Review

International Journal of Impotence Research (2007) 19, 296–302. doi:10.1038/sj.ijir.3901527; published online 7 December 2006

Erectile dysfunction and hypertension

R Kloner1

1Heart Institute, Good Samaritan Hospital (USC), Los Angeles, CA, USA

Correspondence: Dr R Kloner, Heart Institute, Good Samaritan Hospital (USC), 1225 Wilshire Blvd, 9th Floor Research, Los Angeles, CA 90017, USA. E-mail: rkloner@goodsam.org

Received 10 August 2006; Revised 21 September 2006; Accepted 27 September 2006; Published online 7 December 2006.

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Abstract

Recent analyses suggest that about 67–68% of men with hypertension have some degree of erectile dysfunction (ED). With about 25 million men in the US with hypertension, substantial numbers of hypertension-related ED exist that tend to be of a more severe nature than the general population. Men with ED are also more likely to have hypertension. Thiazide diuretic and beta-blocker therapy may contribute to ED. Phosphodiesterase-5 (PDE5) inhibitors are effective therapy in men with ED owing to hypertension who are taking antihypertensive medicines including those on multiple antihypertensive medicines. The addition of PDE5 inhibitors to usual common antihypertensive medicines (diuretics, beta blockers, calcium blockers, angiotensin converting enzyme inhibitors and angiotensin receptor blockers) results in either no or small additive reductions in blood pressure (BP) and no increase in serious clinical adverse events. There are however precautions regarding the use of PDE5 inhibitors in patients taking alpha blockers for either hypertension or benign prostatic hypertrophy, as some patients may develop orthostatic hypotension. Organic nitrates remain an absolute contraindication for PDE5 inhibitors because synergistic and symptomatic reductions in BP may occur in some patients with this drug combination.

Keywords:

hypertension, erectile dysfunction, phosphodiesterase inhibitors, cardiovascular risk factors, alpha blockers

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Introduction

Risk factors for erectile dysfunction (ED) are also risk factors for coronary artery disease. These include diabetes, smoking, lipid abnormalities (low levels of high-density lipoprotein cholesterol, high levels of total cholesterol), hypertension, obesity and lack of physical activity.1 This review will focus on hypertension as a risk factor for ED; the effect of the phosphodiesterase 5 inhibitors (PDE5 inhibitors: sildenafil, vardenafil and tadalafil) on systemic arterial blood pressure (BP); the effect of the PDE5 inhibitors in men with ED and hypertension taking antihypertensive medicines; the contraindication of PDE5 inhibitors in the setting of organic nitrates; and the effect of PDE5 inhibitors when administered with alpha blockers.

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The association of hypertension with ED

Hypertension or high BP, defined as a BP of greater than or equal to140 mm Hg systolic and/or greater than or equal to90 mm Hg diastolic is estimated to affect approximately 50 million Americans. As the US population ages hypertension is predicted to increase. Several studies have linked hypertension with ED. In the Massachusetts Male Aging study of 1994, Feldman et al1 reported the presence of ED in 9.6% of a general population and 15% in patients with treated hypertension.

More recent analyses of hypertensive patients suggest that the prevalence of ED in hypertensive populations is even higher. Burchardt et al.2 mailed the International Index of Erectile Function (IIEF) questionnaire to 476 male patients with hypertension who were being cared for at a hypertension center. One hundred and four patients (mean age 62.2 years) completed the questionnaire. Of these, 68.3% had some degree of ED. ED was mild in 7.7%, moderate in 15.4% and severe in 45.2%. Compared to the general population of ED cases, patients with hypertension had more severe ED (45.2% in hypertensives versus approx10% in a general population as reported by the Massachusetts Male Aging Study). There was a trend for patients treated with diuretics and beta blockers to demonstrate the highest incidence of ED whereas those treated with alpha blockers had the lowest incidence. The authors concluded that ED was more prevalent in patients with hypertension than in age-matched controls and that the degree of ED was more severe in patients with hypertension than the general male population. Another very recent study by Giuliano et al.3 also confirmed a very high rate of ED among hypertensive patients. They performed a survey of 7689 patients (mean age 59 years) using the Sexual Health Inventory in Men (SHIM) questionnaire. In 3906 men with hypertension alone (no diabetes), ED was present in 67% (defined as a SHIM score of <21). The 67% number is very similar to the 68% figure reported by Burchardt et al.2 Giuliano also reported that in 2377 men with diabetes that ED was present in 71%. Of 1186 men with both hypertension and diabetes, ED was present in 77%. Of these men with ED, 80% classified the symptoms as bothersome and ED was untreated in 65%; however, the majority of men said that they wanted treatment. The authors concluded that patients with hypertension and/or diabetes have a high prevalence of bothersome, untreated ED. These studies, taken together, do suggest that hypertension patients are more likely to have ED. Another way to view this association is to determine whether men with ED are more likely to have hypertension than men without ED. Sun et al.4 recently reported that in men with ED, 41% had hypertension versus 19% in age-matched men without ED. This association remained after controlling for other variables such as age and census region. Seftel et al.5 examined 272 325 patients with ED in a large database. They observed that 42% of the patients had hypertension. They also observed that 42% of these men with ED had hyperlipidemia, 20% had diabetes and 11% had depression. The authors concluded that ED shared common risk factors associated with cardiovascular-risk factors.

Thus, patients with hypertension are more likely to have ED; and patients with ED are more likely to have hypertension.

The mechanism by which hypertension may cause ED is likely related to endothelial dysfunction associated with hypertension. Long-standing hypertension may cause oxidate stress, endothelial cell injury and its sequella, including the inability of the arteries, arterioles and sinusoids of the corpus cavernosum to dilate properly. It is also possible that non-endothelium-dependent impairment of vasodilatation such as damage to smooth muscle cells contributes to ED in the hypertensive patient. Another contributing factor may be the antihypertensive medicines themselves. For example, thiazide diuretics and beta blockers are known to worsen ED.6, 7 In general, the calcium channel blockers and angiotensin converting enzyme inhibitors do not worsen ED compared to placebo.7 Of note, there are some small reports suggesting that angiotensin receptor blockers may actually improve ED.8 The mechanisms for the worsening of ED by thiazide diuretics has been postulated to be secondary to alterations in electrolytes, serum zinc deficiency or volume depletion, but the exact mechanism remains elusive.9 If ED is indeed related to a thiazide, patients may show improvement after several weeks of stopping the thiazide and switching to an antihypertensive agent that does not worsen ED.

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What effect do the PDE5 inhibitors have on systemic arterial BP?

PDE5 is localized to smooth muscle cells that supply the vasculature of not only the genitals but also the systemic arteries and veins.10, 11 Therefore, when PDE5 inhibitors are administered, they block the breakdown of cyclic guanosine monophosphate (GMP) in the systemic vasculature and the systemic arteries and veins dilate. As mild vasodilators, the PDE5 inhibitors are associated with small, usually clinically insignificant reductions in BP in healthy individuals (Table 1). Sildenafil reduces BP by about 8/6 mm Hg (decrease in systolic/decrease in diastolic BP); vardenafil reduces BP by 7/8 mm Hg, and tadalafil reduces BP by 1.6/0.8 mm Hg in the supine position and by 0.2/4.6 mm Hg in the standing position. Increases in heart rate tend to be minimal, usually less than 5 beats/min.10, 11, 12, 13, 14, 15, 16 In general, the effects of the PDE5 inhibitors on BP are more pronounced in the standing position. The reduction in systolic BP with tadalafil 10 mg in coronary artery disease patients (who had higher baseline BP than healthy volunteers) was 7 mm Hg in the standing position and thus greater than in healthy volunteers.15 This finding likely represents an epi-phenomenon in that when vasodilators are administered, the reduction in BP tends to be greater when given to patients with higher versus lower baseline BP.


Although intravenous sildenafil was associated with a dose-related reduction of systolic BP (systolic BP=131plusminus12 mm Hg with placebo; 129plusminus12 mm Hg with 20 mg; 124plusminus14 mm Hg with 40 mg, and 122plusminus13 mm Hg with 80 mg of intravenous sildenafil;10 oral doses of 50–200 mg were not associated with dose-dependent fall in either systolic or diastolic BP.10, 17

In summary, PDE5 inhibitors are mild vasodilators that can result in small reductions in systemic arterial pressures that in general are not clinically significant.

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Are PDE5 inhibitors effective for ED in men with hypertension receiving antihypertensive therapy?

The answer to this question is yes. We studied the efficacy and safety of sildenafil in men with ED including those taking multiple antihypertensive medicines. The efficacy of sildenafil in these patients with hypertension was about 70%.18 Pickering et al.19 also studied the efficacy and safety of sildenafil in men who were taking multiple antihypertensive medicines. This study included males older than 18 years with a documented history of ED confirmed by a SHIM score <21 and in a stable relationship. They had to have a history of hypertension, being treated with two or more antihypertensive medications and on a stable dose for at least 4 weeks. Two hundred and eighty-three patients received placebo and 279 received sildenafil. There were 307 subjects who were taking two antihypertensive medicines whereas 222 were taking three or more. The percentage of patients who reported improved erections in the sildenafil group was 71 versus 17.6% in the placebo group; the percentage of patients who reported successful sexual intercourse attempts was 62.4% in the sildenafil group versus 26.1% in the placebo group.

As thiazide diuretics are recommended by the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure,20 but thiazide diuretics themselves may be associated with the development of ED, we tested whether the PDE5 inhibitor tadalafil could demonstrate efficacy for treating ED in patients who were hypertensive and receiving thiazide diuretics.21 Data from 14 randomized, double-blind, placebo-controlled trials to test the efficacy of tadalafil 20 mg was utilized for this analysis. One hundred and sixty-three patients were identified, who were receiving thiazide diuretics (116 in the tadalafil groups and 47 in the placebo groups). Of note, a higher percentage of patients on thiazides had severe ED at baseline, which is consistent with studies suggesting that thiazides may exacerbate ED; however, these same patients tended to be older, and had other comorbidities compared to patients not on thiazides. Tadalafil improved the IIEF in patients taking thiazides from 14.0 at baseline to 23.4 after therapy; it increased the Sexual Encounter Profile Question 2 (SEP2) from 44.5 to 78.8% and SEP3 from 21.0 to 66.1% versus placebo (P<0.001 versus placebo for all the three measures). Tadalafil's improvement in ED in hypertensive patients on thiazides was similar to its improvement in patients not taking thiazides. For patients on thiazides – a positive global assessment question (GAQ) response (% yes) was recorded in 87.4% of patients receiving tadalafil versus 32.6% for patients taking placebo (P<0.001 tadalafil versus placebo). In patients not taking thiazides the response to tadalafil versus placebo (85.2 versus 38.2; P<0.001) was similar. Therefore, the PDE5 inhibitor tadalafil was quite effective in treating ED even in patients on thiazide diuretics.21

Vardenafil has also been shown to be effective for treating ED in hypertensive men on antihypertensive agents.22 Van Ahlen et al.22 studied the safety and efficacy of vardenafil in men with arterial hypertension and ED, receiving at least one antihypertensive medicine. This was a multicenter, randomized, double-blind placebo-controlled study of 354 patients. Patients were randomized to receive placebo or vardenafil 5–20 mg over 12 weeks. Vardenafil significantly improved the mean response to SEP2 (success of vaginal insertion) and 3 (maintenance of erection). For SEP2, vardenafil was successful in 83% of the men versus 58% for those on placebo; for SEP3 vardenafil was successful in 67 versus 35% for placebo (P<0.0001 versus placebo). Responses to the GAQ showed improved erections in 80% of vardenafil patients versus 40% of the placebo patients (P<0.0001). Average number of antihypertensives per patient was 1.4–1.5. The efficacy of vardenafil was unaffected by the type of antihypertensive agent the patient was taking. Vardenafil did not significantly alter the BP or heart rate compared to placebo. Headache (3.1%) and flushing (1.6%) were the most commonly reported treatment-emerging adverse events and in general were mild-to-moderate in severity as well as transient. The authors concluded that vardenafil improved erectile function in men with hypertension treated with antihypertensive medicines including those on multiple antihypertensive medicines without significantly altering BP.

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Effect of PDE5 inhibitors plus usual antihypertensive medicines on BP

In general, when a PDE5 inhibitor is administered on top of antihypertensive medicines, there are small additive reductions in BP that are similar to the reduction in BP that occurs with the PDE5 inhibitor alone. In one early study by Webb et al.,11 which was a double-blind, placebo-controlled, crossover study, 16 hypertensive men who were being treated with amlodipine (5–10 mg per day) received a single oral dose of sildenafil (100 mg) or placebo 2 h after their usual dose of amlodipine. The additional reduction of BP on top of amlodipine was -8 mm Hg systolic (supine) and -10 mm Hg systolic (standing), and -7 mm Hg diastolic (supine) and -8 mm Hg diastolic (standing), numbers that are similar to the effect of sildenafil on BP in patients not on amlodipine. Hence, sildenafil caused an additive – not a synergistic or multiplicative effect upon reduction of BP in the setting of the calcium blocker, amlodipine. Zusman et al.23 then studied the effect of sildenafil in a broader group of patients that were part of randomized, double-blind, placebo-controlled studies in which patients received placebo versus sildenafil and were either on no antihypertensives, diuretics, beta blockers, alpha blockers, ACE inhibitors or calcium channel blockers. Sildenafil appeared to have either no effect or minimal effect on BP in this study.23

Studies on tadalafil showed either no change or minor augmentation of BP lowering effects with concomitant use of all major classes of antihypertensive therapy.24 There were no further decreases in BP with the calcium channel blocker amlodipine when tadalafil was added. There were small changes in BP when tadalafil was administered in the presence of the beta blocker metoprolol (-7/-4 mm Hg; standing BP) or thiazide diuretic (-6/-4 mm Hg). There were small additive effects observed when tadalafil was administered to patients taking the angiotensin converting enzyme inhibitor enalapril (-3/-1 mm Hg) or various angiotensin receptor blockers (-8/-4 mm Hg).

Vardenafil was studied in a double-blind, two-way crossover manner in 22 men with hypertension who were taking 30 or 60 mg of nifedipine per day. Patients were randomly assigned to receive either vardenafil 20 mg or placebo. There were small changes in hemodynamic effects with the addition of vardenafil.13 In other studies, vardenafil was associated with minimal additional reductions in BP when it was administered to patients on a variety of antihypertensive medications.25, 26 Thus, in summary, when PDE5 inhibitors are given to patients with hypertension on antihypertensive medications, there are either no or small additive drops in BP.

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Does the addition of PDE5 inhibitors to antihypertensive agents increase their adverse events?

In studies in which sildenafil versus placebo was administered to patients on antihypertensive medicine, there was no increase in treatment discontinuations owing to adverse events in patients receiving sildenafil.27 In a study by Kloner et al.,18 the incidence of treatment-related adverse events potentially related to the lowering of BP (hypotension, flushing, dizziness) was not different in patients receiving sildenafil plus no antihypertensive medicines, versus sildenafil plus 1, 2 or greater than or equal to3 antihypertensive medicines. Furthermore, there were no patients who developed angina, coronary artery disease or myocardial infarction when sildenafil was administered on top of antihypertensive medication. In a study by Pickering et al.,19 treatment adverse events related to sildenafil, such as headache, flushing, dyspepsia and others, were similar among patients who were taking multiple antihypertensive medications to those that had been reported for patients on sildenafil not on antihypertensives.

Also, there was no increased incidence of adverse events (except flushing) in patients receiving tadalafil and single or multiple antihypertensive agents.14, 24 In studies assessing the use of vardenafil in patients on antihypertensive medicines, there was no increase in adverse events.22 Thus, PDE5 inhibitors can be safely administered with usual antihypertensive agents including diuretics, beta blockers, calcium blockers and angiotensin receptor blockers. There is a precaution, however, with alpha blockers that will be explained below.

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The nitrate contraindication

All three PDE5 inhibitors are contraindicated in patients taking organic nitrates (including short-acting or long-acting nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, amyl nitrate and others). Organic nitrates increase cyclic GMP production whereas PDE5 inhibitors decrease cyclic GMP breakdown. Therefore, there is a synergistic drop in BP when PDE5 inhibitors are given with organic nitrates that results in symptomatic hypotension in some patients.11, 12, 13, 15, 16

If a patient has taken a PDE5 inhibitor and then develops chest pain, when is it safe to re-introduce nitroglycerin? The original American College of Cardiology/American Heart Association guidelines suggested that for sildenafil, 5–6 half-lines or 24 h pass before nitrates are given to a patient who has taken sildenafil (half-life is about 4 h).28 Studies comparing nitrate interaction between sildenafil versus tadalafil confirmed that there was a lack of interaction between sildenafil and nitrate 24 h after sildenafil was administered.15 There is an unpublished study suggesting a lack of interaction with nitroglycerin at 24 h after vardenafil, consistent with its 4 h half-life.13 Finally, one study suggests an interaction between tadalafil (half-life 17.5 h) and nitroglycerin that is present at 24 h after a dose of tadalafil but that is gone by 48 h and beyond.29

Thus, although all three PDE5 inhibitors are contraindicated in patients receiving either short-acting or long-acting nitrates, should a patient with ED take a PDE5 inhibitor and then develop angina, nitroglycerin should not be reintroduced until after 24 h for sildenafil or vardenafil and after 48 h for tadalafil. Of course, other antianginal and anti-ischemic therapies may be used – such as beta blockers, calcium blockers, aspirin, morphine, statins and percutaneous coronary intervention. None of these are contraindicated with PDE5 inhibitors. The American College of Cardiology/American Heart Association Guidelines address the approach to the patient who has developed hypotension in the setting of PDE5 inhibitors plus nitrates.28

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Interactions of PDE5 inhibitors with alpha blockers

As described earlier, most studies to date showed small additive drops in BP when PDE5 inhibitors were given to patients already taking beta blockers, calcium blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers and diuretics. An exception to these findings can be the alpha blockers, which in some patients may be associated with an increase in orthostatic hypotension when administered with PDE5 inhibitors. Alpha blockers of course may be used for treating hypertension, benign prostatic hypertrophy or both.

In an unpublished study (but described in the package insert12), 2/20 patients with benign prostatic hypertrophy receiving 4 mg doxazosin plus 50 mg sildenafil simultaneously developed symptomatic postural hypotension, whereas no orthostatic hypotension was observed with the combination of 4 mg doxazosin plus a 25 mg dose of sildenafil. The labeling initially was that precaution is advised such that a 50 or 100 mg dose of sildenafil should not be taken within a 4-h window of alpha blocker administration, whereas a 25-mg dose of sildenafil may be taken at any time in relationship to an alpha blocker.

As of June 2006, there was a change in the labeling bringing the precaution for sildenafil and alpha blockers in line with that of the other PDE5 inhibitors. The wording for the precaution is now: 'Caution is advised when PDE5 inhibitors are co-administered with alpha blockers. PDE5 inhibitors, including VIAGRA, and alpha-adrenergic blocking agents are both vasodilators with BP lowering effects. When vasodilators are used in combination, an additive effect on BP may be anticipated. In some patients, concomitant use of these two drug classes can lower BP significantly leading to symptomatic hypotension (e.g. dizziness, light headedness, fainting).'

The precaution goes on to suggest that patients should be on stable alpha-blocker therapy before PDE5 inhibition and that lowest doses of the PDE5 inhibitors be used to initiate therapy. Conversely, if a patient is already taking an optimal dose of PDE5 inhibitor and an alpha blocker needs to be started, the alpha blocker should be started at the lowest dose. Other variables such as intravascular volume status and use of other antihypertensives should be considered when using a combination of PDE5 inhibitor and alpha blocker.

There was initially a contraindication for the use of vardenafil in patients on alpha blockers. Initial studies showed that 10 mg vardenafil plus 10 mg terazosin given simultaneously to healthy subjects resulted in a standing systolic BP of less than 85 mm Hg in 6/8 patients. Twenty-milligram doses also were associated with hypotension in 2/9 patients given terazosin. Even when 20 mg of vardenafil was separated from terazosin 10 mg by 6 h, 7/28 subjects had a reduction in standing systolic BP <85 mm Hg.30

The interaction was less prominent when vardenafil was given with tamsulosin (an alpha 1a blocker, 0.4 mg used for benign prostatic hypertrophy). Vardenafil 10 mg plus tamsulosin given simultaneously resulted in 2/16 healthy subjects dropping their standing systolic BP to less than 85 mm Hg; 1/24 dropped their standing BP to this level when vardenafil plus tamsulosin administration were separated by 6 h.30

As a patient's response to PDE5 inhibitor plus alpha blocker may depend on whether the patient has been on the alpha blocker chronically or acutely, a series of studies examined the interaction of vardenafil plus tamsulosin or terazosin in benign prostatic hypertrophy patients who had been on stable alpha blocker therapy. In these studies, zero to few patients dropped their systolic BP to <85 mm Hg whether the two drugs were administered simultaneously or were given 6 h apart.30, 31, 32 Largely as a result of some of these newer analyses, the labeling for vardenafil has changed to a precaution (and not a contraindication) for using vardenafil in patients receiving alpha blockers. The labeling does recommend starting with the lowest dosages of both drugs.

In one study,33 20 mg tadalafil plus 8 mg doxazosin given simultaneously in healthy subjects caused a decrease in BP to <85 mm Hg in 28 versus 6% in the placebo (no tadalafil) group. Three subjects became dizzy. In contrast, 10 or 20 mg of tadalafil given with 0.4 mg tamsulosin (alpha 1a blocker) was not associated with drops in standing systolic BP to <85 mm Hg. Although tadalafil was initially contraindicated with alpha blockers other than tamsulosin, that contraindication has now been removed. There is now a precaution for the use of tadalafil with alpha blockers. Again, low starting doses are encouraged.

Thus, all three PDE5 inhibitors now carry precautions regarding the use of alpha blockers, warning of the possible development of orthostatic hypotension with drug combination, but no longer are the PDE5 inhibitors contraindicated with alpha blockers.32

Although this article focuses on patients with controlled hypertension, should men with ED who have uncontrolled or severe hypertension receive treatment for ED? This issue was raised in the Second Princeton Consensus Conference.34 In general, the consensus was that in these patients the cardiovascular problem (severe hypertension) should be treated before initiating therapy for sexual dysfunction.

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Conclusions

  1. Patients with hypertension may also have ED. Ask hypertensive patients about their sexual health.
  2. Patients with ED may have hypertension. Be sure to ask patients presenting with ED about their cardiovascular-risk factors, including hypertension.35 Be sure to obtain a BP reading on these men. These men should also be assessed for the presence of dyslipidemia, diabetes, smoking, obesity and lack of physical exertion.
  3. PDE5 inhibitors are in general effective and safe in hypertensive patients taking antihypertensive medications, including multiple antihypertensive medicines.
  4. PDE5 inhibitors are contraindicated in patients taking organic nitrates owing to a synergistic drop in BP.
  5. PDE5 inhibitors should be used with caution in patients receiving alpha blockers as some patients may develop orthostatic hypotension. The lowest starting doses should be considered.
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