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Alcohol (Ethyl Alcohol, Ethanol) - Effects, Abuse, and Consequences

This article provides information on the history, effects, abuse, and consequences of alcohol (ethyl alcohol, ethanol) consumption. It discusses the prevalence of alcohol use disorder, signs and symptoms of alcohol dependence, pharmacokinetics and metabolism of ethanol, and the impact of chronic alcohol consumption on vital organs.

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Alcohol (Ethyl Alcohol, Ethanol) - Effects, Abuse, and Consequences

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  1. بنام خدا

  2. Alcohols

  3. 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 drugThe cause of vast medical and societal costsUSA Approximately 75% of adults drinks alcohol regularly About 8% of the general population (alcohol-use disorder)

  4. 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

  5. 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

  6. 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

  7. 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)

  8. Metabolism of ethanol Cytochrome P4502E1, 1A2, and 3A4 Alcohol oxidation generates an excess of (NADH) Contribute to metabolic disorders of chronic alcoholism Lactic acidosis and hypoglycemia (acute alcohol poisoning)

  9. Oxidation of alcohol to acetaldehyde by ADH, CYP2E1 and catalase

  10. 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

  11. 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 H2O2

  12. 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

  13. 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 memoryEnhance 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

  14. Blood alcohol concentration (BAC) and clinical effects in nontolerant individuals

  15. Pharmacodynamics of Acute Ethanol Consumption HeartSignificant depression of myocardial contractility (blood concentration above 100 mg/dL) Smooth MuscleVasodilator Depression of the vasomotor center Direct smooth muscle relaxation Acetaldehyde In severe cases Hypothermia

  16. 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

  17. 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

  18. 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 NMDAreceptors Down-regulation of GABA mediated responses  Alcohol affects local concentrations of Serotonin  Opioids  Dopamine

  19. 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

  20. 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

  21. 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

  22. Consequences of Chronic Alcohol Consumption  Blood (bone marrow) Proliferation inhibition of all cellular elementsThrough metabolic and nutritional effects  Alcohol-related folic acid deficiency Mild anemia (most common)  Gastrointestinal bleeding Iron deficiency anemia  Severe liver disease Hemolytic syndromes

  23. 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

  24. Central Role of Pyruvate in Ethanol-induced Hypoglycemia

  25. 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

  26. 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

  27. 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

  28. Systemic Effects Associated with Alcoholism

  29. Alcohol-Drug Interactions

  30. 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

  31. 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

  32. 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

  33. Time course of events during the alcohol withdrawal syndrome

  34. 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 transaminasesNaltrexone (Cap 25, 50 mg) Long-acting opioid antagonist Once a day in an oral dose of 50 mg Dose-dependent hepatotoxicityAcamprosate (Tab 333 mg) NMDA-receptor antagonist GABAA-receptor activator 666 mg 3 times dailyThe most common adverse effects Nausea, vomiting, diarrhea and rash Other Drugs Ondansetron, Topiramate, Baclofen

  35. 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

  36. 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

  37. 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

  38. 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

  39. Major Pathway of Methanol & Isopropanol Metabolism

  40. Pathways of Ethylene Glycol Metabolism

  41. پایان

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