Alcohol Pharmacology and Neurobiology Vijay A Ramchandani Ph

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 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 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 ADH 2 and ADH 3 loci White American Black American Asian ADH 2*1 95% 85% 15% ADH 2*2 <5% 85% ADH 2*3 <5% 15% <5% ADH 3*1 50% 85% 95% ADH 3*2 50% 15% 5% – 15% of Black Americans have ADH 2*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 ALDH 2 gene • 50% of Asians have ALDH 2*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 [%] Effects 0. 02 -0. 03 Mood elevation. Slight muscle relaxation. 0. 05 -0. 06 Relaxation and Warmth. Increased reaction time. Decreased fine muscle coordination. 0. 08 -0. 09 Impaired balance, speech, vision, hearing, muscle coordination. Euphoria. 0. 14 -0. 15 Gross impairment of physical and mental control. 0. 20 -0. 30 Severely intoxicated. Very little control of mind or body. 0. 40 -0. 50 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 Glutamate Excitatory Input k Opioid Receptors Enkephalin Inhibitory Neuron Dopamine Receptors Dopamine Neuron m Opioid Receptors GABA Neuron REWARD GABA-A Receptors 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, 5 HT • 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 + NMDA 5 HT 3 NMDA, 5 HT 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