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© The Canadian Journal of Urology™; 18(Supplement 1); April 2011
29
All healthcare providerswho prescribe PDE-5i must
be aware that they are contraindicatedwith concurrent
use of nitrates which can lead to pronounced vascular
smoothmuscle relaxation and possible death. Patients
with cardiac risk factors who are taking nitrates or
may require initiation of nitrate therapy should be
informed of these risks and should seek other forms
of treatment for their ED. Non-arteritic anterior
ischemic optic neuropathy (NAION) has also been
recognized as a rare side effect in patients taking
PDE-5i. NAION is a sudden painless ischemic event
of the optic nerve resulting in visual field defects and
impaired light perception.
28
Health Canada and the
World Health Organization have advised patients to
contact their physician and stop PDE-5i medication
immediately should any visual disturbances occur.
Any previous history of NAION or visual difficulty
should be documented prior to initiation of PDE-5i
therapy in patients with ED.
Intraurethral and intracavernosal ED therapy
For those patients who are refractory to PDE-5i
oral therapy, a variety of local pharmacologic
options may be attempted. Similar to the PDE-
5/cGMP mechanism, prostaglandin E1 (PGE1)
stimulates adenyl cyclase to increase cyclic adenosine
monophosphate (cAMP) levels leading to arteriolar
vasodilation, penile smooth muscle relaxation, and
penile erection. Alprostadil [MUSE] is a synthetic
PGE1 analog available as a small pellet that can be
inserted into the urethra where it then diffuses into
both the corpora spongiosum and cavernosa, Table 5.
29
Minimal side effects and drug interactions are noted
due to its local application and absorption. Rarely,
penile pain, burning, and vaginal discomfort in sexual
partners may be encountered.
Intracavernosal (IC) injection therapies such as
alprostadil [Caverject, Edex (US only)], papaverine,
and phentolamine can be effective second line options
in patients with ED, Table 5. Alprostadil is an injectable
PGE1 analogwith amechanismof action identical to its
intraurethral counterpart.
29
Side effects include pain at
the injection site, hematoma, and priapism (prolonged
erection). Papaverine is a non-selective PDEi that can
increase levels of cAMP. Both priapism (up to 35%)
and corporal fibrosis (up to 33%) can result from its
use.
30
Phentolamine is an alpha blocker that is used
in conjunction (no effect when used alone) with the
two previously mentioned IC therapies potentiating
their effects on penile vasculature and smooth
muscle. Combination IC medications such as Tri-mix
(alprostadil, papaverine, and phentolamine) have
been shown to produce synergistic action resulting in
high success rates (up to 87%) for sexual function.
31
However, these combinations have not been officially
approved for use by Health Canada or the US FDA.
Hypogonadism
Pathophysiology
Testosterone is primarily produced by the Leydig cell
in the male testes. Its production is regulated by the
TABLE 5.
Transurethral (TU) and intracavernosal (IC) therapy for erectile dysfunction (ED)
Name (Brand)
Dosage
Mechanism of action
Side effects/Notes
Alprostadil TU
250 mcg-1000 mcg
Synthetic PGE1 stimulates
Painful erection;
(MUSE)
Max 2 administrations
increased levels of cAMP
urethral pain; bleeding;
per 24 hrs
bleeding; priapism (rare)
Alprostadil IC
2.5 mcg-20 mcg*
Same as above
Penile pain, fibrosis
(Caverject, Edex†)
Max 1x daily and
hematoma; priapism (rare)
3x weekly
Papaverine IC‡
15 mg-60 mg
Non-selective PDEi
Priapism; fibrosis
(monotherapy)
increases cAMP and cGMP
5 mg-20 mg
(combination therapy)
Phentolamine IC‡
0.5 mg-1 mg
Alpha blocker inhibiting
Hypotension; reflex
(combination therapy
sympathetic tone to penis
tachycardia
with papaverine)
*Neurogenic ED may require lower starting dose. Severe vascular ED may require higher doses.
†Not available in Canada
‡Not approved by Health Canada for this use.
Pharmacology for common urologic diseases: 2011 review for the primary care physician