3 Clinical psychopharmacology3.3 Pharmacodynamics
3.3.2.6 Sedative hypnotics
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Written by Resident Doctor Committee · Published
Benzodiazepines at the GABA-A receptor
GABA is the main inhibitory transmitter, and the GABA-A receptor is a pentameric chloride channel.
Benzodiazepines bind their own site between the alpha and gamma subunits, separate from the GABA site, on the ionotropic GABA-A receptor, not GABA-B or GABA-C.
They increase chloride influx, which hyperpolarises the neuron.
Positive allosteric modulators increase how often the channel opens when GABA is bound but do nothing to the channel without GABA.
Drug | Action on the channel | Overdose |
|---|---|---|
Benzodiazepine | Needs GABA bound, so its effect has a ceiling | Relatively safe alone; alprazolam is the outlier with more severe toxicity |
Barbiturate | Opens the channel directly at high concentrations | Potentially fatal |
Opioids and benzodiazepines together impair breathing and protective arousal, and this greatly raises overdose risk.
Subunits and effects
Alpha subunit | Effect |
|---|---|
Alpha-1 | Sedation, amnesia, anticonvulsant effect; forms the omega-1 (BZ1) site |
Alpha-2 and alpha-3 | Anxiolysis, muscle relaxation |
Alpha-5 | Memory; concentrated in the hippocampus |
Adverse effects of benzodiazepines
Paradoxical disinhibition is agitation or aggression instead of sedation, most often where frontal restraint is weakened: older people, dementia, learning or intellectual disability, brain injury and children.
Anterograde amnesia stops new memories being encoded after a dose, while memories formed earlier stay retrievable.
Z-drugs
Zolpidem, zopiclone and zaleplon are chemically distinct from benzodiazepines but act at the same benzodiazepine site on GABA-A, not GABA-B.
Zolpidem prefers the alpha-1 (omega-1) site, but the selectivity is incomplete and does not prevent amnesia, falls, dependence or complex sleep behaviours.
Zopiclone characteristically causes a bitter, metallic taste, which zolpidem does not.
Zopiclone is contraindicated by respiratory, muscle-relaxant or hepatic problems; pre-existing memory impairment is not a contraindication but calls for caution and a lower dose.
Choosing a hypnotic by half-life
Hypnotic | Half-life | Consequence |
|---|---|---|
Zaleplon | About 1 hour | Shortest, so least next-day hangover |
Zolpidem | 2 to 3 hours, no active metabolites | Suits sleep-onset insomnia; least residual impairment for someone who must drive early |
Zopiclone | About 5 hours | Longer overnight effect |
Temazepam | About 8 to 10 hours, intermediate | Covers sleep onset and maintenance; no long-lived active metabolite, so clears by morning |
Nitrazepam | 24 to 30 hours | Hangover and accumulation |
Accumulation happens with a long half-life or a long-lived active metabolite given nightly, and causes next-day impairment.
Diazepam forms desmethyldiazepam, with a half-life of up to about 100 hours, which can build up and cause confusion or falls.
Tolerance and withdrawal
Tolerance can reduce hypnotic benefit within weeks, and physical dependence can develop at prescribed doses.
Withdrawal causes anxiety, insomnia, tremor, sweating and sensory hypersensitivity, and in severe cases seizures, delirium or psychosis.
High doses, long use, a short half-life and rapid reduction raise withdrawal risk.
Orexin receptor antagonists
Orexin stabilises wakefulness, and its loss contributes to narcolepsy.
Dual orexin receptor antagonists, such as daridorexant, block OX1 and OX2 receptors, removing orexin's wake-promoting drive, and are licensed for insomnia.
They are contraindicated in narcolepsy, which is orexin deficient.
They largely preserve sleep stage proportions, whereas benzodiazepines reduce slow-wave and rapid eye movement sleep.
Their commonest adverse effects are headache and somnolence.