The exact mechanism of action for thiazide diuretics, including chlorthalidone, 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+.5,6 Thiazide diuretics inhibit sodium reabsorotion by blocking the the Na+/Cl- cotransporter in the distal convoulted tubule.7-9 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.5,10 Due to renal filtration dependence, thiazides may be less effective in patients with moderate to severe chronic kidney disease (glomerular filtration rate [GFR] <30 mL/min per 1.73 m2).11,12
While the above mechanism lowers blood pressure initially, the kidney detects the decreased blood flow and reacts by stimulating the renin-angiotensin system.5,10,13 The resulting increase in angiotensin II induces vasoconstriction, increased peripheral vascular resistance, and increased blood pressure. In addition, angiotensin II stimulates the secretion of aldosterone from the adrenal cortex, which leads to increased renal sodium absorption and potassium excretion. Thus, extracellular volume and cardiac output levels are restored over a few weeks.
Nevertheless, in those who respond to thiazide treatment, reduced blood pressure is sustained by a long-term reduction in peripheral vascular resistance. There are several theories of how thiazide-diuretics lead to this decrease in peripheral vascular resistance but the exact mechanism is not fully understood. Some have suggested that chlorthalidone has direct vasodilatory actions on vascular endothelium or smooth muscle.1,14,15 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.2,3,5,10,13,16
References
- 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.
- Duarte JD, Cooper-DeHoff RM. Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics. Expert Rev Cardiovas Ther. 2010;8(7):793-802.
- Freis ED, Reda D, Materson B. Volume (weight) loss and blood pressure response following thiazide diuretics. Hypertension 1988;12.
- 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.
- 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.
- Reilly RF, Ellison DH. Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy. Physiol Rev. 2000;80(1):277-313.
- 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.
- 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.
- Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Supplements. 2012(2):337-414.
- Seldin DW, Giebisch GH. Diuretic Agents : Clinical Physiology and Pharmacology. San Diego, CA: Academic Press; 1997.
- 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.
- 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.
- Tobian L. Why do thiazide diuretics lower blood pressure in essential hypertension? Annu Rev Pharmacol. 1967;7(1):399-408.