1. Toxic Alcohols John Kashani D.O. Attending, St. Joseph’s Emergency Department Staff Toxicologist, New Jersey Poison Center

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. Introduction Less common but potentially toxic alcohols include diethylene glycol, benzyl alcohol and the glycol ethers

11. Ethylene Glycol Coolant mixtures Antifreeze Air craft de-icing solutions Solvent (inks, pesticides and adhesives) Brake fluid Heat exchangers and condensers Glycerin substitute

12. Propylene glycol Commonly used as a diluent for parental preparations Environmentally safe alternative to ethylene glycol antifreeze

13. Benzyl alcohol +

14. Methanol Antifreeze (window washer fluid) Anti icing agent Octane booster Ethanol denaturant Extraction agent Solvent Fuel source

15. Methanol Varnish and paint removers Industrial solvent Manufacture of acetic acid, formaldehyde and inorganic acids

16. Isopropanol Synthesis of acetone, glycerin Solvent for oils, gums and resins Deicing agent Rubbing alcohol Hair care products, skin lotion and aerosols

17. Diethylene glycol Solvent Sprinkler antifreeze Paints, cosmetics + HEAA

18. Glycol ethers Solvents Semiconductor industry Fingernail polishes and removers Dyes, ink, cleaners, degreasers Brake fluid, car wax, injector cleaner Various household cleaning products

19. Pharmacology and Kinetics Exposure may occur dermally, pulmonary and GI –Pulmonary absorption depends on vapor pressure Rapidly absorbed by the gastrointestinal route

20. Pharmacology and Kinetics Time to peak concentration –Ethylene glycol = 1 - 4 hrs –Methanol, isopropyl alcohol = 30 - 60 minutes VD is 0.6L/kg

21. 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

22. 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

23. 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

24. (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

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

26. Isopropyl alcohol CH3CHOHCH3 ADH CH3COCH3Acetone

27. The Usual Suspects

28. Formic acid Metabolic acidosis Inhibits cytochrome oxidase: –Decreased ATP production Increased anaerobic glycolysis & lactate

29. R-OH NAD+NADH + H+ ADH

30. Pyruvate Lactate Acetyl-CoA CO 2 NAD+ NADH H+ NADH H+ NAD+ NADH NAD+

31. 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

32. 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

33. Clinical Manifestations ATN may develop secondary to calcium oxalate crystalluria Cranial nerve deficits have been reported with ethylene glycol

34. Clinical Manifestations Ispopropanol ingestion usually does not cause major toxicity unless a large amount is ingested –CNS depression, hemorrhagic gastritis and tracheobronchitis

35. 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

36. Diagnosis The absence of crystals is an unreliable finding The urine of a patient with ethylene glycol ingestion may fluoresce –Short lived, unreliable

37. Calcium oxalate Crystals

38. The “Osmolar Gap” Measured Serum Osmolarity Minus Calculated Serum Osmolarity [ 2(NA) + BUN/2.8 + Glucose/18+Etoh/4.6]

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

41. 0 Time since Ingestion mEq/L mOsm AG OG

42. 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

43. 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

44. Management Sodium bicarbonate as needed Inhibition of Alcohol dehydrogenase –Ethanol –Fomepizole

45. 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

46. Fomepizole…because shit happens

47. (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

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

49. 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

50. 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

51. 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

52. 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

53. 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

54. 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

55. Toxic alcohol Pearls “ketosis without acidosis” = isopropyl alcohol Inhibition of alcohol dehydrogenase with fomepizole

56. The End