Digoxin

Question 1

What is the structure of cardiac glycosides (i.e. digoxin)? (Don’t memorize)

Answer 1

• Steroid nucleus (necessary for activity)
• 5-member lactone ring at C17 (necessary for activity)
• Series of sugar groups at C3 (affects pharmacokinetic properties)
• Lack of ionizing group(s)

Question 2

Describe the pharmacodynamics of digoxin.

Answer 2

• Inotropic effects (increase myocardial contractility)
  - Na/K pump inhibited => more sodium inside the cell; less K pumped into the cell
  - Increase Ca++ flux into sarcomere
• Anti-arrhythmic effects
  - Therapeutic levels cause a vagotonic effect that is useful in slowing AV conduction in patients with atrial fibrillation

Question 3

How does digoxin achieve its inotropic effects?

Answer 3

Primary action: inhibits the Na, K-ATPase enzyme/pump in cell membrane

• This inhibition increases the intensity of the interaction of actin and myosin filaments in the sarcomere => Increases [Ca++]
• This leads to increased myocardial contractility
• Causes increased sympathetic tone

Question 4

How does digoxin achieve its anti-arrhythmic effects?

Answer 4

Primary action=> slow conduction through the AV node/rate control (vagotonic effect)

• Slows ventricular response rate to atrial fibrillation (but doesn’t fix a-fib)
• Can have pro-arrhythmogenic (tachyarrhythmic) effects

Question 5

In what ways does digoxin work on other organ systems (ie toxicities)?

Answer 5

• GI: Anorexia, nausea and vomiting, abdominal pain, diarrhea
• CNS effects: Disorientation, nightmares, hallucinations, vision (green -yellow color, blurring)

*increased automaticity, AV block

Question 6

What are the clinical uses of digoxin?

Answer 6

• CHF with normal sinus rhythm
  
  • Patients with large, dilated hearts, JVD, S3 gallop rhythm
  • Diuretics, ACE inhibitors also effective, probably safer over years
• Use in patients with atrial fibrillation to slow AV conduction (“rate control”)

Question 7

What are major drug-drug interactions with digoxin?

Answer 7

• Absorption reduced by oral antacids (e.g. Mg, Al hydroxides)
  - Will bind digoxin in the GI, lower the bioavailability
• Quinidine (reduces renal clearance of digoxin by about 50%!!!)
  - Digoxin plasma level increases => possible digoxin toxicity
• Amiodarone (additive effects on A-V node conduction)
  - Ventricular rate decreases
• Verapamil, propranolol (additive effects on A-V node conduction blockages)
  - Again, excessively slow ventricular response/ventricular asystole (with one another and with digoxin)

Question 8

What is the therapeutic range of digoxin?

Answer 8

Therapeutic range: 0.5 - 2.5 ng/ml (narrow)

Question 9

What contraindications are associated with digoxin?

Answer 9

• Ventricular tachycardia, VF
  
  • May cause or worsen
• Wolff-Parkinson-White syndrome
  
  • May encourage conduction down accessory pathway (V-tach)
• 1st, 2nd and 3rd degree AV or SA block
  
  • May worsen any AV block
• Hypertrophic cardiomyopathy (Idiopathic hypertrophic sub aortic stenosis)
  
  • May worsen degree of functional obstruction.
• Relative contraindications: hypoxia, hypokalemia (ie with hydrochlorothiazide/furosemide)
• Toxic levels increase automaticity of all areas of the heart except the SA node

Question 10

Describe the pharmacokinetics of digoxin.

Answer 10

• Bioavailability 60-95% (best with capsule)
• Can be given slowly IV
• Redistribution over about 8 hours
• Clearance 80% renal, t1/2 30-40 hours (normal GFR)
• Markedly high Vd (approx. 6-7 L/kg).

Question 11

What are the major indications for digoxin?

Answer 11

Congestive heart failure

Arrhythmia (rate control)

Question 12

What should be done if digoxin related arrhythmia occurs?

Answer 12

1) Correct hypoxia, electrolyte, and acid/base abnormalities
2) Treat arrhythmias
3) Consider anti-digoxin Fab fragments (Digibind) in severe cases