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

also is a potent muscarinic receptor antagonist (Richelson, 1999;
Roth et al., 2004). Accordingly, xerostomia is a prominent side effect
of these drugs. A paradoxical side effect of clozapine is increased
salivation and drooling, possibly the result of partial agonist properties
of this drug (Richelson, 1999).
Infants and young children are especially susceptible to the
toxic effects of muscarinic antagonists. Indeed, cases of intoxication
in children have resulted from conjunctival instillation for ophthalmic
refraction and other ocular effects. Systemic absorption occurs either
from the nasal mucosa after the drug has traversed the nasolacrimal
duct or from the GI tract if the drug is swallowed. Poisoning with
diphenoxylate-atropine (LOMOTIL, others), used to treat diarrhea, has
been extensively reported in the pediatric literature. Transdermal
preparations of scopolamine used for motion sickness have been
noted to cause toxic psychoses, especially in children and in the elderly.
Serious intoxication may occur in children who ingest berries or
seeds containing belladonna alkaloids. Poisoning from ingestion and
smoking of jimson weed is seen with some frequency today.
Table 9–2 shows the oral doses of atropine causing undesirable
responses or symptoms of overdosage. These symptoms are predictable
results of blockade of parasympathetic innervation. In cases
of full-blown atropine poisoning, the syndrome may last 48 hours
or longer. Intravenous injection of the anticholinesterase agent
physostigmine may be used for confirmation. If physostigmine does
not elicit the expected salivation, sweating, bradycardia, and intestinal
hyperactivity, intoxication with atropine or a related agent is
almost certain. Depression and circulatory collapse are evident only
in cases of severe intoxication; the blood pressure declines, convulsions
may ensue, respiration becomes inadequate, and death due to
respiratory failure may follow after a period of paralysis and coma.
Measures to limit intestinal absorption should be initiated
without delay if the poison has been taken orally. For symptomatic
treatment, slow intravenous injection of physostigmine rapidly abolishes
the delirium and coma caused by large doses of atropine, but
carries some risk of overdose in mild atropine intoxication. Since
physostigmine is metabolized rapidly, the patient may again lapse
into coma within 1-2 hours, and repeated doses may be needed
(Chapter 10). If marked excitement is present and more specific
treatment is not available, a benzodiazepine is the most suitable
agent for sedation and for control of convulsions. Phenothiazines or
agents with antimuscarinic activity should not be used, because their
antimuscarinic action is likely to intensify toxicity. Support of respiration
and control of hyperthermia may be necessary. Ice bags and
alcohol sponges help to reduce fever, especially in children.
CLINICAL SUMMARY
Drugs that target muscarinic receptors have a wide variety
of therapeutic uses. For example, muscarinic agonists
are used in the treatment of urinary retention and
xerostomia; muscarinic antagonists are used in the
treatment of overactive bladder, chronic obstructive pulmonary
disease, and increased GI motility; and both
groups of agents have important uses in ophthalmology.
The cloning of five distinct muscarinic receptor
subtypes and their subsequent genetic deletion in mice
has raised the expectation that one might greatly
improve the therapeutic utility of drugs that interact
with muscarinic receptors by the development of subtype-selective
agonists and antagonists. By targeting
unique subsets of receptors that control muscarinic
responses within a particular organ, unwanted side
effects that typify the use of these drugs could be
avoided. Subtype-selective muscarinic receptor agonists
and antagonists show particular promise in the
treatment of CNS disorders such as Alzheimer’s disease
and Parkinson disease. Although complete selectivity
has been difficult to achieve, the development of
allosteric modulators may allow enhanced selectivity
and new therapeutic uses in the future.
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CHAPTER 9
MUSCARINIC RECEPTOR AGONISTS AND ANTAGONISTS