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The Alcohols By S. Bohlooli, Ph.D History • The alcohol had important place in humankind for at least 8000 years • The diluted alcoholic beverages were preferred over water, In western countries • Today, 75% of US adult population drinks alcohol regularly • About 10% of the general population in the US are alcohol abuser. Basic Pharmacology of Ethanol • Pharmacokinetics – Ethanol is a small water soluble molecule – Presence of food delays absorption – Vd approximates total body water – Over 90% of alcohol consumed is oxidized in the liver. – Rate of oxidation follows zero order kinetics. Metabolism of ethanol • Alcohol Dehydrogenase pathway • Microsomal ethanol oxidizing system (MEOS). • Acetaldehyde metabolism Alcohol Dehydrogenase (ADH) pathway Ethanol CH3CH2OH NADPH + O2 NAD+ Alcohol Dehydrogenase (ADH) Θ Fomepizole MEOS NADH NAD+ Acetaldehyde CH3CHO Aldehyde Dehydrogenase NADH Acetate CH3COO- NADP+ Disulfiram Θ Microsomal Ethanol Oxidizing System (MEOS) • At concentration below 100 mg/dl the MEOS has little contribution to the ethanol metabolism. • During chronic consumption there is an induction in enzyme activity • Enzyme inducing drugs like phenobarbital may increase activity of MEOS. Acetaldehyde metabolism • It seems several enzymes are responsible for acetaldehyde metabolism • The primary enzyme system is aldehyde dehydrogenase • The product is acetate • Oxidation of acetaldehyde is inhibited by disulfiram. • Co-cosumption of ethanol and disulfiram leads to acetaldeyde accumulation. • Facial flushing, nausea, dizziness and headache are the main unpleasant reaction. Pharmacodynamics of acute ethanol consumption • Central nervous system – Sedation, relief of anxiety, – Slurred speech, impaired judgment, disinhibited behavior – Condition called “intoxication” or “drunkenness” – There is too different between tolerant and nontolerant individuals – At higher blood concentration: • Coma, respiratory depression and death. Ethanol Mechanism of action • Enhances the action of GABA at GABAA • Inhibits the action of Glutamate at NMDA • Disruption of biological membranes through reduction in lipid viscosity (fluidization) Effect on Heart • Depression of myocardial contractility (blood concentration > 100 mg/dl) • It seems that acetaldehyde is responsible for ultra structural changes Effect on Smooth Muscle • Vasodilator – Depression of vasomotor center – Direct effect • Relaxes Uterus Consequences of Chronic Alcohol Consumption • Liver and gastrointestinal tract • Nervous system – Tolerance and physical dependence – Neurotoxicity • • • • • • Cardiovascular system Blood Endocrine system and electrolyte balance Fetal alcohol syndrome Immune system Increased risk of cancer Liver and gastrointestinal tract • About 15-30% chronic heavy drinkers develop sever liver disease: – Alcoholic fatty liver – Alcoholic hepatitis – Cirrhosis and liver failure • Increased ratio of NADH/NAD+reduced gluconeogenesis, hypoglycemiaa nd ketoacidosis • Excess of Acetaldehyde (very reactive compound) • Decreased level of Glutathione • Hormonal factors • Increased gastric and pancreatic secretion. • Altered mucosal barriers • Malabsorption of water soluble vitamines Nervous system • Tolerance and physical dependence – Metabolic tolerant – Neurotransmitters, receptors, ion channels, enzymes that participate in signal transduction pathway – Acute increase in local concentration of serotonin, opioids, and dopamine – Withdrawal syndrome • Hyperexcitability, convulsion, toxic psychosis – Dose, rate and duration of alcohol consumption Nervous system • Neurotoxicity – Generalized symmetric peripheral nerve injury – Gait disturbance and ataxia – Wernicke-Korsakoff syndrome • Thiamine deficiency – Impaired visual acuity Cardiovascular system • Heavy alcohol consumption dilated cardiomyopathy – Depressed function of mitochondria and sarcoplasmic reticulum, intracellular accumulation of fatty acids and phospholipids up regulation of voltage dependent calcium channels. – Arrhythmias • Arrhythmias Seizure, syncope and sudden death during alcohol withdrawal • Hypertension • Low coronary heart disease high HDL Blood • Mild anemia alcohol related folic acid deficiency • Hemolytic syndromes • Abnormalities in platelets and leukocytes Endocrine system and electrolyte balance • Gynecomastia and testicular atrophy • Alcoholic with chronic liver diseases ascites, edema and effusions. • Low potassium • Hypoglycemia, ketosis Fetal alcohol syndrome • Heavy drinking in first trimester – Retard body growth – Microcephaly – Poor coordination – Underdevelopment of mild facial region Immune system • Alteration in: – Chemotaxis of Granulocytes – Lymphocyte response to mitogens – T cell numbers – Natural killer cell activity – Level of tumor necrosis factor Increased risk of cancer • Increased risk for cancer of: – The mouth, pharynx, larynx, esophagus and liver – Breast • Alcoholic beverages may carry potential carcinogens Alcohol – Drug interactions • Pharmacokinetics – Chronic intake: • Alcohol induced increase drug metabolism • Increased level of Acetaminophen toxicity – Acute intake: • Drug metabolism inhibition • Pharmacodynamics – Additive central nervous system depression Management of acute alcohol intoxication • Degree of intoxication depends on: – The blood ethanol concentration – The rapidity of the rise of the alcohol level – The time during which the blood level maintained. Management of alcohol withdrawal syndrome • The major objective of drug therapy is prevention of: – Seizure – Delirium – Arrhythmias • Potassium, magnesium and phosphate balance • Thiamine therapy • Replacement therapy with long acting sedativehypnotic drugs Pharmacotherapy of alcoholism • Disulfiram – – – – slow elimination rate Inhibitor of other drug’s metabolism (phenytion, isoniazide) Compliance is low Some drugs have Disulfiram like effect : metronidazole, sulfonylurea hypoglycemic drugs • Naltrexone – Decreased rate of relapse – Reduced alcohol craving • Acamprosate – Weak NMDA receptor antagonist – GABAA Activator – Reduce replapse Pharmacology of other alcohols • Methanol • Ethylene Glycol • Drug therapy: ethanol, fomepizole