A-20. Drugs used for treatment of heart failure II: Cardiac glycosides

Question 1

Cardiac Glycosides

Answer 1

Digoxin
Digitoxin
Strophanthins( e.g. ouabain)

Question 2

Cardiac Glycosides (MOA)

Answer 2

Bind and inhibit Na/K-ATPase (20-30% ATPases inhibited = therapeutic effect) → ↑ IC Na + → Na/Ca exchange slows (or reverses) → IC Ca ++ ↑ → more Ca in SR → trigger Ca enters through L-type Ca channel
→ AP from trigger Ca ++ initiates higher Ca ++ current from SR → positive inotropy
- (Ca ++ storage ↓ in some HF due to SERCA dysfunction → glycosides restore SERCA function).

• Also stimulate vagus centrally → ACh at cardiac M2 receptors open K + channels →
  hyperpolarization → slows sinus and AV nodes → bradycardia.

Question 3

Cardiac Glycosides (Kinetics)

Answer 3

Digoxin : faster onset, oral, not metabolized, kidney elimination, DOA 36-40 hr, lower protein binding.

Digitoxin : slower onset, oral, metabolized and eliminate by liver , DOA 5-7 days, higher protein binding.

Both drugs have a narrow therapeutic index

Question 4

Digoxin (Indications)

Answer 4

1. CHF - NYHA stages III-IV (when ACE-I / diuretics fail). does not ↓ mortality.
2. Atrial flutter and atrial fibrillation - digoxin vagal stimulation ↓ aberrant automaticity.
3. Used rarely in supraventricular tachycardia for AV node slowing, (mainly if associated with HF).

Question 5

Digoxin (Contraindications)

Answer 5

Absolute :
1. Hypertrophic CMP.
2. WPW - digoxin ↑ AV node refractory
period, which may stimulate conduction through the accessory pathway.
3. AV block - vagal effects can exacerbate
heart block.
4. Diastolic HF - ↑ contractility from digoxin can ↓ diastolic relaxation.

Relative :

1. Sinus Bradycardia and sick sinus syndrome.
2. With other negative chronotropes (verapamil, diltiazem, amiodarone).
3. Circumstances with ↑ digitalis sensitivity (hypokalemia, etc).
4. Renal failure → use digitoxin instead.

Question 6

Digoxin Toxicity (Symptoms and Treatment)

Answer 6

1. Hyperkalemia - via Na/K-ATPase inhibition.
2. Arrhythmias - PVCs are most common, but many other arrhythmias can be seen.
   (More than 20-30% ATPases blocked → IC Ca ++ too high → delayed afterdepolarization
   (DAD) → slight ↑ in membrane potential after normal cardiac AP → extrasystoles (PVC,
   ventricular tachycardia, ventricular fibrillation)).
3. Vagal stimulation plus excess IC Ca ++ can lead to ventricular bigeminy or AV block.
   (Bradycardia can result from vagal
   stimulation).
4. ECG signs characteristic of digoxin toxicity: shortened QT , scooped ST depression and T inversion.
5. Vision Issues - color vision disturbances, blurred vision, photosensitivity, xanthopsia (yellow vision).
6. Neuro Issues - HA, anxiety, nightmare, hallucinations, lethargy, disorientation.
7. GI Issues - via ATPase inhibition in GI tract: nausea, vomiting, abdominal pain.

Treatment :

• Atropine for vagal stimulation symptoms.
• Lidocaine/phenytoin (type I/B antiarrhythmics) for ventricular tachycardias.
• Digiban - digitalis binding Ab (used for mainly suicide attempts related to psychiatric
  symptoms) .

Question 7

factors / substances that increase digoxin toxicity and drug interactions (6).

Answer 7

1. Hypokalemia - mostly with K-wasting diuretics, sometimes via diarrhea/vomiting; glycosides bind competitively to ATPase’s K + binding site, so less K + → ↑ digitalis binding.
   * Always monitor K levels when diuretic and glycoside used together.
   * ACE-I, ARB and K-sparing diuretics can also → hyperkalemia → ↓ digitalis binding / effect.
2. Hypercalcemia - can increase risk of DAD → ES / Vtach.
3. Hypomagnesemia - Mg needed for ATPase function → ↓ Mg with digoxin → increased digoxin effect (ex: loop diuretics waste Mg).
4. Renal Damage - ↑ half-life of digoxin, due to its renal elimination. always monitor BUN/creatinine in renal patients on digoxin. often must switch to digitoxin instead due to hepatic elimination.
   * Amiodarone, verapamil, diltiazem and
   quinidine all compete with digoxin for renal elimination.
5. Beta Blockers - digoxin should be used cautiously with BBs due to combined inhibitory effects of both drugs on SA/AV nodes.
6. Antibiotics - digoxin is inactivated in GI tract by flora → abx ↑ serum levels.