1. Copyright Alcohol Medical Scholars Program1 Alcohol: Pharmacology and Neurobiology Vijay A. Ramchandani, Ph.D. Indiana University School of Medicine

2. 2 Copyright Alcohol Medical Scholars Program Outline Pharmacokinetics –Absorption –Distribution –Metabolism Pharmacodynamics –CNS effects –Tolerance –Alcohol as a reinforcer –Neuropharmacological effects

3. 3 Copyright Alcohol Medical Scholars Program 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

4. 4 Copyright Alcohol Medical Scholars Program Distribution Volume of distribution = Total Body Water Gender Differences in body composition

5. 5 Copyright Alcohol Medical Scholars Program Metabolism –90-98% metabolized in liver Alcohol Acetaldehyde 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 Alcohol dehydrogenase Aldehyde dehydrogenase

6. 6 Copyright Alcohol Medical Scholars Program Metabolism Alcohol Acetaldehyde Acetate –Aldehyde dehydrogenase usually not rate-limiting –Accumulation of acetaldehyde associated with headache, gastritis, nausea, dizziness (hangover) –Aldehyde dehydrogenase inhibition (disulfiram) Alcohol dehydrogenase Aldehyde dehydrogenase

7. 7 Copyright Alcohol Medical Scholars Program Metabolism: Genetic Variation Genetic variation in alcohol metabolizing enzymes Alcohol Dehydrogenase (ADH) –Polymorphism occurs at ADH2 and ADH3 loci ADH2*1 ADH2*2 ADH2*3 ADH3*1 ADH3*2 White American 95% <5%<5% 50% 50% Black American 85% <5%15% 85% 15% Asian 15% 85%<5% 95% 5% –15% of Black Americans have ADH2*3 allele  increased alcohol metabolic rate

8. 8 Copyright Alcohol Medical Scholars Program 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

9. 9 Copyright Alcohol Medical Scholars Program 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

10. 10 Copyright Alcohol Medical Scholars Program 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

11. 11 Copyright Alcohol Medical Scholars Program Concentration-Effect Relationship BAC [%]Effects 0.02-0.03Mood elevation. Slight muscle relaxation. 0.05-0.06Relaxation and Warmth. Increased reaction time. Decreased fine muscle coordination. 0.08-0.09Impaired balance, speech, vision, hearing, muscle coordination. Euphoria. 0.14-0.15Gross impairment of physical and mental control. 0.20-0.30Severely intoxicated. Very little control of mind or body. 0.40-0.50Unconscious. Deep coma. Death from respiratory depression

12. 12 Copyright Alcohol Medical Scholars Program 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

13. 13 Copyright Alcohol Medical Scholars Program 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

14. 14 Copyright Alcohol Medical Scholars Program 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

15. 15 Copyright Alcohol Medical Scholars Program Alcohol as a Reinforcer: Neural Systems Activation of mesocorticolimbic system

16. 16 Copyright Alcohol Medical Scholars Program 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

17. 17 Copyright Alcohol Medical Scholars Program Reinforcement: Neurochemical systems Enkephalin Inhibitory Neuron REWARD Glutamate Excitatory Input Enkephalin or Dynorphin Inhibitory Neuron GABA Inhibitory Neuron GABA Inhibitory Feedback Dopamine Neuron GABA Neuron Ventral Tegmental Area (VTA) Nucleus Accumbens (NAc) Dopamine Receptors GABA-A Receptors Presynaptic Opioid Receptors ( ,  ?)  Opioid Receptors  Opioid Receptors

18. 18 Copyright Alcohol Medical Scholars Program Neuropharmacology: GABA Effects on GABA system –Interaction with GABA-A receptor and facilitation of GABA transmission Sedative and anxiolytic effects Withdrawal

19. 19 Copyright Alcohol Medical Scholars Program 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

20. 20 Copyright Alcohol Medical Scholars Program 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

21. 21 Copyright Alcohol Medical Scholars Program Neuropharmacology: Summary ExperienceTransmitter/Receptor euphoria/pleasureDopamine, Opioids anxiolysis/ataxia  GABA sedation/amnesia  GABA +  NMDA nausea5HT 3 neuroadaptationNMDA, 5HT stressCRF withdrawalGABA, NMDA (  Ca,  Mg)

22. 22 Copyright Alcohol Medical Scholars Program Implications for Pharmacotherapy Disulfiram Naltrexone Acamprosate Benzodiazepines SSRIs

23. 23 Copyright Alcohol Medical Scholars Program