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Thiazides versus loop diuretics in the treatment of hypertension

Thiazides versus loop diuretics in the treatment of hypertension
Author:
Rajiv Agarwal, MD
Section Editor:
George L Bakris, MD
Deputy Editor:
John P Forman, MD, MSc
Literature review current through: Jan 2024.
This topic last updated: Oct 04, 2022.

INTRODUCTION — Diuretics, particularly thiazide-type and thiazide-like diuretics, are commonly used in the treatment of hypertension. Diuretics lower the blood pressure, at least initially, by inducing sodium and fluid loss.

(See "Use of thiazide diuretics in patients with primary (essential) hypertension".)

(See "Mechanism of action of diuretics".)

Loop diuretics are commonly used to treat edematous states. (See "General principles of the treatment of edema in adults".)

The major differences between thiazide and loop diuretics in the treatment of hypertension are discussed in this topic. The mechanism of action and side effects of diuretics, and different effects of thiazide and loop diuretics on calcium balance, are discussed in detail elsewhere:

(See "Mechanism of action of diuretics".)

(See "Use of thiazide diuretics in patients with primary (essential) hypertension", section on 'Side effects'.)

(See "Loop diuretics: Dosing and major side effects", section on 'Major side effects'.)

(See "Time course of loop and thiazide diuretic-induced electrolyte complications".)

(See "Diuretic-induced hyperuricemia and gout".)

(See "Diuretics and calcium balance".)

ANTIHYPERTENSIVE DIFFERENCES BETWEEN THIAZIDE AND LOOP DIURETICS

Patients without chronic kidney disease — When used in patients with primary hypertension and relatively normal kidney function, the thiazide diuretics, particularly chlorthalidone and indapamide, are more effective antihypertensive drugs than the loop diuretics [1-6]. (See "Use of thiazide diuretics in patients with primary (essential) hypertension".)

The difference in efficacy is probably related to duration of action of these diuretics [4]. Commonly used loop diuretics, such as furosemide and bumetanide, have a short duration of action (less than six hours); the antihypertensive efficacy of these medications may be limited since the initial fluid loss can be counteracted by activation of the renin-angiotensin-aldosterone system, leading to sodium retention during the period when the diuretic effect has worn off [7].

Longer-acting loop diuretics are available; torsemide, for example, has a duration of action up to 12 hours. In a blinded, randomized trial, furosemide, given twice daily, and torsemide, given once daily, produced similar systolic pressure reductions in patients with chronic kidney disease (CKD) [8]. Thus, once-daily torsemide appears to be as effective as an equivalent dose of twice-daily furosemide in reducing blood pressure. Whether torsemide is as effective an antihypertensive agent as thiazide diuretics is unknown.

Patients with chronic kidney disease — It is a commonly held belief that the above observations do not necessarily apply to patients with CKD and that thiazide diuretics are less effective in such patients. However, several studies indicate that thiazide diuretics are effective in such patients.

All diuretics are less effective in patients with impaired kidney function. Both thiazide and loop diuretics must reach the lumen of the renal tubule to act, a process mediated by organic acid transporters in the proximal tubule [9]. As glomerular filtration rate (GFR) decreases, organic acid levels increase, and these acids compete with diuretics for transport into the tubular lumen. Thiazides are less effective in competing with accumulating organic acids than loop diuretics in this setting [9]. Thiazide diuretics are therefore considered by many to be less effective in patients with a GFR less than 30 mL/min [10]. Because fluid retention is thought to play a major role in the elevation in blood pressure in CKD, such patients are often prescribed loop diuretics as antihypertensive agents, rather than thiazide diuretics. (See "Overview of hypertension in acute and chronic kidney disease".)

However, several interventional studies suggest that thiazides are effective even among patients with advanced CKD [11-15]. The following examples illustrate the range of findings:

The best data come from a blinded trial of 160 patients with advanced CKD (estimated GFR [eGFR] 15 to 29 mL/min/1.73 m2) and uncontrolled hypertension (defined as 24-hour ambulatory blood pressure ≥130 mmHg systolic or ≥80 mmHg diastolic) despite antihypertensive therapy including an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), or a beta blocker [15]. Patients were randomly assigned to chlorthalidone, 12.5 mg daily titrated to a maximum of 50 mg daily, or placebo. At 12 weeks, the decrease in 24-hour ambulatory systolic pressure was greater in the chlorthalidone group (by 11.0 versus 0.5 mmHg); ambulatory diastolic pressure also declined (by 4.9 versus 1.0 mmHg). Chlorthalidone led to a reduction in urine albumin-to-creatinine ratio and a reversible reduction in eGFR, which was larger among patients who were also taking a loop diuretic. Hypokalemia (10 versus 0 percent), hyponatremia (11 versus 8 percent), and dizziness (25 versus 16 percent) were more common with chlorthalidone. Serious adverse events leading to hospitalization occurred in eight patients assigned to chlorthalidone and 11 patients assigned to placebo.

Previous, smaller studies yielded similar findings:

A blinded, randomized, crossover trial of 23 patients with hypertension and an eGFR <30 mL/min/1.73 m2 compared furosemide (60 mg/day) with hydrochlorothiazide (25 mg/day), each for three months [12]. The effects on blood pressure were similar; mean arterial pressure decreased from 101 to 93 mmHg with furosemide and to 94 mmHg with hydrochlorothiazide. Patients were then placed on a combination of the two drugs, which produced an even greater antihypertensive effect, although with more adverse metabolic consequences. (See "Use of thiazide diuretics in patients with primary (essential) hypertension", section on 'Side effects' and "Loop diuretics: Dosing and major side effects", section on 'Major side effects' and "Diuretic-induced hyperuricemia and gout".)

In another study of 60 patients with normal kidney function and 60 patients with CKD (mean eGFR 39 mL/min/1.73 m2), 25 mg/day of chlorthalidone for eight weeks lowered blood pressure to a similar degree in both groups (by 20/9 and 23/10 mmHg) [14].

OTHER DIURETICS — The potassium-sparing agents triamterene and amiloride have a minimal antihypertensive effect and are not widely used as initial therapy for primary hypertension [16], although amiloride may be valuable in treating resistant hypertension [17].

By comparison, the mineralocorticoid receptor antagonists spironolactone (with which there is the widest experience as monotherapy) and eplerenone are more potent antihypertensive agents. In view of their apparent ability to reduce cardiac and kidney fibrosis [18], aldosterone antagonists have become widely used [19,20]. (See "Treatment of hypertension in patients with heart failure".)

Mineralocorticoid receptor antagonists are also preferred agents in patients with resistant hypertension. This issue is discussed in detail elsewhere.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertension in adults".)

SUMMARY

Diuretics lower the blood pressure by inducing sodium and fluid loss. (See "Use of thiazide diuretics in patients with primary (essential) hypertension" and "Mechanism of action of diuretics".)

Among patients with normal kidney function, thiazide diuretics, particularly chlorthalidone and indapamide, have a greater antihypertensive effect than the loop diuretics. This may be related to the longer duration of action of thiazide compared with most loop diuretics. (See 'Patients without chronic kidney disease' above.)

Although it is a commonly held belief that thiazide diuretics are not effective antihypertensive agents in patients with chronic kidney disease (CKD), they appear to be as effective as loop diuretics in such patients. (See 'Patients with chronic kidney disease' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Norman Kaplan, MD, who contributed to earlier versions of this topic review.

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Topic 3871 Version 21.0

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