Transcript Ethanol
ALCOHOL MEDPHARM 03/24/2010 The Spectrum of Alcohol Use Saitz R. N Engl J Med 2005;352:596-607 UNHEALTHY ALCOHOL USE THE PROBLEM 8.2 million in US are alcohol dependent Dependence =“ lack of control” 85,000 Deaths Disability-medical & psychiatric Secondhand effects-MVCs Cost $ 185 billion UNHEALTHY ALCOHOL USE EPIDEMIOLOGY PREVALENCE Outpatients 7-20% ED patients 30-40% Trauma patients 50% ALCOHOL DEPENDENCE ALCOHOLISM • Clinically significant impairment or distress with 3 or more: Tolerance Continued use in spite of Withdrawal psychological/physical Time spent disability Change in lifestyle Desire to cut back Hazard rates for age at onset of DSM-IV alcohol abuse and alcohol dependence Hasin, D. S. et al. Arch Gen Psychiatry 2007;64:830-842. Copyright restrictions may apply. Body weight (pounds) Drinks in one hour 1 2 3 4 5 100 30 60 90 120 150 120 25 50 75 100 125 140 22 44 66 88 110 160 19 39 58 78 97 180 17 34 52 69 86 200 16 31 47 62 78 Blood alcohol concentration (BAC) mg/dl Factors Affecting Ethanol Absorption 1. Concentration of ethanol 2. Blood flow at site of absorption 3. Irritant properties of ethanol 4. Rate of ingestion 5. Type of beverage Absorption of ethanol from the duodenum and jejunum is much more rapid than from the stomach; hence the rate of gastric emptying is an important determinant of the rate of absorption of orally administered ethanol. DISTRIBUTION: To body water. Women Men General Scheme for Ethanol Oxidation 1. < 10% ethanol excreted in breath, sweat and urine 2. ~ 90% ethanol removed by oxidation ADH OH + NAD + ALDH 3. Most of this ethanol oxidation occurs in the liver 4. Ethanol cannot be stored in the liver 5. No major feedback mechanisms to pace the rate of ethanol metabolism to the physiological conditions of the liver cell 6. Kinetics are zero-order O O + NADH + H+ + NADH + H+ OH + NAD + O OH SCoA CO 2 O O Fatty acids Ketone bodies Cholesterol METABOLISM OF ETHANOL CH3CH2OH Ethanol Women have less ADH than men NAD Alcohol dehydrogenase NADH H | CH3C=O Acetaldehyde NAD Asians may have Aldehyde dehydrogenase an inactive ALDH OH | CH3C=O Acetate NADH CoA ATP Acetyl-CoA Citric acid cycle CO2 + H2O + Calories CYP2E1 FOMEPIZOLE ALCOHOL AND CARBOHYDRATE METABOLISM • Alcoholic hypoglycemia • Alcoholic ketoacidosis • Lactic acidosis CONSEQUENCES OF INCREASED NADH/NAD RATIO Ethanol NAD NADH Acetoacetate LIVER Pyruvate NAD Lactate -Hydroxybutyrate Acetone BLOOD KIDNEY KETONEMIA LACTIC ACIDEMIA Urine Secretion HYPERURICEMIA Urate Gout ? MECHANISM OF ALCOHOLIC HYPOGLYCEMIA Liver Glycogen BLOOD GLUCOSE Glucose – Depleted by fasting NADH DHAP Gluconeogenesis NAD NAD -glycero- P PEP NADH Pyruvate NADH Lactate OAA Malate NAD Alanine MECHANISM FOR DECREASED FATTY ACID OXIDATION C18-FA-CoA + NAD + FAD CONCENTRATION DECREASED BY ETOH OXIDATION CO2 + H2O AcCoA + C16-FA-CoA + NADH + NAD FADH2 OAA TCA cycle + respiratory chain LIVER TRIGLYCERIDE SYNTHESIS INCREASED BY ETHANOL OXIDATION ETHANOL OXIDATION Acetyl-CoA NADP NADH NADPH NAD Dihydroxyacetone phosphate -glycerophosphate Fatty Acids Triglycerides DISORDERS ASSOCIATED WITH INCREASING BLOOD ALCOHOL LEVELS: DIRECT TOXIC EFFECTS Alcohol and Alcoholism Pharmacologic Direct Withdrawal Toxic effect Syndromes Nutritional deficiency Liver Disease Unknown Adverse Effects on the Nervous System • Intoxication • “Pathologic intoxication • “Blackouts” • Coma ALCOHOL & THE BRAIN GABA & GLUTAMATE • STIMULATION • SEDATION • INTOXICATION • WITHDRAWAL Sx Low doses stimulate the glutamate system with arousal & increased energy High doses inhibit glutamate , augment GABA suppressing dopaminergic for sedation DOPAMINE & OPIATE • REINFORCEMENT,REWARD, & PLEASURE • CRAVING • SUSTAINED USE • RELAPSE AFTER LONG ABSTINENCE Endogenous opioids released Inhibit GABA pathways and enhance dopaminergic signals Neurochemical Circuits Involved in Alcohol Dependence and Craving Anton R. N Engl J Med 2008;359:715-721 ALCOHOL INTOXICATION BEHAVIORAL SYNDROME • Exhilaration, excitement • Loquacity, assertiveness • Loss of behavioral inhibitions • Progresses to stupor and coma CEREBELLAR SYNDROME • Dysarthria • Ataxia of gait and limbs • Progresses to marked generalized loss of coordination “ALCOHOLIC BLACKOUTS” • Intoxicated but not drowsy or stuporous • New memories not recorded during intoxication • Duration of a few hours • Permanent retrograde amnesia for period of intoxication • Mechanism not understood • No implications regarding prognosis of alcoholism ALCOHOLIC COMA: CLINICAL FEATURES • Life threatening: not well appreciated • Often complicated by other drug ingestion • Kills by respiratory depression or by complicating states: - subdural hematoma - hypoglycemia - meningitis - pancreatitis - pneumonia - UGI hemorrhage - hypothermia - hepatitis - portosystemic encephalopathy ALCOHOL • • • • Polyneuropathy Cerebellar atrophy Pontine myelinolysis WKS • Wernicke - Korsakoff Syndrome (WKS) • Wernicke’s confusion cranial nerve palseys incoordination • Korsakoff’s amnesia confabulation ALCOHOL: THE MAJOR CAUSE OF LIVER CIRRHOSIS IN DEVELOPED NATIONS All other (20%) Alcoholic cirrhosis (80%) Pathogenesis of Alcoholic Liver Injury Theories Centrilobular hypoxia PMN infiltration & activation Inflammatory cell infiltration & activation Antigenic adduct formation Injurious cytokines & endotoxin ALCOHOL • Heart - Cardiomyopathy • Peripheral vascular system- hypertension • Protective effect with moderate doses Child With Facial Characteristics of Fetal Alcohol Syndrome Sokol, R. J. et al. JAMA 2003;290:2996-2999. Copyright restrictions may apply. TOLERANCE TO CHRONIC ALCOHOL METABOLIC TOLERANCE Decreased blood level NEURONAL TOLERANCE Decreased effect Increased metabolism Increased metabolism INCREASED CONSUMPTION Medication Treatment for Alcohol Withdrawal Kosten T and O'Connor P. N Engl J Med 2003;348:1786-1795 ALCOHOL WITHDRAWAL • Benzodiazepines (lorazepam or others) Decreased severity of withdrawal Sx Reduced risk of seizures and DTs LATE WITHDRAWAL: DELIRIUM TREMENS • Profound confusion, disorientation, misperceptions • Hallucinations, paranoid delusions • Motor hyperactivity: Tremor, restlessness, agitation, hyperreflexia • Autonomic hyperactivity: Tachycardia, profuse sweating, mydriasis • Leads to dehydration, hypotension, shock, hyperthermia • Mortality: Inadequately treated 10-15% adequately treated 2-4% ALCOHOLISM TREATMENT • DISULFIRAM - ALDH INHIBITOR • NALTREXONE - OPIOID ANTAGONIST • ACAMPROSATE – MECHANISM ? Alcohol Dehydrogenase Microsomes Acetaldehyde Metabolites BLOOD Drugs LIVER BLOOD LIVER Alcohol Alcohol Dehydrogenase Microsomes Acetaldehyde Metabolites Drugs Alcohol Dehydrogenase Microsomes Acetaldehyde Metabolites C BLOOD Alcohol LIVER LIVER Drugs B BLOOD A Alcohol Alcohol Drugs Alcohol Dehydrogenase Microsomes Acetaldehyde Metabolites D The Role of Ethanol in the Formation of N-acetyl-p-benzoquinone-imine (NAPQI), the Toxic Metabolite of Acetaminophen (APAP), and the Dynamics of Enzyme Induction Lee, W. M. N Engl J Med 2003;349:474-485