Pharmacodynamics Schematic diagram of the (α1)2(β2)2(γ2) GABAA receptor complex that depicts the five-protein subunits that form the receptor, the chloride (Cl−) ion channel pore at the center, the two GABA active binding sites at the α1 and β2 interfaces and the<unk>  <unk> D) allosteric binding site at the α1 and γ2 interface.<unk> s work by increasing the effectiveness of the endogenous chemical, GABA, to decrease the excitability of neurons. This reduces the communication between neurons and, therefore, has a calming effect on many of the functions of the brain. GABA controls the excitability of neurons by binding to the GABAA receptor. The GABAA receptor is a protein complex located in the synapses between neurons. All GABAA receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for the neurotransmitter gamma-aminobutyric acid (GABA), while a subset of GABAA receptor complexes also contain a single binding site for<unk> s. Binding of<unk> s to this receptor complex does not alter binding of GABA. Unlike other positive allosteric modulators that increase ligand binding,<unk>  binding acts as a positive allosteric modulator by increasing the total conduction of chloride ions across the neuronal cell membrane when GABA is already bound to its receptor. This increased chloride ion influx hyperpolarizes the neuron's membrane potential. As a result, the difference between resting potential and threshold potential is increased and firing is less likely. Different GABAA receptor subtypes have varying distributions within different regions of the brain and, therefore, control distinct neuronal circuits. Hence, activation of different GABAA receptor subtypes by<unk> s may result in distinct pharmacological actions. In terms of the mechanism of action of<unk> s, their similarities are too great to separate them into individual categories such as anxiolytic or hypnotic. For example, a hypnotic administered in low doses produces anxiety-relieving effects, whereas a<unk>  marketed as an anti-anxiety drug at higher doses induces sleep. The subset of GABAA receptors that also bind<unk> s are referred to as<unk>  receptors <unk> R). The GABAA receptor is a heteromer composed of five subunits, the most common ones being two αs, two βs, and one γ (α2β2γ1). For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). GABAA receptors that are made up of different combinations of subunit subtypes have different properties, different distributions in the brain and different activities relative to pharmacological and clinical effects.<unk> s bind at the interface of the α and γ subunits on the GABAA receptor. Binding also requires that alpha subunits contain a histidine amino acid residue, (i.e., α1, α2, α3, and α5 containing GABAA receptors). For this reason,<unk> s show no affinity for GABAA receptors containing α4 and α6 subunits with an arginine instead of a histidine residue. Once bound to the<unk>  receptor, the<unk>  ligand locks the<unk>  receptor into a conformation in which it has a greater affinity for the GABA neurotransmitter. This increases the frequency of the opening of the associated chloride ion channel and hyperpolarizes the membrane of the associated neuron. The inhibitory effect of the available GABA is potentiated, leading to sedative and anxiolytic effects. For instance, those ligands with high activity at the α1 are associated with stronger hypnotic effects, whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits have good anti-anxiety activity. The<unk>  class of drugs also interact with peripheral<unk>  receptors. Peripheral<unk>  receptors are present in peripheral nervous system tissues, glial cells, and to a lesser extent the central nervous system. These peripheral receptors are not structurally related or coupled to GABAA receptors. They modulate the immune system and are involved in the body response to injury.<unk> s also function as weak adenosine reuptake inhibitors. It has been suggested that some of their anticonvulsant, anxiolytic, and muscle relaxant effects may be in part mediated by this action.<unk> s have binding sites in the periphery, however their effects on muscle tone is not mediated through these peripheral receptors. The peripheral binding sites for<unk> s are present in immune cells and gastrointestinal tract. Pharmacokinetics<unk>  Half-life (range, hours) Speed of Onset Alprazolam 6–15 Intermediate Flunitrazepam -26 Fast Chlordiazepoxide –30 Intermediate Clonazepam –60 Slow Diazepam –80 Fast Lorazepam –20 Intermediate Midazolam -2.5 Fast Oxazepam –10 Slow Prazepam –200 Slow A<unk>  can be placed into one of three groups by its elimination half-life, or time it takes for the body to eliminate half of the dose. Some<unk> s have long-acting active metabolites, such as diazepam and chlordiazepoxide, which are metabolised into desmethyldiazepam. Desmethyldiazepam has a half-life of 36–200 hours, and flurazepam, with the main active metabolite of desalkylflurazepam, with a half-life of 40–250 hours. These long-acting metabolites are partial agonists. * Short-acting compounds have a median half-life of 1–12 hours. They have few residual effects if taken before bedtime, rebound insomnia may occur upon discontinuation, and they might cause daytime withdrawal symptoms such as next day rebound anxiety with prolonged usage. Examples are brotizolam, midazolam, and triazolam. * Intermediate-acting compounds have a median half-life of 12–40 hours. They may have some residual effects in the first half of the day if used as a hypnotic. Rebound insomnia, however, is more common upon discontinuation of intermediate-acting<unk> s than longer-acting<unk> s. Examples are alprazolam, estazolam, flunitrazepam, clonazepam, lormetazepam, lorazepam, nitrazepam, and temazepam. * Long-acting compounds have a half-life of 40–250 hours. They have a risk of accumulation in the elderly and in individuals with severely impaired liver function, but they have a reduced severity of rebound effects and withdrawal. Examples are diazepam, clorazepate, chlordiazepoxide, and flurazepam.
Benzodiazepine
Synthetic cannabinoids
Antidepressant
Alcohol 
Gabapentinoid
Substituted amphetamine
Methamphetamine
Antipsychotic