Anxiolytic, Sedative and Hypnotic Drugs Overview

Anxiolytic, Sedative and Hypnotic Drugs

• Overview:
  • Anxiolytics treat anxiety symptoms.
  • Sedatives calm patients without inducing sleep.
  • Hypnotics promote sleep.
  • These drugs can be used for anticonvulsant, antiepileptic, and muscle relaxant purposes.
• Anxiety Symptoms: Include tachycardia, sweating, palpitations, tremor, trembling, gastrointestinal disorders, and sleep disturbances.
• Benzodiazepines (BZDs):
  • Over 2000 benzodiazepines have been synthesized, with over 100 used clinically.
  • Common BZDs include alprazolam, chlorodiazepoxide, clonazepam, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, temazepam, and triazolam.
  • Types are determined by:
    • Drug's half-life (t½).
    • Presence and half-life of active metabolites.
    • Speed of absorption, solubility, and passage into the CNS.
  • Long t½ BZDs/metabolites are suitable for anxiety treatment, while short t½ BZDs/metabolites are better for promoting sleep.
• BZD Mechanism of Action:
  • BZDs interact with specific BZD1, BZD2, and BZD3 receptors in the brain.
  • These receptors are located near GABA receptors and chloride ion channels, forming a complex.
  • BZDs enhance GABA's inhibitory effect, leading to chloride channel opening, resulting in sedation.
• Pharmacological Actions of BZDs:
  • Anxiolytic: BZDs reduce anxiety by inhibiting neuronal circuits in the limbic system at low doses.
  • Sedative and Hypnotic: All BZDs possess sedative properties, with some inducing hypnosis at higher doses.
  • Anticonvulsant: Some BZDs exhibit anticonvulsant activity, used to treat epilepsy.
  • Muscle Relaxant: BZDs relax skeletal muscle spasticity by increasing presynaptic inhibition in the spinal cord.
  • Amnesia: Short-acting BZDs are used as premedication for anxiety-provoking procedures to induce amnesia (e.g., endoscopy, bronchoscopy, dental).
• Therapeutic Uses of BZDs:
  • Anxiety (with or without psychotic states).
  • Panic attacks.
  • Insomnia.
  • Alcohol withdrawal.
  • Sleepwalking (somnambulism) in children.
  • Muscle spasms from various causes (e.g., epilepsy).
  • Anesthesia and sedation for endoscopies.
• BZD Safety and Pharmacology:
  • BZDs are relatively safe, with the lethal dose being over 1000 times higher than the therapeutic dose.
  • Sleep Disorders: Not all BZDs are effective hypnotics, but those commonly prescribed include:
    • Flurazepam (long-acting).
    • Temazepam (intermediate-acting).
    • Triazolam (short-acting).
  • Pharmacokinetics:
    • Absorption and distribution: BZDs are rapidly and fully absorbed orally, distributing throughout the body.
    • Duration of action: The half-life of BZDs determines their therapeutic usefulness.
      • Long-acting BZDs form active metabolites with long half-lives, leading to prolonged effects.
    • Tolerance and Dependence: Tolerance can develop with chronic use, with cross-tolerance among BZDs.
      • Dependence develops earlier with short t1/2 BZDs (e.g., alprazolam, lorazepam) compared to long t1/2 BZDs (e.g., diazepam).
• Barbiturates:
  • Potent antidotes for convulsant drugs: Barbiturates can abolish convulsions arising from conditions like tetanus, eclampsia, and local anesthetic overdoses (e.g., procaine, cocaine).
  • Respiratory Depression: High doses of ultra-short-acting barbiturates induce death due to respiratory failure, caused by the depression of the respiratory center.
  • Cardiovascular effects: Hypnotic and anesthetic doses of barbiturates lower blood pressure by reducing cardiac output. Toxic doses can lead to heart failure.
  • Tolerance: Tolerance can develop within 14 days of continuous use, possibly due to enzyme induction.
  • Psychological and Physical Dependence: Regular doses of 0.4 g/day or more can lead to dependence.
    • Withdrawal symptoms start 8-38 hours after cessation and last 8-14 days.
      • Symptoms include anxiety, twitching, intention tremor, weakness, dizziness, visual distortion, nausea, delirium, convulsions, and coma.
  • Pharmacokinetics:
    • Barbiturates are absorbed orally and distributed throughout the body, from the brain to skeletal muscle and adipose tissues.
    • They readily cross the placenta and can depress the fetus.
    • Excretion is primarily hepatic, with little urinary excretion except for phenobarbital.
  • Contraindication:
    • Pulmonary insufficiency.
    • Hepatic failure.
    • Porphyria.
    • Elderly patients due to potential paradoxical effects (e.g., excitation, paranoia, suicidal tendency).
  • Acute Adverse Effects:
    • Coma.
    • Respiratory and circulatory failure, leading to renal failure.
    • Allergic reactions (especially with phenobarbital).
• Trichloroethanol Derivatives:
  • Chloral hydrate: Converted in the body to active trichloroethanol by alcohol dehydrogenase, with hypnotic effects.
    • Gastric irritation can occur when diluted in water, but flavored solutions reduce irritation.
    • Induces sleep within 30 minutes, lasting 6-8 hours.
    • Trichloroethanol is inactivated by conjugation with glucuronic acid.
  • Other chloral derivatives: Triclofose and chloralbetaine are alternatives.
  • Drug Interactions:
    • Ethanol: Trichloroethanol competitively inhibits the conversion of ethanol to acetaldehyde, increasing ethanol plasma concentration.
      • Chronic chloral use followed by alcohol ingestion can cause vasodilation, hypotension, and tachycardia.
    • Warfarin: Enhances anticoagulant effect.
• Other Hypnotic Drugs:
  • Antidepressants: Can be effective long-term for managing chronic anxiety disorders, particularly in patients with substance addiction or dependence.
  • Phenothiazines:
    • Promethazine: A long-acting hypnotic, especially in children. Also an H1 receptor antagonist (antihistamine).
    • Trimeprazine: Used for short-term sedation and hypnosis in children. Also an antihistamine.
  • Zolpidem:
    • New hypnotic drug, not a benzodiazepine structurally, but acts on BZD1 receptors.
    • As effective as flunitrazepam.
    • Rapid onset and short half-life, providing hypnotic effects for approximately 5 hours.
    • Metabolized by CYP450 system to inactive products.
    • Drugs that induce CYP450 (e.g., rifampin) shorten zolpidem's half-life.
    • Similar drugs in action: Zaleplon and eszopiclone.
  • Meprobamate and Chlormezanone: Centrally acting muscle relaxants with sedative-hypnotic effects.
  • Bromides: