:: Asian Journal of Andrology ::

New oral agents for erectile dysfunction: what is changing in our practice?

Antonio Aversa^1,2, Andrea Fabbri²

¹AFaR-CRCCS, Fatebenefratelli-Isola Tiberina Hospital and ²Endocrinology Unit, Department of Internal Medicine, University of Rome Tor Vergata, 00133 Rome, Italy

Asian J Androl 2001 Sep; 3: 175-179

Keywords: erectile dysfunction; oral medicine; therapy; phosphodiesterase inhibitors; apomorphine; nitric oxide

Abstract

Erectile dysfunction (ED) is a highly prevalent disorder affecting an estimated 152 million men worldwide and is associated with a variety of behavioral risk factors, such as cigarette smoking and excessive alcohol consumption, as well as numerous age-related medical conditions, notably type-2 diabetes mellitus and cardiovascular disease. A rational step-wise approach which includes comprehensive medical and sexual history, a focused physical examination and essential laboratory tests such as fasting glucose, lipid profile and testosterone assay is to be preferred. Current diagnostic work-up does not recommend any of the specialized tests which were previously considered mandatory-i.e. penile pharmacotesting, Duplex ultrasound and nocturnal penile tumescence. Hormonal replacement therapy is appropriate only in the hypogonadal male with ED. Prior to direct intervention, the physician should consider altering modifiable risk factors or causes, although frequently insufficient to reverse ED completely. When indicated, oral therapy with new molecules (phosphodiesterase inhibitors or apomorphine) is the first-line treatment for the majority of patients because of potential benefits and lack of invasiveness.

1 Introduction

Male erectile dysfunction (ED) is defined as the consistent or recurrent inability to attain and/or maintain penile erection sufficient for sexual performance for at least three months duration^[1]. Epidemiological studies to date indicate that ED is a universal problem in aging males and it has been projected that by 2025 it will affect approximately 350 million men worldwide^[2], with only 20 % seeking for treatment. In addition to age, it may result from psychological, neurological, hormonal, arterial, or cavernosal impairment and more frequently, from a combination of these factors. The prevalence of ED is significantly higher in men suffering from cardiovascular diseases, depression and benign prostatic hyperplasia, as well as in patients with chronic illness, pelvic trauma and surgery, alcoholism, heavy smoking and drug treatment for concomitant medical conditions^[3]. In the last few years the clinical context of the diagnosis and treatment of ED has changed a lot. There is a general trend away from taking up invasive surgical solutions; oral compounds with enhanced selectivity have been developed phosphodiesterase (PDE) inhibitors or are under active clinical study (centrally active agents). In this article we shall review the different classes of new oral compounds along with their characteristics, efficacy and safety profiles and propose a modern approach to male ED.

2 Physiology of penile erection

Penile erection is a neurovascular event modulated by psychological factors and hormonal status^[4]. Upon sexual stimulation, nerve impulses cause the release of neurotransmitters from the cavernous nerve terminals and of relaxing factors from the endothelial cells in the penis, resulting in the relaxation of smooth muscle in the arteries and arterioles supplying the erectile tissue and a several-fold increase in penile blood flow. At the same time, relaxation of the trabecular smooth muscle increases the compliance of the sinusoids, facilitating rapid filling and expansion of the sinusoidal system. The subtunical venular plexuses are thus compressed between the trabeculae and the tunica albuginea, resulting in almost total occlusion of venous outflow. These events trap the blood within the corpora cavernosa and raise the penis from a dependent position to an erect position, with an intracavernous pressure of approximately 100 mm Hg (the phase of full erection). During masturbation or sexual intercourse, both of which trigger the bulbocavernous reflex, the ischiocavernous muscles forcefully compress the base of the blood-filled corpora cavernosa and the penis becomes even harder, with an intracavernous pressure reaching several hundred millimeters of mercury (the phase of rigid erection). During this phase, the inflow and outflow of blood temporarily cease. Detumescence can be the result of a cessation of neurotransmitter release, the breakdown of second messengers by phosphodiesterases (PDEs), or sympathetic discharge during ejaculation. Contraction of the trabecular smooth muscle reopens the venous channels, the trapped blood is expelled, and flaccidity returns^[5].

3 Etiology of erectile dysfunction

There is a general agreement to consider ED a vasculogenic disease, which results from arteriogenic or venogenic incompetence. In reality, it seems to be a misnomer as major studies on the pathophysiology of ED have shown that in most occasions it is due to the inability of the cavernosal smooth muscle to trap blood within the corpora cavernosa. The current thought is that the smooth muscle cells are somehow altered (either in function or structure) during aging, diabetes, hypoxia^[6], inadequate androgen milieu or exposure to certain medications (e.g., antihypertensives and antidepressants). Therefore, the major hit is a myopathy of unknown origin. When a critical amount of the smooth muscle is affected by this myopathy, the cavernosal smooth muscle is unable to relax adequately to allow attainment of intracorporeal pressure sufficient to compress the subtunical veins and prevent the egress of blood out of the cavernosa. In accordance with these mechanisms, drugs designed to enhance corporeal smooth muscle relaxation theoretically may be effective as erectogenic agents^[7].

Psychological issues are very common in younger patients and may represent an adaptive behavior to preserve man's or couple's psychological equilibrium, so that sexual symptoms may demonstrate an interplay of both psychological and organic etiologies. In regard to the prevailing opinions on the psychological causes, the primary and secondary dysfunctions are distinguish. The primary dysfunction commonly includes the mental illnesses i.e, depression, psychosis, obsessive-compulsive disorders, schizophrenia, which is very difficult to treat. The secondary dysfunction is usually triggered by an identifiable event, i.e., fear of the vagina, hostility toward women, interpersonal conflicts with the partner or conditioned patterns of premature ejaculation. The clinician may identify the stressors and their relationship to the symptom so that treatment seems to be easier^[8]. Decreased libido, referred to as hypoactive sexual desire is a very common complaint among psychogenic patients (incidence 15-20 %), despite normal circulating levels of bioavailable testosterone; sometimes there may be an age-related decline in the testosterone levels. Other common causes are hypogonadism, hyperprolactinemia or prolonged use of drugs affecting the central nervous system^[9]. Orgasmic/ejaculatory dysfunction or premature ejaculation is frequent in young men with limited sexual experience. The older man with failing erectile function and difficulty in maintaining his erection may also develop premature ejaculation as he worries about his ability to maintain his erection before ejaculation^[10].

4 Drug delivery and tissue selectivity

Orally active drugs for ED need special features, including easy absorption from the gastrointestinal tract, rapid attainment to the target tissue without affecting the vascular system, and negligible deposition in other tissues. The development of any drug for ED must take into consideration the cause of the dysfunction and it is well established that the nitric oxide (NO)/cGMP mechanism plays a key role in mediating penile smooth muscle cell relaxation and erection^[11]. One could visualize that if a drug initiates its action several hours after ingestion, it would be a day-after pill rather than on demand pill. The ability of a drug to select the target tissue (penis) while bypassing other tissues (vascular system) depends upon the fact that human corporeal smooth muscle is known to be rich in PDE-5, which is also abundant in the aorta and some part of the peripheral vascular smooth muscle. For this reason, PDE-5 inhibition plays a central role in penile vascular and corpus cavernosal smooth muscle relaxation. During sexual stimulation, NO is released from nitrergic neurons and endothelial cells of the cavernous bodies, diffusing across the cell membrane and binding to soluble guanylyl cyclase, which in turn converts GTP to cGMP, and prompts relaxation of smooth muscle tissues. Relaxation of the penile vasculature allows blood to fill in sinusoidal spaces, thereby causing erection. PDE-5 hydrolyzes intracellular cGMP, thus controlling its amount inside the cell and reinforcing the nitrergic signal into vascular and smooth muscle cells. However, PDE-5 inhibition is not 100 % specific and PDE-5 inhibitor sildenafil does cross-react with other PDE enzymes^[12]. More selective inhibitors (IC351, vardenafil) have recently been designed and are under current clinical evaluation. They are more selective (Table 1) and show promising efficacy and safety profiles.

Table 1. In vitro enzymatic inhibition by different PDE inhibitors (IC₅₀ nmol/L).

PDE isoform	Sildenafil	IC-351	Vardenafil
PDE-1	60	>10.000	257
PDE-2	>10.000	>10.000	>10.000
PDE-3	2600	>10.000	3600
PDE-4	1800	>10.000	5700
PDE-5	3.8	1.0	0.7
PDE-6	7.4	780	15.7

5 Phosphodiesterase inhibitors

5.1 Sildenafil

Sildenafil citrate (Viagra^TM) acts by blocking cGMP degradation via PDE inhibition, and in turn enhances the effect of NO in inducing smooth muscle relaxation and erection. As indicated before, the most prominent effect of the drug is the inhibition of PDE-5, the most abundant enzyme identified in the human corpus cavernous, but sexual stimulation is mandatory for sildenafil to produce its beneficial pharmacological effects, so that it is generally considered a peripheral conditioner^[13]. After three years from its launch, it has been prescribed to more than 10 million patients worldwide and has been evaluated in clinical studies in diverse patient populations demonstrating up to 80 % efficacy (at flexible doses of 25-50-100 mg) compared with 25 % of men taking placebo, a finding that is statistically highly significant^[14]. Efficacy was present regardless of the patient age, the etiology of ED (psychogenic, organic or mixed) and the baseline severity of the condition^[15]. However, in selected groups of severe ED patients, i.e., with long-standing diabetes, hypertension, arteriosclerosis or after radical prostatectomy, there may be up to 50 % failures. It is noteworthy that retrospective analysis of clinical data revealed that two-thirds of men responded to sildenafil had a successful intercourse on the first or second use the drug^[15]. However, the remaining third might require up to sixth uses of sildenafil until they had their first successful intercourse. This is consistent with the fact that many factors contribute to successful therapy, included patient (and partner) anxiety^[16]. One of the factors is the time needed (6090 min) for complete absorption before an optimal effect on erection occurs in the absence of concomitant meal assumption. Moreover, it is reasonable to postulate that, especially in older patients in the absence of complete PDE-5 inhibition, partial dephosphorylation of cGMP will decrease the erectile response. Therefore, men who do not initially respond to sildenafil, should be encouraged to try up to a maximum dose of 100 mg on 6-8 occasions before a lack of response is considered.

Side effects related to vasodilatation are the most common adverse events observed after sildenafil administration. Headache (16 %), flushing (10 %), nasal congestion (4 %) and gastro-esophageal reflux (7 %) occur approximately 1 h after intake, whereas visual disturbances (blue-green hues, hypersensitivity to light) occur quite seldom (3 %) and are more frequent after 100 mg dosage. Overall discontinuation due to adverse events in placebo-controlled studies was comparable in the sildenafil (2.5 %) and placebo (2.3 %) groups^[17]. Long-term cardiovascular safety and, in particular, the potential for sildenafil-related death and/or serious adverse events in men with ischemic heart disease have been of primary concern, but post-marketing data indicated that the rate of death and/or serious adverse events reported to FDA is not inconsistent with the baseline mortality rate in men of this age and health status^[18]. Indeed, sildenafil potentiates the hypotensive effects of nitrates and is absolutely contraindicated in patients who are concurrently using organic nitrates in any form. However, in all studies sildenafil therapy alone did not modify systolic and diastolic blood pressure or heart rate when compared with placebo. More important, in the placebo-controlled studies, 30 % out of 2,722 patients receiving sildenafil were also taking antihypertensive medications; for these patients the tolerability of sildenafil treatment was comparable to those not taking antihypertensive drugs. These observations indicate that antihypertensive therapy is compatible with sildenafil administration.

5.2 IC-351

IC-351 (Cialis^TM) is a novel PDE-5 inhibitor with efficacy profile comparable to sildenafil in clinical trials (60 %-70 % in ED of any etiology) but the higher selectivity on PDE-6 (Table 1) makes it a safer drug^[19]. It is rapidly absorbed independent of meals and reaches a maximum plasma concentration at 2 hours, has a mean half-life of 17.5 hours with low hepatic clearance. In elderly subjects, the mean plasma concentration is 25 % greater than those of the controls, whereas in diabetic and hepatic insufficiency patients, it is comparable to the controls. IC-351 at flexible doses of 10, 20, 25 mg was significantly superior to placebo in all studies and all doses improved erectile function as assessed by clinical questionnaires^[19]. The most common adverse events were headache and back pain (about 15 %-20 %), myalgia and dyspepsia (<10 %). The side effects were dose-dependent, mild to moderate in intensity, and tended to disappear over time. Contraindications in cardiovascular patients are similar to sildenafil. Preliminary data indicate a higher success rate of IC-351 in diabetic patients (about 65 % vs 50 % in sildenafil) with only 11 % reporting dyspepsia as a major side effect, which may be related to diabetic gastro-paresis. It is under registration in the USA and EU.

5.3 Vardenafil

Vardenafil (Remedy^TM) is another PDE-5 inhibitor four- to five-fold more potent than sildenafil with identical pharmacology, efficacy and safety profiles. It has a much higher selectivity on PDE-5 (Table 1). Preliminary reports indicate an overall success rate of about 60 %-70 % (placebo 25 %) in ED of any etiology with a few adverse events consisting of headache (<10 %), dyspepsia and rhinitis (<5 %). The drug is effective 1 h after ingestion with a half-life of about 8 h, which are comparable to sildenafil but with less side effects. Contraindications are identical to those of sildenafil. It is under registration in the USA and EU and more than 1000 patients has been administered vardenafil on demand at flexible doses of 5, 10 and 20 mg, the latter being the most well accepted.

6 Centrally acting drugs

6.1 Apomorphine

Apomorphine hydrochloride (Ixense^TM, Uprima^TM) is a centrally acting drug for ED. It has been in the market in EU as a sublingual preparation at doses of 2 and 3 mg. It is rapidly absorbed (within 10 min), independent of meals and has a half-life of about 4 h. More than 3.000 men with a diagnosis of ED, aged 18-70 years, have received the drug at doses of 2 or 4 mg and over 75,000 prescriptions have been administered in clinical trials. The majority (75 %) had moderate or severe ED on admission to the studies and 31 % had hypertension, 16 % coronary heart disease, and 16 % dyslipidemia and diabetes. Erections occurred rapidly (10-25 min) after sublingual administration only in the presence of sexual stimulation, that makes the drug not an aphrodisiac. The success rate at 4 mg was 55 % (vs. placebo 38 %). The majority of attempts for intercourse (50 %) was successful at 4 mg in patients recorded on a per-attempt basis. It may be prescribed in cardiovascular patients in whom moderated physical activity is not contraindicated or even in patients taking nitrates. The most common but infrequent adverse event is nausea (15 %), which is declined with use or decreased dosage; however, there was about 1 % vasovagal syncope, especially when the dosage was titrated up to 6 mg. Thus, caution must be taken in patients with pre-existing neurovegetative disturbances, i.e. orthostatic hypotension or diabetic neuropathy.

6.2 Melanotan II

Melanotan II or PT-141 (Palatin^TM) is an -melanocite stimulating hormone (MSH) analog currently under development as an intramuscular formulation. It is a non-selective melanocortin receptor agonist, which in animals regulates sexual behavior including penile erection, sexual motivation and, in female rat the secretion of sexual attractants from the preputial gland. In a preliminary study, it led to penile erection sufficient for sexual intercourse in the absence of sexual stimulation in the majority of men as measured by Rigiscan^® and an increased sexual desire that was evaluated with clinical questionnaires. Nausea and yawning were the most common reported side-effects^[21]. In the future, modification of drug delivery may enhance acceptability for clinical use.

7 Conclusions

The success of sildenafil, the first approved oral therapy for male ED, has spurred the development of increasingly selective PDE-inhibitors and has radically changed the clinical approach to men complaining ED. Many diagnostic tests used in the past, i.e. penile intracavernous pharmacotesting, dynamic Duplex ultraosund, nocturnal penile tumescence monitoring, may now be considered investigational, since they do not give information on the therapeutic options for the patients^[22]. A Viagra-test at home represents a reasonable approach to male ED, since it provides information about the man's capacity to achieve and maintain an erection during the sexual congress, a situation which approaches to reality more than the office setting. The availability of orally active drugs has doubled the number of subjects consulting the andrologists for erectile disorders. Amongst this group will be ED patients secondary to concomitant underlying disease, e.g., cardiovascular diseases or diabetes, so that the general practitioner should be aware of the efficacy and safety profiles of each individual drug. The use of centrally active drugs seems to be a valid alternative when PDE-inhibitors are contraindicated or not tolerated (recent myocardial infarction, the use of nitrates or the presence of retinitis pigmentosa). Furthermore, we must consider the increasing interest in other potential oral therapeutic options, including new -adrenoreceptor antagonists such as phentolamine, or the combination of L-arginine plus yohimbine, despite a relative paucity of randomized clinical trials on these compounds. Another alternative that one could foresee in non-responders to oral compounds (about 30 % out of the total patients) could be a salvage therapy based on the use of drug combinations with different mechanism of action (e.g., central initiators and peripheral vasodilators). However, no controlled study on this issue is available at the moment, which makes this approach empirical.

Acknowledgments

The authors wish to thank Ms. Diane Sarachman for revising the language of the manuscript.

References

[1] Jardin A, Wagner G, Khoury S, Giuliano F, Padma-Nathan H, Rosen R, editors. Recommendations of the 1st International Consultation on Erectile Dysfunction. London: Health Publication Ltd; 2000: p 1-16.
[2] Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999; 84: 50-6.
[3] Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychological correlates: results of the Massachusetts male aging study. J Urol 1994; 151: 54-9.
[4] Fabbri A, Aversa A, Isidori A. Erectile dysfunction: an overview. Hum Reprod Update 1997; 3: 455-66.
[5] Lue TF. Erectile dysfunction. New Engl J Med 2000; 342: 1802-13.
[6] Aversa A, Basciani S, Visca P, Arizzi M, Gnessi L, Frajese G, Fabbri A. Platelet-Derived GrowthFactor (PDGF) and PDGF-receptors in rat corpus cavernosum: changes in expression after transient in vivo hypoxia. J Endocrinol 2001; 170: 395-402.
[7] Rajfer J. Opportunities and challenges in oral therapy. Int J Impotence Res 2000; 12: S 59-61.
[8] Levine SB. Intrapsychic and interpersonal aspect of impotence: psychogenic erectile dysfunction. In: Rosen RC, Leiblum SR, editors. Erectile Disorders. New York: Guildford Press; 1996. p 198-225.
[9] Aversa A, Rocchietti-March M, Botta D, Caprio M, Pezzella P, Fabbrini E, et al. Pharmacology of male sexual dysfunctions. Minerva Endocrinol 1998; 23: 17-25.
[10] Mc Cullough AR, Fine JL. Psychosexual issues in the man, woman, and couple. In: Hellstrom WJG, editor. The Handbook of Sexual Dysfunction. San Francisco: The Amerrican Society of Andrology; 1999. p 53-56.
[11] Lugg JA, Gonzales-Cadavid NF, Rajfer J. The role of nitric oxide in erectile function. J Androl 1995; 16: 2-6.
[12] Fabbri A, Aversa A, Isidori A. Sildenafil, erectile dysfunction. J Endocrinol Invest 1999; 22: 486-91.
[13] Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. New Engl J Med 1998; 338: 1397-404.
[14] Sadovski R, Miller T, Moskowitz R, Hackett G. Three-year update of sildenafil citrate (Viagra^®) efficacy and safety. Int J Clin Pract 2001; 55: 115-28.
[15] Eid JF. Sildenafil citrate: current clinical experience. Int J Impotence Res 2000; 12: S 62-S 6.
[16] Aversa A, Rocchietti-March M, Isidori A, Fabbri A. Anxiety-induced failure in erectile response to intracorporeal prostaglandin-E1 in non-organic male impotence: a new diagnostic approach. Int J Androl 1996; 19: 307-13.
[17] Morales A, Gingell C, Collins M, Wicker PA, Osterloh IH. Clinical safety of oral sildenafil citrate (Viagra^TM) in the treatment of erectile dysfunction. Int J Impot Res 1998; 10: 69-75.
[18] Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, Russell RO Jr, Zusman RM. ACC/AHA Expert Consensus Document. Use of Sildenafil (Viagra^TM) in patients with cardiovascular disease. J Am Coll Cardiol 1999; 33: 273-83.
[19] Padma-Nathan H, McMurray JG, Pullman WE, Whitaker JS, Saoud JB, Ferguson KM, Rosen RC. for the IC-351 On-Demand Dosing Study Group. On-Demand IC-351 (Cialis^TM) enhances erectile function in patients with erectile dysfunction. Int J Impotence Res 2001; 13: 2-9.
[20] Heaton JPW. Apomorphine: an update of clinical trial results. Int J Impotence Res 2000; 12: S 67-73.
[21] Wessells H, Levine N, Hadley ME, Dorr R, Hruby V. Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with melanotan II. Int J Impotence Res 2000; 12: S 74-9.
[22] Aversa A, Isidori AM, Caprio M, Cerilli M, Frajese V, Fabbri A. Penile pharmacotesting in diagnosing male erectile dysfunction: evidence for a lack of accuracy and specificity. Int J Androl 2001, in press.

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Correspondence to: Antonio Aversa, MD, PhD, Endocrinology Unit, University of Rome Tor Vergata, c/o Fatebenefratelli-Isola Tiberina Hospital, Isola Tiberina 39, 00186 Roma.
Tel: +39-06-683 7405, Fax: +39-06-683406,
E-mail: amfaversa@yahoo.com
Received 2001-08-15 Accepted 2001-08-21