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2.1.6.1.1 Cardiac glycoside teaching resources
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Problems for Discussion
Cardiac Glycosides
SUBSTANCES INCLUDED
NB. This monograph will focus on digoxin however the toxicological mechanisms and treatment are similar for the other poisonings.
OVERVIEW
Digoxin causes a large number of cardiac effects in overdose leading to both brady- and tachyarrhythmias. Acute poisoning is usually less severe than chronic toxicity. The specific antidote, digoxin FAB antibodies, are reserved for the treatment of severe poisonings but may be life saving.
MECHANISM OF TOXICITY
Digoxin inhibits the sodium/potassium ATPase transport mechanism in myocardial and cardiac conducting tissue. Digoxin binds to the 'oubain binding site' and prevents potassium being transported into the cell which leads to 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 AV nodal block and decreased conduction velocity throughout the His-Purkinje system.
The binding of digoxin to the sodium/potassium ATPase transport system is inhibited by high concentrations of potassium and the concentration of activity of this enzyme is increased by the presence of magnesium. Thus both hypokalaemia and hypomagnesaemia increase digoxin toxicity and hyperkalaemia and hypermagnesaemia are protective.
See also
mechanisms behind drug induced arrhythmias
DRUG AND DISEASE INTERACTIONS
Various other drugs may have effects on slowing the AV node (e.g.
verapamil and
beta blockers) or may lead to hypokalaemia and hypomagnesaemia (e.g. diuretics) or alter renal 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
Absorption
Digoxin is a water soluble drug and is not well absorbed. Oral bioavailability is about 50-80%. Digitoxin bioavailability is 80%.
Distribution
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. 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 is likely to 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.
CLINICAL EFFECTS
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.
- ECG changes
- Bradyarrhythmia
- Supraventricular tachycardia
- Ventricular tachycardia
Cardiac effects
ECG changes
Early ECG changes in digoxin overdose include extrasystoles 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.
Bradyarrhythmias
Bradyarrhythmias include 2nd and 3rd degree heart block and slow atrial fibrillation.
Supraventricular tachycardia
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 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,
magnesium.
INVESTIGATIONS
All patients should have an urgent ECG, electrolytes (especially potassium and magnesium), digoxin concentrations.
These will need to be repeated regularly until clinical effects resolve.
Blood concentrations
Conversion factors
- Digoxin
- microgram/L x 1.28 = nmol/L
- nmol/L x 0.781 = microgram/L
- Digitoxin
- microgram/L x 1.31 = nmol/L
- nmol/L x 0.765 = microgram/L
Digoxin concentrations taken 6 or more hours after ingestion correlate 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 digoxin concentrations may serve to confirm an overdose however they are not a good guide to the need for specific treatment.
Digoxin concentrations rise rapidly with the administration of digoxin Fab fragments and then only direct measurement of free digoxin concentrations will indicate the amount of digoxin still unbound.
Biochemistry
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, no attempt should be made to correct hyperkalaemia. The high potassium is an indicator of antagonism at the potassium binding site. Thus, potassiums over 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. This is due to the use of diuretics and the renal excretion of potassium over preceding days.
TREATMENT
Supportive
All patients with a significant ingestion of digoxin should have cardiac monitoring and intravenous access. Normal saline is the intravenous fluid of choice as glucose may worsen hypokalaemia.
GI Decontamination
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 or have any acute on chronic exposure.
Gastric lavage should be used very cautiously, 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
Vomiting should be controlled reasonably aggressively with medium to high doses of metoclopramide (10-50 mg IV) as the increased vagal tone associated with vomiting may increase the cardiac toxicity and may disturb electrolytes. If metoclopramide is ineffective use of a 5HT3 antagonist (ondansetron, tropisetron, dolasetron etc.) is indicated.
Arrhythmias
The primary treatment of all these major cardiac complications is digoxin Fab fragments. If these are unavailable heart block should be treated with atropine and temporary pacing and tachyarrhythmias may be treated with magnesium.
Elimination enhancement
Extracorporeal methods of elimination do not significantly increase digoxin clearance.
Repeat dose charcoal is clearly of benefit after
yellow oleander poisoning and should be used in all such ingestions (da Silva et al, 2003). There is a small increase in clearance of digoxin with repeat doses of activated charcoal as there is some
enterohepatic circulation. Repeat dose charcoal increases clearance of digitoxin in animal models.
Antidotes
Digoxin Fab fragments
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.
Indications
- 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 nmol/L (15.6 microgram/L) 6 hours after an acute overdose*
- Digoxin concentration > 10 nmol/L (7.8 microgram/L) in chronic toxicity*
*The rationale for using digoxin concentrations greater than this is that the time for the digoxin concentrations to fall would require such prolonged monitoring that it is more cost effective to give digoxin Fab fragments.
Adverse effects
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, 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.
Dose
Fab fragments bind to digoxin in a one to one ratio. Thus the dose of 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.
Dose calculation
From dose ingested,
1 x 40 mg vial of digoxin Fab fragments binds to 0.6 mg of digoxin. Thus an ingestion of 3 mg of digoxin requires 5 vials.
From serum digoxin concentration
Total body burden of digoxin = concentration in microgram/litre (nmol/litre x 1.28) x weight (kg) x volume of distribution.
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 nmol/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 microg/L
- If the patient is a 80 kg man then the volume of distribution may be as high as 700 L and therefore up to 7000 microg or 7 mg of digoxin has been ingested
- As a 40 mg vial binds about 0.6 mg of digoxin this patient requires 11 or 12 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
By titration
A third method of dosing digoxin Fab fragments is to titrate it against clinical effects, 4-6 vials of digoxin Fab fragments can be given and repeated depending on the clinical effect. This may be most useful in patients with hyperkalaemia or heart block rather than patients with ventricular tachyarrhythmias where the treatment is more urgent.
Magnesium
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
Atropine should be given to all patients with bradyarrhythmia at a dose of 1 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.
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 and digitalis poisoning. Ventricular ectopics and
tachycardias are common in chronically digoxin-poisoned patients, but are rare in oleander-poisoned patients, who are normally young and previously healthy. Repeated doses of
charcoal have a clear role in oleander poisoning (de Silva et al, 2003).
Also, these other substances are predominantly hepatically cleared rather than renally cleared and they bind to digoxin Fab fragments only weakly. This means that substantially larger doses of digoxin antibody may be required. For toad venom an initial dose of 10 vials (400 mg) should be given with subsequent doses titrated against effect (Brubacher et al, 1996). For treatment of yellow oleander poisoning the effective treatment dose was 1200 mg (30 vials) (Eddlestone et al, 2000)..
Finally, though measurable digoxin concentrations may be elevated due to cross reactivity, they will not accurately reflect the amount of Na+-K+-ATPase inhibition. In fact, obtaining different results on different digoxin assays is characteristic and therefore helpful in the diagnosis of these poisonings.
Magnesium may be a particularly useful antidote for these other cardiac glycosides.
LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP
Patients should be monitored until digoxin concentrations return to within the normal range (if digoxin Fab fragments have not been given).
REFERENCES
Kinlay S & Buckley NA. Magnesium sulfate in the treatment of ventricular arrhythmias due to digoxin toxicity. J Toxicol Clin Toxicol 1995;33(1):51-55.
Lewander WJ, Gaudreault P, Einhorn A, Henretig FM, Lacouture PG, Lovejoy FH, Jr. Acute pediatric digoxin ingestion. A ten-year experience. American Journal of Diseases of Children 1986;140:770-773.
Marchlinski FE, Hook BG, Callans DJ. Which cardiac disturbances should be treated with digoxin immune Fab (ovine) antibody? American Journal of Emergency Medicine 1991;9:24-8.
Wells TG, Young RA, Kearns GL. Age-related differences in digoxin toxicity and its treatment. Drug Safety 1992;7:135-151.
Woolf AD, Wenger TL, Smith TW, Lovejoy FH, Jr. Results of multicenter studies of digoxin-specific antibody fragments in managing digitalis intoxication in the pediatric population. American Journal of Emergency Medicine 1991;9:16-20
Brubacher JR, Ravikumar PR, Bania T, Heller MB, Hoffman RS. Treatment of toad venom poisoning with digoxin-specific Fab fragments. Chest. 1996 Nov;110(5):1139-41.
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