Digoxin

Article Author:
Marie Nicole David
Article Editor:
Mrin Shetty
Updated:
5/30/2020 10:42:06 PM
PubMed Link:
Digoxin

Indications

Digoxin comes from the foxgloves plant known as Digitalis purpurea. It is a cardiotonic glycoside and belongs to the digitalis class. The chemical formula of digoxin is C41 H64 O14. Cardiac glycosides, including digitalis and digoxin, have long-standing use in clinical practice. This drug received approval from the FDA in 1954 and is used to treat various heart problems such as atrial flutter, atrial fibrillation, heart failure with its associated symptoms, and to induce fetal demise prior to an abortion. Superior therapies with milder adverse effects and better safety profiles have now replaced it, such as beta-blockers and calcium-channel blockers. In current practice, it is reserved as a backup drug when first-line agents are ineffective. Its optimal use is in the treatment of mild to moderate heart failure in adult patients and to increase myocardial contraction.

Digoxin is beneficial in patients with systolic heart failure, better known as heart failure with reduced ejection fraction (HFrEF), with an ejection fraction below 40%.[1]  However, it has no benefit in mortality reduction.

It is used for rate control in atrial fibrillation or atrial flutter when conventional therapies have not achieved goal heart rate. Digoxin should not be administered in cases of pre-excitation caused by accessory pathways as digoxin induces AV blockade and may trigger ventricular tachyarrythmias. It is ineffective in states of high sympathetic activity. Beta-blockers are preferable in such cases.

Supraventricular tachycardias that are not rate 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.

Mechanism of Action

Digoxin has two 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 Na-K ATPase 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, decreases the heart rate. The rise in calcium levels leads to prolongation of phase 4, and phase 0 of the cardiac action potential thus increases the refractory period of the AV node. Slower conduction through the AV node carries a decreased ventricular response.[2]

Another use of digoxin is to induce fetal death prior to 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 massaged post-injection. Intravenous injections are metabolized more efficiently than the intramuscular injections and are the preferred route, as only about 80% of the drug is absorbed in intra-muscular injections as 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, thereby decreasing the drug's absorption. Macrolides interfere with normal gut microbiota, which normally metabolizes digoxin and thus can lead to higher absorbed concentrations. Metoclopramide decreases digoxin absorption. Indomethacin and spironolactone decrease the clearance of the drug. 

Important considerations during administration include[4]:

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

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

Adverse Effects

Digoxin toxicity is clinically relevant as it can lead to fatal cardiac arrhythmias. The estimated frequency is at 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. But 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 levels of digoxin stimulate atrial activation, thus atrial tachycardias, which, 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[5]:

  • 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

Digoxin may present interactions with the following:

  • Azole antifungals, which inhibit the transport of digoxin via human P-glycoprotein
  • Macrolide antibiotics, which 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, it is essential to draw blood at least 6 to 8 hours after the last dose. 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 for renal function, and electrolytes require close monitoring.[7]

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 changes such as a decreased QT interval, prolongation of the PR interval and T wave inversion or flattening. In the case of 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 while reversing the effects of digoxin, it 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 a lot of 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 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 a lot of concerns among researchers. It seems to increase mortality risks.

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 all 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

References

[1] Grubb A,Mentz RJ, Pharmacological management of atrial fibrillation in patients with heart failure with reduced ejection fraction: review of current knowledge and future directions. Expert review of cardiovascular therapy. 2020 Feb;     [PubMed PMID: 32066285]
[2] Ren Y,Ribas HT,Heath K,Wu S,Ren J,Shriwas P,Chen X,Johnson ME,Cheng X,Burdette JE,Kinghorn AD, Na{sup} {/sup}/K{sup} {/sup}-ATPase-Targeted Cytotoxicity of ( )-Digoxin and Several Semisynthetic Derivatives. Journal of natural products. 2020 Feb 25;     [PubMed PMID: 32096998]
[3] Lunney M,Ruospo M,Natale P,Quinn RR,Ronksley PE,Konstantinidis I,Palmer SC,Tonelli M,Strippoli GF,Ravani P, Pharmacological interventions for heart failure in people with chronic kidney disease. The Cochrane database of systematic reviews. 2020 Feb 27     [PubMed PMID: 32103487]
[4] Djohan AH,Sia CH,Singh D,Lin W,Kong WK,Poh KK, A myriad of electrocardiographic findings associated with digoxin use. Singapore medical journal. 2020 Jan;     [PubMed PMID: 32043160]
[5] Fu JL,Yu Q,Li MD,Hu CM,Shi G, Deleterious cardiovascular effect of exosome in digitalis-treated decompensated congestive heart failure. Journal of biochemical and molecular toxicology. 2020 Feb 11;     [PubMed PMID: 32045083]
[6] Mutlu M,Aslan Y,Kader Ş,Aktürk-Acar F,Dilber E, Clinical signs and symptoms of toxic serum digoxin levels in neonates. The Turkish journal of pediatrics. 2019;     [PubMed PMID: 31951334]
[7] Angraal S,Nuti SV,Masoudi FA,Freeman JV,Murugiah K,Shah ND,Desai NR,Ranasinghe I,Wang Y,Krumholz HM, Digoxin Use and Associated Adverse Events Among Older Adults. The American journal of medicine. 2019 Oct     [PubMed PMID: 31077654]
[8] Negroni MS,Marengo A,Caruso D,Tayar A,Rubiolo P,Giavarini F,Persampieri S,Sangiovanni E,Davanzo F,Carugo S,Colombo ML,Dell'Agli M, A Case Report of Accidental Intoxication following Ingestion of Foxglove Confused with Borage: High Digoxinemia without Major Complications. Case reports in cardiology. 2019;     [PubMed PMID: 31871798]
[9] Kusumoto FM,Schoenfeld MH,Barrett C,Edgerton JR,Ellenbogen KA,Gold MR,Goldschlager NF,Hamilton RM,Joglar JA,Kim RJ,Lee R,Marine JE,McLeod CJ,Oken KR,Patton KK,Pellegrini CN,Selzman KA,Thompson A,Varosy PD, 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: Executive summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. Heart rhythm. 2019 Sep;     [PubMed PMID: 30412777]