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SILDENAFIL CITRATE IN THE TREATMENT OF ERECTILE DYSFUNCTION ASSOCIATED WITH HYPERTENSION.

Byline: Abdul Monim Al-Qasim and Syed Tabrez Ali

ABSTRACT

Sildenafil citrate is a potent inhibitor of the electrolytic enzyme type V phosphodiesterase (PDE5) in the corpus cavernosum and therefore increases the penile responses to sexual stimulation associated with erectile dysfunction (ED), which is a common complaint for the patients with hypertension and those taking antihypertensive agents. We evaluated the efficacy of sildenafil citrate compared with placebo in treated and untreated hypertensive subjects with established ED. In this study both the patients taking and those not taking antihypertensive medications treated with 100 mg oral dose of sildenafil showed significant improvement than placebo in the mean scores for the questions of the International Index of Erectile Function (IIEF). Mean domain of erectile function, orgasmic function, intercourse satisfaction and overall satisfaction showed a significantly positive improvement (pandlt;0.001) in both types of sildenafil treated patients in comparison with the placebo group. However, the sexual-desire domain in

sildenafil treated men with respect to their placebo group showed a non-significant difference. The therapeutic response to the sildenafil in these patients with ED was not affected by whether they were taking concomitant antihypertensive medication.

Sildenafil citrate is an effective and well-tolerated treatment for ED in patients taking antihypertensive medication and represents an exciting class of drug with plelotropic effect with potential clinical application in a variety of cardiovascular conditions.

INTRODUCTION

Although hypertension itself is asymptomatic, it is often associated with severe erectile dysfunction (ED) (Burchardt et al., 2000). This link can be partially explained by the recognized association between traditional vascular risk factors and ED (Sullivan et al., 2001; Solomon et al., 2003). In USA, for example, approximately 36% and 20% of men in their 5th decade have hypertension and ED, respectively, while both these figures increase to over 60% by the age of 70 years (Johannes et al., 2000). With the global increase in life expectancy, obesity rates and the associated vascular disease, one can foresee a burgeoning health burden from both hypertension and ED (Ayta et al., 1999; Murray and Lopez, 1996). Addressing these linked vascular disorders with a single agent is a novel yet logical approach, particularly when considering that antihypertensive drug treatment has often been implicated as a cause of ED. Erectile dysfunction (ED) is a highly prevalent disease, as well as a major sexual concern for men (Braun et al.,2000; Martin-Morales et al., 2001; Papaharitou et al., 2006). The prevalence of ED is increasing with age. The Massachusetts Male Aging Study (MMAS) demonstrated a 40% prevalence of ED in men aged 40 years that increased to almost 70% in men aged 70 years (Feldman et al., 1994). As the proportion of older people in the population increases, it has been estimated that the worldwide prevalence of ED will double from 152 million men in 1995 to 322 million men in 2025 (Aytac et al., 1999).

ED is also associated with other conditions such as age, smoking, hypertension, heart disease, diabetes, and as a consequence of radical prostatectomy. Cardiovascular disease (CVD) and ED share common risk factors and reflect endothelial dysfunction (Kostis et al., 2005, Viachopoulos et al., 2009). There is an increasing body of evidence that ED is the first sign of CVD in men with free medical history and may present well before CVD with a mean time-interval of even 3 years (Montorsi et al.,2003).

The availability of phosphodiesterase type 5 inhibitors (PDE5i) has resulted in increasing numbers of patients seeking medical help for erectile function problems, but has also altered dramatically the medical management of ED (Hatzichristou and Pescatori, 2001; Lewis et al., 2001; Steers et al., 2001). Sildenafil citrate, the first agent in the class of phosphodiesterase-5 (PDE5) inhibitors to receive regulatory approval, has been shown to have mild transient peripheral vasodilatory and hypotensive effects (Gillies et al., 2002), in addition to its beneficial effects in the penile asculature. Furthermore, new data suggest that sildenafil has beneficial effects in several chronic Corresponding author: email: shazali_2004@hotmail.com J. basic appl. sci. 24 conditions. It has been recently approved for the treatment of idiopathic pulmonary hypertension (Galie et al., 2005),and numerous articles have suggested that PDE5 may improve endothelial function (Katz et al., 2000; Desouza et al., 2002; Halcox et al., 2002; Valchopoulos et al., 2003; Valchopoulos et al., 2004; Gori et al., 2005; Hitata et al., 2005). Sildenafil is a highly selective inhibitor of PDE type 5 (Boolell et al., 1996; Gberkor et al., 2002). It enhances nitric oxide (NO) mediated relaxation of human corpus cavernosum in vitro (Ballard et al., 1998; Stief et al., 1998; Gemalmaz et al., 2001). Sildenafil, by inhibiting phosphodiesterase, increases the intracellular

concentrations of cyclic guanosine 3', 5' monophosphate (cGMP), causing an amplification of the endogenous NOcGMP signaling pathway. Oral sildenafil (100 mg) produces transient decreases in systolic (8-10 mmHg) and diastolic (3-to 6 mmHg) blood pressure in healthy male volunteers (Molares et al., 1998). Sildenafil was initially introduced for clinical use in the treatment of coronary heart disease. In addition to the effects of the nitric oxidecGMP signaling pathway on cavernosal smooth muscle, clinical findings have suggested that vascular tone in the pulmonary, coronary, and other vascular tissues expressed by PDE-5 is also influenced by this signal transduction mechanism. This has led to the emergence of novel therapeutic indications for sildenafil over a range of cardiovascular conditions that are either well-established risk factors or comorbidities with erectile dysfunction (Ravilpati et al., 2007).

Studies using sildenafil have suggested that there is a shallow dose-response curve for haemodynamic effects. However, the effect of 100 mg sildenafil in hypertensive subjects on multiple antihypertensive therapies and in hypertensive subjects with no antihypertensive therapy has not been tested in a large study. In the present study we have evaluated the efficacy of sildenafil citrate in men having erectile dysfunction receiving concomitant treatment with antihypertensive agents.

MATERIALS AND METHODS

For experimental purposes after getting the permission from the local ethical committee, a total of 168 male patients (70% of whom were taking some kind of antihypertensive medication) aged between 20 to 65 years were randomized to 100 mg of sildenafil citrate (Viagra TM Pfizer, USA) or placebo for 6 weeks to 6 months with a clinical diagnosis of erectile dysfunction for at least 6 months. Patients were excluded if they had penile anatomical defect, a recent (within the previous 6 months) history of stroke, myocardial infraction, or lifethreatening arrhythmia, a resting blood pressure andlt;.90/50 mmHg or andlt;170/110 mmHg or receiving regular treatment with nitrates or anticoagulants.

Impotence was determined according to the method of Bancroft and Bell (1985) as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance.

Informed consent was obtained from 100 screened subjects who were using 100 mg of oral sildenafil citrate and placebo in the treatment of erectile dysfunctions in both groups who were taking antihypertensive medications or who were not taking any antihypertensive agent. Subject's home and clinical practice centers in the local vicinities, were randomized to receive sildenafil citrate (100 mg), but not more than once daily, for 12 months. Self-reported ability to achieve and maintain an

erection for sexual intercourse was determined according to the International Index of Erectile Function (IIEF) a multidimensional scale for assessment of erectile dysfunction (15 questions) according to the method described by Rosen et al., (1997).

Based on the scores of (IIEF)-5, efficacy was assessed for the five separate response domains of male sexual functions including erectile function (question 1 through 5 and 15), orgasmic function (question 9 and 10), sexual desire (question 11 and 12), intercourse/masturbation satisfaction (questions 6,7 and 8), and overall satisfaction (question 13 and 14). The IIEF demonstrates the sensitivity and specificity for detecting treatment-related changes in patients with erectile dysfunction. Comparisons between mean responses for patients taking versus not taking antihypertensive agents in both the

sildenafil/placebo groups were analyzed using Student's ttest for the significant differences. In all instances probability (pandlt;0.05) was regarded as statically significant.

RESULTS

The mean (+- SE) scores for domain of the erectile function (five questions; possible total score, 1 to 30) for 100 men in sildenafil group than the placebo group for both patients taking and those not taking antihypertensive agents is presented in figure-1. Sildenafil group showed a highly significant and positive response in erectile function (pandlt;0.001) than the placebo group.

Mean orgasmic function domain score (two questions; possible total score, 0-12) presented in Figure-2 showed a similar positive response in sildenafil group when compared with the placebo subjects (pandlt;0.001).

A comparison regarding the sexual desire domain (two questions; possible total score, 0-12); between the sildenafil treated men with respect to their age matched placebo group showed a non-significant difference (Fig.3).

The mean domain scores for the intercourse/masturbation satisfaction (three questions; possible total score, 0-12);and overall satisfaction (two questions; possible total score, 0-12) for the sildenafil group and the placebo group is presented in Figures 4 and 5. These results indicated a highly significant and positive response for both the domains in sildenafil treated groups (pandlt;0.001).

All results were tabulated according to the mean (+-SE) scores for Domains of the International Index of erectile Function for men receiving sildenafil citrate in comparison with the age matched placebo group.

At the end of the treatment, improved erections were reported by 70% of the patients receiving sildenafil and taking concomitant antihypertensive medication and by 75% of patients in the sildenafil group who were not taking any antihypertensive agent. The values for placebo groups were 20% and 25% respectively and were significantly different (pandlt;0.001) from the values for the corresponding sildenafil group (data not shown).

DISCUSSION

A substantial number of men with hypertension and those taking antihypertensive agents have ED (Prisant et al., 1994). Treatment with oral sildenafil can provide these patients with a therapy that is effective and well tolerated.However the mechanism responsible for the haemodynamics effect of sildenafil requires clarification. The vasodilatory mechanism is known to interact with both nitrate and a-blocker therapy. PDE5 inhibitors are contraindicated with nitrates due to the ubstantial potentiation of hypotensive effects. Sildenafil citrate has been shown to increase renin production in normotensive men (Chen et al., 2003), a possible mechanism limiting its vascular vasodilatory effect. Unfortunately, we did not measure renin values during this study to confirm this hypothesis.

The use of sildenafil and other PDE-5 inhibitors in subjects at risk of cardiovascular disease has not been associated with adverse effects on cardiovascular morbidity or mortality (Boshier et al., 2004; Derry et al., 2002). Data from clinical trials performed in the general population of men with ED, including those with cardiovascular disease, show that the incidence of cardiovascular adverse events is not increased in men taking sildenafil and is similar to that observed in the

general population of men with ED (Behr-Roussel et al., 2005; Deforge et al., 2006). This study has demonstrated that men with resistant hypertension are more likely to have severe ED and may have an improved quality of life on sildenafil. ecause sildenafil is a mixed arterial venous dilator (Jackson et al., 1999), and many antihypertensive agents exhibit irect or indirect vasodilating properties, it was important to determine whether treatment with sildenafil might potentiate the decrease in blood pressure achieved with the antihypertensive agents. Although large-scale drug-drug interaction studies have not been conducted with sildenafil and the antihypertensive agents, no synergistic interaction was observed in a ouble-blind, placebo-controlled crossover study in which sildenafil (100mg) was co administered with calcium channel

blocker amlodipine to men with essential hypertension (Webb et al., 1999).

The present study assessed the efficacy of sildenafil in the patients with ED who were treated with sildenafil either with or without concomitant antihypertension medications. The therapeutic response to sildenafil in these patients with ED was not affected by whether they were taking concomitant antihypertensive medication. Overall sexual improvement changes were similar in sildenafil treated patients taking antihypertensive medications and those not taking any antihypertensive medication. Importantly antihypertensive agents taken by the patients had no affect on the adverse event profile of sildenafil. These results reflect the different mechanism of action of sildenafil and the various antihypertensive

agents. Sildenafil causes levels of cGMP to increase in vascular smooth muscle, thereby resulting in vasodilation (Kloner et al., 1999) whereas antihypertensive agents exert their therapeutic effects by mechanism other than the nitric oxide-cGMP pathway.

In conclusion, the result of this study suggests that sildenafil citrate is an effective and well-tolerated treatment for ED in patients taking concomitant antihypertensive medication.

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Webb, DJ. Freestone, S. And Allen, MJ. 1999. Sildenafil citrate and blood pressure lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am. J. Cardiol. (Suppl. 5A): 21C-28C. SILDENAFIL CITRATE IN THE TREATMENT OF ERECTILE DYSFUNCTION ASSOCIATED WITH HYPERTENSION Abdul Monim Al-Qasim and Syed Tabrez Ali Department of Physiology, Faculty of Medicine, Umm-Al-Qura University, Makkah, SaudiArabia
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Publication:Journal of Basic & Applied Sciences
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