Anxiolytics & Hypnotics

Drugs that allay anxiety (anxiolytics/sedatives) and those that induce sleep (hypnotics) form a continuum acting largely on the GABA-A receptor–chloride channel complex. For NEET PG, the highest-yield cluster is benzodiazepine pharmacology, the Z-drugs, buspirone, flumazenil reversal, and the dependence/withdrawal profile.

Definition & classification

A sedative reduces excitement and calms the patient, whereas a hypnotic induces and maintains sleep resembling natural sleep. The same drug at a low dose sedates and at a higher dose hypnotises — it is a dose-continuum, not separate classes. Anxiolytic refers specifically to relief of pathological anxiety without (ideally) excessive sedation.

Class	Prototype agents	Primary site of action
Benzodiazepines (BZDs)	Diazepam, lorazepam, alprazolam, midazolam, clonazepam, oxazepam	GABA-A receptor (γ subunit, BZD site)
Z-drugs (non-BZD hypnotics)	Zolpidem, zopiclone, eszopiclone, zaleplon	GABA-A α1 subunit selective
Barbiturates	Phenobarbitone, thiopentone	GABA-A (barbiturate site), distinct from BZD
5-HT1A partial agonist	Buspirone	Serotonergic, NOT GABA
Melatonin agonist	Ramelteon, melatonin	MT1/MT2 receptors
Orexin antagonist	Suvorexant, lemborexant	OX1/OX2 receptors
Antihistaminic sedatives	Diphenhydramine, doxylamine, hydroxyzine	H1 blockade

High-yield: Buspirone, ramelteon, suvorexant and antihistamines do NOT act on the GABA-A chloride channel — a favourite single-best-answer "odd one out".

Pharmacology of benzodiazepines

Mechanism — positive allosteric modulation

BZDs bind a specific site at the interface of the α and γ2 subunits of the pentameric GABA-A receptor (the classic combination is α1β2γ2). They are positive allosteric modulators: they have NO intrinsic activity and cannot open the chloride channel by themselves; they require endogenous GABA. By binding, they increase the frequency of chloride channel opening, causing hyperpolarisation and neuronal inhibition.

High-yield: Mnemonic — Benzodiazepines increase Frequency; BarBiturates increase the duration ("B for Bar, both Bs" prolong opening). At high doses barbiturates open the channel directly (GABA-mimetic), which is why barbiturate overdose is far more lethal — there is no ceiling effect.

Subunit specificity governs effects:

• α1 → sedation, anterograde amnesia, anticonvulsant, ataxia (target of zolpidem).
• α2/α3 → anxiolysis and muscle relaxation.
• α5 → memory/cognition.

Pharmacological actions

1. Sedation–hypnosis → reduced sleep latency, increased total sleep, suppression of REM and slow-wave (stage N3) sleep.
2. Anxiolysis at sub-hypnotic doses.
3. Anticonvulsant (diazepam, lorazepam, clonazepam, midazolam).
4. Centrally-acting muscle relaxation (diazepam in spasticity, tetanus).
5. Anterograde amnesia — exploited for endoscopy/procedures (midazolam).

BZDs flatten the dose–response and have a ceiling effect on CNS depression when used alone, which is why pure oral BZD overdose rarely kills — danger arises when combined with alcohol or opioids.

Pharmacokinetics & classification by duration

Duration of action depends on lipid solubility (onset) and on active metabolites (offset). Diazepam, chlordiazepoxide and flurazepam form the long-lived active metabolite N-desmethyldiazepam (nordiazepam, t½ up to ~100 h) → accumulation on repeat dosing.

Group	Examples	Notable feature
Short-acting	Triazolam, midazolam, oxazepam	Rebound anxiety/insomnia; midazolam = procedural sedation
Intermediate	Lorazepam, alprazolam, temazepam, clonazepam	Lorazepam = status epilepticus, alcohol withdrawal
Long-acting	Diazepam, chlordiazepoxide, flurazepam	Active metabolites accumulate, esp. in elderly

High-yield (LOT): Lorazepam, Oxazepam and Temazepam undergo only glucuronidation (Phase II conjugation) — no oxidative (CYP) metabolism. They have no active metabolites and are therefore PREFERRED in the elderly, in liver disease, and in alcohol withdrawal with hepatic impairment. Mnemonic: "LOT" are safe in liver disease.

Z-drugs (non-benzodiazepine hypnotics)

Zolpidem, zopiclone, eszopiclone and zaleplon are structurally non-benzodiazepine but bind the same BZD site, with relative selectivity for the α1 subunit. Hence they are predominantly hypnotic with minimal anxiolytic, muscle-relaxant or anticonvulsant action.

• Rapid onset, short half-life (zaleplon shortest, ~1 h) → reduce sleep latency with less next-day hangover.
• Less REM suppression and less tolerance/dependence than classical BZDs (still not zero).
• Reversed by flumazenil.
• Adverse: complex sleep-related behaviours — sleep-driving, sleep-eating, somnambulism (FDA boxed warning for zolpidem/zopiclone/eszopiclone). Zopiclone classically causes a bitter/metallic taste.

High-yield: Z-drugs act at the BZD site (α1-selective) and ARE reversible by flumazenil — they are NOT GABA-independent.

Buspirone — the non-sedating anxiolytic

Feature	Buspirone
Mechanism	5-HT1A partial agonist (also weak D2 effects); no GABA action
Onset of anxiolysis	Delayed, 1–2 weeks (NOT for acute/PRN anxiety)
Sedation	Minimal
Dependence/withdrawal	None — no abuse liability
Muscle relaxant/anticonvulsant	Absent
Use	Chronic generalised anxiety disorder (GAD), esp. patients with substance-abuse history
Caution	Avoid with MAO inhibitors (hypertensive crisis); CYP3A4 substrate

High-yield: Buspirone is the anxiolytic of choice when you want to avoid sedation, dependence and CNS depression, but it is useless for an acute panic attack because of its slow onset. It does NOT show cross-tolerance with BZDs, so it cannot cover BZD withdrawal.

Flumazenil — the antidote

• Competitive antagonist at the benzodiazepine site of GABA-A.
• Reverses BZD- and Z-drug-induced sedation/respiratory depression; given IV; rapid onset.
• Short t½ (~1 h) — shorter than most BZDs → re-sedation is common; repeat dosing or infusion may be needed.
• Does NOT reverse barbiturates, alcohol, opioids or GABA acting at other sites.

High-yield: Flumazenil can precipitate acute withdrawal and convulsions in BZD-dependent patients and is contraindicated in patients on BZDs for epilepsy or in mixed overdose with TCAs (unmasks pro-convulsant TCA toxicity). Use cautiously — diagnostic/therapeutic, not routine.

Overdose flow: Suspected BZD overdose → ABC + supportive care/ventilation FIRST → consider flumazenil only if isolated BZD ingestion and no contraindication → watch for re-sedation (flumazenil outlasts by less than the BZD) → repeat/infuse as needed.

Dependence, tolerance & withdrawal

Tolerance develops to the sedative/hypnotic effect (less to anxiolytic) over weeks. Physical dependence develops with regular use beyond a few weeks. Risk is highest with short-acting, high-potency agents (alprazolam, lorazepam, triazolam) because plasma levels fall rapidly.

Withdrawal syndrome

Onset depends on half-life: short-acting → 1–2 days; long-acting (diazepam) → may be delayed up to a week.

Features: rebound anxiety and insomnia, tremor, sweating, irritability, perceptual disturbance, and in severe cases seizures and delirium (a barbiturate-like withdrawal — potentially life-threatening).

High-yield: Abrupt discontinuation of a high-dose, short-acting BZD can cause withdrawal seizures. Taper slowly, or switch to a long-acting agent (diazepam) and taper. NEVER stop chronic high-dose BZDs abruptly.

Stepwise withdrawal management: Convert to equivalent diazepam dose → reduce by ~10–25% every 1–2 weeks → adjunct counselling/CBT → monitor for seizures.

Clinical selection — exam scenarios

Indication	Drug of choice / preferred
Status epilepticus (first-line)	IV lorazepam (or IV diazepam; IM/buccal/IN midazolam if no IV access)
Acute panic / severe acute anxiety	Short-course alprazolam/lorazepam
Generalised anxiety disorder (long-term)	SSRI/SNRI first-line; buspirone if avoiding dependence
Insomnia in elderly	Short-acting Z-drug at lowest dose, or ramelteon; avoid long-acting BZDs
Alcohol withdrawal (good liver)	Chlordiazepoxide / diazepam (long-acting, "self-tapering")
Alcohol withdrawal + liver disease	Lorazepam / oxazepam (LOT — no CYP metabolism)
Procedural sedation / endoscopy	Midazolam (amnesia, short, water-soluble IV)
Spasticity / tetanus / muscle spasm	Diazepam
Restless legs / periodic limb movement	Clonazepam
Night terrors / somnambulism (in children)	Clonazepam / low-dose BZD

High-yield (geriatrics): In the elderly, AVOID long-acting BZDs (diazepam, flurazepam, chlordiazepoxide) and high anticholinergic antihistamines — they cause accumulation, daytime sedation, cognitive impairment, falls and hip fractures. They are on the Beers list. Prefer short-acting agents at the lowest dose for the shortest time, or melatonin-receptor agonists.

Adverse effects

• CNS: sedation, drowsiness, ataxia, impaired psychomotor performance, anterograde amnesia, paradoxical excitation/disinhibition (more in elderly and children).
• Respiratory depression — dangerous in COPD, sleep apnoea, and with opioids/alcohol (synergistic).
• Tolerance & dependence (discussed above).
• Rebound insomnia/anxiety on stopping short-acting agents.
• Pregnancy: older data linked first-trimester diazepam to cleft lip/palate (weak); near-term use → floppy infant syndrome and neonatal withdrawal. BZDs are best avoided in pregnancy.
• Driving/operating machinery impairment — counsel patients.

Drug interactions

• Additive CNS depression with alcohol, opioids, antihistamines, antipsychotics — the commonest cause of fatal "BZD" overdose is co-ingestion.
• CYP3A4 inhibitors (erythromycin, ketoconazole, grapefruit juice, ritonavir) raise levels of midazolam, triazolam, alprazolam.
• CYP inducers (rifampicin, phenytoin) reduce levels of oxidatively-metabolised BZDs.
• LOT drugs (glucuronidated) are relatively interaction-free.

Effect on sleep architecture

Parameter	Effect of BZDs
Sleep latency	Decreased
Total sleep time	Increased
REM sleep	Decreased
Slow-wave sleep (N3)	Decreased
Awakenings	Decreased
On withdrawal	REM rebound → vivid dreams/nightmares

High-yield: BZDs suppress both REM and slow-wave sleep; on stopping, REM rebound produces nightmares — a tested association. Ramelteon and melatonin, by contrast, preserve natural sleep architecture.

Key differentials & "compare" facts

• BZD vs barbiturate: BZD increases frequency, barbiturate increases duration of Cl⁻ channel opening; barbiturates also directly open the channel at high dose (no ceiling → lethal in overdose). Barbiturates are strong enzyme inducers; BZDs are not.
• Buspirone vs BZD: Buspirone — slow onset, no sedation, no dependence, no muscle relaxation, no anticonvulsant action, no cross-tolerance.
• Zolpidem vs lorazepam: zolpidem α1-selective hypnotic, minimal anxiolysis; lorazepam broad GABA-A action, anxiolytic + anticonvulsant.
• Flumazenil vs naloxone: flumazenil reverses BZDs (GABA-A site); naloxone reverses opioids (μ receptor). Neither reverses barbiturates.

Newer & adjunct agents (quick)

• Ramelteon / melatonin — MT1/MT2 agonists; for sleep-onset insomnia; no dependence; safe in elderly; no abuse potential.
• Suvorexant, lemborexant — orexin (hypocretin) receptor antagonists; promote sleep by blocking wakefulness drive; caution in narcolepsy.
• Hydroxyzine — H1 antihistamine with anxiolytic use, no dependence.
• Daridorexant — newer dual orexin antagonist.

Recently asked / exam angle

• Mechanism stems: "Benzodiazepines increase the frequency of GABA-A chloride channel opening" — repeatedly tested; barbiturates increase duration.
• Subunit: BZDs bind the α–γ2 interface; zolpidem is α1-selective.
• LOT drugs (lorazepam, oxazepam, temazepam) — glucuronidation only, preferred in liver disease and elderly — classic single-best-answer.
• Flumazenil — competitive BZD antagonist; can precipitate seizures; short t½ → re-sedation; contraindicated in mixed TCA overdose.
• Buspirone — 5-HT1A partial agonist, delayed onset, no dependence, not for acute anxiety, used in GAD with substance-abuse history.
• Status epilepticus — IV lorazepam first-line.
• Drug of choice for alcohol withdrawal with deranged LFTs — lorazepam/oxazepam.
• Withdrawal seizures with abrupt cessation of short-acting high-potency BZDs (alprazolam).
• Zopiclone — metallic/bitter taste; Z-drugs → complex sleep behaviours.
• Geriatric prescribing / Beers criteria — avoid long-acting BZDs.
• Floppy infant syndrome with peripartum BZD use.

Rapid revision

1. BZDs = positive allosteric modulators → increase frequency of Cl⁻ channel opening; need endogenous GABA.
2. Barbiturates increase duration and open the channel directly at high dose → no ceiling → lethal overdose.
3. BZD binding site = α–γ2 subunit interface; zolpidem is α1-selective.
4. LOT — Lorazepam, Oxazepam, Temazepam — glucuronidated, no active metabolite, safe in liver disease & elderly.
5. Diazepam/chlordiazepoxide → active metabolite nordiazepam (t½ ~100 h) → accumulation.
6. Lorazepam IV = first-line for status epilepticus; midazolam = procedural sedation.
7. Buspirone = 5-HT1A partial agonist, slow onset (1–2 wk), no sedation/dependence, GAD; useless acutely.
8. Flumazenil = competitive BZD-site antagonist; short t½ → re-sedation; can cause seizures, avoid in TCA co-ingestion.
9. Z-drugs act at the BZD site (α1), reversible by flumazenil; cause sleep-driving/eating; zopiclone → bitter taste.
10. BZDs suppress REM & slow-wave sleep; stopping → REM rebound/nightmares.
11. Abrupt stop of short-acting high-potency BZD → withdrawal seizures; taper or switch to diazepam.
12. In the elderly, avoid long-acting BZDs (falls, fractures, Beers list); prefer ramelteon/melatonin or low-dose short-acting agents.