Angiotensin Receptor Blockers

ARBs are another key class of agents whose role in managing patients with hypertension has been further defined by recently completed studies. ARBs are inhibitors of the angiotensin-1 (ATI) receptors (Fig. 5-3). ATI receptor stimulation evokes a pressor response via a host of accompanying effects on catecholamines, aldosterone, and thirst. Consequently, inhibition of ATI receptors directly prevents this pressor response and results in up-regulation of the RAAS. Up-regulation of the RAAS results in elevated levels of angiotensin II, which have the added effect of stimulating the angiotensin-2 (AT2) receptors. AT2-receptor stimulation is generally associated with antihypertensive activity; however, long-term effects of AT2-receptor stimulation that involve cellular growth and repair are relatively unknown. What is clear is that ARBs differ from ACE inhibitors in that the former causes up-regulation of the RAAS while the latter blocks the breakdown of bradykinin. The therapeutic relevance resulting from these pharmacologic differences has yet to be fully evaluated through long-term clinical comparative trials in hypertensive patients. However, data from other patient populations (heart failure, high-risk coronary artery disease patients) suggest that the clinical benefits of ARBs are less robust than those of ACE inhibitors.81,

At this point, ARBs have emerged as an effective class of antihypertensives whose low incidence of side effects and demonstrated clinical role in patients with specific comorbidities have afforded them an attractive position in the antihypertensive armamentarium. Like ACE inhibitors, the antihypertensive effectiveness of ARBs is greatly enhanced by combining them with diuretics. Furthermore, they have proven their value as well-tolerated alternatives to ACE inhibitors for patients with CKD, diabetes mellitus, and post-AMI (Table 5-5). As of late, the addition of ARBs to standard therapy for patients with heart failure (HF), including ACE inhibitors, have demon-

strated additional incremental benefits for patients with systolic dysfunction or dia-

stolic dysfunction or as alternatives to ACE inhibitors when ACE inhibitors are 85

not tolerated. Comparative studies with alternate (non-ACE inhibitors) antihyper-

84 52

tensive regimens in patients with type 2 diabetes and left ventricular hypertrophy have demonstrated their usefulness as effective antihypertensives in these special populations. Studies (the Irbesartan Diabetic Nephropathy Trial [IDNT] and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL; NIDDM refers to noninsulin-dependent diabetes mellitus]) have demonstrated superiority of delaying progression toward renal dysfunction for ARBs relative to alternat-

ive antihypertensives in type 2 diabetics. Although better tolerated than ACE inhibitors, ARBs have not been shown to demonstrate superiority of outcomes relative to ACE inhibitors. This key observation, in addition to their relatively higher acquisition cost, has mitigated the growth of ARB use relative to ACE inhibitors.

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