Toxicology and Overdose

Mechanistic groupings of exposure

• Intentional self-poisoning: the most common reason adults present with a large single ingestion; acetaminophen, salicylates, and prescribed psychotropics dominate because they are in the home medicine cabinet.
• Unintentional therapeutic misadventure: staggered supratherapeutic ingestion of acetaminophen from stacking combination opioid–acetaminophen and cold products is the classic stem — no single toxic dose, no usable nomogram, yet real hepatotoxicity.
• Recreational use and opioid use disorder: illicitly manufactured fentanyl and its analogs now drive most U.S. overdose deaths (CDC surveillance), often as an unrecognized adulterant in counterfeit pills or stimulants.
• Pediatric exploratory ingestion: toddlers, small body mass, "one pill can kill" agents (sulfonylureas, calcium channel blockers, TCAs, camphor, opioids).
• Iatrogenic and drug–drug interactions: serotonin syndrome from adding linezolid, tramadol, or an MAOI to an SSRI; CYP inhibition raising levels of narrow-index drugs.
• Occupational/environmental: organophosphate pesticides, carbon monoxide from faulty heaters or house fires, methanol from adulterated spirits.

Modifiable risk factors

• Chronic alcohol use: induces CYP2E1 and depletes glutathione, shifting acetaminophen toward NAPQI.
• Fasting/malnutrition, anorexia, cachexia: low glutathione reserve, same mechanism.
• Polypharmacy and benzodiazepine–opioid co-prescription: additive respiratory depression; the CDC Clinical Practice Guideline for Prescribing Opioids advises avoiding this combination and co-prescribing naloxone for higher-dose or high-risk patients.
• Unsecured medication storage and absence of take-home naloxone.
• Untreated substance use disorder, recent detoxification or release from incarceration: lost tolerance is a potent risk multiplier.

Non-modifiable risk factors

• Prior suicide attempt: the single strongest predictor examiners plant in a psychiatric stem.
• Age extremes: toddlers and elderly patients with cognitive impairment.
• Underlying hepatic or renal disease: impaired metabolism and clearance.
• Pharmacogenetics: CYP2D6 ultrarapid metabolizers convert codeine or tramadol to morphine excessively — a classic pediatric post-tonsillectomy death vignette.
• Pregnancy: fetal salicylate and CO accumulation exceed maternal levels.

• Absorption and distribution alterations: Toxins reach systemic circulation via gastrointestinal, inhalational, transdermal, or parenteral routes; lipophilic agents accumulate in fatty tissues while hydrophilic agents distribute to aqueous compartments, affecting duration and intensity of effects

• Receptor and enzyme interactions: Most toxins exert effects through agonism, antagonism, or inhibition of cellular receptors (e.g., opioid receptors, alpha/beta-adrenergic receptors) or enzyme systems (e.g., acetylcholinesterase, monoamine oxidase), causing physiologic derangement

• Oxidative stress and cellular injury: Many toxins generate reactive oxygen species (ROS) or deplete antioxidant systems, leading to lipid peroxidation, DNA damage, and mitochondrial dysfunction; acetaminophen depletion of glutathione is prototypical

• Metabolic acidosis and electrolyte derangement: Certain toxins (methanol, ethylene glycol, salicylates, metformin) produce unmeasured anion gap metabolic acidosis; direct cellular toxicity and impaired renal excretion exacerbate electrolyte abnormalities

• Central nervous system and respiratory depression: Sedatives, opioids, and alcohol enhance GABAergic inhibition or depress brainstem respiratory centers, reducing minute ventilation and promoting hypoxia and hypercapnia

• Cardiovascular dysfunction: Sympathomimetics cause tachycardia, hypertension, arrhythmias through catecholamine excess; cardiotoxic agents (anticholinergics, antiarrhythmics, NSAIDs) directly impair cardiac contractility and conduction

• Opioid toxidrome: Miosis (pinpoint pupils), respiratory depression, altered mental status, hypothermia; presentation ranges from subtle sedation to profound coma with apnea and aspiration risk

• Anticholinergic toxidrome ("hot as a hare, dry as a bone, red as a beet, mad as a hatter"): Hyperthermia, anhidrosis, mydriasis, flushed skin, agitation, confusion, hallucinations; tachycardia and arrhythmias may develop; associated with atropine, antihistamines, tricyclic antidepressants (TCAs), antipsychotics

• Cholinergic toxidrome (organophosphates, carbamates): SLUDGE symptoms (Salivation, Lacrimation, Urination, Defecation, Gastroenteritis, Emesis); miosis, bronchospasm, bradycardia, muscle fasciculations progressing to paralysis; central respiratory depression

• Sympathomimetic toxidrome (cocaine, amphetamines, pseudoephedrine): Hypertension, tachycardia, hyperthermia, mydriasis, agitation, psychosis; risk of myocardial infarction, stroke, arrhythmias; seizures in severe cases

• Sedative-hypnotic toxidrome (benzodiazepines, barbiturates, GHB): Altered mental status, respiratory depression, hypotension, ataxia; progression from drowsiness to coma with absent reflexes

• Salicylate toxidrome: Mixed respiratory alkalosis (hyperventilation from direct respiratory center stimulation) and metabolic acidosis; altered mental status, hyperthermia, pulmonary edema; classic "salicylate triad" is rare

• Serotonin syndrome: Agitation, confusion, hyperreflexia, clonus (especially lower extremities), hyperthermia, mydriasis; may progress to rhabdomyolysis and DIC; triggered by MAOI + SSRI interactions, tramadol overdose, or linezolid use

• Important clinical pearls: Vital sign abnormalities (respiratory depression, bradycardia, hypotension) often signal serious toxicity; absence of expected signs does not exclude poisoning; presentation evolves over hours (e.g., delayed hepatotoxicity with acetaminophen)

• Clinical toxidrome recognition: Systematic evaluation of mental status, pupils, respiratory rate, temperature, and skin findings often identifies the toxin class without laboratory confirmation; toxidrome approach is faster and more sensitive than waiting for toxicology screens

• Urine and serum drug screening: Qualitative immunoassays detect common drugs (opioids, benzodiazepines, cocaine, amphetamines, THC, PCP); limited specificity (false positives with NSAIDs, sympathomimetics) and do not guide acute management; quantitative levels (digoxin, theophylline, lithium, acetaminophen, salicylate) inform prognosis and treatment decisions

• Anion gap metabolic acidosis with osmolar gap: Calculate both gaps to narrow differential; alcohols (ethylene glycol, methanol), aspirin, and metformin produce high anion gaps; osmolar gap suggests ingestion of volatile or osmotically active substances

• Electrocardiography: Prolonged QT, wide QRS complex (TCAs, antipsychotics, some stimulants), peaked T waves (hyperkalemia from rhabdomyolysis), atrioventricular blocks (digoxin, calcium channel blockers, beta-blockers)

• Imaging studies: Chest X-ray assesses for aspiration pneumonia or pulmonary edema (particularly with salicylates or opioids); cranial imaging only if focal neurologic deficits suggest alternative diagnosis

• Specialized testing: Acetaminophen and salicylate levels at 4+ hours post-ingestion (before peak levels); arterial blood gas for respiratory status; electrolytes, creatinine, liver and renal function; lactate and creatine kinase (rhabdomyolysis); pregnancy test in all reproductive-age females

• Important diagnostic considerations: Timing of ingestion critical for nomogram-based interventions; co-ingestions common and complicate interpretation; patient reliability varies so collateral history and pill bottles essential; negative urine drug screen does not exclude overdose

General Supportive Care (First-Line Foundation)

• Airway management: Intubation with rapid-sequence induction for GCS ≤8, airway protection failure, or anticipated deterioration; bag-valve-mask ventilation temporizes
• Oxygen supplementation: Target SpO₂ ≥94%; avoid hyperoxia in pure opioid toxicity but normalize in mixed presentations
• IV access and fluid resuscitation: Two large-bore IVs; judicious fluids for hypotension while avoiding pulmonary edema (particularly with salicylates or opioids)
• Continuous cardiac monitoring and pulse oximetry
• Temperature management: Active rewarming for hypothermia; cooling measures (ice packs, cold saline) for hyperthermia

Toxin-Specific Antidotes (Must Know)

• Opioid overdose: Naloxone (Narcan) 0.4–2 mg IV/IM/IN; repeat every 2–3 minutes to maximum 10 mg if no response; continuous infusion (0.5–1.6 mg/hour) if recurrent respiratory depression; note: half-life shorter than many opioids so redosing or infusion required
• Acetaminophen toxicity: N-acetylcysteine (NAC) most effective when given within 8–10 hours of ingestion; use Rumack-Matthew nomogram at 4+ hours post-ingestion to determine need; IV protocol: 150 mg/kg loading dose over 1 hour, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours
• Anticholinergic toxicity: Physostigmine (eserine) 1–2 mg IV given for life-threatening symptoms (severe agitation, seizures, arrh

Complications of the poisoning itself

• Aspiration pneumonitis and hypoxic-ischemic brain injury: obtunded patients lose airway reflexes; signaled by new infiltrate, fever, or failure to awaken after naloxone. Airway loss is the immediate emergency in every overdose.
• Acetaminophen fulminant hepatic failure: NAPQI-driven centrilobular necrosis peaks at 72–96 hours — markedly elevated transaminases (often in the thousands), rising INR, hypoglycemia, encephalopathy. Rising INR and lactate despite NAC, or the King's College criteria (arterial pH below 7.3 after resuscitation, or the triad of grade III–IV encephalopathy, marked INR elevation, and creatinine elevation) mandate immediate transplant-center referral per AASLD acute liver failure guidance. Emergency.
• Salicylate cerebral and pulmonary toxicity: uncoupled oxidative phosphorylation plus CNS glucose depletion produce agitation then coma; noncardiogenic pulmonary edema and altered mental status are EXTRIP indications for hemodialysis regardless of level, as is severe acidemia or renal failure. Emergency.
• Rhabdomyolysis with AKI and compartment syndrome: from prolonged immobility, seizures, or hyperthermia; flagged by markedly elevated CK, tea-colored urine, dipstick blood without RBCs, hyperkalemia.
• Dysrhythmia and shock: sodium-channel blockade (TCAs) widens QRS and precipitates ventricular tachycardia; recognize the shockable pair as ventricular fibrillation / pulseless VT.

Complications of treatment

• Naloxone-precipitated withdrawal: vomiting with aspiration risk, agitation, occasionally flash pulmonary edema — titrate to ventilation, not to alertness.
• N-acetylcysteine anaphylactoid reaction: histamine release from the IV loading infusion, not IgE-mediated; flushing, urticaria, bronchospasm. Slow or hold the infusion, give an antihistamine, then resume — do not abandon NAC.
• Flumazenil-induced seizures: unmasked withdrawal in benzodiazepine-dependent patients or unopposed convulsant effect with TCA co-ingestion; this is why it is essentially never given in undifferentiated overdose.
• Physostigmine bradyasystole/seizure: avoid with QRS widening.
• Intubating the salicylate patient: abolishing compensatory hyperventilation causes catastrophic acidemia — match the prior minute ventilation. Emergency.
• Alkalinization hypokalemia: potassium must be repleted or the urine will not alkalinize.

• Check an acetaminophen level in every intentional overdose: it is silent early, cheap to detect, and lethal if missed. Draw at 4 hours or later post-ingestion and plot on the Rumack-Matthew nomogram; if the time of ingestion is unknown, the ingestion was staggered, or presentation is delayed beyond the nomogram's window, start N-acetylcysteine empirically rather than waiting.
• The single best next step in an unresponsive patient with a respiratory rate of 6 is ventilation, then naloxone — titrate to restored respiratory drive, not to a fully awake patient. Naloxone's duration is shorter than that of methadone, extended-release oxycodone, and many fentanyl analogs, so observe and consider an infusion.
• Mixed respiratory alkalosis plus anion-gap metabolic acidosis in a tinnitus patient is salicylate until proven otherwise. Alkalinize serum and urine with sodium bicarbonate (ion trapping), replete potassium, and call nephrology early; per EXTRIP, altered mental status, pulmonary edema, renal failure, or a very high level drive hemodialysis.
• Wide QRS after overdose = sodium-channel blockade. Give hypertonic sodium bicarbonate for QRS widening in TCA toxicity; also remember a terminal R wave in aVR. Physostigmine is the classic distractor here — it can precipitate asystole.
• Flumazenil is the trap answer for undifferentiated sedative overdose; seizure risk in dependence or TCA co-ingestion outweighs benefit.
• Elevated osmolar gap with severe acidosis and no ketones points to methanol (visual disturbance, putaminal necrosis) or ethylene glycol (calcium oxalate crystalluria, AKI): fomepizole blocks alcohol dehydrogenase, hemodialysis removes the parent alcohol and metabolites.
• Activated charcoal only within about an hour of ingestion and only with an intact or protected airway (AACT/EAPCCT position statements); it does not bind alcohols, lithium, iron, or hydrocarbons, and gastric lavage is essentially obsolete.
• Call the U.S. Poison Control hotline, 1-800-222-1222 — an acceptable and often correct "next step" in management.