Rationale For Drugs Treating Heart Failure

As mentioned earlier, many different classes of drugs have been tested clinically and preclinical^ in the treatment of HF. This section will review the different types of drugs that have been evaluated in the treatment of HF, starting with established agents (i.e., ACE inhibitors) and followed by more speculative agents. Older drugs [i.e., digoxin (9) and amiodorone (10)] that have been used extensively, but with few documented mortality benefits, will not be reviewed here.

Renin-Angiotensin - The activity of the renin-angiotensin system is elevated in patients with heart failure. Reduced cardiac output leads to renal hypoperfusion and to increased synthesis and release of renin into the circulation. Renin cleaves angiotensinogen to angiotensin I, and angiotensin converting enzyme (ACE) cleaves angiotensin I to angiotensin II (11 - 13). Increased production of angiotensin II has multiple physiological and biochemical actions. Angiotensin II binding to ATi receptors on smooth muscle cells causes contraction, vasoconstriction and increases peripheral vascular resistance, which deleteriously augments cardiac afterload (14). As a vasoconstrictor, angiotensin II causes hypertension that induces left ventricular remodeling and hypertrophy. Angiotensin II binding to cardiomyocyte ATi receptors directly stimulates hypertrophy leading to left ventricular enlargement, reduced myocyte contractility and reduced cardiac output (15, 16). Angiotensin II increases Na+ transport in the renal proximal tubule, and stimulates aldosterone secretion from the adrenal cortex (17). Increased levels of aldosterone promote Na+ and water retention producing increased cardiac preload and afterload, thereby diminishing cardiac performance. Thus, interruption of the renin-angiotensin system has been one of the most effective treatments for HF. This has been accomplished through the use of ACE inhibitors, angiotensin (AT-i) receptor antagonists and vasopeptidase inhibitors (ACE/NEP inhibitors).

ACE Inhibitors - A number of clinical trials have established the benefits of ACE inhibitors which improve cardiac function, and more importantly, reduce mortality compared to placebo. ACE inhibitors were originally designed for the treatment of hypertension, but the CONSENSUS trial in 1987 and SOLVD trial in 1991 with enalapril, and the SAVE trial with captopril showed that the drugs had significant benefits in the treatment of HF (18 - 20). Ten ACE inhibitors are presently listed in the 2000 Physician's Desk Reference (54th Edition, Medical Economics Company, Montvale, NJ), and the use of an ACE inhibitor as first-line treatment for HF is in the general practice. However, a recent review of the prescribing practices of physicians indicates that the full benefits of ACE inhibitors in HF may not yet have been achieved. It appears that ACE inhibitors are being under prescribed in HF, and when prescribed, the doses used to treat HF are often lower than those doses which showed benefits in the HF clinical trials (21, 22).

Angiotensin Receptor Blockers (ATi antagonists) - Like ACE inhibitors before them, ATi receptor antagonists have found their way from use as anti-hypertensive agents to use in the treatment of HF. ATi receptor antagonists were believed to offer an advantage over ACE inhibitors in the treatment of HF due to their lack of side effects, i.e., lack of the cough that is commonly encountered during the use of ACE inhibitors. The ELITE trial using losartan (1) in over 770 elderly patients suffering from systolic left ventricular dysfunction suggested that losartan had clinical benefits superior to the ACE inhibitor captopril in terms of both reduced mortality and reduced hospitalizations for those patients on i (23). However, when the study was repeated with a larger study population (ELITE II), these results were not replicated. In fact, there was a trend toward better benefit from the ACE inhibitor used than from 1 (24). As a result of this study, the use of ATi receptor antagonists in HF rather than ACE inhibitors has been questioned. However, studies are ongoing which are examining the potential additive benefit of using both ACE inhibitors and ATi blockers as combination therapy for HF (25). At present, there are five ATi receptor antagonists commercially available for hypertension [losartan (1), irbesartan (2), valsartan (3), eprosartan (4) and candesartan (5)], and should HF become an indication for this class of drug, one likely would view the class as highly competitive.

Atrial Natriuretic Peptides - During heart failure, atrial concentrations of atrial natriuretic peptides (ANPs) are increased (26). Atrial natriuretic peptides are synthesized and stored in specialized atrial cells, which are released into the circulation following atrial stretching (27). ANPs cause natriuresis and diuresis and promote vascular smooth muscle relaxation (28). They also reduce the production of renin, aldosterone and arginine vasopressin (29). All of these effects of the ANPs have the potential to decease blood pressure, blood volume and cardiac afterload. Atrial natriuretic peptides are inactivated by neutral endopeptidases. Thus, inhibition of these enzymes (NEP inhibitors) leads to an increase in the concentration of the ANPs, and this has been viewed as a new potential treatment of HF.

ACE/NEP Inhibitors (Vasopeptidase Inhibitors) - A very exciting second generation family of ACE inhibitors are the dual metalloprotease inhibitors (ACE/NEP or vasopeptidase inhibitors) such as omapatrilat (6) and sampatrilat (7) (30). These compounds are dual ACE and neutral endopeptidase (NEP) inhibitors. NEP hydrolyzes the vasorelaxant atrial natriuretic peptides (ANPs), and inhibition of NEP produces a more sustained effect from ANPs resulting in vasodilation. Recent reviews on vasopeptidase inhibitors have summarized the rationale and advances in the field (31 - 33). Most of the clinical study thus far has been done with omapatrilat (6, ACE ICso = 5 nM; NEP ICso = 8 nM) (34 - 36). The IMPRESS trial included over 570 patients with HF, and omapatrilat produced significant advantages over the potent ACE inhibitor lisinopril (37). These results have prompted another clinical trial (OVERTURE) which will examine the long-term effects of 6 in the treatment of HF in over 4000 patients. Because of its unique mechanism of action and excellent clinical results in hypertension and HF, 6 was granted priority review by the FDA, and it is anticipated that 6 will be launched sometime in 2000/2001. A second

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

Get My Free Ebook


Post a comment