3. ALCOHOL OVERDOSE Kobra Naseri PharmD, PhD of Pharmacology

4. ETHANOL POISONING

5. INTRODUCTION INTRODUCTION  Ethanol (ethyl alcohol,C2H5OH) - is derived from fermentation of sugars in fruits, cereals, and vegetables.  Ethanol:  the most frequently abused intoxicant

6. PHARMACOLOGY OF ETHANOL CNS depressant:  inhibits neuronal activity  behavioral stimulation at low blood level Cross tolerance:  BZD & barbiturates Absorption:  proximal small bowel Excretion:  2% ~ 10% by lungs, in urine, in sweat

7.  Ethanol is readily absorbed (peak30-120 min)  (Vd=0.5-0.7L/kg).  It is rapidly absorbed by diffusion across the lipid membranes of the stomach and small intestine.  Coingestion of food or decreased GI motility produces a delay in absorption and increases the gastric metabolism of ethanol. PHARMACOKINETICS

8. 90% metabolized in the liver by one of the two pathways: 1. cytosol: –alcohol dehydrogenase –aldehyde dehydrogenase 2. microsomal alcohol oxidizing system Metabolism of ethanol

9. Alcohol dehydrogenase Acetaldehyde Syndrome Aldehyde dehydrogenase Acetaldehyde Syndrome The mediator of liver toxicity METABOLIC PATHWAY

10. Adult : 6-10 mL/kg Children : 4 mL/kg

11. Slurred speech Disinhibited behavior CNS depression Decreased motor coordination & control Hypotension: –decrease in total peripheral resistance Reflex tachycardia SYMPTOMS OF INTOXICATION

12. HYPOTHERMIA  Depresses central thermoregulatory mechanisms  Decreases shivering  Enhances heat loss through vasodilatation  Sedative effects:  lack of behavioral adjustment against exposure to the cold environment

13. MANAGEMENT OF INTOXICATION  Airway protection  Adequate ventilation  IVF replacement  O 2 supply  EKG monitoring  Thiamine (50 - 100 mg) IV  Glucose supply (if hypoglycemic)  Active charcoal (if co-ingestion is suspected)  Re-warming (if hypothermic)

14.  Treatment is mainly supportive.  Protect the airway to prevent aspiration.  Glucose & thiamine administered.  Glucagon is not effective for alcohol induced hypoglycemia.  Correct hypothermia with gradual rewarming.  Do not induced vomiting or activated charcoal and gastric lavage in pure ethanol intoxication. Consider gastric lavage only if the alcohol ingestion was massive and recent( within 30-45 min.).

15.  Hemodialysis efficiently removes ethanol but enhanced removal is rarely needed because supportive care is usually sufficient.  Hemoperfusion and forced diuresis are not effective.

16. Legal definition of ethanol intoxication: BAC > 100 mg/dl BAC correlates poorly with degree of intoxication (because of tolerance) BLOOD ALCOHOL CONC.

17. EFFECTS IN NON-ALCOHOLICS

18. STAGING OF WITHDRAWAL

19. Rx : ALCOHOL WITHDRAWAL Hydration with D5NS (IV) Cross-reacting drugs: –BZD or Phenobarbital Thiamine (IV) Magnesium sulfate (IV) Admission: –fail to respond to 2 doses of sedative

20. Methanol

21. Physical Nature  Wood alcohol  CH3OH  Colorless liquid  Boiling point: 65°C

22. Source  Anti-freeze agents  Solvents  Cleaning agents  Industrial alcohol  Dye

23. Poisoning  Poisoning is common.  Adulterated beverages (substituting methanol for ethanol)  Mis-swallowing accidentally  Suicide or homicide  Ingestion of just 0.15 mL/kg of 100% methanol may cause toxicity.  Fatal dose : 60-240 mL

24.  Pediatric cases are usually accidental.  Adult cases usually involve suicidal ingestion or ingestion of methanol as an alcohol substitute.  Toxic effects are typically severe, if untreated.  Death may occur in untreated patients.  Inhalation or dermal absorption can produce toxicity.

25. Absorption  Gastrointestinal Tract  Skin  Respiratory Tract

26. Metabolic Pathway Methanol Formaldehyde Formic acid CO 2 + H 2 O Alcohol dehydrogenase Aldehydedehydrogenase Tetrahydrofolate

27. Methanol Metabolism  Enzyme Involved: –Alcohol Dehydrogenase(Rate-Limiting) –AldehydeDehydrogenase  Toxic Products: –Formaldehyde –Formic acid

28. Formic Acid Toxicity  Inhibition of mitochondrial cytochrome oxidase: –Histotoxic Hypoxia –Metabolic Acidosis

29. Elimination  Liver (predominates)  Lung  Kidney  Elimination half life: 3 hours

30. Clinical feature  Incubation Time 12-72 hours  Factors influencing time to symptoms : –Amount Ingested –Concomitant Ethanol Intoxication –The individual’s Folate Status

31. Premortal Vital Signs  Hyperpnea usually develops to compensate metabolic acidosis (Kussmaul’s Respirations)  Sudden Respiratory Arrest  Tachycardia  Blood pressure is stable until death  Hypotension may develop late in severe cases.

32. Neurologic Toxicity  Neurologic Symptoms: –Headache –Dizziness –Amnesia –Restlessness –Acute Mania –Lethargy –Confusion –Coma –Convulsions –Parkinsonism may develop as a sequelae of severe intoxication.

33. Ophthalmologic Toxicity  Occur when serum pH drops below 7.2  Low pH → intracellular concentration of formate ↑  Improvement of vision with correction of acidosis, because formate moves out of the cell  Formate is an inhibitor of cytochrome oxidase, which could inhibit ATP formation in the optic nerve leading to a stasis of axoplasmic flow, axonal swelling, optic disc edema and finally loss of visual function

34. Ophthalmologic Toxicity Symptoms:  Blurred Vision  Photophobia  Eye Pain  Partial or complete loss of vision  Visual hallucinations (bright lights, snowstorm, dancing spots, flashes)

35. Ophthalmologic Toxicity Signs:  Optic discs hyperemia  Retinal edema  Retinal vessels engorgement  Papilledema  Papillary dilation  Loss of papillary reflex

36. Gastrointestinal Toxicity  Hemorrhagic Gastritis  Acute Pancreatitis  Symptoms: Abdominal Pain Nausea Vomiting Diarrhea Liver Function Impairment

37. Laboratory Tests  Essential Tests: 1.Serum Electrolytes (Hyperkalemia) 2.Leukocytosis 3.Amylase elevations 4.BUN and Creatinine 5.Glucose (Hyperglycemia) 6.Arterial Blood Gases  Elevated anion gap acidosis supports the diagnosis. 7.Osmolar gap 8.Elevated lactate levels 9.Serum Methanol Level (greater than 20 mg/dL)

38. Early diagnosis  History-taking  Increased osmolar gap  Blood methanol detection

39. Late diagnosis  Visual symptoms  Metabolic acidosis with increased anion gap  History of alcohol consumption and methanol contact

40. Treatment  Supportive Care  Hemodialysis  Folic acid  Antidotes  Sodium Bicarbonate

41. Supportive Treatment  Airway management in comatose patient  Intravenous Fluids  Cardiac Monitoring  Oxygen Supply  Ipecac is contraindicated (CNS depression)  Activated charcoal is not effective  Sodium bicarbonate

42. Fomepizole Ethanol Antidotes

43. Fomepizole  Fomepizole(Antizol)  Fomepizoleis the preferred agent  4-methylpyrazole (4-MP) “Fomepizole”:a more potent inhibitor of alcohol dehyrogenase  No side effect of CNS depression as in ethanol therapy

44. Fomepizole Indications:  A history of ingestion when a serum level is not immediately available  A Serum methanol level greater than 20 mg/dL  Unexplained metabolic acidosis with elevated anion and osmolar gaps

45. Fomepizole  Metabolic acidosis with elevated anion gap accompanied by visual signs and symptoms  Unexplained coma with a high osmolar gap  Clinical evidence of toxicity

46. Fomepizole Contraindication  Disulfiram  Allergic reaction to fomepizole  Relative contraindication  Metronidazole  GI Ulceration  Child < 5 years  Severe Hepatic Disease

47. Fomepizole  L.D: 15mg/kg (IV)  M.D: 10mg/kg/12h for 4 doses then 15mg/kg/12h  Each dose is diluted in 100 mL normal saline or D5W and infused over 30 minutes.

48. Ethanol  Ethanol is a preferential substrate for alcohol dehydrogenase.  Once alcohol dehydrogenase metabolism is blocked, methanol is eliminated slowly via pulmonary and renal excretion.

49. Ethanol Indications:  A history of ingestion when a serum level is not immediately available  A Serum methanol level greater than 20 mg/dL  Unexplained metabolic acidosis with elevated anion and osmolar gaps

50. Ethanol  Metabolic acidosis with elevated anion gap accompanied by visual signs and symptoms  Unexplained coma with a high osmolar gap  Clinical evidence of toxicity  It may be used if fomepizole is not available

51. Ethanol Loading Dose Gram/kg of Ethanol 10% (Oral)  Non-Drinker/Child 0.88  Average Drinker 1.4  Chronic Drinker 2 Maintenance Dose  100 mg/kg/hour of Ethanol 10% (Oral)  Increase M.D. 2-3 times during hemodialysis  Ethanol Conc. to 100 -150 mg%

52. Enhanced Elimination  Hemodialysis effectively removes methanol and its toxic metabolites  Elimination rates: -142 ~ 286 ml/min (methanol) -148 ~ 203 ml/min (formate)  Peritoneal dialysis also removes methanol but not as effectively

53. Adjunctive Treatment  Folate or tetrahydrofolate(Leucovorin) to hasten elimination of formic acid.  Leucovorin1mg/kg Max 50 mg/dose/IV/4-6 hours until methanol becomes undetectable.  Folate 1mg/kg Max 50 mg/dose/P.O/4-6 hours until methanol becomes undetectable.

54. Metabolic Pathway Methanol Formaldehyde Formic acid CO 2 + H 2 O Alcohol dehydrogenase Aldehydedehydrogenase Tetrahydrofolate

55.  Ethylene glycol is a sweet, odorless and colorless liquid. Overdose ETHYLENE GLYCOL

56. Introduction  It is a common component of antifreeze used in:  Heating and cooling systems  Brake Fluid  Inks  It is used as an industrial solvent in:  Paints  Plastics  It is used in synthesis of:  Resins  Synthetic Fibers  Waxes

57. Epidemiology  Poisoning is uncommon.  Death occurs in patients who do not receive medical care.  Poisoning most commonly occurs:  Accidental ingestion  Suicidal Attempt

58. Pathophysiology  E.G Glycoaldehyde Glyoxalate Pyridoxine Oxalate Glycine Itself is non-toxic Toxicity being to… ADH

59. Fatal dose in adult : 100 mL Ethylene glycol

60. Clinical feature  The first phase: 3 min –12 hours  Resemble ethanol intoxication without alcohol smell  Nausea, Vomiting & hematemesis  The major effects are on the CNS Coma Seizure Nystagmus

61. The second Phase: 12 –14 hours  Tachycardia  Mild Hypertension  Pulmonary edema  CHF  Due to deposition of calcium oxalate within the vascular tree, myocardium and lung parenchyma

62. The third phase: 24 –72 hours  Flank pain  CVA Tenderness (costovertebral angle)  Acute tubular necrosis

63. Treatment  Focus treatment:  Supportive care  Treatment with fomepizole  Treatment with ethanol  Hemodialysis as indicated.

64. Adjunctive Therapy  Pyridoxine and thiamine to hasten elimination of toxic ethylene glycol metabolites. Pyridoxine Dose 1 to 2 mg/kg administered intravenously every 6 hours until ethylene glycol level is undetectable.

65. Thiamine Dose  Adult dose is 100 mg/I.V. over 5 minutes every 6 hours until ethylene glycol level is undetectable.  Pediatric dose is 50 mg/I.V. over 5 minutes every 6 hours until ethylene glycol level is undetectable. Sodium Bicarbonate  Sodium bicarbonate should not be used routinely but may be used as a temporarily for life-threatening acidosis prior to hemodialysis.