Basic HTML Version
© The Canadian Journal of Urology™; 18(Supplement 1); April 2011
4
excessive alcohol intake, drug abuse, lack of exercise,
and obesity.
8
Once patients have been diagnosed with
ED and have received advice about making lifestyle
changes and modifying their risk factors, most men
will request a “quick fix” using medical treatment.
PDE-5 inhibitors
The mainstays of first-line medical treatments for ED
are the phosphodiesterase-type 5 (PDE-5) inhibitors
and counseling.
8
If these first-line treatments are
unsuccessful, the patient may be referred to a specialist
and be offered second-line treatments (such as vacuum
devices, injectable agents, or intraurethral therapy)
and, failing those, third-line treatments (such as a
penile implant).
8
The mechanism of action of PDE-5 inhibitors is
based on the normal biochemical pathway for an
erection. In the normal erectile response, nitric oxide
produced upon arousal increases the production of
cyclic guanosine monophosphate (cGMP), which
causes vasodilation and an erection.
9
PDE-5 enzymes
then cause the breakdown (metabolism) of cGMP.
In ED, men are given a PDE-5 inhibitor to prevent
the breakdown of cGMP and increase nitric oxide
and cGMP concentrations, which leads to a stronger,
longer-lasting erection.
9
It was previously believed that hypogonadism,
or low levels of serum testosterone, only impact a
patient’s libido. We now know that testosterone is a
precursor of nitric oxide and affects the ability to obtain
an erection and the quality of an erection.
Low testosterone levels contribute to the
development of ED by increasing smooth muscle
apoptosis, reducing erectile tissue relaxation, and
reducing nitric oxide production.
10,11
Sildenafil (Viagra) was the first PDE-5 inhibitor
approved in Canada. This was followed by the
approval of tadalafil (Cialis) and then vardenafil
(Levitra). Originally, all three drugs were prescribed
to be taken as needed 45minutes before the anticipated
sexual activity. In clinical trials of all three of these
drugs, it was reported that, on average, 32% of men
responded within 16 minutes of taking the drug. In
clinical practice, physicians should advise patients
to take the PDE-5 inhibitor at least one hour before a
planned sexual encounter and to remind patients that
some sexual stimulation (foreplay) is needed for the
drug to take effect. This is because arousal is required
to cause the initial release of nitric oxide, which is then
potentiated under the influence of the PDE-5 inhibitor.
Each drug has a different half life, which affects
the “window of opportunity” where the drug has
its maximum efficacy. The absorption of the drugs
may also depend on whether they are taken with or
without food or alcohol. Different PDE-5 inhibitors
also have different other pharmacokinetic properties
and adverse effects.
12
Only a few head-to-head
trials have compared the characteristics of different
PDE-5 inhibitors or patient preferences for these
drugs. Typically, in clinical practice, a patient will be
offered prescriptions for two or three different PDE-5
inhibitors and given instructions about how to achieve
an optimal response. The patient will be told attempt
to achieve successful intercourse after taking one of
the PDE-5 inhibitors, on four to six occasions. The
patient is instructed to repeat this with the second or
third PDE-5 inhibitor, if needed. The patient will thus
determine which preparation works best for him and
his sexual lifestyle.
PDE-5 inhibitors are contraindicated for men who
are taking nitrates of any type. An unpredictable
number of men taking a nitrate and a PDE-5 inhibitor
could sustain a significant bout of hypotension that
may precipitate a stroke or myocardial infarction.
13-15
In 2009, a lower-dose (5 mg), daily form of tadalafil
was approved in Canada. The rationale for developing
this product was that the patient would always be
ready for a sexual encounter, be more compliant, and
have greater satisfaction. The lower dose would result
in a steady, sustained blood level of the drug without
peaks and valleys, thereby reducing the incidence of
the potential side effects of headache, flushing, and
backache.
There have been some recent trails subsequent to the
original registration trials for the PDE-5 inhibitors. One
trial that compared daily vardenafil versus on-demand
vardenafil for the treatment of ED following radical
prostatectomy found no difference in the recovery of
erectile function.
16
Another trial of ED treatment looked
at “erection hardness scale” outcomes and reported that
82% of men using sildenafil had an erection that was
firm enough to achieve satisfactory sexual activity.
17
Another study compared treatment with sildenafil
versus placebo in men who had “mild ED,” that is,
they had an International Index of Erectile Function
(IIEF) score of 22 to 25 out of 25.
18
In this 8-week,
double blind study, 176menwere randomized to either
placebo or flexible dosing with 25 mg, 50 mg, or 100
mg of sildenafil. In all outcomes – IIEF scores, Erectile
Dysfunction Inventory of Sexual Satisfaction (EDITS)
scores, Quality of Erection Questionnaire (QEQ)
scores, and Erection Hardness Score (EHS) – men who
received sildenafil had significantly improved scores
compared to men who received placebo. These men
with mild ED did not have any significant differences
BARKIN