Heart Failure Drugs

Question 1

Digoxin MOA

Answer 1

Cardiac glycoside
Competes with K+ and blocks Na-K-ATPase, increasing intracellular Na+ concentration. Increased Na+ concentration inside the cell reduces the action of the Na-Ca2+ exchanger, increasing cytosolic Ca2+. This Ca2+ is sequestered in the SR (via SERCA) for use later during contraction (via RyR2).
Overall effect: increase in contractility

Question 2

Which transporters move Ca2+ both into the SER and out of the SER?

Answer 2

SERCA brings Ca2+ into the SER

RyR2 releases Ca2+ into the cytosol from the SER for contraction

Question 3

What is levosimendan?

Answer 3

Ca2+ sensitizer

Increases actin-troponin-tropomyosin sensitivity to Ca2+

Question 4

What is the autonomic effect of digoxin at a low dose?

Answer 4

Parasympathomimetic: increased Ca2+ causes increased release of Ach from the synaptic terminals. Inhibits the SA and blocks A-V conduction due to the increased action of M2.
This is useful for treating A-fib

Question 5

What is the autonomic effect of digoxin at a high dose?

Answer 5

Sympathomimetic: increased Ca2+ causes increased release of NE from the synaptic terminals. Increased heart contractility due to the action of B1 receptors

Question 6

What effects does digoxin have in the GIT?

Answer 6

Anorexia, nausea, vomiting and diarrhea

Due to both smooth muscle contraction and through CNS chemoreceptor trigger zone stimulation

Question 7

What effects does digoxin have in the CNS?

Answer 7

Vagal and chemoreceptor trigger zone stimulation
Disorientation, hallucination, visual disturbances (altered colour perception)
Gynecomastia (rare)

Question 8

What characteristics does the ECG of someone taking digoxin have?

Answer 8

Early and brief shortening of the action potential due to increased K+ conductance caused by increased intracellular Ca2+
Increased PR interval caused by decrease in AV conduction velocity and flattening of T wave
Resting membrane potential is less negative, easy premature depolarization

Question 9

What is the toxic response of digoxin?

Answer 9

Arrhythmia, including ventricular arrhythmia and AV blockage

Question 10

Use of digoxin in congestive heart failure:

Answer 10

Effective but does not prolong life

Drug accumulates in the body and dosing regiments must be carefully designed and monitored

Question 11

Use of digoxin in a-fib:

Answer 11

Unlike CCBs and BBs, digoxin does not have negative inotropic effects

Question 12

Digoxin half life

Answer 12

1.5 days

Question 13

Digoxin Vd

Answer 13

High - high tissue protein binding

Can be replaced by quinidine –> increasing serum digoxin levels

Question 14

Interaction between K+ and digoxin

Answer 14

K+ and digoxin inhibit each other’s binding to Na-K ATPase (competitive)
Hypokalemia facilitates digoxin action
Hyperkalemia reduces digoxin action

Question 15

Interaction between Ca2+ and digoxin

Answer 15

Ca2+ facilitates the toxic effects of digoxin
Hypercalcemia increases the risk of digoxin induced arrhythmia
Hypocalcemia renders digoxin less effective

Question 16

Interaction between Mg2+ and digoxin

Answer 16

Mg2+ inhibits actions of digoxin

Digitalis-induced vomiting may deplete serum magnesium and facilitate toxicity

Question 17

How does verapamil affect digoxin?

Answer 17

Lowers digoxin clearance in the liver and kidney (via p-glycoprotein efflux pump)
Replaces digoxin from tissue protein binding
Increases digoxin concentration in the blood

Question 18

How to loop diuretics and thiazides affect digoxin?

Answer 18

May significantly reduce serum K+ and thus precipitate digitalis toxicity

Question 19

Signs of digoxin toxicity

Answer 19

CNS: malaise, confusion, depression, vertigo, colour vision change
GI: anorexia, nausea, intestinal cramping, diarrhea
CVS: palpitations, syncope, arrhythmias, bigeminy ventricular premature contraction, bradycardia, cardiac affect (in very high doses)

Question 20

How do you correct digoxin toxicity?

Answer 20

Correct potassium deficiencies (oral or IV)
Mild toxicities can be solved by omitting 1 or 2 doses of digitalis
Antiarrhythmic drugs: Lidocaine for ventricular arrhythmia, beta blocker or CCB for supraventricular arrythmia
Severe toxicity treated with Digibind, an anti-digoxin antibody (Fab fragments)

Question 21

How are dobutamine and dopamine used in heart failure?

Answer 21

Useful in acute failure in which systolic function is markedly depressed
These drugs are not appropriate for chronic failure because of tolerance, lack of oral efficacy and significant arrhythmogenic effects

Question 22

Inamrinone (amrinone) and milrinone MOA

Answer 22

Acts by inhibiting the enzyme phosphodiesterase-3
Leading to increased intracellular concentrations of cAMP-PKA
Phosphorylates L- Ca channels on plasma membrane, causing increased Ca++ entry into the cell, and phosphorylates ryanodine-Ca++ channel, leading to more calcium release. Heart contraction is increased
Phosphorylates MLCK and inactivates MLCK, causes vasodilation

Question 23

How are inamrinone (amrinone) and milrinone used?

Answer 23

Only IV for short term therapy

Only for acute heart failure or severe exacerbation of CHF.

Question 24

ADR of inamrinone (amrinone) and milrinone:

Answer 24

GI upset, arrhythmia, thrombocytopenia, liver toxicity. Milrinone is safer in term of bone marrow and liver toxicities

Question 25

MOA of BNP

Answer 25

Released by ventricular myocytes when they are stretched. It is increased in heart failure.
BNP activates guanylyl cyclase, which increases cGMP causing vasodilation (arterioles AND veins)

Question 26

Nesiritide

Answer 26

Recombinant human BNP used to treat acute decompensated congestive heart failure
T1/2 is 18 min
IV

Question 27

What is the adverse effect of nesiritide?

Answer 27

Hypotension

Question 28

How is furosemide used in heart failure?

Answer 28

Used to reduce volume immediately in pulmonary congestion and severe edema associated with acute heart failure

Question 29

What do angiotensin II and aldosterone do locally in the heart?

Answer 29

Facilitate heart remodeling and fibrosis

Question 30

How do B1 antagonists reduce mortality in heart failure?

Answer 30

Carvedolol, metoprolol
Decrease apoptosis
Decrease heart rate
Reduce remodeling by inhibiting mitogenic activity of catecholamine
Upregulate beta receptor
Effective in patients with hypertrophic cardiomyopathy
Not of value in acute failure (because they decrease heart contraction) and may be detrimental if systolic dysfunction is markedly decreased

Question 31

Which drugs reduce mortality in heart failure?

Answer 31

ACEI, ARB
Spinorolactone, eplerenone
Carvedilol ( α and β blocker)
Metoprolol, bisoprolol, nebivolol (β1 blocker)

Question 32

Ivabradine MOA

Answer 32

Inhibits SA node funny channel and reduces HR, but does not suppress contractility

Question 33

Sacubitril MOA

Answer 33

ARNI ( ARB+ neprilysin inhibitor) (valsartan+ sacubitril)
Neprilysin is the enzyme to degrade natreuretic peptide (BNP) and bradykinin
Sacubitril is neprilysin inhibitor

Question 34

Why use an ARNI ( ARB+ neprilysin inhibitor) (valsartan+ sacubitril)?

Answer 34

In patients with chronic symptomatic heart failure who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality

Question 35

How do you manage chronic heart failure?

Answer 35

Limit physical activity
Reduce weight
Reduce water intake
Control hypertension
Na+ restriction
Diuretics
Angiotensin antagonists
Digoxin
Beta blockers
Vasodilators

Question 36

How do you manage acute left heart failure?

Answer 36

1. O2
2. Morphine IV or IH (calm down patient)
3. Furosemide IV
4. Digoxin IV (no repeat until 4 h later)
5. Nitroprusside iv infusion, quickly reduce both artery and venous pressure (remember avoiding light, wrapping all tube and bag in foil paper)
6. Life support
7. Treat the cause (surgery to correct valvular disorders)