Chemistry and Pharmacodynamics
Digoxin is the prototype drug of the cardiac glycoside class and the only drug in the class used for medicinal purposes.
- Steroid nucleus with 4 fused rings
- Lactone ring
- Glycoside attachment composed of 3 sugars
Mechanism of action
- Digoxin reversibly inhibits the Na+-K+ ATPase of myocytes, resulting in:
- ↑ Intracellular Na+ → ↓ Na+-calcium (Ca2+) antiporter exchange → ↓ Ca2+ efflux
- ↑ Intracellular Ca2+ → ↑ Ca2+ binding to contractile proteins → ↑ cardiac contractility
- ↑ Vagal tone:
- ↑ Refractory period → ↓ conduction velocity in the atrioventricular (AV) node
- ↓ Sinoatrial (SA) node automaticity
- ↑ Cardiac contractility (positive inotropy) → ↑ cardiac output
- AV and SA node slowing → ↓ heart rate
- Blood pressure is not significantly impacted.
- May cause characteristic changes to a resting ECG (“digitalis effect”):
- ↑ PR interval (due to ↓ AV conduction)
- ↓ QT interval
- Classic finding: “scooped” ST-segment depressions
- Flattened or inverted T wave
- Oral and IV forms are available.
- Oral absorption:
- Passive, nonsaturable diffusion in the proximal small intestine
- Food may delay, but not impact, the extent of absorption.
- Extensive in peripheral tissues:
- Distribution phase: 6–8 hours
- Higher concentrations in heart, liver, kidney, and skeletal muscle
- Protein binding:
- Approximately 25% is protein bound.
- Uremic patients: Digoxin is displaced from plasma protein binding sites.
Metabolism and excretion
- Minimal hepatic metabolism:
- Approximately 16% of an absorbed dose is metabolized to active metabolites.
- Does not interact with the cytochrome P450 system
- Predominantly excreted in the urine (50%–70% as an unchanged drug)
Congestive heart failure
- 2nd-line therapy for heart failure with reduced ejection fraction:
- Provides a positive inotropic effect
- ↓ Symptoms of heart failure and the need for hospitalization
- Not shown to improve mortality
- 1st-line choice in patients with heart failure with reduced ejection fraction complicated by atrial fibrillation.
Digoxin is indicated for rate control when other therapies are ineffective or contraindicated:
- Atrial fibrillation
- Atrial flutter
- Supraventricular tachycardia
Digoxin has a very narrow therapeutic window and several signs of toxicity:
- Arrhythmias can occur through multiple mechanisms:
- ↑ Intracellular Ca2+ → delayed afterdepolarizations and ↑ automaticity
- Slowed conduction
- GI symptoms:
- Neurologic symptoms:
- Yellow vision (xanthopsia)
Warnings and precautions
- As with all AV node-blocking agents, digoxin should not be used in supraventricular tachyarrhythmias caused by an accessory pathway (e.g., Wolff-Parkinson-White syndrome).
- Avoid in sinus node disease and AV block
- Acute coronary syndrome:
- Use caution in patients with an acute MI.
- May ↑ myocardial oxygen demand → ischemia
- Hypertrophic cardiomyopathy with left ventricular outflow tract obstruction:
- Outflow obstruction may worsen.
- Due to digoxin’s positive inotropic effects
- Thyroid disease:
- Use caution in patients with hypothyroidism or hyperthyroidism.
- May cause significant changes in digoxin clearance
Drug interactions may lead to:
- ↑ AV blocking/bradycardic effect:
- Calcium channel blockers
- Beta blockers
- ↑ Risk of toxicity due to:
- ↑ Digoxin concentration:
- Hypokalemia and/or hypomagnesemia:
- Loop diuretics
- Thiazide diuretics
- ↑ Digoxin concentration:
- Factors affecting digoxin levels:
- Advanced age
- Low lean body mass
- Renal impairment
- Certain medications
- Potential triggers for toxicity:
- The most serious manifestation of digoxin overdose
- May be any type of arrhythmia (except rapidly-conducted atrial arrhythmias)
- May be life-threatening
- GI symptoms:
- Abdominal pain
- Neurologic symptoms:
- Vision changes
- Serum digoxin concentration:
- ↑ Level is indicative of toxicity.
- Draw 4–6 hours after the dose to avoid false elevation.
- Level does not always correlate with toxicity.
- ↑ Serum K+ level:
- Due to Na+-K+ ATPase inhibition
- Degree of elevation correlates with mortality risk
- Note: Hypokalemia is a potential trigger for digoxin toxicity.
- BUN and creatinine → renal dysfunction may be a precipitating factor
- Evaluate for arrhythmia
- Note: The “digitalis effect” does not correlate with toxicity.
- Antidote: digoxin-specific antibody (Fab) fragments
- Supportive treatment:
- Bradyarrhythmias: atropine or temporary pacemaker
- Hypotension: bolus IV fluids
- Correct electrolyte abnormalities.
- Life-threatening arrhythmia treatment
- Activated charcoal can be given for acute digoxin intoxication within 1–2 hours.
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