NEJM -- Use of Diuretics in Patients with Hypertension

Use of Diuretics in Patients with Hypertension
Michael E. Ernst, Pharm.D., and Marvin Moser, M.D.

Thiazide diuretics became available in the late 1950s and were the first effective oral antihypertensive agents with an acceptable side-effect profile.1,2 A half-century later, thiazides remain important medications for the treatment of hypertension. These agents reduce blood pressure when administered as monotherapy, enhance the efficacy of other antihypertensive agents, and reduce hypertension-related morbidity and mortality. This review focuses on thiazides, the diuretics most often indicated for long-term therapy for hypertension; loop diuretics and potassium-sparing agents are briefly considered.

Clinical Pharmacology of Thiazides

Chemistry and Mechanism of Action

Diuretic therapy for hypertension originated in 1937 with the discovery that sulfonamides caused acidemia and mild diuresis by inhibiting carbonic anhydrase in the proximal tubule.3,4 Chlorothiazide, a benzothiadiazine derivative, was isolated during a search for more potent inhibitors of carbonic anhydrase5; chlorothiazide was found to be a more effective diuretic and also to unexpectedly increase the excretion of chloride, rather than bicarbonate.6 This effect on excretion eventually led to identification of the upstream portion of the distal convoluted tubule as the major site of action of the thiazides, where they interfere with sodium reabsorption by inhibiting the electroneutral sodium–chloride symporter (Figure 1).7 Activity against carbonic anhydrase, although maintained by some thiazides, is considered irrelevant to their mechanism of action, since sodium that is rejected proximally is reabsorbed downstream in the renal tubule in the thick ascending limb. Despite structural variation among the different congeners, the term thiazide diuretic includes all diuretics believed to have a primary action in the distal tubule.

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NEJM -- Use of Diuretics in Patients with Hypertension