Erectile Dysfunction and Hypertension

REVIEW Erectile dysfunction and hypertension

R Kloner

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

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

Keywords: hypertension; erectile dysfunction; phosphodiesterase inhibitors; cardiovascular risk factors; alpha blockers

Introduction The association of hypertension with ED

Risk factors for erectile dysfunction (ED) are also Hypertension or high BP, defined as a BP of risk factors for coronary artery disease. These X140 mm Hg systolic and/or X90 mm Hg diastolic include diabetes, smoking, lipid abnormalities is estimated to affect approximately 50 million (low levels of high-density lipoprotein cholesterol, Americans. As the US population ages hypertension high levels of total cholesterol), hypertension, is predicted to increase. Several studies have linked obesity and lack of physical activity.1 This review hypertension with ED. In the Massachusetts Male will focus on hypertension as a risk factor for ED; the Aging study of 1994, Feldman et al1 reported the effect of the phosphodiesterase 5 inhibitors (PDE5 presence of ED in 9.6% of a general population and inhibitors: sildenafil, vardenafil and tadalafil) on 15% in patients with treated hypertension. systemic arterial blood pressure (BP); the effect of More recent analyses of hypertensive patients the PDE5 inhibitors in men with ED and hyperten- suggest that the prevalence of ED in hypertensive sion taking antihypertensive medicines; the contra- populations is even higher. Burchardt et al.2 mailed indication of PDE5 inhibitors in the setting of the International Index of Erectile Function (IIEF) organic nitrates; and the effect of PDE5 inhibitors questionnaire to 476 male patients with hyperten- when administered with alpha blockers. sion 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%, Correspondence: Dr R Kloner, Heart Institute, Good moderate in 15.4% and severe in 45.2%. Compared Samaritan Hospital (USC), 1225 Wilshire Blvd, 9th Floor Research, Los Angeles, CA 90017, USA. to the general population of ED cases, patients with E-mail: [email protected] hypertension had more severe ED (45.2% in hyper- Received 10 August 2006; revised 21 September 2006; tensives versus B10% in a general population as accepted 27 September 2006; published online 7 December reported by the Massachusetts Male Aging Study). 2006 There was a trend for patients treated with diuretics Erectile dysfunction and hypertension R Kloner 297 and beta blockers to demonstrate the highest note, there are some small reports suggesting that incidence of ED whereas those treated with alpha angiotensin receptor blockers may actually improve blockers had the lowest incidence. The authors ED.8 The mechanisms for the worsening of ED concluded that ED was more prevalent in patients by thiazide diuretics has been postulated to be with hypertension than in age-matched controls and secondary to alterations in electrolytes, serum that the degree of ED was more severe in patients zinc deficiency or volume depletion, but the exact with hypertension than the general male popula- mechanism remains elusive.9 If ED is indeed related tion. Another very recent study by Giuliano et al.3 to a thiazide, patients may show improvement also confirmed a very high rate of ED among after several weeks of stopping the thiazide and hypertensive patients. They performed a survey of switching to an antihypertensive agent that does 7689 patients (mean age 59 years) using the Sexual not worsen ED. Health Inventory in Men (SHIM) questionnaire. In 3906 men with hypertension alone (no diabetes), ED was present in 67% (defined as a SHIM score What effect do the PDE5 inhibitors have of o21). The 67% number is very similar to the on systemic arterial BP? 68% figure reported by Burchardt et al.2 Giuliano also reported that in 2377 men with diabetes that PDE5 is localized to smooth muscle cells that supply ED was present in 71%. Of 1186 men with both the vasculature of not only the genitals but also hypertension and diabetes, ED was present in 77%. the systemic arteries and veins.10,11 Therefore, when Of these men with ED, 80% classified the symptoms PDE5 inhibitors are administered, they block the as bothersome and ED was untreated in 65%; how- breakdown of cyclic guanosine monophosphate ever, the majority of men said that they wanted (GMP) in the systemic vasculature and the systemic treatment. The authors concluded that patients with arteries and veins dilate. As mild vasodilators, the hypertension and/or diabetes have a high preva- PDE5 inhibitors are associated with small, usually lence of bothersome, untreated ED. These studies, clinically insignificant reductions in BP in healthy taken together, do suggest that hypertension patients individuals (Table 1). Sildenafil reduces BP by are more likely to have ED. Another way to view about 8/6 mm Hg (decrease in systolic/decrease in this association is to determine whether men with diastolic BP); vardenafil reduces BP by 7/8 mm Hg, ED are more likely to have hypertension than 4 and tadalafil reduces BP by 1.6/0.8 mm Hg in men without ED. Sun et al. recently reported that the supine position and by 0.2/4.6 mm Hg in the in men with ED, 41% had hypertension versus 19% standing position. Increases in heart rate tend to in age-matched men without ED. This association be minimal, usually less than 5 beats/min.10–16 In remained after controlling for other variables such 5 general, the effects of the PDE5 inhibitors on BP as age and census region. Seftel et al. examined are more pronounced in the standing position. The 272 325 patients with ED in a large database. They reduction in systolic BP with tadalafil 10 mg in observed that 42% of the patients had hypertension. coronary artery disease patients (who had higher They also observed that 42% of these men with ED baseline BP than healthy volunteers) was 7 mm Hg had hyperlipidemia, 20% had diabetes and 11% had in the standing position and thus greater than in depression. The authors concluded that ED shared healthy volunteers.15 This finding likely represents common risk factors associated with cardiovascular- an epi-phenomenon in that when vasodilators are risk factors. administered, the reduction in BP tends to be greater Thus, patients with hypertension are more likely when given to patients with higher versus lower to have ED; and patients with ED are more likely to baseline BP. have hypertension. Although intravenous sildenafil was associated The mechanism by which hypertension may with a dose-related reduction of systolic BP (systolic cause ED is likely related to endothelial dysfunction BP ¼ 131712 mm Hg with placebo; 129712 mm Hg associated with hypertension. Long-standing hypertension may cause oxidate stress, endothelial cell injury and its sequella, including the inability a of the arteries, arterioles and sinusoids of the corpus Table 1 Effect of PDE5 inhibitors on BP cavernosum to dilate properly. It is also possible Sildenafil (100 mg) À8.4/À5.5 mm Hg (systolic/diastolic) that non-endothelium-dependent impairment of supineb vasodilatation such as damage to smooth muscle Tadalafil (20 mg) À1.6/À0.8 mm Hg (systolic/diastolic) cells contributes to ED in the hypertensive patient. supine Vardenafil (20 mg) À7/À8 mm Hg (systolic/diastolic) Another contributing factor may be the anti- supine hypertensive medicines themselves. For example, thiazide diuretics and beta blockers are known Abbreviations: BP, blood pressure; PDE5, Phosphodiesterase-5. 6,7 a to worsen ED. In general, the calcium channel Data taken from 2006 PDR. b blockers and angiotensin converting enzyme inhibi- Minus signs indicate a reduction in BP in the supine position in 7 tors do not worsen ED compared to placebo. Of healthy volunteers.

International Journal of Impotence Research Erectile dysfunction and hypertension R Kloner 298 with 20 mg; 124714 mm Hg with 40 mg, and 14.0 at baseline to 23.4 after therapy; it increased the 122713 mm Hg with 80 mg of intravenous sildena- Sexual Encounter Profile Question 2 (SEP2) from fil;10 oral doses of 50–200 mg were not associated 44.5 to 78.8% and SEP3 from 21.0 to 66.1% versus with dose-dependent fall in either systolic or placebo (Po0.001 versus placebo for all the three diastolic BP.10,17 measures). Tadalafil’s improvement in ED in hyper- In summary, PDE5 inhibitors are mild vasodilators tensive patients on thiazides was similar to its that can result in small reductions in systemic improvement in patients not taking thiazides. For arterial pressures that in general are not clinically patients on thiazides – a positive global assessment significant. question (GAQ) response (% yes) was recorded in 87.4% of patients receiving tadalafil versus 32.6% for patients taking placebo (Po0.001 tadalafil versus placebo). In patients not taking thiazides Are PDE5 inhibitors effective for ED in men the response to tadalafil versus placebo (85.2 versus with hypertension receiving antihyperten- 38.2; Po0.001) was similar. Therefore, the PDE5 sive therapy? inhibitor tadalafil was quite effective in treating ED even in patients on thiazide diuretics.21 The answer to this question is yes. We studied the Vardenafil has also been shown to be effective for efficacy and safety of sildenafil in men with ED treating ED in hypertensive men on antihyper- including those taking multiple antihypertensive tensive agents.22 Van Ahlen et al.22 studied the medicines. The efficacy of sildenafil in these safety and efficacy of vardenafil in men with arterial patients with hypertension was about 70%.18 Pick- hypertension and ED, receiving at least one anti- ering et al.19 also studied the efficacy and safety of hypertensive medicine. This was a multicenter, sildenafil in men who were taking multiple anti- randomized, double-blind placebo-controlled study hypertensive medicines. This study included males of 354 patients. Patients were randomized to older than 18 years with a documented history of ED receive placebo or vardenafil 5–20 mg over 12 confirmed by a SHIM score o21 and in a stable weeks. Vardenafil significantly improved the mean relationship. They had to have a history of hyper- response to SEP2 (success of vaginal insertion) and 3 tension, being treated with two or more antihyper- (maintenance of erection). For SEP2, vardenafil was tensive medications and on a stable dose for at least successful in 83% of the men versus 58% for those 4 weeks. Two hundred and eighty-three patients on placebo; for SEP3 vardenafil was successful in 67 received placebo and 279 received sildenafil. There versus 35% for placebo (Po0.0001 versus placebo). were 307 subjects who were taking two antihyper- Responses to the GAQ showed improved erections tensive medicines whereas 222 were taking three in 80% of vardenafil patients versus 40% of or more. The percentage of patients who reported the placebo patients (Po0.0001). Average number improved erections in the sildenafil group was 71 of antihypertensives per patient was 1.4–1.5. The versus 17.6% in the placebo group; the percentage of efficacy of vardenafil was unaffected by the type patients who reported successful sexual intercourse of antihypertensive agent the patient was taking. attempts was 62.4% in the sildenafil group versus Vardenafil did not significantly alter the BP or heart 26.1% in the placebo group. rate compared to placebo. Headache (3.1%) and As thiazide diuretics are recommended by the flushing (1.6%) were the most commonly reported Seventh Report of the Joint National Committee on treatment-emerging adverse events and in general the Prevention, Detection, Evaluation and Treatment were mild-to-moderate in severity as well as of High Blood Pressure,20 but thiazide diuretics transient. The authors concluded that vardenafil themselves may be associated with the develop- improved erectile function in men with hyper- ment of ED, we tested whether the PDE5 inhibitor tension treated with antihypertensive medicines tadalafil could demonstrate efficacy for treating ED including those on multiple antihypertensive in patients who were hypertensive and receiving medicines without significantly altering BP. 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 Effect of PDE5 inhibitors plus usual identified, who were receiving thiazide diuretics antihypertensive medicines on BP (116 in the tadalafil groups and 47 in the placebo groups). Of note, a higher percentage of patients In general, when a PDE5 inhibitor is administered on thiazides had severe ED at baseline, which is on top of antihypertensive medicines, there are consistent with studies suggesting that thiazides small additive reductions in BP that are similar to may exacerbate ED; however, these same patients the reduction in BP that occurs with the PDE5 tended to be older, and had other comorbidities inhibitor alone. In one early study by Webb et al.,11 compared to patients not on thiazides. Tadalafil which was a double-blind, placebo-controlled, improved the IIEF in patients taking thiazides from crossover study, 16 hypertensive men who were

International Journal of Impotence Research Erectile dysfunction and hypertension R Kloner 299 being treated with amlodipine (5–10 mg per day) potentially related to the lowering of BP (hypo- received a single oral dose of sildenafil (100 mg) or tension, flushing, dizziness) was not different in placebo 2 h after their usual dose of amlodipine. The patients receiving sildenafil plus no antihyper- additional reduction of BP on top of amlodipine was tensive medicines, versus sildenafil plus 1, 2 or À8 mm Hg systolic (supine) and À10 mm Hg systolic X3 antihypertensive medicines. Furthermore, there (standing), and À7 mm Hg diastolic (supine) and were no patients who developed angina, coronary À8 mm Hg diastolic (standing), numbers that are artery disease or myocardial infarction when silde- similar to the effect of sildenafil on BP in patients nafil was administered on top of antihypertensive not on amlodipine. Hence, sildenafil caused an medication. In a study by Pickering et al.,19 treat- additive – not a synergistic or multiplicative effect ment adverse events related to sildenafil, such as upon reduction of BP in the setting of the calcium headache, flushing, dyspepsia and others, were blocker, amlodipine. Zusman et al.23 then studied similar among patients who were taking multiple the effect of sildenafil in a broader group of patients antihypertensive medications to those that had been that were part of randomized, double-blind, place- reported for patients on sildenafil not on antihyper- bo-controlled studies in which patients received tensives. placebo versus sildenafil and were either on no Also, there was no increased incidence of adverse antihypertensives, diuretics, beta blockers, alpha events (except flushing) in patients receiving tada- blockers, ACE inhibitors or calcium channel block- lafil and single or multiple antihypertensive ers. Sildenafil appeared to have either no effect or agents.14,24 In studies assessing the use of vardenafil minimal effect on BP in this study.23 in patients on antihypertensive medicines, there Studies on tadalafil showed either no change or was no increase in adverse events.22 Thus, PDE5 minor augmentation of BP lowering effects with inhibitors can be safely administered with usual concomitant use of all major classes of antihyper- antihypertensive agents including diuretics, beta tensive therapy.24 There were no further decreases blockers, calcium blockers and angiotensin receptor in BP with the calcium channel blocker amlodipine blockers. There is a precaution, however, with alpha when tadalafil was added. There were small blockers that will be explained below. changes in BP when tadalafil was administered in the presence of the beta blocker metoprolol (À7/À4 mm Hg; standing BP) or thiazide diuretic (À6/À4 mm Hg). There were small additive effects The nitrate contraindication observed when tadalafil was administered to patients taking the angiotensin converting enzyme All three PDE5 inhibitors are contraindicated in inhibitor enalapril (À3/À1 mm Hg) or various angio- patients taking organic nitrates (including short- tensin receptor blockers (À8/À4 mm Hg). acting or long-acting nitroglycerin, isosorbide Vardenafil was studied in a double-blind, two- dinitrate, isosorbide mononitrate, amyl nitrate and way crossover manner in 22 men with hypertension others). Organic nitrates increase cyclic GMP pro- who were taking 30 or 60 mg of nifedipine per day. duction whereas PDE5 inhibitors decrease cyclic Patients were randomly assigned to receive either GMP breakdown. Therefore, there is a synergistic vardenafil 20 mg or placebo. There were small drop in BP when PDE5 inhibitors are given changes in hemodynamic effects with the addition with organic nitrates that results in symptomatic of vardenafil.13 In other studies, vardenafil was hypotension in some patients.11–13,15,16 associated with minimal additional reductions in If a patient has taken a PDE5 inhibitor and then BP when it was administered to patients on a variety develops chest pain, when is it safe to re-introduce of antihypertensive medications.25,26 Thus, in sum- nitroglycerin? The original American College of mary, when PDE5 inhibitors are given to patients Cardiology/American Heart Association guidelines with hypertension on antihypertensive medications, suggested that for sildenafil, 5–6 half-lines or 24 h there are either no or small additive drops in BP. 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 Does the addition of PDE5 inhibitors interaction between sildenafil and nitrate 24 h after to antihypertensive agents increase their sildenafil was administered.15 There is an unpub- adverse events? lished study suggesting a lack of interaction with nitroglycerin at 24 h after vardenafil, consistent In studies in which sildenafil versus placebo was with its 4 h half-life.13 Finally, one study suggests administered to patients on antihypertensive med- an interaction between tadalafil (half-life 17.5 h) and icine, there was no increase in treatment disconti- nitroglycerin that is present at 24 h after a dose of nuations owing to adverse events in patients tadalafil but that is gone by 48 h and beyond.29 receiving sildenafil.27 In a study by Kloner et al.,18 Thus, although all three PDE5 inhibitors are con- the incidence of treatment-related adverse events traindicated in patients receiving either short-acting

International Journal of Impotence Research Erectile dysfunction and hypertension R Kloner 300 or long-acting nitrates, should a patient with ED take patient is already taking an optimal dose of PDE5 a PDE5 inhibitor and then develop angina, nitrogly- inhibitor and an alpha blocker needs to be started, cerin should not be reintroduced until the alpha blocker should be started at the lowest after 24 h for sildenafil or vardenafil and after 48 h dose. Other variables such as intravascular volume for tadalafil. Of course, other antianginal and status and use of other antihypertensives should be anti-ischemic therapies may be used – such as beta considered when using a combination of PDE5 blockers, calcium blockers, aspirin, morphine, sta- inhibitor and alpha blocker. tins and percutaneous coronary intervention. None There was initially a contraindication for the use of these are contraindicated with PDE5 inhibitors. of vardenafil in patients on alpha blockers. Initial The American College of Cardiology/American studies showed that 10 mg vardenafil plus 10 mg Heart Association Guidelines address the approach terazosin given simultaneously to healthy subjects to the patient who has developed hypotension in the resulted in a standing systolic BP of less than 85 mm setting of PDE5 inhibitors plus nitrates.28 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 Interactions of PDE5 inhibitors with alpha subjects had a reduction in standing systolic BP blockers o85 mm Hg.30 The interaction was less prominent when varde- As described earlier, most studies to date showed nafil was given with tamsulosin (an alpha 1a small additive drops in BP when PDE5 inhibitors blocker, 0.4 mg used for benign prostatic hypertro- were given to patients already taking beta blockers, phy). Vardenafil 10 mg plus tamsulosin given calcium blockers, angiotensin converting enzyme simultaneously resulted in 2/16 healthy subjects inhibitors, angiotensin receptor blockers and diure- dropping their standing systolic BP to less than tics. An exception to these findings can be the alpha 85 mm Hg; 1/24 dropped their standing BP to this blockers, which in some patients may be associated level when vardenafil plus tamsulosin administra- with an increase in orthostatic hypotension when tion were separated by 6 h.30 administered with PDE5 inhibitors. Alpha blockers As a patient’s response to PDE5 inhibitor plus of course may be used for treating hypertension, alpha blocker may depend on whether the patient benign prostatic hypertrophy or both. has been on the alpha blocker chronically or acutely, In an unpublished study (but described in the a series of studies examined the interaction of package insert12), 2/20 patients with benign pro- vardenafil plus tamsulosin or terazosin in benign static hypertrophy receiving 4 mg doxazosin plus prostatic hypertrophy patients who had been on 50 mg sildenafil simultaneously developed sympto- stable alpha blocker therapy. In these studies, zero to matic postural hypotension, whereas no orthostatic few patients dropped their systolic BP to o85 mm Hg hypotension was observed with the combination of whether the two drugs were administered simulta- 4 mg doxazosin plus a 25 mg dose of sildenafil. The neously or were given 6 h apart.30–32 Largely as a labeling initially was that precaution is advised result of some of these newer analyses, the labeling such that a 50 or 100 mg dose of sildenafil should for vardenafil has changed to a precaution (and not a not be taken within a 4-h window of alpha blocker contraindication) for using vardenafil in patients administration, whereas a 25-mg dose of sildenafil receiving alpha blockers. The labeling does recom- may be taken at any time in relationship to an alpha mend starting with the lowest dosages of both drugs. blocker. In one study,33 20 mg tadalafil plus 8 mg doxazo- As of June 2006, there was a change in the labeling sin given simultaneously in healthy subjects caused bringing the precaution for sildenafil and alpha a decrease in BP to o85 mm Hg in 28 versus 6% blockers in line with that of the other PDE5 inhi- in the placebo (no tadalafil) group. Three subjects bitors. The wording for the precaution is now: ‘Caution became dizzy. In contrast, 10 or 20 mg of tadalafil is advised when PDE5 inhibitors are co-administered given with 0.4 mg tamsulosin (alpha 1a blocker) was with alpha blockers. PDE5 inhibitors, including not associated with drops in standing systolic BP to VIAGRA, and alpha-adrenergic blocking agents are o85 mm Hg. Although tadalafil was initially contra- both vasodilators with BP lowering effects. When indicated with alpha blockers other than tamsulo- vasodilators are used in combination, an additive sin, that contraindication has now been removed. effect on BP may be anticipated. In some patients, There is now a precaution for the use of tadalafil concomitant use of these two drug classes can lower with alpha blockers. Again, low starting doses are BP significantly leading to symptomatic hypotension encouraged. (e.g. dizziness, light headedness, fainting).’ Thus, all three PDE5 inhibitors now carry precau- The precaution goes on to suggest that patients tions regarding the use of alpha blockers, warning of should be on stable alpha-blocker therapy before the possible development of orthostatic hypotension PDE5 inhibition and that lowest doses of the PDE5 with drug combination, but no longer are the PDE5 inhibitors be used to initiate therapy. Conversely, if a inhibitors contraindicated with alpha blockers.32

International Journal of Impotence Research Erectile dysfunction and hypertension R Kloner 301 Although this article focuses on patients with antihypertensive drugs and nutritional hygienic treatment in controlled hypertension, should men with ED who hypertensive men and women. Treatment of Mild Hyperten- have uncontrolled or severe hypertension receive sion Study (TOMHS). Hypertension 1997; 29: 8–14. 8 Fogari R, Zoppi A, Poletti L, Marasi G, Mugellini A, Corradi L. treatment for ED? This issue was raised in the 34 Sexual activity in hypertensive men treated with valsartan or Second Princeton Consensus Conference. In gen- carvedilol: a crossover study. Am J Hypertens 2001; 14: 27–31. eral, the consensus was that in these patients the 9 Keene LC, Davies PH. Drug-related erectile dysfunction. cardiovascular problem (severe hypertension) Adverse Drug React Toxicol Rev 1999; 18: 5–24. 10 Jackson G, Benjamin N, Jackson N, Allen MJ. Effects of should be treated before initiating therapy for sexual sildenafil citrate on human hemodynamics. Am J Cardiol dysfunction. 1999; 83: 13C–20C. 11 Webb DJ, Freestone S, Allen MJ, Muirhead GJ. Sildenafil citrate and blood-pressure-lowering drugs: Results of drug interaction studies with an organic nitrate and a calcium Conclusions antagonist. Am J Cardiol 1999; 83: 21C–28C. 12 Sildenafil Prescribing Information. Pfizer Inc.: New York, 2004. 1. Patients with hypertension may also have ED. 13 Product monograph for Levitra (Vardenafil hydrochloride) Ask hypertensive patients about their sexual Bayer Health Care: West Haven, CT and Glaxo SmithKline: Research Triangle Park, NC, 2003. health. 14 Emmick JT, Stuewe SR, Mitchell M. Overview of the 2. Patients with ED may have hypertension. Be sure cardiovascular effects of tadalafil. Eur Heart J Suppl 2002; 4: to ask patients presenting with ED about their H32–H47. cardiovascular-risk factors, including hyperten- 15 Kloner RA, Mitchell M, Emmick JT. Cardiovascular effects of 35 tadalafil. Am J Cardiol 2003; 92: 37M–46M. sion. Be sure to obtain a BP reading on these 16 Kloner RA, Jarow JP. Erectile dysfunction and sildenafil citrate men. These men should also be assessed for the and cardiologists. Am J Cardiol 1999; 83: 576–582. presence of dyslipidemia, diabetes, smoking, 17 Zusman RM, Morales A, Glasser DB, Osterloh IH. Overall obesity and lack of physical exertion. cardiovascular profile of sildenafil citrate. Am J Cardiol 1999; 3. PDE5 inhibitors are in general effective and safe 83(Suppl 5A): 35C–44C. 18 Kloner RA, Brown M, Prisant LM, Collins M, for the Sildenafil in hypertensive patients taking antihypertensive Study Group. Effect of sildenafil in patients with erectile medications, including multiple antihypertensive dysfunction taking antihypertensive therapy. Am J Hypertens medicines. 2001; 14: 70–73. 4. PDE5 inhibitors are contraindicated in patients 19 Pickering TG, Mancia G, Glasser DB, Orazem J. Safety of Viagra (sildenafil citrate) in men with erectile dysfunction and taking organic nitrates owing to a synergistic arterial hypertension who are taking multiple antihyperten- drop in BP. sive treatments. Am J Hypertens 2002; 15(Suppl 1): A55–A56. 5. PDE5 inhibitors should be used with caution in 20 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, patients receiving alpha blockers as some patients Izzo Jr JL et al. The Seventh report of the joint national may develop orthostatic hypotension. The lowest committee on prevention, detection, evaluation, and treatment of high blood pressure: The JNC 7 report. JAMA 2003; 289: starting doses should be considered. 2560–2572. 21 Kloner RA, Sadovsky R, Johnson EG, Mo D, Ahuja S. Efficacy of tadalafil in the treatment of erectile dysfunction in hypertensive men on concomitant thiazide diuretic therapy. References Int J Impotence Res 2005; 17: 450–454. 22 Van Ahlen H, Wahle K, Kupper W, Yassin A, Reblin T, 1 Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, Neureither M. Safety and efficacy of vardenafil, a selective McKinlay JB. Impotence and its medical and psychosocial phosphodiesterase 5 inhibitor, in patients with erectile correlates: results of the Massachusetts Male Aging Study. dysfunction and arterial hypertension treated with multiple J Urol 1994; 151: 54–61. antihypertensives. J Sex Med 2005; 2: 856–864. 2 Burchardt M, Burchardt T, Baer L, Kiss AJ, Pawar RV, Shabsigh 23 Zusman RM, Prisant LM, Brown MJ, for the Sildenafil A et al. Hypertension is associated with severe erectile Study Group. Effect of sildenafil citrate on blood pressure dysfunction. J Urol 2000; 164: 1188–1191. and heart rate in men with erectile dysfunction taking 3 Giuliano FA, Leriche A, Jaudinot EO, deGendre AS. concomitant antihypertensive medication. J Hypertens 2000; Prevalence of erectile dysfunction among 7689 patients 18: 1865–1869. with diabetes or hypertension, or both. Urology 2004; 64: 24 Kloner RA, Mitchell M, Emmick JT. Cardiovascular effects of 1196–1201. tadalafil in patients on common antihypertensive therapies. 4 Sun P, Swindle R. Are men with erectile dysfunction more Am J Cardiol 2003; 92(Suppl): 47M–57M. likely to have hypertension than men without erectile 25 Padma-Nathan H, Porst H, Eardley I, Thibonnier M. Efficacy dysfunction? A naturalistic national cohort study. J Urol and safety of vardenafil, a selective phosphodieserase 5 2005; 174: 244–248. inhibitor, in men with erectile dysfunction on antihyperten- 5 Seftel AD, Sun P, Swindle R. The prevalence of hyper- sive therapy (abstract). Am J Hypertens 2002; 15: 48A. tension, hyperlipidemia, diabetes mellitus, and depression 26 Kloner RA, Mohan P, Segerson T, Thibonnier M, Norenberg C, in men with erectile dysfunction. J Urol 2004; 171(6 Part 1): Padma-Nathan H. Cardiovascular safety of vardenafil in 2341–2345. patients receiving antihypertensive medications: a post–hoc 6 Wassertheil-Smoller S, Blaufox D, Oberman A, Davis BR, analysis of fine placebo-controlled trials. J Am Coll Cardiol Swencionis C, Knerr MO et al. for the TAIM Research Group. 2003; 41(Suppl A): 276A–277A. Effect of antihypertensive on sexual function and quality of 27 Pfizer Inc., New York, NY. [Based on a retrospective analysis life: The TAIM Study. Ann Intern Med 1991; 114: 613–620. of the intent-to-treat population from 25 double-blind, 7 Grimm Jr RH, Grandits GA, Prineas RJ, McDonald RH, Lewis placebo-controlled, fixed and flexible-dose, clinical trials]. CE, Flack JM et al. 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International Journal of Impotence Research Erectile dysfunction and hypertension R Kloner 302 28 Cheitlin MD, Hutter Jr AM, Brindis RG, Ganz P, Kaul S, prostatic hypertrophy. Am J Hypertension 2004; 17: 16A, Russell Jr RO et al. ACC/AHA expert consensus document. Abstract OR35. Use of sildenafil (Viagra) in patients with cardiovascular 32 Kloner RA. Pharmacology and drug interaction effects of the disease: American College of Cardiology/American Heart phosphodiesterase 5 inhibitors: focus on a-blocker inter- Association. J Am Coll Cardiol 1999; 33: 273–282. actions. Am J Cardiol 2005; 96: 42M–46M. 29 Kloner RA, Hutter AM, Emmick JT, Mitchell MI, Denne J, 33 Kloner RA, Jackson G, Emmick JT, Mitchell MI, Bedding A, Jackson G. Time course of the interaction between tadalafil Warner MR et al. Interaction between the phosphodiesterase 5 and nitrates. J Am Coll Cardiol 2003; 42: 1855–1860. inhibitor tadalafil and 2 a-blockers, doxazosin and tamsulosin 30 Bayer Health Care, Glaxo Smith Kline, and Presented to in healthy normotensive men. J Urol 2004; 172: 1935–1940. US Food and Drug Administration Cardiovascular and 34 Kostis JB, Jackson G, Rosen R, Barrett-Connor E, Billups K, Renal Drugs Advisory Committee: Levitra tablets, 2003, (data Burnett AL et al. Sexual dysfunction and cardiac risk (the on file). Second Princeton Consensus Conference). Am J Cardiol 2005; 31 Auerbach S, Gittelman M, Mazzu A, Sundaresan P, White W. 96: 313–321. Coadministered vardenafil (for erectile dysfunction) and 35 Kloner RA. Hypertension as a risk for erectile dysfunction: tamsulosin do not induce hypotension in patients with benign implications for sildenafil use. J Clin Hypertens 2000; 2: 33–36.

International Journal of Impotence Research