Reference Range

Folk healers and physicians have used digitalis preparations for over 200 years to treat various illnesses. Like many other medications, digitalis was originally derived from a plant (foxglove). Digitalis strengthens the force of contractions of weakened hearts, but it is not a cardiac vitamin that can make a strong heart stronger. Digoxin and digitoxin are the main digitalis products.^[1]Digoxin is absorbed quickly from the gastrointestinal tract with a bioavailability of between 75% and 95%. It is eliminated primarily through kidneys; therefore, it has a half-life of 36-48 hours in patients who have normal kidney function and 3.5-5 days in patients who are anuric.^[2]

Therapeutic levels of digoxin are 0.8-2.0 ng/mL. The toxic level is >2.4 ng/mL.^[3]

Interpretation

The toxic range for digoxin is greater than 2.5 ng/mL. About 10% of patients may show toxicities at levels less than 2 ng/mL (particularly in hypokalemia, hypomagnesemia, hypoxia, heart disease, and hypercalcemia

Collection and Panels

See the list below:

Serum separator tube (SST)
After achievement of steady state in 1-2 weeks, blood should be drawn 6-8 hours after the last oral dose.

Times to sample are as follows:

Trough: Just before next dose (levels drawn earlier than 6 h after a dose will be artificially elevated)
Therapeutic level: 0.8-2.0 ng/mL

Description

Specimen must not be drawn within 6 hours of dosing digoxin for therapeutic drug monitoring. It is not removed significantly by dialysis. Hypokalemia increases toxicity. Digitalis toxicity is not a laboratory diagnosis but a clinical diagnosis. Treatment of digoxin overdose with digiband can interfere with measurement of digoxin levels depending on the digoxin assay.

Elimination of digoxin is reduced by quinidine, verapamil, and amiodarone.^[2]General adult dose of digoxin is 0.75-1.5 mg for digitalization and 0.125-0.5 mg daily for maintenance. Approximately 25% is bound with plasma proteins; only small amounts are metabolized in liver or lumen of large intestine. About 50-75% is excreted unchanged in urine.^[4]In patients with normal renal function, achieving a steady state in an undigitalized patient takes about a week.

Digoxin inhibits sodium-potassium–activated ATPase, thereby decreasing sodium efflux and the trans-membrane potential. Blockade of efflux of sodium increases calcium in myocytes resulting in increased activation of contractile proteins in the cardiac muscle.^[5]This results in increased inotropy.^{[6, 7]}The resting transmembrane potential and action potential of electrically excitable cells is also affected by sodium potassium ATPase. The resultant increase in vagal tone decreases conduction through the atrioventricular node (AVN).

Therapeutically, it has been used for ventricular rate control in the therapy of supraventricular tachyarrhythmias. Nevertheless, the same mechanism may be responsible for bradyarrhythmias in cases of toxicity.^[8]Spontaneous depolarization of pacemaker or other cells enhanced by digoxin may result in tachyarrhythmias seen in cases of digoxin toxicity. Triggered dysrhythmias may be the result of delayed after-depolarizations brought on by intracellular calcium overload.^[9]Because of its narrow therapeutic index, toxicity may result even with mildly increased digoxin level.

Exaggeration of its pharmacologic activity results in toxicity. Digoxin toxicity may manifest with nausea, vomiting, dizziness, headache, weakness, syncope, confusion, disorientation, delirium, hallucinations, and seizures in addition to cardiac dysrhythmias. Therefore, elderly patients who are taking digoxin and who have mental status changes should be evaluated for digoxin toxicity.^[9]Seeing yellow-green halos around objects may be a presenting feature of digoxin toxicity.^[10]

Life-threatening ventricular dysrhythmia may develop at any stage in an acute massive ingestion.^{[6, 11]}An asymptomatic period of several hours may precede the symptoms of acute poisoning. Gastrointestinal symptoms are usually the earliest manifestations of toxicity. Hyperkalemia may result from acute poisoning of the sodium-potassium ATPase. Additionally, it may produce associated electrocardiographic abnormalities. Serum digoxin levels may be greatly increased when minimal symptoms are present if digoxin level is obtained before complete distribution of digoxin. There may be a good correlation of toxicity with hyperkalemia but poor correlation with the serum digoxin level.^[12]

Indications/Applications

See the list below:

Heart failure
Atrial fibrillation
Atrial flutter

Considerations

Chronic digoxin toxicity is usually seen in the elderly. Its clinical features may mimic gastroenteritis and influenza. Psychiatric symptoms or mental status changes may be presenting features of digoxin toxicity. Almost any cardiac arrhythmia may be evident, but ventricular arrhythmias occur more often in chronic than in acute poisonings.^{[6, 11]}

The serum digoxin level may not accurately predict the severity of chronic toxicity. Coexisting disease (eg, heart disease, renal dysfunction, hepatic dysfunction, hypothyroidism, and chronic obstructive pulmonary disease), electrolyte disturbances (eg, hypokalemia, hypomagnesemia, and hypercalcemia), and hypoxia all may worsen digoxin toxicity.^{[7, 9]}

Drug interactions potentially resulting in digoxin toxicity include indomethacin, clarithromycin, erythromycin amiodarone, spironolactone, quinidine, procainamide, beta-blockers, and calcium channel blockers; particularly the interaction between digoxin and clarithromycin has been reported to increase in hospital admissions for digoxin toxicity in elderly patients.^[13]Decreases in renal function and lean body mass may change the pharmacokinetics of digoxin in the elderly, leading to toxicity at normally therapeutic doses.^[14]

Failures to digoxin-specific Fab antibody fragment therapy have been attributed to inadequate dosing, moribund state before administration, and incorrect diagnosis of digoxin toxicity.^[15]Endogenous digoxin-like substances may produce positive test results in patients not taking digoxin in uremia, severe agonal states, and postmortem (high postmortem level may not have high antemortem level).^[16]

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