Toxic AlcoholsJohn 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

CH2OHCHO

Ethylene glycol

Glycoaldehyde

CH2OHCOOH Glycolic Acid

CHOCOOH Glyoxylic Acid

Glycine + Benzoic Acid

Hippuric Acid

Oxalic Acid

Alpha-hydroxy-beta-ketoadipic acid

thiamine

Mg++

B6

ADH

ADH

ADH

CH3OH

CH2O

CHOOH

CO2 + H2O

Methanol

Formaldehyde

Formic Acid

Folate

ADH

ADH

Isopropyl alcohol

CH3CHOHCH3

ADH

CH3COCH3 Acetone

The Usual Suspects

Formic acid

• Metabolic acidosis

• Inhibits cytochrome oxidase:

– Decreased ATP production

• Increased anaerobic glycolysis & lactate

R-OH

NAD+ NADH + H+

ADH

Pyruvate Lactate

Acetyl-CoA

CO2

NAD+

NADH H+

NADH H+ NAD+

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 Mole Wgt mOsm/L*

Methanol 32 34

Ethanol 46 23

Ethylene glycol 62 19

Acetone 58 18

Isopropanol 60 18

Salicylate 180 6

* At 100 mg/dl

0

50

100

150

200

250

0 100 200 300 400 500 600 700 800

Concentration (mg/dl)

osm

ola

r g

ap methanol

ethanol

ethylene glycol

0 Time since Ingestion

mEq/L mOsmAG

OG

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

CH2OHCHO

Ethylene glycol

Glycoaldehyde

CH2OHCOOH Glycolic Acid

CHOCOOH Glyoxylic Acid

Glycine + Benzoic Acid

Hippuric Acid

Oxalic Acid

Alpha-hydroxy-beta-ketoadipic acid

Thiamine 100 mg IV/day

Mg++

B6 100 mg/day

ADH

ADH

ADH

X

CH3OH

CH2O

CHOOH

CO2 + H2O

Methanol

Formaldehyde

Formic Acid

Folate

ADH

ADH

X

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