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

234 efficient, resulting in the delivery of ~ 0.5 mg of scopolamine
over 72 hours.
SECTION II
NEUROPHARMACOLOGY
Xerostomia is common, drowsiness is not infrequent, and
blurred vision occurs in some individuals. Mydriasis and cycloplegia
can occur by inadvertent transfer of the drug to the eye from the
fingers after handling the patch. Rare but severe psychotic episodes
have been reported. As noted earlier, the preoperative use of scopolamine
to produce tranquilization and amnesia is no longer recommended.
Given alone in the presence of pain or severe anxiety,
scopolamine may induce outbursts of uncontrolled behavior.
For many years, the belladonna alkaloids and subsequently
synthetic substitutes were the only agents
helpful in the treatment of Parkinson disease. Levodopa
combined with carbidopa (SINEMET) and dopamine
receptor agonists are currently the most important treatments
for Parkinson disease, but alternative or concurrent
therapy with muscarinic receptor antagonists may
be required in some patients (Chapter 22). Centrally
acting muscarinic antagonists are efficacious in preventing
extrapyramidal side effects such as dystonias or
parkinsonian symptoms in patients treated with
antipsychotic drugs (Chapter 16). The muscarinic
antagonists used for Parkinson disease and druginduced
extrapyramidal symptoms include benztropine
mesylate (COGENTIN, others), trihexyphenidyl
hydrochloride (ARTANE, others), and biperiden; all are
tertiary amines that readily gain access to the CNS.
Current evidence based on studies using muscarinic receptor
knockout mice, subtype-selective drugs, and early-stage clinical trials
suggest that selective blockade of specific muscarinic receptor
subtypes in the CNS may have important therapeutic applications.
For example, selective M 1
and M 4
muscarinic antagonists may be
efficacious for the treatment of Parkinson disease with fewer side
effects than nonselective muscarinic antagonists, while selective M 3
antagonists may be useful in the treatment of obesity and associated
metabolic abnormalities (Wess et al., 2007).
Uses in Anesthesia. The use of anesthetics that are relatively nonirritating
to the bronchi has virtually eliminated the need for prophylactic
use of muscarinic receptor antagonists. Atropine commonly is
given to block responses to vagal reflexes induced by surgical
manipulation of visceral organs. Atropine or glycopyrrolate is used
with neostigmine to block its parasympathomimetic effects when
the latter agent is used to reverse skeletal muscle relaxation after surgery
(Chapter 11). Serious cardiac arrhythmias have occasionally
occurred, perhaps because of the initial bradycardia produced by
atropine combined with the cholinomimetic effects of neostigmine.
Anticholinesterase Poisoning. The use of atropine in large doses
for the treatment of poisoning by anticholinesterase organophosphorus
insecticides is discussed in Chapter 10. Atropine also may be
used to antagonize the parasympathomimetic effects of pyridostigmine
or other anticholinesterases administered in the treatment of
myasthenia gravis. It does not interfere with the salutary effects at the
skeletal neuromuscular junction. It is most useful early in therapy,
before tolerance to muscarinic side effects of anticholinesterases
have developed.
Other Therapeutic Uses of Muscarinic Antagonists. Methscopolamine
bromide (PAMINE) is a quaternary ammonium derivative of scopolamine
and therefore lacks the central actions of scopolamine. Although
formerly used to treat peptic ulcer disease, at present it is primarily used
in certain combination products for the temporary relief of symptoms
of allergic rhinitis, sinusitis, and the common cold.
Homatropine methylbromide, the methyl derivative of homatropine,
is less potent than atropine in antimuscarinic activity but
four times more potent as a ganglionic blocking agent. Formerly
used for the treatment of irritable bowel syndrome and peptic ulcer
disease, at present it is primarily used with hydrocodone as an antitussive
combination (HYCODAN, others).
Contraindications and Adverse Effects
Most contraindications, precautions, and adverse effects are predictable
consequences of muscarinic receptor blockade: xerostomia,
constipation, blurred vision, dyspepsia, and cognitive impairment.
Important contraindications to the use of muscarinic antagonists
include urinary tract obstruction, GI obstruction, and uncontrolled
(or susceptibility to attacks of) angle-closure glaucoma. Muscarinic
receptor antagonists also are contraindicated (or should be used with
extreme caution) in patients with benign prostatic hyperplasia.
These adverse effects and contraindications generally are of more
limited concern with muscarinic antagonists that are administered
by inhalation or used topically in ophthalmology.
Toxicology of Drugs with
Antimuscarinic Properties
The deliberate or accidental ingestion of natural belladonna alkaloids
is a major cause of poisonings. Many histamine H 1
receptor
antagonists, phenothiazines, and tricyclic antidepressants also block
muscarinic receptors, and in sufficient dosage, produce syndromes
that include features of atropine intoxication.
Among the tricyclic antidepressants, protriptyline and
amitriptyline are the most potent muscarinic receptor antagonists,
with an affinity for the receptor that is ~ one-tenth of that reported
for atropine. Since these drugs are administered in therapeutic doses
considerably higher than the effective dose of atropine, antimuscarinic
effects are often observed clinically (Chapter 15). In addition,
overdose with suicidal intent is a danger in the population using
antidepressants. Fortunately, most of the newer antidepressants and
selective serotonin reuptake inhibitors have more limited anticholinergic
properties (Cusack et al., 1994).
Like the tricyclic antidepressants, many of the older antipsychotic
drugs have antimuscarinic effects. These effects are most
likely to be observed with the less potent drugs, e.g., chlorpromazine
and thioridazine, which must be given in higher doses. The newer
antipsychotic drugs, classified as “atypical” and characterized by
their low propensity for inducing extrapyramidal side effects, also
include agents that are potent muscarinic receptor antagonists. In
particular, clozapine binds to human brain muscarinic receptors with
high affinity (10 nM, compared to 1-2 nM for atropine); olanzapine