A-19. Drugs used for treatment of heart failure I: Drugs decreasing the load on the heart. Drugs of acute cardiac failure

Question 1

Possible Treatment Strategies in HF

Answer 1

1. ACE-I and AT 1 -atg - ↓ afterload/preload; inhibition of remodeling
2. Beta Blockers - inhibit increased sympathetic activity; decrease mortality risk; only used until certain
   stages of HF, not for acute decompensation
3. Diuretics - ↓ preload (+ some have venodilator effects, i.e. loop diuretics)
4. Venodilators - ↓ preload
5. Positive Inotropes - dobutamine, digoxin, PDE inhibitors, Ca-sensitizers

Question 2

Drugs Decreasing the Load of the Heart

Answer 2

1. beta blockers
2. diuretics
3. ACE-I/AT1 atg
4. venodilators

Question 3

Drugs of Acute Heart Failure

Answer 3

1. sympathomimetics (β-1 Agonists: Dobutamine, Dopamine, Norepinephrine).
2. PDE3 inhibitors (Bipyridines: Amrinone, Milrinone. Methylxanthines: Aminophylline, Theophylline).
3. Ca ++ -sensitizers (Levosimendan, Pimobendan).

Question 4

Dobutamine

Answer 4

most selective to β-1.
short half-life.
continuous parenteral admin.
inotropic effect is helpful in AHF but tachycardia further exhausts heart!

Tolerance develops in ~72 hrs
(tachyphylaxis) via β-1 downregulation.

Indications :

1. acute decompensation of CHFacute HF.
2. post-MI.
3. cardiogenic shock

Question 5

Dopamine (dose-dependent effect at different receptors)

Answer 5

1. 0.5-2.5 mcg/kg/min → D receptors →
   ↑RBF → indicated for kidney shock.
2. 2.5-5.0 mcg/kg/min → D and β-1 receptors → same indications/side fx as dobutamine.
3. 5.0-10.0 mcg/kg/min → α-1 → also vasoconstricts.

Question 6

Norepinephrine

Answer 6

less reflex tachycardia due to less β-2 effect,
highest effect at α-1

strong vasoconstriction → reflex
bradycardia.

Indications :
1. cardiogenic shock

Question 7

PDE3 Inhibitors (MOA)

Answer 7

PDE3 inhibition → ↑ cAMP → positive
ino-/dromo-/chronotropy (+ inactivation of
myosin light chain kinase → vascular SM
relaxation → arteriolar vasodilation → ↓
afterload).

Question 8

Amrinone and Milrinone (indications, side effects)

Answer 8

Amrinone-
Indications:
1. acute HF (for refractory pts tolerant to
dopamine/dobutamine).

Side Effects :

1. worsened liver function
2. thrombocytopenia
3. tachycardia (so not for long-term tx).
4. hypotension

Milrinone-
20x potency, same sfx, but no
thrombocytopenia → more often used.

Question 9

Aminophylline and Theophylline (administration and indications)

Answer 9

Aminophylline - parenteral.
Theophylline - oral.

Indications : same as bipyridines, plus
pulmonary edema.

Question 10

Calcium Sensitizers (MOA, disadventage, indications)

Answer 10

MOA: Interact with troponin C to ↑contractility without ↑ Ca level → not arrhythmogenic!

Disadvantage: as contractility ↑ - diastolic
relaxation can be inhibited.

Indications : severe acute heart failure

Question 11

Levosimendan (MOA, kinetics)

Answer 11

MOA : binds troponin C → stabilizes conformation necessary for interaction of actin + myosin.
binds in a Ca-dependent manner, so does not affect relaxation.

Kinetics : parenteral admin

Question 12

Pimobendan

Answer 12

MOA : increases affinity of troponin C to Ca, also inhibits PDE.

Kinetics : oral admin

Question 13

Nesiritide

Answer 13

BNP analog.
MOA: ↑ cGMP in SM → venous / arteriolar dilation.
Na loss via diuresis.