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Highlights of Toxicology Mark Kostic, MD Acetaminophen (APAP) Metabolism: o Glucuronidation and sulfation o CYP 2E1 NAPQI (toxic metabolite) Therapeutic doses reduced by glutathione Toxicity in OD o NAPQI hepatocellular necrosis Dx: 4 hr level on Rumack-Matthews nomogram Tx: N-acetylcysteine (NAC) o 140 mg/kg then 70 mg/kg q4 po or IV treat x 24 hrs if no toxic effect, if LFTs increased, treat til better o Acetadote – FDA approved IV NAC – 21 hr continuous infusion Load 150 mg/kg over 1 hr; then 50 mg/kg over 4 hrs (12.5 mg/kg/hr); then 100 mg/kg over 16 hrs (6.25 mg/kg/hr) o Unknown time of ingestion NAC x 12-24 hrs and re-assess o Repeated supertherapeutic if LFTs up tx til better Transplant criteria: o Arterial pH < 7.3 (after IV fluids) OR o INR >6 + Cr > 3.4 + Gr III or IV encephalopathy o Also Lactate > 3.0 after IVF Alcohols Consider MeOH or EG in any patient with unexplained increased anion gap metabolic acidosis (esp if does not improve with IVF) EtOH in a child may cause hypoglycemia All may cause an osmol gap, but a normal Osm gap does not rule out intoxication Toxicity takes time, all removed by dialysis Level AG End organ Rx of Metabolites Antidote acidosis toxicity Adjuncts intox Retina, Formic optic Fomepizole, Methanol + +++ Folate acid nerve, EtOH brain None Ethanol ++ (except Acetic acid AKA) Glycolic acid, Ethylene Fomepizole, Thiamine, ++ +++ Oxalic acid Kidneys Glycol EtOH B6 (Ca Oxalate) Isopropanol +++ Acetone 1 Anticonvulsants Most work through CNS Na channel inactivation Nystagmus ataxia mental status depression Phenytoin: low levels first order kinetics Higher levels zero order kinetics Carbamazepine: can rarely see paradoxical sz, alternating mental status Valproic Acid: hyperammonemia, incr LFTs, carnitine deficiency Enterohepatic circulation Antihistamines/Anticholinergics (antimuscarinics) Toxidrome o Peripheral: hot/dry skin, dry mucous membranes, dec GI motility, flushed, urinary retention, mydriasis o Central: agitated delirium, sedation/coma, sz, mild hyperthermia o *patients rarely manifested all symptoms* Diphenhydramine Quinidine (Na ch blocking/”membrane stabilizing”) effects o Looks like TCA OD o Tx bicarb Dx: Physostigmine: 1-2 mg IV over 4 minutes (atropine at bedside, monitors) o May seize o Avoid with TCA effect on ECG Antipsychotics Dopamine (D2) receptor antagonists Typical: Phenothiazines, Butyrophenones (haloperidol, droperidol) o Higher rate of akathesia, dystonia, parkinsonism o Cardiac: Na and K ch blockade QTc prolongation, toursades Esp thioridazine, mesoridazine, haldol, droperidol o Neuroleptic Malignant Syndrome (NMS) Hyperthermia + rigidity + mental status change + autonomic instability A spectrum Tx: benzos, support, intubate if needed, treat rhabdo Atypical o Clozapine, Olanzapine, Quetiapine, Risperidone, etc Sedation, tachycardia, orthostatic hypotension, prolonged QTc Botulism Mech: presynaptic blockade of ACH release Sx: dizzy, fatigue, sore throat GI sxs diplopia, dysarthria, dysphagia ptosis, ataxia, descending paralysis, resp failure Foodborne (ingestion of pre-formed toxin): Type A (West of Mississippi); Type B (East of Mississippi); Type E (Pacific northwest) Infantile (spore ingestion): floppy, constipated baby o Associated with honey prior to age 1 yr 2 o Antitoxin not effective o BabyBIG (Bolulism Immune Globulin Intravenous [human]) Contact local health dept or CDC for either antidote Neither antidote removes toxin already bound to the nerve terminal Wound (spores grow and release toxin in an anaerobic environment) Beta Blockers Usually well tolerated if no baseline heart disease Propranolol: lipid soluble (crosses BBB sz, MS change), membrane stabilizing activity (prolonged QRS) Sx: bradycardia, hypotensive, hypoglycemia in kids Tx: o Judicious IV fluids o Atropine (likely won’t work) o Vasopressors (may not work) o Glucagon (5 mg doses q 15 min, then drip) o Hi-dose Insulin and glucose o IABP o Lipids o Pacers may increase rate, but don’t improve BP o Decontaminate (consider WBI) Calcium Channel Blockers Typically more dangerous than most BBs Selectivity lost in OD Hypotensive, bradycardic, hyperglycemic with normal mental status Treatment similar to BBs except: o Calcium early (several amps to raise total Ca to mid to hi teens) o Glucagon less helpful, insulin/glucose more helpful (better studied) Carbon Monoxide Main source: incomplete combustion of fossil fuels Presents with flu-like illness 200x greater affinity for hemoglobin Also shifts Oxy-Hgb dissociation curve to left Tx: 100% O2 o Hyperbaric O2 may reduce incidence of delayed neurologic sequelae Indications: Definite: LOC, COHgb>25%, Age >50, metabolic acidosis, cerebellar dysfunction Relative: pregnancy, persistent neuro deficit, cardiac ischemia, hi levels Caustic Ingestion Amount of injury is pH, concentration, and volume dependent 3 Endoscopy recommended between 12-24 hrs Button batteries must be removed ASAP if lodged in esophagus Clonidine Central alpha2 (inhibitory) agonist decreased sympathetic outflow Mimics opioid OD 1-2 pills toxic in toddlers Tx: support, alpha agonist for hypotension, narcan Cyanide “bitter almonds” smell (50%) Blocks oxidative phosphorylation Metabolic acidosis, “arteriolization” of venous blood, AMS, sz Closed space fires Tx: o Lilly antidote kit Amyl Nitrite pearls, Sodium Nitrite, Sodium thiosulfate o Hydroxocobalamin Dextromethorphan Optical isomer of levorphanol (an opioid), but has no analgesic activity Binds to PCP site on NMDA receptor o Abused for its potential euphoria and hallucinogenic qualities o Nystagmus, AMS Blocks pre-synaptic serotonin reuptake Decontamination Not a benign procedure! Activated Charcoal – 1 gm/kg o Repeat dose Whole Bowel Irrigation o Sustained release products, packers, things not bound by AC Gastric lavage o Life threatening OD, no antidote, airway protected, soon after ingestion (rarely indicated) Digoxin (Cardiac Glycosides) Inhibits Na+/K+ ATPase raised intracellular Na+ increased gradient at Na+//Ca++ exchanger raised intracellular Ca++ Increases vagal tone Decrease conduction through SA and AV nodes Glycosides in plants: oleander, foxglove, lily of the valley, red squill Presentation any dysrhythmia except afib/flutter with RVR o Acute hyperkalemia, n/v, higher levels o Chronic more common, K nl/hi/low, 4 Typically: dehydration and renal insuff inc levels o Classic ECG: bidirectional Vtach, PAT with block Tx: Digibind o Acute OD and crashing – 10-20 vials o Chronic OD: #vials = level(ng/ml) x wt (kg) 100 Enhanced Elimination Sodium bicarbonate – urine alkalinization Multi-dose activated charcoal Hemodialysis Hydrocarbons Aliphatics (gasoline, kerosene, mineral spirits) o Aspiration pneumonitis ARDS o Pediatric mortality o Most dangerous low viscosity, hi volatility Aromatics (benzene, toluene, xylene) o Sniffing, huffing, bagging o Highly addictive Halogenated (methylene chloride, carbon tet, TCE) o Myocardial sensitization Hydrofluoric Acid Ingestion o Mech: binds intracellular Calcium and Mag hypocalcemia efflux of K+ hyperkalemia dysrhythmias/death o Highly lethal o Tx: Ca++ chloride IV(central line) Dermal o Classic: pt presents with severe hand pain and redness several hrs after using rust remover, or doing glass etching o Severe tissue burns/necrosis due to binding with Ca++ o Tx: Decontaminate, Ca++ gluconate gel, Ca++ gluconate local infiltration, Ca++ infusion via Bier block or intra-arterial Hydrogen Sulfide Sewer gas, “knock down gas”, multiple victims Colorless, odor of rotten eggs Permanently binds to hemoglobin and inhibits oxidative phosphorylatioin Tx: Hi flow O2 Iron “Toxic dose” > 40 mg/kg of elemental iron Stages (for board exams only!) o 1 – GI 5 o 2 – quiescent o 3 – systemic toxicity (hypotension, acidosis, coma, sz) o 4 – hepatic failure o 5 – late complications (SBO, GOO) Mech: o direct caustic o disrupts oxidative phosphorylation o free radical formation, lipid peroxidation o inhibits thrombin formation o periportal hepatic necrosis Dx: Fe levels, +/- KUB Tx: o Volume o Deferoxamine 15 mg/kg/hr (100 mg DFO binds 9 mg Fe) Isoniazid Mech: interferes with pyridoxine (cofactor needed for GABA synthesis) Sx: persistent seizures with subsequent metabolic acidosis Tx: Pyridoxine o Gram for gram of INH ingested o Unknown amount ingested 5 gm (70 mg/kg peds) Lithium Unknown mechanism Renal clearance (handled like sodium) Sx: o Acute: GI > neuro, higher levels needed to be toxic o Chronic: neuro > GI, lower levels Other effects: nephrogenic DI (rare), flattened T waves Tx: IV fluids (saline), hemodialysis Local Anesthetics AmIdes (LIdocaine, BupIvicaine, MepIvicaine, PrIlocaine); Esters (Procaine, Benzocaine, cocaine, Tetracaine) More allergic rxns to esters (PABA) CNS toxicity (seizures) well before cardiac (mostly from inadvertent IV) Potential for methemoglobinemia (benzocaine) Lidocaine max doses: o Without epi: 4.5 mg/kg (31 ml of 1% for 70 kg pt) o With epi: 7 mg/kg (49 ml of 1% for 70 kg pt) MAO Inhibitors Inhibits Monoamine Oxidase increased pre-synaptic levels of NE, DA, 5HT Symptoms from OD of MAOI or its interaction with other meds (e.g. serotonin syndrome) or foods containing tyramine o Hemodynamic instability, altered mental status, rigidity, tremor, hyperthermia, etc 6 Tx: cooling, BZDs, alpha agonist (not dopamine) for hypotension, Nipride for HTN, paralysis if needed Metals - Acute severe GI effects unless the elemental form ingested - reacts with sulfhydryl groups (inactivating enzymes) Arsenic, Thallium o Diffuse systemic toxicity o ARDS, ARF, shock, pancreatitis o Painful neuropathy, alopecia o Carcinogen Mercury o Elemental Only toxic if inhaled ARDS o Salt GI, ARF o Organic CNS Lead o Neurotoxicity, esp kids o Anemia, abdominal pain, constipation, HTN, renal insufficiency Urine levels for As, Hg; whole blood for Pb Tx: po Succimer, IM BAL Methemoglobinemia Nitrites (well water, kids < 6mo), aniline dyes, dapsone, pyridium, benzocaine Ferrous iron (Fe2+) oxidized to Ferric (Fe3+) which can’t carry O2 Shifts O2 dissociation curve to left “chocolate blood”, SOB, MS change, central cyanosis not responsive to O2, measured O2 Sat – 85%, calculated sat – normal Tx: Methylene blue 1-2 mg/kg IV o Do not give if G6PD def Methylxanthines Theophylline, Caffeine (hi doses) Acute vs Chronic Mech: o Blockade of adenosine receptors, increases glutamate --> seizures o Increases catecholamine release Presentation o N/V (more if acute OD), persistent sz, very tachycardic Theo levels o Acute danger if > 80-100, chronic if > 40 Tx: BZDs, IVF, MDAC, dialysis 7 Mushrooms Species Amanita phalloides Toxin Onset of Sx (hr) Effects Tx AC, pcnG, Silibinin, hemoperfusion, ?NAC Pyridoxine, BZDs - Cyclopeptides (amatoxin) 5-24 Hepatic failure Monomethylhydrazine 5-10 CNS (sz) Coprine 0.5-2 Amanita muscaria Ibotenic acid, muscimol 0.5-2 Psilocybe Psilocybin 0.5-1 Orelline > 24 ARF GI irritants 0.5-3 N/V/D IVF Muscarine 0.5-2 SLUDGE atropine Gyrometra escuelenta Coprinus atramentaruis Cortinarius orellanus Chlorphyllum Clitocybe, Inocybe Ald DH disulfiramlike CNS GABAergic, delirium, hallucinations CNS hallucinations BZD BZD HD “6 hr rule” o N/V < 6 hrs from ingestion --> less likely to be hepatotoxic species o N/V > 6 hrs from ingestion --> hepatotoxic o Caution: may have mixed ingestion Mustard Gas Alkylating agent, forming cross-links between purine bases Powerful irritant and vesicant (blisters) Dermal symptoms and pulmonary effects often delayed several hours Tx: support, early decon Nicotine Potentially toxic ingestion in a kid: o 1 whole cigarette o 3 cigarette butts o 1 transdermal patch Sx: nausea, vomiting, diarrhea; initial tachycardia and hypertension followed by bradycardia and hypotension, fasciculations followed by paralysis 8 Tx: supportive Opioids Narcan indication – to prevent intubation Narcan drip: 2/3 the dose required to wake the pt, given per hr Seizures: norproxyphene, normeperidine Propoxyphene may have quinidine-like effects o May also be relatively resistant to narcan Methadone – cardiotoxicity (prolonged QT with doses > 300 mg/d) Buprenorphine – partial agonist/antagonist, highly potent; replacing methadone in heroin maintenance therapy; Significant toxicity to the opiate naive Immunoassays check for morphine and codeine (less sensitivity for semisynthetics; does not assay for synthetics) Withdrawal: not life-threatening, very uncomfortable Organophosphates/Carbamates/Nerve Agents OP – permanently disable acetylcholinesterase (AchE) Carbamates – reversible bind AchE Nerve agents – highly potent OPs that rapidly and irreversibly bind to AchE Sx: SLUDGE or DUMBELLS (cholinergic excess) Death typically a combination of respiratory and CNS toxicity Decontamination (esp dermal) Tx: o Atropine – overcomes muscarinic overload goal is drying of secretions o Pralidoxime (2-PAM) Rejuvenates the enzyme 1 gm IV over 10-5 min, then 500 mg/hr (peds 25 mg/kg bolus, 20 mg/kg/hr) o Valium Even if not seizing Found to be synergistic with 2-PAM in improving survival Plants Vast majority of pediatric exposures are non-toxic Nausea and vomiting most common effect Toxic plants often require a tea to concentrate toxin Example of often abused plant: Jimson Weed persistent anticholinergic effects Ricin Made from ground castor bean husks Toxicity from chewing castor beans Potential weapon Toxalblumin 9 o 2 subunits – one binds to the cell wall, allowing the other to enter and disable the 60s ribosome high lethality, no tx except support Salicylates Absorption: erratic, often delayed (esp if enteric coated) Mech: o Uncouples oxidative phosphorylation o Central stimulation of respiratory center o Enhance lipolysis o GI irritation o Inc cap permeability --> pulmonary and cerebral edema Presentation o Mixed acid/base – prim resp alk with prim metab acidosis (inc anion gap) o N/v, hyperdynamic, some hyperthermia Acute vs Chronic o Chronic – sicker at lower levels Levels: need to be repeated often (q2hrs) o Underestimate body burden if acidemic Tx: o Decontamination (extra dose of charcoal) o Volume o Urine alkalinization Increase clearance of ASA Prevent acidemia o Hemodialysis Scorpion Envenomation Most cause only pain Bark scorpion (AZ) – neurotoxin o Tx – benzos, opiates, antivenom if available Sedative-Hypnotics (BZDs, Barbs, GHB, “muscle relaxants”, chloral hydrate) Most enhance effects of GABA OD rarely life threatening with supportive care Benzos – sedation; GHB – deep coma with agitated awakenings Dangerous withdrawal syndrome o Benzos, GHB, barbs Flumazenil rarely, if ever, indicated Chloral hydrate o Effects enhanced with EtOH = “mickey finn” SSRIs Sedation 10 May see Serotonin Syndrome if used in combination with another serotonergic med o Mental status change, rigidity (tremor, fasciculations, clonus), hyperthermia, autonomic instability, hi CPK o Indistinguishable from NMS except by history o Tx: BZDs, cyproheptadine (periactin – serotonin blocker) Snake Envenomation Crotalid – pit vipers o Rattlesnakes, copperheads, cottonmouths o Local necrosis, hematoxins o Tx – antivenom – “Crofab” Not fasciotomy!!! Elapids o Coral snakes, cobras o Neurotoxin --> respiratory failure, Tx – antivenom Spider envenomation Black widow o Mech: opening of cation channels Ca entry persistent depolarization and release of ACH at NMJ o Sx: pain/paresthesias at bite site (may see local diaphoresis) migration severe abdominal, back or chest pain with hypertension, diaphoresis o Tx: benzos, opiates, antivenom Brown recluse o Necrotic ulcers, slow to heal, supportive care o Rare systemic effects (fevers, chills, hemolysis) Sulfonylureas Mech: increase insulin release Hypoglycemia within 4 - 8 hrs of OD All asymptomatic ingestions need to observed for at least 12 hrs Tx if hypoglycemic (no prophylactic glucose!) o IV dextrose Paradoxically causes more insulin release o Octreotide Prevents insulin release from pancreas Sympathomimetics Cocaine, amphetamines, ecstasy, PCP, ketamine, ephedra, etc. Tachycardia, HTN, mydriasis, diaphoresis, agitation CVAs Cocaine o Sodium channel blocker (like a TCA) o Cardiac ischemia (up to 72 hrs out) TX: Benzos, benzos, benzos 11 o Cocaine MI – treat like any other MI, except no BBs if acutely intoxicated (benzos) TCAs Presentation o Altered MS, seizures, tachycardia, widened QRS, hypotension TX: o Sz – BZDs o Altered MS – early intubation o Hypotension –norepinephrine o Widened QRS/Ventricular dysrhythmia – multiple amps of Bicarb Give for QRS > 120 ms Activated Charcoal not useful with: Metals (including Li and Fe) – any molecule with a charge Caustics Hydrocarbons Alcohols Potentially Radio-opaque substances Metals Cocaine/heroin packets Chloral hydrate Possibly enteric coated products Persistent Seizures – think of: INH Theophylline Pediatric “One Pill Can Kill” (or at least injure) Sulfonylureas TCAs Calcium Channel Blockers Cocaine Alcohols Opiates Quinine Hydrocarbon aspiration Clonidine Methyl salicylate (“oil of wintergreen”) OP insecticides Most common Tox-related causes of death Pediatric o Hydrocarbon aspiration o CO o APAP 12 Adult o APAP Supportive Care is the KEY!!! Protect the airway Support the BP (Norepinephrine) Treat seizures and/or agitation with benzodiazepines o Beware of using antipsychotics in the undifferentiated psychotic patient!! Check CPK if any down time Consider the indications for decontamination Standard tox workup: o Chem 7, APAP, ECG o Do you really need that Urine Drug Screen? If febrile, consider: o NMS, SS o Malignant hyperthermia o Sympathomimetic, anticholinergic, ASA o Infection (esp aspiration) Remember to call your regional Poison Control Center!!!!! 1-800-222-1222 13