ATLANTA — Stubbornly refractory hypertension can be approached with a number of drug combinations and other novel treatments, Dr. Angela L. Brown said at a meeting sponsored by the International Society on Hypertension in Blacks.
The combination of a diuretic and an inhibitor of the renin-angiotensin-aldosterone system (RAAS) is probably the most popular choice, said Dr. Brown of Washington University, St. Louis. This combination makes physiological sense because the two classes of drugs have complementary modes of action—as the diuretic decreases fluid volume, the RAAS inhibitor decreases pulmonary vascular resistance. RAAS inhibitors also counteract the relative increase in blood pressure from diuretic-induced renin secretion. The combination is well tolerated and effective in low-renin populations and African Americans.
Another popular combination is an ACE inhibitor with a calcium channel blocker (CCB). The ACE inhibitor blocks the renin-angiotensin system, is effective in high-renin hypertension, works in all populations—especially whites, Hispanics, and young patients—and produces arterial and venous vasodilation. The CCB blocks the sympathetic nervous system, provides excellent efficacy, produces arterial vasodilation, is effective in low-renin hypertension, and works in all populations, particularly African Americans and the elderly.
Theoretical considerations suggest that an ACE inhibitor along with an angiotensin II receptor blocker (ARB) should also work, but studies have not shown enhanced blood pressure reduction, although the combination does result in significant reduction in proteinuria.
The combination of a dihydropyridine CCB (such as amlodipine, nifedipine, or isradipine) with a nondihydropyridine CCB, such as verapamil or diltiazem, may be more effective. The dihydropyridines are less likely to decrease cardiac output and may cause an acute reflux tachycardia. The nondihydropyridines lower the pulse rate and may have a negative inotropic affect. The nondihydropyridines also inhibit the cytochrome P450 system and slow metabolism of the dihydropyridine CCBs. There's good evidence that this combination decreases blood pressure, Dr. Brown said.
Two other treatments for refractory hypertension—insulin sensitizers or statins—take into account common comorbidities such as dyslipidemia and obesity.
Thiazolidinedione insulin sensitizers can bind to peroxisome proliferator-activated receptor gamma (PPARγ) in fat and muscle to lower insulin resistance. Studies have shown such receptors are also plentiful in the kidney, and that two mutations in the PPARγ gene are associated with severe hypertension in humans. Pioglitazone seems to result in significant decreases in systolic blood pressure in clinical trials.
The statins reduce cholesterol, are atheroprotective and stabilize atherosclerotic plaques, have antioxidative effects, reduce inflammation and thrombus formation, and improve endothelial function. A small study has now shown that statins can reduce the magnitude of angiotensin-induced increases in blood pressure.
Nitrates are effective for the acute treatment of severe hypertension and aortic dissection, but long-term use is hampered by tachyphylaxis and tolerance. Some studies have suggesed intermittent dosing of long-acting nitrates led to a decrease in the augmentation index of the reflected pulse wave, thus lowering systolic blood pressure.
Dr. Brown has received research support from GlaxoSmithKline and Novartis, is a consultant for Pfizer, and is on speakers' bureaus for five pharmaceutical companies. The meeting was cosponsored by the American Society of Hypertension.