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Monday, August 11, 2025

Anxiolytics, sedatives, and hypnotics


Introduction

  • Anxiolytics, sedatives, and hypnotics are a broad pharmacological group of central nervous system (CNS) depressants used to treat anxiety, sleep disorders, and related conditions.

  • The three terms describe drugs based on their predominant clinical use:

    • Anxiolytics: Primarily relieve anxiety without necessarily causing sedation.

    • Sedatives: Calm or reduce agitation, producing relaxation and drowsiness.

    • Hypnotics: Induce and maintain sleep.

  • Many drugs in this group share overlapping pharmacodynamic properties; the classification often depends on the dose and clinical application.

  • Key therapeutic goals include reducing pathological anxiety, promoting sleep in insomnia, and calming the patient before surgery or diagnostic procedures.

General Mechanism of Action

  • Most agents act by enhancing inhibitory neurotransmission in the CNS, predominantly through gamma-aminobutyric acid (GABA) pathways.

  • GABA-A receptor modulators: Benzodiazepines, barbiturates, non-benzodiazepine hypnotics.

  • Some act through melatonin receptor agonism (ramelteon) or histamine receptor antagonism (first-generation antihistamines).

  • Decrease neuronal excitability by increasing chloride ion influx into neurons, leading to hyperpolarization and reduced firing rate.

Pharmacological Classes

1. Benzodiazepines

  • Act as positive allosteric modulators at GABA-A receptors.

  • Increase frequency of chloride channel opening events in response to GABA.

  • Used for anxiety disorders, insomnia, muscle relaxation, seizure control, alcohol withdrawal.

  • Examples: Diazepam, Lorazepam, Alprazolam, Temazepam, Midazolam.

2. Non-benzodiazepine Hypnotics (“Z-drugs”)

  • Structurally unrelated to benzodiazepines but act on the same GABA-A receptor subtypes, particularly α1 subunit.

  • Shorter half-lives, reduced risk of next-day sedation.

  • Primarily used for insomnia.

  • Examples: Zolpidem, Zaleplon, Eszopiclone.

3. Barbiturates

  • Enhance GABA-mediated chloride influx by increasing duration of channel opening.

  • At high doses, can directly activate GABA-A channels without GABA present.

  • Rarely used for anxiety or insomnia due to high risk of dependence and toxicity.

  • Examples: Phenobarbital, Secobarbital, Pentobarbital.

4. Melatonin Receptor Agonists

  • Act on MT1 and MT2 receptors in the suprachiasmatic nucleus to regulate circadian rhythm.

  • Used in insomnia, particularly with sleep-onset difficulties.

  • Example: Ramelteon.

5. Antihistamines (First-generation)

  • Block H1 histamine receptors in the brain, causing sedation.

  • Used for mild insomnia or premedication before procedures.

  • Examples: Diphenhydramine, Hydroxyzine, Doxylamine.

6. Other Agents

  • Buspirone: Partial agonist at 5-HT1A receptors; non-sedating anxiolytic, no dependence.

  • Chloral hydrate: Sedative-hypnotic rarely used today due to adverse effects.

  • Dexmedetomidine: α2-adrenergic agonist used for sedation in ICU settings.

Pharmacokinetics

  • Absorption: Most agents are well absorbed orally; onset varies from minutes to hours depending on lipid solubility.

  • Distribution: Highly lipophilic agents cross the blood-brain barrier rapidly.

  • Metabolism: Many are metabolized by hepatic CYP450 enzymes; some have active metabolites prolonging effect.

  • Elimination: Half-lives range from minutes (ultrashort-acting) to days (long-acting).

Clinical Indications

Anxiolytics

  • Generalized anxiety disorder.

  • Panic disorder.

  • Acute situational anxiety.

  • Anxiety associated with medical procedures.

Sedatives

  • Pre-anesthetic medication to reduce anxiety and induce calm.

  • ICU sedation.

  • Muscle relaxation in certain neurological conditions.

Hypnotics

  • Short-term management of insomnia.

  • Sleep initiation or maintenance disorders.

  • Adjunct to anesthesia.

Advantages and Disadvantages

Advantages

  • Rapid relief of anxiety or induction of sleep.

  • Multiple administration routes available (oral, IV, IM).

  • Effective in a variety of CNS-related disorders.

Disadvantages

  • Risk of tolerance and physical dependence.

  • Potential for misuse and abuse.

  • CNS depression leading to respiratory compromise at high doses.

Adverse Effects

Common

  • Drowsiness, sedation.

  • Impaired coordination.

  • Cognitive slowing, memory impairment.

  • Dizziness, lightheadedness.

Serious

  • Respiratory depression (especially with barbiturates or in combination with alcohol/opioids).

  • Dependence and withdrawal syndromes.

  • Paradoxical reactions: agitation, aggression (rare).

  • Complex sleep-related behaviors with Z-drugs (sleepwalking, sleep-driving).

Contraindications

  • Severe respiratory insufficiency.

  • Acute narrow-angle glaucoma (benzodiazepines).

  • Severe hepatic impairment (some agents).

  • Pregnancy and lactation for most agents due to fetal/neonatal CNS depression risk.

  • History of substance abuse (relative contraindication).

Precautions

  • Use lowest effective dose for shortest possible duration.

  • Avoid abrupt discontinuation to prevent withdrawal.

  • Caution in elderly: increased risk of falls, confusion, delirium.

  • Dose adjustments in hepatic or renal impairment.

Drug Interactions

  • CNS depressants (alcohol, opioids, antihistamines): additive sedation, respiratory depression.

  • CYP450 inhibitors (ketoconazole, erythromycin): increased plasma levels of certain agents.

  • CYP450 inducers (rifampin, carbamazepine): reduced drug levels and efficacy.

Withdrawal and Dependence

  • Chronic use can lead to physical and psychological dependence.

  • Withdrawal symptoms: anxiety, insomnia, tremors, sweating, seizures (severe cases).

  • Gradual tapering recommended for discontinuation.

Special Populations

Elderly

  • Increased sensitivity to CNS depressants.

  • Prefer short-acting agents with no active metabolites.

Pregnancy

  • Risk of teratogenicity and neonatal withdrawal; avoid unless benefits outweigh risks.

Hepatic Impairment

  • Reduce doses; choose agents with minimal hepatic metabolism if necessary.

Renal Impairment

  • Adjust dose for drugs with renal excretion.

Examples of Commonly Used Agents

Benzodiazepines

  • Diazepam: long-acting; anxiety, muscle spasms, seizures.

  • Lorazepam: intermediate-acting; anxiety, sedation, seizures.

  • Alprazolam: short-intermediate acting; panic disorder, anxiety.

  • Midazolam: short-acting; procedural sedation.

  • Temazepam: intermediate-acting; insomnia.

Z-drugs

  • Zolpidem: sleep initiation.

  • Zaleplon: very short-acting; difficulty falling asleep.

  • Eszopiclone: sleep initiation and maintenance.

Barbiturates

  • Phenobarbital: seizure disorders, pre-anesthesia.

  • Secobarbital: short-acting sedative-hypnotic.

Others

  • Buspirone: non-sedating anxiolytic.

  • Ramelteon: melatonin receptor agonist for sleep-onset insomnia.

  • Hydroxyzine: antihistamine with anxiolytic and sedative effects.

Clinical Use Principles

  • Match drug choice to symptom pattern (e.g., difficulty falling asleep vs. staying asleep).

  • Evaluate for underlying causes of anxiety or insomnia before initiating long-term therapy.

  • Combine pharmacological treatment with non-drug interventions such as cognitive-behavioral therapy, sleep hygiene education, relaxation techniques.





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