Alcohol overdose

2. Alcohol overdose KobraNaseri PharmD, PhD of Pharmacology

3. ETHANOL POISONING

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

5. 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

6. PHARMACOKINETICS • 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.

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

8. Alcohol dehydrogenase Aldehyde dehydrogenaseAcetaldehyde Syndrome The mediator of liver toxicity METABOLIC PATHWAY

9. Adult : 6-10 mL/kg Children : 4 mL/kg Ethanol Toxic Dose

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

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

12. MANAGEMENT OF INTOXICATION • Airway protection • Adequate ventilation • IVF replacement • O2 supply • EKG monitoring • Thiamine (50 - 100 mg) IV • Glucose supply (if hypoglycemic) • Active charcoal (if co-ingestion is suspected) • Re-warming (if hypothermic)

13. 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.).

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

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

16. EFFECTSIN NON-ALCOHOLICS

17. STAGING OF WITHDRAWAL

18. 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

19. Methanol

20. Physical Nature • Wood alcohol • CH3OH • Colorless liquid • Boiling point: 65°C

21. Source • Anti-freeze agents • Solvents • Cleaning agents • Industrial alcohol • Dye

22. 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

23. 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.

24. Absorption • Gastrointestinal Tract • Skin • Respiratory Tract

25. Metabolic Pathway Methanol Alcohol dehydrogenase Formaldehyde Aldehydedehydrogenase Formic acid Tetrahydrofolate CO2+ H2O

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

27. Formic Acid Toxicity • Inhibition of mitochondrial cytochrome oxidase: –Histotoxic Hypoxia –Metabolic Acidosis

28. Elimination • Liver (predominates) • Lung • Kidney • Elimination half life: 3 hours

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

30. 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.

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

32. 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 cytochromeoxidase, 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

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

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

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

36. 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)

37. Early diagnosis • History-taking • Increased osmolar gap • Blood methanol detection

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

39. Treatment • Supportive Care • Hemodialysis • Folic acid • Antidotes • Sodium Bicarbonate

40. 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

41. Antidotes Fomepizole Ethanol

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

43. 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

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

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

46. 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.

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

48. 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

49. 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

50. 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%