Pharmacodynamics +<unk>  Site Ki (nM) Species Ref 19.6 Human 1.41 Human 2,100 Human 5-HT1A 3,800 Human 5-HT2A 70 Human 5-HT2C α1 130 Human α2 6,600 Human β >10,000 Monkey/rat D2 2,300 Human H1 7.2–25 Human H2 398 Human H3 >100,000 Human H4 15,100 Human 25 Human Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.<unk>  acts by decreasing the reuptake of norepinephrine and to a lesser extent serotonin (5-HT) in the brain. Its affinity for the human norepinephrine transporter (NET) is 1.41 nM, 19.6 nM for the serotonin transporter and 2,100 nM for the dopamine transporter. TCAs act to change the balance of naturally occurring chemicals in the brain that regulate the transmission of nerve impulses between cells.<unk>  increases the concentration of norepinephrine and serotonin (both chemicals that stimulate nerve cells) and, to a lesser extent, blocks the action of another brain chemical, acetylcholine. The therapeutic effects of<unk> , like other antidepressants, appear slowly. Maximum benefit is often not evident for at least two weeks after starting the drug.<unk>  is a TCA. It was thought that TCAs work by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin by neurons. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. TCAs are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. A precise mechanism for their analgesic action is unknown, but it is thought that they modulate anti-pain opioid systems in the central nervous system via an indirect serotonergic route. TCAs are also effective in migraine prophylaxis, but not in abortion of acute migraine attack. The mechanism of their anti-migraine action is also thought to be serotonergic, similar to psilocybin. Pharmacokinetics Metabolic studies indicate that<unk>  is well absorbed from the gastrointestinal tract and is rapidly sequestered in tissues. Relatively low plasma levels are found after administration, and only a small amount of unchanged drug is excreted in the urine of dogs and rabbits. Preliminary studies indicate that demethylation of the secondary amine moiety occurs to a significant extent, and that metabolic transformation takes place in the liver. It penetrates the brain rapidly in mice and rats, and moreover that which is present in the brain is almost all unchanged drug. Studies on the disposition of radioactive<unk>  in human test subjects showed significant plasma levels within 2 hours, peaking at 8 to 12 hours, then declining gradually. Urinary excretion studies in the same subjects showed significant amounts of radioactivity in 2 hours. The rate of excretion was slow. Cumulative urinary excretion during 16 days accounted for approximately 50% of the drug. The fecal route of excretion did not seem to be important.<unk>  has uniquely low dosing among TCAs, likely due to its exceptionally long terminal half-life. It is used in dosages of 15 to 40 mg/day, whereas most other TCAs are used at dosages of 75 to 300 mg/day. The maximum dose is 60 mg/day. Therapeutic levels of<unk>  are typically in the range of 70 to 250 ng/mL (266-950 nmol/L), which is similar to that of other TCAs
Protriptyline
Pargyline
Butriptyline
Bromperidol decanoate
Carbidopa/levodopa
Fluorodopa
Ciladopa
Cupiennin