Diuretic-Related Side Effects: Development and Treatment

Domenic A. Sica, MD

In This Article

Other Adverse Effects

Adverse effects of thiazide and thiazide-like diuretics on male sexual function, including decreased libido, erectile dysfunction, and difficult ejaculation have been reported in several studies with an incidence that varies from 3%-32%.[5,66,67,68,69] As an example, in the MRC trial, in which 15,000 hypertensive subjects received either placebo, thiazide (bendrofluazide), or a ß blocker (propranolol) for 5 years, impotence was 22-fold and four-fold higher in those receiving bendrofluazide, compared with placebo or a ß blocker, respectively.[5] In this trial, impotence was the most frequent principal reason for withdrawal from antihypertensive therapy. Another smaller trial reported on by Chang et al.[70] also found a higher frequency of decreased libido, difficulty in gaining and sustaining an erection, and trouble in ejaculating in thiazide-treated patients. Multivariate analysis suggested that these findings were not mediated by either low-serum K+ or by the observed fall in BP.

In a study by Wassertheil-Smoller et al.[69] problems with sexual interest, erection, and orgasm were greater among men receiving chlorthalidone compared with those given placebo or atenolol. Of note, in this trial, weight loss corrected the problem of chlorthalidone-induced sexual dysfunction. Also, use of a diuretic in combination with other antihypertensive agents has been associated with a higher incidence of sexual dysfunction symptoms than with the use of a diuretic alone. The mechanism by which thiazides effect erectile function or libido is unclear, although it has been suggested that these drugs wield a direct effect on vascular smooth muscle cells and/or decrease the response to catecholamines; however, patients with diuretic-related impotence can respond to sildenafil without any additional drop in BP.[71]

Impotence and decreased libido are the more frequent sexual side effects with spironolactone.[66] Gynecomastia, another fairly frequent complication of spironolactone therapy, may be associated with mastodynia and is typically bilateral. One study reported that 91 (13%) of 699 men prescribed spironolactone, alone or in association with another antihypertensive treatment, developed dose-related gynecomastia that was reversible. At daily doses of ≤50 mg, the incidence of gynecomastia was 6.9%; at daily doses of ≥150 mg, the incidence was 52.2%.[72] The sexual side effects of spironolactone have been attributed to endocrine dysfunction; spironolactone is structurally similar to the sex hormones and inhibits the binding of dihydrotestosterone to androgen receptors, thus producing an increased clearance of testosterone.[73] Eplerenone is another aldosterone-receptor antagonist which is more selective than spironolactone and is devoid of the sexual side effects seen with spironolactone.[74]