The exact mechanism of action for thiazide diuretics, including hydrochlorothiazide (HCTZ), is not completely understood. There appear to be several mechanisms, which include an acute diuretic effect as well as a chronic decrease in peripheral vascular resistance.1-5
The distal convoluted tubule in the kidney reabsorbs about 5-10% of the body’s filtered Na+.4,6,7 Thiazide diuretics inhibit sodium reabsorption by blocking the Na+/Cl-cotransporter in the distal convoluted tubule.8-11 Along with sodium excretion, there is a concomitant increase in water excretion leading to an acute response of reduced cardiac output and reduced blood pressure.4,12 Because of the dependence on renal filtration, thiazides may be less effective in patients with moderate-severe chronic kidney disease (GFR < 30 ml/min/1.73 M2).13,14
While the above mechanism lowers blood pressure initially, the kidney detects the decreased blood flow and reacts by stimulating the renin-angiotensin system.4,12 The resulting increase in angiotensin II induces vasoconstriction, increased peripheral vascular resistance, and increased blood pressure.4,12 In addition, angiotensin II stimulates the secretion of aldosterone from the adrenal cortex, which leads to increased renal sodium absorption and potassium excretion.4,12 Thus, extracellular volume and cardiac output levels are restored over a few weeks.4,12
Nevertheless, in those who respond to thiazide treatment, reduced blood pressure is sustained by a long-term reduction in peripheral vascular resistance.4,12,15 There are several theories of how thiazide-diuretics lead to this decrease in peripheral vascular resistance, but the exact mechanism is not fully understood.3,15,16 Some have suggested that HCTZ has direct vasodilatory actions on vascular endothelium or smooth muscle. Proposed mechanisms include inhibition of smooth muscle carbonic anhydrase as well as calcium desensitization. Others have suggested that the effect is indirect through a long-term vascular response to sodium and fluid loss.1,2,4,12,17
- Duarte JD, Cooper-DeHoff RM. Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics. Expert Rev Cardiovasc Ther 2010; 8 (6): 793-802.
- Freis ED, Reda DJ, Materson BJ. Volume (weight) loss and blood pressure response following thiazide diuretics. Hypertension 1988; 12 (3): 244-250.
- Pickkers P, Garcha RS, Schachter M, Smits P, Hughes AD. Inhibition of carbonic anhydrase accounts for the direct vascular effects of hydrochlorothiazide. Hypertension 1999; 33 (4): 1043-1048.
- Tamargo J, Segura J, Ruilope LM. Diuretics in the treatment of hypertension. Part 1: thiazide and thiazide-like diuretics. Expert Opin Pharmacother 2014; 15 (4): 527-547.
- Pickkers P, Hughes AD, Russel FG, Thien T, Smits P. Thiazide-induced vasodilation in humans is mediated by potassium channel activation. Hypertension 1998; 32 (6): 1071-1076.
- Reilly RF, Ellison DH. Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy. Physiol Rev 2000; 80 (1): 277-313.
- Seely JF, Dirks JH. Site of action of diuretic drugs. Kidney Int 1977; 11 (1): 1-8.
- Ellison DH, Velazquez H, Wright FS. Thiazide-sensitive sodium chloride cotransport in early distal tubule. Am J Physiol 1987; 253 (3 Pt 2): F546-554.
- Hropot M, Fowler N, Karlmark B, Giebisch G. Tubular action of diuretics: distal effects on electrolyte transport and acidification. Kidney Int 1985; 28 (3): 477-489.
- Wilson IM, Freis ED. Relationship between plasma and extracellular fluid volume depletion and the antihypertensive effect of chlorothiazide. Circulation 1959; 20: 1028-1036.
- Ali SS, Sharma PK, Garg VK, Singh AK, Mondal SC. The target-specific transporter and current status of diuretics as antihypertensive. Fundam Clin Pharmacol 2012; 26 (2): 175-179.
- van Brummelen P, Man in 't Veld AJ, Schalekamp MA. Hemodynamic changes during long-term thiazide treatment of essential hypertension in responders and nonresponders. Clin Pharmacol Ther 1980; 27 (3): 328-336.
- Bennett WM, McDonald WJ, Kuehnel E, Hartnett MN, Porter GA. Do diuretics have antihypertensive properties independent of natriuresis? Clin Pharmacol Ther 1977; 22 (5 Pt 1): 499-504.
- KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl (2011) 2013; 3 (1): i-150.
- Zhu Z, Zhu S, Liu D, Cao T, Wang L, Tepel M. Thiazide-like diuretics attenuate agonist-induced vasoconstriction by calcium desensitization linked to Rho kinase. Hypertension 2005; 45 (2): 233-239.
- Colas B, Slama M, Collin T, Safar M, Andrejak M. Mechanisms of methyclothiazide-induced inhibition of contractile responses in rat aorta. Eur J Pharmacol 2000; 408 (1): 63-67.
- Tobian L. Why do thiazide diuretics lower blood pressure in essential hypertension? Annu Rev Pharmacol 1967; 7: 399-408.