Sedatives: Anxiolytics & Alcohol Lesson 19

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 ~

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 ~

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 ~

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 ~

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

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

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

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 ~

Effects on Liver Fatty Liver free fatty acids enlarged reversible 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

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 ~

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

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 ~

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

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

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

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

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 ~