A19. Drugs used for treatment of heart failure I: Drugs decreasing the load on the heart. Drugs of acute cardiac failure. Pharmacotherapy of chronic heart failure.

Question 1

List the drug groups that decrease the load on the heart.

Answer 1

1. Diuretics: Furosemide (commonly used for acute heart failure), Thiazide (more for CHF). Decreases preload.
2. ACE inhibitors/ Angiotensin R blocker: decrease afterload, decrease remodeling of the heart. Sacubitril ( AR blocker + Neprilysin inhibitor (the enzyme that breaks down ANP / BNP) (combination with valsartan?)
3. Beta Blockers: decrease sympathetic tone, used in chronic heart failure (NOT acute though)
4. Vasodilators: nitroprusside, nitrates used in acute heart failure. Hydralazine maybe in Chronic heart failure.
5. Ivabradine: inhibits the funny current channels, slowing down the SA node.
6. Nesiritide: Natriuretic peptide analogue, cGMP effect → diuretic + vasodilation.

Question 2

What is the MOA of Nesiritide?

Answer 2

Nesiritide is a BNP analog that increases cGMP. Nesiritide causes arteriolar and venous dilation, reducing afterload and preload. Also cause natriuresis.

Question 3

What is the MOA of Beta Blockers?

Answer 3

They decrease the sympathetic tone..

Question 4

What is the MOA of Furosemide?

Answer 4

Furosemide is a diuretic so it will cause uresis, which will decrease the volume in the circulation –> decreasing the preload.

Question 5

List the drugs used in acute heart failure.

Answer 5

1. Sympathomimetic drugs: (cardiogenic shock, grade 4 chronic heart failure) dobutamine, dopamine and norepinephrine.
2. CPDE-3 inhibitor: Milrinone (used in patients who have desensitized effect from dobutamine).
3. Calcium sensitizers: Levosimendan
4. Natriuretic peptide analog: Nesiritide
5. Provide oxygen
6. Discontinue beta blockers + AR inhibitors
7. Pulmonary Edema in Acute left ventricular failure treat with morphine to get fluids out of the lungs and furosemide (loop diuretics).
8. (postive airway pressure/mechanical ventilation assistance)
9. BP increase - nitrates
10. Preload therapy/ volume therapy
11. Treat underlying causes: ex: Arrhythmia

Question 6

List the drugs used in Chronic Heart failure.

Answer 6

Beta blockers….etc.

Question 7

List the diuretics used in heart failure.

Answer 7

1. Furosemide + other loop diuretics
2. Spironolactone
3. Eplerenone

Question 8

List the Angiotensin-converting enzyme inhibitors and receptor blockers.

Answer 8

1. Captopril

2. Benazepril, Enalapril, others.

3. Losartan, candesartan, others.

Question 9

List the Positive inotropic drugs.

Answer 9

1. Cardiac glycosides: digoxin, (digitoxin?)
2. Sympathomimetics: dobutamine

Question 10

List the Beta Blockers used in heart failure.

Answer 10

1. Carvedilol
2. Metoprolol
3. Bisoprolol

Question 11

List the Vasodilators.

Answer 11

1. Nitroprusside
2. Hydralazine + isosorbide dinitrate
3. Nesiritide

Question 12

What is the MOA and pharmacokinetics of Dobutamine?

Answer 12

MOA: selective β1 agonist

Pharmacokinetics: given in infusion.

Question 13

Dopamine

Answer 13

MOA: 1. D1 action, low dose affects D1 more. vasodilation in renal artery, prevents renal failure in cardiogenic shock… some debate over how only cortical arteries dilate and not medullary, and the medulla is more susceptible to hypoxia 2. In medium dose, β1 agonism occurs. tachycardia may be more severe though, and so it’s not normally used like this. 3. In high dose, α1 agonism occurs.. not as good for heart. neither is epinephrine in heart failure.

Question 14

Norepinephrine

Answer 14

MOA: α1 agonist, in high dose β1 agonist as well. strong vasoconstrictor → reflex bradycardia.

Question 15

Pharmacokinetics of Nesiritide?

Answer 15

Pharmacokinetics:

Question 16

What are the side effects of taking nesiritide?

Answer 16

Side effects:

Question 17

What are the clinical indications and contraindications of taking nesiritide?

Answer 17

Clinical Indications: ??

Contraindications:??

Question 18

What is the MOA of Milrinone?

Answer 18

1. Milrinone is a cPDE-3 inhibitor meaning that it inhibits phosphodiesterase (cyclic phosphodiesterase-3).
2. It decreases CAMP breakdown leading to cAMP ↑ and sympathetic activity ↑.
3. This will lead to calcium overload (very arrhythmogenic), increase in cardiac contractility (positive inotropic agent), causes arteriolar dilation (vasodilator, pulmonary vascular resistance) in HF, but watch out for hypotension.

Question 19

What are the indications of Milrinone use?

Answer 19

Attempted for chronic HF, but increased mortality. Advantage: can still work if person becomes desensitized to dobutamine.

Question 20

What are the side effects of Dobutamine use?

Answer 20

SE: 1. May cause tachycardia, have to find balance between positive inotropic effects and tachycardias. 2. prolonged use may lead to dobutamine-resistant cardiogenic shock. cells down-regulate β receptors.

Question 21

Indications for Norepinephrine use?

Answer 21

Indication: needed when diastolic pressure is too low or unmeasurable. again have to find balance. Sometimes can be used alone with cardiogenic shock, or combined with dobutamine but all are arrhythmogenic, may cause SCD

Question 22

What is the MOA and pharmackinetics of Levosimendan?

Answer 22

Levosimendan is a calcium sensitizers: positive inotropic agent.

MOA: change calcium affinity of troponin C. increases contractility w/o a rise in intracellular calcium. Pharmacokinetics: IV infusion, action lasts for 1 week, seems to bind strongly in order to persist

Question 23

What are the indications of Levosimendan?

Answer 23

1. Grade 4 CHF, acute decompensation.
2. So far probably not indicated for cardiogenic shock, but it would probably work.

(Note: much less arrhythmogenic than others, also it’s expensive)