Toxidromes and Antidotes

In depth

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The first hour: approach to the poisoned patient

Stabilize first, identify second. Support airway and breathing, check a fingerstick glucose in anyone with altered mental status, and titrate naloxone to breathing, not full arousal. Give thiamine 100 mg IV with dextrose to malnourished or alcohol-dependent patients (Merck). Start continuous ECG and SpO₂, get a 12-lead, measure core temperature and call the poison center (1-800-222-1222) early, one of AHA 2023's top 10 messages.

• Every intentional overdose: acetaminophen (silent early) and salicylate levels, electrolytes with anion gap, measured osmolality, ethanol, venous gas with lactate, CK, ECG and a pregnancy test.
• Co-oximetry (COHb, MetHb) after smoke exposure or for cyanosis with a normal PaO₂; drug levels (digoxin, lithium, valproate, iron) when the history fits.
• Urine immunoassays show exposure, not cause; standard opiate screens miss fentanyl, methadone, buprenorphine and often oxycodone.

A high anion gap points to toxic alcohols, salicylates, metformin, iron, isoniazid, or lactate from cyanide or CO. The osmolar gap is measured osmolality minus (2 × Na + glucose ÷ 18 + BUN ÷ 2.8 + ethanol ÷ 3.7), normally under 10 (Berend 2014). Baseline gaps vary (−2 ± 6 mOsm in 305 ED patients, Hoffman 1993), and the gap shrinks as a toxic alcohol becomes acid, so a normal osmolar gap never excludes one.

Decontamination, enhanced elimination and ECMO

Activated charcoal is considered for a potentially toxic dose of an adsorbable drug, ideally within 1 h (AACT/EAPCCT 2005), only in a patient who is awake or intubated; the window is often extended for delayed-release products (beyond 4 h for extended-release or high-risk acetaminophen, Dart 2023). Gastric lavage 'should not be performed routinely, if at all' (AACT/EAPCCT 2013).

• Multiple-dose charcoal: only for life-threatening carbamazepine, dapsone, phenobarbital, quinine or theophylline (AACT/EAPCCT 1999); needs a protected airway and a working gut.
• Whole bowel irrigation: polyethylene glycol solution by NG tube until the effluent is clear, for sustained-release or enteric-coated drugs, iron, lithium, potassium and drug packets; not with ileus, obstruction, perforation, instability or an unprotected airway (AACT/EAPCCT 2015).
• Urine alkalinization to pH 7.5 or higher: first-line for salicylate poisoning that does not meet dialysis criteria; hypokalemia is its commonest complication (AACT/EAPCCT 2004).

Extracorporeal removal suits small, water-soluble, weakly protein-bound poisons with a small volume of distribution, not drugs held in tissue or on protein: EXTRIP recommends against it for TCAs, digoxin, calcium channel blockers and propranolol, and suggests it for atenolol or sotalol only with kidney impairment and refractory instability. Intermittent hemodialysis is EXTRIP's preferred modality; CRRT is the fallback.

VA-ECMO supports a structurally normal heart while the liver and kidneys clear the drug. AHA 2023 rates it reasonable (2a) for poison-induced cardiogenic shock, arrest or dysrhythmias refractory to maximal therapy, but unproven (2b) for vasodilatory shock or cellular poisons, which flow does not correct. Evidence is observational: 12 of 14 (86%) ECLS patients survived versus 23 of 48 (48%) treated without it (Masson 2012).

Acetaminophen: nomogram, regimens and stopping rules

CYP2E1 turns a small fraction of each dose into NAPQI, which glutathione neutralizes; in overdose glutathione runs out and NAPQI kills zone 3 hepatocytes. Nausea or nothing on day 1, rising AST and ALT at 24–72 h, peak injury with coagulopathy, encephalopathy and AKI at 72–96 h, recovery after day 5 (Merck). In probable-risk patients, hepatotoxicity was 6.1% when NAC started within 10 h versus 26.4% at 10–24 h (Smilkstein 1988, 2,540 patients).

The US treatment line starts at 150 mcg/mL at 4 h and halves every 4 h; it applies only to a single acute ingestion at a known time, and a level drawn before 4 h cannot be plotted. The 2023 US–Canada consensus (Dart 2023) adds a high-risk line starting at 300 and these rules:

• Extended-release product, or anticholinergic or opioid co-ingestion: repeat a level that is under the line but over 10 mcg/mL 4–6 h later.
• Repeated supratherapeutic ingestion: treat a level over 20 mcg/mL or an abnormal AST/ALT.
• Above the 300 line many clinicians give more NAC; the evidence sets no dose.

Anaphylactoid reactions (flushing, urticaria, wheeze) are concentration-related histamine release: in SNAP (Bateman 2014, 222 patients) the 12-h regimen cut severe reactions from 31 patients to 5, and vomiting, retching or rescue antiemetic at 2 h from 71 of 109 to 39 of 108. A prior reaction does not rule out NAC in a later overdose (Dart 2023).

NAC does not stop automatically at 20–21 h: stop only when the level is under 10 mcg/mL, INR under 2.0, AST/ALT normal or 25–50% below peak, and the patient is well (Dart 2023; ACMT 2026); otherwise continue the last bag's rate. Hemodialysis is added for a level of 900 mcg/mL or more with acidosis or altered consciousness (Dart 2023). Call a transplant center for arterial pH under 7.30 after resuscitation; INR over 6.5 with creatinine over 3.4 mg/dL and grade III–IV encephalopathy; or lactate over 3.5 mmol/L early or 3.0 after fluids (King's College; Bernal 2002; Merck).

Salicylates, toxic alcohols and lithium

Salicylate stimulates the respiratory center and uncouples oxidative phosphorylation: hyperpnea with a respiratory alkalosis plus high-gap metabolic acidosis, then fever, noncardiogenic pulmonary edema, cerebral edema and low brain glucose despite a normal serum glucose. Enteric-coated tablets delay the peak; repeat levels every 2 h until clearly falling. Chronic toxicity in older adults mimics sepsis or delirium and kills at lower levels.

Alkalinize to a urine pH of 7.5–8.5 (Merck), replace potassium (hypokalemic kidneys cannot make alkaline urine), give dextrose for any neurologic change and involve nephrology early.

Methanol and ethylene glycol are harmless until alcohol dehydrogenase converts them: methanol to formic acid (optic nerve and putamen injury, 'snowfield' vision after a 12–18 h latent period, Merck), ethylene glycol to glycolic acid, most of the gap, and oxalate (calcium oxalate crystals, AKI, hypocalcemia with long QT). Isopropanol becomes acetone: ketosis and an osmolar gap without acidosis. Fomepizole goes to 15 mg/kg every 12 h after four maintenance doses (autoinduction), every 4 h during dialysis, until the level is under 20 mg/dL with a normal pH (label); add folic or folinic acid for methanol, thiamine and pyridoxine for ethylene glycol. On fomepizole, normal kidneys clear ethylene glycol (Brent 1999), but methanol's half-life is 54 h (Brent 2001), so methanol is dialyzed more often.

Lithium (label target 0.8–1.2 mEq/L) is handled like sodium, so dehydration, AKI, thiazides, ACE inhibitors, ARBs and NSAIDs raise levels. Acute overdose in a lithium-naive patient causes vomiting and diarrhea with high levels that redistribute; chronic toxicity causes tremor, hyperreflexia, ataxia, confusion and seizures at lower levels, because lithium is already in the brain. Give isotonic saline, stop interacting drugs, irrigate the bowel for large sustained-release ingestions (charcoal does not bind lithium) and dialyze by EXTRIP; cerebellar deficits can persist (label).

Cardiotoxic drugs: TCAs, β-blockers, CCBs, digoxin, LAST

TCAs block fast sodium channels (wide QRS, VT, low contractility), α1 receptors (hypotension), muscarinic receptors (delirium, tachycardia), potassium channels (long QT) and GABA-A receptors (seizures). In Boehnert 1985 (49 patients), no one with a limb-lead QRS under 100 ms had seizures or ventricular dysrhythmias, 34% at 100 ms or more seized, and ventricular dysrhythmias occurred only at 160 ms or more; a terminal R in aVR of 3 mm or more was 81% sensitive (Liebelt 1995). Deterioration is abrupt; observe at least 6 h with serial ECGs.

Hypertonic sodium bicarbonate works through the sodium load and the alkalemia: AHA 2023 class 1 for TCAs, 2a for other sodium channel blockers (diphenhydramine, flecainide, lamotrigine, venlafaxine). Bolus until the QRS narrows, within AHA's ceilings (pH 7.50–7.55, sodium 150–155). Treat seizures with benzodiazepines, not phenytoin, and never give physostigmine. For refractory cases, lidocaine (class Ia or Ic agents) and lipid emulsion are 2b, VA-ECMO 2a.

β-blockers lower cAMP: bradycardia, AV block, poor contractility and, mainly in children, hypoglycemia; propranolol also blocks sodium channels and sotalol prolongs QT. Verapamil and diltiazem slow the heart and depress output; dihydropyridines dilate arterioles with reflex tachycardia until large doses erase the difference. CCBs block insulin release, so glucose rises with severity (Levine 2007), unlike β-blockers. Sustained-release ingestions can deteriorate late; 24-h observation is common.

High-dose insulin is an inotrope: the poisoned myocardium switches to glucose, and insulin lets it in. Give 1 unit/kg with dextrose, then 1–10 units/kg/h (AHA 2023), started early alongside vasopressors because its effect builds slowly. Hypoglycemia and hypokalemia were common in a case series (Holger 2011); typical protocols check glucose every 15–30 min during titration and potassium every 1–2 h.

Digoxin inhibits Na⁺/K⁺-ATPase: hyperkalemia in acute poisoning and increased automaticity with AV block (PVCs, atrial tachycardia with block, bidirectional VT); chronic toxicity adds confusion and yellow-green vision. Before Fab, potassium above 5.5 in acute poisoning predicted death (Bismuth 1973). Fab resolves dysrhythmias in 50–90%, usually within 30–45 min; calcium for the hyperkalemia appears neither harmful nor helpful, and dialysis does not remove digoxin (AHA 2023). After Fab, potassium can fall fast and total digoxin levels mislead for days (label).

Local anesthetic systemic toxicity (LAST) usually starts with perioral numbness, tinnitus, agitation or seizures but can present as dysrhythmia or arrest; bupivacaine is the most cardiotoxic. ASRA 2020: over 70 kg, about 100 mL of 20% lipid over 2–3 min then 250 mL over 15–20 min (under 70 kg, 1.5 mL/kg then 0.25 mL/kg/min); rebolus and double the rate if unstable, up to 12 mL/kg. Benzodiazepines for seizures, epinephrine under 1 mcg/kg, no vasopressin, β-blockers, CCBs or local anesthetics; observe 4–6 h after cardiovascular instability.

Opioids and sympathomimetics

Opioids kill by hypoventilation, hypoxemia and arrest. Fentanyl is 50–100 times as potent as morphine (CDC), acts within minutes, can cause chest-wall rigidity with rapid IV doses and is missed by standard opiate screens; carfentanil and nitazenes may need repeated naloxone. Naloxone's half-life is 30–81 min (label), shorter than methadone or extended-release opioids, so watch for re-sedation: repeat doses or an infusion of two-thirds of the waking dose per hour (AHA 2023), and observe until mental status and vital signs normalize.

Buprenorphine is a high-affinity partial agonist with a ceiling on respiratory depression in adults unless combined with benzodiazepines, alcohol or other sedatives; because it dissociates slowly, reversal needs large naloxone doses (label). After the overdose, ED-initiated buprenorphine kept 78% in treatment at 30 days versus 37% with referral (D'Onofrio 2015), and every patient should leave with naloxone (AHA 2025).

Cocaine, methamphetamine, MDMA and synthetic cathinones kill through hyperthermia, dysrhythmias, coronary vasospasm, stroke, dissection and rhabdomyolysis. Sedate first (benzodiazepines, antipsychotics or ketamine; AHA 2023 class 1), because agitation makes the heat, and cool fast. Cocaine also blocks sodium channels: wide-complex tachycardia gets bicarbonate or lidocaine (2a), and vasospasm gets nitrates, phentolamine or a CCB (2a). β-blockers remain contested, with studies showing both benefit and harm (AHA 2023). MDMA adds hyponatremia from vasopressin release and water loading.

Serotonin toxicity, NMS and malignant hyperthermia

Hunter criteria (Dunkley 2003; 84% sensitive, 97% specific): with a serotonergic drug, any of spontaneous clonus; inducible or ocular clonus with agitation or diaphoresis; tremor with hyperreflexia; or hypertonia with temperature above 38 °C plus ocular or inducible clonus. Anticholinergic toxicity has normal tone and reflexes with dry skin. Stop the drugs, give benzodiazepines and cool physically; with temperature above 39 °C plus rigidity or agitation (Chiew and Isbister 2025; IBCC uses about 41 °C), intubate and paralyze with a nondepolarizing agent, never succinylcholine.

Malignant hyperthermia is a pharmacogenetic crisis: an RYR1 variant floods muscle with calcium on exposure to a trigger. MHAUS: stop triggers, hyperventilate with 100% oxygen at 10 L/min, give dantrolene 2.5 mg/kg IV and repeat until signs resolve (more than 10 mg/kg is occasionally needed), cool above 39 °C and stop below 38 °C, treat hyperkalemia, and call the hotline (1-800-644-9737).

Carbon monoxide, cyanide, methemoglobin and organophosphates

CO displaces oxygen from hemoglobin, shifts the dissociation curve left and impairs mitochondrial respiration. Standard pulse oximeters read COHb as oxyhemoglobin, so SpO₂ and PaO₂ look normal; diagnose by co-oximetry. COHb half-life is about 4.5 h on room air, 1.5 h on 100% oxygen and 20 min at 3 atm (Merck). Consider hyperbaric oxygen for loss of consciousness, neurologic or cardiac findings, COHb over 25%, or pregnancy at lower levels (Merck). In Weaver 2002 (152 patients) three hyperbaric sessions cut 6-week cognitive sequelae from 46% to 25%; other trials were negative (Scheinkestel 1999, Annane 2011).

Cyanide blocks cytochrome oxidase, so cells cannot use oxygen: lactate climbs and venous blood stays bright red. In fire victims a lactate over 10 mmol/L was a sensitive marker of toxic cyanide levels (Baud 1991). Give hydroxocobalamin on suspicion (AHA 2023 class 1) with 100% oxygen; a second 5 g dose may follow (label). It reddens skin and urine (urine for up to 35 days), disturbs colorimetric labs and dialysis blood-leak detectors, and raises BP.

Methemoglobinemia (benzocaine sprays, dapsone, nitrites) gives chocolate-brown blood and an SpO₂ near 85%; methylene blue 1–2 mg/kg is class 1 (AHA 2023) but may fail or cause hemolysis in G6PD deficiency (about 2% of Americans).

Organophosphates inhibit acetylcholinesterase, producing muscarinic, nicotinic (fasciculations, weakness, paralysis) and CNS effects. The inhibited enzyme 'ages' into a permanent form, while carbamates release it within about 48 h (Merck). Atropinize to a clear chest, HR over 80 and SBP over 80, then infuse 10–20% of the loading dose per hour, up to 2 mg/h in adults (AHA 2023). Pralidoxime is 'reasonable' (2a), yet in a 235-patient placebo-controlled trial mortality was 24.8% with it and 15.8% without (Eddleston 2009, not significant). Intubate early with rocuronium, not succinylcholine; the intermediate syndrome (neck flexor, proximal, cranial nerve and respiratory weakness) follows at 24–96 h (Senanayake 1987).

Withdrawal syndromes in brief

Withdrawal mimics sepsis, serotonin toxicity and NMS; ask about home drugs, pumps and last doses.

Exam pearls

• Every intentional overdose gets an acetaminophen level; plot only levels drawn at 4 h or later.
• Salicylates: respiratory alkalosis plus high-gap acidosis; never let PaCO₂ rise after intubation.
• QRS ≥100 ms or R in aVR ≥3 mm: sodium bicarbonate; no physostigmine for TCAs.
• CCB poisoning raises glucose; high-dose insulin needs dextrose and potassium checks.
• Digoxin: acute hyperkalemia or bidirectional VT calls for Fab; levels mislead after Fab.
• Toxic alcohols: osmolar gap early, anion gap late; methanol blinds, ethylene glycol makes oxalate crystals and AKI.
• CO: normal SpO₂ and PaO₂; COHb half-life about 4.5 h on air, 1.5 h on 100% oxygen.
• Organophosphates: atropine until the chest is dry, not to pupil size; avoid succinylcholine.
• Serotonin toxicity is fast with clonus; NMS is slow with rigidity; malignant hyperthermia starts with rising EtCO₂.