1、Copyright Alcohol Medical Scholars Program,1,Alcohol: Pharmacology and Neurobiology,Vijay A. Ramchandani, Ph.D. Indiana University School of Medicine,Copyright Alcohol Medical Scholars Program,Outline,Pharmacokinetics Absorption Distribution Metabolism Pharmacodynamics CNS effects Tolerance Alcohol
2、as a reinforcer Neuropharmacological effects,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
3、of drinking Food consumption and composition Gastric emptying and gastric metabolism Hepatic first pass,Copyright Alcohol Medical Scholars Program,Distribution,Volume of distribution = Total Body Water Gender Differences in body composition,Copyright Alcohol Medical Scholars Program,Metabolism,Metab
4、olism 90-98% metabolized in liverAlcohol Acetaldehyde AcetateAlcohol 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 dehyd
5、rogenase,Copyright Alcohol Medical Scholars Program,Metabolism,MetabolismAlcohol Acetaldehyde AcetateAldehyde dehydrogenase usually not rate-limiting Accumulation of acetaldehyde associated with headache, gastritis, nausea, dizziness (hangover) Aldehyde dehydrogenase inhibition (disulfiram),Alcohol
6、dehydrogenase,Aldehyde dehydrogenase,Copyright Alcohol Medical Scholars Program,Metabolism: Genetic Variation,Genetic variation in alcohol metabolizing enzymes Alcohol Dehydrogenase (ADH) Polymorphism occurs at ADH2 and ADH3 lociADH2*1 ADH2*2 ADH2*3 ADH3*1 ADH3*2 White American 95% 5% 5% 50% 50% Bla
7、ck American 85% 5% 15% 85% 15% Asian 15% 85% 5% 95% 5%15% of Black Americans have ADH2*3 allele increased alcohol metabolic rate,Copyright Alcohol Medical Scholars Program,Metabolism: Genetic Variation,Genetic variation in alcohol metabolizing enzymes Aldehyde Dehydrogenase (ALDH) Polymorphism at th
8、e ALDH2 gene 50% of Asians have ALDH2*2 allele decreased elimination of acetaldehyde (and alcohol) flushing response,Copyright Alcohol Medical Scholars Program,Pharmacokinetics: Gender Differences,Gender Differences in absorption Differences in gastric ADH activity in volume of distribution Differen
9、ces 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,Pharmacodynamics: CNS Effects,Alcohol is a CNS depres
10、sant 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,Concentration-Effect Relationship,Copyright Alcohol Medical
11、 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,Copyright Alcohol Medical Scholars Program,Tolerance: Significanc
12、e,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 determinan
13、ts exist Low Response predicts alcoholism,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 Nega
14、tive reinforcing effects: Relief of stress and negative emotions Relief of withdrawal symptoms,Copyright Alcohol Medical Scholars Program,Alcohol as a Reinforcer: Neural Systems,Activation of mesocorticolimbic system,Copyright Alcohol Medical Scholars Program,Alcohol as a Reinforcer: Evidence,Animal
15、 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 Anim
16、als will bar-press repeatedly for intra-cranial injections of alcohol into the VTA,Copyright Alcohol Medical Scholars Program,Reinforcement: Neurochemical systems,Enkephalin Inhibitory Neuron,REWARD,Glutamate Excitatory Input,Enkephalin or Dynorphin Inhibitory Neuron,GABA Inhibitory Neuron,GABA Inhi
17、bitory Feedback,Dopamine Neuron,GABA Neuron,Ventral Tegmental Area (VTA),Nucleus Accumbens (NAc),Dopamine Receptors,GABA-A Receptors,Presynaptic Opioid Receptors (m, d?),m Opioid Receptors,k Opioid Receptors,Copyright Alcohol Medical Scholars Program,Neuropharmacology: GABA,Effects on GABA system In
18、teraction with GABA-A receptor and facilitation of GABA transmission Sedative and anxiolytic effects Withdrawal,Copyright Alcohol Medical Scholars Program,Neuropharmacology: DA, Opioids,Effects on Dopamine system Increase dopamine in mesocorticolimbic system Reinforcing, rewarding effects Effects on
19、 Opioid peptide system Activation of opioid peptide system Reinforcing and rewarding effects (Mu) Aversion (Kappa) Craving,Copyright Alcohol Medical Scholars Program,Neuropharmacology: NMDA, 5HT,Effects on NMDA Glutamate system Blockage of NMDA receptor (allosteric effect) Sedative/hypnotic effects
20、Neuroadaptation Withdrawal Effects on Serotonin system Neuroadaptation, aversion Effects on stress hormones Stress response,Copyright Alcohol Medical Scholars Program,Neuropharmacology: Summary,Experience Transmitter/Receptor euphoria/pleasure Dopamine, Opioids anxiolysis/ataxia GABA sedation/amnesia GABA + NMDA nausea 5HT3 neuroadaptation NMDA, 5HT stress CRF withdrawal GABA, NMDA ( Ca, Mg),Copyright Alcohol Medical Scholars Program,Implications for Pharmacotherapy,Disulfiram Naltrexone Acamprosate Benzodiazepines SSRIs,Copyright Alcohol Medical Scholars Program,
