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Tuesday, August 19, 2025

Antidotes


Introduction

Antidotes are therapeutic agents used to neutralize or counteract the effects of poisons, toxins, or drug overdoses. They work by blocking the toxic agent’s receptor activity, accelerating its elimination, or directly neutralizing it. While supportive care (airway, breathing, circulation, fluids, and monitoring) remains the cornerstone of poisoning management, specific antidotes play a lifesaving role in targeted toxic exposures.

The effectiveness of antidotes depends on early recognition of poisoning, prompt administration, and appropriate dosing, often in specialized toxicology or emergency care settings.

Classification of Antidotes

1. Chelating Agents (Heavy Metal Poisoning)

  • Generic Names:

    • Dimercaprol (BAL)

    • Succimer (DMSA)

    • Edetate calcium disodium (EDTA)

    • Deferoxamine

    • Deferasirox, deferiprone

    • Penicillamine

  • Mechanism: Bind toxic metals to form water-soluble complexes excreted in urine.

  • Uses:

    • Lead: EDTA, succimer.

    • Arsenic, mercury, gold: dimercaprol, succimer.

    • Iron: deferoxamine, deferasirox.

    • Copper (Wilson’s disease): penicillamine, trientine.

2. Receptor Antagonists / Agonists

  • Opioid Antagonist: naloxone, naltrexone – reverse opioid-induced respiratory/CNS depression.

  • Benzodiazepine Antagonist: flumazenil – reverses sedation from benzodiazepines.

  • Anticholinergic Antagonist: physostigmine – reverses central/peripheral anticholinergic toxicity.

  • Cholinesterase Reactivator: pralidoxime (2-PAM) – reverses organophosphate poisoning by reactivating acetylcholinesterase.

  • Muscarinic Antagonist: atropine – blocks muscarinic effects of organophosphates and carbamates.

3. Enzyme Inhibitors / Cofactors

  • Methanol/Ethylene Glycol Poisoning:

    • Fomepizole – inhibits alcohol dehydrogenase.

    • Ethanol (alternative) – competitive substrate for alcohol dehydrogenase.

  • Cyanide Poisoning:

    • Hydroxocobalamin – binds cyanide to form cyanocobalamin.

    • Sodium thiosulfate – enhances conversion to thiocyanate.

    • Sodium nitrite – induces methemoglobinemia, binding cyanide.

  • Isoniazid (INH) Toxicity: pyridoxine (vitamin B6) replenishment.

  • Methemoglobinemia: methylene blue – reduces ferric iron to ferrous state in hemoglobin.

4. Binding Agents (Toxin Sequestration)

  • Activated Charcoal: Adsorbs many drugs/toxins in the GI tract (not effective for metals, alcohols, caustics).

  • Cholestyramine: Binds cardiac glycosides, enterohepatic toxins.

  • Specific Antibody Fragments (Fab):

    • Digoxin immune Fab – for digoxin toxicity.

    • CroFab / Antivenins – for snake, scorpion, and spider envenomations.

5. Antimetabolite Antidotes

  • Methotrexate Toxicity: leucovorin (folinic acid), glucarpidase (carboxypeptidase G2).

  • 5-Fluorouracil Toxicity: uridine triacetate.

  • Cytarabine Overdose: no specific antidote; supportive only.

6. Oxidation / Reduction Modulators

  • Acetaminophen (Paracetamol) Toxicity: N-acetylcysteine (NAC) replenishes glutathione, detoxifying NAPQI.

  • Methemoglobinemia: methylene blue, ascorbic acid.

  • Hydrogen sulfide poisoning: nitrites (inducing methemoglobin).

7. Endogenous Substance Antagonists / Mimics

  • Warfarin Toxicity: vitamin K (phytonadione), prothrombin complex concentrate (PCC), fresh frozen plasma.

  • Heparin Overdose: protamine sulfate (binds and neutralizes heparin).

  • Direct Oral Anticoagulant (DOAC) Overdose:

    • Idarucizumab (for dabigatran).

    • Andexanet alfa (for apixaban, rivaroxaban).

8. Other Specific Antidotes

  • Beta-blocker Toxicity: glucagon (increases cAMP independent of beta-receptors).

  • Calcium Channel Blocker Toxicity: calcium gluconate/chloride, high-dose insulin therapy.

  • Sulfonylurea Overdose: octreotide (inhibits insulin release).

  • Carbon Monoxide Poisoning: 100% oxygen, hyperbaric oxygen therapy.

  • Digitalis Toxicity: digoxin immune Fab.

  • Snake/Scorpion/Spider Bites: specific antivenoms.

  • Lead/Arsenic/Mercury: chelating agents (EDTA, dimercaprol, succimer).

Representative Antidotes (By Toxin)

Toxin/PoisonAntidote (Generic Names)Mechanism
AcetaminophenN-acetylcysteineRestores glutathione
OpioidsNaloxone, naltrexoneOpioid receptor antagonists
BenzodiazepinesFlumazenilGABA-A receptor antagonist
OrganophosphatesAtropine, pralidoximeMuscarinic antagonist, AChE reactivator
Methanol/Ethylene glycolFomepizole, ethanolAlcohol dehydrogenase inhibitors
CyanideHydroxocobalamin, sodium thiosulfate, nitritesDetoxification pathways
HeparinProtamine sulfateHeparin neutralizer
WarfarinVitamin K, PCC, fresh frozen plasmaReplaces clotting factors
DigoxinDigoxin immune FabAntibody neutralization
LeadEDTA, succimer, dimercaprolChelation
IronDeferoxamine, deferasiroxChelation
IsoniazidPyridoxineReplaces vitamin B6
MethotrexateLeucovorin, glucarpidaseFolate rescue/enzymatic inactivation
Beta-blockersGlucagonIncreases cAMP
Calcium channel blockersCalcium salts, high-dose insulinRestores cardiac contractility
Carbon monoxideOxygen, hyperbaric oxygenDisplaces CO from hemoglobin

Contraindications and Precautions

  • Flumazenil: Contraindicated in benzodiazepine-dependent patients (seizure risk).

  • Naloxone: May precipitate acute withdrawal in opioid-dependent patients.

  • Pralidoxime: Ineffective in carbamate poisoning; use only for organophosphates.

  • Dimercaprol: Contraindicated in iron or cadmium poisoning (worsens toxicity).

  • N-acetylcysteine: Rare hypersensitivity reactions (anaphylactoid).

  • Vitamin K (IV): Risk of anaphylaxis; oral or slow IV administration preferred.

Adverse Effects (Generalized)

  • Chelators: Nephrotoxicity, hypotension, bone marrow suppression.

  • Antagonists (naloxone, flumazenil): Withdrawal, seizures (flumazenil).

  • N-acetylcysteine: Nausea, vomiting, rash, bronchospasm (rare).

  • Atropine: Anticholinergic syndrome (delirium, tachycardia, urinary retention).

  • Glucagon: Nausea, vomiting, hyperglycemia.

  • Hydroxocobalamin: Red discoloration of skin/urine, hypertension.

Clinical Considerations

  • Timely administration is crucial: e.g., NAC is most effective within 8–10 hours after acetaminophen overdose.

  • Supportive care remains essential alongside antidote use.

  • Combination therapy often required: e.g., atropine + pralidoxime in organophosphate poisoning, or multi-drug regimens for CINV prevention.

  • Dose adjustments required in renal/hepatic impairment for many antidotes (EDTA, deferoxamine, NAC).

  • Special populations (pregnancy, pediatrics, elderly) require careful consideration regarding safety and dosing.




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