Pharmacologic Interventions for Heart Failure: A Comprehensive Guide. || pharmacyteach

Pharmacologic Interventions for Heart Failure: A Comprehensive Guide

   

OVERVIEW

Heart failure (HF) is a complex, progressive disorder in which the heart is unable to pump sufficient blood to meet the needs of the body. Its cardinal symptoms are dyspnea, fatigue, and fluid retention. HF is due to an impaired ability of the heart to adequately fill with and/or eject blood. It is often accompanied by abnormal increases in blood volume and interstitial fluid. Underlying causes of HF include but are not limited to, atherosclerotic heart disease, hypertensive heart disease, valvular heart disease, and congenital heart disease.

 

A. Role of physiologic compensatory mechanisms in the progression of HF

 

Chronic activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system(RAAS) is associated with remodeling of cardiac tissue, loss of myocytes, hypertrophy, and fibrosis. This prompts additional neurohormonal activation, creating a vicious cycle that, if left untreated, leads to death.

 

B. Goals of pharmacologic intervention in HF

The goals of treatment are to alleviate symptoms, slow disease progression, and improve survival. The following classes of drugs are effective: 1) angiotensin-converting enzyme (ACE) inhibitors, 2) angiotensin receptor blockers, 3) aldosterone antagonists, 4) ẞblockers, 5) diuretics, 6) direct vaso, and venodilators, 7) hyperpolarization-activated cyclic nucleotide-gated channel blockers, 8) inotropic agents, 9) the combination of a neprilysin inhibitor with an angiotensin receptor blocker, and 10) recombinant Type natriuretic peptide (Figure 18.1). Depending on the severity of HF and individual patient factors, one or more of these classes of drugs are administered. Pharmacologic intervention provides the following benefits in HF: reduced myocardial workload, decreased extracellular fluid volume, improved cardiac contractility, and a reduced rate of cardiac remodeling. Knowledge of the physiology of cardiac muscle contraction is essential for understanding the compensatory responses evoked by the failing heart, as well as the actions of drugs used to treat HF.

 

II. PHYSIOLOGY OF MUSCLE CONTRACTION

The myocardium, like smooth and skeletal muscle, responds to stimulation by depolarization of the membrane, which is followed by shortening of the contractile proteins and ends with relaxation and return to the resting state (repolarization). Cardiac myocytes are interconnected in groups that respond to stimuli as a unit, contracting together whenever a single cell is stimulated.

 

A. Action potential

Cardiac myocytes are electrically excitable and have a spontaneous, intrinsic rhythm generated by specialized "pacemaker" cells located in the sino-atrial (SA) and atrioventricular (AV) nodes. Cardiac myocytes also have an unusually long action potential, which can be divided into five phases (0 to 4). Figure.1 illustrates the major ions contributing to depolarization and repolarization of cardiac myocytes.

Figure. 1: Action potential of the cardiac myocyte. ATPase= Adenosine triphosphatase 

 

B. Cardiac contraction

The force of contraction of the cardiac muscle is directly related to the concentration of free (unbound) cytosolic calcium. Therefore, agents that increase intracellular calcium levels (or that increase the sensitivity of the contractile machinery to calcium) increase the force of contraction (inotropic effect). The movement of calcium in cardiac myocytes is illustrated in Figure. 2.

Figure 2:- Ion movements during the contraction of cardiac muscle

C. Compensatory physiological responses in HF

The failing heart evokes four major compensatory mechanisms to enhance cardiac output (Figure. 3).

1.     Increased sympathetic activity:

 Baroreceptors sense a decrease in blood pressure and activate the sympathetic nervous system. In an attempt to sustain tissue perfusion, this stimulation of Adrenergic receptors results in an increased heart rate and a greater force of contraction of the heart muscle. In addition, vasoconstriction enhances venous return and increases cardiac preload. An increase in preload (stretch on the heart) increases stroke volume, which, in turn, increases cardiac output. These compensatory responses increase the workload of the heart, which, in the long term, contributes to further decline in cardiac function.

   

2.     Activation of the renin-angiotensin-aldosterone system (RAAS):

A fall in cardiac output decreases blood flow to the kidney, prompting the release of renin. Renin release is also stimulated by increased sympathetic activity resulting in increased formation of angiotensin II and release of aldosterone. This results in increased peripheral resistance (afterload) and retention of sodium and water. Blood volume increases and more blood is returned to the heart. If the heart is unable to pump this extra volume, venous pressure increases and peripheral and pulmonary edema occur. In addition, high levels of angiotensin II and aldosterone have direct detrimental effects on cardiac muscle, favoring remodeling, fibrosis, and inflammatory changes. Again, these compensatory responses increase the workload of the heart, contributing to further decline in cardiac function.

Figure 3:- Cardiovascular consequences of Heart Failure. 

3.     Activation of natriuretic peptides:

An increase in preload also increases the release of natriuretic peptides. Natriuretic peptides, which include atrial, B-type, and C-type, have differing roles in HF; atrial and B-type natriuretic peptides are the most important. Activation of the natriuretic peptides ultimately results in vasodilation, natriuresis, inhibition of renin and aldosterone release, and a reduction in myocardial fibrosis. This beneficial response may improve cardiac function and HF symptoms.

 

4.     Myocardial hypertrophy:

Initially, stretching of the heart muscle leads to a stronger contraction of the heart. However, excessive elongation of the fibers results in weaker contractions and a diminished ability to eject blood. This type of failure is termed "systolic failure" or HF with reduced ejection fraction (HFrEF) and is the result of the ventricle being unable to pump effectively. Patients with HF may have "diastolic dysfunction," a term applied when the ability of the ventricles to relax and accept blood is impaired by structural changes such as hypertrophy. The thickening of the ventricular wall and subsequent decrease in ventricular volume decrease the ability of heart muscle to relax. In this case, the ventricle does not fill adequately, and the inadequacy of cardiac output is termed "diastolic HF" or HF with preserved ejection fraction (HFpEF). Diastolic dysfunction, in its pure form, is characterized by signs and symptoms of HF in the presence of a normal functioning left ventricle. However, both systolic and diastolic dysfunction commonly coexist in HF.

 

D. Acute (decompensated) HF

If the compensatory mechanisms adequately restore cardiac output, HF is said to be compensated. If the compensatory mechanisms fail to maintain cardiac output, HF is decompensated and the patient develops worsening HF signs and symptoms. Typical HF signs and symptoms include dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, fatigue, and peripheral edema.

 

E. Therapeutic strategies in HF

Chronic HF is typically managed by fluid limitations (less than 1.5 to 2 L daily); low dietary intake of sodium (less than 2000 mg/d); treatment of comorbid conditions; and judicious use of diuretics.

Specifically for HFrEF, inhibitors of the RAAS, and inhibitors of the sympa. The tic nervous system and drugs that enhance the activity of natriuretic peptides have been shown to improve survival and reduce symptoms, Inotropic agents are reserved for acute signs and symptoms of HF and are used mostly in the inpatient setting. Drugs that may precipitate or exacerbate HF, such as nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, nondihydropyridine calcium channel blockers, and some antiarrhythmic drugs, should be avoided if possible.

 

III. INHIBITORS OF THE RENIN ANGIOTENSIN ALDOSTERONE SYSTEM

The compensatory activation of the RAAS in HF leads to an increased workload on the heart and a resultant decline in cardiac function. Therefore, inhibition of the RAAS is an important pharmacological target in the management of HF.

 

A. Angiotensin-converting enzyme inhibitors

Angiotensin-converting enzyme (ACE) inhibitors are a part of standard pharmacotherapy in HFrEF. These drugs block the enzyme that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II. They also diminish the inactivation of bradykinin (Figure 4).

 

1. Actions: ACE inhibitors decrease vascular resistance (afterload) and venous tone (preload), resulting in increased cardiac output. ACE inhibitors also blunt the usual angiotensin II mediated increase in epinephrine and aldosterone seen in HF. ACE inhibitors improve clinical signs and symptoms of HF and have been shown to significantly improve patient survival in HF.

 

2. Therapeutic use: ACE inhibitors may be considered for patients with asymptomatic and symptomatic HFrEF. Importantly, ACE inhibitors are indicated for patients with all stages of left ventricular failure. These agents should be started at low doses and titrated to target or maximally tolerated doses in the management of HFrEF.

ACE inhibitors are also used in the treatment of hypertension (see Chapter 16). Patients who have had a recent myocardial infarction or are at high risk for a cardiovascular event also benefit from long-term ACE inhibitor therapy.

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3. Pharmacokinetics: ACE inhibitors are adequately absorbed following oral administration. Food may decrease the absorption of captopril, so it should be taken on an empty stomach. Except for captopril and injectable enalapril, ACE inhibitors are prodrugs that require activation by hydrolysis via hepatic enzymes. Renal elimination of the active moiety is important for most ACE inhibitors except fosinopril, which also undergoes fecal excretion. Plasma half-lives of active compounds vary from 2 to 12 hours, although the inhibition of ACE may be much longer.

4. Adverse effects: These include postural hypotension, renal insufficiency, hyperkalemia, a persistent dry cough, and angioedema (rare). Because of the risk of hyperkalemia, potassium levels must be monitored, particularly with concurrent use of potassium supplements, potassium-sparing diuretics, or aldosterone antagonists. Serum creatinine levels should also be monitored, particularly in patients with underlying renal disease. The potential for symptomatic hypotension with ACE inhibitors is much more common if used concomitantly with a diuretic. ACE inhibitors are teratogenic and should not be used in pregnant women. Please see Chapter 16 for a full discussion of ACE inhibitors.

Figure 4:- Effects of ACE inhibitors. {Note: The reduced retention of sodium and water results from two causes;  decreased production of angiotensin II and aldosterone.} 

 

B. Angiotensin receptor blockers

Angiotensin receptor blockers (ARBs) are orally active compounds that are competitive antagonists of the angiotensin II type 1 receptor. Because ACE inhibitors inhibit only one enzyme responsible for the production of angiotensin II, ARBs have the advantage of more complete blockade of the actions of angiotensin II. However, ARBs do not affect bradykinin levels. Although ARBs have actions similar to those of ACE inhibitors, they are not therapeutically identical. Even so, ARBs are a substitute for patients who cannot tolerate ACE inhibitors.

 

1. Actions: Although ARBs have a different mechanism of action than ACE inhibitors, their actions on preload and afterload are similar. Their use in HF is mainly as a substitute in patients who cannot tolerate ACE inhibitors due to cough or angioedema, which are thought to be mediated by elevated bradykinin levels. ARBS are also used in the treatment of hypertension (see Chapter 16).

 

2. Pharmacokinetics: ARBs are orally active and are dosed once daily, with the exception of valsartan [val-SAR-tan], which is dosed twice daily. They are highly plasma protein bound. Losartan [loe-SAR-tan) differs in that it undergoes extensive first-pass hepatic metabolism, including conversion to an active metabolite. The other drugs have inactive metabolites. Elimination of metabolites and parent compounds occurs in urine and feces.

 

3. Adverse effects: ARBs have an adverse effect and drug interaction profile similar to that of ACE inhibitors. However, the ARBs have a lower incidence of cough and angioedema. Like ACE inhibitors, ARBs are contraindicated in pregnancy.

 

C. Aldosterone receptor antagonists

Patients with HF have elevated levels of aldosterone due to angiotensin II stimulation and reduced hepatic clearance of the hormone. Spironolactone [spir-ON-oh-LAK-tone] and eplerenone [ep-LER-e-none] are antagonists of aldosterone at the mineralocorticoid receptor, thereby preventing salt retention, myocardial hypertrophy, and hypokalemia. Spironolactone also has affinity for androgen and progesterone receptors and is associated with endocrine-related adverse effects such as gynecomastia and dysmenorrhea. Aldosterone antagonists are indicated in patients with symptomatic HFrEF or HFrEF and recent myocardial infarction.

 

IV. B-BLOCKERS

Although it may seem counterintuitive to administer drugs with negative inotropic activity in HF, evidence clearly demonstrates improved systolic function and reverses cardiac remodeling in patients receiving ẞ-blockers. These benefits arise in spite of an occasional, initial exacerbation of symptoms. The benefit of ẞ-blockers is attributed, in part, to their ability to prevent the changes that occur because of chronic activation of the sympathetic nervous system. These agents decrease heart rate and inhibit release of renin in the kidneys. In addition, ẞ-blockers prevent the effects of norepinephrine on the cardiac muscle fibers, decreasing remodeling, hypertrophy, and cell death. Three ẞ-blockers have shown benefit in HFrEF: bisoprolol, carvedilol, and long-acting metoprolol succinate. Carvedilol is a nonselective ẞ-adrenoreceptor antagonist that also blocks a-adrenoreceptor, whereas bisoprolol and metoprolol succinate are ẞ₁-selective antagonists. [Note: The pharmacology of ẞ-blockers is described in detail in Chapter 7.] ẞ-Blockade is recommended for all patients with chronic, stable HFrEF. Bisoprolol, carvedilol, and meto-prolol succinate reduce morbidity and mortality associated with HFrEF. Treatment should be started at low doses and gradually titrated to target doses based on patient tolerance and vital signs. Both carvedilol and metoprolol are metabolized by the cytochrome P450 2D6 isoenzyme, and inhibitors of this metabolic pathway may increase levels of these drugs and increase the risk of adverse effects. In addition, carvedilol is a substrate of P-glycoprotein (P-gp). Increased effects of carvedilol may occur if it is coadministered with P-gp inhibitors. B-blockers should also be used with caution with other drugs that slow AV conduction, such as amiodarone, verapamil, and diltiazem.

 

V. DIURETICS

Diuretics reduce signs and symptoms of volume overload, such as dyspnea on exertion, orthopnea, and peripheral edema. They decrease plasma volume and, subsequently, decrease venous return to the heart (preload), decreasing cardiac workload and oxygen demand. Diuretics may also decrease afterload by reducing plasma volume, thereby decreasing blood pressure. Loop diuretics are the most commonly used diuretics in HF. These agents are used for patients who require extensive venous.

 

Conclusion:

Heart failure (HF) is a complex and progressive condition that impairs the heart’s ability to effectively pump blood. It is driven by a cycle of compensatory physiological mechanisms that, while initially beneficial, ultimately contribute to further cardiac dysfunction. Understanding the underlying pathophysiology of HF, including the role of neurohormonal activation, myocardial remodeling, and fluid retention, is crucial for developing effective treatment strategies. Pharmacologic interventions, such as ACE inhibitors, beta-blockers, aldosterone antagonists, and diuretics, play a vital role in managing symptoms, slowing disease progression, and improving survival. Properly tailored therapy, lifestyle modifications, and early intervention remain key in enhancing patient outcomes and mitigating the burden of heart failure.

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