Toxicology & Antidotes

Analgesics and CNS depressants

Acetaminophen. At normal doses it is mostly conjugated (glucuronidation, sulfation). In overdose those pathways saturate, more drug is oxidized by CYP2E1 to the toxic metabolite NAPQI, glutathione is depleted, and NAPQI injures hepatocytes, producing centrilobular (zone 3) necrosis. Patients may look well early, with liver injury evolving over the next days. N-acetylcysteine regenerates glutathione and works best within 8–10 hours; the Rumack-Matthew nomogram (serum level vs time since ingestion) decides who needs it.

Salicylates. Aspirin overdose causes tinnitus, vomiting, and hyperthermia, with an early respiratory alkalosis (respiratory center stimulation) followed by anion-gap metabolic acidosis. Sodium bicarbonate alkalinizes the urine to trap and excrete salicylate; hemodialysis is used for severe toxicity.

Opioids. Respiratory depression, miosis (pinpoint pupils), and CNS depression. Naloxone is a short-acting opioid antagonist; because it can wear off before the opioid does, watch for re-narcotization and repeat the dose. Naltrexone is a long-acting antagonist used for maintenance, not rescue.

Benzodiazepines. Sedation with relatively preserved respiration unless combined with alcohol or opioids. Flumazenil is a competitive antagonist at the GABA-A benzodiazepine site, but it is used cautiously because it can precipitate seizures in chronic benzodiazepine users or in mixed overdoses (e.g., with TCAs).

Toxic alcohols

Metabolism makes the poison. Methanol and ethylene glycol are converted by alcohol dehydrogenase into toxic acids, producing an anion-gap metabolic acidosis (with an elevated osmolal gap from the unmetabolized alcohol). Fomepizole inhibits alcohol dehydrogenase and is preferred over ethanol, which acts as a competing substrate; hemodialysis removes both the alcohol and its acids in severe cases.

Cardiovascular drugs and anticoagulants

Digoxin. Inhibits Na⁺/K⁺-ATPase. Toxicity causes nausea, vomiting, blurry yellow-green vision (xanthopsia), and arrhythmias. ACUTE toxicity causes HYPERKALEMIA, and the potassium level predicts mortality. Hypokalemia, hypomagnesemia, and renal failure potentiate toxicity. Antidote: digoxin-specific antibody (Fab) fragments, while correcting potassium and magnesium.

β-blockers and calcium channel blockers. Overdose causes bradycardia and hypotension. Glucagon is the β-blocker antidote: it raises intracellular cAMP through its own receptor, independent of the blocked β receptor, restoring heart rate and contractility. IV calcium and high-dose insulin are adjuncts.

Tricyclic antidepressants. Block cardiac fast sodium channels (QRS widening, ventricular arrhythmias) and add anticholinergic effects and seizures. Sodium bicarbonate raises serum sodium and pH to overcome the channel block.

Metals and chelators

Iron. A common overdose in young children. Free iron generates free radicals and cell death: early vomiting and GI bleeding, metabolic acidosis, and radiopaque tablets on abdominal X-ray, then shock, and later gastric scarring and strictures. Antidote: deferoxamine (parenteral chelator); deferasirox is an oral option for chronic iron overload.

Lead. Inhibits ALA dehydratase and ferrochelatase, causing microcytic anemia with basophilic stippling and elevated protoporphyrin. Clues: Burton gingival lines, wrist or foot drop, abdominal pain, encephalopathy and developmental delay in children, and lead lines on long-bone X-rays. Sources include old paint in older housing. Chelate with succimer (oral, children), EDTA, or dimercaprol (BAL) for severe cases.

Other metals. Arsenic, mercury, and gold are chelated by dimercaprol; copper in Wilson disease by penicillamine.

Poisons of oxygen delivery and use

Carbon monoxide. Binds hemoglobin with ~200–250× the affinity of oxygen, cutting oxygen-carrying capacity and shifting the dissociation curve LEFT so tissues receive less oxygen. Sources: car exhaust in a closed garage, faulty heaters, house fires. Headache is the first sign; skin may be cherry red. PaO₂ is normal while true SaO₂ is low, and standard pulse oximetry reads falsely normal, so carboxyhemoglobin must be measured directly. Treat with 100% oxygen or hyperbaric oxygen.

Cyanide. Inhibits cytochrome c oxidase (complex IV), halting the electron transport chain; cells cannot use oxygen and switch to anaerobic metabolism, producing severe lactic acidosis despite normal saturation. Bitter almond breath. Sources: house fires and nitroprusside infusions. Antidotes: hydroxocobalamin (preferred; binds cyanide to form cyanocobalamin), sodium thiosulfate (sulfur donor that converts cyanide to thiocyanate), and nitrites (induce methemoglobin, which binds cyanide).

Methemoglobinemia. Oxidizing drugs (e.g., dapsone, nitrites, benzocaine) convert heme iron from Fe²⁺ to Fe³⁺, which cannot carry oxygen: chocolate-brown blood and cyanosis that does not correct with oxygen. Methylene blue reduces it back to Fe²⁺.

Other classic pairs: isoniazid → pyridoxine (vitamin B6); sulfonylurea hypoglycemia → octreotide plus glucose; organophosphates → atropine plus pralidoxime; anticholinergics → physostigmine.