Anxiolytic and Hypnotic Drugs Overview

Anxiolytic and Hypnotic Drugs

• Benzodiazepines are widely used anxiolytic drugs—safe and effective.
• Mechanism of action: Benzodiazepines act on γ-aminobutyric acid (GABA) receptors. GABA is the major inhibitory neurotransmitter in the central nervous system (CNS).
• GABA receptors are composed of five subunits (α, β, and γ) that span the postsynaptic membrane.
• Binding of GABA to its receptor triggers the opening of the central ion channel, allowing chloride ions to pass through the pore.
• Chloride influx causes hyperpolarization of the neuron and decreases neurotransmission by inhibiting the formation of action potentials.
• Benzodiazepines enhance the binding of GABA, increasing chloride influx and the inhibitory effect.

Therapeutic Uses

• Anxiety disorders, depression, and schizophrenia: These drugs are not for everyday stress; rather, for severe anxiety, short-term use is recommended; they have less tolerance than sedatives or hypnotics; long-acting agents are better than short-acting due to less abrupt withdrawal reactions.
• Muscle disorders: Diazepam is useful for muscle spasms (e.g., muscle strains). It is effective for muscle spasticity in conditions like multiple sclerosis and cerebral palsy.
• Premedication for endoscopic and bronchoscopy procedures: Short-acting agents are best.
• Seizures: Diazepam is used in grand mal seizures, status epilepticus, and acute alcohol withdrawal. Clonazepam is used for absence epilepsy.
• Sleep disorders: Benzodiazepines have sedative and calming effects but not all have hypnotic effects. They reduce sleep latency and increase stage 2 non-REM sleep.

Classification of Benzodiazepines

• Long-acting: Diazepam, clonazepam, chlordiazepoxide, clorazepate, flurazepam.
• Intermediate-acting: Lorazepam, alprazolam, temazepam.
• Short-acting: Triazolam, midazolam, oxazepam.

Dependence

• High doses can cause prolonged psychological and physical dependence.
• Withdrawal symptoms include confusion, anxiety, agitation, restlessness, insomnia, and tension.

Adverse Effects

• Common: Drowsiness and confusion (more pronounced at higher doses), ataxia.
• Precaution: Avoid in liver disease, acute narrow-angle glaucoma, alcohol/CNS depressant interaction, and pregnancy/breastfeeding.

Other Anxiolytic and Hypnotic Agents

• Zolpidem: Not a benzodiazepine, acts on BZ receptors, short acting, less rebound withdrawal.
• Hydroxyzine: Antihistamine with antiemetic and sedative effects; used prior to surgery.

Benzodiazepine Antagonist

• Flumazenil: GABA receptor antagonist that rapidly reverses benzodiazepine effects. Short half-life; repeated doses needed for sustained reversal.

Barbiturates

• Previously mainstay for sedation and sleep maintenance—now largely replaced by benzodiazepines.
• Problems: Enzyme induction, tolerance, physical dependence, severe withdrawal, and a narrow safety margin.
• Mechanism of action: Interact with GABA receptors to enhance GABAergic transmission; block excitatory glutamate receptors.
• Examples: Thiopental (ultra-short acting), Phenobarbital (long-acting), used for anesthesia induction, convulsive disorders.

Non-barbiturate Sedatives

• Chloral hydrate: Prodrug, converted to trichloroethanol, effective as a sedative/hypnotic, irritating to the gut, epigastric distress.

Antihistamines

• Diphenhydramine: Sedative properties, mild insomnia.
• Chlorpheniramine: Other antihistamines.

Ethanol

• Anti-anxiety and sedative effects, serious toxic potential.
• Chronic use leads to liver disease, gastritis, and nutritional deficiency.
• Cardiotoxicity is a risk in heavy drinkers.
• Benzodiazepines are the preferred therapy for alcohol withdrawal.

Disulfiram

• Blocks the oxidation of acetaldehyde to acetic acid.
• Causes acetaldehyde accumulation, leading to flushing, tachycardia, hyperventilation, and nausea.
• Used in patients wanting to stop alcohol consumption.

Buspirone

• Anti-anxiety partial agonist at serotonin receptors, does not cause dependence. It does not work on the GABA system.

Melatonin

• Secreted by the pineal gland. Promotes sleep; Ramelteon is a melatonin receptor agonist.
• Side effects include gastrointestinal disturbances.