Sedative and alcohols

• Sedative-hypnotics


  A chemically heterogenous class of drugs, almost all causes a dose-dependent CNS depressant effects
• Sedative-hypnotics


  • Produce sedation (anxiolytic) - relief of anxiety; calming effect
  • Produce hypnosis - drowsiness & encourage sleep & maintenance of state of sleep
  • Cause graded dose-dependent depression of CNS function
• Chemical classification of sedative-hypnotics

  • Benzodiazepines (BZD)
  • Barbiturates
  • Non-BZD (Zolpidem, Zaleplon, Eszopiclone, Ramelteon, Tasimelteon, Suvorexant, Buspirone)
• Benzodiazepines (BZD)

  • Short-acting (t1/2 <5 hrs): Midazolam, Triazolam
  • Intermediate-acting (t1/2 5-24 hrs): Alprazolam, Clonazepam, Estazolam, Lorazepam, Oxazepam, Temazepam
  • Long-acting (t1/2 >24 hrs): Chlordiazepoxide, Clorazepate, Diazepam, Flurazepam, Prazepam, Quazepam
• Barbiturates

  • Ultra-short acting (DOA: <3 hrs): Thiopental
  • Intermediate acting (DOA: 3-6 hrs): Pentobarbital, Amobarbital, Secobarbital
  • Long-acting (DOA: 10-12 hrs): Phenobarbital
• Non-BZD


  • Zolpidem, Zaleplon, Eszopiclone (Imidazopyridine, Pyrazolopyrimidine, Cyclopyrrolone)
  • Ramelteon, Tasimelteon (Melatonin receptor agonists)
  • Suvorexant
  • Buspirone (Partial 5-HT1A agonist)
• Pharmacokinetics of sedative-hypnotics


  1. Absorption & distribution - Lipid-soluble, rapidly absorbed from GIT, CNS effects terminated via rapid redistribution

  2. Metabolism - Many BZDs converted to active metabolites, Barbiturates extensively metabolized, Chloral hydrate oxidized to Trichloroethanol

  3. Excretion - Water-soluble metabolites excreted in urine
• Molecular biology of GABAA receptor


  • GABA is a major inhibitory neurotransmitter
  • GABAA receptor-Cl- ion channel composed of 5 subunits (2 α, 2 β, 1 γ)
  • GABA binds between α1 & β2 subunits, BZD binds between α1 & γ2 subunits, Barbiturates bind at a different site
• Benzodiazepines (BZD)


  Agonist at BZD receptors, Increases frequency of GABA-mediated chloride ion channel opening, Flumazenil is an antagonist that reverses CNS effects
• Zolpidem, Zaleplon, Eszopiclone


  Not BZDs but exert CNS effects by binding with certain BZD receptors (BZ1 or ω1 subtypes), Antagonized by Flumazenil
• Barbiturates


  Increases duration of GABA-mediated chloride ion channel opening, Less selective - blocks excitatory neurotransmitter glutamate
• Clinical uses of sedative-hypnotics

  • Relieve anxiety (anxiolytic)
  • For insomnia (hypnotic)
  • For sedation & amnesia before and during medical procedures
  • Treatment of epilepsy & seizure states
  • As a component of balanced anesthesia
  • For control of ethanol and other sedative-hypnotic withdrawal states
  • For muscle relaxation in specific neuromuscular disorders
  • As diagnostic aid or for treatment in psychiatry
• Zolpidem, Zaleplon, Eszopiclone


  Bind selectively to a subgroup of GABAA receptors (acting like a BZD), Used for insomnia & sleep disorders, Fewer side effects than BZDs, Flumazenil can reverse effects, Lack anti-convulsant, anti-anxiety, and muscle relaxant effects, Rebound insomnia on withdrawal
• Buspirone


  Partial agonist at 5-HT1A, Precise mechanism for anxiolysis unknown, Used for generalized anxiety disorder, Fewer side effects than BZDs, No anti-convulsant and muscle relaxant activity, Minimal tolerance and withdrawal symptoms, Slow onset of action
• Melatonin receptor agonists (Ramelteon, Tasimelteon)


  Activate melatonin receptors (MT1 & MT2) to decrease latency of sleep onset, Used for insomnia and sleep disorders, Fewer side effects, No direct effects on GABA-ergic neurotransmission, Minimal rebound insomnia or withdrawal symptoms, Minimal abuse liability
• Clinically important alcohols and their antagonists

  • Ethanol
  • Methanol
  • Ethyl glycol (EG)
  • For alcohol withdrawal: Thiamine, Sedative-hypnotics
  • For treatment of drug dependence: Disulfiram, Naltrexone, Acamprosate
  • For acute methanol or EG poisoning: Ethanol, Fomepizole
• Ethanol


  Small water-soluble molecule rapidly absorbed from GIT, Metabolized via alcohol dehydrogenase and microsomal ethanol oxidizing system (CYP2E1/Catalase), Acetaldehyde oxidized to acetate
• Tasimelteon


  Activates Melatonin receptors (MT1 & MT2) → decreases latency of sleep onset
• Tasimelteon


  • Used for insomnia and sleep disorders (Difficulty in falling sleep)
  • Side effects include dizziness, fatigue, endocrine changes (Decreased testosterone, Increased in Prolactin)
  • No direct effects on the GABA-ergic neurotransmission
  • Minimal rebound insomnia or withdrawal symptoms
  • Minimal abuse liability
• Clinically Important Alcohols


  • Ethanol
  • Methanol
  • Ethyl glycol (EG)
• Treatment for Alcohol Withdrawal

  • Thiamine
  • Sedative-Hypnotics
• Treatment of Drug Dependence

  • Disulfiram
  • Naltrexone
  • Acamprosate
• Treatment for Acute Methanol or EG Poisoning

  • Ethanol
  • Fomepizole
• Ethanol Pharmacokinetics


  • Small water-soluble molecule that is absorbed rapidly from the GIT
  • 2 major metabolic pathways for alcohol metabolism to aldehyde: Alcohol dehydrogenase and Microsomal Ethanol Oxidizing System (CYP2E1/Catalase)
  • Acetaldehyde is oxidized to Acetate by Aldehyde dehydrogenase
  • Ethanol metabolism increases the NADH/NAD+ ratio
• Ethanol metabolism increases NADH/NAD+ ratio

  Leads to lactic acidosis, fasting hypoglycemia, ketoacidosis, and hepatosteatosis
• Acute Effects of Ethanol


  • CNS effects: Sedation, Loss of inhibition, impaired judgement, slurred speech, ataxia
  • Other organ effects: Slight cardiac depression, Vasodilation, Hypothermia, Uterine muscle relaxation
• Chronic Effects of Ethanol

  • Tolerance & Dependence: Cross-tolerance with BZD and Barbiturates, Marked psychological & physical dependence
  • Liver Disease: Most common complication of chronic alcohol abuse
  • Gastrointestinal System: Irritation, Inflammation, Bleeding, & Scarring of gut wall
  • CNS: Peripheral neuropathy
  • Endocrine System: Gynecomastia, Testicular atrophy & Salt retention due to altered steroid metabolism in cirrhotic liver
  • Cardiovascular System: Increased incidence hypertension, anemia, & dilated cardiomyopathy
  • Fetal Alcohol Syndrome: Mental retardation, Growth deficiency, microcephaly, Characteristic underdevelopment of midface region
  • Neoplasia: Increase incidence of neoplastic disease in GIT, Small increase in the risk of breast cancer
• Management for Alcohol Intoxication

  1. Prevention of severe respiratory depression & aspiration vomitous

  2. Correction of electrolyte imbalance, hypoglycemia and ketoacidosis

  3. Thiamine to protect against Wernicke-Korsakoff syndrome
• Management for Alcohol Withdrawal Syndrome

  1. Blood pressure elevation, tremor, anxiety, and insomnia (6-8 hrs) → Less symptoms, anxiety and sleep disturbances

  2. Delirium Tremens: Severe acute reaction after discontinuation, Hallucinations, Autonomic instability, Delirium, Diaphoresis after 48-72 hrs of discontinuation, Treated with long-acting benzodiazepines (Diazepam, Chlordiazepoxide)
• Wernicke-Korsakoff Syndrome


  Results from B1 deficiency, Wernicke Encephalopathy (Confusion, Ophthalmoplegia, Ataxia) → Korsakoff syndrome (Irreversible memory loss, confabulation, personality changes), Treated with IV Thiamine (before dextrose)
• Methanol Poisoning


  Methanol → Formaldehyde → Formic acid (toxic), Sources include wood alcohol, Windshield cleaners, Solvents, Photocopier toner, Causes visual dysfunction, severe acidosis, gastrointestinal distress, SOB, loss of consciousness, coma, Treated with Ethanol or Fomepizole
• Ethylene Glycol Poisoning


  Ethylene glycol → toxic aldehyde and oxalic acid, Sources include industrial exposure and self-administration (Antifreeze), Causes severe acidosis and renal damage, Treated with Ethanol or Fomepizole