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Spironolactone and Chlorthalidone: A Novel and Effective Antihypertensive Regimen?


Neither chlorthalidone nor spironolactone can be ignored in today's antihypertensive armamentarium. Both agents, alone or in combination, have appealing indications.

A recent podcastand article2 visited resuscitation of an “old” antihypertensive agent-the thiazide diuretic chlorthalidone. They told the upside of the chlorthalidone story.

Despite its advantages, however, chlorthalidone has its downsides. Like other thiazides, it increases weight and insulin resistance, lowers potassium levels, and can lead to volume depletion and hyponatremia. In fact, with its longer half-life, it may be associated with more insulin resistance than its thiazide cousins. Recent data also suggest that chlorthalidone activates the sympathetic nervous system.3 Heightened activity is not a good thing for hypertensive patients. The activation may be a consequence of chlorthalidone-induced elevations of both angiotensin and aldosterone levels.

That axis may be where something new can be combined with chlorthalidone for benefit-namely spironolactone.

Spironolactone has been around for a while, but it is unrecognized as a potent antihypertensive. This aldosterone receptor antagonist has become a remarkable addition to therapy in patients with resistant hypertension.4 Evidence is also emerging to suggest that a combination of spironolactone and chlorthalidone is synergistic. The two disparate diuretics may become a novel and efficacious antihypertensive regimen.

Seventeen patients with previously untreated essential hypertension underwent baseline sympathetic nerve activity measurements.3 They then underwent crossover therapy with
• 12 weeks of chlorthalidone as monotherapy
•  Chlorthalidone plus spironolactone, and
•  Chlorthalidone plus irbesartan, an angiotensin receptor blocker

In group 1, chlorthalidone decreased 24-hour ambulatory blood pressures from 135 ± 3/84 ± 2 to 124 ± 2/78 ± 2 mm/Hg. But monotherapy with chlorthalidone increased sympathetic nerve activity. Although a combination of irbesartan plus chlorthalidone was as effective in lowering blood pressure, it did not reduce the chlorthalidone-mediated rise in sympathetic activity (group 3). However, sympathetic activity was returned to baseline when spironolactone was added to chlorthalidone. Blood pressure did well with the addition. Also noted was that chlorthalidone monotherapy increased markers for insulin resistance. Adding spironolactone in combination with it obviated this downside. 

Yes, the study is small. Bigger numbers need to follow. But neither chlorthalidone nor spironolactone can be ignored in today’s antihypertensive armamentarium. Spironolactone indications are increasing. It has demonstrated efficacy in resistant hypertension complicating obstructive sleep apnea.4 Both agents, alone or in combination, have appealing indications.

Be on the lookout for more and larger studies.


1. Rutecki GW, Wright B. Chlorthalidone for hypertension: time to resuscitate an old, tried-and-true agent? June 13, 2012. http://www.consultantlive.com/display/article/10162/2089916.
2. Rutecki GW. Leaving a “legacy effect” on hypertension: a 22-year-old revisit to SHEP. July 12, 2012. http://www.consultantlive.com/display/article/10162/2089903.
3. Raheja P, Price A, Wang Z, et al. Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients. Hypertension. 2012 Jun 25; [Epub ahead of print].
4. Adams M, Bellone JM, Wright BM, Rutecki GW. Evaluation and pharmacologic approach to patients with resistant hypertension. Postgrad Med. 2012;124:74-82.


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