The Toxicology Of Alcohols, Jordan Barnett MD
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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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04/13/23Jordan B. Barnett, MD FACEP 2
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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04/13/23Jordan B. Barnett, MD FACEP 3
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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04/13/23Jordan B. Barnett, MD FACEP 4
• 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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04/13/23Jordan B. Barnett, MD FACEP 5
• 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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04/13/23Jordan B. Barnett, MD FACEP 6
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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04/13/23Jordan B. Barnett, MD FACEP 7
Clinical Features
• 1. Visual Symptoms
• 2. CNS Depression
• 3. Abdominal pain, nausea and vomiting
• 4. Metabolic acidosis.
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04/13/23Jordan B. Barnett, MD FACEP 8
Important Note
• Methanol is less intoxicating than ethanol so patients may have toxic levels with no evidence of intoxication!
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04/13/23Jordan B. Barnett, MD FACEP 9
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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04/13/23Jordan B. Barnett, MD FACEP 10
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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04/13/23Jordan B. Barnett, MD FACEP 11
Anion Gap Acidosis
• Methanol poisoning can cause a zero plasma bicorbonate.
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04/13/23Jordan B. Barnett, MD FACEP 12
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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04/13/23Jordan B. Barnett, MD FACEP 13
Treatment
• General Supportive Measures
• Correction of metabolic acidosis
• Preventio of conversion of methanol to formate
• Elimination of methanol and formate
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04/13/23Jordan B. Barnett, MD FACEP 14
Remember the ABCs
• Check glucose,
• Thiamine
• Naloxone
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04/13/23Jordan B. Barnett, MD FACEP 15
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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04/13/23Jordan B. Barnett, MD FACEP 16
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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04/13/23Jordan B. Barnett, MD FACEP 17
Glucose and Ethanol Therapy
• Frequent glucose monitoring – hypoglycemia possible!
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04/13/23Jordan B. Barnett, MD FACEP 18
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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04/13/23Jordan B. Barnett, MD FACEP 19
Hemodialysis
• Treatment of choice for significant methanol intoxications
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04/13/23Jordan B. Barnett, MD FACEP 20
4-Methylpyrazole
• A potent alcohol dehydrogenase inhibitor is undergoing clinical evaluation for both methanol and ethylene glycol intoxications.
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04/13/23Jordan B. Barnett, MD FACEP 21
Ethylene Glycol
• Straight chain polyalcohol
• Detergents, paints, pharmaceuticals, polishes, antifreeze, coolants.
• Often substituted unwisely for alcohol
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04/13/23Jordan B. Barnett, MD FACEP 22
Pathophysiology
• Liver
• Kidney
• Toxic Metabolites include glycoaldehyde, glycolate, glyoxalate, and oxalate
• Oxidative phosphorylation, proein synthesis, and slfhydryl containing enzymes inhibited
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04/13/23Jordan B. Barnett, MD FACEP 23
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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04/13/23Jordan B. Barnett, MD FACEP 24
Clinical Features
• CNS Depression
• Cardiopulmonary Toxicity
• Renal Toxicity
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04/13/23Jordan B. Barnett, MD FACEP 25
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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04/13/23Jordan B. Barnett, MD FACEP 26
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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04/13/23Jordan B. Barnett, MD FACEP 27
12 hours to 72 hours
• Cardiopulmonary symptoms
• Tachycardia, tachypnea, hypertension.
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04/13/23Jordan B. Barnett, MD FACEP 28
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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04/13/23Jordan B. Barnett, MD FACEP 29
Calcium oxalate crystals
• Positive birefringent calcium oxalate crystals in the urine are pathognomonic of the poisoning.
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04/13/23Jordan B. Barnett, MD FACEP 30
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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04/13/23Jordan B. Barnett, MD FACEP 31
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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04/13/23Jordan B. Barnett, MD FACEP 32
Within 1 to 2 hours
• Gastric lavage with a nasogastric tube
• Activated charcoal only if coingestants are suspected
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04/13/23Jordan B. Barnett, MD FACEP 33
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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04/13/23Jordan B. Barnett, MD FACEP 34
Hemodialysis
• Indicated if patient has an acidosis
• Renal dysfunction
• Ethylene glycol level of 25 mg/dl or grater
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04/13/23Jordan B. Barnett, MD FACEP 35
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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04/13/23Jordan B. Barnett, MD FACEP 36
Ethanol Metabolsim
• 15 to 20 mg/dl per hour
• Chronic alcoholics 30 mg/dl /hr
• Zero order kinetics
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04/13/23Jordan B. Barnett, MD FACEP 37
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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04/13/23Jordan B. Barnett, MD FACEP 38
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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04/13/23Jordan B. Barnett, MD FACEP 39
Clinical features
• Sedative hypnotic
• Ataxia, slurred speech, nystagmus,lethargy, distortion of perceptions
• Tachycardia
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04/13/23Jordan B. Barnett, MD FACEP 40
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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04/13/23Jordan B. Barnett, MD FACEP 41
Always evaluated Alcoholic for….
• Head neck injury
• Hypoglycemia
• Electrolyte abnormalities
• Meningitis
• Myopathy, neuropathy
• Cardiac – GI bleed – Pancreatitis
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04/13/23Jordan B. Barnett, MD FACEP 42
Treatment
• Supportive
• Thiamine
• Dextrose
• Wernicke’s = thiamine
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04/13/23Jordan B. Barnett, MD FACEP 43
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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04/13/23Jordan B. Barnett, MD FACEP 45
Ethanol Withdrawal
• Within hours
• Irritibility, tremors, insomnia
• As symptoms worsen, tachycardia, hypertension, diaphoresis
• Hallucinations, visual, auditory, olfactory
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04/13/23Jordan B. Barnett, MD FACEP 46
Rum Fits
• Grand mal
• 7-48 hours after abstinence
• Status epilepticus rare
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04/13/23Jordan B. Barnett, MD FACEP 47
Delirium tremens
• 48 to 100 h after abstinence
• Hyperthermia, tachycardia, hypertension
• Agitation
• Can Cause death
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04/13/23Jordan B. Barnett, MD FACEP 48
Treatment
• Supportive
• Benzos
• Phenobarbital acceptable
• Phenyton not effective in preventing withdrawal seizures.
• Treat cofactor deficencies
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04/13/23Jordan B. Barnett, MD FACEP 49
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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04/13/23Jordan B. Barnett, MD FACEP 51
Clinical Features
• CNS Depression
• Abdominal Pain, vomiting
• Hypotension
• Ketosis
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CNS Effects
• Can last for 24 hours
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04/13/23Jordan B. Barnett, MD FACEP 53
Gastric
• Hemorrhagic gastritis
• Hypotension
• Rhabdomyolysis
• ATN
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04/13/23Jordan B. Barnett, MD FACEP 54
Laboratory
• Elevated osmolal gap
• Acetonemia
• Acetonuria
• Absent acidosis
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04/13/23Jordan B. Barnett, MD FACEP 55
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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04/13/23Jordan B. Barnett, MD FACEP 56
Summary Slide
Alcohol Osmolar Gap
Anion Gap Ketosis Signs Symptoms
Methanol + +++ - Visual, Papilledema
Ethylene Glycol
+ +++ - Renal Failure, Ca Oxylate
Isopropyl + - +++ Hemor. Gastritis