Digoxin

Mechanism of Action

Digoxin has 2 principal mechanisms of action, which are selectively employed depending on the indication:

1. Positive ionotropic: It increases the force of contraction of the heart by reversibly inhibiting the activity of the myocardial sodium=potassium adenosinetriphosphatase pump, an enzyme that controls the movement of ions into the heart. Digoxin induces an increase in intracellular sodium that will drive an influx of calcium in the heart and cause an increase in contractility. Cardiac output increases with a subsequent decrease in ventricular filling pressures.[2]
2. 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 decreasing the heart rate. The rise in calcium levels leads to the prolongation of phase 4 and phase 0 of the cardiac action potential, thus increasing the AV node's refractory period. Slower conduction through the AV node carries a decreased ventricular response.[2]

Another use of digoxin is to induce fetal death before a second-trimester abortion. Digoxin kills the cells and poisons the tissues of the fetus. The kidneys excrete digoxin in direct proportion to the glomerular filtration rate; the liver metabolizes 16%. Digoxin has a half-life that varies from 36 to 48 hours, which may increase in cases of renal failure.[3]

Administration

It is best to administer digoxin intravenously to achieve rapid digitalization. Intramuscular injections are highly discussed. No more than 2 mL of the drug should be injected at the same site. The injection should be made deep into the muscle, and the overlying area should be massaged post-injection. Intravenous injections are metabolized more efficiently than intramuscular injections and are the preferred route, as only about 80% of the drug is absorbed in intra-muscular injections compared to intravenous dosing. There is a risk of local irritation or myonecrosis.

Digoxin has an oral bioavailability of approximately 75%, although intake efficacy might diminish when taking digoxin with high-fiber foods. Some patients possess gut flora that metabolizes digoxin to dihydrodigoxin, decreasing the drug's absorption. Macrolides interfere with normal gut microbiota, which normally metabolizes digoxin and can lead to higher absorbed concentrations. Metoclopramide decreases digoxin absorption. Indomethacin and spironolactone decrease the clearance of the drug. 

Important considerations during administration include:

• Requesting an electrocardiogram before digoxin administration is important.              
• Electrolytes, mainly potassium levels, must be assessed and normalized before digoxin administration.
• If bradycardia is present, re-evaluate and withhold treatment as necessary.[4]

Clinical staff should monitor the plasma digoxin level at least 6 or 12 hours post-administration of the last loading dose, as this is the time to achieve steady-state levels. The recommended thresholds of therapeutic serum digoxin levels are 0.5 to 2 ng/mL.

Adverse Effects

Digoxin toxicity is clinically relevant as it can lead to fatal cardiac arrhythmias. The estimated frequency is about 0.8 to 4% of patients on steady digoxin therapy. The rate of toxicity increases as serum digoxin concentration reaches over 2.0 ng/mL. However, toxicity can also occur at lower levels, especially in the setting of other risk factors such as low body weight, advanced age, decreased renal function, and hypokalemia.

Symptoms may be mild and include nausea, vomiting, and anorexia. Visual side effects might include color changes, also known as xanthopsia. However, yellow or green-tinted vision is usually associated with digoxin toxicity. Patients may also highlight blurry vision or photopsia. At toxic levels, digoxin is proarrhythmic. An impaired ventricle is more prone to ventricular tachyarrhythmias and ectopy. Abnormally high digoxin levels stimulate atrial activation; thus, atrial tachycardias in a patient on digoxin is highly suggestive of toxicity. These atrial tachycardias are persistent and resolve with a decrease in serum digoxin levels.

Other common side effects include:

• Rash
• Headache
• Gynecomastia
• Weakness

Contraindications

Digoxin is contraindicated in the following conditions:

• Acute myocardial infarction
• Hypersensitivity to the drug
• Ventricular fibrillation
• Myocarditis
• Hypomagnesemia
• Hypokalemia
• Wolf-Parkinson-White syndrome [5]

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; hyperthyroidism does the opposite

Digoxin may present interactions with the following:

• Azole antifungals, which inhibit the transport of digoxin via human P-glycoprotein
• Macrolide antibiotics inhibit P-glycoprotein, thus increasing intestinal drug absorption
• Rifampin
• Dronedarone
• Loop diuretics
• Quinidine
• Intravenous calcium products

Monitoring

Digoxin has a narrow therapeutic index. The recommended serum levels stand between 0.8 to 2 ng/mL.[6] When measuring a digoxin serum level, drawing blood at least 6 to 8 hours after the last dose is essential. The toxicity increases as the serum drug levels increase above 2.0 ng/mL. The prescriber needs to check levels with any recent change in medication. The kidneys excrete approximately 70% of digoxin in direct proportion to the patient's glomerular filtration rate. The physician must request regular electrocardiograms and bloodwork to assess renal function; electrolytes require close monitoring.[7] Digoxin levels should be checked one week after starting the medication and regularly afterward. 

Electrocardiogram changes seen with digoxin demonstrate a downsloping ST-segment depression, also known as a "reverse check" sign. The ST segments may appear "scooped" without abnormal Q waves or T wave inversions.[8] Regular intake of digoxin results in decreased QT interval, prolongation of the PR interval, and T wave inversion or flattening. In the case of an overdose, the patient should receive digoxin immune fab. This molecule binds to the digoxin, making it unable to bind to its active sites. Digoxin immune fab use requires caution because reversing the effects of digoxin will reduce serum potassium levels.

Toxicity

Overdose of digoxin may provoke troublesome arrhythmias or malignant hyperkalemia.[8] The association between digoxin use and mortality has raised many concerns among researchers, as there is some evidence that it seems to increase mortality risks. Digoxin has a very narrow therapeutic index, and its administration is subject to drug-drug interactions and comorbidities. In the case of an overdose, digoxin immune fab is the reversal agent.

The following conditions indicate the use of digoxin immune fab:

• Any digoxin-related life-threatening dysrhythmia
• Refractory hyperkalemia
• Serum digoxin concentration over 15 ng/mL at any time or above 10 ng/mL 6 hours post-ingestion
• Acute ingestion of 10 mg in adults
• Acute ingestion of 4 mg in children
• Chronic elevation of serum digoxin concentration with altered mental status, dysrhythmias, or severe gastrointestinal symptoms

Enhancing Healthcare Team Outcomes

Overdose of digoxin may provoke troublesome arrhythmias and malignant hyperkalemia. The association between digoxin use and mortality has raised many concerns among researchers. It seems to increase mortality risks. That is why digoxin therapy requires an interprofessional team to prescribe and oversee therapy. This team includes clinicians, specialists, mid-level practitioners, nurses, and pharmacists, all sharing information and coordinating activities to optimize therapy and prevent adverse effects. 

Digoxin has a very narrow therapeutic index, and its administration is subject to drug-drug interactions and comorbidities. The treatment of digoxin toxicity primarily focuses on supportive therapy with intravenous hydration and electrolyte repletion.[9] It requires the contribution of the medical workforce. Without timely and specific intervention, the patient is at significant risk of dying. If digoxin toxicity is confirmed, after assessing serum blood levels and electrocardiogram, the clinician should:

• Request pharmacy to provide digoxin immune fab and check the patient medication profile for drug interactions.
• Take into account nephrology's input if indications exist for the use of emergent hemodialysis.
• Maintain supportive care with intravenous hydration and electrolyte repletion.
• Refer the patient to the intensive care unit.