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© The Canadian Journal of Urology™; 18(Supplement 1); April 2011
oxybutynin avoid first pass metabolism in the upper
gastrointestinal tract leading to lower incidences
of both dry mouth and constipation.
56
In addition,
extended release forms of both oxybutynin and
tolterodine have been shown to provide similar
efficacy to their immediate release formulations but
also demonstrated improved tolerability among
patients.
57
Newer generations of antimuscarinics that have
been approved for use for OAB have demonstrated
equal efficacy and improved side effect profiles
compared to oxybutynin and tolterodine. Trospium
[Sanctura (US), Trosec (Canada)] has been available for
over 20 years in Europe and shows lower rates of dry
mouth and CNS side effects secondary to its inability
to cross the blood brain barrier.
58
Solifenacin [Vesicare]
and darifenacin [Enablex] have been reported to have
improved M3 receptor selectivity.
59,60
Both trospium
and solifenacin should be dose titrated in those with
baseline renal impairment. Fesoterodine [Toviaz (US
only)] was the latest approved antimuscarinic (2009)
for treatment of OAB. Its maximumdose of 8 mg/day
has been shown to be more effective than maximum
doses of tolterodine (4 mg/day) but can lead to more
instances of dry mouth.
61,62
The decision to prescribe one of the many
antimuscarinics mentioned above can often be a
difficult one for the primary care physician. With each
demonstrating clinical efficacy, the decision should
primarily hinge on patient tolerability of side effects.
Each formulation has different side effect profiles and
change in medication dose or mode of administration
should not be frowned upon when treating patients
with OAB. Most antimuscarinics are metabolized via
the cytochrome P450 systemwhich can create a risk for
drug-drug interactions.
63
Drug prescription labels and
safety information profiles should be checked by both
the prescribing physician and pharmacy especially in
those patients taking a multitude of medications for
other medical conditions.
Prostate cancer
Pathophysiology
Similar to BPH, prostate cancer cellular growth is
mediated by testosterone andDHT under control of the
hypothalamic-pituitary axis.
64
Release of gonadotropin
releasing hormone (GnRH) by the hypothalamus
to the anterior pituitary promotes LH secretion and
subsequent testosterone production in the testes.
Physiologic negative feedback mechanisms regulate
this system. Hormonal therapies for neoadjuvant/
adjuvant prostate cancer treatment, local prostate
cancer recurrence, or metastatic/high risk disease
target this axis to achieve cancer control. Surgical
bilateral orchiectomy has been the historical gold
standard for hormone ablationwith testosterone levels
falling to < 20 ng/dL (0.69 nmol/L) postoperatively.
Chemical or pharmacologic castration using LHRH
agonists (LHRHA), LHRH antagonists (LHRHAN),
and androgen receptor blockers (antiandrogens) can
achieve testosterone levels < 50 ng/dL (1.73 nmol/L).
65
As more literature is published suggesting lower
levels of testosterone improve outcomes in metastatic
prostate cancer, different pharmacologic agents and
formulations are continuously developed to achieve
lower levels of androgen hormone.
66
Pharmacology
LHRH agonists and antagonists
LHRHA therapy creates a pharmacologic negative
feedback loop by constant stimulation of the anterior
pituitary leading to decreased levels of LH and
testosterone production. After the initial dose, there
is a transient hormonal surge of LH that then becomes
down-regulated after approximately 2 weeks.
64
This
surge in LH and testosterone can be dangerous with
advanced prostate cancer as bone pain from bony
metastases, BOO, or neurologic compromise secondary
to imminent spinal metastasis can all occur during this
time period. Initial blockade with an antiandrogen can
be helpful in this setting.
LHRHA can be administered every 1 to 6 months
in a variety of different formulations. These include
leuprolide [Lupron, Eligard], goserelin [Zoladex],
buserelin [Suprefact], and triptorelin [Trelstar], Table
8a. Side effects of all LHRHA include hot flashes,
decreased libido, erectile dysfunction, anemia,
mood changes, and loss of bone mineral density.
67
LHRHAN such as degarelix [Firmagon] work by
inhibiting binding of the LH receptor in the pituitary
gland. Therefore, there is no hormonal surge as seen
with LHRHA making it useful in those patients with
impending cord compression or BOO from advanced
prostate cancer.
On a related note, there are significant concerns
over the long term use of any LHRHA or LHRHAN
inducing osteoporosis and increasing fracture risk
in men. Strategies to reduce this risk are becoming
commonplace in the management of this chemically
induced hypogonadism. Bisphosphonates are used to
treat or prevent those prostate cancer patients at risk
for hormonal induced osteoporosis, osteopenia, or
pathologic fracture.
68,69
Historically, zoledronic acid
[Zometa] was the first approved agent for preventing
33
Pharmacology for common urologic diseases: 2011 review for the primary care physician