Copyright Alcohol Medical Scholars Program1 Alcohol: Pharmacology and Neurobiology M.R. Zarrindast

2 Outline Pharmacokinetics –Absorption –Distribution –Metabolism Pharmacodynamics –CNS effects –Tolerance –Alcohol as a reinforcer –Neuropharmacological effects

3 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 Distribution Volume of distribution = Total Body Water Gender Differences in body composition

5 Pharmacokinetic Microsomal ethanol oxidating system (MEOS) Ethanol acetaldehyde NAD+ NADH NADPH+O2 NADP+ NAD+ NADH alcohodehydrogenase MEOS Aldehyde dehydrogenase Acetate

6 Pharmacokinetic Alcohol dehydrogenase pathway Microsomal ethanol oxidating system (MEOS) Alcohol dehydrogenase pathway 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 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

8 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

9 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

10 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

11 Effects of alcohol on organs CNS Cardiovascular Liver GIT Blood Kidney Endocrine System smooth muscle Metabolic effect Increase risk of cancer

12 Pharmacodynamics of acute ethanol consumption: 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

13 CNS CNS depressant Chronic excessive: -brain damage -memory loss -sleep disturbances -psychosis Respiration, moderate amount, depressed respiration

14 CNS Effects No specific receptor for ethanol has been identified. It was believed that ethanol’s primary effect is disruption of biologic membranes through reduction in lipid viscosity Neurotransmission by GABA & glutamate in the CNS (GABA A & NMDA receptors)

15 Pharmacodynamics of acute ethanol consumption: Heart Significant depression of myocardial contractility Impaired myocardial function Acetaldehyde is implicated as a cause of heart abnormalities by altering myocardial stores of catecholamines

16 Cardiovascular System Increase in HR (muscles activity, reflex) Depression of cardiovascular system due to acute use & toxicity (depression of vasomotor system) Hypothermia (vasodilatation due to effect on CNS) Chronic use: cardiomyopathy & arrhythmia Effect on HDL & LDL Hyperlipidemia (sympathic activity & decrease in lipoprotein lipase)

17 Pharmacodynamics of acute ethanol consumption: Smooth muscles Vasodilator ( CNS & direct effect on smooth muscles) Hypothermia (vasodilation) Uterine relaxants

18 Consequences of chronic alcohol consumption: Alcoholic fatty liver (reversible)  alcoholic hepatitis & finally cirrhosis  NADH/NAD + (oxidation of ethanol): accumulation of fat en the liver (  synthesis of TG) Increase in gastric & pancreatic secretion (gastritis & pancreatitis, release of histamine in GI) Hemorrhage in GI (anemia) Protein malnutrition Damage to intestine (diarrhea, weight loss, Vit deficiency) Thiamine deficiency (Korsakoff’s psychosis) Blood (anemia due to folic acid deficiency & bone marrow depression )

19 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

20 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 –Cross-tolerance to other depressant drugs –Genetic determinants exist –Low Response predicts alcoholism

21 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 Negative reinforcing effects: –Relief of stress and negative emotions –Relief of withdrawal symptoms

22 Alcohol as a Reinforcer: Neural Systems Activation of mesocorticolimbic system

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24 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

25 Neuropharmacology: GABA Effects on GABA system –Interaction with GABA-A receptor and facilitation of GABA transmission Sedative and anxiolytic effects Withdrawal

26 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

27 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

28 Neuropharmacology: Summary ExperienceTransmitter/Receptor euphoria/pleasureDopamine, Opioids anxiolysis/ataxia  GABA sedation/amnesia  GABA +  NMDA nausea5HT 3 neuroadaptationNMDA, 5HT stressCRF withdrawalGABA, NMDA (  Ca,  Mg)

29 Implications for Pharmacotherapy Disulfiram Naltrexone Acamprosate Benzodiazepines SSRIs

30 Liver & GIT  NADH/NAD + :  glucogenesis, hypoglycemia, and ketoacidosis, Promotion TG synthesis from free fatty acid  accumulation of fat in the liver parenchima

31 Liver & GIT Increase in gastric & pancreatic secretion (gastritis & pancreatitis, release of histamine in GI) Hemorrhage in GI (anemia) Protein malnutrition Damage to intestine (diarrhea, weight loss, Vit deficiency) Thiamine deficiency (Korsakoff’s psychosis) Blood (anemia due to folic acid deficiency & bone marrow depression )

32 Liver  NADH/NAD + :  glucogenesis, hypoglycemia, and ketoacidosis, Promotion TG synthesis from free fatty acid  accumulation of fat in the liver parenchima  cirrhosis & hepatitis (specially in females) Enzyme induction

33 GI Irritation, bleeding,

34 CNS Peripheral neuropathy, thiamine deficiency (Wernicke- Korsakoff syndrome) Endocrine system Gynecomastia, testicular atrophy, disorders of fluid and electrolytes.

35 Nervous system Tolerance &physical dependence Tolerance: CNS adaptation, minor degree of metabolic tolerance, cross tolerance with another sedative-hypnotics.

36 Kidney & Endocrine system Kidney: Diuresis due to excess of water intake & inhibition of ADH Endocrine system: gynecomastia, testicular atrophy due to steroid imbalance Alternation of whole body K + due to vomiting & diarrhea

37 Fetal alcohol syndrome Teratogenic effects: mental retardation, congenital malformation Fetal alcohol syndrome Retatrded body growth, microcephaly, poor coordination, underdevelopment of midfacial region, minor joint anomalies.

38 Management of alcohol withdrawal syndrome Agitation, anxiety, insomnia, reduction of seizure threshold. Thiamine administration, electrolyte balance, long-acting sedative-hypnotics (diazepam, chlordizepoxide) Clonidine & propranolol

39 Alcoholism tratment Disulfiram Inhibitor for aldehydedehydrogenase   acetaldehyde  extreme discomfort : flushing, headache, nausea, vomiting sweating, hypotension & confusion Naltroxene, fluxetine

40 Methanol Methanol  formaldehyde  formic acid  acidosis & visual disturbance Treatment: IV ethanol administration (copetitive substra for alcoholdehydrogenase)

41 Ethylene glycol Ethylen glycol  oxalic acid Treatment: ethanol administration, dialysis, fompizol (an alcohol dehydrogenase inhibitor)

42 Pharmacodynamic For many years it was believed that ethanol’s primary effect is disruption of biologic membranes through reduction in lipid viscosity Enhances the action of GABA at GABA A receptors Inhibition the ability of glutamate (NMDA)

43 Any questions?