ACE antagonists

FIGURE 9.20 Design of multiple ligancl activity, (a) Dual histamine HI receptor and leukotriene receptor antagonist incorporating known antihistaminic properties of cyproheptadine and LTD4. (b) Joint ACE/NEP inhibitor formed from incorporating similarities in substrate structures for both enzymes. From [57],... 

ACE inhibitors inhibit the degradation of bradykinin and potentiate the effects of bradykinin by about 50-100-fold. The prevention of bradykinin degradation by ACE inhibitors is particularly protective for the heart. Increased bradykinin levels prevent postischemic reperfusion arrhythmia, delays manifestations of cardiac ischemia, prevents platelet aggregation, and probably also reduces the degree of arteriosclerosis and the development of cardiac hypertrophy. The role of bradykinin and bradykinin-induced NO release for the improvement of cardiac functions by converting enzyme inhibitors has been demonstrated convincingly with use of a specific bradykinin receptor antagonist and inhibitors of NO-synthase. 

In the treatment of hypertension, ACE inhibitors are as effective as diuretics, (3-adrenoceptor antagonists, or calcium channel blockers in lowering blood pressure. However, increased survival rates have only been demonstrated for diuretics and (3-adrenoceptor antagonists. ACE inhibitors are approved for monotherapy as well as for combinational regimes. ACE inhibitors are the dtugs of choice for the treatment of hypertension with renal diseases, particularly diabetic nephropathy, because they prevent the progression of renal failure and improve proteinuria more efficiently than the other diugs. 

AT r-antagonists Hyperkalemia (less frequent compared with ACE inhibitors)... 

ACE inhibitors - AT antagonists - Alpha blockers - Beta blockers Isolated syslolic hypertension (older patienls) - Diuretics preferred (generally Thiazides) - Long-acting dihydropyridine calcium channel blocker... 

In clinical trials, ATI antagonists have proven to be as effective as ACE inhibitors in hypertension, congestive heart failure, and renal failure [3]. The favorable side effect profile of ATI antagonists argues for a greater use of these diugs. At present, due to still higher costs, they are indicated in patients who do not tolerate ACE inhibitor treatment. 

ACE inhibitors do not completely block aldosterone synthesis. Since this steroid hormone is a potent inducer of fibrosis in the heart, specific antagonists, such as spironolactone and eplerenone, have recently been very successfully used in clinical trials in addition to ACE inhibitors to treat congestive heart failure [5]. Formerly, these drugs have only been applied as potassium-saving diuretics in oedematous diseases, hypertension, and hypokalemia as well as in primary hyperaldosteronism. Possible side effects of aldosterone antagonists include hyperkalemia and, in case of spironolactone, which is less specific for the mineralocorticoid receptor than eplerenone, also antiandrogenic and progestational actions. 

ACE-I, angiotensin-converting enzyme inhibitor Aid Ant, aldosterone antagonist ARB, angiotensin receptor blocker BB, beta-blocker CCBA, calcium channel blocking agent DirVaso, direct vasodilator. 

P-Blockers and ACE inhibitors are also indicated for post-myocardial infarction for the reduction of cardiovascular morbidity and mortality, as are aldosterone antagonists, in post-myocardial infarction patients with reduced left ventricular systolic function and diabetes or signs and symptoms of heart failure.2,48... 

Patients with asymptomatic left ventricular systolic dysfunction and hypertension should be treated with P-blockers and ACE inhibitors. Those with heart failure secondary to left ventricular dysfunction and hypertension should be treated with drugs proven to also reduce the morbidity and mortality of heart failure, including P-blockers, ACE inhibitors, ARBs, aldosterone antagonists, and diuretics for symptom control as well as antihypertensive effect. In African-Americans with heart failure and left ventricular systolic dysfunction, combination therapy with nitrates and hydralazine not only affords a morbidity and mortality benefit, but may also be useful as antihypertensive therapy if needed.66 The dihydropyridine calcium channel blockers amlodipine or felodipine may also be used in patients with heart failure and left ventricular systolic dysfunction for uncontrolled blood pressure, although they have no effect on heart failure morbidity and mortality in these patients.49 For patients with heart failure and preserved ejection fraction, antihypertensive therapies that should be considered include P-blockers, ACE inhibitors, ARBs, calcium channel blockers (including nondihydropyridine agents), diuretics, and others as needed to control blood pressure.2,49... 

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