DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 9–3
Muscarinic Receptor Antagonists Used in the Treatment of Overactive Urinary Bladder
NONPROPRIETARY t 1/2
DAILY DOSE
NAME TRADE NAME (HOURS) PREPARATIONS a (ADULT)
Oxybutynin DITROPAN, others 2-5 IR 10-20 mg b
OXYTROL ER 5-30 mg b
GELNIQUE Transdermal patch 3.9 mg
Topical gel
100 mg
Tolterodine DETROL 2-9.6 c IR 2-4 mg b,d
6.9-18 c ER 4 mg b,d
Trospium chloride SANCTURA 20 IR 20-40 mg e
35 ER 60 mg e
Solifenacin VESICARE 55 IR 5-10 mg b
Darifenacin ENABLEX 13-19 ER 7.5-15 mg f
Fesoterodine TOVIAZ 7 ER 4-8 mg
a
Preparations are designated as follows: IR, immediate-release tablet; ER, extended-release tablet or capsule.
b
Doses may need to be reduced in patients taking drugs that inhibit CYP3A4.
c
Longer times in indicated ranges are seen in poor metabolizers.
d
Doses should be reduced in patients with significant renal or hepatic impairment.
e
Doses should be reduced in patients with significant renal impairment; dosage adjustments also may be needed in patients with hepatic impairment.
f
Doses may need to be reduced in patients taking drugs that inhibit CYPs 3A4 or 2D6.
Inhibition of a particular complement of receptors in the bladder may
give rise to synergism and clinical efficacy. Tolterodine is metabolized
by CYP2D6 to 5-hydroxymethyltolterodine. Since this metabolite
possesses similar activity to the parent drug, variations in
CYP2D6 levels do not affect the net antimuscarinic activity or duration
of action of the drug. However, in patients who poorly metabolize
tolterodine via CYP2D6, the CYP3A4 pathway becomes
important in tolterodine elimination. Because it is often difficult to
assess which patients will be poor metabolizers, tolterodine doses
may need to be reduced in patients taking drugs that inhibit CYP3A4
(dosage adjustments generally are not necessary in patients taking
drugs that inhibit CYP2D6). Patients with significant renal or
hepatic impairment also should receive lower doses of the drug.
Fesoterodine, a new agent, is a prodrug that is rapidly hydrolyzed to
the active metabolite of tolterodine.
Trospium, a quaternary amine, is as effective as oxybutynin with
better tolerability. Trospium is the only antimuscarinic used for overactive
bladder that is eliminated primarily by the kidneys; 60% of the
absorbed trospium dose is excreted unchanged in the urine, and dosage
adjustment is necessary for patients with impaired renal function.
Solifenacin is relatively selective for muscarinic receptors of
the M 3
subtype, giving it a favorable efficacy:side effect ratio (Chapple
et al., 2004). Solifenacin is significantly metabolized by CYP3A4;
thus, patients taking drugs that inhibit CYP3A4 should receive lower
doses.
Like solifenacin, darifenacin is relatively selective for M 3
receptors. It is metabolized by CYP2D6 and CYP3A4; as with tolterodine,
the latter pathway becomes more important in patients who
poorly metabolize the drug by CYP2D6. Darifenacin doses may need
to be reduced in patients taking drugs that inhibit either of these CYPs.
Flavoxate hydrochloride, a drug with direct spasmolytic
actions on smooth muscle, especially of the urinary tract, is used for
the relief of dysuria, urgency, nocturia, and other urinary symptoms
associated with genitourinary disorders (e.g., cystitis, prostatitis, urethritis).
Flavoxate also has weak antihistaminic, local anesthetic,
analgesic, and, at high doses, antimuscarinic effects.
GI Tract. Muscarinic receptor antagonists were once
widely used for the management of peptic ulcer.
Although they can reduce gastric motility and the secretion
of gastric acid, antisecretory doses produce pronounced
side effects, such as xerostomia, loss of visual accommodation,
photophobia, and difficulty in urination
(Table 9–2). As a consequence, patient compliance in
the long-term management of symptoms of acidpeptic
disease with these drugs is poor.
Pirenzepine, a tricyclic drug similar in structure to
imipramine, has selectivity for M 1
over M 2
and M 3
receptors
(Caulfield, 1993; Caulfield and Birdsall, 1998). However, pirenzepine’s
affinities for M 1
and M 4
receptors are comparable, so it does
not possess total M 1
selectivity. Telenzepine, an analog of pirenzepine,
has higher potency and similar selectivity for M 1
muscarinic
receptors. Both drugs are used in the treatment of acid-peptic disease
in Europe, Japan, and Canada, but not currently in the U.S. At
therapeutic doses of pirenzepine, the incidence of xerostomia,