Medically reviewed by Fedorchenko Olga Valeryevna, PharmD. Last updated on 2020-04-07
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Digoxin is indicated in the management of chronic cardiac failure where the dominant problem is systolic dysfunction. Its therapeutic benefit is greatest in those patients with ventricular dilatation.
Digoxin is specifically indicated where cardiac failure is accompanied by atrial fibrillation.
Digoxin is indicated in the management of certain supraventricular arrhythmias, particularly chronic atrial flutter and fibrillation.
The dose of digoxin for each patient has to be tailored individually according to age, lean body weight and renal function.
Suggested doses are intended only as an initial guide.
In cases where cardiac glycosides have been taken in the preceding two weeks the recommendations for initial dosing of a patient should be reconsidered and a reduced dose is advised.
The difference in bioavailability between injectable digoxin and oral formulations must be considered when changing from one dosage form to another. For example if patients are switched from oral to the I.V. formulation the dosage should be reduced by approximately 33%.
Adults and paediatric populations over 10 years
Rapid oral loading:
If medically appropriate, rapid digitalisation may be achieved in a number of ways, such as 750 to 1500 micrograms (0.75 to 1.5 mg) as a single dose.
Where there is less urgency, or greater risk of toxicity e.g. in the elderly, the oral loading dose should be given in divided doses six hours apart, with approximately half the total dose given as the first dose. Clinical response should be assessed before giving each additional dose.
Slow oral loading:
In some patients, example those with mild heart failure, digitalisation may be achieved more slowly with doses of 250 to 750 micrograms (0.25 to 0.75 mg) daily for one week followed by an appropriate maintenance dose. A clinical response should be seen within one week.
The maintenance dosage should be based upon the percentage of the peak body stores lost each day through elimination. The choice between slow and rapid oral loading depends on the clinical state of the patient and the urgency of the condition.
The following formula has had wide clinical use:
Ccr is creatinine clearance corrected to 70 kg bodyweight or 1.73 m2 body surface area. If only serum creatinine (Scr) concentrations are available, a Ccr (corrected to 70 kg bodyweight) may be estimated in men as
NOTE: Where serum creatinine values are obtained in micromol/l, these may be converted to mg/100 ml (mg %) as follows:
Where 113.12 is the molecular weight of creatinine.
For women, this result should be multiplied by 0.85.
N.B. These formulae cannot be used for creatinine clearance in children.
In practice, this will mean that most patients with heart failure will be maintained on 125 to 250 micrograms (0.125 to 0.25 mg) digoxin daily; however in those who show increased sensitivity to the adverse effects of digoxin, a dose of 62.5 micrograms (0.0625 mg) daily or less may suffice.
Conversely, some patients may require a higher dose.
Neonates, infants and paediatric populations up to 10 years of age
If cardiac glycosides have been given in the two weeks preceding commencement of digoxin therapy, it should be anticipated that optimum loading doses of digoxin will be less than those recommended below.
In the newborn, particularly in the premature infant, renal clearance of digoxin is diminished and suitable dose reductions must be observed, over and above general dosage instructions.
Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight or body surface area, as indicated in the schedule below. Children over ten years of age require adult dosages in proportion to their body weight.
Oral loading dose:
This should be administered in accordance with the following schedule:
Preterm neonates less than 1.5 kg
25 micrograms/kg per 24 h.
Preterm neonates 1.5 kg to 2.5 kg
30 micrograms/kg per 24 h.
Term neonates to 2 years
45 micrograms/kg per 24 h.
2 to 5 years
35 micrograms/kg per 24 h.
5 to 10 years
25 micrograms/kg per 24 h.
The loading dose should be administered in divided doses with approximately half the total dose given as the first dose and further fractions of the total dose given at intervals of 4 to 8 h, assessing clinical response before giving each additional dose.
The maintenance dose should be administered in accordance with the following schedule:
daily dose = 20 % of 24 h loading dose.
Term neonates and children up to 10 years:
daily dose = 25 % of 24 h loading dose.
These dosage schedules are meant as guidelines and careful clinical observation and monitoring of serum digoxin levels should be used as a basis for adjustment of dosage in these paediatric patient groups.
The possibility of reduced renal function and lower lean body mass should be taken into account when dealing with elderly patients. If necessary, the dosage should be reduced and adjusted to the changed pharmacokinetics to prevent elevated serum dioxin levels and the risk of toxicity. The serum dioxin levels should be checked regularly and hypokalaemia should be avoided.
The dosing recommendations should be reconsidered if patients are elderly or there are other reasons for the renal clearance of digoxin being reduced. A reduction in both initial and maintenance doses should be considered.
Method of administration:
For oral use only.
Digoxin is contraindicated in:
- intermittent complete heart block or second degree atrioventricular block, especially if there is a history of Stokes-Adams attacks.
- arrhythmias caused by cardiac glycoside intoxication.
- supraventricular arrhythmias associated with an accessory atrioventricular pathway, as in the Wolff-Parkinson-White syndrome, unless the electrophysiological characteristics of the accessory pathway and any possible deleterious effect of digoxin on these characteristics have been evaluated. If an accessory pathway is known or suspected to be present and there is no history of previous supraventricular arrhythmias, digoxin is similarly contraindicated.
- ventricular tachycardia or ventricular fibrillation.
- hypertrophic obstructive cardiomyopathy, unless there is concomitant atrial fibrillation and heart failure but even then caution should be exercised if digoxin is to be used.
Patients receiving digoxin should have their serum electrolytes and renal function (serum creatinine concentration) assessed periodically; the frequency of assessments will depend on the clinical setting.
Serum concentrations of digoxin may be expressed in Conventional Units of nanograms/ml or SI Units of nanomol/l. To convert nanograms/ml to nanomol/l, multiply nanograms/ml by 1.28.
The serum concentration of digoxin can be determined by radioimmunoassay.
Blood should be taken six hours or more after the last dose of digoxin.
There are no rigid guidelines as to the range of serum concentrations that are most efficacious. Post hoc analyses of heart failure patients in the Digitalis Investigation Group trial suggest that the optimal trough digoxin serum level may be 0.5 nanogram/ml (0.64 nanomol/l) to 1.0 nanogram/ml (1.28 nanomol/l).
Digoxin toxicity is more commonly associated with serum digoxin concentrations greater than 2 nanogram/ml. However, serum digoxin concentration should be interpreted in the clinical context. Toxicity may occur with lower digoxin serum concentrations. In deciding whether a patient's symptoms are due to digoxin, the clinical state together with the serum potassium level and thyroid function are important factors.
Determination of the serum digoxin concentration may be very helpful in making a decision to treat with further digoxin, but other glycosides and endogenous digoxin-like substances, including metabolites of digoxin, can interfere with the assays that are available and one should always be wary of values which do not seem commensurate with the clinical state of the patient. Observations while temporary withholding digoxin might be more appropriate.
Arrhythmias may be precipitated by digoxin toxicity, some of which can resemble arrhythmias for which the drug could be advised. For example, atrial tachycardia with varying atrioventricular block requires particular care as clinically the rhythm resembles atrial fibrillation.
Many beneficial effects of digoxin on arrhythmias result from a degree of atrioventricular conduction blockade. However, when incomplete atrioventricular block already exists the effects of a rapid progression in the block should be anticipated. In complete heart block the idioventricular escape rhythm may be suppressed.
In some cases of sinoatrial disorder (i.e. Sick Sinus Syndrome) digoxin may cause or exacerbate sinus bradycardia or cause sinoatrial block.
The administration of digoxin in the period immediately following myocardial infarction is not contraindicated. However, the use of inotropic drugs in some patients in this setting may result in undesirable increases in myocardial oxygen demand and ischaemia, and some retrospective follow-up studies have suggested digoxin to be associated with an increased risk of death. The possibility of arrhythmias arising in patients who may be hypokalaemic after myocardial infarction and are likely to be haemodynamically unstable must be borne in mind. The limitations imposed thereafter on direct current cardioversion must also be remembered.
Treatment with digoxin should generally be avoided in patients with heart failure associated with cardiac amyloidosis. However, if alternative treatments are not appropriate, digoxin can be used to control the ventricular rate in patients with cardiac amyloidosis and atrial fibrillation.
Digoxin can rarely precipitate vasoconstriction and therefore should be avoided in patients with myocarditis.
Beri-beri heart disease
Patients with beri-beri heart disease may fail to respond adequately to digoxin if the underlying thiamine deficiency is not treated concomitantly.
Digoxin should not be used in constrictive pericarditis unless it is used to control the ventricular rate in atrial fibrillation or to improve systolic dysfunction.
Digoxin improves exercise tolerance in patients with impaired left ventricular systolic dysfunction and normal sinus rhythm. This may or may not be associated with an improved haemodynamic profile. However, the benefit of digoxin in patients with supraventricular arrhythmias is most evident at rest, less evident with exercise.
In patients receiving diuretics and an ACE inhibitor, or diuretics alone, the withdrawal of digoxin has been shown to result in clinical deterioration.
The use of therapeutic doses of digoxin may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram.
Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity.
Severe respiratory disease
Patients with severe respiratory disease may have an increased myocardial sensitivity to digitalis glycosides.
Hypokalaemia sensitises the myocardium to the actions of cardiac glycosides.
Hypoxia, hypomagnesaemia and hypercalcaemia
Hypoxia, hypomagnesaemia and marked hypercalcaemia increase myocardial sensitivity to cardiac glycosides.
Administering digoxin to a patient with thyroid disease requires care. Initial and maintenance doses of digoxin should be reduced when thyroid function is subnormal. In hyperthyroidism there is relative digoxin resistance and the dose may have to be increased. During the course of treatment of thyrotoxicosis, dosage should be reduced as the thyrotoxicosis comes under control.
Patients with malabsorption syndrome or gastro-intestinal reconstructions may require larger doses of digoxin.
Chronic congestive cardiac failure
Although many patients with chronic congestive cardiac failure benefit from acute administration of digoxin, there are some in whom it does not lead to constant, marked or lasting haemodynamic improvement. It is therefore important to evaluate the response of each patient individually when digoxin is continued long-term.
Direct current cardioversion:
The risk of provoking dangerous arrhythmias with direct current cardioversion is greatly increased in the presence of digitalis toxicity and is in proportion to the cardioversion energy used.
For elective direct current cardioversion of a patient who is taking digoxin, the drug should be withheld for 24 h before cardioversion is performed. In emergencies, such as cardiac arrest when attempting cardioversion the lowest effective energy should be applied.
Direct current cardioversion is inappropriate in the treatment of arrhythmias thought to be caused by cardiac glycosides.
Digoxin tablets contain lactose.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.
Since central nervous system and visual disturbances have been reported in patients receiving digoxin, patients should exercise caution before driving, using machinery or participating in dangerous activities.
Summary of the safety profile
In general, the adverse reactions of digoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect.
Hence, adverse reactions are less common when digoxin is used within the recommended dose range or therapeutic serum concentration range and when there is careful attention to concurrent medications and conditions.
Tabulated list of adverse reactions
Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as:
Very common > 1/10
Common > 1/100 and < 1/10
Uncommon > 1/1000 and < 1/100
Rare > 1/10,000 and < 1/1000
Very rare < 1/10,000, including isolated reports.
Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Adverse drug reactions identified through post-marketing surveillance were considered to be rare or very rare (including isolated reports).
System Organ Class
Blood and lymphatic system disorders
Metabolism and nutrition disorders
Psychosis, apathy, confusion
Nervous system disorders
CNS disturbances, dizziness
Visual disturbances (blurred or yellow vision)
Arrhythmia, conduction disturbances, bigeminy, trigeminy, PR prolongation, sinus bradycardia
Supraventricular tachyarrhythmia, atrial tachycardia (with or without block), junctional (nodal) tachycardia, ventricular arrhythmia, ventricular premature contraction, ST segment depression
Nausea, vomiting, diarrhoea
Intestinal ischaemia, intestinal necrosis
Skin and subcutaneous tissue Disorders
Skin rashes of urticarial or scarlatiniform character may be accompanied by pronounced eosinophilia
Reproductive system and breast disorders
Gynaecomastia can occur with long term administration
General disorders and administration site conditions
Fatigue, malaise, weakness
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme:
Symptoms and signs
Signs and symptoms of digoxin toxicity become more frequent with levels above 2.0 nanograms/ml (2.56 nanomol/l) although there is considerable inter-individual variation. However, in deciding whether a patient's symptoms are due to digoxin, the clinical state, together with serum electrolyte levels and thyroid function are important factors. In patients undergoing haemodialysis, digoxin use is associated with increased mortality; patients with low pre-dialysis potassium concentrations are most at risk.
In adults without heart disease, clinical observation suggests that an overdose of digoxin of 10 to 15 mg was the dose resulting in death of half of the patients. If more than 25 mg of digoxin was ingested by an adult without heart disease, death or progressive toxicity responsive only to digoxin-binding Fab antibody fragments resulted.
Cardiac manifestations are the most frequent and serious sign of both acute and chronic toxicity. Peak cardiac effects generally occur 3 to 6 hours following overdose and may persist for the ensuing 24 hours or longer. Digoxin toxicity may result in almost any type of arrhythmia. Multiple rhythm disturbances in the same patient are common. These include paroxysmal atrial tachycardia with variable atrioventricular (AV) block, accelerated junctional rhythm, slow atrial fibrillation (with very little variation in the ventricular rate) and bi directional ventricular tachycardia.
Premature ventricular contractions (PVCs) are often the earliest and most common arrhythmia. Bigeminy or trigeminy also occur frequently.
Sinus bradycardia and other bradyarrhythmias are very common.
First, second, third degree heart blocks and AV dissociation are also common.
Early toxicity may only be manifested by prolongation of the PR interval.
Ventricular tachycardia may also be a manifestation of toxicity.
Cardiac arrest from asystole or ventricular fibrillation due to digoxin toxicity is usually fatal.
Acute massive digoxin overdose can result in mild to pronounced hyperkalaemia due to inhibition of the sodium-potassium (Na+-K+) pump. Hypokalaemia may contribute to toxicity.
Gastrointestinal symptoms are very common in both acute and chronic toxicity. The symptoms precede cardiac manifestations in approximately half of the patients in most literature reports. Anorexia, nausea and vomiting have been reported with an incidence up to 80 %. These symptoms usually present early in the course of an overdose.
Neurologic and visual manifestations occur in both acute and chronic toxicity. Dizziness, various CNS disturbances, fatigue and malaise are very common. The most frequent visual disturbance is an aberration of colour vision (predominance of yellow green). These neurological and visual symptoms may persist even after other signs of toxicity have resolved.
In chronic toxicity, non-specific non-cardiac symptoms, such as malaise and weakness, may predominate.
In children aged 1 to 3 years without heart disease, clinical observation suggests that an overdose of digoxin of 6 to 10 mg was the dose resulting in death in half of the patients.
If more than 10 mg of digoxin was ingested by a child aged 1 to 3 years without heart disease, the outcome was uniformly fatal when Fab fragment treatment was not given.
Most manifestations of chronic toxicity in children occur during or shortly after digoxin overdose.
The same arrhythmias or combination of arrhythmias that occur in adults can occur in paediatrics. Sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen less frequently in the paediatric population.
Paediatric patients are more likely to present with an AV conduction disturbance or a sinus bradycardia.
Ventricular ectopy is less common, however in massive overdose, ventricular ectopy, ventricular tachycardia and ventricular fibrillation have been reported.
In neonates, sinus bradycardia or sinus arrest and/or prolonged PR intervals are frequent signs of toxicity. Sinus bradycardia is common in young infants and children. In older children, AV blocks are the most common conduction disorders.
Any arrhythmia or alteration in cardiac conduction that develops in a child taking digoxin should be assumed to be caused by digoxin, until further evaluation proves otherwise.
The frequent non-cardiac manifestations are similar to those seen in adults are gastrointestinal, CNS and visual. However, nausea and vomiting are not frequent in infants and small children.
In addition to the undesirable effects seen with recommended doses, weight loss in older age groups and failure to thrive in infants, abdominal pain due to mesenteric artery ischaemia, drowsiness and behavioural disturbances including psychotic manifestations have been reported in overdose.
After recent ingestion, such as accidental or deliberate self-poisoning, the load available for absorption may be reduced by gastric lavage. Gastric lavage increases vagal tone and may precipitate or worsen arrhythmias. Consider pre-treatment with atropine if gastric lavage is performed. Treatment with digitalis Fab antibody usually renders gastric lavage unnecessary. In the rare instances in which gastric lavage is indicated, it should only be performed by individuals with proper training and expertise.
Patients with massive digitalis ingestion should receive large doses of activated charcoal to prevent absorption and bind digoxin in the gut during enteroenteric recirculation.
If hypokalaemia is present, it should be corrected with potassium supplements either orally or intravenously, depending on the urgency of the situation. In cases where a large amount of digoxin has been ingested hyperkalaemia may be present due to release of potassium from skeletal muscle. Before administering potassium in digoxin overdose the serum potassium level must be known.
Bradyarrhythmias may respond to atropine but temporary cardiac pacing may be required. Ventricular arrhythmias may respond to lignocaine or phenytoin.
Dialysis is not particularly effective in removing digoxin from the body in potentially life-threatening toxicity.
Digoxin-specific antibody Fab is a specific treatment for digoxin toxicity and is very effective. Rapid reversal of the complications that are associated with serious poisoning by digoxin, digitoxin and related glycosides has followed I.V. administration of digoxin-specific (ovine) antibody fragments (Fab). For details, consult the literature supplied with antibody fragments.
Pharmacotherapeutic group: Cardiac therapy, cardiac glycosides, digitalis glycosides.
ATC code: C01AA05
Mechanism of action
Digoxin increases contractility of the myocardium by direct activity. This effect is proportional to dose in the lower range and some effect is achieved with quite low dosing; it occurs even in normal myocardium although it is then entirely without physiological benefit. The primary action of digoxin is specifically to inhibit adenosine triphosphatase, and thus sodium-potassium (Na+-K+) exchange activity, the altered ionic distribution across the membrane resulting in an augmented calcium ion influx and thus an increase in the availability of calcium at the time of excitation-contraction coupling. The potency of digoxin may therefore appear considerably enhanced when the extracellular potassium concentration is low, with hyperkalaemia having the opposite effect.
Digoxin exerts the same fundamental effect of inhibition of the Na+-K+ exchange mechanism on cells of the autonomic nervous system, stimulating them to exert indirect cardiac activity. Increases in efferent vagal impulses result in reduced sympathetic tone and diminished impulse conduction rate through the atria and atrio-ventricular node. Thus, the major beneficial effect of digoxin is reduction of ventricular rate.
Intravenous administration of a loading dose produces an appreciable pharmacological effect within 5 to 30 mins, while using the oral route the onset of effect occurs in 0.5 to 2 hours.
The PROVED trial designed to determine the effectiveness of digoxin in 88 patients with chronic, stable mild to moderate heart failure. Withdrawal of digoxin or its continuation was performed in a prospective, randomised, double-blind, placebo-controlled multicentre trial of patients with chronic, stable mild to moderate heart failure secondary to left ventricular systolic dysfunction who had normal sinus rhythm and were receiving long-term treatment with diuretic drugs and digoxin. Patients withdrawn from digoxin therapy showed worsened maximal exercise capacity (p = 0.003) an increased incidence of treatment failures (p = 0.039) and a decreased time to treatment failure (p = 0.037). Patients who continued to receive digoxin had a lower body weight (p = 0.044) and heart rate (p = 0.003) and a higher left ventricular ejection fraction (p = 0.016). The overall percentage of participants having one or more adverse event was similar in the two groups: 59 % in the placebo group and 69 % in the digoxin group. The types of adverse event were unspecified
The RADIANCE trial examined the effects of discontinuation of digoxin in stable NYHA class II and III patients who were receiving diuretics and ACE inhibitors. The 178 patients were initially stabilised on a combination of captopril or enalapril, diuretics and digoxin, then randomised to continue digoxin therapy or change to placebo. The relative risk of worsening disease in the placebo group was 5.9 compared to the digoxin group. Withdrawal of digoxin was accompanied by worsening symptoms, reduced exercise tolerance, and a deteriorating quality of life, indicating that patients with CHF were at considerable risk from discontinuation of the drug in spite of the continuation of therapy with diuretics and ACE inhibitors. Approximately 56 % in the placebo group and 49% in the digoxin group experienced unspecified side effects.
In the DIG trial, 6800 patients with heart failure were randomised to receive digoxin or placebo. No difference was found in all-cause mortality between patients who were treated with digoxin and those who were given placebo. In the digoxin group, there was a trend toward a decrease in the risk of death attributed to worsening heart failure (risk ratio, 0.88; 95% confidence interval, 0.77 to 1.01; p = 0.06). However, the patients who received digoxin had significantly (p<0.001) fewer hospital admissions when the drug was given in addition to diuretics and ACE inhibitors. Digoxin therapy was most beneficial in patients with ejection fractions of â‰¤25%, patients with enlarged hearts (cardiothoracic ratio of >0.55), and patients in NYHA functional class III or IV. In the DIG study, 11.9 % of patients in the digoxin arm and 7.9 % of patients in the placebo arm were suspected of having digoxin toxicity, the most common symptoms being new episodes of ventricular fibrillation, supraventricular arrhythmia, tachycardia, or advanced atrioventricular block.
The AFFIRM study involved a total of 4060 patients recruited to a randomised, multicentre comparison of two treatment strategies in patients with atrial fibrillation and a high risk of stroke or death. The primary end point was overall mortality. There were 356 deaths among the patients assigned to rhythm-control therapy (amiodarone, disopyramide, flecainide, moricizine, procainamide, propafenone, quinidine, sotalol, and combinations of these drugs) and 310 deaths among those assigned to rate-control [Î²-blockers, calcium-channel blockers (verapamil and diltiazem), digoxin, and combinations of these drugs) therapy (mortality at five years, 23.8% and 21.3%, respectively; hazard ratio, 1.15 [95% confidence interval, 0.99 to 1.34]; p=0.08). More patients in the rhythm-control group than in the rate-control group were hospitalised, and there were more adverse drug effects in the rhythm-control group as well.
Indirect cardiac contractility changes also result from changes in venous compliance brought about by the altered autonomic activity and by direct venous stimulation. The interplay between direct and indirect activity governs the total circulatory response, which is not identical for all subjects. In the presence of certain supraventricular arrhythmias, the neurogenically mediated slowing of AV conduction is paramount.
The degree of neurohormonal activation occurring in patients with heart failure is associated with clinical deterioration and an increased risk of death. Digoxin reduces activation of both the sympathetic nervous system and the (renin-angiotensin) system independently of its inotropic actions, and may thus favourably influence survival. Whether this is achieved via direct sympathoinhibitory effects or by re-sensitising baroreflex mechanisms remains unclear.
The Tmax following IV administration is approximately 1 to 5 hours, while the Tmax for oral administration is 2 to 6 hours. Upon oral administration, digoxin is absorbed from the stomach and upper part of the small intestine. When digoxin is taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When taken with meals high in fibre, however, the amount absorbed from an oral dose may be reduced.
The bioavailability of orally administered digoxin is approximately 63 % in tablet form and 75 % as oral solution.
The initial distribution of digoxin from the central to the peripheral compartment generally lasts from 6 to 8 h. This is followed by a more gradual decline in serum digoxin concentration, which is dependent upon digoxin elimination from the body. The volume of distribution is large (Vdss = 510 litres in healthy volunteers), indicating digoxin to be extensively bound to body tissues. The highest digoxin concentrations are seen in the heart, liver and kidney, that in the heart averaging 30-fold that in the systemic circulation. Although the concentration in skeletal muscle is far lower, this store cannot be overlooked since skeletal muscle represents 40 % of total body weight. Of the small proportion of digoxin circulating in plasma, approximately 25 % is bound to protein.
The majority of digoxin is excreted by the kidneys as an intact drug, although a small fraction of the dose is metabolised to pharmacologically active and inactive metabolites. The main metabolites of digoxin are dihydrodigoxin and digoxygenin.
The major route of elimination is renal excretion of the unchanged drug.
Digoxin is a substrate for P-glycoprotein. As an efflux protein on the apical membrane of enterocytes, P-glycoprotein may limit the absorption of digoxin. P-glycoprotein in renal proximal tubules appears to be an important factor in the renal elimination of digoxin.
Following I.V. administration to healthy volunteers, between 60 and 75 % of a digoxin dose is recovered unchanged in the urine over a six day follow-up period. Total body clearance of digoxin has been shown to be directly related to renal function, and percent daily loss is thus a function of creatinine clearance. The total and renal clearances of digoxin have been found to be 193 Â± 25 ml/min and 152 Â± 24 ml/min in a healthy control population.
In a small percentage of individuals, orally administered digoxin is converted to cardioinactive reduction products (digoxin reduction products or DRPs) by colonic bacteria in the gastrointestinal tract. In these subjects over 40 % of the dose may be excreted as DRPs in the urine. Renal clearances of the two main metabolites, dihydrodigoxin and digoxygenin, have been found to be 79 Â± 13 ml/min and 100 Â± 26 ml/min, respectively.
In the majority of cases however, the major route of digoxin elimination is renal excretion of the unchanged drug.
The terminal elimination half-life of digoxin in patients with normal renal function is 30 to 40 h.
Since most of the drug is bound to the tissues rather than circulating in the blood, digoxin is not effectively removed from the body during cardiopulmonary by-pass. Furthermore, only about 3 % of a digoxin dose is removed from the body during 5 h of haemodialysis.
Special patient populations
In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be observed. This is especially pronounced in the premature infant since renal clearance reflects maturation of renal function. Digoxin clearance has been found to be 65.6 Â± 30 ml/min/1.73m2 at three months, compared to only 32 Â± 7 ml/min/1.73m2 at one week. By 12 months digoxin clearance of 88 Â± 43 ml / min / 1.73m2 has been reported. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight and body surface area.
The terminal elimination half-life of digoxin is prolonged in patients with impaired renal function, and in anuric patients may be of the order of 100 h.
Hepatic impairment has little effect on digoxin clearance.
Age-related declines in renal function in elderly patients can result in a lower rates of digoxin clearance than in younger subjects, with reported digoxin clearance rates in the elderly of 53 ml/min/1.73m2.
Digoxin clearance is 12% - 14% less in females than males and may need to be considered in dosing calculations.
Digoxin showed no genotoxic potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the carcinogenic potential of digoxin.
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