Sedative-Hypnotic Drugs and Alcohol Notes

Sleep Cycle

  • Non-Rapid Eye Movement (NREM)

    • Stage 1: Aware of surroundings but relaxed.

    • Stage 2: Unaware of surroundings but easily awakened.

    • Stage 3 & 4: Deeper stages of sleep.

      • Important for physical rest and restoration.

  • REM Stage

    • Characterized by:

      • Bursts of rapid eye movement (REM).

      • Increased autonomic activity.

      • Dreaming.

      • Active state of sleep.

      • Known as paradoxical sleep.

EEG Patterns During Sleep

The EEG patterns observed during the stages of sleep are as follows:

  • Beta (13 to 30 Hertz): Awake, alert, or eyes open.

  • Alpha (8 to 13 Hertz): Awake, relaxed, and eyes closed.

  • Theta (4 to 8 Hertz).

  • Delta (0.5 to 4 Hertz).

  • Epilepsy spiking: The spiking occurs during 0 to 2 seconds.

  • Increasing depth of sleep: There are 2 stages of sleep, REM and non-REM sleep. The sleep stages reverse through 4-3-2-1 before REM sleep begins.

Mechanism of Action of Sedative-Hypnotic Drugs

  • Brain activity is highly affected by gamma-aminobutyric acid (GABA).

    • Regulates the chlorine channel.

    • The GABA binds to GABAA receptor.

    • Reduces generation of action potentials and inhibits neuronal activity.

  • Hypnotic drugs bind to specific receptor sites.

    • Increase the inhibitory effects of GABA.

Chloride Ion Channel

The chloride ion channel is represented diagrammatically with the following features:

  • Extracellular region at the top and intracellular region at the bottom.

  • A downward arrow from Cl– indicates the path of chloride ion through the ion channel.

  • Two GABA molecules are marked on both sides of the channel in the upper region.

  • Two alphas, two betas, and one gamma are marked near the entrance of the channel.

  • Two Barbiturates are marked in the middle, and Benzodiazepines, Flumazenil, and Zolpidem are marked just below the right entrance of the channel.

Barbiturate Sedatives and Hypnotics

  • High doses:

    • Depression of CNS.

  • Low doses:

    • Decrease in the activity of the reticular activating system (RAS).

      • Promote sedation or sleep.

  • Effects on sleep cycle:

    • Increase in stage 2 sleep, decrease in slow-wave sleep, and suppression of REM sleep.

  • Pharmacokinetics:

    • Well absorbed through oral administration.

    • Enzyme induction.

      • Increase in the amount of drug-metabolizing enzymes in the liver.

  • Barbiturate drugs:

    • Phenobarbital:

      • Clinical applications: Seizures, anxiety.

      • Mechanism: Increases the seizure threshold and reduces anxiety by enhancing GABAergic inhibition in the CNS.

      • Dosage: 50-100mg orally 2-3 times daily for anxiety; 100-300mg daily for seizures.

      • Overdose: Respiratory depression, hypotension, coma; treatment includes supportive care, and in some cases, activated charcoal or hemodialysis.

    • Pentobarbital and amobarbital:

      • Clinical applications: Insomnia, preanesthetic sedation.

      • Mechanism: Depresses the CNS by potentiating GABA, leading to sedation and hypnosis.

      • Dosage: 100-200mg orally for insomnia; 3-5mg/kg IV for preanesthetic sedation.

        • Overdose: Similar to phenobarbital; management focuses on respiratory and cardiovascular support.

    • Secobarbital:

      • Clinical applications: Insomnia.

      • Mechanism: Similar to other barbiturates, it enhances GABAergic inhibition to induce sleep.

      • Dosage: 100-200mg orally at bedtime.

      • Overdose: CNS and respiratory depression; treatment is mainly supportive.

  • Adverse effects:

    • Drowsiness, dry mouth, lethargy, and incoordination.

    • Mental confusion and memory difficulties in elderly patients.

    • Mild overdose can cause symptoms similar to alcohol intoxication.

    • Prolonged use can lead to tolerance and physical dependence.

    • Overdose results in extensive cardiovascular and CNS depression.

  • Contraindications:

    • Affect patients who have acute intermittent porphyria.

    • Barbiturates should be avoided during pregnancy.

  • Potentiate actions of:

    • CNS depressant drugs.

    • Alcohol.

Benzodiazepines

  • Used to treat anxiety.

  • Mechanism: Enhance the effect of the neurotransmitter GABA at the GABAA receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties.

  • Increase the inhibitory activity of GABA.

  • Lipid soluble: Do not cause enzyme induction.

  • Eliminated by way of the urinary tract.

  • Drugs:

    • Flurazepam:

      • Clinical applications: Insomnia.

      • Mechanism: Long-acting benzodiazepine that enhances GABAergic inhibition to promote sleep.

      • Dosage: 15-30mg orally at bedtime.

      • Overdose: Marked by drowsiness, confusion, and respiratory depression; managed with supportive care and flumazenil (a benzodiazepine antagonist) if necessary.

    • Temazepam:

      • Clinical applications: Insomnia.

      • Mechanism: Intermediate-acting benzodiazepine that facilitates GABA activity to aid in sleep.

      • Dosage: 7.5-30mg orally at bedtime.

        • Overdose: Similar to flurazepam, but typically less severe; treatment includes monitoring and supportive measures.

    • Triazolam:

      • Clinical applications: Insomnia.

      • Mechanism: Short-acting benzodiazepine that quickly induces sleep by increasing GABAergic inhibition.

      • Dosage: 0.125-0.25mg orally at bedtime.

      • Overdose: Can cause significant CNS depression; managed with flumazenil and supportive care.

  • Effects on sleep cycle:

    • Increased NREM stage 2 and decreased stage 4.

    • No suppression of REM.

  • Advantages:

    • Do not cause REM rebound.

    • Less tolerance levels.

    • Do not induce microsomal metabolizing enzymes.

  • Adverse effects:

    • Flurazepam: Sedation or hangover effects.

    • Triazolam: Rebound insomnia and increased daytime anxiety.

  • Flumazenil:

    • Benzodiazepine receptor antagonist.

    • Used to reverse depressant effects.

  • Should not be used during pregnancy:

  • Drug interactions:

    • Potentiate the actions of other CNS depressant drugs.

    • Cimetidine:

      • Causes enzyme inhibition.

      • Increases the duration of action.

Miscellaneous Hypnotic Drugs

  • Diverse group of drugs.

  • Differ in chemical structures and pharmacologic characteristics.

  • Bind selectively to a subunit of the benzodiazepine receptor.

  • Increase the inhibitory effects of GABA.

  • Examples:

    • Eszopiclone:

      • Clinical applications: Insomnia.

      • Mechanism: Non-benzodiazepine hypnotic that enhances GABAergic inhibition, similar to benzodiazepines but with a different chemical structure.

      • Dosage: 1-3mg orally at bedtime.

      • Overdose: CNS depression; managed with supportive care.

    • Zaleplon:

      • Clinical applications: Insomnia (for sleep onset).

      • Mechanism: Ultra-short-acting non-benzodiazepine hypnotic that selectively binds to the benzodiazepine receptor to promote sleep.

      • Dosage: 5-10mg orally at bedtime.

      • Overdose: Symptoms include drowsiness, confusion, and lethargy; treatment is supportive.

    • Zolpidem:

      • Clinical applications: Insomnia.

      • Mechanism: Non-benzodiazepine hypnotic that enhances GABAergic inhibition, particularly useful for initiating sleep.

      • Dosage: 5-10mg orally at bedtime.

      • Overdose: Can cause CNS depression, respiratory depression, and coma; managed with supportive care and, if necessary, flumazenil.

    • Chloral hydrate:

      • Clinical applications: Sedation in children.

      • Mechanism: Depresses the CNS, although its exact mechanism is not fully understood; it is metabolized to trichloroethanol, which is responsible for its hypnotic effects.

      • Dosage: 5-10mg orally at bedtime.

      • Overdose: Can cause severe respiratory depression, cardiac arrhythmias, and hypotension; treatment focuses on supportive care.

    • Ramelteon:

      • Clinical applications: Insomnia (for sleep onset).

      • Mechanism: Melatonin receptor agonist that helps regulate the sleep-wake cycle by activating melatonin receptors in the brain.

      • Dosage: 8mg orally at bedtime.

      • Overdose: Limited data available; likely to cause drowsiness and dizziness, managed symptomatically.

Preferred Therapy for Insomnia and Sedation

  • Insomnia:

    • Zolpidem or eszopiclone.

  • For insomnia coupled with anxiety:

    • Benzodiazepines:

      • Flurazepam or quazepam.

  • Zaleplon or ramelteon helps induce sleep.

  • Sedation:

    • Benzodiazepines.

Alcohol

  • Pharmacological effects:

    • CNS

    • Vascular

    • Gastrointestinal

    • Renal

    • Nutritional

  • Metabolism:

    • Alcohol is readily absorbed and distributed to all body tissues.

    • Constantly metabolized in the liver.

    • Chronic use of alcohol leads to the development of enzyme induction.

  • Adverse effects:

    • Acute inebriation.

    • Extensive CNS depression.

    • Chronic consumption:

      • Progressive changes in cell function.

      • Drug tolerance.

      • Physical dependence.

      • Alterations in body metabolism.

  • Cautions and contraindications:

    • Intoxicated patients must be kept under observation.

    • Contraindicated in patients who have hepatic or renal disease, ulcers, epilepsy, or hyperacidity

    • Consumption during pregnancy can cause harmful effects to the fetus.

  • Clinical indications:

    • When applied to the skin:

      • Produces a cooling effect.

      • Acts as a bactericidal agent.

    • Cold remedies and cough syrups produce sedation and hypnosis.

    • Disulfiram is used to treat alcoholism.

      • Interferes with the metabolism of alcohol.