A summary of toxins and their antidotes

Very often the college gets lazy and lists a few toxins, with the intention that the candidates can then write down the matching antidotes. It is quick to mark (tick tick tick) and requires little though from the question writers. The candidates also appreciate it; it is easy marks, and having appeared many times in the past papers, the act of matching poisons and their antidotes has become an automatism for many of us. Unfortunately, this specific panel of toxins has not been seen for a few years. Previous examples include the following SAQs:

• Question 3 from the first paper of 2022
• Question 28.1 from the second paper of 2009
• Question 14.2 from the first paper of 2008
• Question 2 from the first paper of 2007
• Question 1c from the second paper of 2004

The question usually looks something like this:  "List an antidote  (one (1) drug specific to the agent) in the event of an overdose with each of the agents listed below in the table." A table of toxins is then provided. The table below is not from any specific question - it has been concocted from all previous college answers to questions of this form. Some poison-antidote combinations have been added by the author here because they are worth knowing, even if they have never come up in such a question. These errata are italicised so people can tell which are the "canonical" college answers and which are the fevered rant of a madman.

In the list provided by the college, there are standard drugs which everyone would know the antidotes for, and non-standard ones which may not be totally familiar to people without a toxicology background.

Pyridoxine is the antidote for isoniazid

Pyridoxine is a co-factor in the synthesis of GABA; isoniazid interferes with this synthesis, and causes seizures in overdose. The supplementation of pyridoxine seems to prevent the worst of isoniazid toxicity (it seems the inhibition of lactate metabolism is not such a big deal).

Carnitine is the antidote for valproate

Or so it is thought. The most disturbing aspects of valproate toxicity are valproate-induced hyperammonaemic encephalopathy and hepatotoxicity. Carnitine deficiency is implicated in both, and seems to be caused by chronic valproate administration more so than acute. The reason for the efficacy of carnitine in valproate overdose seems to stem from its central role in beta-oxidation of long chain fatty acids (which is the metabolic pathway taken by valproate). It appears to hasten the resolution of coma, and it seems to protect the liver from necrosis; the mechanism is thought to be the prevention of accumulation of toxic metabolites of valproate. (Incidentally, carnitine is also being considered as a rescue therapy for propofol infusion syndrome)

Dimercaprol is the antidote for lead poisoning

And mercury, antimony, gold, chrome, cobalt and nickel poisoning. First developed to treat arsenic poisoning during the Second World War, dimercaprol (or British Anti-Lewisite, BAL) is a chelating agent which competes for heavy metal ions with the thiol groups of enzymes, thus preventing the inactivation of those enzymes. The metal-dimercaprol complex is then renally excreted.

Dimercaprol itself is horribly toxic, and its use in heavy metal poisoning is limited to situations where heavy metal levels are high, toxicity is already severe, and water-soluble analogues of dimercaprol (eg. DMPS and DMSA) are not available.

Rationale for the use of selected antidotes

This is more of an aside, used to address the expectations of Question 3 from the first paper of 2022, where "the rationale for use of the pharmacological intervention including the mechanism of action" was expected for the antidotes to digoxin, tricyclics, beta blockers and lignocaine. Beta blocker overdose, digoxin toxicity and  tricyclic antidepressant overdose are covered in detail elsewhere, and local anaesthetic toxicity is one of the syllabus items from the First Part exam, making this short summary somewhat redundant; but to collect all these items together here felt like the right thing to do. 

Rationale for digoxin-specific Fab fragments in digoxin overdose:

• Remove free digoxin from the active target sites: the Fab has a 100 – 1000 times higher affinity for digoxin than does Na+/K+ ATPase.
• Increase removal from tissues: The circulating Fab acts as a digoxin sink, increasing the gradient for free digoxin to enter the circulation; this increases the renal clearance of digoxin by 20-30% (Chan and Buckley, 2014).
• Increase renal clearance: Digoxin/Fab complexes are removed by both renal clearance and hepatic metabolism, but it's mainly renal: the digoxin-antibody complexes are filtered through the glomeruli  (which is surprising, consider their size) and reabsorbed in the proximal tubules while the digoxin is excreted. 
• The serum digoxin assay will thereafter measure both the free drug and the Fab-bound fraction, and is therefore not to be believed.

Rationale for sodium bicarbonate in tricyclic antidepressant overdose:

• Increase protein binding of TCAs in an alkaline bloodstream, thus decreasing the biologically active free fraction.
• Increase the availability of sodium in sodium bicarbonate, as a substrate for the voltage-gated channels. (this corrects the QRS prolongation and prevents arrhythmias)
• Decreased binding of TCAs to the voltage-gated sodium channel - apparently this binding is affected by subtle changes in pH, and this receptor family has a greater affinity for TCAs at acidic pH. 
• Correction of metabolic acidosis  to enhance cardiac contractility by improving catecholamine sensitivity
• Volume expansion (dilutes TCA concentration)
• Cellular membrane hypopolarisation results from the bicarbonate-induced intracellular shift of potassium. Apparently, this somehow "decreases sodium channel blockade by voltage-dependent drug-binding changes".

Rationale for high dose insulin euglycaemic therapy in beta-blocker overdose:

• Inotropic effect: Insulin is a potent positive inotrope in high doses because of its effects on various calcium-handling pathways, particularly those mediated by PI3K (Engebretsen et al, 2011).
• Afterload reducing effect: Insulin produces vasodilation, which improves local microcirculation (due to enhancement of endothelial nitric oxide synthase activity) - apparently this can "achieve perfused capillary density similar to that of exercising muscle
• Metabolic effect: Insulin assists myocardial uptake of carbohydrates, which is the preferred fuel substrate of the heart under stressed conditions (whereas normally free fatty acids are preferred).

Rationale for lipid infusion in local anaesthetic toxicity:

• Lipid sink: the highly lipid-soluble local anaesthetic molecules are absorbed into the lipid emulsion droplets, which decreases the free fraction of the drug in the circulation
• Tissue extraction: because the free fraction in the circulation drops, redistribution from target tissues (CNS, myocardium) will occur, reducing toxicity in those organs
• Lipid shuttle: the fatty droplets of lipid emulsion act as a carrier which delivers the local anaesthetic to the liver, enhancing the rate of elimination (apparently this is also referred to as a "lipid subway")
• Metabolic changes in the myocardium:  the increased fatty acid supply reverses local-anaesthetic-induced reduction in fatty acid metabolism in the cardiac mitochondria
• Inoconstrictor effects though the inhibition of nitric oxide release and some positive inotropic effects, which appears to be an intrinsic property of the lipid emulsion
• Reversal of cardiac sodium channel blockade by a mechanism apparently related to fatty acid-mediated modulation of cardiac sodium channels