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

with tiotropium having the slower onset. The effects of ipratropium
last for 4-6 hours, while tiotropium’s effects persist for 24 hours
so that the drug is amenable to once-daily dosing (Barnes and
Hansel, 2004).
Therapeutic Uses of Muscarinic
Receptor Antagonists
Muscarinic receptor antagonists have been used in the
treatment of a wide variety of clinical conditions, predominantly
to inhibit effects of parasympathetic activity
in the respiratory tract, urinary tract, GI tract, eye,
and heart. Their CNS effects have resulted in their use
in the treatment of Parkinson disease, the management
of extrapyramidal side effects of antipsychotic
drugs, and the prevention of motion sickness. The
major limitation in the use of the nonselective drugs is
often failure to obtain desired therapeutic responses
without concomitant side effects. While the latter usually
are not serious, they can be sufficiently disturbing
to decrease patient compliance, particularly during
long-term administration. To date, selectivity has
mainly been achieved by local administration, e.g., by
pulmonary inhalation or instillation in the eye, since
few available muscarinic antagonists show absolute
selectivity. The development of allosteric modulators
that recognize sites unique to particular receptor subtypes
is currently considered an important approach to
the development of selective drugs for the treatment of
specific clinical conditions (Conn et al., 2009b).
Respiratory Tract. Ipratropium (ATROVENT, others) and
tiotropium (SPIRIVA) are important agents in the treatment
of chronic obstructive pulmonary disease; they
are less effective in most asthmatic patients (Barnes,
2004; Barnes and Hansel, 2004; Gross, 2004). These
agents often are used with inhaled long-acting β 2
adrenergic
receptor agonists, although there is little evidence
of true synergism. Ipratropium is administered four
times daily via a metered-dose inhaler or nebulizer;
tiotropium is administered once daily via a dry powder
inhaler. The therapeutic uses of ipratropium and
tiotropium are discussed further in Chapter 36.
Ipratropium also is FDA-approved for use in
nasal inhalers for the treatment of the rhinorrhea associated
with the common cold or with allergic or nonallergic
perennial rhinitis. Although the ability of
muscarinic antagonists to reduce nasopharyngeal secretions
may provide some symptomatic relief, such therapy
does not affect the natural course of the condition.
It is probable that the contribution of first-generation
antihistamines employed in nonprescription cold
medications is due primarily to their antimuscarinic
properties, except in conditions with an allergic basis
(Chapter 32). The uncomplicated common cold will
generally last 2 weeks if treated and 14 days if
untreated; cold medications may, however, ameliorate
some of the symptoms.
Genitourinary Tract. Overactive urinary bladder can be
successfully treated with muscarinic receptor antagonists.
These agents can lower intravesicular pressure,
increase capacity, and reduce the frequency of contractions
by antagonizing parasympathetic control of the
bladder; they also may alter bladder sensation during
filling (Chapple et al., 2005). Muscarinic antagonists
can be used to treat enuresis in children, particularly
when a progressive increase in bladder capacity is the
objective, and to reduce urinary frequency and increase
bladder capacity in spastic paraplegia (Chapple, 2000;
Goessl et al., 2000).
The muscarinic receptor antagonists indicated for overactive
bladder are oxybutynin (DITROPAN, others), tolterodine (DETROL), trospium
chloride (SANCTURA), darifenacin (ENABLEX), solifenacin
(VESICARE), and fesoterodine (TOVIAZ); available preparations and
dosages are summarized in Table 9–3. Although some comparison
trials have demonstrated small but statistically significant differences
in efficacy between agents (Chapple et al., 2005), whether these efficacy
differences are clinically significant is uncertain. The most
important adverse reactions are consequences of muscarinic receptor
blockade and include xerostomia, blurred vision, and GI side
effects such as constipation and dyspepsia. CNS-related antimuscarinic
effects, including drowsiness, dizziness, and confusion, can
occur and are particularly problematic in elderly patients. CNS
effects appear to be less likely with trospium, a quaternary amine,
and with darifenacin and solifenacin; the latter agents are relatively
selective for M 3
receptors and therefore have minimal effects on M 1
receptors in the CNS, which appear to play an important role in
memory and cognition (Kay et al., 2006). Adverse effects can limit
the tolerability of these drugs with continued use, and patient
acceptance declines. Xerostomia is the most common reason for
discontinuation.
Oxybutynin, the oldest of the antimuscarinics currently used
to treat overactive bladder disorders, is associated with a high incidence
of antimuscarinic side effects, particularly xerostomia. In an
attempt to increase patient acceptance, oxybutynin is marketed as a
transdermal system (OXYTROL) that is associated with a lower incidence
of side effects than the oral immediate- or extended-release
formulations; a topical gel formulation of oxybutynin (GELNIQUE)
also appears to offer a more favorable side effect profile. Because of
the extensive metabolism of oral oxybutynin by enteric and hepatic
CYP3A4, higher doses are used in oral than transdermal administration;
the dose may need to be reduced in patients taking drugs that
inhibit CYP3A4.
Tolterodine shows selectivity for the urinary bladder in animal
models and in clinical studies, resulting in greater patient acceptance;
however, studies on isolated receptors do not reveal a unique
subtype selectivity (Abrams et al., 1998, 1999; Chapple, 2000).
231
CHAPTER 9
MUSCARINIC RECEPTOR AGONISTS AND ANTAGONISTS