Noncompliance with antihypertensive therapy plays a significant role in inadequate blood pressure control. A key reason for poor patient compliance is sexual dysfunction-one of the foremost side effects of antihypertensive agents.
Erectile dysfunction (ED) affects about 30 million American men.1 The prevalence is higher among men with hypertension than among those who are normotensive-and ED is even more common in patients who are receiving antihypertensive therapy than in those who are not treated.
In this article, we discuss how to achieve blood pressure control while minimizing sexual side effects, and we delineate safe, effective treatment options for ED in patients who have hypertension.
Feldman and colleagues2 evaluated the incidence and prevalence of ED in the general population using results from the Massachusetts Male Aging Study, a random, cross-sectional, sample survey of 1709 men between the ages of 40 and 70 years. During the baseline phase of the study, 52% of participants who completed a self-administered questionnaire reported that they experienced some degree of ED. The prevalence of minimal ED was 17%; moderate ED, 25%; and complete ED, 10%. The age-adjusted probability of complete impotence was 15% in participants with treated hypertension compared with 9.6% in the sample as a whole.2
The follow-up phase of this study used data from initial study participants who were free of ED.3 A total of 194 new cases of ED were detected, for a crude incidence of 25.9 cases per 1000 man-years (95% confidence interval [CI], 22.5 to 29.9). The incidence of ED was significantly higher in men with treated hypertension at baseline (42.5%) than in men with untreated hypertension (26.5%). After adjusting for age, the relative risk of ED in men with treated hypertension was 1.96 (CI, 1.11 to 2.07) compared with 1.54 (CI, 0.98 to 2.42) in men with hypertension who were not receiving therapy.3 In a smaller study of 101 male outpatients who were being treated for hypertension, the prevalence of ED was 27%, and the prevalence of ED correlated with the degree of blood pressure elevation and the presence of concomitant vascular disease.4
The exact mechanism of ED induced by antihypertensive therapy is not completely understood (Box I). ED may be linked to diminished penile perfusion pressure associated with a decrease in mean arterial pressure and underlying peripheral vascular disease, or it may be an intrinsic drug side effect.4 Historically, increased rates of ED associated with centrally acting antihypertensive agents (methyldopa, guanethidine, reserpine, and clonidine) were attributed to alterations in sympathetic nervous system outflow and diminished libido.5 A number of studies have evaluated the effect on erectile function of antihypertensive agents currently in common use.
Diuretics. These are among the most widely used antihypertensive agents. They are relatively inexpensive and effective, and they are recommended in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) as first-line therapy in uncomplicated hypertension.6 Diuretics have been associated with an increased frequency of ED. Because they have no known CNS activity, it is believed that they induce ED by decreasing vascular resistance.
In a randomized, placebo-controlled trial, Chang and colleagues7 evaluated the effect of diuretics on sexual function in 176 men with mild hypertension. Participants were randomized into 6 treatment groups: hydrochlorothiazide, 50 mg; hydrochlorothiazide with potassium chloride, 40 mmol; hydrochlorothiazide with potassium chloride, 40 mmol, and magnesium oxide, 20 mmol; hydrochlorothiazide with triamterene, 100 mg; chlorthalidone, 50 mg; or placebo. After 2 months, patients treated with diuretics reported significant increases in ED compared with those who received a placebo.7
In the Treatment of Mild Hypertension Study (TOMHS)-a 4-year, double-blind, randomized controlled trial-902 patients, aged 45 to 69 years, with stage 1 diastolic hypertension, received placebo or 1 of 5 active drugs (acebutolol, amlodipine, chlorthalidone, doxazosin, or enalapril).8 After 24 months, a significantly higher incidence of ED was reported in patients receiving chlorthalidone than in those receiving placebo (17.1% vs 8.1%, P = .025). However, the difference between the 2 groups was insignificant after 48 months. In fact, at 48 months, there were no substantial differences in the incidence of ED between any of the treatment groups.
β-Blockers. These agents, also recommended in JNC VII as first-line therapy in uncomplicated hypertension,6 have long been associated with ED. Burnett and Chahine9 studied 50 patients who were to receive propranolol for various cardiovascular indications; all participants reported normal sexual function before therapy was initiated. Sexual dysfunction developed in 47% of patients (varying degrees of ED in 43% and decreased libido in 4%).
Two different mechanisms may be responsible for ED induced by β-blockers. These drugs cross the blood-brain barrier and thus suppress sympathetic outflow; this may result in a loss of libido, sedation, and sexual dysfunction. Nonselective β-blockers may also inhibit the β2-receptors responsible for vasodilatation, an effect that results in unopposed α1 vasoconstriction.9 Cardioselective β-blockers may be associated with a lower incidence of ED. In the TOMHS, 76 men with stage 1 hypertension who received the cardioselective β-blocker acebutolol (400 to 800 mg/d) did not show a significant increase in ED compared with those who were given placebo.8
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). These agents, which are recommended in JNC VII as first-line treatment for hypertension in patients with certain comorbid conditions, have not been associated with high rates of ED.6 The low rate of associated ED is likely attributable to the fact that the effect of ACE inhibitors and ARBs is confined to the renin-angiotensin system; these agents do not affect the sympathetic nervous system. In the TOMHS, the incidence of ED in patients treated with enalapril was similar to that in patients given placebo.8
Corradi and colleagues10 compared the effect of ACE inhibitors and β-blockers on erectile function in a double-blind, randomized, cross-over trial. Ninety men with hypertension, aged 40 to 49 years, who had no history of ED, were treated with atenolol, 100 mg/d, or lisinopril, 20 mg/d, for 16 weeks. Blood pressure reduction was similar in both groups. After 4 weeks, the number of episodes of sexual intercourse declined in participants who were receiving atenolol (from 7.8 to 4.5 per month, P < .01 vs placebo) and in those who were receiving lisinopril (from 7.2 to 4.8 per month, P < .05 vs placebo); there was no significant difference between the 2 groups. However, after 16 weeks of treatment, the sexual activity tended toward recovery in the lisinopril group (7.7 episodes of intercourse per month). In patients who received atenolol, the mean number of episodes of intercourse per month remained significantly lower than in those who took placebo (4.0 vs 7.5 episodes of intercourse per month, P < .01). Cross-over treatment confirmed this decrease in sexual activity. The number of patients who reported diminished libido after the second 16 weeks of treatment was significantly higher in the atenolol group (11%) than in the lisinopril group (2%).10
Selection of appropriate therapy. Because of the risks posed by noncompliance, it is important to discuss with patients the potential sexual side effects of a prescribed antihypertensive agent. If ED occurs, switching to an agent with fewer sexual side effects may be an option. However, if compelling reasons exist for the use of a particular antihypertensive agent (eg, a β-blocker in a patient with previous myocardial infarction), several options for the treatment of associated ED are available.
When a patient presents with ED, the first step is to rule out underlying conditions. The cause of ED may be organic, psychogenic, or mixed. Organic causes are listed in the Table.
Obtain a detailed medical and sexual history for all patients with ED. Include questions about the use of tobacco, alcohol, and other drugs, and screen for depression and anxiety disorders.
Perform a complete physical examination that includes evaluation for penile deformities, neurologic deficits, and peripheral vascular disease. In a study of outpatients who presented to a urology clinic for ED, the history and physical examination led to the diagnosis in 70% of patients.11
Recommended laboratory studies for all patients with hypertension in whom ED develops include a chemistry panel, thyroid function studies, measurement of fasting blood glucose level, and a lipid panel. In patients younger than 65 years, also order measurements of serum testosterone and prolactin levels (Box II).11
Phosphodiesterase-5 (PDE-5) inhibitors. Pharmacotherapy for erectile dysfunction has advanced greatly since the introduction of PDE-5 inhibitors. Phosphodiesterases are a diverse family of proteins made up of 11 isoenzymes. In human cavernosal smooth muscle cells, PDE-5 appears to be the predominant enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). PDE-5 inhibition increases intracellular cGMP levels, which facilitates cavernosal smooth muscle relaxation, dilates penile blood vessels, and enhances erectile function. The clinical efficacy of these drugs depends on their selectivity for PDE-5. PDE-5 inhibitors are very safe, and most adverse reactions are attributed to the presence of PDE-5 in other tissues.12,13 However, these agents are contraindicated in patients who require treatment with nitrates and in those with angina who may need nitroglycerine.
Sildenafil. Introduced in 1998, sildenafil was the first PDE-5 inhibitor. It was originally investigated as a potential therapy for coronary artery disease. Sildenafil, 100 mg, has been shown to produce transient decreases in systolic (8 to 10 mm Hg) and diastolic (3 to 6 mm Hg) blood pressure in healthy volunteers. Peak decreases are observed 1 hour after dosing, a time that coincides with peak plasma concentrations. These changes generally return to pretreatment values by 4 to 8 hours after dosing.
Studies have demonstrated the efficacy and safety of sildenafil in patients with hypertension who are taking antihypertensive medications. Brown and colleagues14 performed a post hoc subanalysis of 10 double-blind, placebo-controlled studies that examined the efficacy and safety of sildenafil in men who had been receiving antihypertensive therapy (a diuretic, β-blocker, α-blocker, ACE inhibitor, or calcium channel blocker) for 6 weeks to 6 months. After treatment with sildenafil, significant improvement in erectile function was reported by 70% of the patients who received concurrent antihypertensive therapy and by 72% of those who did not receive such therapy.
The incidence of sildenafil-related adverse effects in patients receiving antihypertensive therapy (34%) was similar to that in patients who were not receiving antihypertensive therapy (38%).14 The most common adverse reactions were headache, flushing, indigestion, visual changes, and sinus congestion. These reactions are caused by the presence of PDE-5 in other tissues. The number of antihypertensive medications a patient received had no effect on the number of adverse events: of those who received 1 antihypertensive agent, 35% (168 of 487) reported adverse events; of those who received 2 agents or 3 agents, 31% (55 of 178) and 41% (16 of 39), respectively, reported adverse reactions. Adverse events potentially related to changes in blood pressure were few (dizziness, 2%; hypotension, less than 1%; and syncope, 0%) and were similar to those observed in patients who were not receiving any antihypertensive medication. There were no other cardiovascular events.14
Tadalafil. This is a new, highly selective inhibitor of PDE-5 whose chemical structure is significantly different from that of the other PDE-5 inhibitors. It has few effects on other PDE isoforms, including PDE-6, so no visual side effects have been observed.
Studies have shown that tadalafil significantly improves erectile function. In 5 randomized, double-blind, placebo-controlled trials lasting 12 weeks, a total of 1112 men with varying degrees of ED were treated with tadalafil. At a dose of 20 mg, 73% to 80% of sexual intercourse attempts were completed successfully between 30 minutes and 36 hours after dosing. Subgroup analysis revealed no differences in adverse events between men who did and those who did not receive concurrent antihypertensive therapy.15 Thus, efficacy is similar to that seen with other PDE-5 inhibitors.
Vardenafil. The chemical structure of this highly selective inhibitor of PDE-5 is very similar to that of sildenafil. The efficacy of vardenafil for the treatment of ED has been demonstrated in a large population of patients, including many who had recently undergone retropubic prostatectomy. With respect to successful attempts at intercourse, results with vardenafil were significantly better than with placebo. Its overall side- effect profile was similar to that of other PDE-5 inhibitors.16
To date, no randomized head-to-head trials have compared the efficacy of the different PDE-5 inhibitors or their relative effects on concomitant antihypertensive therapy.
Older treatment modalities. Since the introduction of PDE-5 inhibitors, other modalities for the treatment of ED, such as urethral suppositories, penile injections, and vacuum pumps, have fallen into disuse. These modalities are cumbersome to use; however, they may be an alternative in patients with contraindications to PDE-5 inhibitors. n
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