Download The Alcohols

The Alcohols
By
S. Bohlooli, Ph.D
History
• The alcohol had important place in
humankind for at least 8000 years
• The diluted alcoholic beverages were
preferred over water, In western countries
• Today, 75% of US adult population drinks
alcohol regularly
• About 10% of the general population in the
US are alcohol abuser.
Basic Pharmacology of
Ethanol
• Pharmacokinetics
– Ethanol is a small water soluble molecule
– Presence of food delays absorption
– Vd approximates total body water
– Over 90% of alcohol consumed is oxidized in
the liver.
– Rate of oxidation follows zero order kinetics.
Metabolism of ethanol
• Alcohol Dehydrogenase pathway
• Microsomal ethanol oxidizing system
(MEOS).
• Acetaldehyde metabolism
Alcohol Dehydrogenase (ADH) pathway
Ethanol
CH3CH2OH
NADPH + O2
NAD+
Alcohol Dehydrogenase
(ADH)
Θ
Fomepizole
MEOS
NADH
NAD+
Acetaldehyde
CH3CHO
Aldehyde
Dehydrogenase
NADH
Acetate
CH3COO-
NADP+
Disulfiram
Θ
Microsomal Ethanol Oxidizing
System (MEOS)
• At concentration below 100 mg/dl the
MEOS has little contribution to the ethanol
metabolism.
• During chronic consumption there is an
induction in enzyme activity
• Enzyme inducing drugs like phenobarbital
may increase activity of MEOS.
Acetaldehyde metabolism
• It seems several enzymes are responsible for
acetaldehyde metabolism
• The primary enzyme system is aldehyde
dehydrogenase
• The product is acetate
• Oxidation of acetaldehyde is inhibited by
disulfiram.
• Co-cosumption of ethanol and disulfiram leads
to acetaldeyde accumulation.
• Facial flushing, nausea, dizziness and headache
are the main unpleasant reaction.
Pharmacodynamics of acute
ethanol consumption
• Central nervous system
– Sedation, relief of anxiety,
– Slurred speech, impaired judgment,
disinhibited behavior
– Condition called “intoxication” or
“drunkenness”
– There is too different between tolerant and
nontolerant individuals
– At higher blood concentration:
• Coma, respiratory depression and death.
Ethanol Mechanism of action
• Enhances the action of GABA at GABAA
• Inhibits the action of Glutamate at NMDA
• Disruption of biological membranes
through reduction in lipid viscosity
(fluidization)
Effect on Heart
• Depression of myocardial contractility
(blood concentration > 100 mg/dl)
• It seems that acetaldehyde is responsible
for ultra structural changes
Effect on Smooth Muscle
• Vasodilator
– Depression of vasomotor center
– Direct effect
• Relaxes Uterus
Consequences of Chronic Alcohol
Consumption
• Liver and gastrointestinal tract
• Nervous system
– Tolerance and physical dependence
– Neurotoxicity
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Cardiovascular system
Blood
Endocrine system and electrolyte balance
Fetal alcohol syndrome
Immune system
Increased risk of cancer
Liver and gastrointestinal tract
• About 15-30% chronic heavy drinkers develop sever liver
disease:
– Alcoholic fatty liver
– Alcoholic hepatitis
– Cirrhosis and liver failure
• Increased ratio of NADH/NAD+reduced
gluconeogenesis, hypoglycemiaa nd ketoacidosis
• Excess of Acetaldehyde (very reactive compound)
• Decreased level of Glutathione
• Hormonal factors
• Increased gastric and pancreatic secretion.
• Altered mucosal barriers
• Malabsorption of water soluble vitamines
Nervous system
• Tolerance and physical dependence
– Metabolic tolerant
– Neurotransmitters, receptors, ion channels,
enzymes that participate in signal
transduction pathway
– Acute increase in local concentration of
serotonin, opioids, and dopamine
– Withdrawal syndrome
• Hyperexcitability, convulsion, toxic psychosis
– Dose, rate and duration of alcohol consumption
Nervous system
• Neurotoxicity
– Generalized symmetric peripheral nerve injury
– Gait disturbance and ataxia
– Wernicke-Korsakoff syndrome
• Thiamine deficiency
– Impaired visual acuity
Cardiovascular system
• Heavy alcohol consumption dilated
cardiomyopathy
– Depressed function of mitochondria and sarcoplasmic
reticulum, intracellular accumulation of fatty acids
and phospholipids up regulation of voltage dependent
calcium channels.
– Arrhythmias
• Arrhythmias Seizure, syncope and sudden
death during alcohol withdrawal
• Hypertension
• Low coronary heart disease  high HDL
Blood
• Mild anemia  alcohol related folic acid
deficiency
• Hemolytic syndromes
• Abnormalities in platelets and leukocytes
Endocrine system and electrolyte
balance
• Gynecomastia and testicular atrophy
• Alcoholic with chronic liver diseases 
ascites, edema and effusions.
• Low potassium
• Hypoglycemia, ketosis
Fetal alcohol syndrome
• Heavy drinking in first trimester
– Retard body growth
– Microcephaly
– Poor coordination
– Underdevelopment of mild facial region
Immune system
• Alteration in:
– Chemotaxis of Granulocytes
– Lymphocyte response to mitogens
– T cell numbers
– Natural killer cell activity
– Level of tumor necrosis factor
Increased risk of cancer
• Increased risk for cancer of:
– The mouth, pharynx, larynx, esophagus and
liver
– Breast
• Alcoholic beverages may carry potential
carcinogens
Alcohol – Drug interactions
• Pharmacokinetics
– Chronic intake:
• Alcohol induced increase drug metabolism
• Increased level of Acetaminophen toxicity
– Acute intake:
• Drug metabolism inhibition
• Pharmacodynamics
– Additive central nervous system depression
Management of acute alcohol
intoxication
• Degree of intoxication depends on:
– The blood ethanol concentration
– The rapidity of the rise of the alcohol level
– The time during which the blood level
maintained.
Management of alcohol withdrawal
syndrome
• The major objective of drug therapy is
prevention of:
– Seizure
– Delirium
– Arrhythmias
• Potassium, magnesium and phosphate balance
• Thiamine therapy
• Replacement therapy with long acting sedativehypnotic drugs
Pharmacotherapy of alcoholism
• Disulfiram
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–
–
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slow elimination rate
Inhibitor of other drug’s metabolism (phenytion, isoniazide)
Compliance is low
Some drugs have Disulfiram like effect : metronidazole,
sulfonylurea hypoglycemic drugs
• Naltrexone
– Decreased rate of relapse
– Reduced alcohol craving
• Acamprosate
– Weak NMDA receptor antagonist
– GABAA Activator
– Reduce replapse
Pharmacology of other alcohols
• Methanol
• Ethylene Glycol
• Drug therapy: ethanol, fomepizole