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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