Table of Contents
- Bufadienolides from toad venom (cha'n su)
This monograph will focus on digoxin however the toxicological mechanisms and treatment are similar for the other poisonings.
Cardiac glycosides cause a large number of cardiac effects in overdose leading to both brady- and tachyarrhythmias. The specific antidote, digoxin Fab antibodies, are potentially life-saving but due to their expense, are generally best given by titration and reserved for the treatment of severe poisonings.
MECHANISM OF TOXICITY
Cardiac glycosides inhibit the sodium-potassium adenosine triphosphatase (Na+ /K+ -ATPase) transporter in myocardial and cardiac conducting tissue. They prevent potassium being exchanged for sodium which leads to hyperkalemia and intracellular increases in sodium and subsequently calcium ions. These effects lead to increased automaticity and excitability with both early and late after-depolarisations. Digoxin also causes SA and AV nodal block.
Cardiac glycosides compete with potassium for binding to the Na+ /K+ -ATPase transporter. The activity of this transporter is also increased by the presence of magnesium. Thus both hypokalaemia and hypomagnesaemia increase cardiac glycoside activity and to some extent hyperkalaemia and hypermagnesaemia are therefore protective. However, in severe poisoning there is often marked hyperkalemia and this may be directly responsible for cardiac arrhythmias.
DRUG AND DISEASE INTERACTIONS
Various other drugs may have effects on slowing the AV node (e.g., verapamil, diltiazem and beta blockers) or may lead to hypokalaemia and hypomagnesaemia (e.g. diuretics) or alter P-glycoprotein (P-gp) mediated clearance of digoxin (e.g. quinidine, verapamil, diltiazem, amiodarone, indomethacin, spironolactone). Patients with myocardial disease, respiratory disease or hypothyroidism have increased sensitivity to digoxin.
KINETICS IN OVERDOSE
Digoxin is a water soluble drug and is not well absorbed. Oral bioavailability is about 60–80%.
Digitoxin bioavailability is 80%.
Cardiac glycosides in plants may also be slowly and erratically absorbed.
Digoxin has a large volume of distribution (adults 7–8 L/kg, neonates 10 L/kg, infants 16 L/kg) with high concentrations of tissue binding particularly in cardiac tissue.
The digitoxin volume of distribution is smaller at 0.5–1 L/kg.
Metabolism - Elimination
Digoxin is predominantly excreted renally and the half-life varies with renal function. In the presence of normal renal function the half-life is 24–48 hours, however, this may increase in overdose as the active secretion of digoxin in the kidney becomes saturated. There is some enterohepatic circulation.
Digitoxin is primarily hepatically metabolised with no decrease in clearance with renal failure. Digitoxin has extensive enterohepatic circulation.
Many plant related cardiac glycosides also undergo enterohepatic circulation.
Patients initially complain of nausea, vomiting and diarrhoea. In chronic toxicity, confusion and visual changes may develop. However the most serious manifestations are in the cardiovascular system.
Early ECG changes in digoxin overdose include extra-systoles and minor degrees of AV nodal block. In addition, there may be ST depression. This is usually a characteristic 'reverse tick' ST depression but may mimic ischaemic changes. These findings are also very common at therapeutic concentrations and do not indicate significant toxicity.
Bradyarrhythmias include 2nd and 3rd degree heart block and slow atrial fibrillation.
Junctional and atrial tachycardias occur. These may often have rates in the order of 80 to 100 bpm and thus could be considered an accelerated escape rhythm or slow supraventricular tachycardia.
Ventricular tachycardias are due to increased automaticity and early and late after-depolarisations. Ventricular fibrillation may also complicate poisoning. There is a high mortality associated with ventricular tachycardia and it warrants immediate intervention with digoxin Fab fragments or, if these are not available, insulin or magnesium.
All patients should have an urgent ECG, electrolytes (especially potassium and magnesium), renal function and digoxin concentrations.
These will need to be repeated regularly until clinical effects resolve.
- microgram/L x 1.281 = nanomol/L
- nanomol/L x 0.781 = microgram/L
- microgram/L x 1.31 = nanomol/L
- nanomol/L x 0.765 = microgram/L
Digoxin concentrations taken 6 or more hours after ingestion correlate reasonably well with clinical signs. Earlier concentrations may be difficult to interpret as digoxin may still be in a distribution phase and therefore plasma concentrations do not correlate with tissue concentrations. Thus early digoxin concentrations may serve to confirm an overdose; however they are not a good guide to the need for specific treatment.
Total digoxin concentrations rise rapidly with the administration of anti-digoxin Fab fragments and then only direct measurement of free digoxin concentrations will indicate the amount of digoxin still unbound.
Urgent measurement of potassium, sodium, magnesium, calcium and bicarbonate is necessary. Any hypokalaemia, hypomagnesaemia or an imbalance of the other electrolytes should be corrected. However, mild to moderate hyperkalaemia should not be corrected. The high potassium is an indicator of antagonism at the potassium binding site. Thus, potassium levels greater than 6 mEq/L are usually present in severe acute toxicity. However, in chronic toxicity occurring in patients with heart disease, normokalaemia or hypokalaemia is more common from the use of diuretics. In addition, hyperkalaemia may occur due to the concurrent use of spironolactone and angiotensin blocking agents.
DIFFERENCES IN TOXICITY WITHIN THIS CLASS
Digitoxin and plant and animal cardiac glycosides have similar clinical manifestations; however they differ in a number of respects. There are clear differences in the incidence of particular arrhythmias between yellow oleander (Thevetia peruviana) and digitalis poisoning. Ventricular ectopics and tachycardias are common in patients with chronic digoxin toxicity, but are rare in oleander-poisoned patients, who are normally young and previously healthy.
Cardiac glycosides other than digoxin are predominantly cleared by the liver rather than the kidneys. They also have much lower affinity for anti-digoxin Fab fragments. This means that substantially larger doses of anti-digoxin Fab are required for effect. For example in the treatment of yellow oleander poisoning the effective treatment dose was 1200 mg (30 x 40 mg vials).
Measured digoxin concentrations may be elevated by other cardiac glycosides due to assay cross reactivity. However, the reported ‘digoxin concentration’ does not reflect the amount of Na+ -K+ -ATPase inhibition. Different results on different assays are also typical.
All patients with a significant ingestion of digoxin should have cardiac monitoring and intravenous access.
If presenting within 1–2 hours, patients should be given activated charcoal if they have ingested an acute overdose of more than 0.1 mg/kg of digoxin or have any acute on chronic exposure. Gastric lavage is rarely indicated, if at all, because the increased vagal tone from this procedure may precipitate heart block. Premedication with atropine is strongly advised if gastric lavage is performed.
Treatment of specific complications
Vomiting should be controlled ASAP with medium to high doses of metoclopramide (10–50 mg IV) or a 5HT3 antagonist (ondansetron, tropisetron, dolasetron etc.). Vomiting leads to electrolyte imbalances and increased vagal tone which may increase cardiac toxicity.
In acute digoxin poisoning, the primary treatment of all these major cardiac complications is anti-digoxin Fab fragments. If these are unavailable, heart block should be treated with atropine and temporary pacing and tachyarrhythmias may be treated with insulin for hyperkalaemia and correct other electrolytes (Mg) abnormalities.
With chronic poisoning, bradycardia is often caused by the concomitant administration of beta-blockers and calcium antagonists. Hence it is difficult to define the indications of anti-digoxin Fab and its use is unlikely to alleviate bradycardia in chronic digoxin poisoning.
Extracorporeal methods of elimination do not significantly increase digoxin clearance. Repeat dose charcoal may be useful. They have been shown to increase clearance and perhaps improve outcomes after yellow oleander poisoning and should be used if tolerated in all such ingestions. There is a small increase in clearance of digoxin with repeat doses of activated charcoal as there is some enterohepatic circulation (more significant in those with renal impairment). Repeat dose charcoal also increases clearance of digitoxin in animal models.
Digoxin Fab fragments summary
These digoxin specific antibodies bind rapidly to digoxin removing it from the Na+ -K+ -ATPase pump. The Fab-digoxin complex is then renally excreted. Total digoxin concentrations may increase many fold, however free serum digoxin concentrations fall. The Fab-digoxin complex is excreted with a half-life of 12 to 24 hours; however this may be greatly prolonged in the presence of renal failure.
While Digoxin-Fab binds to digoxin in a 1:1 ratio the volume of distribution of digoxin is at least 10 times greater than Digoxin-Fab so much of the body’s digoxin burden is not available for immediate binding. In practice the clinical response to digoxin-Fab is rapid and most patients can be treated with repeated doses titrated to clinical response. For chronic digoxin toxicity it is suggested to give 40 mg (1 vial) at a time and reassess for further repeat doses after an hour. For acute poisoning it is recommended to give 80 mg (2 vials) and reassess. If patients are haemodynamically unstable a larger initial dose should be given. 1 This may be calculated based on the fact that digoxin-Fab 40 mg binds digoxin 0.5 mg. Hence, for example, ingestion of digoxin 3 mg could require up to 6 vials.
- Life threatening dysrhythmias
- Ventricular tachycardia/ventricular fibrillation
- Third degree heart block
- Cardiac compromise – in patients with underlying cardiac disease
- Serum potassium > 6 mmol/L
- Digoxin concentration > 20 nanomol/L (15.6 microgram/L) 6 hours or more after an acute overdose*
- Digoxin concentration > 10 nanomol/L (7.8 microgram/L) in chronic toxicity*
*The rationale for using this digoxin concentration is that the time for the concentration to fall to a safe level would require such prolonged monitoring that it is more cost effective to give digoxin Fab fragments.
Fab fragments may remove the beneficial effects of digoxin in patients with underlying congestive heart failure or atrial fibrillation. In practice this occurs rarely. In patients with severe underlying cardiac disease, anti-digoxin Fab may be given incrementally until the desired clinical effect is achieved. This strategy can only be used in patients without immediately life-threatening toxicity.
Fab fragments bind to digoxin in a one to one ratio. Thus the dose of anti-digoxin Fab fragments depends on the dose of digoxin that is to be neutralised. The dose may be calculated from the known dose ingested or from the digoxin concentration if digoxin has equilibrated. However, the simplest and most cost-efficient strategy is probably just careful dose titration.
In acute overdose, anti-digoxin Fab fragments are titrated against clinical effects indicating a need for treatment (e.g., AV block and bradycardia); 1–2 vials of anti-digoxin Fab fragments can be given and repeated if the effect does not resolve or recurs (typically, rebound if it occurs will be within 6-12 hours or so). This is most useful in patients with hyperkalaemia and/or heart block. Larger doses are often given initially to patients with ventricular tachyarrhythmias. It is useful to calculate the maximum required dose using one of the methods below to indicate the ceiling dose for titration.
From dose ingested
1 x 40 mg vial of anti-digoxin Fab fragments binds to approximately 0.5 mg of digoxin. Thus, an ingestion of 3 mg of digoxin should require up to at most 5 vials.
From serum digoxin concentration
Total body burden of digoxin = concentration in microgram/L or nanomol/L/1.281) x weight (kg) x volume of distribution (L/kg).
This uses the average volume of distribution (adults 7–8 L/kg, neonates 10 L/kg; infants 2–24 months 16 L/kg; children 2–10 years 13 L/kg) and the measured digoxin concentration.
For example, a patient with a concentration of 13 nanomol/L six hours after an overdose can have the amount of digoxin they have absorbed calculated as follows:
- Convert the units to microgram/L from SI units by dividing by 1.281 thus the concentration is approximately 10 microgram/L
- If the patient is an 80 kg man then the volume of distribution may be as high as 700 L and therefore up to 7000 microgram or 7 mg of digoxin has been ingested
- As a 40 mg vial binds about 0.5 mg of digoxin this patient requires, at mazimum, 13 or 14 vials of digoxin Fab fragments
Thus, in an adult the number of 40 mg vials = concentration in microgram/L (nmol/L/1.28) x weight (kg)/75
Magnesium enhances the activity of the Na+ -K+ -ATPase without altering digoxin concentrations or digoxin binding. It may be useful in situations where digoxin Fab fragments are indicated but are not immediately available. The calcium channel blocking properties of magnesium mean that it is useful in tachyarrhythmias but may paradoxically initially worsen AV block in bradyarrhythmias.
Atropine should be given to all patients with bradyarrhythmia at a dose of 0.6 to 1.2 mg IV in an adult, repeated as necessary. If other antiarrhythmic drugs are required, Class 1b drugs should be used as they do not impair AV nodal conduction. Class 1a antiarrhythmic drugs are contraindicated.
Insulin has been shown to be effective in animal models of severe cardiac glycoside toxicity. Its action may be through reducing hyperkalemia and/or stimulating Na+ -K+ -ATPase activity in cardiac muscle. Human experience is very limited and it is unclear what the optimal dose is, but a 10 unit dose is commonly used for hyperkalemia from other causes.
LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP
Patients should be monitored until clinical signs resolve and digoxin concentrations return to within the therapeutic range (if anti-digoxin Fab fragments have not been given).
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