4.3 Clinical Toxicology, Overdose Management, and Antidotes
Key Takeaways
- Single-dose activated charcoal (1 g/kg) is most effective within 1 to 2 hours of toxic ingestion, but is ineffective for heavy metals, lithium, toxic alcohols, and caustics.
- Acetaminophen toxicity results from CYP2E1-mediated formation of NAPQI depleting hepatic glutathione; intravenous N-acetylcysteine (NAC) acts as a glutathione precursor and must be guided by the Rumack-Matthew nomogram.
- Salicylate poisoning produces a mixed respiratory alkalosis and high anion gap metabolic acidosis; management centers on urinary alkalinization with sodium bicarbonate and mandatory potassium repletion.
- Toxic alcohols require early differentiation: methanol produces blinding retinal and putaminal injury from formic acid, whereas ethylene glycol causes acute kidney injury from calcium oxalate crystallization; both are treated with fomepizole.
- Serotonin syndrome is defined by neuromuscular clonus and hyperreflexia triggered by serotonergic excess, whereas neuroleptic malignant syndrome (NMS) is characterized by lead-pipe rigidity, hyporeflexia, and slow onset from dopamine blockade.
Last updated: August 2026
4.3 Clinical Toxicology, Overdose Management, and Antidotes
Clinical toxicology encompasses the rapid evaluation, resuscitation, diagnosis, and antidote-directed management of drug overdoses and chemical poisonings. The PEBC Evaluating Examination frequently tests toxic mechanisms, toxidrome differentiation, decontamination limits, and specific antidote pharmacotherapy.
1. General Principles of Resuscitation and Decontamination
Emergency toxicological stabilization prioritizes the clinical "ABCDEs" (Airway, Breathing, Circulation, Disability, Exposure), correction of hypoglycemia (dextrose), thiamine administration in suspected alcoholism/Wernicke encephalopathy, and targeted antidote delivery.
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| GASTROINTESTINAL DECONTAMINATION MODALITIES |
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| 1. Single-Dose Activated Charcoal (SDAC: 1 g/kg PO/NG within 1-2 hours) |
| - Ineffective: Iron, Lithium, Lead, Toxic Alcohols, Strong Acids/Alkalis (PHAILS)|
| - Contraindicated: Unprotected airway, bowel perforation, hydrocarbon ingestion |
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| 2. Multiple-Dose Activated Charcoal (MDAC: 0.5 g/kg q2-4h) |
| - Effective for: Carbamazepine, Dapsone, Phenobarbital, Quinine, Theophylline |
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| 3. Whole Bowel Irrigation (WBI: PEG-ELS 1.5-2 L/h until clear effluent) |
| - Indications: Sustained-release tablets, Iron, Lithium, Illicit Body Packers |
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| 4. Urinary Alkalinization (IV NaHCO3 targeting urine pH 7.5 - 8.5) |
| - Indications: Salicylates, Phenobarbital, Methotrexate |
| - Prerequisite: Must correct hypokalemia (K+) to prevent paradoxical aciduria |
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Extracorporeal Enhanced Elimination (Hemodialysis)
Hemodialysis efficiently eliminates toxins with low molecular weight ($<500\text{ Da}$), low protein binding ($<70-80%$), high water solubility, and a small apparent volume of distribution ($V_d < 1\text{ L/kg}$):
\mathbf{I} & \text{Isopropanol (refractory hypotension)} \\ \mathbf{S} & \text{Salicylates (level } > 6.5-7.2\text{ mmol/L [}90-100\text{ mg/dL], coma, ARDS)} \\ \mathbf{T} & \text{Theophylline (acute level } > 500\text{ }\mu\text{mol/L [}90-100\text{ mg/L])} \\ \mathbf{U} & \text{Uremia} \\ \mathbf{M} & \text{Methanol (level } > 15-20\text{ mmol/L, visual defects, severe acidosis)} \\ \mathbf{B} & \text{Barbiturates (phenobarbital with refractory shock/coma)} \\ \mathbf{L} & \text{Lithium (level } > 4.0\text{ mmol/L acute, or } > 2.5\text{ chronic with neurotoxicity)} \\ \mathbf{E} & \text{Ethylene Glycol (level } > 15-20\text{ mmol/L, renal failure, severe acidosis)} \end{cases}$$ --- ## 2. Clinical Toxidrome Differentiation A toxidrome is a constellation of clinical signs and symptoms characteristic of a specific pharmacological class of poison: | Toxidrome | Vital Signs | Mental Status | Pupils | Skin / Mucosa | Bowel / Bladder | Hallmark Diagnostic Features | |:---|:---|:---|:---|:---|:---|:---| | **Anticholinergic** | $\uparrow$ HR, $\uparrow$ BP, $\uparrow$ Temp | Agitated delirium, hallucinations | Mydriasis (dilated, sluggish) | **Anhidrosis (dry skin)**, flushed, dry mucosa | $\downarrow$ Bowel sounds, urinary retention | "Blind as a bat, mad as a hatter, red as a beet, hot as a hare, dry as a bone." Axillae are bone dry. | | **Cholinergic** | $\downarrow$ HR (or $\uparrow$), $\downarrow$ BP | Confusion, coma, seizures | Miosis (pinpoint) | **Diaphoresis (wet skin)**, salivation, lacrimation | Diarrhea, hyperactive sounds, incontinence | **DUMBELS / SLUDGEM**: Salivation, Lacrimation, Urination, Defecation, GI cramping, Emesis, Miosis, Bronchorrhea. | | **Sympathomimetic** | $\uparrow\uparrow$ HR, $\uparrow\uparrow$ BP, $\uparrow\uparrow$ Temp | Hyperalert, paranoia, agitation | Mydriasis (reactive) | **Diaphoresis (wet skin)**, warm | Normal / Hyperactive sounds | Distinguished from anticholinergic by **prominent diaphoresis and moist axillae** (cocaine, amphetamines). | | **Opioid** | $\downarrow$ HR, $\downarrow$ BP, $\downarrow\downarrow$ RR, $\downarrow$ Temp | Sedation, coma | Miosis (pinpoint) | Cool, pale | $\downarrow$ Bowel sounds, constipation | Classic triad: **CNS depression + Respiratory depression + Pinpoint miosis** (Naloxone responsive). | | **Sedative-Hypnotic** | Mild $\downarrow$ HR, $\downarrow$ BP, mild $\downarrow$ RR | Stupor, coma, ataxia | Normal / Variable | Normal | $\downarrow$ Bowel sounds | CNS depression with relatively stable vital signs and absence of pinpoint pupils (benzodiazepines, barbiturates). | ### Serotonin Syndrome vs. Neuroleptic Malignant Syndrome vs. Malignant Hyperthermia ``` +--------------------------------------------------------------------------------------+ | HYPERTHERMIC TOXICOLOGICAL EMERGENCIES MATRIX | +--------------------------------------------------------------------------------------+ | SEROTONIN SYNDROME (SS): | | - Etiology : Serotonergic excess (SSRIs + MAOIs, TCAs, Tramadol, Linezolid, Fentanyl) | | - Onset : Rapid (<24 hours) | | - Features : Spontaneous / Inducible CLONUS, Hyperreflexia (legs > arms), Diaphoresis| | - Treatment: Stop agents, Benzodiazepines, Cyproheptadine (5-HT2A antagonist) | | | | NEUROLEPTIC MALIGNANT SYNDROME (NMS): | | - Etiology : Dopamine D2 blockade (Antipsychotics) or DA agonist withdrawal | | - Onset : Gradual (days to weeks) | | - Features : "LEAD-PIPE" Rigidity, Hyporeflexia, Extreme Hyperthermia, High CK / WBC | | - Treatment: Stop neuroleptic, ICU cooling, Bromocriptine (DA agonist), Dantrolene | | | | MALIGNANT HYPERTHERMIA (MH): | | - Etiology : RYR1 receptor mutation triggered by Volatile Anesthetics / Succinylcholine | - Features : Masseter spasm, rapid hyperthermia, metabolic acidosis, rhabdomyolysis | | - Treatment: Discontinue trigger, 100% O2, IV Dantrolene (1-2.5 mg/kg boluses) | +--------------------------------------------------------------------------------------+ ``` --- ## 3. High-Yield Specific Toxicities and Mechanisms ### Acetaminophen (APAP) Hepatotoxicity and N-Acetylcysteine Acetaminophen is metabolized at therapeutic doses via glucuronidation ($50-60\%$) and sulfation ($30-40\%$). A small fraction ($<10\%$) is oxidized by **CYP2E1** to the highly reactive electrophile **N-acetyl-p-benzoquinone imine (NAPQI)**, which is rapidly detoxified by conjugation with endogenous hepatic **glutathione**. ``` [Acetaminophen (Toxic Ingestion)] | +----------------------+----------------------+ | (Saturated Pathways) | (Shunted Pathway) v v [Phase II Glucuronide / Sulfate] [CYP2E1] (Non-Toxic) | v [NAPQI] | +-----------------------------+-----------------------------+ | | v (+ Hepatic Glutathione / NAC) v (Glutathione Stores <30%) [Mercapturic Acid / Cysteine Conjugate] [Covalent Binding to Hepatocyte Proteins] (Non-Toxic Urine Excretion) | v [Centrilobular Hepatic Necrosis] ``` - **The Rumack-Matthew Nomogram**: Evaluates hepatotoxicity risk strictly for **single acute ingestions with known ingestion time between $4$ and $24\text{ hours}$**. - The Canadian treatment line starts at **$1000\text{ }\mu\text{mol/L}$ ($150\text{ mcg/mL}$)** at $4\text{ hours}$ post-ingestion. - **N-Acetylcysteine (NAC) Mechanism**: Replenishes hepatic glutathione stores, serves as a direct glutathione surrogate, enhances non-toxic sulfation, and improves microcirculatory perfusion. - **Dosing Protocols**: Intravenous 21-hour 3-bag protocol ($150\text{ mg/kg}$ over $1\text{ h}$, $50\text{ mg/kg}$ over $4\text{ h}$, $100\text{ mg/kg}$ over $16\text{ h}$) or simplified 2-bag protocol ($200\text{ mg/kg}$ over $4\text{ h}$, $100\text{ mg/kg}$ over $16\text{ h}$). NAC is continued beyond standard infusion until APAP is undetectable, ALT/AST are normal or clearly declining, and INR $<1.5$. ### Salicylate (Aspirin) Toxicity Salicylates exhibit complex biphasic acid-base derangements: 1. **Early Phase**: Direct stimulation of the medullary respiratory center causes hyperventilation and a **primary respiratory alkalosis**. 2. **Late Phase**: Uncoupling of mitochondrial oxidative phosphorylation, inhibition of Krebs cycle dehydrogenases, and stimulation of lipolysis lead to accumulation of lactic acid, pyruvate, and ketoacids, producing a **primary high anion gap metabolic acidosis**. 3. **Net Clinical State**: **Mixed Primary Respiratory Alkalosis and Primary High Anion Gap Metabolic Alkalosis**. - *Management*: Volume resuscitation, IV **Sodium Bicarbonate** infusion (targets urine $\text{pH } 7.5-8.5$ to trap ionized salicylate in tubular fluid), mandatory **potassium repletion**, and emergent **hemodialysis** for severe poisonings (salicylate $>6.5-7.2\text{ mmol/L}$, altered mental status, pulmonary edema, or renal failure). ### Toxic Alcohols: Methanol vs. Ethylene Glycol vs. Isopropanol $$\text{Osmolal Gap} = \text{Measured Osmolality} - \left(2 \cdot [\text{Na}^+] + [\text{Glucose}] + [\text{Urea}]\right) \quad (\text{Normal } < 10-15\text{ mOsm/kg})$$ | Feature | Methanol | Ethylene Glycol | Isopropyl Alcohol | |:---|:---|:---|:---|:---| | **Common Sources** | Windshield washer fluid, bootleg liquor | Engine antifreeze / coolants | Rubbing alcohol, hand sanitizers | | **Metabolic Enzyme** | Alcohol Dehydrogenase (ADH) | Alcohol Dehydrogenase (ADH) | Alcohol Dehydrogenase (ADH) | | **Toxic Metabolite** | **Formic Acid (Formate)** | **Glycolic Acid $\to$ Oxalic Acid** | **Acetone** (Ketone, not an organic acid) | | **Hallmark Target Toxicity** | **Optic papillitis, retinal edema ("snowstorm" vision), putaminal necrosis** | **Calcium oxalate crystal nephropathy (ATN), hypocalcemia, QTc prolongation** | **Hemorrhagic gastritis, CNS depression without metabolic acidosis** | | **Acid-Base Profile** | High Anion Gap Metabolic Acidosis + Elevated Osmolal Gap | High Anion Gap Metabolic Acidosis + Elevated Osmolal Gap | **Elevated Osmolal Gap + Ketonemia WITHOUT Metabolic Acidosis** | | **Specific Antidote** | **Fomepizole** (or Ethanol) + IV Folinic / Folic Acid | **Fomepizole** (or Ethanol) + IV Thiamine & Pyridoxine | Supportive care; **Fomepizole is NOT indicated** (acetone is not toxic) | --- ## 4. Comprehensive Antidote Master Table | Toxic Substance / Overdose | Specific Antidote | Antidote Mechanism of Action | Clinical Pearls & Administration | |:---|:---|:---|:---|:---| | **Acetaminophen** | **N-Acetylcysteine (NAC)** | Replenishes glutathione; direct antioxidant and NAPQI scavenger | Nomogram guided; IV 21-hour or simplified 2-bag protocol | | **Opioids** | **Naloxone** | Competitive antagonist at $\mu$, $\kappa$, $\delta$ opioid receptors | Titrate to restore respiratory rate (target $10-12\text{ bpm}$), not full arousal; short $t_{1/2}$ ($30-90\text{ min}$) requires repeat dosing | | **Benzodiazepines** | **Flumazenil** | Competitive antagonist at $\text{GABA}_A$ benzodiazepine site | **Caution**: Contraindicated in chronic benzo users or co-ingested proconvulsants/TCAs (precipitates refractory seizures/status) | | **Beta-Blockers** | **Glucagon** | Stimulates myocardial adenylyl cyclase via non-adrenergic receptors $\to \uparrow$ cAMP | First-line: Glucagon ($3-10\text{ mg}$ IV bolus + infusion); High-Dose Insulin-Euglycemia Therapy (HIET); Lipid Emulsion | | **Calcium Channel Blockers** | **Calcium Chloride / Gluconate + HIET** | Overcomes $\text{Ca}^{2+}$ channel blockade; HIET provides direct myocardial carbohydrate fuel | Calcium IV boluses; High-Dose Insulin ($1\text{ unit/kg}$ bolus $+ 1-10\text{ units/kg/h}$ infusion) with dextrose and $\text{K}^+$ support | | **Digoxin** | **Digoxin-Specific Fab Fragments (DigiFab)** | Binds free intravascular digoxin molecules; complex excreted renally | Indications: Life-threatening arrhythmia, hyperkalemia ($[\text{K}^+] > 5.0\text{ mmol/L}$), acute ingestion $>10\text{ mg}$ ($4\text{ mg}$ in child) | | **Toxic Alcohols (Methanol / Ethylene Glycol)** | **Fomepizole (4-Methylpyrazole)** | Potent competitive inhibitor of Alcohol Dehydrogenase (ADH, $>8000\times$ affinity vs ethanol) | Loading dose $15\text{ mg/kg}$ IV over $30\text{ min}$, then $10\text{ mg/kg}$ q12h $\times 4$ doses; hemodialysis clears parent alcohol and metabolites | | **Cyanide** | **Hydroxocobalamin (Cyanokit)** | Cobalt ion chelates cyanide, forming non-toxic **cyanocobalamin** (Vitamin $\text{B}_{12}$) excreted in urine | $5\text{ g}$ IV over $15\text{ min}$; turns skin/urine deep red; alternative: Sodium nitrite $+$ Sodium thiosulfate | | **Carbon Monoxide** | **100% Normobaric / Hyperbaric $\text{O}_2$** | Competitively displaces CO from hemoglobin, reducing carboxyhemoglobin half-life | Half-life in room air: $300\text{ min}$; on $100\%\ \text{O}_2$: $90\text{ min}$; Hyperbaric $\text{O}_2$ ($2.8-3.0\text{ atm}$): $20-30\text{ min}$ | | **Iron** | **Deferoxamine** | Chelates ferric iron ($ ext{Fe}^{3+}$) to form water-soluble **ferrioxamine** | Excreted in urine, turning it classic "vin rosé" (red-orange); indicated for shock, severe acidosis, or iron $>90\text{ }\mu\text{mol/L}$ | | **Lead, Arsenic, Mercury** | **Dimercaprol (BAL), Succimer (DMSA)** | Sulfhydryl donor that chelates heavy metals | Succimer is water-soluble oral chelator; BAL is IM in peanut oil (check peanut allergy) | | **Copper (Wilson's Disease / Poisoning)** | **Penicillamine, Trientine** | Chelates copper ions; enhances urinary excretion | Co-administer pyridoxine (vitamin $\text{B}_6$) with penicillamine | | **Sulfonylureas** | **Octreotide** | Somatostatin analog; suppresses glucose-stimulated insulin secretion from $\beta$-cells | $50-100\text{ }\mu\text{g}$ SC/IV q8-12h; prevents rebound hypoglycemia associated with repeated dextrose boluses alone | | **Isoniazid (INH)** | **Pyridoxine (Vitamin $\text{B}_6$)** | Restores GABA synthesis by bypassing inhibited pyridoxal-5-phosphate | Dose equals gram-for-gram of INH ingested (or empiric $5\text{ g}$ IV); terminates INH-induced refractory status epilepticus | | **Anticholinergics** | **Physostigmine** | Tertiary amine acetylcholinesterase inhibitor; crosses blood-brain barrier | Reverses central and peripheral anticholinergic delirium; **contraindicated in TCA overdose** (triggers asystole) | | **Local Anesthetic Toxicity (LAST)** | **20% Intravenous Lipid Emulsion (ILE)** | "Lipid sink" partitions lipophilic local anesthetics (bupivacaine) from cardiac tissue | $1.5\text{ mL/kg}$ IV bolus, then $0.25\text{ mL/kg/min}$ infusion; indicated for refractory cardiovascular collapse | | **Heparin / Enoxaparin** | **Protamine Sulfate** | Positively charged basic peptide that neutralizes negatively charged heparin | $1\text{ mg}$ protamine neutralizes $100\text{ units}$ unfractionated heparin; neutralizes $\sim 60-75\%$ of enoxaparin anti-Xa activity | | **Direct Factor Xa Inhibitors** | **Andexanet Alfa / 4-Factor PCC** | Decoy protein binding anti-Xa agents (Andexanet) or concentrates coagulation factors | Indicated for life-threatening bleeding on apixaban or rivaroxaban | | **Dabigatran** | **Idarucizumab (Praxbind)** | Humanized Fab fragment with $350\times$ higher affinity for dabigatran than thrombin | $5\text{ g}$ IV ($2 \times 2.5\text{ g}$ vials) provides immediate reversal for emergency surgery or life-threatening hemorrhage |Test Your Knowledge
A 22-year-old individual is brought to the emergency department exactly 6 hours after ingesting an acute overdose of 30 tablets of regular-strength acetaminophen (325 mg per tablet). The patient is fully alert with mild nausea. Laboratory analysis reveals a serum acetaminophen concentration of 1200 µmol/L (normal therapeutic range 66-132 µmol/L). What is the most appropriate initial management step?
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A 29-year-old patient who takes sertraline 150 mg daily is prescribed tramadol 100 mg QID for severe musculoskeletal pain following an orthopedic injury. Within 24 hours of starting tramadol, the patient develops profound agitation, diaphoresis, ocular clonus, spontaneous ankle clonus, hyperactive bowel sounds, and a body temperature of 38.8°C. What toxidrome is present, and what is the primary initial pharmacological management?
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A 45-year-old patient is admitted to the intensive care unit with profound high anion gap metabolic acidosis (arterial pH 7.10, serum bicarbonate 8 mmol/L), an elevated osmolal gap of 35 mOsm/kg, acute oliguric renal failure, and needle-shaped calcium oxalate crystals visible on urinalysis. What is the definitive mechanism of the first-line antidote indicated for this poisoning?
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A 56-year-old patient presents to the emergency department following an intentional massive overdose of atenolol. The patient is profoundly bradycardic (heart rate 32 bpm) and hypotensive (blood pressure 70/35 mmHg) that fails to respond to multiple boluses of intravenous atropine and 2 L of isotonic crystalloid fluids. Which pharmacological agent is the first-line antidote indicated to restore myocardial chronotropy and inotropy?
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