DIURETICS
Among the first orally effective
drugs to become available, diuretics are being used even more frequently
because their effectiveness has been reiterated and, with lower doses, their
side effects minimized. However, concerns have been raised about potential
long-term disadvantages and the current choices of diuretics.
Diuretics differ in structure and
major site of action within the nephron (Fig. 7-1). The site of action
determines their relative efficacy, as expressed in the maximal percentage of
filtered sodium chloride excreted (Brater, 2000). Agents acting in the proximal
tubule (site I) are seldom used to treat hypertension.
Treatment is usually initiated with a thiazide-type diuretic (acting at site III, the distal convoluted tubule). Chlorthalidone and indapamide are structurally different from, but still related to, the thiazides and will be covered with them. If renal function is significantly impaired (i.e., serum creatinine exceeding 1.5 mg/dL), a loop diuretic (acting at site II, the thick ascending limb of the loop of Henle) or metolazone likely will be needed. A potassium-sparing agent (acting at site IV) may be given with the diuretic to reduce the likelihood of hypokalemia. By themselves, potassium-sparing agents are relatively weak antihypertensives.
ANGIOTENSIN-CONVERTING ENZYME
INHIBITORS
There are four ways to reduce the
activity of the reninangiotensin system in humans (Fig. 7-12). The first way,
the use of β-blockers to reduce renin release from the juxtaglomerular (J-G)
cells, has been covered. The second way, direct inhibition of the activity of
renin, has recently become clinically feasible. The third way is to inhibit the
activity of the angiotensin-converting enzyme (ACE), which converts the
inactive decapeptide angiotensin I (AI) to the potent hormone angiotensin II
(AII); i.e., ACEIs. The fourth way is to use a competitive antagonist that
attaches to the AII receptors and blocks the attachment of the native hormone,
i.e., angiotensin receptor blockers (ARBs). Multiple ARBs are now available and
all remain patent-protected. Nonetheless, their higher cost seems not to have
slowed their acceptance.
Multiple studies have documented an
equal antihypertensive efficacy between the multiple ACEIs and ARBs now
available with no consistent differences in the outcomes associated with their
use (Matchar et al., 2008).
Using data from 26 large-scale trials, the Blood Pressure Trialist (2007) conclude that “there are similar blood pressure-dependent effects of ACEI and ARB for the risks of stroke, CHD, and heart failure. For ACEI, but not for ARB, there is evidence of blood pressure-independent effects [of approximately 9%] on the risk of major coronary disease events.” In an even more recent meta-analysis, ACEIs and ARBs were equally protective against MI and mortality, but ARBs had an 8% lower incidence of strokes (Reboldi et al., 2008).
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