Digoxin

Digoxin is an antiarrhytmic agent / inotropic agent belonging to Cardiac Glycosides class.

Digoxin is approved for the treatment of Heart failure, Atrial fibrillation and atrial flutter. It is also used in treatment of Supraventricular tachycardia and fetal supraventricular tachyarrhythmia.

Digoxin absorption from gastrointestinal tract is variable with bioavailability of 63% (as tablet) and 75% (as oral solution). It is widely distributed in tissues which crosses the placenta and enters the breast milk. The volume of distribution was found to be 7 L/kg with plasma protein binding of Approx 25%. It gets metabolised to active and inactive metabolites, mainly di-hydrodigoxin and digoxygenin. It gets excreted via urine (50-70% as unchanged drug) with elimination half-life of 36-48 hours.

The common side effects associated with Digoxin include headache, sedation, Gynecomastia, hypotension, dizziness, asthenia, bradycardia, dry mouth, vomiting, fatigue and upper abdominal pain, etc.

Digoxin is available in the dosage forms such as tablets ,oral solution and injections.

Digoxin is available in India, Italy, USA, Switzerland.

Digoxin, belonging to cardiac glycoside class, acts as a Antiarrhythmic agent. Digoxin works by affecting the certain minerals (sodium and potassium) inside heart cells. This decreases strain on the heart and helps to maintain a normal, steady, and strong heartbeat..

Digoxin has two principle mechanisms of action which are selectively employed depending on the indication:

Positive Ionotropic and AV Node Inhibition.

• In Positive Ionotropic it increases the force of contraction of the heart by reversibly inhibiting the activity of the myocardial Na-K ATPase pump.
• While in AV node Inhibition Digoxin has vagomimetic effects on the AV node. By stimulating the parasympathetic nervous system, it slows electrical conduction in the atrioventricular node, therefore, decreases the heart rate.

The onset of action of Digoxin occurs within 1-2 hours for oral and 5-60 minutes for IV.

The Duration of Action for Digoxin within 3-4 days.

The Tmax was found within 2-6 hous and Cmax in blood reached upto 1.32 ± 0.18 ng/ml^-1.

Digoxin is available in the form of tablets, oral solution and Injections.

• For Tablets and Oral Solution:

Digoxin tablets and oral solution should be taken orally by mouth with or without water.

• For Injection:

Each dose should be given by the intravenous infusion over 10 - 20 minutes. The total loading dose should be administered in the divided doses with approximately half of the total dose given as the first dose and further fractions of the total dose given at intervals of 4 - 8 hours.

Digoxin is approved for the treatment of Heart failure and Atrial fibrillation and atrial flutter. It is also used in the treatment of Supraventricular tachycardia and fetal supraventricular tachyarrhythmia.

The main mechanism of action of digitalis is on the sodium-potassium ATPase of cardiac myocyte. It reversibly inhibits the ATPase resulting in increased intracellular sodium levels. The build-up of intracellular sodium leads to a shift of sodium extracellularly through another channel in the exchange for calcium ions. This influx of intracellular calcium assists with the myocyte contractility. Digoxin also has the direct effects on the conduction through increased vagal tone. Digoxin stimulates the vagus nerve leading to prolonged conduction through the sinoatrial (SA) and atrioventricular (AV) nodes.

Digoxin is approved for use in the following clinical indications:

• Heart Failure

Digoxin is indicated for the treatment of mild to moderate heart failure in adults. Digoxin increases the left ventricular ejection fraction and improves heart failure symptoms as evidenced by improved exercise capacity and decreased heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, Digoxin should be used in combination with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor.

Digoxin increases myocardial contractility in pediatric patients with heart failure.

• Atrial Fibrillation

Digoxin is indicated for the control of ventricular response rate in adult patients with chronic atrial fibrillation.

Although not approved there have been certain off label uses documented for Digoxin:

• Supraventricular tachycardias that are not controlled by traditional therapies may benefit from digoxin.

• Digoxin use has shown some success in the treatment of fetal supraventricular tachyarrhythmia. The lowest effective dose should be administered to the mother as digoxin might cause uterine contractions and result in abortion.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Digoxin is available in various dosage strength : 0.05 mg/ml; 0.1 mg/ml, 0.25 mg/ ml; 0.0625 mg, 0.125 mg, 0.1875 mg, 0.25 mg.

Digoxin should be used for the treatment of essential or primary Heart Failure.

• Heart Failure:  In this, the limit of water and salt intake was suggested and It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

• Atrial Fibrillation: Some foods can negatively affect your heart health and have been shown to increase the risk of heart complications, like Atrial fibrillation as well as heart disease. Diets high in processed foods, such as fast food, and items high in added sugar, like soda and sugary baked goods, have been linked to increased heart disease risk. They can also lead to other negative health outcomes like weight gain, diabetes, cognitive decline, and certain cancers.

The dietary restriction should be individualized as per the patient requirements.

Digoxin may be contraindicated in the following

• Acute myocardial infarction
• Hypersensitivity to the drug
• Ventricular fibrillation
• Myocarditis
• Hypomagnesemia
• Hypokalemia
• Wolf-Parkinson-White syndrome

Its use requires caution in cases of:

• Hypercalcemia/hypocalcemia
• Renal impairment
• Diseased SA node
• Bradycardia
• AV block
• Restrictive cardiomyopathy
• Constrictive pericarditis
• Thyroid disease - hypothyroidism leads to delayed drug clearance, and hyperthyroidism does the opposite.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

• Use in Patients with the Accessory AV Pathway (Wolff-Parkinson-White Syndrome)

Patients with Wolff-Parkinson-White syndrome who develop atrial fibrillation are at high risk of ventricular fibrillation. Treatment of these patients with digoxin leads to greater slowing of conduction in the atrioventricular node than in accessory pathways, and the risks of rapid ventricular response leading to ventricular fibrillation are thereby increased.

• Use in Patients with Sinus Node Disease and AV Block

Because digoxin slows sinoatrial and AV conduction, the drug commonly prolongs the PR interval. Digoxin may cause severe sinus bradycardia or sinoatrial block particularly in patients with pre-existing sinus node disease and may cause advanced or complete heart block in patients with pre-existing incomplete AV block. In such patients consideration should be given to the insertion of a pacemaker before treatment with digoxin.

• Misidentification of Digoxin Toxicity

Some signs and symptoms (anorexia, nausea, vomiting, and certain arrhythmias) can equally result from digoxin toxicity as from congestive heart failure. Misidentification of their etiology might lead the clinician to continue or increase digoxin dosing, when dosing should actually be suspended. When the etiology of these signs and symptoms is not obvious, measurement of serum digoxin levels may be helpful.

• Use in Patients with Preserved Left Ventricular Systolic Function

Patients with certain disorders involving heart failure associated with preserved left ventricular ejection fraction may not benefit from digoxin treatment and may be particularly susceptible to adverse reactions when they are treated with digoxin.

In patients with hypertrophic cardiomyopathy (formerly called idiopathic hypertrophic subaortic stenosis), the positive inotropic effect of digoxin leads to an increased subvalvular outflow gradient and therefore, may compromise cardiac output. Digoxin is rarely beneficial in patients with this condition. Chronic constrictive pericarditis is not generally associated with any inotropic defect, so heart failure of this etiology is unlikely to respond to treatment with digoxin. By slowing the resting heart rate, digoxin may actually decrease cardiac output in these patients. Digoxin as an inotropic agent is of limited value in patients with restrictive cardiomyopathies, although it has been used for ventricular rate control in the subgroup of patients with atrial fibrillation. In addition, patients with amyloid heart disease may be more susceptible to toxicity from digoxin at therapeutic levels because of an increased binding of digoxin to extracellular amyloid fibrils.

• Use in Patients with Impaired Renal Function

Digoxin is primarily excreted by the kidneys; therefore, patients with impaired renal function require smaller than usual maintenance doses of digoxin. Because of the prolonged elimination half-life, a longer period of time is required to achieve an initial or new steady-state serum concentration in patients with renal impairment than in patients with normal renal function. If appropriate care is not taken to reduce the dose of digoxin, such patients are at high risk for toxicity, and toxic effects will last longer in such patients than in patients with normal renal function.

• Use in Patients with Electrolyte Disorders

In patients with hypokalemia or hypomagnesemia, toxicity may occur at concentrations within therapeutic range because potassium or magnesium depletion sensitizes the myocardium to digoxin. Therefore, it is desirable to maintain normal serum potassium and magnesium concentrations in patients being treated with digoxin. Serum potassium levels should be carefully monitored when digoxin is given to patients at high risk of hypokalemia (e.g., those receiving diuretics, corticosteroids, or other drugs that commonly lead to potassium loss; those with gastrointestinal losses through diarrhea, vomiting, or nasogastric suction; or those with potassium-losing endocrinopathies or nephropathies).

Digoxin toxicity is also more likely in the presence of hypomagnesemia. Hypomagnesemia is common in most of the same conditions in which hypokalemia appears. Most notably, it is commonly seen in alcoholics and in patients with diabetes mellitus or hypercalcemia.

Because digoxin’s therapeutic and toxic effects are all largely mediated by intracellular calcium distribution, they are affected by abnormalities in serum calcium levels. Hypercalcemia increases the risk of digoxin toxicity, while digoxin may be therapeutically ineffective in the presence of hypocalcemia.

• Use During Electrical Cardioversion

Reduction of digoxin dosage may be desirable prior to electrical cardioversion to avoid induction of ventricular arrhythmias, but the physician must consider the consequences of a rapid increase in ventricular response to atrial fibrillation if digoxin is with held 1 to 2 days prior to cardioversion. If there is a suspicion that digitalis toxicity exists, elective cardioversion should be delayed. If it is not prudent to delay cardioversion, the energy level selected should be minimal at first and carefully increased in an attempt to avoid precipitating ventricular arrhythmias.

• Use in Thyroid Disorders and Hypermetabolic States

Hypothyrodism may reduce the requirements for digoxin. Heart failure and atrial arrhythmias resulting from hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hypoxia, or arteriovenous shunt) are best treated by addressing the underlying condition. Atrial arrhythmias associated with hypermetabolic states (e.g., hyperthyroidism) are particularly resistant to digoxin treatment. Large doses of digoxin are not recommended as the only treatment of these arrhythmias and care must be taken to avoid toxicity if large doses of digoxin are required. In hypothyroidism, the digoxin requirements are reduced. Digoxin responses are normal in patients with compensated thyroid disease.

• Use in Patients with Acute Myocardial Infarction

In patients with acute myocardial infarction, particularly if they have ongoing ischemia, the use of inotropic drugs, such as digoxin, may result in undesirable increases in myocardial oxygen demand and ischemia. Moreover, the use of digoxin may result in potentially detrimental increases in coronary vascular resistance mediated through alpha adrenergic receptor stimulation. Use in Patients with Myocarditis Digoxin can precipitate vasoconstriction and may promote production of pro-inflammatory cytokines. Therefore, avoid digoxin in patients with myocarditis.

• ECG Changes During Exercise

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 changes on the electrocardiogram during exercise testing that may be indistinguishable from those of ischemia. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity. Digoxin does not significantly decrease heart rate during exercise.

Consumption of alcohol is not recommended while receiving this medicine as it may increase the risk of adverse effects and lowers the blood pressure.

Digoxin levels in human milk are lower than those in maternal serum. The estimated exposure that a nursing infant would be expected to receive via breastfeeding would be far below the usual infant maintenance dose. Therefore, this amount should have no pharmacologic effect upon the infant. Nevertheless, caution should be exercised when digoxin is administered to a nursing woman.

Teratogenic Effects (Pregnancy Category C)

Animal reproduction studies have not been conducted with digoxin. It is also not known whether digoxin can cause fetal harm when administered to pregnant women or can affect reproductive capacity. Digoxin should be given to a pregnant woman only if clearly needed.

• Banana: Avoid eating banana when you are on digoxin as it increases the potassium level in the body. Excess potassium can lead to the heart failure or irregular heartbeat.
• Fiber Rich Foods: Foods rich in the fiber like wheat bran muffins and psyllium interact with digoxin and reduce the absorption of digoxin from the digestive tract. So take digoxin 1 hour before or 2 hours after eating foods that are rich in fiber.
• Salt Substitutes: Digoxin interacts with foods that contain salt substitutes, where potassium is replaced by sodium. Due to this interaction, the effectiveness of digoxin in treating heart failure may be decreased.
• Senna and St.John's Wort:Digoxin interacts with both Senna and St. John's wort, which lead to a reduction in the amount and activity of digoxin in the body.
• Black Licorice with Glycyrrhizin:When you are on digoxin, avoid black licorice in your diet as it may result in irregular heartbeat and heart attack.
• Hawthorn Berry and Siberian Ginseng:These herbs interact with digoxin and increase the activity of digoxin in the body.

The adverse reactions related to molecule Digoxin can be categorized as

• Common Adverse effects:

Hemodynamic compromise, Dizziness, peripherial ischemia, dry mouth, asthenia and somnolence.

• Less Common adverse effects:

Asymptomatic and symptomatic hypotension, burning, crawling, itching, numbness.

• Rare adverse effects:

Bradycardia, decompensated heart failure, cardiac arrest, and heart block.

The clinically relevant drug interactions of Digoxin is briefly summarized here.

• Drug which increases digoxin level:

ACE inhibitors (e.g. captopril), angiotensin receptor blockers (e.g. telmisartan), NSAIDs (e.g. indomethacin), COX-2 inhibitors, calcium channel blockers (e.g. verapamil, felodipine, tinapamil), antiarrhythmics (e.g. amiodarone, flecainide) antibiotics (e.g. erythromycin, tetracyclines), vasopressin receptor antagonist (tolvaptan, conivaptan), itraconazole, quinine, alprazolam, propantheline, nefazodone, atorvastatin, ciclosporin, epoprostenol, ritonavir, telaprevir, ranolazine, lapatinib, ticagrelor may increase digoxin levels.

• Drug which decreases digoxin levels:

Antacids, bulk-laxatives, kaolin-pectin, acarbose, neomycin, penicillamine, rifampicin, some cytostatics, metoclopramide, sulfasalazine, adrenaline, salbutamol, cholestyramine, phenytoin, St. John's wort, bupropion, and supplemental enteral nutrient may decrease digoxin levels.

Pediatric Use

Digoxin increases myocardial contractility in pediatric patients with congestive heart failure. There are no clinical efficacy studies demonstrating benefit in pediatric patients with heart failure. There are no controlled randomized studies of digoxin in pediatric patients with atrial tachyarrhythmias.

Geriatic Use

The majority of the clinical experience increased with digoxin has been in the elderly population. This experience has not identified differences in response or adverse effects between the elderly and younger patients. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, which should be based on renal function, and it may be useful to monitor renal function

• Symptoms:

Gastrointestinal effects are often the first sign of toxicity which include anorexia, nausea, vomiting, diarrhoea, abdominal pain, and bloating.

Cardiac manifestations including palpitations, syncope, multiple rhythm disturbance, prolongation of the PR interval, AV conduction disturbance or sinus bradycardia, and ventricular arrhythmias.

Neurologic and visual effects (e.g. dizziness, fatigue, malaise, weakness, drowsiness, behavioural disturbance, and aberration of colour vision) may also occur.

• Management:

Gastric lavage is rarely performed, consider pre-treatment with atropine.

In acute poisoning, large doses of activated charcoal prevent further absorption of digoxin and decrease serum levels by intestinal binding of digoxin.

If hypokalaemia is present, oral or IV K supplements are given. Digoxin-specific antibody Fab is a specific treatment for digoxin toxicity and is very effective.

Pharmacodynamics:

Digoxin is a positive inotropic and negative chronotropic drug, meaning that it increases the force of the heartbeat and decreases the heart rate. The reduce in heart rate is particularly useful in cases of atrial fibrillation, a condition characterized by a fast and irregular heartbeat. The relief of heart failure symptoms during digoxin therapy has been demonstrated in clinical studies by increased exercise capacity and reduced hospitalization due to heart failure and reduced heart failure-related emergency medical visits. Digoxin has a narrow therapeutic window. Digoxin poses a risk of rapid ventricular response that can cause ventricular fibrillation in patients with an accessory atrioventricular (AV) pathway. Cardiac arrest as a result of ventricular fibrillation is fatal. An increased risk of fatal severe or complete heart block is present in individuals with pre-existing sinus node disease and AV block who take digoxin.

Pharmacokinetics :

• Absorption

Digoxin is approximately 70-80% absorbed in the first part of the small bowel. The bioavailability of an oral dose varies from 50-90%, however, oral gelatinized capsules of digoxin are reported to have a bioavailability of 100%. Tmax, or the time to reach the maximum concentration of digoxin was measured to be 1.0 h in one clinical study of healthy patients taking 0.25 mg of digoxin with a placebo. Cmax, or maximum concentration, was 1.32 ± 0.18 ng/ml−1 in the same study, and AUC (area under the curve) was 12.5 ± 2.38 ng/ml−1. If digoxin is ingested after a meal, absorption is slowed but this does not change the total amount of absorbed drug. If digoxin is taken with meals that are in fiber, absorption may be decreased. Patients with malabsorption due to a variety of causes may have a reduced ability to absorb digoxin. P-glycoprotein, located on cells in the intestine, may interfere with digoxin pharmacokinetics, as it is a substrate of this efflux transporter. P-glycoprotein can be induced by other drugs, therefore reducing the effects of digoxin by increasing its efflux in the intestine.

• Distribution

Following drug administration, a 6- to 8-hour tissue distribution phase is observed. This is followed by a much more gradual decline in the serum concentration of the drug, which is dependent on the elimination of digoxin from the body. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its sites of action, but that with chronic use, the steady-state post-distribution serum concentrations are in equilibrium with tissue concentrations and correlate with pharmacologic effects. In individual patients, these post-distribution serum concentrations may be useful in evaluating therapeutic and toxic effects.

Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution. Digoxin crosses both the blood-brain barrier and the placenta. At delivery, the serum digoxin concentration in the newborn is similar to the serum concentration in the mother. Approximately 25% of digoxin in the plasma is bound to protein. Serum digoxin concentrations are not significantly altered by large changes in fat tissue weight, so that its distribution space correlates with lean (i.e., ideal) body weight, not total body weight.

• Metabolism

Sixteen percent of digoxin is metabolized. The end metabolites include 3-β-digoxigenin, 3-keto-digoxigenin, and their glucuronide and sulfate conjugates. The metabolism of digoxin is not dependent on cytochrome P450 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system.

• Excretion

Elimination of digoxin is predominantly renal, although in adult volunteers about a quarter of serum digoxin is eliminated through the intestine, excreted in bile or secreted directly into the lumen by P-glycoprotein. Elimination of digoxin follows first order kinetics. Following intravenous administration to healthy volunteers, 50% to 70% of a digoxin dose is excreted unchanged in the urine. Renal excretion of digoxin is proportional to glomerular filtration rate. The serum half-life of digoxin in pediatric patients is reported to be 18 to 36 hours, and in adults it is typically 36 to 48 hours. The half-life in anuric patients is prolonged to 3.5 to 5 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or cardiopulmonary bypass because most of the drug is bound to tissue.

1. Eichhorn EJ, Gheorghiade M. Digoxin. Progress in cardiovascular diseases. 2002 Jan 1;44(4):251-66.doi: https://doi.org/10.1053/pcad.2002.31591
2. Ehle M, Patel C, Giugliano RP. Digoxin: clinical highlights: a review of digoxin and its use in contemporary medicine. Critical pathways in cardiology. 2011 Jun 1;10(2):93-8.doi: 10.1097/HPC.0b013e318221e7dd
3. https://go.drugbank.com/drugs/DB00390
4. https://reference.medscape.com/drug/lanoxin-digoxin-342432
5. https://www.mims.com/india/drug/info/digoxin?type=full&mtype=generic
6. https://www.ncbi.nlm.nih.gov/books/NBK556025/#article-90909.s6
7. https://oxfordmedicaleducation.com/prescribing/digoxin-loading/