【Pharmacology】Drug for Heart Failure

Drug for Heart Failure

Review: 【Pharmacology】Heart Failure

Content:

1. Beta-blockers
2. Angiotensin-converting enzyme (ACE) inhibitors
3. Angiotensin receptor blockers (ARBs)
4. Angiotensin receptor-neprilysin inhibitor
5. Aldosterone antagonists
6. Loop diuretics
7. Vasodilators
8. Digoxin
9. Reference

1. Beta-blockers

work by binding to beta-1 receptors in the heart

• blocking the action of norepinephrine
• reducing heart rate and contractility
• decreases cardiac output and blood pressure

*Decreased heart rate allows more diastolic filling time, so the stroke volume is typically not reduced.

via blockade of the alpha 1 receptors of the renal juxtaglomerular complex,

• certain beta-blockers may also reduce renin secretion
• reducing the severity of angiotensin II-induced vasoconstriction & aldosterone-induced volume expansion

***however is not beta-blockers primary mechanism of action.

Review:【Pharmacology】Adrenergic drug (adrenergic antagonists)

Currently only three have proven to reduce mortality in heart failure patients

Drug: 

• Bisoprolol
• Carvedilol
• Carvedilol blocks 
• beta-1 receptors in the heart
• alpha-1 receptors located on the smooth muscles of arteries and veins.
• By preventing norepinephrine from activating the alpha-1 receptor, 
• Carvedilol causes vessels to dilate 
• reducing total peripheral resistance
• Metoprolol

2. Angiotensin-converting enzyme (ACE) inhibitors

• selectively inhibit the angiotensin-converting enzyme
• reduces angiotensin II production 
• reduce its effects on vasoconstriction as well as ADH and aldosterone secretion.
• increases levels of a potent vasoactive peptide called bradykinin.
• Angiotensin II: vasoconstrictor
• bradykinin: endogenous vasodilator, degraded by ACE
• When ACE inhibition occurs, 
• Angiotensin II levels drop
• bradykinin levels rise.
• blood vessels become dilated
• total peripheral resistance is reduced
• blood pressure is lowered 
• reducing the effort needed to pump blood around the body.

Drugs: 

• Captopril
• Enalapril
• Fosinopril
• Lisinopril
• Quinapril
• Ramipril

3. Angiotensin receptor blockers (ARBs)

• works on the same angiotensin pathway
• However instead of blocking the enzyme that drives angiotensin II production, 
• ARBs work by binding to AT1 receptors located on vascular smooth muscle & other tissues such as heart 
• directly blocking the actions of angiotensin II.
• effects are similar to ACE inhibitors that is 
• less vasoconstriction and less ADH and aldosterone secretion  
• lowers blood pressure
• prevents damage to the heart and kidneys

ARBs a good alternative to ACE inhibitors

• because ARBs do not inhibit ACE, they do not cause bradykinin levels to rise.
• bradykinin not only contributes to the vasodilation but also contributes to some of the side effects of ACE inhibitors
• such as cough and angioedema.

Drugs:

• Candesartan
• Losartan
• Telmisartan
• Valsartan

4. Angiotensin receptor-neprilysin inhibitor

Shortfall of ACE inhibitors and angiotensin receptor blockers (ARBs) 1

Despite being treated with an ACE inhibitor or angiotensin receptor blocker, many heart failure patients continue to suffer from cardiovascular events.

Hence, increasing the beneficial effects of natriuretic peptides has gained significant interest as a therapeutic approach in the management of heart failure.

Neprilysin

• circulating enzyme that degrades several endogenous vasoactive peptides, including 
• ANP
• BNP
• CNP
• terminates their positive actions.

Angiotensin receptor-neprilysin inhibitor 

• combines angiotensin receptor blocker and neprilysin inhibitor 
• simultaneously block angiotensin II receptor & inhibit neprilysin enzyme 
• preventing it from breaking down natriuretic peptides.
• increased longevity of natriuretic peptides 
• enhancement of their beneficial effects.

Drug: Sacubitril/Valsartan

5. Aldosterone antagonists

Shortfall of ACE inhibitors and angiotensin receptor blockers (ARBs) 2

In some cases they don t suppress the excessive formation of aldosterone sufficiently. Therefore, select patients with moderate to severe heart failure can also benefit from aldosterone antagonists.

Aldosterone antagonists 

• work by competitively blocking the binding of aldosterone to the mineralocorticoid receptor
• decreasing the reabsorption of sodium and water 
• decreasing the excretion of potassium 
• leading to cardioprotective effects.
• also refer to this class of drugs as Potassium-sparing diuretics.

Drug:

• Eplerenone
• Spironolactone

6. Loop diuretics

Now, although aldosterone antagonists have been shown to lower blood pressure and exert some diuretic effect. In order to alleviate symptoms of volume overload, a more potent class of drugs called loop diuretics is needed.

Review: 【Pharmacology】Diuretics

Primary use of loop diuretics: relieve symptoms associated with pulmonary congestion and peripheral edema

• by inhibiting the luminal sodium-potassium-chloride cotransporter located in the thick ascending limb of the loop of Henle 
• about 20% to 30% of the filtered sodium is managed.
• reduce reabsorption of a much greater proportion of sodium.
• Sodium excreted along with the water
• significant decrease in 
• plasma volume
• cardiac workload
• oxygen demand 
• thus relieving signs and symptoms of volume excess

Drugs:

• Bumetanide
• Furosemide
• Torsemide

7. Vasodilators

Patient who intolerant of ACE inhibitors or angiotensin receptor blockers (ARBs), usually because of significant renal dysfunction. The blood pressure can be controlled with another class of drugs referred to as vasodilators.

Drug:

• Isosorbide dinitrate
• releases nitric oxide (NO) in the vascular smooth muscle cell 
• activates guanylyl cyclase (GC)
• an enzyme that catalyzes the formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP).
• Increased intracellular cGMP activates a series of reactions
• cause decrease in intracellular calcium concentrations.
• leads to smooth muscle relaxation and thus vasodilation.
• Hydralazine 
• appears to have multiple effects on the vascular smooth muscle, which include
• stimulation of nitric oxide release from the vascular endothelium 
• stimulating cGMP production
• decreasing calcium concentration
• opening of potassium channels
• inhibition of calcium release from the sarcoplasmic reticulum
• altogether contribute to smooth muscle relaxation and subsequent vasodilation.

8. Digoxin

Review: 【Pharmacology】Antiarrhythmic

For patients intolerant to ACE inhibitors or beta-blockers

Digoxin increase cells' contractility, specifically the contractility of cardiac muscle cells.

• by inhibiting the sodium potassium ATPase pump in cardiac muscle cells
• which is responsible for moving sodium ions out of the cell and bringing potassium ions into the cell.
• This inhibition cause when sodium concentration in the cardiac cell increases, 
• sodium-calcium exchanger pushes the excess sodium ions out while bringing additional calcium ions in.
• causes an increase in the intracellular calcium
• available to the contractile proteins.
• increased force of contraction and thus increased cardiac output

9. Reference

https://youtu.be/AJV1BsRnImA

Related Link: 【Pharmacology】Arrhythmic  【Pharmacology】Antiarrhythmic