Highlights of Toxicology
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 of |AG acidosis |Metabolites |End organ |Antidote |Rx |
| |intox | | |toxicity | |Adjuncts |
|Methanol |+ |+++ |Formic acid |Retina, optic |Fomepizole, EtOH |Folate |
| | | | |nerve, brain | | |
|Ethanol |++ |None (except |Acetic acid |- |- |- |
| | |AKA) | | | | |
|Ethylene Glycol |++ |+++ |Glycolic acid, |Kidneys |Fomepizole, EtOH |Thiamine, B6 |
| | | |Oxalic acid (Ca | | | |
| | | |Oxalate) | | | |
|Isopropanol |+++ |- |Acetone |- |- |- |
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
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
• 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,
• 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
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
• 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
Mushrooms
|Species |Toxin |Onset of Sx |Effects |Tx |
| | |(hr) | | |
|Amanita phalloides |Cyclopeptides |5-24 |Hepatic failure |AC, pcnG, Silibinin, |
| |(amatoxin) | | |hemoperfusion, ?NAC |
|Gyrometra escuelenta |Monomethylhydrazine |5-10 |CNS (sz) |Pyridoxine, BZDs |
|Coprinus atramentaruis |Coprine |0.5-2 |Ald DH |- |
| | | |disulfiramlike | |
|Amanita muscaria |Ibotenic acid, muscimol |0.5-2 |CNS - GABAergic, delirium, | |
| | | |hallucinations |BZD |
|Psilocybe |Psilocybin |0.5-1 |CNS - hallucinations |BZD |
|Cortinarius orellanus |Orelline |> 24 |ARF |HD |
|Chlorphyllum |GI irritants |0.5-3 |N/V/D |IVF |
|Clitocybe, Inocybe |Muscarine |0.5-2 |SLUDGE |atropine |
• “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
• 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 semi-synthetics; 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
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
• 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
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
• 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
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