Pharmacology and Neurobiology of Alcohol

Alcohol: Pharmacology and Neurobiology Vijay A. Ramchandani, Ph.D. Indiana University School of Medicine Copyright Alcohol Medical Scholars Program 1 Outline • Pharmacokinetics – Absorption – Distribution – Metabolism • Pharmacodynamics – – – – CNS effects Tolerance Alcohol as a reinforcer Neuropharmacological effects Copyright Alcohol Medical Scholars Program 2 Pharmacokinetics: Absorption • Rapidly absorbed primarily from duodenum • Rate of absorption is extremely variable • Peak blood alcohol concentration (BAC) depends on: – – – – – Amount and alcohol concentration of beverage Rate of drinking Food consumption and composition Gastric emptying and gastric metabolism Hepatic first pass Copyright Alcohol Medical Scholars Program 3 Distribution • Volume of distribution = Total Body Water • Gender Differences in body composition Copyright Alcohol Medical Scholars Program 4 Metabolism • Metabolism – 90-98% metabolized in liver Alcohol Alcohol dehydrogenase Acetaldehyde Aldehyde dehydrogenase Acetate – Alcohol dehydrogenase saturates at low to moderate BACs (Michaelis-Menten kinetics) – Apparent zero-order kinetics at moderate BACs • Alcohol Elimination Rate = 7 g per hr • Disappearance Rate = 0.015% per hr Copyright Alcohol Medical Scholars Program 5 Metabolism • Metabolism Alcohol Alcohol dehydrogenase Acetaldehyde Aldehyde dehydrogenase Acetate – Aldehyde dehydrogenase usually not rate-limiting – Accumulation of acetaldehyde associated with headache, gastritis, nausea, dizziness (hangover) – Aldehyde dehydrogenase inhibition (disulfiram) Copyright Alcohol Medical Scholars Program 6 Metabolism: Genetic Variation Genetic variation in alcohol metabolizing enzymes • Alcohol Dehydrogenase (ADH) – Polymorphism occurs at ADH2 and ADH3 loci ADH2*1 95% 85% 15% ADH2*2 <5% <5% 85% ADH2*3 <5% 15% <5% ADH3*1 50% 85% 95% ADH3*2 50% 15% 5% White American Black American Asian – 15% of Black Americans have ADH2*3 allele  increased alcohol metabolic rate Copyright Alcohol Medical Scholars Program 7 Metabolism: Genetic Variation Genetic variation in alcohol metabolizing enzymes • Aldehyde Dehydrogenase (ALDH) – Polymorphism at the ALDH2 gene • 50% of Asians have ALDH2*2 allele  decreased elimination of acetaldehyde (and alcohol)  flushing response Copyright Alcohol Medical Scholars Program 8 Pharmacokinetics: Gender Differences • Gender Differences – in absorption • Differences in gastric ADH activity – in volume of distribution • Differences in body composition and total body water (TBW) – in metabolism • Differences in liver volume, ADH activity? • Effect of menstrual cycle on alcohol pharmacokinetics • Effect of sex hormones (OC) on alcohol PK Copyright Alcohol Medical Scholars Program 9 Pharmacodynamics: CNS Effects • Alcohol is a CNS depressant • Apparent stimulatory effects result from depression of inhibitory control mechanisms in the brain • Characteristic response: euphoria, impaired thought processes, decreased mechanical efficiency Copyright Alcohol Medical Scholars Program 10 Concentration-Effect Relationship BAC [%] 0.02-0.03 Effects Mood elevation. Slight muscle relaxation. 0.05-0.06 0.08-0.09 Relaxation and Warmth. Increased reaction time. Decreased fine muscle coordination. Impaired balance, speech, vision, hearing, muscle coordination. Euphoria. 0.14-0.15 0.20-0.30 0.40-0.50 Gross impairment of physical and mental control. Severely intoxicated. Very little control of mind or body. Unconscious. Deep coma. Death from respiratory depression Copyright Alcohol Medical Scholars Program 11 Tolerance: Definitions • Tolerance: The phenomenon of decreased effect with prolonged exposure to a drug • Acute tolerance: during the time-course of a single exposure to drug • Chronic tolerance: over repeated use of drug Copyright Alcohol Medical Scholars Program 12 Tolerance: Significance • Why is tolerance to alcohol important? – One of the determinants of increased alcohol consumption • maintains or aggravates alcohol dependence • increases risk of organic complications of alcoholism – – – – Diagnostic criteria for alcoholism by DSM-IV Cross-tolerance to other depressant drugs Genetic determinants exist Low Response predicts alcoholism Copyright Alcohol Medical Scholars Program 13 Alcohol as a Reinforcer • Reinforcer: a substance whose pharmacological effects drive the user to continue to use it. • Positive reinforcing effects: – Gain pleasure – Altered consciousness – Conform to behavior of peers • Negative reinforcing effects: – Relief of stress and negative emotions – Relief of withdrawal symptoms Copyright Alcohol Medical Scholars Program 14 Alcohol as a Reinforcer: Neural Systems Activation of mesocorticolimbic system Copyright Alcohol Medical Scholars Program 15 Alcohol as a Reinforcer: Evidence • Animal models of alcohol preference – Selectively bred animal lines show innate differences in limbic structures and neurotransmitter function • Animal models of self-administration – Animals trained to chronically self-administer alcohol show differences in neurotransmitter levels in the mesolimbic system – Animals will bar-press repeatedly for intra-cranial injections of alcohol into the VTA Copyright Alcohol Medical Scholars Program 16 Reinforcement: Neurochemical systems Enkephalin or Dynorphin Inhibitory Neuron Enkephalin Inhibitory Neuron k Opioid Receptors Glutamate Excitatory Input Dopamine Receptors Dopamine Neuron GABA Neuron m Opioid Receptors GABA-A Receptors REWARD GABA Inhibitory Feedback GABA Inhibitory Neuron Presynaptic Opioid Receptors (m, d?) Ventral Tegmental Area (VTA) Nucleus Accumbens (NAc) Copyright Alcohol Medical Scholars Program 17 Neuropharmacology: GABA • Effects on GABA system – Interaction with GABA-A receptor and facilitation of GABA transmission • Sedative and anxiolytic effects • Withdrawal Copyright Alcohol Medical Scholars Program 18 Neuropharmacology: DA, Opioids • Effects on Dopamine system – Increase dopamine in mesocorticolimbic system • Reinforcing, rewarding effects • Effects on Opioid peptide system – Activation of opioid peptide system • Reinforcing and rewarding effects (Mu) • Aversion (Kappa) • Craving Copyright Alcohol Medical Scholars Program 19 Neuropharmacology: NMDA, 5HT • Effects on NMDA Glutamate system – Blockage of NMDA receptor (allosteric effect) • Sedative/hypnotic effects • Neuroadaptation • Withdrawal • Effects on Serotonin system • Neuroadaptation, aversion • Effects on stress hormones • Stress response Copyright Alcohol Medical Scholars Program 20 Neuropharmacology: Summary Experience euphoria/pleasure anxiolysis/ataxia sedation/amnesia nausea neuroadaptation stress withdrawal Transmitter/Receptor Dopamine, Opioids  GABA  GABA +  NMDA 5HT3 NMDA, 5HT CRF GABA, NMDA ( Ca, Mg) Copyright Alcohol Medical Scholars Program 21 Implications for Pharmacotherapy • • • • • Disulfiram Naltrexone Acamprosate Benzodiazepines SSRIs Copyright Alcohol Medical Scholars Program 22 Copyright Alcohol Medical Scholars Program 23