Drugs for Heart Failure



Drugs for Heart Failure



Classification of Drugs for Heart Failure







aDigoxin immune Fab is an antidote for severe digoxin toxicity.


bAlso lisinopril (PRINIVIL), ramipril (ALTACE), and others.


cAlso candesartan (ATACAND) and others.


dAlso bisoprolol (ZEBETA), metoprolol (LOPRESSOR), and others.


eAlso torsemide (DEMADEX) and bumetanide.




Overview


In the United States, heart failure affects nearly 5 million individuals, is the primary cause of more than 40,000 deaths per year, and is a contributing factor in an additional 220,000 deaths. The overall mortality rate in patients with heart failure is about eight times as high as that in the normal population, and the 5-year mortality rate for patients with heart failure approaches 50%.



Pathophysiology of Heart Failure


Heart failure is the end stage of a number of cardiovascular disorders that ultimately impair the ability of the ventricle to fill with blood or to eject blood into the circulation. Ischemic heart disease is the most common cause of heart failure. Other important causes of heart failure include hypertension, valvular disorders, arrhythmias, viral and congenital cardiomyopathy, and constrictive pericarditis. Less commonly, heart failure results from severe anemia, thiamine deficiency, or the use of certain anticancer drugs, such as doxorubicin (see Chapter 45). Over time, these disorders produce molecular and cellular changes in cardiac myocytes and connective tissue that lead to a series of structural and functional alterations in the ventricular wall. This process, known as cardiac or ventricular remodeling, is characterized by cardiac dilatation, ventricular wall thinning, interstitial fibrosis, and wall stiffness. These changes impair the ability of the heart to relax or contract.


Cardiac remodeling is believed to result primarily from the activation of neuroendocrine systems in response to myocardial ischemia, excessive stretch of muscle fibers, or other pathologic stimuli. The neuroendocrine systems implicated in this process include the renin-angiotensin-aldosterone axis, the sympathetic nervous system, various inflammatory cytokines, and local mediators such as endothelin. These mediators activate biochemical pathways that induce myocyte hypertrophy, apoptosis, collagen production, fibrosis, and other effects that lead to cardiac remodeling and loss of ventricular function. For example, angiotensin II, which is formed locally in the myocardium in response to mechanical stretch and other stimuli, can induce collagen production and proliferation of fibroblasts. Chronic sympathetic nervous system stimulation of the injured myocardium produces myocyte hypertrophy, increases production of myocardial cytokines (e.g., tumor necrosis factor α), and ultimately leads to myocyte death via activation of apoptotic pathways.


The hallmark of heart failure is a reduction in stroke volume and cardiac output at any given diastolic muscle fiber length, as determined by measuring the ventricular end-diastolic pressure (preload). The reduced stroke volume can be caused by diastolic dysfunction or systolic dysfunction and is manifested as an inability of the ventricles either to fill properly or to empty properly, respectively. Systolic dysfunction can result from decreased cardiac contractility secondary to a dilated or ischemic myocardium. Diastolic dysfunction can result from decreased compliance (increased stiffness) of ventricular tissue secondary to left ventricular hypertrophy or fibrosis. Hence, both systolic and diastolic heart failure can be caused or exacerbated by the process of cardiac remodeling.


In cases of left ventricular failure (left-sided heart failure), the left ventricle does not adequately pump blood forward, so the pressure in the pulmonary circulation increases. When the increased pressure forces fluid into the lung interstitium, this causes congestion and edema (Fig. 12-1). Pulmonary edema reduces the diffusion of oxygen and carbon dioxide between alveoli and the pulmonary capillaries. This causes hypoxemia (deficient oxygenation of the blood) and can lead to dyspnea (difficulty in breathing), including exertional dyspnea (dyspnea provoked by exercise), orthopnea (intensified dyspnea when lying flat), and paroxysmal nocturnal dyspnea (edema-induced bronchoconstriction when sleeping).


image
FIGURE 12-1 Pathophysiology and treatment of heart failure. ACE, Angiotensin-converting enzyme.

The combination of edema-related hypoxemia and the heart’s failure to pump sufficient blood to adequately perfuse the tissues can lead to generalized tissue hypoxia and organ dysfunction. For this reason, patients with heart failure often experience symptoms of weakness and fatigue and have reduced exercise capacity.


In cases of right ventricular failure (right-sided heart failure), congestion in the peripheral veins leads to ankle edema in the ambulatory patient and to sacral edema in the bedridden patient. It also leads to hepatojugular reflux, characterized by an increase in jugular vein distention when pressure is applied over the liver. Ultimately, right-sided failure can lead to left-sided failure as the left ventricle is forced to work harder in an attempt to maintain cardiac output.


The reduction in cardiac output that occurs in heart failure triggers a cascade of compensatory neuroendocrine responses. Although these responses attempt to restore cardiac output via the Frank-Starling mechanism (see Fig. 12-1), they are often maladaptive and counterproductive. The reduction in tissue perfusion activates both the sympathetic nervous system and the renin-angiotensin-aldosterone system, both of which in turn stimulate vasoconstriction. Arterial vasoconstriction increases aortic impedance to left ventricular ejection and thereby decreases cardiac output, especially in patients with a weak, dilated heart. When angiotensin II stimulates the secretion of aldosterone and antidiuretic hormone, this increases the amount of sodium and water retention, the plasma volume, and the venous pressure. In addition, angiotensin II and sympathetic activation lead to cardiac remodeling and ventricular wall thinning or fibrosis, which often reduce systolic and diastolic function. Hence, the net result of the neuroendocrine responses is often a further reduction in cardiac output and an increase in circulatory congestion.



Mechanisms and Effects of Drugs for Heart Failure


The primary goals of drug therapy for heart failure are to improve symptoms, slow or reverse deterioration in myocardial function, and prolong survival. Drugs can also be used to treat underlying conditions, control arrhythmias, prevent thrombosis, and treat anemia.


The pharmacologic agents used to treat heart failure include drugs that (1) increase cardiac output, (2) reduce pulmonary and systemic congestion, and (3) slow or reverse cardiac remodeling. Cardiac output can be increased by positively inotropic drugs that increase cardiac contractility and by vasodilators that reduce cardiac afterload and the impedance to left ventricular ejection. Vasodilators also reduce venous pressure, circulatory congestion, and edema. Diuretics are used to mobilize edematous fluid and reduce plasma volume, thereby decreasing circulatory congestion. Angiotensin and sympathetic inhibitors have been shown to favorably influence cardiac remodeling and increase survival in persons with heart failure.


Table 12-1 compares the cardiovascular effects of drugs discussed in this chapter. Each of these drugs partly counteracts the loss of myocardial function and the maladaptive responses that occur during heart failure; however, none of the current therapies, either alone or in combination, has been completely satisfactory. Because heart failure has such a high incidence and poor prognosis, a much greater effort has been expended in the search for better means to treat it. The most significant development in recent decades has been the use of angiotensin inhibitors, β-adrenoceptor blockers, and other agents that attenuate cardiac remodeling and reduce the mortality rate in patients with heart failure. Ultimately, however, the successful treatment of patients with heart failure may require the development of drugs that activate genes capable of repairing or replacing myocardial tissue.



TABLE 12-1


Cardiovascular Effects of Drugs Used in the Treatment of Heart Failure*





















































































DRUG CARDIAC CONTRACTILITY HEART RATE PRELOAD REDUCTION AFTERLOAD REDUCTION RISK OF ARRHYTHMIA OTHER EFFECTS
Digoxin + − ++ 0 to + ++ Increases parasympathetic tone and decreases sympathetic tone
Dobutamine ++ + to ++ 0 to + + to ++ + to ++ Increases blood pressure
Milrinone + 0 to ++ ++ ++ ++  
ACE inhibitors 0 0 ++ ++ 0 Reduces blood pressure
Hydralazine 0 + (R) 0 ++ + Reduces blood pressure
Isosorbide dinitrate 0 + (R) ++ + 0 Reduces pulmonary congestion
Nesiritide 0 0 to + (R) ++ ++ 0 Reduces venous and arterial blood pressure
Loop-acting diuretics (furosemide and others) 0 0 + 0 0 Reduces edema and congestion
Carvedilol 0 0 to − 0 + 0 Blocks α- and β-adrenoceptors


image


ACE, Angiotensin converting enzyme.


*Effects are indicated as follows: decrease (−); no change or variable (0); increase ranging from small (+) to large (++); and reflex (R).



Positively Inotropic Drugs


Derived from the Greek words for “fiber” (inos) and “turning” or “to turn” (tropikos), the term inotropic refers to a change in muscle (fiber) contractility. Drugs that increase cardiac contractility are said to have a positive inotropic effect and are commonly referred to as inotropic drugs or agents. The inotropic agents most often used in the treatment of heart failure are the digitalis glycoside called digoxin, the β-adrenoceptor agonist known as dobutamine, and a phosphodiesterase inhibitor named milrinone. These drugs increase cardiac contractility by increasing calcium levels in cardiac myocytes. Dobutamine and milrinone increase calcium influx by increasing intracellular cyclic adenosine monophosphate (cAMP) levels, either by stimulating cAMP formation by adenylyl cyclase (dobutamine) or by inhibiting cAMP breakdown by phosphodiesterase (milrinone). The mechanism by which digoxin increases calcium levels is described later.



Digoxin


Despite the fact that the digitalis glycosides such as digoxin have been used to treat heart failure for more than 200 years, their effectiveness and place in therapy have been difficult to establish. Recent clinical trials indicate that digoxin provides a definite, yet limited, benefit to patients with heart failure caused by systolic dysfunction.



Drug Properties


Many digitalis glycosides have been isolated from plant and animal sources, including the leaves of Digitalis (foxglove) plants and the skin secretions of certain toads. Digoxin is the only digitalis glycoside that is extensively used today, having replaced digitoxin and crude digitalis leaf preparations in the treatment of heart failure and other cardiac disorders.



Chemistry and Pharmacokinetics

The digitalis glycosides are composed of a steroid nucleus, a lactone ring, and three sugar residues linked by glycosidic bonds. The stereochemical configuration of the steroid nucleus of digitalis glycosides is different from that of human steroids, and the digitalis glycosides lack most of the effects produced by gonadal or adrenal steroids.


As shown in Table 12-2, digoxin is adequately absorbed from the gut and has a long half-life of about 36 hours. It is primarily eliminated by renal excretion of the parent compound. Because digoxin has a low therapeutic index, serum concentrations are useful in assessing the adequacy of the dosage and evaluating potential toxicity and should be in the range of 0.5 to 2 ng/mL.



TABLE 12-2


Pharmacokinetic Properties of Positively Inotropic Drugs*





































DRUG ORAL BIOAVAILABILITY ONSET OF ACTION DURATION OF ACTION ELIMINATION HALF-LIFE EXCRETED UNCHANGED IN URINE THERAPEUTIC SERUM LEVEL
Digoxin 75% 1 hr 24 hr 36 hr 60% 0.5-2 ng/mL
Dobutamine NA 1 min <10 min 2 min 0% NA
Milrinone NA 3 min Variable 4 hr 60% NA
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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Drugs for Heart Failure

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