CNS Pharmacology - Sedatives, Hypnotics, and Anxiolytics
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CNS Pharmacology - Sedatives, Hypnotics, and Anxiolytics — Key Facts for FMGE Core concept: Benzodiazepines enhance GABA-A receptor function; barbiturates also enhance GABA but at a different site; both cause CNS depression High-yield point: Flumazenil is the benzodiazepine antagonist; benzodiazepines are safer than barbiturates (less respiratory depression, less addiction) ⚡ Exam tip: Benzodiazepine + alcohol = potentiated CNS depression = dangerous; benzodiazepines are used for alcohol withdrawal and status epilepticus
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CNS Pharmacology - Sedatives, Hypnotics, and Anxiolytics — FMGE Study Guide
GABAergic Transmission
GABA-A Receptors
- Pentameric chloride channel: 2α, 2β, 1γ (or δ, ε, π)
- α and β subunits surround the chloride channel
- GABA binding site is at α-β interface
- Benzodiazepine binding site: At α-γ interface (requires both α and γ subunits)
- Barbiturate binding site: Within the chloride channel (different from BZD site)
Effects of GABA Enhancement
- Benzodiazepines: Increase frequency of chloride channel opening (not duration)
- Barbiturates: Increase duration of chloride channel opening
- Both: Increase chloride conductance → hyperpolarization → neuronal inhibition
Benzodiazepines
Mechanism
- Bind to benzodiazepine site on GABA-A receptor
- Increase affinity of GABA for its binding site
- Result: ↑frequency of chloride channel opening
- NO effect if GABA is absent (only enhances existing GABA effect - explains better safety profile)
Common Benzodiazepines
Long-acting (t1/2 > 24 hours):
- Diazepam: t1/2 20-100 hours; active metabolites (desmethyldiazepam, oxazepam); used for status epilepticus, alcohol withdrawal, muscle spasm
- Chlordiazepoxide: t1/2 long; used for alcohol withdrawal
- Clonazepam: t1/2 18-50 hours; used for seizures, panic disorder
Intermediate-acting (t1/2 10-24 hours):
- Lorazepam: t1/2 10-20 hours; glucuronidated (safe in liver disease); used for status epilepticus (IV), alcohol withdrawal
- Alprazolam: t1/2 12-15 hours; used for panic disorder
- Temazepam: t1/2 10-18 hours; used for insomnia
Short-acting (t1/2 < 10 hours):
- Triazolam: t1/2 2-4 hours; used for insomnia (high addiction potential)
- Midazolam: t1/2 1-4 hours; used for sedation/anesthesia induction, status epilepticus
Uses of Benzodiazepines
- Anxiety disorders: GAD, panic disorder, social anxiety (longer-acting preferred)
- Insomnia: Short-term treatment (2-4 weeks)
- Seizures: Status epilepticus (diazepam, lorazepam IV), seizures (clonazepam)
- Alcohol withdrawal: Prevents delirium tremens (chlordiazepoxide, lorazepam)
- Muscle spasm: Diazepam (also used for tetanus)
- Premedication: Amnesia before procedures
- Anesthesia: Midazolam for sedation
Adverse Effects
- CNS depression: Drowsiness, sedation, impaired coordination
- Anterograde amnesia: Cannot form new memories (useful for procedures)
- Paradoxical excitement: Disinhibition, aggression (especially in children and elderly)
- Respiratory depression: When combined with other CNS depressants (alcohol, opioids)
- Tolerance and dependence: Long-term use leads to physical dependence
- Withdrawal syndrome: Anxiety, insomnia, seizures, tremor, sweating
Contraindications
- Pregnancy (especially first trimester - cleft palate risk)
- Respiratory insufficiency, sleep apnea
- Severe liver disease (lorazepam safer)
- Driving/machinery operators
- History of substance abuse
Overdose Treatment
- Flumazenil: Competitive antagonist at BZD receptor on GABA-A
- Half-life shorter than benzodiazepines (requires repeat dosing)
- Can precipitate seizures in patients with benzodiazepine dependence and in mixed overdoses (TCAs + BZD)
Drug Interactions
- Additive CNS depression with alcohol, opioids, antihistamines, antipsychotics
- Enzyme inducers (carbamazepine, phenytoin) increase metabolism of some BZDs
- Azole antifungals, macrolides inhibit CYP3A4 → increased BZD levels
Barbiturates
Mechanism
- Bind to barbiturate site on GABA-A receptor (within chloride channel)
- Prolong chloride channel opening duration
- Can open channel even without GABA (unlike BZDs - explains higher toxicity)
Classification
Long-acting (used for seizures):
- Phenobarbital: t1/2 50-120 hours; status epilepticus, seizures, neonatal seizures
Short-acting:
- Pentobarbital: t1/2 15-50 hours; sedation, seizures
- Secobarbital: Formerly used for insomnia (largely replaced by BZDs)
Ultra-short acting (anesthetic):
- Thiopental, Methohexital: IV induction of anesthesia; rapid redistribution → short duration
Uses
- Seizures: Phenobarbital for status epilepticus and chronic seizure management
- Anesthesia: Thiopental for induction (rapid onset, redistribution to fat stores)
- Increased intracranial pressure: Reduce ICP (thiopental coma)
Adverse Effects
- CNS depression: More profound than BZDs; respiratory depression at therapeutic doses
- Tolerance: Cross-tolerance with alcohol and BZDs
- Dependence: Severe withdrawal (similar to alcohol - delirium, seizures)
- Enzyme induction: Increases hepatic enzyme synthesis → many drug interactions (warfarin, oral contraceptives, steroids)
- Porphyria attack: Precipitates acute intermittent porphyria (contraindicated)
- Paradoxical excitement: Sometimes causes agitation instead of sedation
Barbiturate vs Benzodiazepine
| Feature | Barbiturates | Benzodiazepines |
|---|---|---|
| Mechanism | Longer chloride channel opening | Increase channel frequency |
| Can open channel alone | Yes (even without GABA) | No (only enhance GABA) |
| Respiratory depression | More severe | Less severe |
| Enzyme induction | Yes | No |
| Tolerance/dependence | More severe | Less severe |
| Antidote | None | Flumazenil |
| Half-life | Variable | Variable |
| Use in pregnancy | Avoid | Avoid (esp. first trimester) |
Non-Benzodiazepine Hypnotics (Z-drugs)
Zolpidem, Zaleplon, Eszopiclone:
- Bind to BZ1 (ω1) subunit of GABA-A receptor (relatively selective for brain)
- Shorter half-life than traditional BZDs
- Used for insomnia (sleep onset, not maintenance)
- Less muscle relaxant and anticonvulsant effect than BZDs
- Same risks: dependence, withdrawal, additive CNS depression with alcohol
- Flumazenil can reverse zolpidem effects (though less reliably than BZDs)
Antihistamines (H1 blockers)
Diphenhydramine, Hydroxyzine, Promethazine:
- Cross BBB → sedation
- Used for insomnia, allergy, motion sickness
- Anticholinergic side effects
- Potentiate other CNS depressants
Buspirone
- 5-HT1A partial agonist
- Anxiolytic without sedation, dependence, or abuse potential
- Takes 1-2 weeks for effect (unlike BZDs which work immediately)
- No cross-tolerance with alcohol/BZDs
- Used for GAD when sedation is undesirable
Alcohol (Ethanol)
CNS Effects
- Low dose: Disinhibition (↑dopamine, ↓GABA inhibition)
- Moderate: Sedation, motor impairment
- High dose: Respiratory depression, coma, death
- Acute intoxication: Slurred speech, ataxia, nystagmus, hypotension
Pharmacokinetics
- Metabolized by alcohol dehydrogenase (ADH) in liver
- First-pass metabolism (significant)
- Zero-order kinetics at high concentrations
- Rate: ~10-15 mL ethanol/hour (one drink/hour)
Chronic Effects
- CNS depression tolerance (upregulated CYP450)
- Physical dependence: Severe withdrawal (delirium tremens, seizures)
- Wernicke-Korsakoff (thiamine deficiency)
- Fetal Alcohol Syndrome: Growth restriction, facial anomalies, intellectual disability
Drug Interactions
- Disulfiram inhibits aldehyde dehydrogenase → acetaldehyde accumulation → flushing, nausea, headache (used for alcohol aversion therapy)
- Additive CNS depression with other sedatives
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