diazepam

**Mechanism of action:** Diazepam binds the benzodiazepine site on the GABA-A receptor (at the interface of the alpha and gamma subunits). It is a positive allosteric modulator that increases the FREQUENCY of Cl- channel opening in the presence of GABA, causing neuronal hyperpolarization. Memory aid: "Frequency = BenZodiazepines" (barbiturates increase DURATION). Unlike barbiturates, benzodiazepines need GABA to be present, so they have a ceiling effect and a higher safety margin when taken alone. Overdose risk rises sharply with co-ingestants such as alcohol, opioids, or barbiturates.

**Pharmacokinetics:** It is highly lipophilic, so it is rapidly absorbed and quickly enters the CNS (fast onset IV). It is hepatically metabolized by CYP450 (CYP2C19 and CYP3A4) via oxidation (phase I) to active metabolites, including desmethyldiazepam (nordiazepam, half-life up to ~100 hr), oxazepam, and temazepam. This gives a long duration of action (half-life ~20-100 hr with metabolites), so it accumulates in the elderly and in liver disease. Redistribution out of the CNS into fat causes a short clinical effect after a single IV dose despite the long half-life. Contrast with the short/intermediate-acting benzodiazepines metabolized by glucuronidation only (phase II), which are safer in the elderly and in hepatic impairment: **Oxazepam, Lorazepam, Temazepam ("OLT")**. Mnemonic for long-acting agents: "Chronic Dependents Fear Dying" is not needed; just remember diazepam, chlordiazepoxide, and flurazepam are long-acting.

**Clinical uses:** - Status epilepticus (IV lorazepam is first-line; diazepam IV or rectal is an alternative; rectal/intranasal diazepam is used for out-of-hospital seizures, including febrile seizure clusters) - Alcohol withdrawal/delirium tremens (long-acting agents such as diazepam or chlordiazepoxide give smoother self-tapering; use lorazepam or oxazepam in liver disease) - Generalized anxiety disorder and panic disorder (short-term or bridging until SSRIs take effect; SSRIs/SNRIs are first-line long term) - Muscle spasm, spasticity, and tetanus - Preoperative sedation, procedural sedation, and amnesia - Acute agitation, and acute cocaine- or stimulant-induced toxicity (e.g., chest pain, agitation) - Insomnia (less used; shorter-acting agents are preferred) - Eclampsia seizure alternative (magnesium sulfate is first-line)

**Adverse effects:** Sedation, anterograde amnesia, ataxia, confusion, and falls (Beers criteria: avoid in elderly), paradoxical agitation, and respiratory depression (especially IV, in COPD, or combined with alcohol/opioids). Tolerance, physical dependence, and abuse potential (Schedule IV). Teratogenicity: first-trimester exposure is linked to a small risk of cleft lip/palate; neonatal exposure near delivery causes "floppy infant" syndrome and neonatal withdrawal.

**Withdrawal:** Abrupt discontinuation after chronic use causes rebound anxiety, insomnia, tremor, tachycardia, hypertension, and seizures. It can be life-threatening and resembles alcohol withdrawal, so taper gradually.

**Overdose/antidote:** Presents with CNS depression, hypotension, bradycardia, and respiratory depression. Treatment is supportive (airway, ventilation). **Flumazenil**, a competitive GABA-A benzodiazepine-site antagonist, reverses effects but can precipitate seizures in chronic users or in co-ingestion of pro-convulsants (e.g., TCAs), so it is used cautiously. It has a short half-life, so re-sedation can occur.

**Drug interactions:** CNS depressants (alcohol, opioids, barbiturates) cause additive respiratory depression. CYP3A4/2C19 inhibitors (cimetidine, omeprazole, ketoconazole, erythromycin, fluoxetine, grapefruit juice) raise levels. Inducers (rifampin, carbamazepine, phenytoin) lower levels.

**High-yield comparisons:** - Benzodiazepines: increase frequency of Cl- opening; antidote flumazenil. - Barbiturates (phenobarbital, thiopental): increase duration of Cl- opening; can directly open the channel at high doses, so higher lethality; no specific antidote. - Nonbenzodiazepine hypnotics (zolpidem, zaleplon, eszopiclone, "Z-drugs"): bind the BZ1 (alpha-1) subtype; reversed by flumazenil; less muscle relaxation and anticonvulsant effect.

**Board pearls:** A patient with alcohol withdrawal and cirrhosis should get lorazepam or oxazepam (not diazepam), since these bypass CYP oxidation. A seizing patient without IV access can receive rectal diazepam, or IM/intranasal midazolam. Benzodiazepines are the first-line treatment for alcohol withdrawal and for stimulant intoxication with agitation. Do not prescribe benzodiazepines for long-term anxiety if an SSRI is appropriate.