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

blurred vision, and central muscarinic disturbances is relatively low.
Central effects are not seen because of the drug’s limited penetration
into the CNS.
Most studies indicate that pirenzepine (100-150 mg per day)
produces about the same rate of healing of duodenal and gastric
ulcers as the H 2
receptor antagonists cimetidine or ranitidine; it also
may be effective in preventing the recurrence of ulcers (Carmine and
Brogden, 1985; Tryba and Cook, 1997). Side effects necessitate drug
withdrawal in <1% of patients. Studies in human subjects have
shown pirenzepine to be more potent in inhibiting gastric acid secretion
produced by neural stimuli than by muscarinic agonists, supporting
the postulated localization of M 1
receptors at ganglionic
sites. Nevertheless, H 2
receptor antagonists and proton pump
inhibitors generally are considered to be the current drugs of choice
to reduce gastric acid secretion (Chapter 45).
Myriad conditions known or supposed to involve increased
tone (spasticity) or motility of the GI tract are treated with belladonna
alkaloids (e.g., atropine, hyoscyamine sulfate [ANASPAZ, others], and
scopolamine) alone or in combination with sedatives (e.g., phenobarbital
[DONNATAL, others]) or antianxiety agents (e.g., chlordiazepoxide
[LIBRAX]). The belladonna alkaloids and their synthetic substitutes
can reduce tone and motility when administered in maximally tolerated
doses, and they might be expected to be efficacious in conditions
simply involving excessive smooth muscle contraction, a point
that is often in doubt. M 3
-selective antagonists might achieve more
selectivity but are unlikely to be better tolerated, as M 3
receptors also
have an important role in the control of salivation, bronchial secretion
and contraction, and bladder motility. Glycopyrrolate (ROBINUL, others),
a muscarinic antagonist that is structurally unrelated to the belladonna
alkaloids, also is used to reduce GI tone and motility; being
a quaternary amine, it is less likely to cause adverse CNS effects than
atropine, scopolamine, and other tertiary amines. Alternative agents
for treatment of increased GI motility and its associated symptoms are
discussed in Chapter 46.
Diarrhea associated with irritation of the lower bowel, such as
mild dysenteries and diverticulitis, may respond to atropine-like
drugs, an effect that likely involves actions on ion transport as well
as motility. However, more severe conditions such as Salmonella
dysentery, ulcerative colitis, and Crohn’s disease respond little if at
all to muscarinic antagonists. The belladonna alkaloids and synthetic
substitutes are very effective in reducing excessive salivation, such
as drug-induced salivation and that associated with heavy-metal poisoning
and Parkinson disease.
Dicyclomine hydrochloride (BENTYL, others) is a weak
muscarinic receptor antagonist that also has nonspecific direct spasmolytic
effects on smooth muscle of the GI tract. It is occasionally used
in the treatment of diarrhea-predominant irritable bowel syndrome.
Eye. Effects limited to the eye are obtained by topical
administration of muscarinic receptor antagonists to
produce mydriasis and cycloplegia. Cycloplegia is not
attainable without mydriasis and requires higher concentrations
or more prolonged application of a given
agent. Mydriasis often is necessary for thorough examination
of the retina and optic disc and in the therapy of
iridocyclitis and keratitis. The belladonna mydriatics
may be alternated with miotics for breaking or preventing
the development of adhesions between the iris and the
lens. Complete cycloplegia may be necessary in the
treatment of iridocyclitis and choroiditis and for accurate
measurement of refractive errors.
Homatropine hydrobromide (ISOPTO HOMATROPINE, others), a
semisynthetic derivative of atropine (Figure 9–2), cyclopentolate
hydrochloride (CYCLOGYL, others), and tropicamide (MYDRIACYL,
others) are agents used in ophthalmological practice. These agents
are preferred to topical atropine or scopolamine because of their
shorter duration of action. Additional information on the ophthalmological
properties and preparations of these and other drugs is
provided in Chapter 64.
Cardiovascular System. The cardiovascular effects of
muscarinic receptor antagonists are of limited clinical
utility. Generally, these agents are used only in coronary
care units for short-term interventions or in surgical
settings.
Atropine may be considered in the initial treatment of patients
with acute myocardial infarction in whom excessive vagal tone
causes sinus bradycardia or AV nodal block. Sinus bradycardia is
the most common arrhythmia seen during acute myocardial infarction
of the inferior or posterior wall. Atropine may prevent further
clinical deterioration in cases of high vagal tone or AV block by
restoring heart rate to a level sufficient to maintain adequate hemodynamic
status and to eliminate AV nodal block. Dosing must be
judicious; doses that are too low can cause a paradoxical bradycardia
(described earlier), while excessive doses will cause tachycardia
that may extend the infarct by increasing the demand for oxygen.
Atropine occasionally is useful in reducing the severe bradycardia
and syncope associated with a hyperactive carotid sinus reflex.
It has little effect on most ventricular rhythms. In some patients,
atropine may eliminate premature ventricular contractions associated
with a very slow atrial rate. It also may reduce the degree of AV
block when increased vagal tone is a major factor in the conduction
defect, such as the second-degree AV block that can be produced by
digitalis. Selective M 2
receptor antagonists would be of potential
utility in blocking ACh-mediated bradycardia or AV block; however,
none is currently available for clinical use.
Central Nervous System. The belladonna alkaloids were
among the first drugs to be used in the prevention of
motion sickness. Scopolamine is the most effective
prophylactic agent for short (4-6 hour) exposures to
severe motion, and probably for exposures of up to several
days. All agents used to combat motion sickness
should be given prophylactically; they are much less
effective after severe nausea or vomiting has developed.
A transdermal preparation of scopolamine (TRANSDERM
SCOP) has been shown to be highly effective when used
prophylactically for the prevention of motion sickness.
The drug, incorporated into a multilayered adhesive
unit, is applied to the postauricular mastoid region, an
area where transdermal absorption of the drug is especially
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CHAPTER 9
MUSCARINIC RECEPTOR AGONISTS AND ANTAGONISTS