1. Toxic Alcohols and Opioids Jamil A. Alarafi, D.O. Jamil A. Alarafi, D.O. 02.01.2007 02.01.2007

2. Toxic Alcohols Ethanol Methyl Alcohol Ethylene Glycol Isopropyl Alcohol

3. Ethanol Everybody's favorite! Unique among abused drugs Unique among abused drugs Most frequently used and abused in most societies Most frequently used and abused in most societies Estimated to contribute to 100,000 deaths/yr Estimated to contribute to 100,000 deaths/yr 40% of MVC’s are related to ETOH use 40% of MVC’s are related to ETOH use

4. Ethanol Pathophysiology CNS Depressant CNS Depressant Absorption: mouth to small bowel Absorption: mouth to small bowel Elimination: Elimination: 2 – 10% from lungs, urine, and sweat Primary metabolized in the liver

5. Ethanol Clinical Features Slurred speech, nystagmus, disinhibited behavior, CNS depression ( a spectrum which my lead to coma), and poor motor coordination and control Slurred speech, nystagmus, disinhibited behavior, CNS depression ( a spectrum which my lead to coma), and poor motor coordination and control Hypotension Hypotension Tolerance Tolerance

6. Ethanol Treatment Mainstay of treatment is supportive Mainstay of treatment is supportive Attention to ABC’s, associated injuries, or co- morbid conditions. Bedside glucose check Thiamine, Folate, Multivitamins, Magnesium, Fluids (D5NS)

7. Ethanol Treatment Careful serial examines are crucial Careful serial examines are crucial Respiratory depression may require intubation Respiratory depression may require intubation Most eliminate ethanol at a rate of 0.20-0.25/hr Most eliminate ethanol at a rate of 0.20-0.25/hr Cocaethylene Cocaethylene Metabolite formed by the combination of ETOH and Cocaine

8. Ethanol Disposition Most rarely require hospitalization and can be sent home as long as certain conditions are in place Most rarely require hospitalization and can be sent home as long as certain conditions are in place State legal limits very State legal limits very Ohio 0.08

9. Methanol Overview Also called methyl alcohol or “wood alcohol” Also called methyl alcohol or “wood alcohol” Colorless,volatile liquid, with a distinctive odor Colorless,volatile liquid, with a distinctive odor Common Sources Sterno, paint removers, varnishes, shellacs, windshield fluids, and antifreeze Sterno, paint removers, varnishes, shellacs, windshield fluids, and antifreeze Toxic Metabolites Formaldehyde & Formic acid Formaldehyde & Formic acid

10. Methanol Pharmacology and Metabolism Rapidly absorbed Rapidly absorbed Transdermal and respiratory absorption has resulted in toxicity Transdermal and respiratory absorption has resulted in toxicity As little as 1.5ml of 100% methanol can produce a toxic level in small children High risk for inhalation exposure: painting, glazing, varnishing, lithography, and printing High risk for inhalation exposure: painting, glazing, varnishing, lithography, and printing

11. Methanol Pharmacology and Metabolism Serum levels peak 30 to 60 minutes Serum levels peak 30 to 60 minutes Half life is 24 to 30 hours Half life is 24 to 30 hours Prolonged by Ethanol Smallest lethal dose Smallest lethal dose 15 mL in adults and 1.5 mL in toddlers

12. Methanol Pharmacology and Metabolism Methanol has little toxicity and produces less inebriation than ethanol Methanol has little toxicity and produces less inebriation than ethanol Methanol  Formaldehyde  Formic Acid  CO2 and Water Methanol  Formaldehyde  Formic Acid  CO2 and Water Formic Acid responsible for much of Anion Gap and Ocular toxicity Formic Acid responsible for much of Anion Gap and Ocular toxicity

13. Methanol Pathophysiology/Clinical Features Optic Neuropathy Optic Neuropathy “Snow blindness”: diplopia, photophobia, and blindness Putaminal Injury Putaminal Injury Parkinsonian type motor dysfunction, hypokinesis, and rigidity Mechanism Mechanism Formic Acid has a high affinity for iron and inhibits mitochondrial cytochrome oxidase, halting cellular respiration Metabolism in the cytosol and mitochondria account for a second mechanism of ATP depletion

14. Methanol Clinical Features Symptoms may not appear until 12 to 18 hours after the ingestion Symptoms may not appear until 12 to 18 hours after the ingestion “Cardinal” signs of toxicity: “Cardinal” signs of toxicity: CNS effects similar to ETOH intoxication with N/V, abdominal pain, visual disturbances, and a wide anion gap metabolic acidosis Coma and seizures can develop in severe cases Coma and seizures can develop in severe cases Hypotension and bradycardia are late findings and suggests a poor outcome

15. Methanol Prognosis Correlates with the degree of acidosis, not with the serum methanol level. Correlates with the degree of acidosis, not with the serum methanol level. Treatment initiation within 8 hours of exposure Treatment initiation within 8 hours of exposure Poor prognosis associated with coma, hypotension, bradycardia, seizures, or arterial pH less than 7.0 Poor prognosis associated with coma, hypotension, bradycardia, seizures, or arterial pH less than 7.0 Patients who survive may have permanent blindness or severe neurologic deficits Patients who survive may have permanent blindness or severe neurologic deficits

16. Methanol Laboratory Features Anion Gap Anion Gap may be delayed 12 to 24 hours Absence with concomitant ethanol, lithium, or bromide ingestion Elevated “Osmolar Gap” Elevated “Osmolar Gap” OG = Meas. Serum Osm. - Cal. Osmolality Normal gap is (-14 to +10) Normal gap is (-14 to +10) Calculated osmolality= 2Na + BUN/2.8 + glucose/18 + ethanol/4.6 Calculated osmolality= 2Na + BUN/2.8 + glucose/18 + ethanol/4.6

17. Ethylene Glycol Overview Viscous, colorless, slightly sweet-tasting Viscous, colorless, slightly sweet-tasting Primarily used in antifreeze and coolants Primarily used in antifreeze and coolants Also in airplane deicing solutions, hydraulic brake fluids, industrial solvents, paints, lacquers, and cosmetics Also in airplane deicing solutions, hydraulic brake fluids, industrial solvents, paints, lacquers, and cosmetics Most poisonings involve Antifreeze Most poisonings involve Antifreeze

18. Ethylene Glycol Epidemiology In 2001, there were 4938 exposures with 16 fatalities In 2001, there were 4938 exposures with 16 fatalities 90% unintentional 90% unintentional Most were children or suicide attempts Most were children or suicide attempts 12% moderate to severe effects 12% moderate to severe effects Rapid treatment is imperative! If treated early and aggressively, death is unlikely, but delay will result in multiorgan failure in 24 to 36 hours If treated early and aggressively, death is unlikely, but delay will result in multiorgan failure in 24 to 36 hours

19. Ethylene Glycol Pharmacology/Metabolism Rapid absorption after ingestion Rapid absorption after ingestion Distributes evenly in the tissues, with peaked levels at 1-4 hours Distributes evenly in the tissues, with peaked levels at 1-4 hours Nonvolatile and inhalation absorption is unlikely Nonvolatile and inhalation absorption is unlikely Half life of 3 to 8.6 hours Half life of 3 to 8.6 hours Toxic doses of 0.2 ml/kg - 1.4 ml/kg Toxic doses of 0.2 ml/kg - 1.4 ml/kg

20. Ethylene Glycol Pathophysiology Metabolized in the liver (70%) and kidneys (30%) to toxic metabolites- aldehydes, glycolate, oxalate, and lactate Metabolized in the liver (70%) and kidneys (30%) to toxic metabolites- aldehydes, glycolate, oxalate, and lactate 2.3% converted to Oxalic acid, of which a small portion complexes with calcium to form calcium oxalate crystals 2.3% converted to Oxalic acid, of which a small portion complexes with calcium to form calcium oxalate crystals These precipitate in kidney, brain, and peripheral tissues These precipitate in kidney, brain, and peripheral tissues these are harmful but the generation of toxic metabolites appear to be most responsible for the lethal effects to target tissues these are harmful but the generation of toxic metabolites appear to be most responsible for the lethal effects to target tissues

21. Ethylene Glycol Clinical Features Four Stages of Ethylene Glycol toxicity Four Stages of Ethylene Glycol toxicity Acute Neurologic CardiopulmonaryRenal Delayed Neurologic Injury

22. Ethylene Glycol Diagnosis Crystalluria is the hallmarks of EG ingestion, however its absence does not exclude the diagnosis Crystalluria is the hallmarks of EG ingestion, however its absence does not exclude the diagnosis Useful test include: Useful test include: Electrolytes, calcium, BUN, Creatinine, glucose, serum osmolality, ethanol level, ABG, ethylene glycol level, EKG, UA Wood’s lamp fluorescence on a freshly voided urine specimen may be helpful if EG is suspected

23. Ethylene Glycol Diagnostic Test Leukocytosis is nonspecific and non-sensitive Leukocytosis is nonspecific and non-sensitive QT prolongation with hypocalcemia secondary to crystal formation QT prolongation with hypocalcemia secondary to crystal formation CPK may be elevated CPK may be elevated Anion gap acidosis seen secondary to metabolites glycolic acid and glyoxylic acid Anion gap acidosis seen secondary to metabolites glycolic acid and glyoxylic acid

24. Methanol and Ethylene Glycol Management Treatment essentially the same Treatment essentially the same As in the OD setting, resuscitation and stabilization are paramount As in the OD setting, resuscitation and stabilization are paramount Gastric emptying is not effective due to rapid absorption Gastric emptying is not effective due to rapid absorption Only if ingestion in last 30 to 60 minutes Only if ingestion in last 30 to 60 minutes Activated charcoal not effective Activated charcoal not effective

25. Methanol and Ethylene Glycol Management Severely obtunded patients should receive attention to ABC’s and “DON’T” therapy (dextrose,oxygen,naloxone, and thiamine) Severely obtunded patients should receive attention to ABC’s and “DON’T” therapy (dextrose,oxygen,naloxone, and thiamine) Forced diuresis is of no value and may cause pulmonary edema or ARDS Forced diuresis is of no value and may cause pulmonary edema or ARDS Early intubation may be indicated Early intubation may be indicated

26. Methanol and Ethylene Glycol Management Treatment goals Treatment goals Correction of Metabolic Acidosis ADH Blockade thereby inhibiting the generation of toxic metabolites Hemodialysis to remove alcohol

27. Methanol and Ethylene Glycol Management Metabolic Acidosis Metabolic Acidosis Large doses of bicarbonate may be required to correct the acidosis Early correction is imperative to reduce the chance of methanol induced visual loss Target pH is 7.45 to 7.50 Bicarbonate may worsen hypocalcemia with Ethylene Glycol

28. Methanol and Ethylene Glycol Management Blocking ADH Blocking ADH Either Ethanol or Fomepizole may be used ETOH ETOH Target level of ethanol is 100 to 150 mg/dL ETOH increases the half-life to 30 hours Methanol and 17 hours Ethylene Glycol Fomepizole Fomepizole blocks ADH and has more predictable pharmacokinetics and improved safety profile more expensive

29. Methanol and Ethylene Glycol Management Hemodialysis Hemodialysis Indications: triad of hx, clinical, and lab results confirm toxic ingestion, EG > 20, ARF, metabolic acidosis Removes preformed metabolites Peritoneal dialysis is less effective Endpoint is undetectable serum ethylene glycol or methanol concentration

30. Isopropyl Alcohol Overview Clear, colorless, slightly bitter Clear, colorless, slightly bitter Second most commonly ingested alcohol Second most commonly ingested alcohol Found in nail polish removers, household disinfectants, and window cleaners, and common rubbing alcohol Found in nail polish removers, household disinfectants, and window cleaners, and common rubbing alcohol Less toxic than methanol or ethylene glycol Less toxic than methanol or ethylene glycol

31. Isopropyl Alcohol Epidemiology In 2002 In 2002 31,187 exposures 91% unintentional 3% moderate to major effects 4 fatalities Fatalities are usually associated with chronic alcoholics with mixed ingestions Fatalities are usually associated with chronic alcoholics with mixed ingestions

32. Isopropyl Alcohol Phamacology/Metabolism Absorption is rapid and complete, with peak serum levels in 30 min, with a half-life of 3-7 hours Absorption is rapid and complete, with peak serum levels in 30 min, with a half-life of 3-7 hours Potentially lethal dose is 150 to 240 mL (2 to 4 mL/Kg) but adults have survived up to 1 Liter Potentially lethal dose is 150 to 240 mL (2 to 4 mL/Kg) but adults have survived up to 1 Liter 80% undergoes hepatic metabolism to acetone 80% undergoes hepatic metabolism to acetone Remaining 20% undergoes renal elimination unchanged Remaining 20% undergoes renal elimination unchanged

33. Isopropyl Alcohol Clinical Features CNS CNS Inebriation with acetone odor Headache, dizziness Neuromuscular dysfunction, confusion, nystagmus Coma in severe ingestions Respiratory depression or failure may occur

34. Isopropyl Alcohol Clinical Features GI GI Gastritis may occur Hematemesis associated with gastritis but not common Abdominal pain, nausea, vomiting common

35. Isopropyl Alcohol Clinical Features Hypotension Hypotension Rare but associated with severe ingestions, mortality rate is 45% Caused by peripheral vasodilatation and direct myocardial depression Sinus tachycardia Sinus tachycardia common but other dysrythmias if found are usually associated with hypoxia, acidosis, or shock Myoglobinuria, ATN, or hemolytic anemias may be present Myoglobinuria, ATN, or hemolytic anemias may be present

36. Isopropyl Alcohol Diagnostic Test: Isopropanol level Isopropanol level electrolytes, osmolality, serum and urine ketones electrolytes, osmolality, serum and urine ketones Ketosis Ketosis most common lab abnormality (from acetone) Increased osmolar gap Increased osmolar gap

37. Isopropyl Alcohol Diagnostic Strategies “Pseudo-renal failure” “Pseudo-renal failure” Early diagnostic clue with elevated creatinine and normal BUN 100mg/dL of Isopropanol falsely elevates the creatinine 1mg/dL CPK should be obtained CPK should be obtained

38. Isopropyl Alcohol Management ABC’s, glucose check, thiamine, narcan ABC’s, glucose check, thiamine, narcan Gastric emptying or charcoal is not useful unless ingestion was large and recent Gastric emptying or charcoal is not useful unless ingestion was large and recent ADH blockade not indicated ADH blockade not indicated Manage hypotension with fluids/vasopressors Manage hypotension with fluids/vasopressors

39. Isopropyl Alcohol Management Dialysis is indicated for refractory hypotension or patients vital signs deteriorate Dialysis is indicated for refractory hypotension or patients vital signs deteriorate Coma not an indication for dialysis Hemodynamic stability without coma in first 6 hours rarely develops significant sequelae Hemodynamic stability without coma in first 6 hours rarely develops significant sequelae Care can generally be supportive in this case

40. Toxic Alcohols Key Concepts Small doses can kill Small doses can kill Latent periods can fool you (EG & Methanol) Latent periods can fool you (EG & Methanol) Double gap acidosis, think: ethylene glycol or methanol ingestions Double gap acidosis, think: ethylene glycol or methanol ingestions Early treatment improves outcomes, you must act quickly Early treatment improves outcomes, you must act quickly Toxicity can not be excluded based on “normal” osmolar gap Toxicity can not be excluded based on “normal” osmolar gap

41. Opioids II

42. Opioids Historical perspective In use for over 5000 years In use for over 5000 years Term for opium is derived from the Greek word for poppy juice Term for opium is derived from the Greek word for poppy juice Receptors and endogenous opioids have been recognized and characterized only in the last 25 years Receptors and endogenous opioids have been recognized and characterized only in the last 25 years

43. Opioids Terms/Definitions: Opioids natural, synthetic, and semi synthetic agent with morphine like properties natural, synthetic, and semi synthetic agent with morphine like properties In the US, heroin and opioid derivatives are abused most often and the cause of most deaths In the US, heroin and opioid derivatives are abused most often and the cause of most deathsOpiate only natural agent only natural agentNarcotics any agent that induces sleep and is nonspecific any agent that induces sleep and is nonspecificEndorphins Any peptide in the three opioid family: enkephalins, B-endorphins, and dynorphins Any peptide in the three opioid family: enkephalins, B-endorphins, and dynorphins

44. Opioids Mechanism of Action: Modulate nociception in the terminals of afferent nerves in the CNS and PNS Modulate nociception in the terminals of afferent nerves in the CNS and PNS Three endogenous receptors OP 1 (delta) OP 1 (delta) OP 2 (kappa) OP 2 (kappa) OP 3 (mu) OP 3 (mu) Concentrated in pain pathways, periaqueductal grey matter, locus ceruleus, limbic system, nucleus raphe

45. Opioids Clinical Features Wide variety of signs and symptoms Wide variety of signs and symptoms Miosis is not universal Miosis is not universal Respiratory effects are variable Respiratory effects are variable Look for shallow respirations, cyanosis, bradypnea, or hypercarbia Diagnostic triad: Diagnostic triad: CNS depression, miosis, and respiratory depression strongly suggest opioid intoxication strongly suggest opioid intoxication

46. Opioids Differential Diagnosis Clonidine Clonidine Periods of apnea that respond to tactile stim Organophosphates and Carbamates Organophosphates and Carbamates Muscle fasciculations, profuse N/V Phenothiazines Phenothiazines CNS depression and miosis Carbon Monoxide exposure Carbon Monoxide exposure Profound CNS depression

47. Opioids Management : Opioids Management : ABC’s…Airway management Interventions may include supplemental oxygen,BiPaP, or BVM leading to intubation GI Decontamination Usually not routine Usually not routine Consider whole bowel irrigation for “body packers” Consider whole bowel irrigation for “body packers” Activated Charcoal 1 g/Kg 1 g/Kg may be beneficial to promote motility with large ingestions may be beneficial to promote motility with large ingestionsHypotension Treat with IV fluids, pressor agents as needed Treat with IV fluids, pressor agents as needed

48. Opioids Reversal Agents Narcan (Naloxone) a pure opioid antagonist with rapid onset of action a pure opioid antagonist with rapid onset of action IV, SC, down ETT, and IM…not effective PO! IV, SC, down ETT, and IM…not effective PO! Acts by competitive binding at the receptor site Acts by competitive binding at the receptor site Revex (Nalmefene) Opioid antagonist alternative with long half-life and rapid onset Opioid antagonist alternative with long half-life and rapid onset PO, IV, SC, IM routes PO, IV, SC, IM routes Initial IV dose is 0.5 to 1.5mg Initial IV dose is 0.5 to 1.5mg

49. Opioids Withdrawal Not life threatening Not life threatening Heroin Half-life : 0.5 hours Heroin Half-life : 0.5 hours Signs and symptoms may include CNS excitation, tachypnea, tachycardia, hypertension, and mydriasis Signs and symptoms may include CNS excitation, tachypnea, tachycardia, hypertension, and mydriasis Care is supportive and focused at minimizing symtoms in tolerant individuals Care is supportive and focused at minimizing symtoms in tolerant individuals Withdrawal can be managed in the outpatient setting Withdrawal can be managed in the outpatient setting Patients who have refractory N/V, electrolyte abnormalities, or those with an uncertain diagnosis should be admitted

50. Opioids Withdrawal Agents Methadone or l-a-acetylmethadol (LAAM) Long and longer acting opioids Long and longer acting opioids Used to treat chronic herion addiction Used to treat chronic herion addiction 20mg PO or 10mg IM 20mg PO or 10mg IM Controls cravings with limited euphoric effect Controls cravings with limited euphoric effect LAAM dose is 30mg PO LAAM dose is 30mg POClonidine Central a2-agonist Central a2-agonist Controls symptoms by suppressing sympathetic hyperactivity Controls symptoms by suppressing sympathetic hyperactivity Dose is 0.1mg PO, patches are an option Dose is 0.1mg PO, patches are an option Hypotension may limit treatment but usually not common in withdraw treatment Hypotension may limit treatment but usually not common in withdraw treatment

51. Opioids Key Concepts Diagnosis is based on history& physical exam Diagnosis is based on history& physical exam Key triad: CNS depression, respiratory depression, and miosis Supportive care is the mainstay, with attention to airway Supportive care is the mainstay, with attention to airway Duration of opioids is longer than narcan Duration of opioids is longer than narcan So…don’t discharge your patient until your certain the opioid properties are fully metabolize This depends on the agents involved! This depends on the agents involved! Opioid withdrawal is supportive and focused at minimizng the symptoms of withdrawal Opioid withdrawal is supportive and focused at minimizng the symptoms of withdrawal

52. THE END!!! Questions?