Antidotes Summary
Reviewed and revised 20 May 2016
OVERVIEW
Antidotes are agents that counteract the effects of a toxic agent on the body. They do not primarily affect the systemic absorption or removal of toxic agents from the body (i.e. decontamination and enhanced elimination respectively)
- Antidotes have a surprisingly minor role in the management of most poisonings, their use is restricted to specific indications. In most poisonings effective supportive care and monitoring will ensure a good outcome
- Some antidotes have established roles in other diseases (e.g. insulin, atropine), but when used as ‘antidotes’ much higher doses may be required to correct the disturbance physiology resulting from intoxication.
- Many antidotes are rarely used, prone to go out of stock and are expensive. As a result stewardship of their use (e.g. training and protocolization) is important to ensure they are used appropriately in conjunction with planning and monitoring of stocks, storage, and access. This is best coordinated on a regional basis.
- For patients in peripheral locations, it is often safer and less expensive to transport an antidote to the patient, rather than the opposite
- In critically ill patients, resuscitation should take priority over antidotal therapy. However, certain antidotes may have benefit in cardiac arrest and during resuscitation (see below). Also, decontamination with Fuller’s Earth and Activated Charcoal is priority following significant paraquat exposure (highly life threatening, difficult to treat)
USE OF ANTIDOTES
Use is based on a benefit-risk analysis
- can be difficult given the paucity of evidence of clinical effectiveness for many antidotes and the relative rarity of their use
- the nature of the toxic agent(s) may be uncertain at the time of presentation
Antidotal therapy should be reserved for agents that:
- have an antidote available
- cause significant toxicity, that exceeds the potential harms of the antidote
- cannot be managed by standard resuscitation, supportive care and monitoring
- cannot be safely and effectively decontaminated before absorption
- are not suitable for enhanced elimination
Most antidote doses should be titrated to the required effect
- repeated doses and the duration required may vary according to the duration of action of the toxic agent, which may be different from the duration of action of the antidote (e.g. repeated naloxone doses or an infusion may be required with long-acting opioids)
- some antidotes have fixed doses to ensure complete receptor/ pathway blockage (e.g. silibinin, fomepizole)
HARMS FROM ANTIDOTES
Many antidotes have an excellent safety profile (e.g. oral vitamin K), others do not (e.g. ). The harms are often well quantified and are an important determinant of the threshold for antidote use.
- distraction from other management priorities (e.g. resuscitation, supportive care and monitoring)
- dosing errors
- hypersensitivity reactions (e.g. NAC, anaphylactoid reaction to vitamin K, allergy to antivenom)
- specific adverse events (e.g.
- excessive antidote effect (e.g. benzodiazepine withdrawal from flumazenil, sympathetic crisis and pulmonary edema from naloxone)
- unanticipated effects in mixed overdoses (e.g. NAC may worsen hypotension in a mixed paracetamol / cardiotoxic overdose)
- interference with laboratory assays (e.g. digoxin levels increase after digibind; intralipid may cause spurious biochemistry results)
- Interference with other therapies (e.g. intralipid may decrease the effectiveness of lipid soluble therapeutic agents)
SUMMARY OF AGENTS AND ANTIDOTES
- Amanita phalloides deathcap mushroom toxicity: Silibinin
- Amphetamines: Benzodiazepines + consider dantrolene
- Anticholinergics: Physostigmine
- Arsenic: Dimercaprol
- Benzodiazepines: Flumazenil
- Beta-blockers: High-dose Insulin Euglycaemic Therapy (HIET), Adrenaline
- Bupivacaine/ local anaesthetics: sodium bicarbonate, intralipid
- Butyrophenones (haloperidol): Benztropine
- Calcium channel blockers: IV calcium, High-dose Insulin Euglycaemic Therapy (HIET)
- Cannabis: ? Flumazenil
- Carbon monoxide: O2, Hyperbaric oxygen
- Cholinergics (Organophosphates): Atropine, Pralidoxime
- Clonidine: ? Naloxone
- Chloroquine: Diazepam, NaHCO3
- Cyanide: Hydroxocobalamin + Sodium thiosulphate + Sodium Nitrate
- Dabigatran: Idarucizimab
- Digoxin: Digibind (Fab), Mg2+
- Dystonic reactions: Benztropine, Diphenhydramine
- Ethylene glycol: Ethanol, 4-methylpyrazole, Pyridoxine, Thiamine
- Envenomation (arthropod, snake, jellyfish): Anti-venoms
- Fluoride: Calcium and Mg2+
- Hydrofluric acid: Calcium gluconate
- Heparin: Protamine
- Hypoglycaemia: Dextrose; octreotide (if oral hypoglcaemic agent)
- Iron: Desferrioxamine
- Isoniazid: Pyridoxine
- Lead: Dimercaprol, BAL
- Malignant hyperthermia: Dantrolene
- Methanol: Ethanol, 4-methylpyrazole, Folate
- Methaemaglobinaemia: Methylene Blue, Ascorbic Acid
- Methotrexate: Carboxypeptidase, Folinic acid
- Neuroleptic malignant syndrome -> Bromocriptine, Amantadine, Dantrolene
- Opioids: Naloxone
- Paracetamol: N-acetylcysteine
- Plutonium: Calcium trisodium pentetate
- Radiation: Potassium iodide
- Rivaroxaban, apixaban: Andexanet
- Sodium channel blockers: NaHCO3
- Serotonin syndrome: Cyproheptadine, Olanzepine, Benzodiazepines
- Sympathomimetics: Adrenegic blockers (avoid beta blockers)
- Tricyclic overdose: NaHCO3
- Vacor (N-3-pyridymethyl-N-p-nitrophenylurea): Nicotinamide
- Valproate: Carnitine + Naloxone
- Warfarin: Vitamin K, FFP, Prothrombinex
CLASSIFICATION
Antidotes can be classified in different ways, an example of a mechanistic classification is shown below.
| 1 | 2 |
|---|---|
| Mechanism | Example(s) |
| Competitive receptor antagonists |
|
| Competitive receptor agonists (direct or indirect) |
|
| Competitive enzyme antagonists |
|
| Chelation of metals |
|
| Alteration of toxic agent’s ionisation state |
|
| 'Lipid sink’ / redistribution |
|
| Replenish depleted molecules |
|
| Reverse toxic effects on target molecules |
|
| Bypass surface receptors to modulate second messengers |
|
| Binding to toxin/ toxicant |
|
| Physiological antagonism |
|
Buckley et al (2016) classify antidotes using the ‘ABC or (3Rs) of antidote mechanisms/actions’ as follows:
| 1 | 2 | 3 | 4 |
|---|---|---|---|
| A | B | C | |
| Action | Absorption/Abate (Reduce dose) | Block/Bypass (Restore function) | Control/Cope with consequences (Rescue and support) |
| Timing | Early | Variable (depends on agent time course) | Variable (depends on recovery time course) |
| Maximal efficacy | Moderate (very time dependent) | High | Low to moderate |
| Dosing adjustment | Fixed (or varies with exposure/concentration) | Titrated against direct toxic effect | Titrated against physiological disturbance |
| Example toxin 1
Methotrexate | Carboxypeptidase | Folinic acid | Colony stimulating factor |
| Example toxin 2
Warfarin | Activated charcoal | Vitamin K1 | Clotting factor replacement |
| Example toxin 3
Benztropine | Activated charcoal | Physostigmine | Benzodiazepines |
However, I prefer to make a distinction between ‘decontamination agents’ such as activated charcoal and true antidotes.
ANTIDOTES IN CARDIAC ARREST
Antidotes that can be considered in the setting of cardiac arrest, according to Buckley et al (2016), include:
| 1 | 2 |
|---|---|
| Agent | Indication |
| A (Airway) atropine, epinephrine (adrenaline), activated charcoal | Abolishing vagal effects and vasoconstriction are favourable for most drugs. Give charcoal to prevent ongoing absorption. |
| B (Breathing) bicarbonate | pH correction mitigates toxicity of many drugs |
| C (Circulation) calcium | CCBs and hydrofluoric acid |
| D diazepam; dextrose, do not stop early | Amphetamines and other stimulants, hypoglycaemia. |
| E ECMO | Worth considering early if available |
| F Fab | Envenoming, digoxin (or colchicine) |
| H Hydroxocobalamin | Cyanide |
| I insulin | CCBs/β-adrenoceptor blockers/hyperkalaemia |
| J joules | Pacing or shock as per resuscitation protocols |
| K correct K+ | Antimalarial overdose, salicylate, QT prolongation |
| L lipid | Local anaesthetics |
| M methylene blue, magnesium | MetHB, refractory shock, QT prolongation/torsade des pointes |
| N Nitrous Oxide | NO response???? |
| P phone the Poison centre! |
EVIDENCE
- most ‘antidotal evidence’ is anecdotal (!) or based on animal studies and uncontrolled human series
- Some agents such as NAC are well established in clinical practice. When NAC is used according to established indications within 8 hours of paracetamol ingestion, paracetamol-induced hepatotoxicity does not occur in clinical practice. An RCT would be unethical
- Some agents clearly lead to reversal of toxic effects (e.g. naloxone for opiates), however improved patient outcomes have not been proven
References and Links
LITFL
- CCC – Approach to Acute Poisoning
- CCC — Does antivenom work?
- Tox Library — Antidotes
- Tox Library — Antidotes and Disposition
- Toxicology Conundrum 031 — The Antidote Challenge
Journal articles
- Bateman DN, Page CB. Antidotes to coumarins, isoniazid, methotrexate and thyroxine, toxins that work via metabolic processes. British Journal of Clinical Pharmacology. 81(3):437-45. 2016. [pubmed] [free full text]
- Buckley NA, Dawson AH, Juurlink DN, Isbister GK. Who gets antidotes? choosing the chosen few. British Journal of Clinical Pharmacology. 81(3):402-7. 2016. [pubmed] [free full text]
- Dart RC, Borron SW, Caravati EM. Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care. Annals of emergency medicine. 54(3):386-394.e1. 2009. [pubmed]
- Sivilotti ML. Flumazenil, naloxone and the ‘coma cocktail’. British Journal of Clinical Pharmacology. 81(3):428-36. 2016. [pubmed] [free full text]
- Thanacoody RH, Aldridge G, Laing W. National audit of antidote stocking in acute hospitals in the UK. Emergency medicine journal : EMJ. 30(5):393-6. 2013. [pubmed]
Critical Care
Compendium
Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.
After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.
He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE. He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.
His one great achievement is being the father of three amazing children.
On Twitter, he is @precordialthump.
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