Cardiac glycosides

Mechanism of Action - The Pump Stopper

• Primary Action: Directly inhibits the $Na^+/K^+$-ATPase pump in cardiac myocytes.
• Ionic Shift: This inhibition leads to ↑ intracellular $Na^+$ concentration.
• Calcium Effect: The high intracellular $Na^+$ reduces the activity of the $Na^+/Ca^{2+}$ exchanger (NCX), which normally pumps $Ca^{2+}$ out.
• Result: ↑ intracellular $Ca^{2+}$ which is stored in the sarcoplasmic reticulum, leading to increased contractility (positive inotropy).

⭐ Exam Favorite: Hypokalemia potentiates digoxin's effects, as digoxin and $K^+$ compete for the same binding site on the $Na^+/K^+$-ATPase. Low potassium = less competition = more digoxin binding and potential toxicity.

Clinical Uses - Heart's Helping Hand

• Systolic Heart Failure (HFrEF):

  • Increases contractility (positive inotropy) to alleviate symptoms.
  • Considered second-line therapy for patients remaining symptomatic on standard guideline-directed medical therapy.
  • ⚠️ Does not improve mortality; used for symptomatic control only.

• Atrial Fibrillation & Atrial Flutter:

  • Slows the ventricular rate (negative chronotropy).
  • Mechanism: ↑ parasympathetic (vagal) tone, which decreases conduction velocity through the AV node.

⭐ Digoxin is uniquely beneficial in patients with concurrent atrial fibrillation and systolic heart failure, as it addresses both rate control and contractility with a single agent.

Toxicity & Management - When Good Goes Bad

• Triggers: ↓K⁺, ↓Mg²⁺, ↓renal function, drugs (e.g., amiodarone, verapamil, quinidine).
• Clinical Features:
  • GI: Nausea, vomiting, abdominal pain (often first signs).
  • CNS: Confusion, weakness, fatigue.
  • Visual: Xanthopsia (yellow-green halos), blurred vision, scotomas.
• EKG Findings:
  • Most common arrhythmia: PVCs.
  • Most specific: Atrial tachycardia with AV block.
  • Bradycardia, heart blocks, hyperkalemia (in acute overdose).

⭐ Hypokalemia is a key precipitant. Low potassium potentiates digoxin's effect by increasing its binding to the Na⁺/K⁺-ATPase pump.

Pharmacokinetics - The Body's Tour

• Absorption:
  • Oral bioavailability: ~75% (tablets).
  • P-glycoprotein substrate: Inhibitors (e.g., verapamil, amiodarone, quinidine) ↑ digoxin levels.
  • Gut flora (Eubacterium lentum) can inactivate it; antibiotics may ↑ absorption.
• Distribution:
  • Large volume of distribution (Vd: 4-7 L/kg); concentrates in tissues (heart, skeletal muscle).
  • Long half-life (t½): ~40 hours, often requiring a loading dose.
• Metabolism & Excretion:
  • Primarily cleared by the kidneys as unchanged drug.
  • ⚠️ Dose reduction is critical in renal dysfunction.

⭐ Due to its very large volume of distribution and extensive tissue binding, digoxin is not effectively removed by hemodialysis in cases of toxicity.

• Mechanism: Directly inhibits the Na+/K+ ATPase pump, leading to increased intracellular Na+, which then decreases Ca2+ efflux, ultimately increasing intracellular calcium and contractility.
• Clinical Use: Primarily for heart failure (positive inotropy) and atrial fibrillation (AV node conduction slowing).
• Toxicity: Very narrow therapeutic index. Toxicity is classically precipitated by hypokalemia.
• ECG Changes: Characteristic ST segment scooping (“Salvador Dalí mustache” sign); toxicity can cause AV block.
• Antidote: Digoxin immune Fab (Digibind) is used for life-threatening toxicity.