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Anesthesia Pharmacology: Anxiolytics and Sedative-Hypnotics
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Ethanol: absorption, metabolism of ethanol, its effects on major organs system, contraindications, acute and chronic toxicities, the mechanism of action of disulfiram
*Note: Chronic ethanol abuse has anesthesia implications.
In consideration of a variety of surgeries including colonic surgery, prostatectomy, ankle surgery, and surgical intervention to treat subdural hematoma, perioperative morbidity increases by 200%-300%. (*Mushlin, P.S. and S. Gelman, "Anesthesia and the Liver", in Clinical Anesthesia (4/e), edited by Paul G. Barish, Bruce F. Cullen and Robert K. Stoelting, Lippincott Williams and Wilkins, p 1084, 2001)
Frequently observed complications include bleeding, cardiopulmonary insufficiency, and infection.
Underlying mechanisms for the is complications include:
Subclinical cardiac insufficiency
Hemostatic imbalance
Immune system deficiencies, and
Possibly an accentuated stress response to surgery or alcohol abstinence (withdrawal).
Ethanol is rapidly absorbed from stomach, small intestine and colon but the rate of absorption from the stomach is influenced by the food content.
Ethanol evenly distributed throughout all fluids and tissues, after absorption.
Placental permeability ensures access of ethanol to the fetus.
Most ethanol molecules are oxidized, with the rate of oxidation insensitive to ethanol concentration (zero-order kinetics).
Most ethanol oxidation occurs in the liver and is catalyzed by alcohol dehydrogenase.
The product is acetaldehyde which is then converted to acetyl CoA.
To a limited extent, in humans, ethanol is also oxidized by mixed function oxidases in liver microsomal membranes.
Genetic polymorphisms occur for both alcohol and aldehyde dehydrogenase.
Mechanism of Action
Ethanol (along with anesthetics) enhances GABA-mediated synaptic inhibition.
Ethanol inhibits glutamate-activated ion channels (excitatory) (predominately the NMDA glutamate receptors at mild intoxicating ethanol concentrations.)
Ethanol may also act by affecting 5-HT3 receptors.
Activation of these receptors results in excitation of inhibitory interneurons.
Serotonin's action at the 5-HT3 receptor subtype is enhanced by ethanol.
Drug-Drug Interactions
Ethanol enhances CNS depression caused by other sedative-hypnotics.
Ethanol interferes with metabolism of drugs that utilize the same hepatic oxidase system.
For example the clearance of phenytoin is prolonged due to competition with ethanol for the same mixed-function hepatic oxidase system.
By contrast, with chronic use, ethanol causes induction of hepatic metabolizing enzymes and can, in this case, increase clearance of many drugs (e.g. phenytoin (Dilantin), Tolbutamide (Orinase)).
Chronic consumers of ethanol are susceptible to acetaminophen hepatoxicity probably due to accumulation of toxic metabolites and glutathione depletion.
Contraindications for ethanol use: Hepatic disease, gastrointestinal ulcer, cardiac or skeletal myopathy, pregnancy, individuals previously addicted to ethanol
Ethanol: Organ Systems: Pharmacological Effects
Central Nervous System
Acute effects (Ethanol is a CNS depressant)
Depression of inhibitory CNS systems may be responsible for apparent stimulation that is observed initially.
With moderate intoxication, mood swings, outgoing, and expansive behavior occur.
General impairment of statements function becomes evident with increased intoxication.
Large amounts of ethanol may lead to severe (even lethal) respiratory depression.
Chronic effects
Chronic and excessive ethanol use results in brain damage, memory loss, sleep disturbances.
Increased risk of seizures.
Neuropsychiatric disturbances including Wernicke's
encephalopathy.
Wernicke's encephalopathy is due to a nutritional thiamine deficiency.
This syndrome is not observed only in alcoholics.
Common causes include chemotherapy-associated prolonged vomiting with lack of nourishment, eating disorders, elderly patients who had been living alone and who have not been maintaining adequate nutrition.
Wernicke's may be precipitated in the hospital by glucose administration to patients who is deficient in thiamine.
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Cardiovascular System
Acute Effects:
Ethanol causes a generalized vasodilation (due to both central effects and effects on the vascular bed)
Moderate doses, however, can cause a vasoconstrictive effect in the heart and brain.
In severe intoxication, cardiovascular depression occurs secondary to central vasomotor effects and respiratory depression.
Chronic Effects:
With chronic use, significant and irreversible damage to the myocardium may occur.
This effect is one of the most important causes of cardiomyopathy.
Gastrointestinal Tract
Ethanol increases gastric secretions by:
(a) Direct action on the stomach (may increase gastrin)
(b) Psychological mechanism (if the individual likes it)
(c) Stimulating sensory endings in the buccal and gastric mucosae.
At high ethanol concentrations (80 proof (40% alcohol)), direct gastric mucosal irritation occurs resulting in congestive hyperemia and inflammation.
These concentrations can result in an erosive gastritis.
Chronic, excessive ethanol consumption may cause either diarrhea or constipation.
Ethanol may also predispose to chronic pancreatitis because of both increased secretion and pancreatic ductal obstruction.
Liver
Chronic use of ethanol promotes hepatic cirrhosis and is associated with an increased risk of cancer and drug toxicity (acetaminophen).
Acute use probably does not produce lasting hepatic changes.
Miscellaneous organ effects
Teratogenic effects:
Ethanol appears to be the most frequent cause of teratogenically-caused mental deficiency in the West.
Inebriation interferes with coitus, decreasing sexual responsiveness in both men and women.
Chronic ethanol abuse may lead to impotence, sterility, testicular atrophy, and gynecomastia.
Feminization in males is due to both hyperestrogenization with reduced rate of testosterone production (due to hepatic damage) and by ethanol's induction of hepatic metabolizing enzymes, increasing the rate of testosterone inactivation.
The resulting "acetaldehyde syndrome" consists of facial flush, headache, hypotension, marked uneasiness, confusion, vomiting and other symptoms.
These unpleasant effects are the basis of the use of disulfiram as part of the treatment of chronic alcoholism.
Disulfiram is converted to ethyldithiocarbamate a very effective chelator of copper and other metals. As a result, ethyldithiocarbamate inhibits the activity of dopamine beta-hydroxylase, alcohol dehydrogenase, and other metalloenzymes.
Hobbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 386-392.
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