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 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)

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 Alcohol oxidation generates an excess of (NADH)
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)

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 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

14. Blood alcohol concentration (BAC) and
clinical effects in nontolerant individuals
Clinical Effect
BAC (mg/dL)
Sedation, slower reaction times
50–100
Impaired motor function, slurred speech, ataxia
100–200
Emesis, stupor
200–300
Coma
300–400
Respiratory depression, death
> 400

15. 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

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 NMDA receptors  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 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

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
Organ
Cardiomyopathy, dysrhythmias
Cardiovascular 
Hypoglycemia, Hypokalemia, Hypothermia, Hyperuricemia,  Metabolic acidosis, Malnutrition
Endocrine & metabolic 
Cancer of mouth, pharynx, larynx, esophagus
Nutritional stomatitis, Esophagitis, Gastritis, Diarrhea, Hepatitis, Peptic ulcer, Cirrhosis, Pancreatitis , Steatosis
Gastrointestinal 
Hypogonadism, Impotence, Infertility
Genitourinary 
Coagulopathy, Anemia (Folate, B12, iron deficiency) Hemolysis , Leukopenia, Thrombocytopenia
Hematologic 
Amnesia, Hallucination, Dementia, Korsakoff psychosis
Wernicke encephalopathy, Myopathy, Polyneuropathy
Neurologic 
Loss of self-restraint, Depression, Mania, Suicide
Psychiatric 
Pneumonia, Respiratory depression, Respiratory acidosis
Respiratory 

29. Alcohol-Drug Interactions
Adverse Effects
Xenobiotics
Additive sedative effect
Antihistamines (H1)
Enhance antiplatelet effect
Aspirin
Disulfiram-like effect
Coprinus mushrooms 
Griseofulvin, Metronidazole
Nitrofurantoin, Chloramphenicol
TCA, Opioids, Phenothiazines
Increased ethanol concentration
Ranitidine, Cimetidine
Potentiates hypoglycemic effect
Oral hypoglycemics
Potentiates vasodilator effect
Vasodilators
Increased warfarin metabolism
Warfarin
Increased incidence of hepatitis
Isoniazid
Increased methadone metabolism
Methadone
Nausea, vomiting, abdominal pain, flushing, diaphoresis, chest pain, headache, vertigo, palpitations
Disulfiram

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 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

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. Clinical Manifestations
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. End-Organ Manifestations
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