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

224 The difficulty in developing subtype selective muscarinic
receptor agonists, coupled with the lack of efficacy and the significant
peripheral side effects of available muscarinic agonists, have
prompted a search for other strategies for selectively activating specific
muscarinic receptor subtypes, such as allosteric agonists and
positive allosteric modulators (PAMs) (Conn et al., 2009b). Selective
muscarinic subtype activators may be useful in the treatment of additional
CNS disorders, including schizophrenia and drug addiction,
and as analgesic agents (Conn et al., 2009b). For example, xanomeline,
a muscarinic agonist with some selectivity for the M 1
and M 4
subtypes that was in clinical development for Alzheimer’s disease,
has an antipsychotic profile in animal models and therapeutic
efficacy in patients with schizophrenia (Mirza et al., 2003; Shekhar
et al., 2008).
SECTION II
NEUROPHARMACOLOGY
Acetylcholine. Although rarely given systemically, ACh
(MIOCHOL-E) is used topically for the induction of
miosis during ophthalmologic surgery; it is instilled
into the eye as a 1% solution (Chapter 64).
Methacholine. Methacholine (PROVOCHOLINE) is administered
by inhalation for the diagnosis of bronchial
airway hyperreactivity in patients who do not have
clinically apparent asthma (Crapo et al., 2000). While
muscarinic agonists can cause bronchoconstriction and
increased tracheobronchial secretions in all individuals,
asthmatic patients respond with intense bronchoconstriction
and a reduction in vital capacity. Accordingly,
contraindications to methacholine testing include severe
airflow limitation, recent myocardial infarction or
stroke, uncontrolled hypertension, or pregnancy. The
response to methacholine also may be exaggerated or
prolonged in patients taking β adrenergic receptor antagonists.
Emergency resuscitation equipment, oxygen,
and medications to treat severe bronchospasm (e.g., β 2
adrenergic receptor agonists for inhalation) should be
available during testing. Methacholine is available as a
powder that is diluted with 0.9% sodium chloride and
administered via a nebulizer.
Bethanechol. Bethanechol (URECHOLINE, others) primarily
affects the urinary and GI tracts. In the urinary tract,
bethanechol has utility in treating urinary retention and
inadequate emptying of the bladder when organic
obstruction is absent, as in postoperative urinary retention,
diabetic autonomic neuropathy, and certain cases of
chronic hypotonic, myogenic, or neurogenic bladder
(Wein, 1991); catheterization can thus be avoided. When
used chronically, 10-50 mg of the drug is given orally
three to four times daily; the drug should be administered
on an empty stomach (i.e., 1 hour before or 2 hours
after a meal) to minimize nausea and vomiting.
In the GI tract, bethanechol stimulates peristalsis,
increases motility, and increases resting lower esophageal
sphincter pressure. Bethanechol formerly was used to
treat postoperative abdominal distention, gastric atony,
gastroparesis, adynamic ileus, and gastroesophageal
reflux; more efficacious therapies for these disorders
are now available (Chapters 45 and 46).
Carbachol. Carbachol (MIOSTAT, ISOPTO CARBACHOL,
others) is used topically in ophthalmology for the treatment
of glaucoma and the induction of miosis during
surgery; it is instilled into the eye as a 0.01-3% solution
(Chapter 64).
Pilocarpine. Pilocarpine hydrochloride (SALAGEN, others)
is used for the treatment of xerostomia that follows
head and neck radiation treatments or that is associated
with Sjögren’s syndrome (Porter et al., 2004;Wiseman
and Faulds, 1995), an autoimmune disorder occurring
primarily in women in whom secretions, particularly
salivary and lacrimal, are compromised (Anaya and
Talal, 1999). Provided salivary parenchyma maintains
residual function, enhanced salivary secretion, ease of
swallowing, and subjective improvement in hydration
of the oral cavity are achieved. Side effects typify
cholinergic stimulation, with sweating being the most
common complaint. The usual dose is 5-10 mg three
times daily; the dose should be lowered in patients with
hepatic impairment.
Pilocarpine (ISOPTO CARPINE, others) is used topically
in ophthalmology for the treatment of glaucoma
and as a miotic agent; it is instilled in the eye as a
0.5-6% solution and also can be delivered via an ocular
insert (Chapter 64).
Cevimeline. Cevimeline (EVOXAC), a quinuclidine derivative
of ACh, is a muscarinic agonist with a high affinity
for M 3
muscarinic receptors on lacrimal and salivary
gland epithelia. Cevimeline has a long-lasting sialogogic
action and may have fewer side effects than
pilocarpine (Anaya and Talal, 1999). Cevimeline also
enhances lacrimal secretions in Sjögren’s syndrome
(Ono et al., 2004). The usual dose is 30 mg three times
daily.
Contraindications, Precautions, and Adverse Effects
Most contraindications, precautions, and adverse effects are predictable
consequences of muscarinic receptor stimulation. Thus,
important contraindications to the use of muscarinic agonists include
asthma, chronic obstructive pulmonary disease, urinary or GI tract
obstruction, acid-peptic disease, cardiovascular disease accompanied
by bradycardia, hypotension, and hyperthyroidism (muscarinic
agonists may precipitate atrial fibrillation in hyperthyroid patients).
Common adverse effects include diaphoresis; diarrhea, abdominal
cramps, nausea/vomiting, and other GI side effects; a sensation of
tightness in the urinary bladder; difficulty in visual accommodation;