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Toxic Alcohols and Opioids Jamil A. Alarafi, D.O. 02.01.2007 Toxic Alcohols Ethanol Methyl Alcohol Ethylene Glycol Isopropyl Alcohol Ethanol Everybody's favorite! Unique among abused drugs Most frequently used and abused in most societies Estimated to contribute to 100,000 deaths/yr 40% of MVC’s are related to ETOH use Ethanol Pathophysiology CNS Depressant Absorption: mouth to small bowel Elimination: 2 – 10% from lungs, urine, and sweat Primary metabolized in the liver Ethanol Clinical Features Slurred speech, nystagmus, disinhibited behavior, CNS depression ( a spectrum which my lead to coma), and poor motor coordination and control Hypotension Tolerance Ethanol Treatment Mainstay of treatment is supportive Attention to ABC’s, associated injuries, or comorbid conditions. Bedside glucose check Thiamine, Folate, Multivitamins, Magnesium, Fluids (D5NS) Ethanol Treatment Careful serial examines are crucial Respiratory depression may require intubation Most eliminate ethanol at a rate of 0.20-0.25/hr Cocaethylene Metabolite formed by the combination of ETOH and Cocaine Ethanol Disposition Most rarely require hospitalization and can be sent home as long as certain conditions are in place State legal limits very Ohio 0.08 Overview Methanol Also called methyl alcohol or “wood alcohol” Colorless,volatile liquid, with a distinctive odor Common Sources Sterno, paint removers, varnishes, shellacs, windshield fluids, and antifreeze Toxic Metabolites Formaldehyde & Formic acid Methanol Pharmacology and Metabolism Rapidly absorbed 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 Methanol Pharmacology and Metabolism Serum levels peak 30 to 60 minutes Half life is 24 to 30 hours Prolonged by Ethanol Smallest lethal dose 15 mL in adults and 1.5 mL in toddlers Methanol Pharmacology and Metabolism Methanol has little toxicity and produces less inebriation than ethanol Methanol Formaldehyde Formic Acid CO2 and Water Formic Acid responsible for much of Anion Gap and Ocular toxicity Methanol Pathophysiology/Clinical Features Optic Neuropathy “Snow blindness”: diplopia, photophobia, and blindness Putaminal Injury Parkinsonian type motor dysfunction, hypokinesis, and rigidity 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 Methanol Clinical Features Symptoms may not appear until 12 to 18 hours after the ingestion “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 Hypotension and bradycardia are late findings and suggests a poor outcome Methanol Prognosis Correlates with the degree of acidosis, not with the serum methanol level. Treatment initiation within 8 hours of exposure 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 Methanol Laboratory Features Anion Gap may be delayed 12 to 24 hours Absence with concomitant ethanol, lithium, or bromide ingestion Elevated “Osmolar Gap” OG = Meas. Serum Osm. - Cal. Osmolality Normal gap is (-14 to +10) Calculated osmolality= 2Na + BUN/2.8 + glucose/18 + ethanol/4.6 Ethylene Glycol Overview Viscous, colorless, slightly sweet-tasting Primarily used in antifreeze and coolants Also in airplane deicing solutions, hydraulic brake fluids, industrial solvents, paints, lacquers, and cosmetics Most poisonings involve Antifreeze Ethylene Glycol Epidemiology In 2001, there were 4938 exposures with 16 fatalities 90% unintentional Most were children or suicide attempts 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 Ethylene Glycol Pharmacology/Metabolism Rapid absorption after ingestion Distributes evenly in the tissues, with peaked levels at 1-4 hours Nonvolatile and inhalation absorption is unlikely Half life of 3 to 8.6 hours Toxic doses of 0.2 ml/kg - 1.4 ml/kg Ethylene Glycol Pathophysiology 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 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 Ethylene Glycol Clinical Features Four Stages of Ethylene Glycol toxicity Acute Neurologic Cardiopulmonary Renal Delayed Neurologic Injury Ethylene Glycol Diagnosis Crystalluria is the hallmarks of EG ingestion, however its absence does not exclude the diagnosis 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 Ethylene Glycol Diagnostic Test Leukocytosis is nonspecific and non-sensitive QT prolongation with hypocalcemia secondary to crystal formation CPK may be elevated Anion gap acidosis seen secondary to metabolites glycolic acid and glyoxylic acid Methanol and Ethylene Glycol Management Treatment essentially the same As in the OD setting, resuscitation and stabilization are paramount Gastric emptying is not effective due to rapid absorption Only if ingestion in last 30 to 60 minutes Activated charcoal not effective Methanol and Ethylene Glycol Management 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 Early intubation may be indicated Methanol and Ethylene Glycol Management Treatment goals Correction of Metabolic Acidosis ADH Blockade thereby inhibiting the generation of toxic metabolites Hemodialysis to remove alcohol Methanol and Ethylene Glycol Management 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 Methanol and Ethylene Glycol Management Blocking ADH Either Ethanol or Fomepizole may be used 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 blocks ADH and has more predictable pharmacokinetics and improved safety profile more expensive Methanol and Ethylene Glycol Management 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 Isopropyl Alcohol Overview Clear, colorless, slightly bitter Second most commonly ingested alcohol Found in nail polish removers, household disinfectants, and window cleaners, and common rubbing alcohol Less toxic than methanol or ethylene glycol Isopropyl Alcohol Epidemiology In 2002 31,187 exposures 91% unintentional 3% moderate to major effects 4 fatalities Fatalities are usually associated with chronic alcoholics with mixed ingestions Isopropyl Alcohol Phamacology/Metabolism 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 80% undergoes hepatic metabolism to acetone Remaining 20% undergoes renal elimination unchanged Isopropyl Alcohol Clinical Features CNS Inebriation with acetone odor Headache, dizziness Neuromuscular dysfunction, confusion, nystagmus Coma in severe ingestions Respiratory depression or failure may occur Isopropyl Alcohol Clinical Features GI Gastritis may occur Hematemesis associated with gastritis but not common Abdominal pain, nausea, vomiting common Isopropyl Alcohol Clinical Features Hypotension Rare but associated with severe ingestions, mortality rate is 45% Caused by peripheral vasodilatation and direct myocardial depression Sinus tachycardia common but other dysrythmias if found are usually associated with hypoxia, acidosis, or shock Myoglobinuria, ATN, or hemolytic anemias may be present Isopropyl Alcohol Diagnostic Test: Isopropanol level electrolytes, osmolality, serum and urine ketones Ketosis most common lab abnormality (from acetone) Increased osmolar gap Isopropyl Alcohol Diagnostic Strategies “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 Isopropyl Alcohol Management ABC’s, glucose check, thiamine, narcan Gastric emptying or charcoal is not useful unless ingestion was large and recent ADH blockade not indicated Manage hypotension with fluids/vasopressors Isopropyl Alcohol Management 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 Care can generally be supportive in this case Toxic Alcohols Key Concepts Small doses can kill Latent periods can fool you (EG & Methanol) Double gap acidosis, think: ethylene glycol or methanol ingestions Early treatment improves outcomes, you must act quickly Toxicity can not be excluded based on “normal” osmolar gap Opioids II Opioids Historical perspective In use for over 5000 years 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 Opioids Terms/Definitions: Opioids 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 Opiate only natural agent Narcotics any agent that induces sleep and is nonspecific Endorphins Any peptide in the three opioid family: enkephalins, B-endorphins, and dynorphins Opioids Mechanism of Action: Modulate nociception in the terminals of afferent nerves in the CNS and PNS Three endogenous receptors OP1 (delta) OP2 (kappa) OP3 (mu) Concentrated in pain pathways, periaqueductal grey matter, locus ceruleus, limbic system, nucleus raphe Opioids Clinical Features Wide variety of signs and symptoms Miosis is not universal Respiratory effects are variable Look for shallow respirations, cyanosis, bradypnea, or hypercarbia Diagnostic triad: CNS depression, miosis, and respiratory depression strongly suggest opioid intoxication Opioids Differential Diagnosis Clonidine Periods of apnea that respond to tactile stim Organophosphates and Carbamates Muscle fasciculations, profuse N/V Phenothiazines CNS depression and miosis Carbon Monoxide exposure Profound CNS depression Opioids Management: ABC’s…Airway management Interventions may include supplemental oxygen,BiPaP, or BVM leading to intubation GI Decontamination Usually not routine Consider whole bowel irrigation for “body packers” Activated Charcoal 1 g/Kg may be beneficial to promote motility with large ingestions Hypotension Treat with IV fluids, pressor agents as needed Opioids Reversal Agents Narcan (Naloxone) a pure opioid antagonist with rapid onset of action IV, SC, down ETT, and IM…not effective PO! Acts by competitive binding at the receptor site Revex (Nalmefene) Opioid antagonist alternative with long half-life and rapid onset PO, IV, SC, IM routes Initial IV dose is 0.5 to 1.5mg Opioids Withdrawal Not life threatening Heroin Half-life : 0.5 hours Signs and symptoms may include CNS excitation, tachypnea, tachycardia, hypertension, and mydriasis Care is supportive and focused at minimizing symtoms in tolerant individuals 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 Opioids Withdrawal Agents Methadone or l-a-acetylmethadol (LAAM) Long and longer acting opioids Used to treat chronic herion addiction 20mg PO or 10mg IM Controls cravings with limited euphoric effect LAAM dose is 30mg PO Clonidine Central a2-agonist Controls symptoms by suppressing sympathetic hyperactivity Dose is 0.1mg PO, patches are an option Hypotension may limit treatment but usually not common in withdraw treatment Opioids Key Concepts Diagnosis is based on history& physical exam Key triad: CNS depression, respiratory depression, and miosis Supportive care is the mainstay, with attention to airway 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! Opioid withdrawal is supportive and focused at minimizng the symptoms of withdrawal THE END!!! Questions?
