Page 5 of 32

PH3.2 | PH3.2 | Sedative and Hypnotic Agents — SDL Guide — SDL Guide (Part 2)

Benzodiazepines — PK, PD, Uses, and ADRs

Benzodiazepines (BZDs) bind to a specific allosteric site on the GABA-A receptor (at the α-γ subunit interface) and potentiate GABA's effect by increasing the frequency of Cl⁻ channel opening — they do not open the channel in the absence of GABA. This ceiling effect is why BZDs have a wider therapeutic index than barbiturates. Their pharmacological effects include sedation, anxiolysis, anticonvulsant activity, amnesia, and muscle relaxation — all consequences of enhanced GABAergic inhibition at different brain regions.

Pharmacokinetically, BZDs are classified by duration of action, which depends on lipophilicity, redistribution, and presence of active metabolites. Diazepam is long-acting (t½ 20-100h) partly because its active metabolite desmethyldiazepam (t½ up to 200h) extends the effect — this explains why repeated dosing in elderly patients causes progressive accumulation and prolonged sedation. Lorazepam has no active metabolite and is therefore preferred in hepatic impairment and in elderly patients requiring benzodiazepine therapy (conjugation only, not oxidation). Midazolam is ultra-short-acting (IV) and is preferred for procedural sedation.

Agent	Duration	Active Metabolite	Key Use
Diazepam	Long (t½ ~40h)	Desmethyldiazepam	Anxiety, SE, muscle spasm, alcohol withdrawal
Lorazepam	Intermediate	None	SE (preferred IV in status), pre-op, hepatic impairment
Midazolam	Short (IV: ~2h)	Minor	Procedural sedation, pre-op, ICU sedation
Temazepam	Short	None	Sleep-onset insomnia
Flurazepam	Long	Active (desalkylflurazepam)	Sleep-maintenance (rarely used now)

Benzodiazepines vs Barbiturates at the GABA-A Receptor

ADRs: daytime sedation, cognitive impairment, anterograde amnesia, ataxia, respiratory depression (especially with opioids or alcohol), tolerance (pharmacodynamic — receptor down-regulation), physical dependence (with use >4 weeks), and withdrawal syndrome (anxiety, insomnia, tremor, seizures — analogous to alcohol withdrawal because both involve GABA-A). Falls and hip fractures are a major risk in elderly patients.

Reversal: flumazenil is a competitive antagonist at the BZD binding site of GABA-A. It reverses BZD-induced sedation and respiratory depression rapidly (onset 1-2 min IV). Caution: short half-life (~1h) means re-sedation occurs if the BZD has a longer duration — may need repeated doses or infusion. Does NOT reverse barbiturate-induced coma.

Barbiturates — PK, PD, Uses, and ADRs

Barbiturates bind to a distinct site on the GABA-A receptor (β-subunit region) and potentiate GABA-A by increasing the duration of Cl⁻ channel opening. Critically, at supra-therapeutic concentrations barbiturates can open the Cl⁻ channel directly without GABA — this explains their dose-dependent respiratory depression without a ceiling, the absence of a specific reversal agent, and their narrow therapeutic index compared to BZDs.

Pharmacokinetically, barbiturates vary widely by duration. Thiopental (ultra-short, IV) is used as a GA induction agent (covered in PH3.1). Phenobarbitone (phenobarbital) is a long-acting barbiturate used primarily as an anticonvulsant (first-line in neonatal seizures, febrile convulsions, and epilepsy in resource-limited settings); its long half-life (80-100h) allows once-daily dosing. Secobarbital and pentobarbital are shorter-acting agents used historically as sedative-hypnotics but now largely obsolete.

A critical pharmacokinetic property of barbiturates is potent CYP450 enzyme induction — phenobarbitone induces CYP1A2, CYP2C9, CYP2C19, and CYP3A4, accelerating the metabolism of warfarin, oral contraceptives, corticosteroids, and many other drugs. This is a major source of drug interactions in patients on polypharmacy.

ADRs: CNS depression (sedation → coma at overdose), respiratory depression (no ceiling effect), paradoxical excitement in elderly and children, enzyme induction (drug interactions), physical dependence, withdrawal seizures, and porphyria precipitation (like thiopental — both induce δ-ALA synthase). Barbiturate overdose has no specific antidote — management is supportive (airway, ventilation, alkalinisation of urine to enhance phenobarbitone excretion).

Z-Drugs and Newer Hypnotics — PK, PD, and Uses

The Z-drugs — zolpidem, zopiclone, and zaleplon — are structurally distinct from benzodiazepines but act at the same BZD binding site of the GABA-A receptor. Their key distinction is relative selectivity for the α₁ subunit of the GABA-A receptor, which mediates sedation and hypnosis, with less activity at α₂ (anxiolysis), α₃ (muscle relaxation), and α₅ (memory) subunits. This selectivity was proposed to produce a cleaner hypnotic effect without the full spectrum of BZD side-effects, though clinically the differences are modest and dependence still occurs.

Zolpidem has rapid onset and short half-life (~2h), making it suitable for sleep-onset insomnia; it is less useful for sleep-maintenance. Zopiclone has a slightly longer action (~5-6h half-life) and is used for both sleep-onset and sleep-maintenance insomnia; patients frequently report a metallic taste (characteristic ADR). Zaleplon has the shortest half-life of the three (~1h), allowing middle-of-night dosing without next-morning impairment.

All Z-drugs carry risks of tolerance, dependence, parasomnias (sleep-walking, sleep-eating, sleep-driving — a unique and clinically important ADR class) and rebound insomnia on withdrawal. They are not safer than BZDs with regard to dependence.

Ramelteon is a selective melatonin MT₁/MT₂ receptor agonist used for circadian-rhythm-related insomnia and sleep-onset delay. No dependence liability, no GABA-A action, not a controlled substance — useful in elderly patients where BZD/Z-drug risk is high. Suvorexant is a dual orexin receptor antagonist (DORA) that blocks the wake-promoting orexin signal; approved for sleep-onset and sleep-maintenance insomnia; no dependence potential comparable to GABA-A agonists.