04/13/23Jordan B. Barnett, MD FACEP 1
The Toxicology of Alcohols
Jordan B Barnett
Copyright 1996-98 © Dale Carnegie & Associates, Inc.
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Methanol
• Methanol is obtained from distillation of wood and is synthesized from carbon oxides and hydrogen. Found at home, in the workplace, antifreeze, paint solvent, duplicating fluid, and fuels such as sterno. It is also found in gasoline additives and home heating fuels.
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Pathophysiology
• Most cases of methanol toxicity result from intentional or accidental oral ingestion.
• Pulmonary and dermal toxicity possible. Inhalation of windshield solvent in an automobile possible!
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• Converted by the liver by alcohol dehydrogenase to formaldehyde.
• Formaldehyde by aldehyde dehydrogenase to formate
• These metabolites are responsible for toxicity.
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• Formate inhibits cytochrome oxidase and mitochondiral respiration leading to cellular hypoxia
• Formate causes anion gap acidosis
• Formate causes anorexia, photophobia, and hyperpnea.
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Ocular toxicity
• Formate concentrats in the vitreous humor and optic nerve
• Structural changes in the eye may be caused by the interference of formate with cytochrome oxidase and Na, K, ATPase in the optic nerve
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Clinical Features
• 1. Visual Symptoms
• 2. CNS Depression
• 3. Abdominal pain, nausea and vomiting
• 4. Metabolic acidosis.
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Important Note
• Methanol is less intoxicating than ethanol so patients may have toxic levels with no evidence of intoxication!
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Visual Impairments
• Photophobia, blurred or indistinct vision, or descriptions of looking at a snowstorm occur in almost all symptomatic cases of methanol poisoning.
• Dilated sluggish pupils
• Hyperemia of the optic disk or papilledema
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Seizures Possible!
• Only 10 percent of autopsied patients had evidence of cerebral edema in a series of 323 patients.
• Putamen is susceptible to hemorrhagic necrosis in methanol intoxication. Residual Parkinsonism has been reported
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Anion Gap Acidosis
• Methanol poisoning can cause a zero plasma bicorbonate.
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Osmolar Gap
• Osm cal =2Na + (Glucose/18) + Bun/2.8
• To correct for the presence of ethanol add
• Ethanol level/4.6
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Treatment
• General Supportive Measures
• Correction of metabolic acidosis
• Preventio of conversion of methanol to formate
• Elimination of methanol and formate
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Remember the ABCs
• Check glucose,
• Thiamine
• Naloxone
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Recent Ingestion?
• Gastric lavage via a nasogastric tube may be indicated if ingestion within 1 to 2 hours
• No to minimal adsoprtion to charcoal
• Cathartics have no role since methanol quickly absorbed
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Ethanol Therapy
• Indicated when the clinical diagnosis of methanol intoxication is suspected
• Both substrates for alcohol dehydrogenase
• Ethanol has 10x the affinity for alcohol dehydrogenase
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Glucose and Ethanol Therapy
• Frequent glucose monitoring – hypoglycemia possible!
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So what about the formate?
• Folinic acid infusion of 1 mg/kg decrease formate accumulation for first dose
• Folate 1 mg/kg every 4 h for 24 h
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Hemodialysis
• Treatment of choice for significant methanol intoxications
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4-Methylpyrazole
• A potent alcohol dehydrogenase inhibitor is undergoing clinical evaluation for both methanol and ethylene glycol intoxications.
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Ethylene Glycol
• Straight chain polyalcohol
• Detergents, paints, pharmaceuticals, polishes, antifreeze, coolants.
• Often substituted unwisely for alcohol
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Pathophysiology
• Liver
• Kidney
• Toxic Metabolites include glycoaldehyde, glycolate, glyoxalate, and oxalate
• Oxidative phosphorylation, proein synthesis, and slfhydryl containing enzymes inhibited
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Pathophysiolgy continued
• Calcium oxalate precipitates in the kidney, brain, liver, blood vessels, pericardium, causing tissue destruction
• Severe anion gap metabolic acidosis
• Hypocalcemia
• Alcohol dehydrogenase yields glyoaldehyde.
• Cofactors of pyridoxal phosphate and thimaine needed
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Clinical Features
• CNS Depression
• Cardiopulmonary Toxicity
• Renal Toxicity
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Central nervous system
• Symptoms usually in 1 to 12 hours after ingestion
• Ataxia, nystagmus, opthalmoplegia, papilledema, optic atrophy, myoclonus, convuslions, hallucinations, stupor or coma
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Anion Gap
• Large anion gap accompanies development of CNS symptoms
• An osmolal gap may be present
• Hypocalcemia is severe…look for tetany and prolonged QT
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12 hours to 72 hours
• Cardiopulmonary symptoms
• Tachycardia, tachypnea, hypertension.
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24 to 72 hours out
• If the patient survives the first two stages of this poisoning….
• Renal toxicity from aldehyde metabolites and oxalic acid
• Oxalate crystals deposit in intratubular regions
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Calcium oxalate crystals
• Positive birefringent calcium oxalate crystals in the urine are pathognomonic of the poisoning.
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So how do you diagnosis this?
• Large anion gap
• Metabolic acidosis
• Osmolal Gap
• Hypocacemia
• Oxalate crystals
• Urine under wood’s lamp
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Treatment
• General Supportive measures
• Correction of metabolic acidosis and electrolyte abnormalities
• Prevention of ethylene glycol metabolism
• Removal of ethylene glycol and its metabolites
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Within 1 to 2 hours
• Gastric lavage with a nasogastric tube
• Activated charcoal only if coingestants are suspected
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Anion gap metabolic acidosis
• Correct with bicarbonate
• Hypocalcemia should be treated with calcium chloride
• Thiamin and pyridoxine needed for detoxification.
• Ethanol therapy! (100-150 mg/dl)
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Hemodialysis
• Indicated if patient has an acidosis
• Renal dysfunction
• Ethylene glycol level of 25 mg/dl or grater
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Ethanol
• Most common abused drug in the country
• 42% of all traffic fatalities, 69% of all drownings, 23 % of all suicidal deaths
• Total mortality per year estimated to be 100,000 per year
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Ethanol Metabolsim
• 15 to 20 mg/dl per hour
• Chronic alcoholics 30 mg/dl /hr
• Zero order kinetics
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Metabolic Derangements
• Multifactorial
• Shifts intracellular redox potential by increasing NADH/NAD ratio, favoring the formation of lactate and b hydroxybutyrate
• Relative starvation
• Fatty acid metabolism increased – AKA
• Hypoglycemia due to glycogen depletion and depletion of pyruvate.
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Deficiencies
• Thiamine
• Thiamine is cofactor for pyruvate dehydrogenase – converts pyruvate into acetyl Coa, in TCA cycle for fatty acid synthesis
• Alpha ketoglutarate dehydrogenase, TCA cycle
• Transketolase – pentose phosphate shunt
• Thiamine needed for neural functions
• Niacin, folate magnesium potassium.
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Clinical features
• Sedative hypnotic
• Ataxia, slurred speech, nystagmus,lethargy, distortion of perceptions
• Tachycardia
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Wernicke’s encelphalopathy
• Consider in any alcoholic with an altered mental status
• Triad of ataxia, opthalmoplegia, and altered mental status.
• Also present, hypothermia, coma, hypotension
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Always evaluated Alcoholic for….
• Head neck injury
• Hypoglycemia
• Electrolyte abnormalities
• Meningitis
• Myopathy, neuropathy
• Cardiac – GI bleed – Pancreatitis
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Treatment
• Supportive
• Thiamine
• Dextrose
• Wernicke’s = thiamine
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Ethanol Withdrawal
• Ethanol exerts direct effects on the benzodiazepine GABA chloride receptor complex.
• Ethanol withdrawal may cause substantial decreases in GABA
• Elevation of norepinephrine plasma concentrations
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CLINICAL FEATURES
• Tremors
• Hallucinations
• Seizures
• DT
• Better –mild, moderate, severe
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Ethanol Withdrawal
• Within hours
• Irritibility, tremors, insomnia
• As symptoms worsen, tachycardia, hypertension, diaphoresis
• Hallucinations, visual, auditory, olfactory
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Rum Fits
• Grand mal
• 7-48 hours after abstinence
• Status epilepticus rare
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Delirium tremens
• 48 to 100 h after abstinence
• Hyperthermia, tachycardia, hypertension
• Agitation
• Can Cause death
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Treatment
• Supportive
• Benzos
• Phenobarbital acceptable
• Phenyton not effective in preventing withdrawal seizures.
• Treat cofactor deficencies
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Isopropranol
• Solvent, disinfectant
• Cleaning agent
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Pathophysiology
• Absorbed from the GI
• Alcohol dehydrogenase to acetone
• 20 % excreted unchanged via kidneys
• First order kinetics
• 29 hour half life
• 2-3 x more potent than ethanol on CNS
• Direct GI irritating and vasodilatory and myocardial depressant effects.
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Clinical Features
• CNS Depression
• Abdominal Pain, vomiting
• Hypotension
• Ketosis
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CNS Effects
• Can last for 24 hours
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Gastric
• Hemorrhagic gastritis
• Hypotension
• Rhabdomyolysis
• ATN
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Laboratory
• Elevated osmolal gap
• Acetonemia
• Acetonuria
• Absent acidosis
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Treatment
• Lavage if in 1-2 hours
• Glucose and thiamine if sensorium altered
• Maintain pressure
• Hemodialysis if persistent hypotension or isopropyl level 400 mg/dl
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Summary Slide
Alcohol Osmolar Gap
Anion Gap Ketosis Signs Symptoms
Methanol + +++ - Visual, Papilledema
Ethylene Glycol
+ +++ - Renal Failure, Ca Oxylate
Isopropyl + - +++ Hemor. Gastritis