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Sedatives: Anxiolytics & Alcohol

Sedatives: Anxiolytics & Alcohol. Lesson 19. Sedative/Anxiolytic Drugs. GABA A agonists (Cl- channels) Barbiturates e.g., phenobarbitol, secobarbitol Benzodiazepines e.g., valium, librium Alcohol ethanol (ETOH) Buspirone (Buspar) 5HT 1A partial agonist ~. ALCOHOL.

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Sedatives: Anxiolytics & Alcohol

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  1. Sedatives: Anxiolytics & Alcohol Lesson 19

  2. Sedative/Anxiolytic Drugs • GABAA agonists (Cl- channels) • Barbiturates • e.g., phenobarbitol, secobarbitol • Benzodiazepines • e.g., valium, librium • Alcohol • ethanol (ETOH) • Buspirone (Buspar) • 5HT1A partial agonist ~

  3. ALCOHOL • Family of structurally similar substances • Methyl: Methanol • Isopropyl: Isopropanol (rubbing) • Ethyl: Ethanol (ETOH); beverage • Ethanol Synthesis • Starch + Sugar + YeastCO2 + ETOH • Self-limiting concentration: 12-14% • No accepted medical use • high abuse potential ~

  4. Pharmacokinetics • Routes: All routes effective • Inhalation - effective but risky • P.O. most common route ~ • Solubility • highly water soluble • somewhat lipid soluble • Small & un-ionized • crosses all membrane barriers • Distributes to all tissues ~

  5. Pharmacokinetics: Metabolism • Per os absorption • 20% stomach / 80% small intestine • Metabolized in liver (90-98%) • Rate slow, fixed: 1/2 oz./hr • Regardless Blood Alcohol Level (BAL) • also coffee, cold shower, etc. • BAL reduced by time or dialysis only • No antidote for overdose ~

  6. Alcohol Dehydrogenase Aldehyde Dehydrogenase Acetyl CoA CO2 H2O Energy Acetate Acetaldehyde Ethanol Metabolism ETOH

  7. Metabolism: Sex Differences • Same dose  greater effects in females • Weight • Muscle / Fat • New evidence: enzymes • males: ETOH dehydrogenase in stomach • higher 1st pass metabolism ~

  8. Alcohol Dose Response Chart BAL Effect Bottles of beer in 1 hr M F .05 euphoria, disinhibition, ¯ coordination 2 2 .10 *legally drunk, ¯ coordination, ­ drowsiness 4 4 .15 significantly ¯ reaction time 6 5 .25 “smashed”, staggering, severe motor ¯ 10 9 .35 surgical anesthesia, possible death 5-10 hrs 14 12 .4-.6 lethal dose 20 16 1 quart whiskey .08

  9. Undesirable Effects • General Depression • Interferes with REM sleep • Withdrawal & Seizures • Blackouts • Wernicke-Korsakoff Syndrome • Severe memory loss • Thiamine deficiency • Fetal Alcohol Syndrome • morphological & cognitive effects ~

  10. Effects on Liver Normal • Fatty Liver • free fatty acids • enlarged • reversible • Hepatitis • cell damage • regeneration w/ abstinence • Cirrhosis: irreversible • cell death • fibrous scar tissue • decreased metabolism  toxicity ~ Fatty Cirrhosis

  11. Other Effects • Effects on Muscle cells • Impairment • Degeneration • Depressed immune function • increased probability of sickness • Reproductive function • males  decreased testosterone • sperm • females  disrupts ovarian cycling ~

  12. Alcohol Dependence High Dependence Liability • Positive & Negative Reinforcer • Aversive Aftereffects • Available/Inexpensive • Socially Acceptable • Easily Administered • Rapid Onset of Effects ~

  13. Dependence: Genetic Component • Sons of Male Alcoholics at > risk • P3 • R. Cloniger (1989) Statistical Evaluation • Type I - Environmental • Late developing - Age = 20-30 • Type II - Genetic • Early onset (teens & younger) • Impulsive risk takers/Suicidal • Violent/Agressive/Crime ~

  14. Liquor-loving Mice • Knockout mice • delete single gene • Increased ETOH appetite • Drank twice as much ETOH • fewer motor effects • 5-HT1B receptor • autoreceptor ~

  15. Treatment • No best program • Success rates: • 1 year: up to 50% • 2 years: 25% • Higher rates: • select populations & short follow-up • Treatment approaches • 12-step programs • Behavioral-Cognitive • Pharmacological ~

  16. Antabuse • Disulfiram • Aversive therapy • Interferes with ETOH metabolism • inhibits aldehyde dehydrogenase • Acetaldehyde  toxic ~

  17. Disulfiram (Antabuse) Alcohol Dehydrogenase Aldehyde Dehydrogenase Acetaldehyde Antabuse • nausea • cramps • sweating ~ ETOH

  18. New Treatments • Naltrexone (opioid antagonist) • Blocks rewarding effects • Relapse prevention • binge after slipping:  50% • Acamprosate (Campral) • Blocks withdrawal effects • NMDA antagonist / GABA agonist • Naltrexone + Acamprosate? • under investigation ~

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