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Erectile Dysfunction
Figure 1: Mechanism of Penile Erection Illustrating the Effects of Subtunical Venule Compression
Flaccid
Tunica albuginea
Rigid
Contracted
smooth muscle Relaxed
smooth muscle
Inflow
Sinusoidal
Spaces
Helicine artery Dilated helicine
artery
Venule
Therapeutic Options for Erectile Dysfunction In 2003, two alternative PDE-5 inhibitors were approved – tadalafil (IC
50
0.9nM) and vardenafil (IC
50
0.7nM). Comparison of the IC
50
values (see
Lifestyle Modifications Table 1) shows that vardenafil is highly selective for PDE-5 compared with
The identification of specific risk factors associated with erectile dysfunction the alternative agents, although this does not necessarily translate into a
provides an opportunity for conservative measures in patients with mild to major difference in the efficacy and overall clinical response. Tadalafil has
moderate erectile dysfunction. Cessation of smoking, weight loss and a half-life of 17.5 hours, which allows for greater spontaneity after drug
exercise are associated with an improvement in erectile function, as well as administration. Vardenafil has a half-life of 4.5 hours, but appears to
improving endothelial function and reducing long-term cardiovascular risk.
9
have a marginally more rapid onset of action. Clinically, there is very little
difference between these agents in terms of erectile response, and the
Oral Pharmacotherapies main contraindication to all of them is concomitant nitrate use by the
Oral pharmacotherapies have become the first-line option in the patient, which can cause significant hypotension. However, independent
management of erectile dysfunction. Provided that there are no comparator trials are still required in order to objectively assess whether
contraindications, the lack of invasiveness makes this an ideal first-line there is any clinical advantage of one agent over another.
option in the majority of patients.
Further Developments in the Use of Phosphodiesterase
Phosphodiesterase Type 5 Inhibitors Type 5 Inhibitors
There are currently three PDE-5 inhibitors approved and available for Due to the longer half-life of tadalafil, there has been much interest in
clinical use. The underlying mechanism of action is the same, but they the potential benefits of regular dosing schedules. SURE (Scheduled Use
differ in the pharmacokinetics and the selectivity for PDE-5 inhibition. versus on demand Regimen Evaluation), a large, multicentre,
The selectivity for PDE5 inhibition is measured by the median inhibition international cross-over and open-label study, compared three-times-a-
concentration (IC
50
), which is the concentration of the drug required to week dosing of tadalafil 20mg to on-demand dosing.
14
The overall
inhibit 50% of the enzyme activity. There are 11 PDE subtypes, and analysis of 4,262 men first demonstrated the safety of regular dosing, but
non-selective inhibition of alternative PDE subtypes results in side did not show any statistically significant difference in terms of efficacy
effects such as visual disturbance (PDE-6). (international index of erectile function (IIEF) score) between the two
groups. Fifty-seven per cent of men preferred the on-demand dosing
Sildenafil was developed in 1998 as the first selective PDE-5 inhibitor schedule. Reports from individual countries involved in the trial have
(IC
50
3.5nM). The time to onset is 30–60 minutes and the half-life of shown some variation. In Italy, 1,058 men (59%) preferred on-demand
sildenafil citrate is 4–5 hours. It is recommended that sildenafil should dosing, although there was a greater benefit in IIEF scores with regular
be taken on an empty stomach, and patients are encouraged to use it dosing – though this was not significant.
15
In Spain there was a similar
on at least eight occasions before considering alternative options. There result, with equal efficacy but preference for on-demand dosing.
16
is a large number of clinical studies that have reported on the efficacy
of sildenafil in erectile dysfunction.
10,11
Although the original studies One of the most frequent indications for the prescription of a PDE-5 in the
were predominantly company-sponsored, data from 11 pooled double- US is impotence post-radical prostatectomy. Evidence is mounting that the
blind trials involving 1,329 patients receiving placebo and 1,338 early use of oral or intracavernosal therapy (so-called ‘rehabilitation’) can
patients receiving sildenafil resulted in a higher incidence of successful give higher rates for the return of spontaneous erections and an improved
erections in the sildenafil group regardless of the aetiology.
12
A further response to drug therapy in the longer term.
17,18
meta-analysis from the pooled results of 14 parallel-group dosing trials
showed that sildenafil treatment resulted in a higher percentage of Testosterone Replacement Therapy
successful intercourse attempts than did placebo (57% versus 21%, Androgens are involved in the central and peripheral pathways
respectively; n=2,283).
13
associated with penile erection. Testosterone is required for NOS
94 EUROPEAN GENITO-URINARY DISEASE 2007
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