Benzodiazepines

Benzodiazepines are positive allosteric modulators of the GABA-A receptor. They treat status epilepticus, alcohol withdrawal, acute anxiety and agitation, catatonia, short-term insomnia and procedural sedation. Dependence limits use beyond 2 to 4 weeks.

Mechanism. They bind the interface between alpha and gamma subunits of GABA-A receptors and increase the frequency of chloride channel opening, enhancing inhibitory transmission. Effects are sedative, anxiolytic, anticonvulsant, muscle relaxant and amnestic.

Pharmacokinetics. Long half-life: diazepam 20 to 100 hours (with active desmethyldiazepam), chlordiazepoxide, clonazepam 30 to 40 hours. Intermediate: lorazepam 10 to 20 hours, temazepam 8 to 20 hours, alprazolam 6 to 12 hours. Short: midazolam 2 to 5 hours. Lorazepam, oxazepam and temazepam are cleared by conjugation, so are preferred in liver disease and older adults.

Differences. Short-acting agents give more rebound and withdrawal. Long-acting agents accumulate and cause daytime sedation. Midazolam is used for rapid sedation and seizure rescue.

• Status epilepticus: lorazepam 4 mg intravenously (0.1 mg/kg), repeated once after 10 to 20 minutes; or diazepam 10 mg intravenously (0.15 to 0.25 mg/kg); or midazolam 10 mg intramuscularly (5 mg for 13 to 40 kg) or buccally 10 mg; rectal diazepam 10 mg (0.5 mg/kg in children).
• Alcohol withdrawal: chlordiazepoxide 20 to 30 mg four times daily, or diazepam 10 to 20 mg four times daily, reducing over 5 to 7 days; lorazepam in liver disease.
• Acute anxiety or agitation: lorazepam 1 to 2 mg or diazepam 5 to 10 mg for no more than 2 to 4 weeks.
• Catatonia: lorazepam 1 to 2 mg intravenously or orally, repeated every 3 to 8 hours.
• Insomnia: temazepam 10 to 20 mg at night for no more than 2 weeks.
• Withdrawal after long use: convert to diazepam, then reduce the dose by 5 to 10% every 1 to 2 weeks over weeks to months.
• Reversal of iatrogenic sedation: flumazenil 200 micrograms intravenously, then 100 micrograms each minute to 1 mg; avoid in chronic use or co-ingested pro-convulsants, due to seizure risk.

Special groups. Pregnancy: avoid regular use; late exposure causes neonatal sedation, floppy infant syndrome and withdrawal. Breastfeeding: avoid long-acting agents, and use short courses of lorazepam if essential. Children: seizure rescue and procedural sedation only. Older adults: avoid or halve doses, because of falls, fractures and delirium. Kidney impairment: reduce doses. Liver impairment: use lorazepam or oxazepam.

Respiratory disease: avoid in severe sleep apnoea, myasthenia gravis and respiratory failure. Regional: diazepam is the most available; co-use with alcohol, khat and opioids is a risk.

Adverse effects. Sedation, cognitive and psychomotor impairment, anterograde amnesia, falls, paradoxical disinhibition, respiratory depression (additive with opioids and alcohol), tolerance, dependence and withdrawal (anxiety, insomnia, tremor, seizures).

Contraindications. Severe respiratory insufficiency, sleep apnoea, myasthenia gravis, and acute alcohol intoxication.

Interactions. Opioids, alcohol, gabapentinoids and sedating drugs (respiratory depression). CYP3A4 inhibitors (ritonavir, ketoconazole, clarithromycin) raise midazolam, alprazolam and triazolam, and ritonavir with oral midazolam is contraindicated. Rifampicin and carbamazepine lower levels.

Monitoring. Sedation and respiratory rate with parenteral use; duration of prescribing; dependence and misuse; falls.

Referral and escalation. Respiratory depression, dependence needing supervised withdrawal, or seizures in withdrawal.