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Their primary mode of action is inhibition of the renin angiotensin aldosterone system, but they also inhibit bradykinin degradation, stimulate the synthesis of vasodilating prostaglandins and, sometimes, reduce sympathetic nervous system activity These latter actions may explain why they exhibit some effect even in patients with low plasma renin activity ACE inhibitors appear to be more effective in younger white patients They are relatively less effective in blacks and older persons and in predominantly systolic hypertension Although as single therapy they achieve adequate antihypertensive control in only about 40 50% of patients, the combination of an ACE inhibitor and a diuretic or calcium channel blocker is potent ACE inhibitors are the agents of choice in persons with type 1 diabetes with frank proteinuria or evidence of renal dysfunction because they delay the progression to end-stage renal disease Many authorities have expanded this indication to include persons with type 2 diabetes and those who have type 1 diabetes with microalbuminuria, even when they do not meet the usual criteria for antihypertensive therapy ACE inhibitors may also delay the progression of nondiabetic renal disease The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that the ACE inhibitor ramipril reduced the number of cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes and also reduced the incidence of new-onset heart failure, renal dysfunction, and new-onset diabetes in a population of patients at high risk for vascular events Although this was not specifically a hypertensive population, the benefits were associated with a modest reduction in blood pressure, and the results inferentially support the use of ACE inhibitors in similar hypertensive patients ACE inhibitors are a drug of choice (usually in conjunction with a diuretic and a -blocker) in patients with congestive heart failure and are indicated also in asymptomatic patients with reduced ejection fraction An advantage of the ACE inhibitors is their relative freedom from troublesome side effects Severe hypotension can occur in patients with bilateral renal artery stenosis; acute renal failure may ensue but is usually reversible with discontinuation of ACE inhibition Hyperkalemia may develop in patients with intrinsic renal disease and type IV renal tubular acidosis (commonly seen in diabetics) and in the elderly A chronic dry cough is common, seen in 10% of patients or more, and may require stopping the drug Skin rashes are observed with any ACE inhibitor Angioedema is an uncommon but potentially dangerous side effect of all agents of this class because of their inhibition of kininase Exposure of the fetus to ACE inhibitors during the second and third trimesters of pregnancy has been associated with a variety of defects due to hypotension and reduced renal blood flow.

Spironolactone and eplerenone are natriuretic in sodiumretaining states, such as heart failure and cirrhosis, but only very weakly so in hypertension These drugs have reemerged in the treatment of hypertension, particularly in resistant patients and are helpful additions to most other antihypertensive medications Consistent with the increasingly appreciated importance of aldosterone in essential hypertension, the aldosterone receptor blockers are effective at lowering blood pressure in all hypertensive patients regardless of renin level, and are also effective in blacks Aldosterone plays a central role in target organ damage, including the development of ventricular and vascular hypertrophy and renal fibrosis Aldosterone receptor antagonists ameliorate these consequences of hypertension, to some extent independently of effects on blood pressure Spironolactone can cause breast pain and gynecomastia in men through activity at the progesterone receptor, an effect not seen with the more specific eplerenone Hyperkalemia is a problem with both drugs, chiefly in patients with chronic kidney disease

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These agents act by causing peripheral vasodilation but with less reflex tachycardia and fluid retention than other vasodilators They are effective as single-drug therapy in approximately 60% of patients in all demographic groups and all grades of hypertension (Table 11 9) For these reasons, they may be preferable to -blockers and ACE inhibitors in blacks and older persons Verapamil and diltiazem should be combined cautiously with -blockers because of their potential for depressing AV conduction and sinus node automaticity as well as contractility

A growing body of data indicates that ARBs can improve cardiovascular outcomes in patients with hypertension as well as in patients with related conditions such as heart failure and type 2 diabetes with nephropathy ARBs have not been compared with ACE inhibitors in randomized controlled trials in patients with hypertension, but two trials comparing losartan with captopril in heart failure and post-

Special Properties Cost of 30 Days Treatment (Average Dosage)1 $6950 (120 mg twice daily) $6150 (240 mg daily) $3450 (240 mg daily) $5327 (240 mg daily) $4680 (240 mg daily) ++ Peripheral Vasodilation ++ Cardiac Automaticity and Conduction Adverse Effects Edema, headache, bradycardia, GI disturbances, dizziness, AV block, congestive heart failure, urinary frequency Same as diltiazem but more likely to cause constipation and congestive heart failure

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