1. Assistant Professor Dr. Shamil AL-Noaimy MBchB, MSc, PhD

2. Objectives: 1. To study the main types of alcohols 2.To take each type in details 3. To have an idea about the clinical importance and systemic organ effects of each type. 4. To study the effect of the human body on the metabolism of alcohols. 5. To study the antidote of alcohols.

3. Alcohol, primarily in the form of ethyl alcohol (ethanol), the most commonly abused drug in the world, consumed. Like other sedative-hypnotic drugs, alcohol in low to moderate amounts relieves anxiety and fosters a feeling of well-being or even euphoria.

5. Pharmacokinetics Ethanol is a small water-soluble molecule that is absorbed rapidly from the gastrointestinal tract. After ingestion of alcohol in the fasting state, peak blood alcohol concentrations are reached within 30 minutes.

6. For an equivalent oral dose of alcohol, women have a higher peak concentration than men, in part because women have a lower total body water content. Over 90% of alcohol consumed is oxidized in the liver; much of the remainder is excreted through the lungs and in the urine.

7. At levels of ethanol usually achieved in blood, the rate of oxidation follows zero-order kinetics, i.e., it is independent of time and concentration of the drug. The typical adult can metabolize 7–10 g (150–220 mmol) of alcohol per hour. Two major pathways of alcohol metabolism to acetaldehyde have been identified. Acetaldehyde is then oxidized by a third metabolic process.

9. The primary pathway for alcohol metabolism involves alcohol dehydrogenase (ADH), a cytosolic enzyme that catalyzes the conversion of alcohol to acetaldehyde This enzyme is located mainly in the liver, but it is also found in other organs such as brain and stomach.

10. A 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. This difference in gastric metabolism of alcohol in women probably contributes to the sex- related differences in blood alcohol concentrations noted above.

11. This enzyme system uses NADPH as a cofactor in the metabolism of ethanol. At blood concentrations below 100 mg/dL (22 mmol/L), the MEOS system contributes little to the metabolism of ethanol.

12. However, when large amounts of ethanol are consumed, the alcohol dehydrogenase system becomes saturated owing to depletion of the required cofactor, NAD+. As the concentration of ethanol increases above 100 mg/dL, there is increased contribution from the MEOS system, which does not rely upon NAD+ as a cofactor.

13. Much of the acetaldehyde formed from alcohol appears to be oxidized in the liver in a reaction catalyzed by mitochondrial NAD-dependent aldehyde dehydrogenase. The product of this reaction is acetate which can be further metabolized to CO2 and water.

14. Some people, primarily of Asian descent, have a genetic deficiency in the activity of the mitochondrial form of aldehyde dehydrogenase. When these individuals drink alcohol, they develop high blood acetaldehyde concentrations and experience a flushing reaction similar to that seen with the combination of disulfiram and ethanol.

15. Central Nervous System: The central nervous system is markedly affected by acute alcohol consumption. Alcohol causes sedation and relief of anxiety and, at higher concentrations, slurred speech, ataxia, impaired judgment, and disinhibited behavior, a condition usually called intoxication or drunkenness

16. These central nervous system effects are most marked as the blood level is rising, because acute tolerance to the effects of alcohol occurs after a few hours of drinking. For chronic drinkers who are tolerant to the effects of alcohol, much higher concentrations are needed to elicit these central nervous system effects.

21. Much attention has focused on alcohol's effects upon neurotransmission by glutamate and GABA. Acute ethanol exposure enhances the action of GABA at GABAA receptors. Ethanol also inhibits the ability of glutamate to open the cation channel associated with the N- methyl-D-aspartate (NMDA) subtype of glutamate receptors.

22. Significant depression of myocardial contractility has been observed in individuals who acutely consume moderate amounts of alcohol, i.e., at a blood concentration above 100 mg/dL. Acetaldehyde is implicated as a cause of cardiac dysfunction by altering myocardial stores of catecholamines.

23. Ethanol is a vasodilator, probably as a result of both central nervous system effects (depression of the vasomotor center) and direct smooth muscle relaxation caused by its metabolite, acetaldehyde.

24. Mechanisms implicated in tissue damage include: 1.increased oxidative stress 2.depletion of glutathione, 3.damage to mitochondria, 4.growth factor dysregulation, 5.potentiation of cytokine induced injury.

25. Liver disease is the most common medical complication of alcohol abuse. Clinically significant alcoholic liver disease may be insidious in onset and progress without evidence of overt nutritional abnormalities. Alcoholic fatty liver, a reversible condition, may progress to alcoholic hepatitis and finally to cirrhosis and liver failure.

26. Women appear to be more susceptible to alcohol hepatotoxicity than men. Another factor that increases the risk of severe liver disease is concurrent infection with hepatitis B or C virus.

27. Chronic alcohol ingestion is by far the most common cause of chronic pancreatitis Chronic alcoholics are prone to develop gastritis and have increased susceptibility to blood and plasma protein loss during drinking, which may contribute to anemia and protein malnutrition

28. Consumption of large amounts of alcohol over extended periods (usually years) often leads to neurologic deficits.

29. Wernicke-Korsakoff syndrome is a relatively uncommon but important entity characterized by paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma and death. It is associated with thiamin deficiency but is rarely seen in the absence of alcoholism.

30. Heavy alcohol consumption of long duration is associated with a dilated cardiomyopathy with ventricular hypertrophy and fibrosis. Heavy drinking are associated with both atrial and ventricular arrhythmias. Alcohol is estimated to be responsible for approximately 5% of cases of hypertension.

31. The most common hematologic disorder seen in chronic drinkers is mild anemia resulting from alcohol-related folic acid deficiency. Iron deficiency anemia may result from gastrointestinal bleeding.

32. Gynecomastia and testicular atrophy in alcoholics with or without cirrhosis suggest a derangement in steroid hormone balance. Disorders of fluid and electrolyte balance, including ascites, edema, and effusions. Due to decreased protein synthesis and portal hypertension. Some alcoholic patients develop hypoglycemia, as a result of impaired hepatic gluconeogenesis.

33. Chronic alcohol use increases the risk for cancer of the mouth, pharynx, larynx, esophagus, and liver. Evidence also points to a small increase in the risk of breast cancer in women.

34. The test result is usually more reliable than with breath, but the requirements are considerably more substantial. Most blood is drawn after the client has refused to offer a breath sample BAC Kit: A sealed kit containing the equipment and documentation necessary for the collection of a blood sample for forensic purposes

35. 1. The blood should be timely taken 2. from a particular identified body 3. by an authorized licensed physician medical technologist, or registered nurse designated by a licensed physician 4. the instruments used were sterile, 5. the blood taken was properly preserved or kept 6. and labeled.

36. 7. if transported or sent, the method and procedures used therein 8. the method and procedures used in conducting the test 9.the identity of the person or persons under whose supervision the tests were conducted is established 10.The type of swab used to disinfect the draw site is also an important issue. A non-alcohol swab must be used

37. The authority lab uses a process known as gas chromatography. Gas chromatography is essentially a function of time and temperature.

38. The sample is first mixed with one of two internal standards, either 1-propanol or t-butanol. Each sample is then tested separately by two different chromatograms, and the lab reports the lower of the two results. Once the sample is diluted, it is then heated to produce a vapor. The vapor is then passed through a glass column. The vapor is then timed and measured as it passes out of (elutes out) the other end of the column..

39. The peak measurement or curve on the chromatograph is then compared with a calibration curve, and the amount of blood alcohol is determined by reading where this sample peak passes over or meets the calibration curve

44. Non tolerant individuals who consume alcohol in large quantities develop typical effects of acute sedative-hypnotic drug overdose along with the cardiovascular effects (vasodilatation, tachycardia )and gastrointestinal irritation. Since tolerance is not absolute, even chronic alcoholics may become severely intoxicated. The average blood alcohol concentration in fatal cases is above 400 mg/dL; however, the lethal dose of alcohol varies because of varying degrees of tolerance.

45. The degree of intoxication depends upon three factors: 1.the blood ethanol concentration, 2.the rapidity of the rise of the alcohol level, 3.the time during which the blood level is maintained. The most important goals in the treatment of acute alcohol intoxication are to prevent severe respiratory depression and aspiration of vomitus.

46. Metabolic alterations may require treatment of hypoglycemia and ketosis by administration of glucose. Thiamine is given to protect against the Wernicke-Korsakoff syndrome. Alcoholic patients who are dehydrated and vomiting should also receive electrolyte solutions. If vomiting is severe, large amounts of potassium may be required as long as renal function is normal. Especially important is recognition of decreased serum concentrations of phosphate, which may be aggravated by glucose administration.

47. The major objective of drug therapy in the alcohol withdrawal period is prevention of seizures, delirium, and arrhythmias. Potassium, magnesium, and phosphate balance should be restored as rapidly as is consistent with renal function. Thiamine therapy is initiated in all cases.

48. Specific drug treatment for detoxification in severe cases involves two basic principles: substituting a long-acting sedative-hypnotic drug for alcohol and then gradually reducing ("tapering") the dose of the long-acting drug. Because of their wide margin of safety, benzodiazepines are preferred for treatment of alcohol withdrawal syndrome. After the alcohol withdrawal syndrome has been treated acutely, sedative-hypnotic medications must be tapered slowly over several weeks.

49. The first approach to pharmacotherapy was to deter drinking with drugs that cause anoxious reaction to alcohol by blocking its metabolism. Disulfiram an inhibitor of aldehyde dehydrogenase, is the drug most commonly used for this purpose More recently, research has focused on identifying drugs that alter brain responses to alcohol. Naltrexone, an inhibitor of opioid receptors, was the first drug of this type.

50. Disulfiram given by itself to nondrinkers has little effect; however, flushing, throbbing headache, nausea, vomiting, sweating, hypotension, and confusion occur within a few minutes after drinking alcohol. The effect may last 30 minutes in mild cases or several hours in severe ones. The alcohol is metabolized as usual, but acetaldehyde accumulates.

51. Management with disulfiram should be initiated only when the patient has been free of alcohol for at least 24 hours. The duration of disulfiram treatment should be individualized and determined by the patient's responsiveness and clinical improvement. The usual oral dose is 250 mg daily taken at bedtime.

52. Naltrexone is an orally available opioid receptor antagonist that blocks the effects of exogenous and, presumably, endogenous opioids Studies in experimental animals first suggested a link between alcohol consumption and opioids. Injection of small amounts of opioids was followed by an increase in alcohol drinking, whereas administration of opioid antagonists inhibited self- administration of alcohol.

53. Naltrexone is taken once a day in a dose of 50 mg for treatment of alcoholism. The combination of naltrexone plus disulfiram should be avoided since both drugs are potential hepatotoxins

54. Other Drugs: Preliminary evidence suggests that Topiramate, a drug used for partial and generalized tonic-clonic seizures may be effective in reducing craving in chronic alcoholics