Chapter 32: Drugs For Urological Systems Flashcards
DRUGS FOR ERECTILE DYSFUNCTION
Alprostadil MUSE, CAVERJECT, EDEX
Avanal STENDRA
Sildenal VIAGRA
Tadalal CIALIS
Vardenal LEVITRA, STAXYN
Alpha blockers
Alfuzosin UROXATRAL
Doxazosin CARDURA
Prazosin MINIPRESS
Silodosin RAPAFLO
Tamsulosin FLOMAX
Terazosin HYTRIN
5 alpha reductase inhibitors
Dutasteride AVODART
Finasteride PROPECIA, PROSCAR
Phosphodiesterase 5 inhibitors
Phosphodiesterase-5 inhibitors
All four PDE-5 inhibitors, sildenafil [sil-DEN-a-fil], vardenafil [var-DEN-
na-fil], tadalafil [ta-DAL-a-fil], and avanafil [a-VAN-a-fil], are equally
effective in treating ED, and the adverse effect profiles of the drugs
are similar. However, these agents differ in the duration of action and
the effects of food on drug absorption.
1. Mechanism of action: Sexual stimulation results in smooth mus-
cle relaxation of the corpus cavernosum, increasing the inflow of
blood (Figure 32.2). The mediator of this response is nitric oxide
(NO). NO activates guanylyl cyclase, which forms cyclic gua-
nosine monophosphate (cGMP) from guanosine triphosphate.
cGMP produces smooth muscle relaxation through a reduction
in the intracellular Ca2+ concentration. The duration of action of cyclic nucleotides is controlled by the action of phosphodiester-
ase (PDE). At least 11 isozymes of PDE have been characterized.
Sildenafil, vardenafil, tadalafil, and avanafil inhibit PDE-5, the iso-
zyme responsible for degradation of cGMP in the corpus caverno-
sum. The action of PDE-5 inhibitors is to increase the flow of blood
into the corpus cavernosum at any given level of sexual stimulation
(Figure 32.3). At recommended doses, PDE-5 inhibitors have no
effect in the absence of sexual stimulation.
Phosphodiesterase 5 inhibitors pharmacokinetics
Pharmacokinetics: Sildenafil and vardenafil have similar phar-
macokinetic properties. Both drugs should be taken approximately
1 hour prior to anticipated sexual activity, with erectile enhance-
ment observed for up to 4 hours after administration. Thus, admin-
istration of sildenafil and vardenafil must be timed appropriately
with regard to anticipated sexual activity. The absorption of both
drugs is delayed by consumption of a high-fat meal. Vardenafil is
also available in an orally disintegrating tablet (ODT) formulation,
which is not affected by a high-fat meal. However, the bioavail-
ability of the ODT formulation may be decreased by water, and
therefore the ODT should be placed under the tongue and not
administered with liquids. The vardenafil ODT provides a higher
systemic bioavailability than the vardenafil film-coated oral tablet,
and these products are not interchangeable. Tadalafil has a slower
onset of action (Figure 32.4) than sildenafil and vardenafil, but a
significantly longer half-life of approximately 18 hours. As such, it
is approved for once-daily dosing (in addition to as-needed dos-
ing). This results in enhanced erectile function for up to 36 hours.
Furthermore, the absorption of tadalafil is not clinically influenced
by food. The timing of sexual activity is less critical for tadalafil
because of its prolonged duration of effect. Of all the PDE-5 inhibi-
tors, avanafil has the quickest onset of action. It should be taken
30 minutes prior to sexual activity. All PDE-5 inhibitors are metabo-
lized by the cytochrome P450 3A4 (CYP3A4) isoenzyme. Dosage
adjustments are recommended in patients with hepatic dysfunc-
tion. For patients with severe renal dysfunction, the dose of silde-
nafil and tadalafil should be reduced, and daily-dose tadalafil and
avanafil are contraindicated in these patients.
P-5-I ADR
Adverse effects: The most frequent adverse effects of the PDE-5
inhibitors are headache, flushing, dyspepsia, and nasal conges-
tion. These effects are generally mild, and men with ED rarely dis-
continue treatment because of side effects. Disturbances in color
vision (loss of blue/green discrimination) may occur with PDE-5
inhibitors, probably because of inhibition of PDE-6 (a PDE found
in the retina that is important in color vision). Tadalafil, however,
does not appear to disrupt PDE-6, and reports of changes in color
vision have been rare with this medication. The incidence of these
reactions appears to be dose dependent. Sudden hearing loss has
also been reported with the use of PDE-5 inhibitors, perhaps due
to changes in sinus pressure because of vasodilation. Tadalafil has
been associated with back pain and myalgias, likely because of
inhibition of PDE-11, an enzyme found in skeletal muscle. There is
an inherent cardiac risk associated with sexual activity. Therefore,
PDE-5 inhibitors should be used with caution in patients with a his-
tory of cardiovascular disease or those with strong risk factors for
cardiovascular disease. PDE-5 inhibitors should not be used more
than once per day. All of the PDE-5 inhibitors have the potential to
cause priapism (a painful, prolonged erection). Although this is a
rare side effect, it is a medical emergency.
P-S-I drug interactions
Drug interactions: Because of the ability of PDE-5 inhibitors
to potentiate the hypotensive activity of NO, administration of
these agents in patients taking any form of organic nitrates (for
example, nitroglycerin products, isosorbide dinitrate, or isosorbide
mononitrate) is contraindicated. PDE-5 inhibitors may produce
additive blood pressure–lowering effects when used in patients
taking α-adrenergic antagonists (used to treat hypertension and/
or alleviate symptoms associated with BPH). The combination of
PDE-5 inhibitors and α-adrenergic antagonists should be used with
caution. Patients should be on a stable dose of the α-adrenergic
antagonist prior to the initiation of the PDE-5 inhibitor, and the
PDE-5 inhibitor should be started at a low dose if this combination
is to be used. Doses of PDE-5 inhibitors may need to be reduced
in the presence of potent inhibitors of CYP3A4, such as clarithro-
mycin, ritonavir, and other protease inhibitors.
Alprostadil
Alprostadil [al-PRAHST-uh-dill] is synthetic prostaglandin E1 (PGE1).
In the penile tissue, PGE1 allows for relaxation of the smooth muscle
in the corpus cavernosum. Alprostadil is available as an intraurethral
suppository and an injectable formulation. Although PDE-5 inhibitors
are considered first-line therapy for the treatment of ED, alprostadil
may be used for patients who are not candidates for oral therapies. In
contrast to oral agents, alprostadil acts locally, which may reduce the
occurrence of adverse effects.
1. Mechanism of action: Alprostadil causes smooth muscle relax-
ation by an unknown mechanism. It is believed that alprostadil
increases concentrations of cyclic AMP (cAMP) within cavernosal
tissue. As a result, protein kinase is activated, allowing trabecu-
lar smooth muscle relaxation and dilation of cavernosal arteries.
Increased blood flow to the erection chamber compresses venous
outflow, so that blood is entrapped and erection may occur.
Pharmacokinetics: Systemic absorption of alprostadil is minimal.
If any alprostadil is systemically absorbed, it is quickly metabolized.
The onset of action of alprostadil is 5 to 10 minutes when given as
a urethral suppository and 2 to 25 minutes when administered by
injection. The resulting erection may last for 30 to 60 minutes, or
longer, depending upon the particular patient.
3. Adverse effects: Since alprostadil is not systemically absorbed,
adverse systemic effects are rare. However, hypotension or head-
ache is a possibility due to PGE1-induced vasodilation. Locally,
adverse effects of alprostadil include penile pain, urethral pain,
and testicular pain. Bleeding from the insertion or injection of
alprostadil is rare. Hematoma, ecchymosis, and rash are possible
from alprostadil injection, although these adverse effects are also
rare. Alprostadil administration may lead to priapism.
Alpha 1 adrenergic antagonist
. α1-Adrenergic antagonists
Terazosin [ter-AY-zoe-sin], doxazosin [dox-AY-zoe-sin], tamsulosin
[tam-SUE-loh-sin], alfuzosin [al-FUE-zoe-sin], and silodosin [sil-oh-
DOE-sin] are selective competitive blockers of the α1
receptor. All five
agents are indicated for the treatment of BPH (Figure 32.1). Prazosin
is an α-blocker that is used off-label in the treatment of BPH. However,
current guidelines do not endorse the use of prazosin for BPH. Please
refer to Chapter 7 for a discussion of α-blockers in the setting of
hypertension.
1. Mechanism of action: α1A receptors are found in the prostate,
α1B receptors are found in the prostate and vasculature, and α1D
receptors are found in the vasculature. By blocking the α1A and α1B
receptors in the prostate, the α-blockers cause prostatic smooth
muscle relaxation, which leads to improved urine flow. Doxazosin,
terazosin, and alfuzosin block α1A and α1B receptors, whereas
tamsulosin and silodosin are more selective for the α1A receptor.
Because doxazosin, terazosin, and alfuzosin block α1B receptors,
these agents decrease peripheral vascular resistance and lower
arterial blood pressure by causing relaxation of both arterial and
venous smooth muscle. In contrast, tamsulosin and silodosin have
less of an effect on blood pressure because they are more selec-
tive for the prostate-specific α1A receptor. In general, α-blockers
cause minimal changes in cardiac output, renal blood flow, and
glomerular filtration rate.
2. Pharmacokinetics: The α-blockers are well absorbed following
oral administration. When taken with food, the absorption of tamsu-
losin, alfuzosin, and silodosin is increased. Therefore, for best effi-
cacy, these agents should be taken with meals (typically supper).
Doxazosin, alfuzosin, tamsulosin, and silodosin are metabolized through the cytochrome P450 (CYP450) system. Silodosin is
also a substrate for P-glycoprotein (P-gp). Terazosin is metabo-
lized in the liver, but not through the CYP system. In general, the
α-blockers have a half-life of 8 to 22 hours, with peak effects 1 to
4 hours after administration. Silodosin requires dosage adjustment
in renal impairment and is contraindicated in patients with severe
renal dysfunction.
3. Adverse effects: α-Blockers may cause dizziness, a lack of
energy, nasal congestion, headache, drowsiness, and orthostatic
hypotension (although to a lesser degree than that observed with
phenoxybenzamine and phentolamine). Tamsulosin and silodosin
inhibit the α1A receptors found on the smooth muscle of the pros-
tate. This selectivity accounts for relatively minimal effects on blood
pressure, although dizziness and orthostasis may occur. These
drugs do not affect male sexual function as severely as phenoxy-
benzamine and phentolamine. However, by blocking α receptors
in the ejaculatory ducts and impairing smooth muscle contrac-
tion, inhibition of ejaculation and retrograde ejaculation have been
reported. Tamsulosin has a caution about “floppy iris syndrome,” a
condition in which the iris billows in response to intraoperative eye
surgery. Figure 32.5 summarizes some adverse effects observed
with α-blockers.
4. Drug interactions: Drugs that inhibit CYP3A4 and CYP2D6 (for
example, verapamil, diltiazem) may increase the plasma concen-
trations of doxazosin, alfuzosin, tamsulosin, and silodosin, while
drugs that induce the CYP450 system (for example, carbamaze-
pine, phenytoin, and St. John’s wort) may decrease plasma con-
centrations. Alfuzosin may prolong the QT interval, so it should
be used with caution with other drugs that cause QT prolongation
(for example, class III antiarrhythmics). Since silodosin is a sub-
strate for P-gp, drugs that inhibit P-gp, such as cyclosporine, may
increase silodosin concentrations.
5-α reductase inhibitors
Finasteride [fin-AS-ter-ide] and dutasteride [doo-TAS-ter-ride] inhibit
5α-reductase. Compared to the α-blockers, which provide patients
with relief from BPH symptoms within 7 to 10 days, these agents may
take up to 12 months to relieve symptoms.
1. Mechanism of action: Both finasteride and dutasteride inhibit the
enzyme 5-α reductase, which is responsible for converting testos-
terone to the more active dihydrotestosterone (DHT). DHT is an
androgen that stimulates prostate growth. By reducing DHT, the
prostate shrinks and urine flow improves. Compared to finasteride,
dutasteride is more potent and causes a greater decrease in DHT.
In order for the 5-α reductase inhibitors to be effective, the pros-
tate must be enlarged. Thus, it is appropriate to use a 5-α reduc-
tase inhibitor in combination with an α-blocker when the prostate is
enlarged. Figures 32.6 and 32.7 summarize important differences
between these two classes of agents. Finasteride and dutasteride
are also used for alopecia, since a reduction in scalp and serum
DHT prevents hair loss.
Pharmacokinetics: Food does not affect the absorption of either
agent. Both are highly protein bound. Finasteride and dutasteride
are metabolized by the CYP450 system. The mean plasma elimi-
nation half-life of finasteride is 6 to 16 hours, while the terminal
elimination half-life of dutasteride is 5 weeks once steady-state
concentrations are achieved, which is typically after 6 months of
therapy.
3. Adverse effects: The 5-α reductase inhibitors cause sexual side
effects, such as decreased ejaculate, decreased libido, ED, gyne-
comastia, and oligospermia. Finasteride and dutasteride have teratogenic potential. Women who are pregnant or of childbearing
age should not handle or ingest either agent, as this may lead
to serious birth defects involving the genitalia in a male fetus.
Although both agents are metabolized by the CYP450 system,
drug interactions are rare. It is not ideal to use a 5-α reductase
inhibitor with testosterone, since both finasteride and dutasteride
inhibit the conversion of testosterone to its active form, DHT.
Tadalafil
Tadalafil is the only PDE-5 inhibitor approved for the treatment of
BPH. PDE-5 is present in the prostate and bladder. As such, inhibi-
tion of PDE-5 by tadalafil allows for vasodilation and relaxation of the
smooth muscle of the prostate and bladder, which thereby improves
symptoms of BPH.
