Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics

Abstract

Thiazide and thiazide-like diuretics are among the most commonly used antihypertensives and have been available for over 50 years. However, the mechanism by which these drugs chronically lower blood pressure is poorly understood. Possible mechanisms include direct endothelial- or vascular smooth muscle-mediated vasodilation and indirect compensation to acute decreases in cardiac output. In addition, thiazides are associated with adverse metabolic effects, particularly hyperglycemia, and the mechanistic underpinnings of these effects are also poorly understood. Thiazide-induced hypokalemia, as well as other theories to explain these metabolic disturbances, including increased visceral adiposity, hyperuricemia, decreased glucose metabolism and pancreatic β-cell hyperpolarization, may play a role. Understanding genetic variants with differential responses to thiazides could reveal new mechanistic candidates for future research to provide a more complete understanding of the blood pressure and metabolic response to thiazide diuretics.

Distinct effects of fixed combinations of valsartan with either amlodipine or hydrochlorothiazide on lipoprotein subfraction profile in patients with hypertension

“…22 Also, thiazides were associated with an adverse impact on insulin resistance. 21 These effects have been proved dose-dependent and the 12.5 mg per day of hydrochlorothiazide used in this study has been considered as likely to avoid metabolic disturbances. 21,23 On the other hand, drugs acting on the renin --angiotensin --aldosterone system, including angiotensin-converting enzyme inhibitors and ARBs, may beneficially modify the lipid profile.…”

“…21 These effects have been proved dose-dependent and the 12.5 mg per day of hydrochlorothiazide used in this study has been considered as likely to avoid metabolic disturbances. 21,23 On the other hand, drugs acting on the renin --angiotensin --aldosterone system, including angiotensin-converting enzyme inhibitors and ARBs, may beneficially modify the lipid profile. Benazepril alone or in combination with amlodipine significantly increased HDL-C levels and decreased lipoprotein (a) levels compared with amlodipine monotherapy in 27 patients with type 2 diabetes after 36 weeks of treatment.…”

“…20 Thiazides increase TG levels and VLDL-C, along with significant increases in total cholesterol and LDL-C levels, by mechanisms that are poorly understood. 15,21 For example, in 1139 Chinese hypertensive patients newly prescribed antihypertensive drugs, thiazide use was associated with increased risk for high total cholesterol levels (X6.2 mmol l À1 or 240 mg dl À1 ) compared with ARBs (odds ratio 3.670, 95% confidence intervals, 1.134 --11.876, P ¼ 0.030) after 4 --16 weeks of treatment. 22 Also, thiazides were associated with an adverse impact on insulin resistance.…”

Possible interactions between garlic and conventional drugs: a review

“…38 It will increase the bioavailability and half-life of hydrochlorothiazide along with a decrease in the clearance and elimination rate constant. The renal damage as evident from the findings of the study could be attributed to the increased lipid peroxidation due to atorvastatin inhibit the metabolizing enzyme and P-glycoprotein by garlic.…”

Analytical Techniques for Determination of Hydrochlorothiazide and its Combinations: A Review

“…Thiazides are preferred in hypertensive patients with osteoporosis; Secondary beneficial effect in hypertensive geriatric patients of reducing the risk of osteoporosis secondary to effect on calcium homeostasis and bone mineralization. Thiazide diuretics used in patients who are at an increased risk for developing hyperkalemia [1]. Thiazides achieve their diuretic action via inhibition of the Na + /Cl − cotransporter (NCC) in the renal distal convoluted tubule [2][3][4].…”