DIGOXIN

• Digoxin


  Positive inotropic effects caused by binding to Na+ K+ ATPase, inhibition of Na pump, decreased transport of Na+ out of myocardial cells, increased intracellular calcium concentration, enhanced myocardial contractility

  
• Digoxin


  • Used in the treatment of CHF, atrial fibrillation, atrial flutter, paroxysmal atrial tachycardia

  
• Therapeutic range for digoxin

  0.8-2 ng/ml

  
• Pharmacodynamic considerations for tachyarrhythmias

  1. Narrow therapeutic range

  2. Used to control ventricular response rate, particularly in CHF

  3. Ventricular rate control usually achieved over 24 hours

  4. Loading dose given in divided doses because of long distribution half-life

  5. Possible to use higher doses to control rate in acute setting

  
• Pharmacodynamic considerations for systolic heart failure

  1. Decreases frequency of hospitalization for exacerbation of heart failure

  2. Necessary to maintain serum concentration in mid to low therapeutic range (< 1.5 ng/ml)

  3. Edema and cardiac output changes with severity of heart failure alter pharmacokinetic parameters
• Absorption of digoxin


  • Completely absorbed from gut
  • In some patients, absorption may be decreased due to digoxin inactivation by gut bacteria or certain drugs

  
• Drugs that can alter digoxin absorption

  • Anticholinergic agents (e.g. atropine, diphenhydramine, phenothiazines, scopolamine, benztropine) slow gastrointestinal motility, increasing contact time in small intestine
  • Antibiotics (clarithromycin, erythromycin, tetracycline) alter gut flora, leading to decreased digoxin metabolism and increased levels
  • Anti-arrhythmic drugs (quinidine, amiodarone, verapamil) inhibit P-glycoprotein in kidney, decreasing renal clearance of digoxin

  
• Bioavailability of digoxin


  • Tablets: 70%
  • Elixir: 80%
  • IV: 100%

  
• Distribution of digoxin


  • Distributed into lean body tissue, not appreciably into adipose or fatty tissues
  • 20-30% bound to albumin
  • Vd: 7L/kg
  • Distributive phase is 6-8 hours

  
• Loading dose administration


  1. For adults with normal renal function, usual approach is total loading dose of approximately 10 mcg/kg based on ideal body weight

  2. Approximately 50% of total load given as first dose, followed by 25% at 6-8 hour intervals orally or IV

  3. Loading carried out over 24 hours with 3-4 divided doses

  4. Onset of effect and negative side effects determined by rate of distribution to site of action (1-4 hours for IV, 2-6 hours for oral)

  
• Metabolism of digoxin


  Takes place in stomach and intestine, involving deglycosylation, reduction of lactone ring, oxidation, and conjugation to polar metabolites

  
• Elimination of digoxin


  • Excreted mostly unchanged in urine
  • Proportion cleared by nonrenal routes (biliary excretion, intestinal clearance)
  • Vd decreases with decrease in renal function
  • In severe renal dysfunction, 18% bound to protein

  
• Available dosage forms of digoxin

  • Tablet (125, 250, 500 mcg)
  • Capsules (50, 100, 200 mcg)
  • Elixir (50 mcg/ml)
  • Parenteral injection (100, 250 mcg/ml)

  
• Sampling for digoxin levels

  • After loading dose, sample at 6-8 hours to avoid falsely elevated levels due to distribution phase
  • Once at steady state (7-14 days), sample just before next dose

  
• Digoxin clearance and creatinine clearance

  • For patients with heart failure, Cl = 1.303(CrCl) + 20
  • For patients without moderate-severe heart failure, Cl = 1.303(CrCl) + 40

  
• Compute booster dose


  BD= [(Cdesired- Cactual) V] /F

  = (1.5-0.6) 595 / 1 = 535.5 mcg

  Rounded to 500 mcg