DIGOXIN INJECTION BP

Indications

• Atrial fibrillation
• Atrial flutter
• Heart failure

Dosage

Children: Neonate (body-weight 2.6 kg and above): Initially 45 micrograms/kg in 3 divided doses for 24 hours, then 10 micrograms/kg daily in 1–2 divided doses. Child 1 month–1 year: Initially 45 micrograms/kg in 3 divided doses for 24 hours, then 10 micrograms/kg daily in 1–

Adults: 62.5–125 micrograms once daily, with dose reduction recommended for elderly patients. An emergency loading dose may be required for rapid digitalisation in atrial fibrillation or flutter, administered initially by intravenous infusion.

Mechanism of action

Digoxin exerts hemodynamic, electrophysiologic, and neurohormonal effects on the cardiovascular system by reversibly inhibiting the Na-K ATPase enzyme. This inhibition leads to increased intracellular sodium, which in turn raises calcium levels in myocardial cells, enhancing contractility. Additionally, digoxin stimulates the parasympathetic nervous system, decreasing heart rate through effects on the sinoatrial and atrioventricular nodes.

Pharmacodynamics

Digoxin is classified as a positive inotropic agent, increasing the force of heart contractions, and a negative chronotropic agent, decreasing heart rate. This dual action is particularly beneficial in managing atrial fibrillation, contributing to symptom relief in heart failure, as evidenced by improved exercise capacity and reduced hospitalizations.

Pharmacokinetics

Digoxin is absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring within 1 to 3 hours after oral administration. It has a distribution half-life of 6 to 8 hours, is primarily eliminated by the kidneys, and has a long elimination half-life of approximately 36 to 48 hours. Due to its renal excretion, dose adjustments may be necessary in patients with impaired renal function.

Contra-indications

• Constrictive pericarditis
• Hypersensitivity to digoxin or any component of the formulation

Adverse effects

• Arrhythmias
• Cardiac conduction disorder
• Cerebral impairment
• Diarrhoea
• Dizziness
• Eosinophilia
• Nausea
• Skin reactions
• Vision disorders
• Vomiting
• Depression
• Decreased appetite
• Asthenia
• Confusion
• Gastrointestinal disorders
• Gynaecomastia
• Headache
• Malaise
• Psychosis
• Thrombocytopenia

Interactions

• St. John's Wort (severe, decreases concentration)
• Propafenone (moderate, increases concentration)
• Isavuconazole (moderate, increases exposure)
• Quinine (moderate, increases concentration)
• Berotralstat (moderate, increases concentration)
• Carbimazole (moderate, affects concentration)
• Ciclosporin (moderate, increases concentration)
• Eliglustat (moderate, increases exposure)
• Fostamatinib (moderate, increases exposure)
• Ledipasvir (moderate, increases exposure)

Precautions

• Careful monitoring in patients with renal impairment
• Monitor serum electrolytes, especially potassium levels
• Adjust dosage in the elderly
• Risk of digoxin toxicity in hypokalemic patients
• Caution in patients with pre-existing cardiac conditions such as sinus node disease and AV block

Pregnancy

Use during pregnancy only if clearly needed. Consult local guidelines for further advice.

Breast-feeding

Amount too small to be harmful.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Digoxin 62.5 microgram tablets
• Digoxin 125 microgram tablets
• Digoxin 250 microgram tablets
• Oral solution
• Solution for injection
• Oral suspension

Mechanism of action

Digoxin exerts hemodynamic, electrophysiologic, and neurohormonal effects on the cardiovascular system. It reversibly inhibits the Na-K ATPase enzyme, leading to various beneficial effects. The Na-K ATPase enzyme functions to maintain the intracellular environment by regulating the entry and exit of sodium, potassium, and calcium (indirectly). Na-K ATPase is also known as the _sodium pump_. The inhibition of the sodium pump by digoxin increases intracellular sodium and increases the calcium level in the myocardial cells, causing an increased contractile force of the heart. This improves the left ventricular ejection fraction (EF), an important measure of cardiac function. Digoxin also stimulates the parasympathetic nervous system via the vagus nerve leading to sinoatrial (SA) and atrioventricular (AV) node effects, decreasing the heart rate. Part of the pathophysiology of heart failure includes neurohormonal activation, leading to an increase in norepinephrine. Digoxin helps to decrease norepinephrine levels through activation of the parasympathetic nervous system. Cardiac glycosides have been used in the treatment of arrhythmias for more than 200 years. Two-pore-domain (K2P) potassium channels regulate cardiac action potential repolarization. Recently, K2P3.1 [tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ channel (TASK)-1] has been implicated in atrial fibrillation pathophysiology and was suggested as an atrial-selective antiarrhythmic drug target. We hypothesized that blockade of cardiac K2P channels contributes to the mechanism of action of digitoxin and digoxin. All functional human K2P channels were screened for interactions with cardiac glycosides. Human K2P channel subunits were expressed in Xenopus laevis oocytes, and voltage clamp electrophysiology was used to record K+ currents. Digitoxin significantly inhibited K2P3.1 and K2P16.1 channels. By contrast, digoxin displayed isolated inhibitory effects on K2P3.1. K2P3.1 outward currents were reduced by 80% (digitoxin, 1 Hz) and 78% (digoxin, 1 Hz). Digitoxin inhibited K2P3.1 currents with an IC50 value of 7.4 uM. Outward rectification properties of the channel were not affected. Mutagenesis studies revealed that amino acid residues located at the cytoplasmic site of the K2P3.1 channel pore form parts of a molecular binding site for cardiac glycosides. In conclusion, cardiac glycosides target human K2P channels. The antiarrhythmic significance of repolarizing atrial K2P3.1 current block by digoxin and digitoxin requires validation in translational and clinical studies. Low concentrations of cardiac glycosides including ouabain, digoxin, and digitoxin block cancer cell growth without affecting Na+,K+-ATPase activity, but the mechanism underlying this anti-cancer effect is not fully understood. Volume-regulated anion channel (VRAC) plays an important role in cell death signaling pathway in addition to its fundamental role in the cell volume maintenance. Here, we report cardiac glycosides-induced signaling pathway mediated by the crosstalk between Na+,K+-ATPase and VRAC in human cancer cells. Submicromolar concentrations of ouabain enhanced VRAC currents concomitantly with a deceleration of cancer cell proliferation. The effects of ouabain were abrogated by a specific inhibitor of VRAC (DCPIB) and knockdown of an essential component of VRAC (LRRC8A), and they were also attenuated by the disruption of membrane microdomains or the inhibition of NADPH oxidase. Digoxin and digitoxin also showed anti-proliferative effects in cancer cells at their therapeutic concentration ranges, and these effects were blocked by DCPIB. In membrane microdomains of cancer cells, LRRC8A was found to be co-immunoprecipitated with Na+,K+-ATPase a1-isoform. These ouabain-induced effects were not observed in non-cancer cells. Therefore, cardiac glycosides were considered to interact with Na+,K+-ATPase to stimulate the production of reactive oxygen species

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 decrease 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. **A note on cardiovascular risk** 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.