/mL, respectively. In a twice-weekly dosing regimen, the C max ranged from 67 to 106 ng/mL at the dose of 1 mg/m and 89 to 120 ng/mL for the 1.3 mg/m dose. In patients with multiple myeloma, the C max of bortezomib followig subcutaneous administration was lower than that of intravenously-administered dose; however, the total systemic exposure of the drug was equivalent for both routes of administration. There is a wide interpatient variability in drug plasma concentrations. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m in patients with multiple myeloma receiving a single- or repeat-dose of 1 mg/m or 1.3 mg/m. Bortezomib distributes into nearly all tissues, except for the adipose and brain tissue. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Over the concentration range of 100 to 1000 ng/mL, bortezomib is about 83% bound to human plasma proteins. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Bortezomib is primarily metabolized by CYP3A4, CYP2C19, and CYP1A2. CYP2D6 and CYP2C9 are also involved in drug metabolism, but to a smaller extent. Oxidative deboronation, which involves the removal of boronic acid from the parent compound, is the main metabolic pathway. Metabolites of bortezomib are pharmacologically inactive and more than 30 metabolites have been identified in human and animal studies. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Bortezomib is eliminated by both renal and hepatic routes. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The mean elimination half-life of bortezomib ranged from 40 to 193 hours following a multiple dosing regimen at a 1 mg/m dose. The half-life ranged from 76 to 108 hours after multiple dosing of 1.3 mg/m bortezomib. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): Following the administration of a first dose of 1 mg/m and 1.3 mg/m, the mean mean total body clearances were 102 and 112 L/h, respectively. The clearances were 15 and 32 L/h after the subsequent dose of 1 and 1.3 mg/m, respectively. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The Lowest published toxic dose (TD Lo ) in mouse was 5 mg/kg/14D following intraperitoneal administration of an intermittent dose and 1.6 mg/kg/12D following subcutaneous administration of a continuous dose. The therapeutic dose of bortezomib is individualized in each patient to prevent overdose. Fatal outcomes occurred in humans following the administration of more than twice the recommended therapeutic dose of bortezomib. The symptoms from overdose included the acute onset of symptomatic hypotension and thrombocytopenia. As there is no known antidote for bortezomib overdosage, monitoring of vital signs and appropriate supportive care should be initiated when drug overdosage is suspected. In monkeys and dogs, increased heart rate, decreased contractility, hypotension, and death were observed with the intravenous dose as low as two times the recommended clinical dose on a mg/m2 basis. A case of a slight increase in the corrected QT interval leading to death occurred in dog studies. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Velcade •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Bortezomib •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bortezomib is a proteasome inhibitor used to treat multiple myeloma in patients who have not been successfully treated with at least two previous therapies.

Both of these drugs are metabolized by CYP2D6. Concomitant administration of these agents may produce a decrease in the metabolic rate of one or both drugs as they compete for metabolism by CYP2D6 enzymes. This may result in elevated serum concentrations of one or both medications and may, therefore, increase the incidence or severity of associated adverse effects. The severity of the interaction is minor.

Question: Does Buspirone and Bortezomib interact? Information: •Drug A: Buspirone •Drug B: Bortezomib •Severity: MINOR •Description: The metabolism of Buspirone can be decreased when combined with Bortezomib. •Extended Description: Both of these drugs are metabolized by CYP2D6. Concomitant administration of these agents may produce a decrease in the metabolic rate of one or both drugs as they compete for metabolism by CYP2D6 enzymes. This may result in elevated serum concentrations of one or both medications and may, therefore, increase the incidence or severity of associated adverse effects. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Bortezomib is indicated for the treatment of adults with multiple myeloma or mantle cell lymphoma. •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bortezomib works to target the ubiquitin-proteasome pathway, an essential molecular pathway that regulates intracellular concentrations of proteins and promotes protein degradation. The ubiquitin-proteasome pathway is often dysregulated in pathological conditions, leading to aberrant pathway signalling and the formation of malignant cells. In one study, patient-derived chronic lymphocytic leukemia (CLL) cells contained 3-fold higher levels of chymotrypsin-like proteasome activity than normal lymphocytes. By reversibly inhibiting proteasome, bortezomib prevents proteasome-mediated proteolysis. Bortezomib exerts a cytotoxic effect on various cancer cell types in vitro and delays tumour growth in vivo in nonclinical tumour models. Bortezomib inhibits the proteasome activity in a dose-dependent manner. In one pharmacodynamic study, more than 75% of proteasome inhibition was observed in whole blood samples within one hour after dosing of bortezomib. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): The ubiquitin-proteasome pathway is a homeostatic proteolytic pathway for intracellular protein degradation: proteins marked with a poly-ubiquitin chain are degraded to small peptides and free ubiquitin by the proteasome, which is a large multimeric protease. Aberrant proteasome-dependent proteolysis, as seen in some malignancies, can lead to uncontrolled cell division, leading to tumorigenesis, cancer growth, and spread. Bortezomib is a reversible inhibitor of the 26S proteasome, which is made up of a 20S core complexed with a 19S regulatory complex. Individual β-subunits allow specific catalytic action of the 20S core. In mammalian cells, bortezomib is a potent inhibitor of the proteasome’s chymotryptic-like activity, which is attributed to the β5-subunit of the 20S core particle. Bortezomib binds to the active site of the threonine hydroxyl group in the β5-subunit. A probing study showed bortezomib also binding to and inhibiting the β1-subunit, which mediates the caspase-like activity of the proteasome, and β1i-subunit, which is an altered subunit that is expressed to form immunoproteasomes in response to cell stress or inflammation. By inhibiting the proteasome-mediated degradation of key proteins that promote cell apoptosis, bortezomib induces a cell cycle arrest during the G2-M phase. It is believed that multiple mechanisms, other than proteasome inhibition, may be involved in the anticancer activity of bortezomib. The anticancer activity of bortezomib was largely associated with suppression of the NF-κB signalling pathway, resulting in the downregulation of anti-apoptotic target genes and expression of anti-apoptic proteins. This may be explained by bortezomib preventing uncontrolled degradation of IκB, which is an inhibitory protein of NF-κB. NOXA, which is a pro-apoptotic factor, induced by bortezomib selectively in cancer cells; thus, it is suggested to be another key mechanism of bortezomib. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Following intravenous administration of 1 mg/m and 1.3 mg/m doses, the mean C max of bortezomib were 57 and 112 ng/mL, respectively. In a twice-weekly dosing regimen, the C max ranged from 67 to 106 ng/mL at the dose of 1 mg/m and 89 to 120 ng/mL for the 1.3 mg/m dose. In patients with multiple myeloma, the C max of bortezomib followig subcutaneous administration was lower than that of intravenously-administered dose; however, the total systemic exposure of the drug was equivalent for both routes of administration. There is a wide interpatient variability in drug plasma concentrations. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m in patients with multiple myeloma receiving a single- or repeat-dose of 1 mg/m or 1.3 mg/m. Bortezomib distributes into nearly all tissues, except for the adipose and brain tissue. •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Over the concentration range of 100 to 1000 ng/mL, bortezomib is about 83% bound to human plasma proteins. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Bortezomib is primarily metabolized by CYP3A4, CYP2C19, and CYP1A2. CYP2D6 and CYP2C9 are also involved in drug metabolism, but to a smaller extent. Oxidative deboronation, which involves the removal of boronic acid from the parent compound, is the main metabolic pathway. Metabolites of bortezomib are pharmacologically inactive and more than 30 metabolites have been identified in human and animal studies. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Bortezomib is eliminated by both renal and hepatic routes. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): The mean elimination half-life of bortezomib ranged from 40 to 193 hours following a multiple dosing regimen at a 1 mg/m dose. The half-life ranged from 76 to 108 hours after multiple dosing of 1.3 mg/m bortezomib. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): Following the administration of a first dose of 1 mg/m and 1.3 mg/m, the mean mean total body clearances were 102 and 112 L/h, respectively. The clearances were 15 and 32 L/h after the subsequent dose of 1 and 1.3 mg/m, respectively. •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): The Lowest published toxic dose (TD Lo ) in mouse was 5 mg/kg/14D following intraperitoneal administration of an intermittent dose and 1.6 mg/kg/12D following subcutaneous administration of a continuous dose. The therapeutic dose of bortezomib is individualized in each patient to prevent overdose. Fatal outcomes occurred in humans following the administration of more than twice the recommended therapeutic dose of bortezomib. The symptoms from overdose included the acute onset of symptomatic hypotension and thrombocytopenia. As there is no known antidote for bortezomib overdosage, monitoring of vital signs and appropriate supportive care should be initiated when drug overdosage is suspected. In monkeys and dogs, increased heart rate, decreased contractility, hypotension, and death were observed with the intravenous dose as low as two times the recommended clinical dose on a mg/m2 basis. A case of a slight increase in the corrected QT interval leading to death occurred in dog studies. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Velcade •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): Bortezomib •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bortezomib is a proteasome inhibitor used to treat multiple myeloma in patients who have not been successfully treated with at least two previous therapies. Output: Both of these drugs are metabolized by CYP2D6. Concomitant administration of these agents may produce a decrease in the metabolic rate of one or both drugs as they compete for metabolism by CYP2D6 enzymes. This may result in elevated serum concentrations of one or both medications and may, therefore, increase the incidence or severity of associated adverse effects. The severity of the interaction is minor.

Does Buspirone and Bosentan interact?

•Drug A: Buspirone •Drug B: Bosentan •Severity: MINOR •Description: Buspirone may decrease the antihypertensive activities of Bosentan. •Extended Description: The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms). •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bosentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET A and ET B receptors in the endothelium and vascular smooth muscle. It displays a slightly higher affinity towards ET A receptors than ET B receptors. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ET A and ET B. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Absolute bioavailability is approximately 50% and food does not affect absorption. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): 18 L •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Greater than 98% to plasma proteins, mainly albumin. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Bosentan is eliminated by biliary excretion following metabolism in the liver. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Terminal elimination half-life is about 5 hours in healthy adult subjects. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): 4 L/h [patients with pulmonary arterial hypertension] •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Stayveer, Tracleer •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): bosentán Bosentan bosentanum •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bosentan is a dual endothelin receptor antagonist used to treat pulmonary arterial hypertension.

The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. The severity of the interaction is minor.

Question: Does Buspirone and Bosentan interact? Information: •Drug A: Buspirone •Drug B: Bosentan •Severity: MINOR •Description: Buspirone may decrease the antihypertensive activities of Bosentan. •Extended Description: The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. •Indication (Drug A): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Indication (Drug B): Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms). •Pharmacodynamics (Drug A): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Pharmacodynamics (Drug B): Bosentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects. •Mechanism of action (Drug A): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Mechanism of action (Drug B): Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET A and ET B receptors in the endothelium and vascular smooth muscle. It displays a slightly higher affinity towards ET A receptors than ET B receptors. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ET A and ET B. •Absorption (Drug A): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Absorption (Drug B): Absolute bioavailability is approximately 50% and food does not affect absorption. •Volume of distribution (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Volume of distribution (Drug B): 18 L •Protein binding (Drug A): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Protein binding (Drug B): Greater than 98% to plasma proteins, mainly albumin. •Metabolism (Drug A): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Metabolism (Drug B): Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound. •Route of elimination (Drug A): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Route of elimination (Drug B): Bosentan is eliminated by biliary excretion following metabolism in the liver. •Half-life (Drug A): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Half-life (Drug B): Terminal elimination half-life is about 5 hours in healthy adult subjects. •Clearance (Drug A): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Clearance (Drug B): 4 L/h [patients with pulmonary arterial hypertension] •Toxicity (Drug A): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Toxicity (Drug B): Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support. •Brand Names (Drug A): Buspar •Brand Names (Drug B): Stayveer, Tracleer •Synonyms (Drug A): Buspiron Buspirona Buspirone Buspironum •Synonyms (Drug B): bosentán Bosentan bosentanum •Summary (Drug A): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. •Summary (Drug B): Bosentan is a dual endothelin receptor antagonist used to treat pulmonary arterial hypertension. Output: The subject drug is known to produce hypertension, this effect can be achieved by different mechanisms. As a consequence, if this agent is used in combination with antihypertensive agents, there could be a decrease in the antihypertensive effects of the antihypertensive agents. The severity of the interaction is minor.