Drugs for Heart Failure

Question 1

Positively Inotropic Drugs

Answer 1

Digoxin
Dobutamine
Milrinone
Levosimendan

Question 2

Positively Inotropic Drugs - MoA

Answer 2

Increase cardiac contractility by increasing Ca levels in cardiac myocytes.

Question 3

Digoxin - MoA

Answer 3

Positive inotropic effect (increase in the force of contraction): increasing intracellular calcium as a result of inhibiting the sodium pump in the plasma membrane. When the sodium pump is inhibited, the concentration of intracellular sodium is increase, thereby increasing the activity of the sodium-calcium exchanger, causing more calcium to enter the cardiac myocyte. The increase in cytoplasmic calcium, stimulates the release of additional calcium from the sarcoplasmic reticulum and increases the rate of myofibril shortening (muscle contraction). These actions increase stroke volume and cardiac output.

Positive Bathmotropic effect

Negative chronotropic effect (a decrease in heart rate):
Increased PNS activity while decreased SNS activity –> decreased HR and AV node conduction velocity, while increased AV node refractory period.

Negative dromotropic effect (decrease in conduction velocity)

Question 4

Digoxin - Clincal use

Answer 4

Heart failure (esp systolic heart failure, not used to treat diastolic).

It does not treat heart failure, or prolong survival, it reduces symptoms and the need for hospitalization.

Slow ventricular rate in pt with atrial fibrillation (by slowing AV node conduction velocity and increasing AV node refractory period –> increased nr of ectopic impulses transmitted to the ventricles.

Question 5

Digoxin - Adverse effects

Answer 5

Increased abnormal impulse formation by evoking spontaneous afterdepolarizations (occur during or after cardiac repolarization –> extrasystoles –> tachycardia)

Decreased QT-interval: shortens ventricular action potential duration by accelerating repolarization

Decreased AV node conduction velocity –> increased PR interval –> ST depression –> “hockey stick configuration” on the ST segment

Most common: GI, cardiac and neurologic reactions

Earlies signs of toxicity:
Anorexia
Nausea
Vomiting

Cardiac arrhythmias (AV block, tachyarrhythmias)
Most common digitalis induces arrhythmia: Atrial tachycardia with AV block
Ventricular arrhythmias

Neurologic effects of Digoxin toxicity: blurred vision, yellow-green or blue chromatopsia, seizures.

Hypokalemia can precipitate arrhythmias in patients receiving digoxin.

Gynecomastia: because of some estrogenic activity

Question 6

Digoxin - Interactions

Answer 6

Antacids and cholestyramine can reduce the absorption of digoxin (should be separated by 2h)

Diltiazem, quinidine, verapamil increase levels –> toxicity

Loop acting thiazide drugs cause hypokalemia –> precipitate digitalis toxicity because reduced K+ concentrations increases digitalis binding to the Na pump.

Digoxin immune fab: antidote. Given iv

Question 7

Dobutamine - MoA

Answer 7

Selectively stimulates cardiac contractility, and causes less tachycardia then the other b-adrenoceptor agonists.

Activates b2-adrenoceptors in vascular smooth muscle, decreases vascular resistance, CO –> augmenting CO.

Increases ca influx by increasing cAMP levels by way of adenylyl cyclase

Question 8

Dobutamine - Clinical use

Answer 8

Acute heart failure
Cardiogenic shock
Heart failure

Question 9

Dobutamine - Adverse effects

Answer 9

Excessive vasoconstriction and tachyarrhythmias

Question 10

Dobutamine - Interactions

Answer 10

Adrenoceptor agonists and antagonists

Question 11

Milrinone - MoA

Answer 11

Inhibits type 3 phosphodiesterase, an enzyme that converts cAMP to inactive 5´-AMP. By increasing the concentration of cAMP in myocyte –> stimulates cardiac contractility. It also increases cAMP in vascular smooth muscle and produces vasodilation.

Increases ca influx by increasing cAMP levels by w inhibiting cAMP breakdown by phosphodiesterase.

Question 12

Milrinone - Clinical use

Answer 12

Short term management of heart failure in patients not responsive to other drugs.
Inotropic support for children awaiting cardiac transplantation.
Other conditions that require myocardial stimulation.

Question 13

Milrinone - Adverse effects

Answer 13

Long term use: thrombocytopenia, ventricular arrhythmias,
Ass with increased mortality in patients with severe heart failure.
Hypotension

Question 14

Calcium sensitizer drug

Answer 14

Levosimendan

Question 15

Levosimendan - MoA

Answer 15

it increases the sensitivity of the heart to calcium, thus increasing cardiac contractility without a rise in intracellular calcium. Levosimendan exerts its positive inotropic effect by increasing calcium sensitivity of myocytes by binding to cardiac troponin C in a calcium-dependent manner. It also has a vasodilatory effect, by opening adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle to cause smooth muscle relaxation.

Question 16

Levosimendan - Clinical use

Answer 16

Acute heart failure

Question 17

Levosimendan - Adverse effects

Answer 17

Headache
Hypotension
Atrial Fibrillation

Question 18

Vasodilators

Answer 18

Angiotensin-Converting Enzyme inhibitors (ACE inhibitors)
Angiotensin receptor blockers (ARBs)
Natriuretic peptide
Neprilysin Inhibitor
Hydralazine and Nitrates

Question 19

ACE inhibitors

Answer 19

Ramipril
Enalapril
Lisinopril

Question 20

ACE inhibitors - MoA

Answer 20

Reduce formation of angiotensin II. Angiotensin II has several actions that contribute to the pathogenesis of heart failure, including vasocontraction and increased secretion of aldosterone and antidiuretic hormone.

Effect:
Decrease plasma V, venous pressure, edema, increase CO by reducing arterial resistance and cardiac afterload.

Counteract adverse effect of angiotensin that contribute to cardiac remodeling in pt with heart failure.

Question 21

ACE inhibitors - Clinical use

Answer 21

Diabetic nephropathy
Hypertension
Heart failure
Acute myocardial infarction: improve survival when adm within 24h of onset of symptoms.

Question 22

ARBs

Answer 22

Valsartan

Candesartan

Question 23

ARBs - MoA

Answer 23

Prevent binding of angiotensin II to AT1 receptor

Question 24

ARBs - Clinical use

Answer 24

Reduce mortality and hospitalization in persons with heart failure. ARB are indicated for persons who cannot tolerate ACE inhibitors.

Question 25

Hydralazine and Nitrates - MoA

Answer 25

H-Relaxes arterial smooth muscle
N-Relaxes venous smooth muscle
The combination of these two drugs reduces cardiac preload and afterload, –> reduced venous pressure and edema and increase cardiac output, respectively.

Question 26

Hydralazine and Nitrates - Clinical use

Answer 26

Used to treat heart failure in pat who cannot tolerate angiotensin inhibitors.

Black patients with heart failure(less effect of ACE inh)

Question 27

Human B-type natriuretic peptide

Answer 27

Nesiritide

Question 28

Nesiritide - MoA

Answer 28

Binds to guanylate cyclase receptors in vascular smooth muscle and endothelial cells, leading to increased intracellular concentration of cyclic guanosine monophosphate cGMP. cGMP acts as a second messenger to dilate venous and arterial smooth muscle, thereby leading to reduction in venous and arterial pressure in patients with heart failure.
Leads to reduced pulmonary capillary wedge pressure –> decrease vascular congestion and dyspnea in decompensated pt w heart failure

Question 29

Nesiritide - Clinical use

Answer 29

Acute decompensated heart failure with dyspnea at rest or with minimal activity.

Question 30

Nesiritide - Adverse effects

Answer 30

Hypotension

Question 31

Neprilysin inhibitor

Answer 31

Sacubitril

Question 32

Sacubitril - MoA

Answer 32

Raises levels of vasoactive peptides (bradykinin, natriuretic peptides) –> decrease cardiac remodeling, vasoconstriction and sodium retention.

Question 33

Sacubitril - Clinical use

Answer 33

Decrease death rates in pt with systolic heart failure

Decrease hospitialization due to heart failure

Hypertension when comb with ACE inh

Question 34

B-adrenoreceptor antagonists

Answer 34

Carvediol (a + b)
Metoprolol
Bisoprolol

Question 35

B-adrenoreceptor antagonists - MoA

Answer 35

The benefits of b-blockers are caused by the ability of these drugs to reduce excessive sympathetic stimulation of the heart and circulation in patients with heart failure.

Carvedilol: increase left ventricular ejection fraction, improve symptoms and slow disease progression

Question 36

B-adrenoreceptor antagonists - Clinical use

Answer 36

Mild to severe heart failure caused by left ventricular systolic dysfunction.

Carvedilol: all pat with symptomatic heart failure who do not have significant hypotension, pulmonary congestion or AV block.
Carvedilol reduces hospitalization and mortality in persons with heart failure when it is added to a standard treatment regimen

Question 37

Aldosterone antagonists

Answer 37

Spironolactone

Eplerenone

Question 38

Aldosterone antagonists - MoA

Answer 38

Compete with aldosterone for the mineralocorticoid receptor in the renal tubules and other tissues. These drugs act on kidneys to increase sodium excretion and decrease potassium excretion.

Question 39

Aldosterone antagonists - Clinical use

Answer 39

Spironolactone: reduce mortality in severe heart failure

Mild to moderate heart failure

Question 40

Aldosterone antagonists - Adverse effects

Answer 40

Hyperkalemia
Gynecomastia
Impotence in some male pat.

Question 41

Diuretics - MoA

Answer 41

Are used to reduce plasma volume and edema, thereby relieve symptoms of volume overload such as dyspnea.

Question 42

Diuretics - Clinical use

Answer 42

Loop diuretics (bumetanide, furosemide, toresemide) have greater natriuretic act then other and are preferred for reducing plasma volume, must be used carefully to avoid, dehydration, hyponatremia and hypokalemia.