1. By S. Bohlooli, Ph.D.

2. 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.

3. 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.

4. Alcohol Dehydrogenase pathway Microsomal ethanol oxidizing system (MEOS). Acetaldehyde metabolism

6. 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.

7. 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.

8. 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.

9. BAC (mg/dL) 1 Clinical Effect 50–100Sedation, subjective "high," slower reaction times 100–200Impaired motor function, slurred speech, ataxia 200–300Emesis, stupor 300–400Coma > 500Respiratory depression, death

10. Enhances the action of GABA at GABA A Inhibits the action of Glutamate at NMDA Disruption of biological membranes through reduction in lipid viscosity (fluidization)

11. Depression of myocardial contractility (blood concentration > 100 mg/dl) It seems that acetaldehyde is responsible for ultra structural changes

12. Vasodilator Depression of vasomotor center Direct effect Relaxes Uterus

13. 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

14. 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

15. 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

16. Neurotoxicity Generalized symmetric peripheral nerve injury Gait disturbance and ataxia Wernicke-Korsakoff syndrome Thiamine deficiency Impaired visual acuity

17. 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

18. Mild anemia  alcohol related folic acid deficiency Hemolytic syndromes Abnormalities in platelets and leukocytes

19. Gynecomastia and testicular atrophy Alcoholic with chronic liver diseases  ascites, edema and effusions. Low potassium Hypoglycemia, ketosis

20. Heavy drinking in first trimester Retard body growth Microcephaly Poor coordination Underdevelopment of mild facial region

21. Alteration in: Chemotaxis of Granulocytes Lymphocyte response to mitogens T cell numbers Natural killer cell activity Level of tumor necrosis factor

22. Increased risk for cancer of: The mouth, pharynx, larynx, esophagus and liver Breast Alcoholic beverages may carry potential carcinogens

23. Pharmacokinetics Chronic intake: Alcohol induced increase drug metabolism Increased level of Acetaminophen toxicity Acute intake: Drug metabolism inhibition Pharmacodynamics Additive central nervous system depression

24. 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.

26. The major objective of drug therapy is prevention of: Seizure Delirium Arrhythmias Potassium, magnesium and phosphate balance Thiamine therapy Replacement therapy with long acting sedative- hypnotic drugs

27. Acamprosate has many molecular effects including actions on GABA, glutamate, serotonergic, noradrenergic, and dopaminergic receptors weak NMDA-receptor antagonist and a GABA A -receptor activator most common adverse effects are gastrointestinal 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

28. Ondansetron:5HT3 antagonist Topiramate: used for partial and generalized tonic-clonic seizures Rimonabant: a CB1 receptor antagonist

29. Methanol Ethylene Glycol Drug therapy: ethanol, fomepizole