Alcohols

1. Alcohols

2. Alcoholic beverages • Malted liquors : obtained by fermentation (conversion of carbohydrates to alcohols) of germinating cereals; are undistilled ---- alcohol content is low (3-6%) e.g beers. • Wines : produced by fermentation of natural sugars as present in grapes and others fruits. These are also undistilled Like : light wines (9-12%); fortified wines (16-22%) distilled beverages are added from outside; effervescent wine (12-16%) bottle before fermentation is complete. ----- wines are called dry when all sugar present has been fermented and sweet when some sugar is left. C. Spirits : distilled after fermentation; e.g. Rum, Gin, Whiskey, Brandy, Vodka etc.(40- 55%). Others : absolute alcohol (ethanol – 99%); rectified spirit (ethyl alcohol – 90%) and proof spirit (50 – 57%)

3. Pharmacokinetics of ethanol : • small water-soluble molecule that is absorbed rapidly from the gastrointestinal tract. • fasting state, peak blood alcohol concentrations are reached within 30 minutes. • presence of food : delays absorption by slowing gastric emptying. • Distribution is rapid • volume of distribution for ethanol approximates total body water (0.5–0.7 L/kg) • women have a higher peak concentration than men (lower total body water content). • In central nervous system, the concentration of ethanol rises quickly (large proportion of blood flow and ethanol readily crosses biologic membranes). • Metabolism : 90% by liver, rest excreted through the lungs and in the urine (7- 10 g/hour). • the rate of oxidation follows zero-order kinetics. • Breath alcohol tests

4. Two major pathways of alcohol metabolism to acetaldehyde 1. Alcohol Dehydrogenase Pathway (ADH): • Found mainly in the liver, but also in the brain and stomach. • significant amount of ethanol metabolism by gastric ADH occurs in the stomach in men, but a smaller amount occurs in women, who appear to have lower levels of the gastric enzyme. • During conversion, hydrogen ion is transferred from alcohol to the cofactor nicotinamide adenine dinucleotide (NAD+) to form NADH. • net result, alcohol oxidation generates an excess of reducing equivalents in the liver, chiefly as NADH. The excess NADH production appears to underlie a number of metabolic disorders that accompany chronic alcoholism.

5. Metabolic disorder due to high NADH • Proper functioning of the cell, the ratio of NAD to NADH must be controlled. Alcohol metabolism generates excess amounts of NADH. Altered NAD/NADH ratio lead to several metabolic disorders: • Fatty liver is the earliest stage and the most common form of alcohol-induced liver disease (reduces the breakdown of fats in the liver). • Metabolic acidosis (formation of abnormally high levels of lactic acid) • Gout (reduce the capacity of the kidney to excrete uric acid).

7. Microsomal Ethanol Oxidizing System (MEOS) • uses NADPH as a cofactor in the metabolism of ethanol, blood concentrations below 100 mg/dL, contributes little to the metabolism of ethanol. • concentration of ethanol increases above 100 mg/dL, there is increased contribution from the MEOS system (the alcohol dehydrogenase system becomes saturated owing to depletion of the required cofactor, NAD+).

8. Acetaldehyde Metabolism • acetaldehyde ----- oxidized in the liver, by mitochondrial NAD-dependent aldehyde dehydrogenase -----CO2 and water.

9. Aldehyde dehydrogenase inhibitors • inhibited by disulfiram • When ethanol is consumed in the presence of disulfiram, acetaldehyde accumulates and causes an unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache. • Other drugs:- metronidazole, trimethoprim inhibit aldehydedehydrogenase and can cause a disulfiram-like reaction if combined with ethanol. • Genetic deficiency of ALDH : disulfiram-like reaction and if less activity, protect against alcoholism.

10. Blood Alcohol Concentration (BAC) and Clinical Effects in Nontolerant Individuals.

11. Pharmacodynamics of Acute Ethanol Consumption • Central Nervous System : - sedation and relief of anxiety • at higher concentrations, slurred speech, ataxia, impaired judgment, and disinhibited behavior, a condition usually called intoxication or drunkenness • Chronic drinkers ---- high concentration (300 – 400mg/dl) ---- CNS effects. • No specific receptor for ethanol. • affect a large number of membrane proteins that participate in signaling pathways, including neurotransmitter receptors (GABA and glutamate, NMDA) for amines, amino acids, and opioids; enzymes such as Na+/K+ ATPase, adenylylcyclase, phosphoinositide-specific phospholipase C; and ion channels such as those for Ca2+. • Commonly glutamate and GABA receptor • "Blackouts"—periods of memory loss that occur with high levels of alcohol—may result from inhibition of NMDA receptor activation.

12. Heart • blood concentration above 100 mg/dL : Significant depression of myocardial contractility • Smooth Muscle : vasodilatation (due to central nervous system effects ;depression of the vasomotor center) and direct smooth muscle relaxation caused by its metabolite, acetaldehyde) • Severe overdose, hypothermia—caused by vasodilation—may be marked in cold environments. • Ethanol also relaxes the uterus and was used intravenously for the suppression of premature labor.

13. Consequences of Chronic Alcohol Consumption Liver :- • 15-30% severe liver disease • Fatty liver (reversible condition) ----- alcoholic hepatitis ----- cirrhosis --- liver failure. Gastrointestinal Tract :- • Chronic pancreatitis and pancreatic stones • Gastritis • Anemia and protein malnutrition (blood and plasma protein loss) • Small intestine : diarrhea, weight loss and multi vitamin deficiency • Malabsorption of water soluble vitamins.

14. Nervous System 1. Tolerance and Physical Dependence : consumption of alcohol in high doses over a long period results in tolerance and in physical and psychologic dependence • Alcohol withdrawal symptoms : hyperexcitability in mild cases and seizures, toxic psychosis, and delirium tremens in severe ones. • Psychologic dependence : a compulsive desire to experience the rewarding effects of alcohol and, for current drinkers, a desire to avoid the negative consequences of withdrawal • Tolerance may result from ethanol-induced up-regulation of a pathway in response to the continuous presence of ethanol. • Dependence may result from overactivity of that same pathway once the ethanol effect disappearing, and before the system has time to return to a normal ethanol-free state.

15. 2. Neurotoxicity • most common neurologic abnormality :- generalized symmetric peripheral nerve injury that begins with distal paresthesias of the hands and feet. • Gait disturbance (due to degenerative change in CNS) and dementia. • Impair visual acuity. • Wernicke – Korsakoff syndrome (due to thiamin deficiency): characterized by paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma and death.

16. 3 .Cardiovascular system : 1. cardiomyopathy and heart failure : Heavy alcohol consumption of long duration :dilated cardiomyopathy with ventricular hypertrophy and fibrosis. • number of changes in heart cells : membrane disruption, depressed function of mitochondria and sarcoplasmic reticulum, intracellular accumulation of phospholipids and fatty acids, and upregulation of voltage-dependent calcium channels. 2. arrhythmias : Heavy drinking causes both atrial and ventricular arrhythmias (release of catecholamines).

17. Cont…… 3. hypertension: 5% of cases (most common cause of reversible HTN). Independent of obesity, salt intake, coffee drinking, or cigarette smoking. 4. coronary heart disease : moderate alcohol consumption actually prevents CHD and even reduces mortality because ethanol's raise serum levels of high-density lipoprotein (HDL) cholesterol, the form of cholesterol that appears to protect against atherosclerosis, its ability to inhibit some of the inflammatory processes that underlie atherosclerosis.

18. Blood • indirectly affects hematopoiesis through metabolic and nutritional effects • directly inhibit the proliferation of all cellular elements in bone marrow. • most common hematologic disorder : in chronic drinkers is mild anemia (folic acid deficiency). • Iron deficiency anemia (gastrointestinal bleeding). • several hemolytic syndromes (hyperlipidemia and severe liver disease).

19. Endocrine System and Electrolyte Balance • gynecomastia and testicular atrophy (steroid hormone imbalance). • Alcoholics with chronic liver disease; ascites, edema, and effusions (due to fluid and electrolyte imbalance decreased protein synthesis and portal hypertension) • K+ imbalance : vomiting and diarrhea • Hypoglycemia (impaired hepatic gluconeogenesis)

20. Fetal Alcohol Syndrome • teratogenic effects, mental retardation and congenital malformation Fetal alcohol syndrome include: (1) intrauterine growth retardation, (2) microcephaly, (3) poor coordination, (4) underdevelopment of midfacial region (appearing as a flattened face), and (5) minor joint anomalies ---- severe cases : congenital heart disease

21. Immune function • Inhibited in the lung (due to suppression of the function of alveolar macrophages, inhibition of chemotaxis of granulocytes, and reduced number and function of T) . • Enhanced in liver, (enhanced function of Kupffer cells; leading to collagen synthesis and fibrosis due to carcinogenic agents TNFα --- cirrhosis, or hepatic failure) and pancreas .

22. Increased Risk of Cancer • cancer of the mouth, pharynx, larynx, esophagus, and liver. • Primary metabolite, acetaldehyde, damage DNA produced by increased cytochrome P450 activity.

23. Alcohol-Drug Interactions • Acetaminophen : hepatotoxic due to increased P450-mediated conversion of acetaminophen to reactive hepatotoxic metabolites. • acute alcohol inhibit metabolism: Phenothiazines, tricyclic antidepressants, and sedativehypnotic drugs due to decreased enzyme activity or decreased liver blood flow.

24. Management of Acute Alcohol Intoxication • most important goals : to prevent severe respiratory depression and aspiration of vomitus. • For hypoglycemia and ketosis by administration of glucose. • Thiamine (Wernicke-Korsakoff syndrome). • Fluid and electrolyte (dehydration and vomiting) • Important is recognition of decreased serum concentrations of phosphate, which may be aggravated by glucose administration. • Low phosphate stores may contribute to poor wound healing, neurologic deficits, and an increased risk of infection.

25. Management of Alcohol Withdrawal Syndrome • mildest form (tremor, anxiety, and insomnia occurs 6–8 hours after alcohol is stopped). • more severe withdrawal (visual hallucinations, total disorientation, and marked abnormalities of vital signs occur). • Alcohol withdrawal is one of the most common causes of seizures in adults. • major objective of drug therapy in the alcohol withdrawal period is prevention of seizures, delirium, and arrhythmias.

26. Cont…… • Potassium, magnesium, and phosphate balance should be restored • Thiamine therapy is initiated in all cases • Specific drug treatment for detoxification in severe cases : substituting a long-acting sedative-hypnotic drug for alcohol and then gradually reducing ("tapering") the dose of the long-acting drug. • Long-acting benzodiazepines (chlordiazepoxide, clorazepate, and diazepam) have the advantage of requiring less frequent dosing because their pharmacologically active metabolites are eliminated slowly

27. Cont…. • disadvantage of the long-acting drugs : their pharmacologically active metabolites may accumulate, especially in patients with compromised liver function. Benzodiazepines administration : • orally in mild or moderate cases, and • parenterally in more severe withdrawal reactions. • Phenothiazine contraindicated for alcohol withdrawal due to its serious adverse effects (eg, increasing seizures)

28. Why short acting benzodiazepines are useful in alcoholic patients with liver disease ? • Short-acting drugs (lorazepam and oxazepam): rapidly converted to inactive water-soluble metabolites that will not accumulate.

29. Cont….. • After treatment, sedative-hypnotic medications must be tapered slowly over several weeks. • Complete detoxification is not achieved with just a few days of alcohol abstinence. Several months may be required for restoration of normal nervous system function, especially sleep.

30. Pharmacotherapy of Alcoholism • Treatment with counseling and drugs can help decrease the rate of relapse for alcoholic patients. • Drugs : naltrexone, disulfiram and acamprosate

31. Naltrexone • orally active opioid receptor antagonist that blocks the effects at mu opiods receptors. • Injection of small amounts of opioids was followed by an increase in alcohol drinking, whereas administration of opioid antagonists inhibited self-administration of alcohol. • It reduce craving for alcohol and to reduce the rate of relapse to either drinking or alcohol dependence. • Dose : 50 gm x od

32. Combination of naltrexone and disulfiram • Avoided because both are potential hepatotoxins. • Administration of naltrexone to patients who are physically dependent upon opioids will precipitate an acute withdrawal syndrome so patients must be opioid free before initiating naltrexone therapy

33. Disulfiram • causes extreme discomfort to patients who drink alcoholic beverages • nondrinkers has little effect; however, flushing, throbbing headache, nausea, vomiting, sweating, hypotension, and confusion occur within a few minutes after drinking alcohol and last for 30 minutes in mild cases, or several hours in severe ones. • acts by inhibiting aldehyde dehydrogenase • rapidly and completely absorbed from the gastrointestinal tract • elimination rate is slow, so that its action may persist for several days after the last dose.

34. Cont… • Several other drugs, eg, metronidazole, certain cephalosporins, sulfonylurea hypoglycemic drugs, and chloral hydrate, have disulfiram-like effects on ethanol metabolism. • Patients should be warned to avoid drinking ethanol while taking these drugs and for several days after they discontinue them

35. Clinical uses of ethanol • As antiseptics • Rubbed into the skin to prevent bedsores • To treat methanol poisoning • Reflex stimulation in fainting/hysteria : 1 drop in nose.

36. Methanol (methyl alcohol, wood alcohol) • absorbed through the skin or from the respiratory or gastrointestinal tract and is then distributed in body water. • Elimination : by oxidation to formaldehyde, formic acid, and CO2: --- methanol toxicity is probably due to folate-dependent production of formate and not to methanol itself or to formaldehyde, the intermediate metabolite

37. Cont… • most characteristic symptom in methanol poisoning is a visual disturbance, called "like being in a snowstorm’’. • severe cases, the odor of formaldehyde present on the breath or in the urine • bradycardia, prolonged coma, seizures, and resistant acidosis all imply a poor prognosis • death in fatal cases is sudden cessation of respiration. • concentrations in excess of 50 mg/dL (an absolute indication for hemodialysis and ethanol treatment), • Formate blood levels (indication of clinical pathology). • Acidosis (due to production of formic acid)

38. Treatment for methanol poisoning Three specific modalities of treatment for severe methanol poisoning: • suppression of metabolism by alcohol dehydrogenase to toxic products, • dialysis to enhance removal of methanol and its toxic products, and • alkalinization to counteract metabolic acidosis.

39. Cont… • Keep the patient in a quiet, dark room; and protect the eyes from light. • Gastric lavage if brought within 2 hours of ingestion • Ethanol (higher affinity than methanol for ADH) 100 mg/dl through NG tube; loading dose 0.7 ml/kg is followed by 0.15 ml/kg/hour drip • Often used i.v for methanol poisoning • Fomepizole : inhibitor of alcohol dehydrogenase • Loading dose : 15 mg/kg i.v followed by 10 mg/kg every 12 hrs till serum levels of methanol falls 20 mg/dl

40. Cont… • Hemodialysis rapidly eliminates both methanol and formate. • Sodium bicarbonate (acidosis) • Folate therapy (50 mg inj.) every 6 hrs – decrease formate level by enhancing its oxidation.