Thiazide diuretics have been a mainstay of the therapy of primary hypertension (formerly called "essential" hypertension). The most popular agent in this class, hydrochlorothiazide, was traditionally used in doses of 50 to 100 mg per day. These doses were associated with metabolic and electrolyte complications. Low-dose therapy has since been demonstrated to be efficacious and to have a much lower incidence of side effects. Chlorthalidone has been shown to provide a greater antihypertensive effect than hydrochlorothiazide and, more importantly, to reduce mortality . No trial has documented a mortality benefit from hydrochlorothiazide.
This topic will review the antihypertensive mechanisms of thiazide therapy, the common side effects of high-dose thiazide diuretics, and the benefits of low-dose therapy. The role of thiazides in the treatment of primary hypertension is discussed elsewhere. (See "Choice of drug therapy in primary (essential) hypertension: Recommendations".)
The mechanisms responsible for the decline in blood pressure (BP) are incompletely understood. The BP response appears to require initial volume loss (averaging about 1.5 kg) since it is not seen in patients who are resistant to the diuretic or who are ingesting a high-salt diet . The BP in responders begins to fall within the first week, but a slow decline can continue for as long as 12 weeks . Longer-acting thiazide diuretics are more effective than short-acting loop diuretics in patients with mild to moderate primary hypertension (formerly called "essential" hypertension) because they maintain the decline in intravascular volume. (See "Thiazides versus loop diuretics in treatment of hypertension".)
The initial hypotensive response is mediated by a modest reduction in plasma volume and cardiac output [3,4]. However, the fall in BP is blunted by hypovolemia-induced activation of the renin-angiotensin system [2,5]. Thus, nonresponders to a thiazide diuretic may have a diuresis that is equivalent to that in responders, but little or no reduction in BP due to a rise in systemic vascular resistance (figure 1) . This relationship explains the synergistic response between a diuretic and an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II-receptor blocker (ARB). These agents block either the generation or the effects of angiotensin II, thereby allowing the full antihypertensive effect of the thiazide to be expressed. (See "Renin-angiotensin system inhibition in the treatment of hypertension".)
Long-term maintenance of the decrease in BP is associated with partial reversal of the initial hemodynamic changes: the plasma volume and cardiac output partially rise toward the baseline level, while the systemic vascular resistance falls [3,4]. Despite near normalization of the plasma volume, it is likely that the plasma volume remains low in relation to the vasodilation-induced increase in the vascular capacity. Two observations are consistent with this hypothesis: (1) the plasma renin activity is persistently elevated; and (2) discontinuation of the diuretic leads to rapid fluid retention before any reversal of the fall in systemic vascular resistance .