6.2 Anxiolytics & Sedatives
Anxiolytics reduce anxiety; sedatives promote calm or sleep. Benzodiazepines are the most commonly prescribed, acting via GABAA receptor modulation.
Benzodiazepines
Mechanism of Action
Bind to benzodiazepine site (α-γ interface) on GABAA receptor
Positive allosteric modulation → ↑ frequency of Cl⁻ channel opening
Enhance GABAergic inhibition (do NOT directly open channel)
Common Benzodiazepines
Short-acting: Triazolam, midazolam (t½ <6h) - insomnia, anesthesia
Intermediate: Alprazolam, lorazepam (t½ 6-24h) - anxiety, panic
Long-acting: Diazepam, clonazepam (t½ >24h) - chronic anxiety, seizures
Clinical Effects
Anxiolytic, sedative, hypnotic, anticonvulsant, muscle relaxant, amnestic
Dose-dependent: low dose = anxiolytic, high dose = sedation/sleep
Adverse Effects & Risks
CNS depression, drowsiness, ataxia, cognitive impairment
Tolerance, dependence, withdrawal (seizures, rebound anxiety)
Respiratory depression (especially with opioids or alcohol)
Antidote: Flumazenil (competitive antagonist)
Buspirone
Mechanism
Partial agonist at 5-HT1A receptors
NOT a GABAA modulator—completely different mechanism from benzodiazepines
Clinical Profile
Anxiolytic for generalized anxiety disorder (GAD)
Delayed onset (1-2 weeks)—not for acute anxiety
No sedation, no dependence, no anticonvulsant activity
Advantages
No abuse potential, no withdrawal, no cognitive impairment
Safe in elderly, no respiratory depression
Z-Drugs (Nonbenzodiazepine Hypnotics)
Examples
Zolpidem (Ambien)
Zaleplon (Sonata)
Eszopiclone (Lunesta)
Mechanism
Bind GABAA receptor at benzodiazepine site
Selective for α₁ subunit → preferential hypnotic effect
Clinical Use
Short-term insomnia treatment
Rapid onset, short half-life (except eszopiclone)
Less muscle relaxation and anticonvulsant effect than benzodiazepines
Adverse Effects
Complex sleep behaviors (sleep-walking, sleep-driving)
Anterograde amnesia, tolerance, mild dependence
Generally safer than benzodiazepines but not risk-free
Other Sedative-Hypnotics
Barbiturates
Phenobarbital, pentobarbital, thiopental
GABAA direct agonists → ↑ duration of Cl⁻ opening
Narrow therapeutic index, high abuse/overdose risk
Largely replaced by benzodiazepines
Melatonin Agonists
Ramelteon: MT₁/MT₂ receptor agonist
Regulates circadian rhythm, sleep-wake cycle
No dependence, safe profile
Orexin Antagonists
Suvorexant, lemborexant: Dual orexin receptor antagonists
Block wake-promoting orexin signaling
Novel mechanism for insomnia
Antihistamines
Diphenhydramine, doxylamine (OTC sleep aids)
H₁ antagonism → sedation (off-target effect)
Anticholinergic side effects (dry mouth, urinary retention)