5.1 Anxiolytics, sedatives, and hypnotics

Anxiolytics and sedatives are crucial drugs that target the central nervous system to manage anxiety and sleep disorders. These medications work by enhancing GABA effects, modulating serotonin receptors, or influencing melatonin pathways to calm the mind and promote relaxation.

While effective, these drugs come with risks like tolerance, dependence, and withdrawal. Understanding their mechanisms, uses, and potential side effects is key for safe and appropriate use in treating anxiety and insomnia.

Classes of anxiolytics and sedatives

GABA receptor modulators

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• Benzodiazepines enhance GABA effects at GABA-A receptors increasing chloride ion influx and neuronal hyperpolarization
• Barbiturates act on GABA-A receptors at a different binding site than benzodiazepines causing prolonged opening of chloride channels
• Z-drugs (zolpidem, zaleplon) selectively bind to specific GABA-A receptor subtypes primarily affecting sleep induction
  • Non-benzodiazepine hypnotics with more targeted effects on sleep

Serotonin and melatonin receptor agents

• Buspirone acts as a partial agonist at 5-HT1A receptors modulating serotonergic neurotransmission without significant sedation
• Melatonin receptor agonists (ramelteon) bind to MT1 and MT2 receptors in the suprachiasmatic nucleus regulating circadian rhythms and sleep-wake cycles

Antihistamines with sedative properties

• Sedating antihistamines (diphenhydramine) block H1 receptors in the central nervous system inducing drowsiness and sleep
  • Commonly used as over-the-counter sleep aids

Effects of anxiolytics and sedatives

Therapeutic uses

• Benzodiazepines treat anxiety disorders, insomnia, and serve as adjuncts in anesthesia
• Z-drugs indicated for short-term treatment of insomnia
• Buspirone used for generalized anxiety disorder with lower risk of sedation and dependence than benzodiazepines
• Melatonin receptor agonists used for insomnia particularly in older adults
• Sedating antihistamines used for occasional sleeplessness

Adverse effects and contraindications

• Benzodiazepines cause sedation, cognitive impairment, and increase fall risk
  • Contraindicated in patients with substance abuse history
  • Use cautiously in elderly patients
• Z-drugs may cause next-day drowsiness, dizziness, and rarely complex sleep behaviors (sleep-walking, sleep-driving)
  • Avoid in patients with severe hepatic impairment
• Buspirone can cause dizziness and nausea
  • Contraindicated with MAO inhibitors
• Melatonin receptor agonists have fewer side effects but may cause headache and dizziness
  • Use cautiously with CYP1A2 inhibitors
• Sedating antihistamines have anticholinergic side effects and cause daytime drowsiness
  • Avoid in patients with narrow-angle glaucoma or prostatic hypertrophy

Drug interactions

• Many anxiolytics and sedatives interact with alcohol and other CNS depressants leading to excessive sedation and respiratory depression
• Benzodiazepines may interact with drugs metabolized by CYP3A4 enzymes (ketoconazole, erythromycin)
• Z-drugs metabolized by CYP3A4 and CYP2C19 enzymes interact with inhibitors or inducers of these pathways
• Buspirone interacts with CYP3A4 inhibitors potentially increasing its effects

Properties of anxiolytics and sedatives

Pharmacokinetics

• Benzodiazepines vary in onset and duration based on lipophilicity and active metabolites
  • Short-acting (alprazolam) have rapid onset and offset
  • Long-acting (diazepam) have slower onset but prolonged effects
• Z-drugs have rapid onset and short half-lives suitable for sleep initiation
  • Undergo hepatic metabolism via CYP3A4 and CYP2C19 enzymes
• Buspirone has low oral bioavailability due to extensive first-pass metabolism and short half-life requiring multiple daily dosing
• Melatonin receptor agonists (ramelteon) have high first-pass metabolism and short half-lives
• Barbiturates exhibit significant pharmacokinetic variability and narrow therapeutic index
  • Induce hepatic enzymes affecting metabolism of other drugs

Pharmacodynamics

• Benzodiazepines and barbiturates enhance GABA-mediated inhibition in the CNS
• Z-drugs selectively modulate specific GABA-A receptor subtypes
• Buspirone lacks sedative and muscle relaxant properties of benzodiazepines
• Melatonin receptor agonists have specific effects on melatonin receptors resulting in fewer next-day residual effects
• Age, hepatic function, and concurrent medications influence pharmacodynamic effects necessitating dose adjustments

Risks of anxiolytic and sedative use

Tolerance and dependence

• Tolerance to sedative effects of benzodiazepines and Z-drugs develops rapidly leading to dose escalation
  • Cross-tolerance between GABAergic agents may occur
• Physical dependence on benzodiazepines can develop within weeks of regular use
  • Characterized by need for continued administration to prevent withdrawal
• Psychological dependence may occur particularly in patients with substance abuse history
• Barbiturate abuse carries high overdose risk due to narrow therapeutic index and tolerance development

Withdrawal syndrome

• Benzodiazepine withdrawal can be severe and potentially life-threatening
  • Symptoms include anxiety, tremors, seizures, and delirium
  • Gradual tapering necessary to minimize withdrawal risks
• Barbiturate withdrawal more severe and dangerous than benzodiazepine withdrawal
• Z-drug discontinuation may lead to rebound insomnia

Long-term use complications

• Chronic benzodiazepine use associated with cognitive impairment and increased fall risk in elderly
• Long-term sedative-hypnotic use may worsen underlying sleep disorders
• Chronic use of sedating antihistamines for sleep linked to increased dementia risk in older adults
• Z-drugs have lower but still significant abuse potential compared to benzodiazepines