Chemical: Drug

diazepam

Source: Drug Bank

Diazepam is a benzodiazepine (BDZ) derivative with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnesic properties and a long duration of action.

It is used to treat anxiety, insomnia, seizures including status epilepticus, muscle spasms, restless legs syndrome, alcohol withdrawal, benzodiazepine withdrawal, and Ménière's disease. Diazepam acts by binding to the benzodiazepine site on the GABAA receptor to enhance the affinity of channel opening by the agonist GABA , which leads to central nervous system depression [Articles:11689393, 751612, 18384456, 15926867].

Pharmacokinetics:

Diazepam can be administered orally, intravenously, intramuscularly or as a suppository. It is rapidly absorbed and metabolized by hepatic P450 system. Very little diazepam is excreted unchanged [Articles:18855614, 18384456]. Hepatic demethylation mediated via CYP2C19 and CYP3A4 results in a active metabolite nordazepan, which is then hydroxylated by CYP3A4 to form Oxazepam. Diazepam can also form a minor active metabolite temazepam via CYP3A4 which then be demethylated by CYP2C19 and CYP3A4 to form oxazepam or be glucuronidated and excreted [Article:18855614]. Study also showed that CYP2B6, CYP2C8, CYP2C9; CYP2C18 and CYP3A4/5 play important roles in diazepam metabolism [Articles:9586962, 8948091, 9633999, 9029042]. Diazepam metabolite oxazepam is glucuronidated by UDP-glucuronosyltransferase (UGT) enzymes and excreted in the urine. UGT2B15 catalizes the glucuronidation of S-oxazepam [Articles:12386133, 15044558]; UGT2B7 and UGT1A9 catalyzes the glucuronidation of R-oxazepam [Article:12386133]. An in vitro study found that diazepam and a few other benzodiazepines inhibited CYP2E1 at micromolar concentrations [Article:9574817]. Deatailed Diazepam metabolism is depicted in the Benzodiazepine PK pathway (http://www.pharmgkb.org/do/serve?objId=PA165111375&objCls=Pathway#).

Genetic polymorphisms of the metabolizing enzymes have been found to influence diazepam pharmacokinetics. Diazepam is partially demethylated by CYP2C19. Studies found that poor metabolizers (PM) of CYP2C19 had significantly lower plasma clearance and longer plasma half-life of diazepam when compared to EM [Articles:2495208, 1505151, 2225709, 12222994]. In a study of 63 Japanese patients emerging from anesthesia, researchers found that the CYP2C19 genotype affected diazepam pharmacokinetics and emergence from general anesthesia [Article:16338280]. Additionally, gender and the UGT2B15 D85Y genotype ([RSID:rs1902023]) were identified as major determinants of S-oxazepam glucuronidation by the human liver [Article:15044558].

Pharmacodynamics

Similar to other benzodiazepine derivatives, the primary target of diazepam is the GABAa receptor, a pentameric protein which forms a chloride selective ion channel, activated by gamma-aminobutyric acid (GABA) [Articles:11689393, 751612, 18384456]. At least 16 different GABAa receptor subunits have been identified, classified into seven subunit families: ¿, ¿, ¿, ¿, ¿, ¿ and ¿ subunits [Article:18651727]. The The most common GABAa-BDZ receptor in the brain is thought to be composed of 2 subunits of alpha1; 2 subunits of beta2 and 1 subunit of gamma2 [Articles:11689393, 12171574, 9426470, 15301992] coded for by GABRA1, GABRB2 and GABRG2 respectively. Diazepam binds to the cleft between subunits alpha1 and gamma2 on the GABAA receptor to induce a conformational change in the receptor [Articles:12171574, 9426470]. This binding pocket is separate from that of the GABA agonist site, which itself is thought to be between the alpha1 and beta2 subunits [Article:9426470]. The general notion of the action of diazepam is that it promotes the binding of the major inhibitory neurotransmitter GABA to the GABAa receptors and enhances the affinity of channel opening by GABA. It does not activate GABAa receptors directly but, instead, is a positive allosteric modulator of the effects of GABA [Article:12171574] and allow lower concentrations of this neurotransmitter to open the Cl- channels [Article:12171574]. An alternative description of the mechanism of action of BDZs exists. In this latter case, the GABAa receptor is thought to exist in different states, and BDZs (diazepam, in particular, in this study) destablizes the closed state, shifts the equilibrium towards a high affinity open state that allows chloride transport [Article:16783415].

Besides the GABAa receptor, BDZs also bind to the Peripheral Benzodiazepine Receptor (PBR); this receptor consists of several subunits, including the isoquinoline binding protein (TSPO, also referred to as a translocator protein); a voltage-dependent anion channel VDAC (VDAC1); an adenine nucleotide transporter ANT (SLC25A4); a PBR-associated protein 1 PRAX-1 (BZRAP1); and another PBR-associated protein PAP7 (ACBD3) [Articles:17692008, 9504140, 12173979, 19133775, 16822554, 16337685]. Benzodiazepines are thought to bind to the subunit encoded by the gene TSPO [Articles:17692008, 19133775, 16822554, 16337685]. This receptor is expressed in abundance in many peripheral organs and tissues as well as in the central nervous system, in the latter case, in glia cells [Articles:9504140, 12173979]. Diazepam, midazolam and flunitrazepam bind equally well to both the GABAa receptor and the peripheral BDZ receptor [Articles:9504140, 12173979]. Studies have shown that the Peripheral Benzodizepine Receptor may play an important role in the human immune system and take part in the pathophysiological processes of several nervous system disorders [Articles:9504140, 12173979].

The detailed mechanism of action of diazepam and other BDZs is depicted in the Benzodiazepine PD Pathway at:

http://www.pharmgkb.org/search/pathway/benzodiazepine/benzodiazepine-pd.jsp.

The Pro385Ser genotype of GABAA alpha 6 (GABRA6) has been associated with diazepam sensitivity and conditions in a study of 51 children of alcoholics [Article:10484961].

Source: PharmGKB

Source: Drug Bank

Source: Drug Bank

Source: Drug Bank

Source: Drug Bank

Source: Drug Bank

Source: Drug Bank

Source: Drug Bank

Source: Drug Bank

Source: Drug Bank

Source: Drug Bank

Source: Drug Bank

Source: Drug Bank

Source: Drug Bank

Source: Drug Bank

Source: Drug Bank