Drugs for Heart Failure

Question 1

What is the main goal of pharmacologic intervention in heart failure?

Answer 1

Reduce preload and afterload

Question 2

Describe systolic failure and how it responds to positive inotropes.

Answer 2

Characterized by reduced cardiac output, contractility, and ejection fraction (< 45%). This responds well to positive inotropes.

Question 3

Describe diastolic failure and how it responds to positive inotropes.

Answer 3

Caused by hypertrophy and stiffness of the myocardium. This is a result of failure of the ventricle to relax. Cardiac output will be reduced, but ejection fraction may remain normal. Doesn’t respond well to positive inotropes.

Question 4

What is the prototype cardiac glycoside? What kind of agent is it? What are its therapeutic uses?

Answer 4

Digoxin is the prototype cardiac glycoside, and the only one used in the US. It is an inotropic agent used to treat heart failure and atrial fibrillation.

Question 5

Describe the pharmacokinetics of digoxin in reference to patients with normal renal function, renal insufficiency, and vasodilator/sympathomimetic therapy.

Answer 5

Normal renal function - half-life is 36-48 hours
Renal Insufficiency - half-life is 3.5-5 days
Vasodilator/sympathomimetic therapy - increased clearnace due to increased RBF

Question 6

Describe the general mechanism of action of digoxin and its two main effects.

Answer 6

Digoxin inhibits the sarcolemmal Na/K ATPase causing increased contractility and prolonged AV node refractory period

Question 7

Describe the mechanism of digoxin’s inotropic effects.

Answer 7

Inhibition of the sarcolemmal Na/K ATPase causes increased intracellular sodium. This inhibits extrusion of calcium through the Na/Ca exchanger –> increased intracellular calcium. Now more calcium is available for sequestration and contraction.

Question 8

How does digoxin hasten action potential, but slow AV node conduciton and prolong AV node refractory period?

Answer 8

Digoxin causes increased intracellular calcium, which activates calcium-dependent potassium channels allowing rapid efflux of potassium and repolarization. Digoxin also increases parasympathetic tone and decreases sympathetic activity to cause prolonged AV node refractoriness and slowed conduction.

Question 9

What are the effects (4) of digoxin toxicity?

Answer 9

1. Elevated resting membrane potential –> delayed afterdepolarizations
2. Arrhythmias - PVCs, AV junctional rhythm, and 2 degree AV block
3. GI disturbances - anorexia, nausea, vomiting, diarrhea
4. CNS disturbances - hallucinations, disorientation, and visual disturbances

Note: Affects all excitable tissues

Question 10

What are the interactions of digoxin with potassium, calcium, and magnesium?

Answer 10

Digoxin and potassium compete for the same site on the ATPase. Hyperkalemia will inhibit digoxin’s effects, while hypokalemia potentiates the effects of digoxin. Hypercalcemia and hypomagnesemia can increase the risk of arrhythmias.

Note: Avoid digoxin use in patients with thiazide diuretics due to increased risk of hypokalemia

Question 11

What are the prototype (2) bipyrdines? What type of agent are bipyridines? What is their therapeutic use?

Answer 11

Prototypes - inamrinone and milrinone

These are positive inotropic agents. they are used for SHORT-TERM support of circulation in decompensated heart failure.

Note: given parenterally

Question 12

What is the mechanism of action of bipyridines?

Answer 12

Drugs like inamrinone and milrinone inhibit PDE-3. This casues increase in intracellular cAMP leading to the activation of PKA. PKA can cause the activation of voltage-gated calcium channels in the myocardium. This increases contractility and activates rapid relaxation. Also, PKA inactivates myosin light chain kinase in venous and arterial smooth muscle resulting in decreased pulmonary/systemic vascular resistance.

Question 13

What are the toxic effects of inamrinone?

Answer 13

nausea, vomiting, arrhythmias, and thrombocytopenia

Question 14

What are the toxic effects of milrinone?

Answer 14

arrhythmias

Question 15

What is the prototype beta-adrenergic agonist? What type of agent is it? What are the therapeutic uses?

Answer 15

Dobutamine is the prototype. It is a positive inotropic agent used for circulatory support in decompensated heart failure.

Question 16

What is the prototype dopaminergic agonist? What type of agent is it? What are the therapeutic uses?

Answer 16

Dopamine is the prototype. It is a positive inotropic agent used for decompensated heart failure.

Question 17

What is the mechanism of action of dopamine and dobutamine?

Answer 17

Both drugs, through the D1 or Beta-1 receptor, cause activation of the Gs-adenylyl cyclase-cAMP-PKA pathway to increase calcium dependent contractility and rapid relaxation.

Question 18

What is dobutamine specifically used for? How is it administerd? What are its main effects(2)?

Answer 18

Used for treatment of systolic failure. Administered parenterally. Increases stroke volume and cardiac output.

Question 19

How do low, intermediate, and high doses change the effect of dopamine? How is it administered?

Answer 19

Low doses - cAMP vasodilation mediated by D1 receptors and inhibiton of norepinephrine release through presynaptic D2 receptors
Intermediate doses - increased contractility and norepinephrine release through the activation of beta receptors
High doses - arterial and venous constriciton mediated by alpha receptors

Administered parenterally

Question 20

How do diuretics reduce strain in heart failure?

Answer 20

Reduce ventricular preload

Question 21

Which diuretics, potassium-sparing, loop, or thiazide would be most effective in management of heart failure?

Answer 21

Loop diuretics are extremely potent and have the greatest effect in treating heart failure. Thiazide diuretics are better used in hypertension. Potassium-sparing diuretics are weak and not used in heart failure.

Question 22

What are the prototype (2) aldosterone antagonists? How do they reduce mortality in heart failure?

Answer 22

Spironolactone and eplerenone are the prototype aldosterone antagonists. Aldosterone is thought to play a role in myocardial/vascular remodeling and barroreceptor dysfunciton in addition to sodium/water retention. Inhibiton of the first two effects is believed to reduce mortality.

Question 23

What are the prototype (2) ADH antagonists and what are they used to treat?

Answer 23

Conivaptan and tolvaptan are the prototypes. They are used to treat CHF and SIADH. However, use in CHF is not recommended.

Question 24

What are the mechanisms of action of conivaptan and tolvaptan? Describe their toxic effects.

Answer 24

Conivaptan will bind to V1 and V2 receptors. Tolvaptan binds to V1 receptors. Toxicity can cause hypernatremia and nephrogenic diabetes insipidus.