Question 7

Digoxin

Digoxin

Fab

Fragments

(Digibind)

• Digibind has a much higher affinity (high affinity (109– 1010 L/mol) for digoxin than the Na+/K+ ATPase digoxin receptor site
• Binds to digoxin in the extracellular spaces preventing digoxin binding to the Na+/K+ ATPase
• Creates a concentration gradient that extracts digoxin from the intracellular space
• Bound digoxin is then renally eliminated with digibind
• If potential for cardiac arrest due to digoxin – antidote of choice

TCA

Sodium bicarbonate

• Alkalinising solution – leading to increased pH.  
• Favours the neutral or non-ionised form of TCA making it less available to bind to sodium channels.  
• Cardiac muscle more inotrope responsive

Sodium load 

• Increased extracellular Na concentration increasing the electrochemical gradient across cardiac cell membranes, potentially attenuating the TCA-induced blockade of rapid sodium channels

Beta

Blockers

Glucagon

• Activates adenylate cyclase in cardiac muscle cells at a site independent from B-adrenergic agents, causing increase in cAMP leading to increased intracellular calcium augmenting contractility.
• Large doses required and tachyphylaxis occurs

High Dose insulin  +/- glucose therapy

Several theories of effect:

• Insulin release from B-islet cells is impaired following overdose (especially Ca blocker)
• Overdose appears to disrupt fatty acid metabolism and create relative insulin resistance in myocardium.
• State of CHO dependence in stressed myocardium and insulin resistance can be overcome with high dose insulin therapy

Atropine

• Anti-cholinergic agent

Lignocaine

Lipid emulsion therapy

• Has been used in poisonings involving other lipophilic medications 
• Thought to act as a lipid “sink”: increasing plasma concentration of lipid – shift of lipophilic medications from tissue to plasma.
• Also providing myocardium with an energy source. Case reports of effect in b blockers and ca channel blockers
• Used as an adjunct to other therapies.

Digoxin

• Digoxin-Fab is a monovalent immunoglobulin
• Its molecular weight is 46,000 Da 
• Its volume of distribution is about 0.4L/kg, i.e. must also distribute at least to some extent into the interstitial fluid.
• 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).
• It is 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. In renal failure, its half life (19 hours) is increased to 130 hours.
• It has a 100 – 1000 times higher affinity for digoxin than does Na+/K+ ATPase.
•  Each vial of DigiFab (38 – 40 mg of Fab) binds approximately 500 mcg of digoxin

• Increased protein binding of TCAs in an alkaline bloodstream, thus decreasing the biologically active free fraction. .
• Increased availability of sodium in sodium bicarbonate, as a substrate for the voltage-gated channels (though the administration of hypertonic saline seemed to have greater antiarrhytmic effect than sodium bicarbonate!)
• 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 greater affinity for TCAs at acidic pH. 
• Correction of metabolic acidosis may play a brutally stupid non-toxicological role by improving the affitnity of catecholamine receptors for their ligands.
• Volume expansion which probably leads to better haemodynamic performance.
• Cellular membrane hypopolarisation results from bicarbonate-induced intracellualr shift of potassium.

• Insulin is a potent positive inotrope in high doses;  this is apparently because of its effects on various calcium-handling pathways, particulalry those mediated by PI3K (Engebretsen et al, 2011).
• It assists myocardial uptake of carbohydrates, which is the preferred fuel substrate of the heart under stressed conditions (whereas normally free fatty acids are preferred).
• It improves the response to catecholamines
• 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". 
• The dose is approximately 0.5-1 unit/kg/hr, but can be titrated up to 10 unit/kg/hr

• Glucagon activates adenylate cyclase, which leads to increased levels of cyclic AMP in the myocytes
• This is the same mechanism of action as the activation og the G-protein-coupled β-receptor
• The net effect is that the blocked receptor is bypassed. Weirdly, bypassing it in other ways (eg. by giving a phosphodiesterase inhibitor) does not seem to have a satisfactory effect, particularly in terms of chronotropy.
• This drug is fairly unwieldy to use, as the dose is a continuous i.v. infusion at a rate of 2–5 mg/hr (maximum: 10 mg/hr);  one patient will require up to 50 mg of glucagon over 24 hours 
• There is tachyphylaxis, reports of treatment failure (Shepherd, 2006) and it may not work for all the β-blockers (eg. it may not be effective for propanolol)

• Its an antimuscarinic drug, which should increase the sinus node rate
• However, this will do little to help the cardiac contractility and the slowed AV node conduction
• Peterson et al (1984) found it "inconsistent in reversing the bradycardia and hypotension"

• Ciechanowicz et al (2012) lists several mechanisms:
• Lipid emulsion acts as a "lipid sink", binding circulating (highly lipohilic) molecules of lignocaine to reduce their bioavailability to the cardiac and CNS voltage-gated sodium channels (eg. free fraction of bupivacaine  is decreased by two thirds)
• Decreased circulating free drug fraction increases the mobilisation out of tissues, and increases the availability of lignocaine to organs of clearance.
• Triglycerides also act directly on cardiac calcium channels to increase myocardial calcium concentration
• Free fatty acid availability may have some sort of metabolic benefit for the fat-hungry myocardium
• The dose of 20% lipid emulsion is 1.5 mL/kg over 1 minute; followed by an infusion of
  15 mL/kg/h. 
• It was first discovered by Weinberg (1998) who was trying to kill rats with bupivacaine (surely there must be an easier way...) - those pre-treated with ;ipid emulsion had their LD50 increased by 50%