L3: Treatment of heart failure

Question 1

What is the source of the digoxin?

Answer 1

– Natural plant derivatives (Foxglove plant).

Question 2

What is the chemistry of digoxin?

Answer 2

– Cardiac glycosides contain a lactone ring and a steroid (aglycone) moiety attached to sugar molecules.

Question 3

What is the pharmacokinetics of digoxin?

Answer 3

– Digoxin distributes to most body tissues and accumulates in cardiac tissue. The concentration of the drug in the heart is twice that in skeletal muscle and at least 15 times that in plasma.

– Has a long half-life 30 to 40 h.

– Elimination is renal. Dose adjustment should be done according to creatinine clearance.

Question 4

What is the mechanism of action of digoxin?

” Inc intracellular Na and Ca”

Answer 4

• Digitalis ↑ cardiac contractility by increasing free intracellular Ca2+ through inhibition of membrane-bound Na+/K+ ATPase enzyme. This result in inhibition of Na+/K+ pump with
• subsequent accumulation of intracellular Na+ and Ca2+ via:
  1. Increase Ca2+ release from the sarcoplasmic reticulum.

2. Displacement of intracellular Ca2+ from its binding sites.
3. Increased intracellular Na+ prevents Ca2+ expulsion from the cell by the Na+/Ca2+ exchanger.

Question 5

What are the autonomic effects of digoxin?

“Inc para and dec symp”

Answer 5

– ↑ vagal activity: By direct and indirect mechanisms (Central vagal stimulation, Reflex vagal stimulation: by sensitization of baroreceptors, ↑ sensitivity of SAN to A.Ch.

– ↓ sympathetic activity due to relieve of hypoxia & improved tissue oxygenation.

Question 6

What are the pharmacological effects of digoxin?

” + ino and bathmo tropic”
“- dromotropic”

Answer 6

▪ ↑ Contractility and COP
▪ ↓ HR: (Bradycardia)
▪ Conduction velocity
▪ ↑ Excitability and automaticity
▪ ECG changes
▪ Normalization of arterial and venous pressures

Question 7

How does digoxin improve contractility and cardiac output?

Answer 7

due to +ve inotropic effect.

Question 8

What does improve in contractility due to digoxin lead to?

Answer 8

• Improvement of RBF → diuresis and ↓ RAAS (i.e. ↓ fluid retention).
• Relief of lung congestion.

Question 9

What causes Bradycardia on adminstration of digoxin?

Answer 9

• ↑ vagal tone and ↓ sympathetic activity on the heart. - Direct inhibition of the AV conducting system

Question 10

What happens to conduction velocity due to administration of digoxin?

Answer 10

• Intra atrial conduction: ↑ due to vagal stimulation.

- A-V conduction: ↓↓ by direct and vagal effects.

Question 11

What does increase in excitability and automaticity due to administration of digoxin lead to?

Answer 11

leading to ectopic foci and arrhythmia of any type (bigeminy, trigeminy, etc.).

Question 12

What are the ECG changes that happen upon administration of digoxin?

Answer 12

• Prolonged PR interval.
• Short QT interval.
• ST segment depression & T-wave inversion.

Question 13

Why is arterial and venous pressure improved upon administration of digoxin?

Answer 13

• due to improved hemodynamics.

Question 14

What is the drug of choice in case of chronic congestive heart failure associated with atrial flutter or fibrillation?

Answer 14

digoxin, because digoxin is the only drug that ↑ contractility and ↓ AV conduction in the same time.

Question 15

What is the drug of choice in cases of atrial flutter alone?

Answer 15

verapamil or beta-blockers are preferred.

Question 16

What is the drug of choice in cases of congestive heart failure not responding to other drugs?

Answer 16

Digoxin

Question 17

What is the initial degitalization of digoxin?

‏حباية في اليوم خمس مرات أسبوعيا

Answer 17

– It is done by giving one tablet 0.25 mg /day (5 days/week) from the start.

– The Cpss will be achieved after 5 t1⁄2 (t 1⁄2 = 40h i.e. after one week for digoxin).

– Rapid (loading) method is done in emergency conditions to achieve rapid Cpss. It is given as 2 tablets (0.5 mg) twice daily for 2 days(2x2x2).

Question 18

what is a maintenance dose of digoxin?

“Very narrow TI”

Answer 18

■ Maintenance dose: one tablet (0.25 mg)/day, 5 days/week.

Question 19

When is digoxin toxicity found?

Answer 19

When its plasma levels exceed 2 ng

Question 20

What are the precautions during digitalis therapy?

Answer 20

– Never give digitalis i.v. before being sure that the patient has not received digitalis during the last 14 days to avoid digitalis toxicity.

– Continuous monitoring of plasma K+ level.

– Mention all the relative contraindications.

Question 21

What are the absolute contraindication of digoxin?

Answer 21

– Heart block
– Hypertrophic obstructive cardiomyopathy (HOCM)
– Wolff-Parkinson-White (WPW) syndrome
– Paroxysmal ventricular tachycardia.

Question 22

What are the relative contraindications of digoxin?

Answer 22

– All causes of bradycardia.

– Systemic hypertension

– Pulmonary hypertension due to chronic lung disease:

– Cardiac diseases:
▪ Acute MI: digitalis ↑ the infarct size and aggravates arrhythmia.
▪ Cardiomyopathy…. digitalis is useless.

– Renal diseases: digoxin must be avoided in renal patients.

– In patients likely to require cardioversion: because digitalis may lead to fatal arrhythmia if given with cardioversion.

Question 23

What are the drugs that may interact with digoxin?

Answer 23

Antacids - Kaolin - Cholestyramine

Metoclopramide

Atropine

Quinidine

Loop diuretics and thiazides

Question 24

How do (Antacids - Kaolin - Cholestyramine) interact with digoxin?

Answer 24

Bind digoxin in the gut and decrease bioavailability (absorption)

Question 25

How do Metoclopramide interact with digoxin?

Answer 25

Increase gut motility leads to decrease digoxin absorption.

Question 26

How do Atropine interact with digoxin?

Answer 26

Decrease gut motility leads to increase digoxin absorption

Question 27

How do Quinidine interact with digoxin?

Answer 27

Decrease renal clearance of digoxin and displace digoxin from plasma proteins. Serum digoxin is increased.

Question 28

How do Loop diuretics and thiazides interact with digoxin?

Answer 28

Thiazides or loop diuretics may cause hypokalemia and hypomagnesemia which can ↑ the risk of digitalis toxicity

Question 29

What is the definition of heart failure?

Answer 29

Heart failure (HF) is a progressive clinical syndrome in which the heart is unable to pump sufficient blood to meet the metabolic demands of the body

Question 30

What is the pathophysiology of heart failure?

“Dec COP which activates RAAS and Sympathetic system, this is initially benefiting but eventually leads to deterioration of the cardiac function”

Answer 30

■ A reduction in COP lead to activation of the sympathetic nervous system and renin–angiotensin–aldosterone axis

■ Although initially beneficial, these alterations ultimately result in further deterioration of cardiac function.

Question 31

How is heart failure treated?

Answer 31

Non-drug therapy = life style modification

Drug therapy

Question 32

What is a non-drug therapy of heart failure?

Answer 32

– Rest.

– Dietary sodium (salt) and fat restriction.

– Avoid stress, smoking and alcohol.

– Weight reduction.

– Control of risk factors e.g. surgical correction of valvular diseases and treatment of hyperthyroidism, hypertension, etc.

– Avoid drugs that ↑ BP: e.g. sympathomimetics, sodium containing drugs, etc.

Question 33

What is the drug therapy or heart failure?

Answer 33

– Diuretics.

– ACEIs.

– Beta-blockers

– spironolactone.

– Vasodilators: nitrates and hydralazine

– Positive inotropic drugs:
▪ Cardiac glycosides (Digitalis).
▪ B1 agonist; dobutamine (used for short term only).
▪ Phosphodiesterase inhibitors: inamrinone & milrinone.

Question 34

What are the goals of therapy of heart failure?

“SS PR HS”

Answer 34

• Relieve symptoms and signs (e.g. oedema)
• Slow disease progression and cardiac remodeling
• Reduce hospital admission
• Improve survival