2. Toxic Alcohols Douglas Eyolfson, MD, FRCP(C) Department of Emergency Medicine Health Sciences Centre

3. Objectives l Review pharmacology of toxic alcohols l Review clinical presentations (suspicions) l Review evaluation strategies when diagnosis is considered l Review immediate and definitive treatments

4. Introduction l Methanol & ethylene glycol most toxic l Common ingredient »Automotive fluids (antifreeze, windshield washer) »De-icing solutions »Solvents & cleaners l Delayed Toxicity

5. Settings of Poisonings l Deliberate »Suicide/homicide attempt l Non-potable intoxicant »Indigent »Cheap substitutes (solvents) l Inadvertent »Amateur EtOH distilling (‘moonshine’) »Transfer from original container (ease of pouring, found in garages) »Multiple poisonings

6. Alcohols l Ethanol »MW = 46 »‘0.08’ g/100ml = 18 mmol/L »benign l Isopropyl alcohol »Relatively benign »Supportive care l Methanol »MW = 32 »Toxic dose >15ml of 40% l Ethylene glycol »MW = 62 »Toxic dose >15ml of 40%

7. Methanol l Parent molecule nontoxic »Toxic metabolites l Colorless, tasteless l Toxicity > 6 mmol/L (20 mg/100ml) l Delayed toxicity (12-18h) »Formic acid  formaldehyde l Inhibit mitochondrial respiration  lactic acidosis l Optic pappilitis & retinal edema  blindness l Ischemic injury basal ganglia

8. Methanol: Metabolism

9. l Rapidly absorbed »Peak 1-2 hours l Elimination (untreated) »Zero-order kinetics »2.7 mmol/L/hr l Elimination (ADH inhibition) »1st-order »Pulmonary & renal »T 1/2 18-54 hours

10. Ethylene Glycol l Parent molecule nontoxic l Toxicity > 3 mmol/L (20 mg/100ml) l Delayed toxicity »CNS depression, cardiovascular instability (12-24h) l Formic acid »Nephrotoxicity (24-72h) l Glycolate »Hypocalcemia l Oxalate acid

11. Ethylene Glycol: Metabolism

12. l Rapidly absorbed »Peak 1-2 hours l Elimination (untreated) »1st-order kinetics »T 1/2 3-9 hours l Elimination (ADH inhibition) »Renal »T 1/2 3-9 hours

13. Evaluation l High index of suspicion »Ingestion source unclear »Nonpotables »Abnormal vital signs (e.g. tachypnea in acidosis) l Labs »Chem 10/AG/LFT’s/Osmol/ETOH/Acet/ASA »Blood gas »+ lactate »Methanol/ethylene glycol l Often delayed/unavailable l Do not wait for result before treating

15. Treatment l ABC’s/supportive care »IV/O 2 /monitor/I&O »Immediate toxicology consult l Gastric Decontamination »No role l Treat Acidosis l Cofactor Therapy l Antidotal therapy l Dialysis

16. Acidosis l Acidemia increases penetration of toxins into cells, increasing toxicity »Methanol  formate »Ethylene glycol  glycolate/glyoxylate/oxalate l Treat Acidosis if pH <7.3 »1-2 mEq/kg NaHCO 3 bolus »NaHCO 3 3 amps/1L at 2 X maintenance

17. Cofactor Therapy l Methanol »Formate  CO2 + H2O: folate-dependant »Folic acid 150mg IV q6h l Ethylene Glycol »Glyoxylate  glycine: pyridoxine-dependant l Pyridoxine 50mg IV »Glyoxylate  α-hydroxy-β-ketoadipate: thiamine-dependant l Thiamine 100mg IV l Give all pending specific assays

18. Alcohol Dehydrogenase Inhibition l Unmetabolized methanol & ethylene glycol nontoxic l Alcohol dehydrogenase (ADH) facilitates first step to toxic metabolites »Methanol  formate »Ethylene glycol  glycoaldehyde l ADH inhibition inhibits progression of toxicity l EtOH l 5-methylpyrazole (Fomepizole)

19. Ethanol l Competitive inhibitor of ADH »ADH affinity for EtOH > methanol/ethylene glycol l Difficult to use »Frequent measurement & titration l Sedative/behavioral effects »Risk of aspiration

20. Fomepizole l Specific competitive inhibitor of ADH l Regular dosing, no titration »15 mg/kg load »10 mg/kg q12h »Adjust dose when dialyzing l No sedation l Definitive therapy if dialysis unavailable l ~$3,000.00/dose

21. Alternatives l IV EtOH and fomepizole unavailable »Isolated communities l Commercial distilled spirits (40% methanol) »Available in most communities »Dilute to 20% »IV or NG »Frequent accuchecks in children

22. Dialysis l Definitive therapy »Immediate nephrology/ICU consult if OD suspected l Always with large methanol ingestions »T 1/2 18-54 hours with methanol l May be unnecessary with ethylene glycol »T 1/2 3-9 hours

23. Multiple Ingestions l Cluster ingestions common »Adolescents »Indigent l Determine if others have consumed from same source »May need police to apprehend patients

24. Preterminal Care l May present late l Irreversible neurologic damage »Discontinuation of treatment considered l Other organs may be undamaged »Suitable for transplant l Consider consult for organ donation

25. Conclusions l Delayed toxicity common »Benign presentation »High level of suspicion l Start treatment as soon as suspected »Cofactors »ADH inhibition l Call poison control/toxicologist early l Suspect multiple ingestions