Transcript Alcohol
بنام خدا Alcohols Alcohol (ethyl alcohol, ethanol) Important place in the history of humankind At least 8000 years Beer and wine Main staple of daily life until the 19th century Present-day role (widely consumed in many societies) As a socially acceptable form of recreation In low to moderate amounts (like other sedative hypnotic drugs) Relieves anxiety Promote a feeling of well-being (or even euphoria) The most commonly abused drug The cause of vast medical and societal costs USA Approximately 75% of adults drinks alcohol regularly About 8% of the general population (alcohol-use disorder) Alcohol (ethyl alcohol, ethanol) Suffering from alcohol abuse Use alcohol in dangerous situations Drinking and driving Combining alcohol with other medications Drinking alcohol in spite of adverse consequences Alcohol dependence Physical dependence Tolerance to alcohol Signs and symptoms upon withdrawal Inability to control their drinking Alcohol (ethyl alcohol, ethanol) The alcohol-use disorders Genetic as well as environmental determinants 30% of all people admitted to hospitals Have coexisting alcohol problems People with chronic alcoholism Generally have poorer outcomes Prenatal exposure to ethanol (each year) Tens of thousands of children with Morphologic and functional defects Pharmacokinetics (ethanol) Small water-soluble molecule Rapid absorption (GI) In the fasting state Peak blood concentrations (30 minutes) The presence of food in the stomach Delays absorption by slowing gastric emptying Pharmacokinetics (ethanol) Rapid distribution Women (higher peak concentration than men) Lower total body water content Differences in first-pass metabolism CNS (concentration of ethanol rises quickly) Receives a large proportion of total blood flow Readily crosses biologic membranes At levels of ethanol usually achieved in blood Rate of oxidation (zero-order kinetics) Metabolism of ethanol Cytochrome P450 2E1, 1A2, and 3A4 Alcohol oxidation generates an excess of (NADH) Contribute to metabolic disorders of chronic alcoholism Lactic acidosis and hypoglycemia (acute alcohol poisoning) Oxidation of alcohol to acetaldehyde by ADH, CYP2E1 and catalase Metabolism of ethanol Alcohol Dehydrogenase Pathway The primary pathway Catalyze the conversion of alcohol to acetaldehyde Located mainly in the liver Small amounts (brain and stomach) Considerable genetic variation in ADH enzymes Alter vulnerability to alcohol-abuse disorders Protective in several ethnic populations East Asians Women Lower levels of the gastric enzyme Sex related differences in blood concentrations Metabolism of ethanol Microsomal Ethanol-Oxidizing System (MEOS) Induction of activity (chronic alcohol consumption) Increases ethanol metabolism Increases clearance of other drugs Generation of toxic byproducts Toxins Free radicals H 2 O2 Metabolism of ethanol Acetaldehyde Metabolism (ALDH) Aldehyde dehydrogenase (liver) Oxidation of acetaldehyde (polymorphism, East Asian) Inhibited by disulfiram Ethanol consumption in the presence of disulfiram Acetaldehyde accumulation Facial flushing Nausea Vomiting Dizziness Headache Disulfiram-like reaction Metronidazole, trimethoprim Pharmacodynamics of Acute Ethanol Consumption Alcohol (CNS depressant) Alcohol’s effects on neurotransmission in the CNS Inhibit actions of Glutamate (excitatory) NMDA receptors affect cognitive function Learning and memory Enhance actions of GABA (inhibitory) Tolerant Vs nontolerant individuals Approximately 30–40% of all traffic accidents At least one person with blood alcohol (near or above the legal level of intoxication) Drunken driving Leading cause of death in young adults Blood alcohol concentration (BAC) and clinical effects in nontolerant individuals BAC (mg/dL) Clinical Effect 50–100 Sedation, slower reaction times 100–200 Impaired motor function, slurred speech, ataxia 200–300 Emesis, stupor 300–400 Coma > 400 Respiratory depression, death Pharmacodynamics of Acute Ethanol Consumption Heart Significant depression of myocardial contractility (blood concentration above 100 mg/dL) Smooth Muscle Vasodilator Depression of the vasomotor center Direct smooth muscle relaxation Acetaldehyde In severe cases Hypothermia Consequences of Chronic Alcohol Consumption Affects the function of several vital organs Liver Nervous system Gastrointestinal tract Cardiovascular system Immune system The tissue damage of chronic alcohol ingestion Direct effects of ethanol and acetaldehyde Metabolic effects Specific mechanisms of tissue damage Increased oxidative stress Depletion of glutathione Damage to mitochondria Growth factor dysregulation Potentiation of cytokine-induced injury Consequences of Chronic Alcohol Consumption Most common complication of alcohol abuse (liver) Severe liver disease (15–30%) Alcoholic fatty liver Alcoholic hepatitis Cirrhosis Liver failure (need for liver transplantation) The risk of developing liver disease Average amount of daily consumption Duration of alcohol abuse Hepatitis B or C virus Women (more susceptible) Chronic pancreatitis Gastritis Blood and protein loss Malnutrition Consequences of Chronic Alcohol Consumption Nervous System Tolerance (small increase in the lethal dose) Physical and psychological dependence Withdrawal syndrome Alcohol withdrawal symptoms Mild cases Hyperexcitability Severe cases Seizures Toxic psychosis Delirium tremens Up-regulation of the NMDA receptors Down-regulation of GABA mediated responses Alcohol affects local concentrations of Serotonin Opioids Dopamine Consequences of Chronic Alcohol Consumption Nervous System Neurotoxicity Generalized symmetric peripheral nerve injury Paresthesia of the hands and feet Degenerative changes Gait disturbances and ataxia Dementia Demyelinating disease (rarely) Wernicke-Korsakoff syndrome (thiamine deficiency) Paralysis of the external eye muscles Ataxia Coma and death Korsakoff’s psychosis Chronic disabling memory disorder Consequences of Chronic Alcohol Consumption Cardiovascular System Cardiomyopathy Heart failure Atrial and ventricular arrhythmias Alcohol withdrawal syndrome Arrhythmias Seizures Syncope Sudden death Hypertension Cause of reversible hypertension (most common ) Responsible for near 5% of cases of hypertension Independent of Obesity Salt intake Coffee drinking Cigarette smoking Consequences of Chronic Alcohol Consumption Coronary heart disease Moderate alcohol consumption actually prevents Coronary heart disease (CHD) Ischemic stroke Peripheral arterial disease Raising serum levels of HDL cholesterol Inhibition some of the inflammatory processes Increasing production of endogenous anticoagulant t-PA Presence of antioxidants Consequences of Chronic Alcohol Consumption Blood (bone marrow) Proliferation inhibition of all cellular elements Through metabolic and nutritional effects Alcohol-related folic acid deficiency Mild anemia (most common) Gastrointestinal bleeding Iron deficiency anemia Severe liver disease Hemolytic syndromes Consequences of Chronic Alcohol Consumption Endocrine System and Electrolyte Balance Derangement in steroid hormone balance Gynecomastia and testicular atrophy Chronic liver disease Disorders of fluid and electrolyte balance Ascites Edema Vomiting and diarrhea Alterations of whole body potassium Severe secondary aldosteronism Muscle weakness (worsened by diuretic therapy) Impaired hepatic gluconeogenesis Hypoglycemia Central Role of Pyruvate in Ethanol-induced Hypoglycemia Consequences of Chronic Alcohol Consumption Fetal Alcohol Syndrome Rapidly crosses the placenta Similar concentrations with maternal blood Chronic maternal alcohol abuse during pregnancy Teratogenic effects Intrauterine growth retardation Microcephaly Underdevelopment of midfacial region Minor joint anomalies Severe cases Congenital heart defects Mental retardation Unknown mechanisms Triggers apoptotic neurodegeneration Consequences of Chronic Alcohol Consumption Immune System Complex effects on the immune system Lung (Inhibition of immune function) Suppression of alveolar macrophages Inhibition of chemotaxis Reduction number and function of T cells Predisposes to infections Liver and pancreas (Hyperactive immune function) Enhanced function of Kupffer cells Increased cytokine production Consequences of Chronic Alcohol Consumption Increased Risk of Cancer Mouth Pharynx Larynx Esophagus Liver Small increase in the risk of Breast cancer in women Acetaldehyde Increase ROS Can damage DNA Chronic inflammation Growth promoting effects Systemic Effects Associated with Alcoholism Organ Effects Cardiovascular Cardiomyopathy, dysrhythmias Endocrine & metabolic Hypoglycemia, Hypokalemia, Hypothermia, Hyperuricemia, Metabolic acidosis, Malnutrition Gastrointestinal Cancer of mouth, pharynx, larynx, esophagus Nutritional stomatitis, Esophagitis, Gastritis, Diarrhea, Hepatitis, Peptic ulcer, Cirrhosis, Pancreatitis , Steatosis Genitourinary Hypogonadism, Impotence, Infertility Hematologic Coagulopathy, Anemia (Folate, B12, iron deficiency) Hemolysis , Leukopenia, Thrombocytopenia Neurologic Amnesia, Hallucination, Dementia, Korsakoff psychosis Wernicke encephalopathy, Myopathy, Polyneuropathy Psychiatric Loss of self-restraint, Depression, Mania, Suicide Respiratory Pneumonia, Respiratory depression, Respiratory acidosis Alcohol-Drug Interactions Xenobiotics Adverse Effects Antihistamines (H1) Additive sedative effect Aspirin Enhance antiplatelet effect Coprinus mushrooms Disulfiram-like effect Griseofulvin, Metronidazole Disulfiram-like effect Nitrofurantoin, Chloramphenicol Disulfiram-like effect TCA, Opioids, Phenothiazines Additive sedative effect Ranitidine, Cimetidine Increased ethanol concentration Oral hypoglycemics Potentiates hypoglycemic effect Vasodilators Potentiates vasodilator effect Warfarin Increased warfarin metabolism Isoniazid Increased incidence of hepatitis Methadone Increased methadone metabolism Disulfiram Nausea, vomiting, abdominal pain, flushing, diaphoresis, chest pain, headache, vertigo, palpitations Management of Acute Alcohol Intoxication Consumption in large quantities Acute sedative-hypnotic drug overdose Cardiovascular effects Vasodilation Tachycardia Gastrointestinal irritation Tolerance Is not absolute The most important goals in treatment Prevention of Severe respiratory depression Aspiration of vomitus Management of Acute Alcohol Intoxication Even with very high blood ethanol levels Probable survival In respiratory and cardiovascular support Fatal blood concentration Above 400 mg/dL Varying degrees of tolerance Correct electrolyte imbalances Potassium Treatment of hypoglycemia Glucose Protection against Wernicke-Korsakoff syndrome Thiamine Management of Alcohol Withdrawal Syndrome The major objective of drug therapy Prevention of Seizures Delirium Arrhythmias Restoration of Potassium, Magnesium, Phosphate Thiamine therapy Initiated in all cases Specific drug treatment for detoxification Benzodiazepines Chlordiazepoxide and diazepam Lorazepam and oxazepam Time course of events during the alcohol withdrawal syndrome Treatment of Alcoholism Adjunctive treatment of alcohol dependence Disulfiram (Tab 200, 250, 500 mg) Inhibiting aldehyde dehydrogenase One a day, 250 mg Increases in hepatic transaminases Naltrexone (Cap 25, 50 mg) Long-acting opioid antagonist Once a day in an oral dose of 50 mg Dose-dependent hepatotoxicity Acamprosate (Tab 333 mg) NMDA-receptor antagonist GABAA-receptor activator 666 mg 3 times daily The most common adverse effects Nausea, vomiting, diarrhea and rash Other Drugs Ondansetron, Topiramate, Baclofen Toxic Alcohols Pathophysiology All alcohols Cause inebriation (dose dependent) Higher molecular weight alcohols More intoxicating than LMW alcohols Isopropanol ≥ ethylene glycol > ethanol > methanol Effects are mediated through Increased GABAergic tone Directly Inhibition of presynaptic GABA Inhibition of NMDA receptors Toxic Alcohols Clinical Manifestations Metabolism of alcohols to toxic organic acids Metabolic acidosis with an elevated anion gap Hallmark of toxic alcohol poisoning Methanol poisoning Formic acid and lactic acid Ethylene glycol poisoning Glycolic acid Isopropanol Exception to formation of acid metabolite Metabolized to acetone Ketosis without acidosis Diagnostic of isopropanol poisoning Methanol End-Organ Manifestations Visual impairment Blurry Defects in color vision Snowfield vision Total blindness (severe poisoning) Physical examination Hyperemia Pallor of optic disc Papilledema CNS toxicity Necrosis Intracranial hemorrhage Renal failure and Pancreatitis Ethylene glycol & Isopropyl alcohol End-Organ Manifestations The most prominent end organ effect Nephrotoxicity Oxalic acid metabolite forms a complex with calcium Precipitate as calcium oxalate in renal tubules Acute renal failure Systemic hypocalcemia Prolongation of QT interval Ventricular dysrhythmias Cerebral edema and intracranial hemorrhage Isopropyl alcohol intoxication Hemorrhagic gastritis Major Pathway of Methanol & Isopropanol Metabolism Pathways of Ethylene Glycol Metabolism پایان