17.2 Specific Antidotes, Mechanisms of Action & Decontamination Strategies

Mechanism of toxicity decides the intervention

Handbook IV.11 asks you to connect how the poison injures biochemistry to how the treatment interrupts that injury. Independent OpenExamPrep teaching in this section covers dermal and ocular irrigation, activated charcoal (timing and the agents it does not adsorb), whole-bowel irrigation for body packers and sustained-release metals, the rarity of gastric lavage, then antidotes by mechanism: N-acetylcysteine, naloxone, fomepizole and historical ethanol, atropine plus pralidoxime, hydroxocobalamin and nitrites for cyanide, chelators as decorporation, digoxin-specific Fab, methylene blue, vitamin K and prothrombin complex concentrate, with physostigmine and flumazenil caveats, and hemodialysis for toxic alcohols, lithium, and salicylate. This material is not an ABT or poison-center product and does not claim official approval, review, or partnership with those bodies.

If section 17.1 named the toxidrome, this section names the tool. A tool without a mechanism is trivia; a mechanism without ABCs is malpractice on an examination item.

Decontamination: remove what is still outside the patient — or still in the gut

Dermal. Remove clothing, jewelry, and shoes. Wash with soap and water for most pesticides and solvents. For hydrofluoric acid, irrigation is followed by calcium (gel, and systemic calcium for significant burns) because the injury is fluoride binding of Ca²⁺/Mg²⁺, not a simple acid pH story. Do not start a neutralization chemistry experiment on human skin.

Ocular. Immediate copious irrigation (liters, not milliliters) until pH approaches physiologic for alkali, which penetrate more than acids. Contact lenses come out. Irrigation is the antidote; an amphoteric rinse product is not a DABT requirement.

Activated charcoal. Typical single dose is about 1 g/kg (adult often 50–100 g) of aqueous charcoal, best within about 1 hour of a potentially toxic ingestion of an adsorbable organic, longer if sustained-release or anticholinergic slowing of gut motility keeps drug in the stomach. Charcoal is not an absorbent sponge for everything. It poorly adsorbs hydrocarbons, metals (iron, lithium, lead, potassium), and alcohols (ethanol, methanol, ethylene glycol, isopropanol). It does not fix caustic acids and alkalis and adds aspiration risk if the airway is unprotected. Multi-dose activated charcoal is a gut dialysis tactic for a short list (theophylline, carbamazepine, phenobarbital, dapsone, quinine in many references): repeated doses interrupt enterohepatic or enteroenteric recirculation, not because "more charcoal is always more better."

Whole-bowel irrigation (WBI). Iso-osmotic polyethylene glycol electrolyte solution (PEG-ELS) is run until rectal effluent is clear, in a patient who can protect the airway or is intubated. Indications that actually match the physics: body packers (internal concealment of drug packets), body stuffers in selected large-load cases, and sustained-release or enteric-coated metals and lithium still sitting in bowel. WBI is not a routine "clean out" after every overdose.

Gastric lavage. Orogastric lavage is rarely indicated: a life-threatening ingestion of a charcoal-adsorbable or otherwise recoverable agent, very recent (minutes, not hours), protected airway, and a team that still knows how to do it without pushing drug into the duodenum. It is not the default for a lithium tablet ingestion 45 minutes ago in an awake adult — that patient is a WBI candidate, not a lavage-first candidate. Syrup of ipecac is obsolete in the emergency department and at home.

Antidotes: name the biochemical target

N-acetylcysteine (NAC) — glutathione precursor versus NAPQI. Acetaminophen overdose saturates conjugation and produces N-acetyl-p-benzoquinone imine (NAPQI) via CYP2E1. Glutathione (GSH) detoxifies NAPQI. NAC supplies cysteine, restoring GSH synthesis; it also has hemodynamic and antioxidant effects in established liver injury. Timed 4-hour (or later plotted) concentrations on the Rumack–Matthew nomogram decide treatment after a single acute ingestion. Chronic or staggered ingestions do not use that nomogram the same way; treat on history, transaminases, and acetaminophen concentration. NAC does not chelate acetaminophen in the gut and does not inhibit alcohol dehydrogenase.

Naloxone — competitive mu-opioid antagonist. It displaces agonists from mu receptors, restoring respiratory drive. Duration is shorter than methadone or some fentanyl analogs, so recurrent hypoventilation is expected. It does nothing for a cholinergic secretory death or a benzodiazepine GABA coma.

Fomepizole — alcohol dehydrogenase inhibitor. Methanol becomes formaldehyde then formic acid (optic disc and basal ganglia injury, anion-gap acidosis). Ethylene glycol becomes glycolaldehyde, glycolate, and oxalate (acidosis, hypocalcemia, oxalate nephropathy). Fomepizole inhibits alcohol dehydrogenase (ADH), blocking that first step. It does not remove parent alcohol or already-formed acids; hemodialysis does. Ethanol is the historical competitive ADH substrate (keep a target serum ethanol high enough to occupy ADH). Ethanol is harder to titrate, intoxicating, and hypoglycemia-prone; fomepizole is preferred where available. Isopropanol to acetone generally does not need fomepizole for acid prevention the way methanol/EG do.

Atropine plus pralidoxime (2-PAM) — muscarinic blockade and acetylcholinesterase regeneration. Organophosphate (and nerve-agent) phosphorylation of AChE produces the cholinergic toxidrome. Atropine is a competitive muscarinic antagonist. The titration endpoint is drying of bronchial secretions and relief of bronchospasm, not pupil size. Huge cumulative doses may be required. Pralidoxime is a nucleophilic oxime that attacks the phosphate on AChE and regenerates the enzyme before aging. After aging, the bond is not oxime-reversible; you then rely on atropine and time for new enzyme synthesis. Oxime also addresses nicotinic neuromuscular weakness that atropine cannot. Carbamates typically do not age AChE; atropine remains essential, and oxime is not the usual first intent unless the agent is unknown or mixed.

Hydroxocobalamin and nitrites — cyanide binding and the methemoglobin detour. Cyanide inhibits cytochrome c oxidase (complex IV), producing histotoxic hypoxia, lactic acidosis, and a classically normal SpO2 with high venous oxygen. Hydroxocobalamin binds cyanide to form cyanocobalamin (vitamin B12), which is excreted in urine; it is preferred in smoke inhalation because it does not require inducing methemoglobin in a patient who may already have carbon monoxide. The older nitrite plus sodium thiosulfate kit: nitrites oxidize hemoglobin to methemoglobin, which binds cyanide as cyanmethemoglobin; thiosulfate donates sulfur so rhodanese can convert cyanide to thiocyanate. Nitrites are the wrong first move when carboxyhemoglobin already occupies oxygen-carrying capacity.

Chelators as decorporation. Decorporation means binding metal and increasing urinary (or fecal) elimination. CaNa2EDTA (calcium disodium edetate) chelates lead (and some other cations) for urinary excretion; the calcium salt is used so you do not strip serum calcium the way Na2EDTA would. DMSA (succimer) is an oral vicinal dithiol used for lead (especially pediatric), and also for selected mercury and arsenic burdens. Deferoxamine chelates ferric iron to ferrioxamine, excreted in urine (classically vin rose color). Prolonged high-dose infusions carry ARDS risk; the drug can also facilitate Yersinia growth. Chelation is not charcoal, not dialysis (though dialysis may still be needed for other reasons), and not indicated by a BEI alone.

Digoxin-specific Fab. Antibody fragments bind free digoxin (and some other cardioactive steroids) with high affinity, reversing Na⁺/K⁺-ATPase inhibition. Indications cluster around life-threatening arrhythmia, potassium >5 mEq/L in acute overdose, and very high concentrations or ingested dose. After Fab, total digoxin concentration rises (bound drug) and is not a marker of failure.

Methylene blue — cofactor for methemoglobin reduction. Oxidizing agents (nitrites, aniline, dapsone, some local anesthetics) convert Fe²⁺ hemoglobin to Fe³⁺ methemoglobin, which cannot carry oxygen. Methylene blue is reduced to leucomethylene blue by NADPH methemoglobin reductase and then reduces metHb back to hemoglobin. It fails in G6PD deficiency (inadequate NADPH) and can itself cause hemolysis in that setting. It is not a cyanide first-line drug in the hydroxocobalamin era and is not an opioid antagonist.

Vitamin K and PCC — restoring gamma-carboxylation versus replacing factors. Warfarin and superwarfarins inhibit vitamin K epoxide reductase, so factors II, VII, IX, and X (and proteins C/S) lack gamma-carboxylation. Vitamin K1 (phytonadione) supplies the cofactor so the liver can synthesize new factors — hours, not seconds. Prothrombin complex concentrate (PCC) (or plasma if PCC is unavailable) replaces the factors immediately in life-threatening bleeding. Superwarfarin (rodenticide) poisoning can need weeks of vitamin K. This is the opposite logic of heparin (antithrombin) and is not treated with methylene blue.

Physostigmine — caveats. A tertiary amine carbamate that inhibits AChE in the central nervous system, it can reverse anticholinergic delirium when the ECG is narrow, the toxin is a true antimuscarinic, and benzodiazepines have not finished the job. Do not use it for tricyclic antidepressant overdose, wide QRS, bradyarrhythmia, or unknown mixed coma. Adverse effects include seizures, cholinergic crisis, and asystole.

Flumazenil — caveats. Competitive benzodiazepine-site antagonist on GABA-A. It can unmask seizures in benzodiazepine-dependent patients and in mixed overdoses with proconvulsants. It is not part of the unknown-coma cocktail. If the patient is only benzodiazepine-naive and iatrogenically oversedated in a controlled setting, the risk–benefit can differ; that is not the typical DABT unknown-overdose stem.

Enhanced elimination: hemodialysis as the prototype

Hemodialysis works when the poison is small, water-soluble, poorly protein-bound, with a small volume of distribution — or when you must correct life-threatening acid–base and electrolyte injury even if some drug is tissue-bound.

Toxic alcohols. Dialysis removes methanol and ethylene glycol and their acid metabolites, and it corrects acidosis. Start fomepizole without waiting for a level if the story and gaps fit, then dialyze for severe acidosis, visual symptoms (methanol), renal failure (EG), or high parent-alcohol concentrations per toxicology consultation.

Lithium. Cation, Vd modest, not charcoal-bound. Dialysis for severe neurologic toxicity, levels commonly cited around >4 mEq/L in acute overdose (or lower, often >2.5 mEq/L, with renal impairment or chronic toxicity), or failing kidneys. Rebound after dialysis occurs as tissue lithium re-equilibrates; serial levels matter.

Salicylate. Uncouples oxidative phosphorylation, causes respiratory alkalosis plus anion-gap acidosis, pulmonary edema, and neuroglycopenia. Urinary alkalinization traps salicylate as the anion (ion trapping) in patients who are not yet dialysis candidates. Hemodialysis for severe acidemia, renal failure, pulmonary edema, altered mentation, very high levels (acute often discussed near 100 mg/dL, chronic lower, roughly 60–80 mg/dL with symptoms — use clinical severity, not a single memorized digit), or failure of alkalinization.

Theophylline, valproate, carbamazepine, and metformin-associated lactic acidosis appear on some dialysis lists; the examination still wants the core triad: alcohols, lithium, salicylate.

Linking mechanism to treatment: four one-line maps (IV.11)

1. NAPQI covalent binding → restore GSH with NAC; charcoal if early and adsorbable; not chelation.
2. ADH-dependent acid metabolites → stop ADH with fomepizole; remove parent and acids with HD.
3. AChE phosphorylation → block muscarinic receptors (atropine) and regenerate AChE (oxime) before aging; irrigate skin so absorption stops.
4. Packet or SR metal still in gut → WBI, not charcoal for lithium/iron; deferoxamine only for absorbed iron, not as a GI decontaminant.

Integrated vignettes

Body packer. A courier swallows tightly wrapped packets of an unknown powder. He is awake. Charcoal does not empty packets and does not bind a metal if that is the cargo. WBI with PEG-ELS, surgical backup if a packet ruptures into a sympathomimetic or opioid catastrophe, and no ipecac.

Windshield-washer methanol. Fomepizole on board inhibits ADH. Visual complaints and a plunging bicarbonate mean formate is already present — hemodialysis, not a larger fomepizole-only bet.

Smoke in a basement fire. Coma, soot, lactic acidosis. Hydroxocobalamin for cyanide without stealing oxygen-carrying capacity; high-flow oxygen for carbon monoxide. Sodium nitrite would add methemoglobin on top of CO.

Sustained-release lithium, 45 minutes, protected airway. Charcoal will not adsorb the cation. WBI is the GI method; HD if levels and neurotoxicity later demand it.

Exam traps

• Charcoal for lithium, iron, or methanol.
• Lavage as the default GI procedure.
• Fomepizole as ADH inducer or as a substitute for dialysis when acids are already high.
• Nitrites first in combined CO plus cyanide smoke inhalation.
• Physostigmine in a wide-complex antidepressant overdose.
• Flumazenil in unknown or mixed coma.
• Reading a total digoxin after Fab as treatment failure.
• Methylene blue in G6PD deficiency.
• Using Na2EDTA (hypocalcemic) instead of CaNa2EDTA.

Key takeaways

• Irrigate first when the chemical is still on the outside; charcoal is early and selective; WBI is for packers and selected SR metals; lavage is rare.
• Antidotes are mechanisms: GSH precursor, mu antagonist, ADH inhibitor, muscarinic block plus oxime, cyanide binders, chelators, Fab, methylene blue, vitamin K/PCC.
• Physostigmine and flumazenil stay behind caveats.
• Hemodialysis carries toxic alcohols, lithium, and salicylate when the chemistry and the patient demand it.