Mechanism of Action of Digoxin (Cardiac Glycoside)

Introduction

Digoxin is a well-known cardiac glycoside used in the treatment of heart failure and atrial fibrillation. Derived from Digitalis lanata, it has both positive inotropic and negative chronotropic effects. Its mechanism involves inhibition of the Na⁺/K⁺-ATPase pump, which indirectly increases intracellular calcium, enhancing myocardial contractility.

Digoxin’s unique pharmacology and toxicity profile make it a frequently tested drug in USMLE, NCLEX, GPAT, NEET-PG, and NAPLEX.

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Mechanism of Action of Digoxin: Step-by-Step

1. Inhibits Na⁺/K⁺-ATPase pump
   Digoxin binds to and inhibits the Na⁺/K⁺-ATPase pump on cardiac cell membranes.
2. ↑ Intracellular Na⁺ concentration
   Inhibition leads to a rise in intracellular sodium, which reduces the activity of the Na⁺/Ca²⁺ exchanger (NCX).
3. ↓ Na⁺/Ca²⁺ exchange → ↑ Intracellular Ca²⁺
   With less sodium exchanged out, less calcium is pumped out of the cell, resulting in increased intracellular calcium.
4. Enhanced calcium availability in sarcoplasmic reticulum
   This increase leads to greater calcium release during systole, enhancing myocardial contraction.
5. Increased cardiac contractility (positive inotropic effect)
   Resulting in improved cardiac output, especially in heart failure patients.
6. Vagal stimulation
   Digoxin also enhances parasympathetic (vagal) tone, leading to slowed AV nodal conduction — useful in atrial fibrillation.

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Pharmacokinetic Parameters of Digoxin

Parameter	Value
Bioavailability	60–80% (oral)
Half-life	~36–48 hours (longer in renal failure)
Protein binding	20–30%
Volume of distribution	Large (~7 L/kg)
Metabolism	Minimal (liver)
Excretion	Renal (mostly unchanged)
Therapeutic index	Narrow

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Clinical Uses of Digoxin

• Chronic heart failure (systolic dysfunction)
• Rate control in atrial fibrillation
• Supraventricular tachycardia (limited use)
• Atrial flutter (with AV block)
• Cardiac output improvement in selected HF patients

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Adverse Effects of Digoxin

• Arrhythmias (bradycardia, AV block, ventricular ectopics)
• GI upset (nausea, vomiting, diarrhea)
• Visual disturbances (yellow vision, halos)
• Fatigue, dizziness, confusion
• Electrolyte disturbances (hypokalemia ↑ toxicity)
• Gynecomastia (rare)

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Comparative Analysis: Digoxin vs Dobutamine

Feature	Digoxin	Dobutamine
Mechanism	Na⁺/K⁺-ATPase inhibition	β1-adrenergic agonist
Onset of action	Slow	Rapid
Route	Oral and IV	IV only
Half-life	Long (~36–48 hrs)	Short (~2 minutes)
Use in acute HF	Not preferred	Preferred
Toxicity risk	High (narrow TI)	Low

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Practice MCQs

Q1. Digoxin increases cardiac contractility by:
a. Inhibiting calcium channels
b. Stimulating β1 receptors
c. Inhibiting Na⁺/K⁺-ATPase ✅
d. Enhancing Na⁺ influx

Q2. What is the effect of digoxin on AV node?
a. Stimulation
b. Suppression ✅
c. No effect
d. Constriction

Q3. Which ion’s change leads to increased intracellular Ca²⁺ due to digoxin?
a. Na⁺ ✅
b. K⁺
c. Mg²⁺
d. Cl⁻

Q4. Digoxin toxicity is enhanced by:
a. Hyperkalemia
b. Hypokalemia ✅
c. Hypernatremia
d. Hypomagnesemia

Q5. Which of the following is a typical visual symptom of digoxin toxicity?
a. Green vision
b. Blurred vision
c. Blue vision
d. Yellow vision ✅

Q6. Which arrhythmia is most common with digoxin toxicity?
a. Ventricular fibrillation
b. AV block ✅
c. Torsades
d. Atrial flutter

Q7. Digoxin has a narrow:
a. Volume of distribution
b. Therapeutic index ✅
c. Half-life
d. Bioavailability

Q8. What is used to treat severe digoxin toxicity?
a. Sodium bicarbonate
b. Digoxin-specific antibody (Fab) ✅
c. Atropine
d. Lidocaine

Q9. What is the effect of digoxin on vagal tone?
a. None
b. Decreases
c. Increases ✅
d. Inhibits

Q10. Which of the following is a known interaction of digoxin?
a. Loop diuretics (↑ toxicity) ✅
b. ACE inhibitors (↓ effect)
c. Antacids (↑ absorption)
d. NSAIDs (↓ half-life)

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FAQs

Q1: How does digoxin help in heart failure?
By increasing myocardial contractility and improving cardiac output.

Q2: Why is digoxin useful in atrial fibrillation?
It slows AV nodal conduction via vagal stimulation, controlling ventricular rate.

Q3: Is digoxin safe in renal failure?
Use with caution. It is renally excreted and requires dose adjustment.

Q4: What are signs of digoxin toxicity?
Nausea, bradycardia, arrhythmia, and yellow vision are classic signs.

Q5: What is the antidote for digoxin toxicity?
Digoxin-specific antibody fragments (Digibind or DigiFab).

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Sparsh Gupta – Review of Pharmacology
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK538271/