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 = hrs –Methanol, isopropyl alcohol = 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

(CH 2 OH)2 CH 2 OHCHO Ethylene glycol Glycoaldehyde CH2OHCOOHGlycolic Acid CHOCOOH Glyoxylic Acid Glycine + Benzoic Acid Hippuric Acid Oxalic Acid Alpha-hydroxy-beta- ketoadipic acid thiamine Mg ++ B6 ADH

CH 3 OH CH 2 O CHOOH CO 2 + H 2 O Methanol Formaldehyde Formic Acid Folate ADH

Isopropyl alcohol CH3CHOHCH3 ADH CH3COCH3Acetone

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 CO 2 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]

SubstanceMole WgtmOsm/L* Methanol3234 Ethanol4623 Ethylene glycol6219 Acetone5818 Isopropanol6018 Salicylate1806 * At 100 mg/dl

0 Time since Ingestion mEq/L mOsm AG 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

(CH 2 OH)2 CH 2 OHCHO 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 X

CH 3 OH CH 2 O CHOOH CO 2 + H 2 O Methanol Formaldehyde Formic Acid Folate 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