alprazolam

MECHANISM: Binds the benzodiazepine site on the GABA-A receptor (at the alpha/gamma subunit interface) and increases the FREQUENCY of Cl- channel opening (barbiturates increase DURATION). It requires GABA to act, so it has a ceiling effect and is safer in overdose than barbiturates. Net effect is neuronal hyperpolarization and CNS inhibition. Effects: anxiolysis, sedation, anticonvulsant, muscle relaxation, anterograde amnesia.

PHARMACOKINETICS: Rapid oral absorption with fast onset. Half-life is about 11 hours (short-to-intermediate acting). It is hepatically metabolized by CYP3A4 via oxidation (phase I) to active metabolites. CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, erythromycin, grapefruit juice) raise levels. CYP3A4 inducers (carbamazepine, rifampin, phenytoin, St. John's wort) lower levels. Mnemonic for the benzodiazepines that avoid oxidation: "OTL" (Oxazepam, Temazepam, Lorazepam) are glucuronidated only, with no active metabolites, so they are preferred in the elderly and in liver disease. Alprazolam is NOT one of these.

CLINICAL USES: Generalized anxiety disorder (short-term). Panic disorder (alprazolam is FDA-approved, but SSRIs/SNRIs are first line for long-term treatment of panic disorder and GAD). Situational anxiety. Other benzodiazepine uses include alcohol withdrawal (chlordiazepoxide, lorazepam, diazepam), status epilepticus (lorazepam, diazepam), procedural sedation (midazolam), and insomnia (triazolam, temazepam).

ADVERSE EFFECTS: Sedation, drowsiness, ataxia, confusion, anterograde amnesia, and falls (especially in the elderly; Beers criteria). Tolerance, physical dependence, and abuse potential (Schedule IV). Paradoxical disinhibition or agitation. Respiratory depression is the main danger when combined with alcohol or opioids (FDA boxed warning for concurrent opioid use). Boxed warnings also cover abuse/misuse/addiction and dependence/withdrawal reactions. Pregnancy: neonatal withdrawal and "floppy infant" syndrome when used near delivery. First-trimester exposure has been associated with possible teratogenicity concerns.

WITHDRAWAL: Abrupt discontinuation causes rebound anxiety, insomnia, tremor, autonomic hyperactivity, and seizures, which can be life-threatening. Short-acting, high-potency agents like alprazolam carry a greater risk of severe withdrawal and interdose rebound. Management is a slow taper, sometimes by switching to a longer-acting agent (e.g., clonazepam or diazepam).

OVERDOSE: Presents with CNS and respiratory depression, usually less severe with benzodiazepines alone than with barbiturates. Treatment is supportive care. Flumazenil is a competitive GABA-A benzodiazepine-site antagonist that can reverse the effects. Use it cautiously, because it can precipitate seizures in chronic users or in coingestion with proconvulsants (e.g., TCAs).

CONTRAINDICATIONS/CAUTIONS: Acute narrow-angle glaucoma, concurrent opioids (avoid or use with caution), respiratory compromise (e.g., severe COPD, sleep apnea), substance use disorder history, and myasthenia gravis.

BOARD PEARLS: 1) Benzodiazepines increase the frequency of Cl- channel opening, whereas barbiturates increase the duration. 2) Alprazolam is a CYP3A4 substrate, so watch for interactions. 3) Alcohol withdrawal and benzodiazepine withdrawal can both cause seizures. 4) For chronic anxiety or panic disorder, start an SSRI first and use a benzodiazepine only as a short-term bridge.