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© The Canadian Journal of Urology™; 18(Supplement 1); April 2011
10
A simple algorithm, which was designed by a
consensus panel and approved by the Canadian
Urological Association, can be used to help diagnose
and manage most patients with typical OAB and
to diminish the risk of missing other significant
pathologies that may mimic the signs and symptoms
of this condition.
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Managing OAB
Behavioral therapy
After a patient has beendiagnosedwithOAB, and other
contributing factors have been identified and treated,
treatment for OAB should begin with behavioral
therapy. Behavioral therapies include physiotherapy
(instructions about Kegel pelvic-floor strengthening
exercises and biofeedback) and strategies for scheduled
voiding, bladder retraining (to adopt longer intervals
between voiding), and fluid management (including
limiting consumption of caffeine).
Antimuscarinic agents
Medical management of OAB focuses on relaxing the
bladder. If the bladder is relaxed, it is less sensitive
to filling and to bladder irritants, which improves the
storage phase in the bladder function cycle. As a result,
the bladder can hold a larger volume of urine, which
leads to less frequency, less urgency, fewer episodes
of urgency with incontinence, and increased bladder
latency time (the time from the first urge to void until
the bladder must be emptied).
The mainstays of pharmacotherapy for OAB are
the antimuscarinics (anticholinergics), which, by
acting on muscarinic receptors in the bladder, reduce
the amplitude of normal and involuntary bladder
contractions. They also improve the functional capacity
of the bladder by increasing the bladder ’s storage
volume at the first involuntary contraction.
2
In the bladder, M3 muscarinic receptors play a
role in stimulating detrusor muscular contraction.
M3 receptors are also found in the salivary gland and
the gut, however. Drugs that block M3 muscarinic
receptors in the bladder can also cause dry mouth
and constipation. M1 muscarinic receptors are found
in the brain, so drugs that block M1 muscarinic
receptors in the bladder could cause a side effect of
confusion, if the drug crossed the blood-brain barrier.
M5 muscarinic receptors are found in cardiac muscle,
so a drug that blocks M5 muscarinic receptors could
result in a prolonged QT interval, which could lead
to an arrhythmia. Drugs that are more selective for
certain muscarinic receptors are expected to have the
fewer side effects and secondary effects.
Side effects of antimuscarinics may include
pupillary dilatation, paralysis of lens accommodation,
tachycardia, changes in mental status, decreased
sweating, dry mouth and respiratory tract, and
inhibition of gastrointestinal (GI) motility.
In addition to blocking muscarinic (cholinergic)
receptors, inhigherdoses, all long-actingantimuscarinics
may result in ganglionic blockade in some patients. Side
effects of ganglionic blockade may include orthostatic
hypotension, impotence, and muscle weakness.
Antimuscarinic agents are contraindicated in
patients who have narrow-angle glaucoma (untreated),
obstructive or atonic disease of the GI and urinary tract,
or myasthenia gravis.
In Canada, many antimuscarinic agents are
available for the medical management of OAB,
see Table 1. Different ones are listed in different
provincial formularies. Drug manufacturers have
focused on developing long-acting, once daily dosage
forms of these drugs, since patients are more likely
to be compliant with this dosing schedule. In most
cases, generic, immediate-release (IR) oxybutynin is
the comparator drug during clinical trials. Patients
showed improved compliance, improved efficacy
(decreased frequency, urgency, and episodes of
incontinence) and fewer side effects with the newer
agents compared with placebo or generic oxybutynin.
Themostworrisome side effect fromantimuscarinics
prescribed for OAB, which is seen mainly in elderly
patients, is confusion or change in cognition. If the
drug crosses the blood brain barrier, that side effect can
be prominent. Various authors have reported potential
CNS impairment in elderly patients who are treated
with antimuscarinics for OAB.
12-15
Antimuscarinics
may cause memory deficits (that patients may
be unaware of), sleep disruption, confusion, or
hallucinations. The extent of CNS deficits depends on
age-related decreases drug elimination and changes
in the blood-brain barrier integrity or in muscarinic
receptors. The side effects also depend on the drug’s
ability to cross the blood-brain barrier or block M1
receptors in the brain.
In one trial looking at potential CNS impairment
with drugs for OAB, patients receiving oxybutynin
extended release (ER) had memory impairment
and significantly lower memory scores compared to
patients receiving placebo or darifenacin.
16
In a similar trial that compared solifenacin versus
placebo or immediate release (IR) oxybutynin, the
authors found no evidence of cognitive impairment
with solifenacin 10 mg versus placebo overall and
at Tmax (6 hrs post-dose). Significant worsening of
cognitive function -- information processing, learning,
BARKIN