Digoxin
Presenter: Dr. Dhriti Das
Phase B, Cardiology
DMCH
Digitalis
• The cardiac glycosides are often called digitalis or digitalis glycosides.
Because most of the drugs come from the digitalis (foxglove) plant.
They are a group of chemically similar compounds that can increase
the contractility of the heart muscle and, therefore, are widely used in
treating heart failure.
• Like the antiarrhythmic drugs, the cardiac glycosides influence the
sodium and calcium ion flows in the cardiac muscle, thereby
increasing contraction of the atrial and ventricular myocardium
(positive inotropic action).
Digoxin
• The digitalis glycosides show only a small difference between
therapeutically effective dose and doses that are toxic or even fatal.
Therefore, the drugs have a low therapeutic index. The most widely
used agent is digoxin.
Mechanism of action:
• A. Regulation of cytosolic calcium concentration: Free cytosolic calcium
concentration at the end of contraction must be lowered for cardiac muscles to
relax. The Na+/Ca2+ exchanger plays an important role in this process by
extruding Ca2+ from myocytes in exchange for Na+. The concentration gradient
for both ions is a major determinant of the net movement of ions. By inhibiting
the ability of the myocyte to actively pump Na+ from the cell, cardiac glycosides
decrease the Na+ concentration gradient and, consequently the ability of the
Na+/Ca2+ exchanger to move Ca2+ out of the cell. Further, the higher cellular
Na+ is exchanged by extracellular Ca+ by the Na+/Ca2+ exchanger resulting in
increased intracellular Ca2+. Because more ca2+ is retained intracellularly , a
small but physiologically important increase occurs in the free Ca2+ that is
available at the next contraction cycle of cardiac muscle.
Mechanism of action
• If the Na+/K+ adenosine triphosphatase is extensively inhibited , the
ionic gradient becomes so disturbed that dysrhythmia may occur.
Increased contractility of the cardiac muscle: Administration of cardiac
glycosides increases the force of cardiac contraction, causing the
cardiac output to more closely resemble that of the normal heart.
Increased myocardial contraction leads to a decrease in end diastolic
volume , thus increasing the efficacy of contraction (ejection fraction).
Mechanism of action
• AV node inhibition : The resulting improved circulation leads to
reduced sympathetic activity, which then reduces peripheral
resistance together, this effects cause a reduction in heart rate. Vagal
tone is also enhanced, so The heart rate decreases and myocardial
oxygen demand decreases. (in normal heart positive inotropic effect
of digoxin is counteracted by compensatory autonomic reflexes). The
rise in calcium levels leads to the prolongation of phade 4 and phase 0
of the action potential, thus increasing the AV node’s refractory
period. Slower conduction through the AV node leads to a delayed
ventricular response.
Indications of digoxin:
1. Heart failure with reduced ejection fraction or systolic heart failure
2. Atrial fibrillation
3. Atrial flutter
4. Supraventricular tachyarrhythmia
5. Supraventricular tachyarrhythmia in fetus in low dose, otherwise it
may induce abortion by uterine contraction
Dosing consideration:
• Higher serum levels of digoxin was associated with increased
mortality (>1.2 ng/ml)
• The initial and generally maintenance oral dose ranges from .0625 to
0.25 mg/day, considered for decades to be the standard daily dose.
The 0.25 mg/day dose considered for decades as the standard daily
dose has been largely replaced by the 0.125 mg/day dose; because at
the lower dose serum digoxin levels (usually after 8 hours) typically
remains less than 1.0 ng/ml in heart failure patients with normal
kidney function.
Pharmacokinetics
• 50 to 80 % of orally administered digoxin is absorbed by the
gastrointestinal tract with an elimination half life of 36 to 48 hours in
large part by renal excretion. Drug discontinuation or dose reduction
becomes important in patients with renal dysfunction or reduced
digoxin clearance or concommitant administration with drugs which
can increase digoxin concentration like spironolactone.
Drug interactions and effect on concentration of digoxin
Adverse effects:
• The direct effect of digoxin on sinoatrial and AV nodal cells and it’s
autonomic modulating properties (lowering sympathetic tone and
augmenting parasympathetic tone) account for many of it’s adverse
effects, including sinus bradycardia and AV nodal blockade, generally
at serum levels >2ng/ml. other digoxin induced
• A)toxic dysrhythmias include atrial tachycardia with AV nodal block
(“paroxysmal atrial tachycardia with block”), other atrial
tachydysrhythmias , ventricular ectopic beats, ventricular tachycardia
and ventricular fibrillation. Andaccelerated conduction overaccessory
bypass tracts.
Adverse effects:
• B) Nausea, vomiting, mental disturbances and visual aberrations (xanthopsia
and photopsia) are some of the systemic manifestations of digoxin toxicity.
• C) Digitalis is a sterol molecule with hormonal effects, and, as such, is a
common causeof gynecomastia and painful breasts in males receiving this
agent chronically.
• D) Rash E) headache F) Weakness
To suppress some digoxin induced dysrhythmias , the intravenous
administration of atropine, potassium, and/or magnesium can be employed,
when appropriate, until serum digoxin concentration lowers down to
acceptable level and the undesirable effects become less problematic. Severe
life threatening toxicity generally requires the administration of anti- digoxin
fragment antigen binding immunotherapy .
Contraindications of digoxin
• Acute myocardial infarction
• Hypersensitivity to the drug
• Ventricular fibrillation
• Myocarditis
• Hypomagnesemia
• Hypokalemia
• Wolf –Parkinson –White syndrome
Precautions 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
Monitoring
• As digoxin has a narrow therapeutic index, the recommended serum
level stands between 0.8 to 2 ng/ml. when measuring a digoxin serum
level, drawing blood at least 6 to 8 hours after the last dose is
essential. The toxicity increases above level 2ng/ml. the level needs to
be checked with any recent change in medication. The kidneys excrete
approximately 70%of digoxin in proportion to glomerular filtration
rate of the individual. Electrocardiograms, bloodwork to assess renal
function and s. electrolytes require close monitoring.
• Digoxin level should be checked one week after starting the
medication and regularly afterwards.
Monitoring
• ECG changes associated with digoxin administration show a
downsloping ST segment depression, also known as a reverse check
sign. The ST segment may appear scooped without abnormal Q waves
or T wave inversions. Regular intake of digoxin results in decreased QT
interval, prolongation of the PR interval, and T inversion or flattening.
• In the case of an overdose, the patient should receive digoxin immune
fab. This molecule binds to digoxin, making it difficult to bind to it’s
active sites. Digoxin immune fab use requires caution because
reversing the effect of digoxin will lead to reduced serum potassium
levels.
Digoxin effect
Digoxin toxicity
Toxicity
• Overdose of digoxin may produce life threatening arrhythmias or malignant
hyperkalemia.
• The following conditions indicate the use of digoxin immune fab:
1. Any digoxin related life threatening dysrhythmia
2. Refractory hyperkalemia
3. Serum digoxin concentration over 15 ng/ml, at any time or above 10 ng/ml 6
hours post-ingestion.
4. Acute ingestion of 10 mg in adults.
5. Acute ingestion of 4 mg in children
6. Chronic elevation of serum digoxin concentration with altered mental status,
dysrhythmias or severe gastrointestinal symptoms.
Treatment of digoxin toxicity
• Digoxin has a narrow therapeutic index, and it’s administration is
subjectto drug- drug interaction and comorbidities. Tghetreatment of
digoxin toxicity primarily focuses on hydration and electrolyte repletion.
It needs timely action. Once digoxin toxicity is confirmed by blood level
or ECG
a) Request pharmacy to provide digoxin immune fab and check the
patient’s medication profile for drug drug interactions.
b) Consultation with nephrology for the need for emergent hemodialysis
c) Maintaining supportive care with intravenous hydration and
electrolyte repletion d) Referral to ICU.
Reference
• Opie’s cardiovascular medicine
• Kanu Chatterjee and Eric J. Topol cardiac drugs
• Lippincott’s pharmacology
• NIH star pearl bookshelf digoxin January 19, 2023 article
• [Link] online ECG library
Thank you