Download Toxic Alcohols

Toxic Alcohols
John Kashani D.O.
Attending, St. Joseph’s Emergency
Department
Staff Toxicologist, New Jersey Poison
Center
Case
• An 18 year old male is brought into the
ED by his mother when he was difficult
to awaken in the AM
• He was partying the night before, he is
not able to provide a history
• He becomes progressively more
obtunded while in the ED
Case
• A 22 year old frustrated medical student
drinks a bottle of formaldehyde he stole
from gross anatomy lab
• He complains of throat and esophageal
irritation and has had multiple episodes
of emesis
Case
• A 65 year old man is found comatosed
• His wife states that he has been
depressed recently and has been
drinking heavily
• An empty bottle of antifreeze was found
in his kitchen garbage can
Case
• A 17 year old female ingests a bottle of
rubbing alcohol
• She appears drunk, has multiple
episodes of emesis and complains of
abdominal pain
Case
• A 25 year old man presents to the ED
with blurry vision
• For the past few days he has been
feeling “cruddy”
• He admits to the ingestion of
homemade everclear 3 days prior
Objectives
• Outline the “toxic” alcohols and
potentially toxic alcohols
• Discuss the pharmacology, kinetics and
pathophysiology of the toxic alcohols
• Discuss the clinical manifestations,
diagnosis and management of patients
poisoned by these agents
Introduction
• Alcohols are hydrocarbons that contain
a hydroxyl group
• A compound with two hydroxyl groups is
called a diol or a glycol
• Toxic alcohols commonly refer to
methanol, ethylene glycol and isopropyl
alcohol
Introduction
• Less common but potentially toxic
alcohols include diethylene glycol,
benzyl alcohol and the glycol ethers
Ethylene Glycol
•
•
•
•
•
•
•
Coolant mixtures
Antifreeze
Air craft de-icing solutions
Solvent (inks, pesticides and adhesives)
Brake fluid
Heat exchangers and condensers
Glycerin substitute
Propylene glycol
• Commonly used as a diluent for
parental preparations
• Environmentally safe alternative to
ethylene glycol antifreeze
Benzyl alcohol
+
Methanol
•
•
•
•
•
•
•
Antifreeze (window washer fluid)
Anti icing agent
Octane booster
Ethanol denaturant
Extraction agent
Solvent
Fuel source
Methanol
• Varnish and paint removers
• Industrial solvent
• Manufacture of acetic acid,
formaldehyde and inorganic acids
Isopropanol
•
•
•
•
•
Synthesis of acetone, glycerin
Solvent for oils, gums and resins
Deicing agent
Rubbing alcohol
Hair care products, skin lotion and
aerosols
Diethylene glycol
• Solvent
• Sprinkler antifreeze
• Paints, cosmetics
+ HEAA
Glycol ethers
•
•
•
•
•
•
Solvents
Semiconductor industry
Fingernail polishes and removers
Dyes, ink, cleaners, degreasers
Brake fluid, car wax, injector cleaner
Various household cleaning products
Pharmacology and Kinetics
• Exposure may occur dermally,
pulmonary and GI
– Pulmonary absorption depends on
vapor pressure
• Rapidly absorbed by the gastrointestinal
route
Pharmacology and Kinetics
• Time to peak concentration
– Ethylene glycol = 1 - 4 hrs
– Methanol, isopropyl alcohol = 30 - 60
minutes
• VD is 0.6L/kg
Pharmacology and Kinetics
• Ethylene glycol and methanol are
metabolized by alcohol dehyrogenase
and aldehyde dehydrogenase
• Isopropanol is metabolized by alcohol
dehydrogenase
• Binding affinities for
– ethanol>methanol>ethylene glycol
Pharmacology and Kinetics
• Methanol metabolism may be delayed
(up to 72 hours)
• The volatility of methanol contributes to
its pulmonary excretion (10-20%)
• Ethylene glycol is metabolized over 3 –
8 hours
– Undergoes multiple oxidations
Pharmacology and Kinetics
• Ethylene glycol is not appreciably
excreted by the lungs
• Isopropanol is rapidly metabolized to
acetone via alcohol dehyrogenase
• 20% is excreted unchanged
• Acetone is predominantly renally
excreted
(CH2OH)2
Ethylene glycol
ADH
CH2OHCHO
Glycoaldehyde
ADH
CH2OHCOOH
Glycolic Acid
ADH
CHOCOOH
thiamine
Mg++
Alpha-hydroxy-betaketoadipic acid
Glyoxylic Acid
B6
Oxalic Acid
Glycine +
Benzoic Acid
Hippuric Acid
CH3OH
Methanol
ADH
CH2O
Formaldehyde
ADH
CHOOH
Folate
CO2 + H2O
Formic Acid
CH3CHOHCH3 Isopropyl
alcohol
ADH
CH3COCH3
Acetone
The Usual Suspects
Formic acid
• Metabolic acidosis
• Inhibits cytochrome oxidase:
– Decreased ATP production
• Increased anaerobic glycolysis &
lactate
NAD+
NADH + H+
R-OH
ADH
NADH
H+
Pyruvate
NAD+
Lactate
NAD+
CO2
NADH
H+
Acetyl-CoA
NADH
NAD+
Clinical Manifestations
• Clinical manifestations may be related
to the parent compound or metabolites
• There may be an initial asymptomatic
period
• Inebriation (unreliable)
– Isopropyl>ethylene glycol>methanol
Clinical Manifestations
• Vasodilation – hypotension and reflex
tachycardia
• Hypoglycemia
• Anion gap acidosis
– Methanol and ethylene glycol
• Visual disturbances (”snow Field”)
– Formic acid is a retinal toxin
Clinical Manifestations
• ATN may develop secondary to calcium
oxalate crystalluria
• Cranial nerve deficits have been
reported with ethylene glycol
Clinical Manifestations
• Ispopropanol ingestion usually does not
cause major toxicity unless a large
amount is ingested
– CNS depression, hemorrhagic
gastritis and tracheobronchitis
Diagnosis
• Both ethylene glycol and methanol
result in an anion gap acidosis
• Isopropyl alcohol usually does not result
in an anion gap acidosis
• Hypocalcemia may be seen in ethylene
glycol intoxication
– Chelation of calcium by oxalate –
calcium oxalate crystals
Diagnosis
• The absence of crystals is an unreliable
finding
• The urine of a patient with ethylene
glycol ingestion may fluoresce
– Short lived, unreliable
Calcium oxalate Crystals
The “Osmolar Gap”
Measured Serum Osmolarity
Minus
Calculated Serum Osmolarity
[ 2(NA) + BUN/2.8 + Glucose/18+Etoh/4.6]
Substance
Methanol
Ethanol
Ethylene glycol
Acetone
Isopropanol
Salicylate
* At 100 mg/dl
Mole Wgt
32
46
62
58
60
180
mOsm/L*
34
23
19
18
18
6
osmolar gap
250
200
methanol
ethanol
ethylene glycol
150
100
50
0
0 100 200 300 400 500 600 700 800
Concentration (mg/dl)
mOsm
mEq/L
0
Time since Ingestion
Quantitative testing
• If quantitative levels are readily
available they can be used to determine
proper management
• Best method is gas chromatography
with flame ionization
– Subject to false positives
Management
•
•
•
•
ABC’s
+/---- NGT aspiration
AC/ipecac/lavage = Bad move
Thiamine and pyridoxine in the setting
of ethylene glycol toxicity
• Folic acid in the setting of methanol
toxicity
Management
• Sodium bicarbonate as needed
• Inhibition of Alcohol dehydrogenase
– Ethanol
– Fomepizole
Ethanol vs Fompepizole
Ethanol:
- Oral or IV
- CNS depression
- Difficult titration
- Frequent levels
- Hypoglycemia
Fomepizole:
- IV
- No CNS depression
- Easy dosing
- No levels to monitor
- More predictable
pharmacokinetcs
- No Hypoglycemia
- Cost
Fomepizole…because shit happens
(CH2OH)2
X
Ethylene glycol
ADH
CH2OHCHO
Glycoaldehyde
ADH
CH2OHCOOH
Glycolic Acid
ADH
Thiamine 100 mg
IV/day
Mg++
Alpha-hydroxy-betaketoadipic acid
CHOCOOH
Glyoxylic Acid
B6 100 mg/day
Oxalic Acid
Glycine +
Benzoic Acid
Hippuric Acid
CH3OH
X
Methanol
ADH
CH2O
Formaldehyde
ADH
CHOOH
Folate
CO2 + H2O
Formic Acid
Case
• An 18 year old male is brought into the
ED by his mother when he was difficult
to wake up in the AM
• Apparently he was partying the night
before, he is not able to provide a
history
• He becomes progressively more
obtunded while in the ED
Case
• A 22 year old frustrated medical student
drinks a bottle of formaldehyde he stole
from gross anatomy lab
• He complains of throat and esophageal
irritation and has had multiple episodes
of emesis
Case
• A 65 year old man is found comatosed
• His wife states that he has been
depressed recently and has been
drinking heavily
• An empty bottle of antifreeze was found
in his kitchen garbage can
Case
• A 17 year old female ingests a bottle of
rubbing alcohol
• She appears drunk, has multiple
episodes of emesis and complain of
abdominal pain
Case
• A 25 year old man presents to the ED
with blurry vision
• For the past few days he has been
feeling “cruddy”
• He admits to the ingestion of
homemade everclear 3 days prior
Toxic alcohol Pearls
• Calcium oxalate crystals, renal failure =
ethylene glycol
• “Snow field vision” = methanol
• Methanol has a slower metabolism and
there may be a significant lag until the
onset of symptoms
• A “normal” osmolar gap does not rule
out the diagnosis
Toxic alcohol Pearls
• “ketosis without acidosis” = isopropyl
alcohol
• Inhibition of alcohol dehydrogenase with
fomepizole
The End