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

230 sympathetic cholinergic fibers, and the skin becomes
hot and dry. Sweating may be depressed enough to raise
the body temperature, but only notably so after large
doses or at high environmental temperatures.
SECTION II
NEUROPHARMACOLOGY
Central Nervous System. Atropine has minimal effects
on the CNS at therapeutic doses, although mild stimulation
of the parasympathetic medullary centers may
occur. With toxic doses of atropine, central excitation
becomes more prominent, leading to restlessness, irritability,
disorientation, hallucinations, or delirium
(see the discussion of atropine poisoning later in the
chapter). With still larger doses, stimulation is followed
by depression, leading to circulatory collapse and respiratory
failure after a period of paralysis and coma.
In contrast to atropine, scopolamine has prominent
central effects at low therapeutic doses; atropine
therefore is preferred over scopolamine for many purposes.
The basis for this difference is probably the
greater permeation of scopolamine across the bloodbrain
barrier. Specifically, scopolamine in therapeutic
doses normally causes CNS depression manifest as
drowsiness, amnesia, fatigue, and dreamless sleep, with
a reduction in rapid eye movement (REM) sleep. It also
causes euphoria and can therefore be subject to abuse.
The depressant and amnesic effects formerly were
sought when scopolamine was used as an adjunct to
anesthetic agents or for preanesthetic medication.
However, in the presence of severe pain, the same doses
of scopolamine can occasionally cause excitement, restlessness,
hallucinations, or delirium. These excitatory
effects resemble those of toxic doses of atropine.
Scopolamine also is effective in preventing motion
sickness, probably by blocking neural pathways from
the vestibular apparatus in the inner ear to the emetic
center in the brainstem.
Muscarinic receptor antagonists have long been used in the
treatment of Parkinson disease. These agents can be effective
adjuncts to treatment with levodopa (Chapter 22). Muscarinic receptor
antagonists also are used to treat the extrapyramidal symptoms
that commonly occur as side effects of conventional antipsychotic
drug therapy (Chapter 16). Certain antipsychotic drugs are relatively
potent muscarinic receptor antagonists (Richelson, 1999; Roth et al.,
2004) and, perhaps for this reason, cause fewer extrapyramidal side
effects.
Ipratropium and Tiotropium
The quaternary ammonium compounds ipratropium
and tiotropium are used exclusively for their effects on
the respiratory tract. When inhaled, their action is confined
almost completely to the mouth and airways. Dry
mouth is the only frequently reported side effect, as the
absorption of these drugs from the lungs or the GI tract
is very inefficient. The degree of bronchodilation
achieved by these agents is thought to reflect the level
of basal parasympathetic tone, supplemented by reflex
activation of cholinergic pathways brought about by
various stimuli. In normal individuals, inhalation of the
drugs can provide virtually complete protection against
the bronchoconstriction produced by the subsequent
inhalation of such irritants as sulfur dioxide, ozone, or
cigarette smoke. However, patients with atopic asthma
or patients with demonstrable bronchial hyperresponsiveness
are less well protected. Although these drugs
cause a marked reduction in sensitivity to methacholine
in asthmatic subjects, more modest inhibition of
responses to challenge with histamine, bradykinin, or
PGF 2α
is achieved, and little protection is afforded
against the bronchoconstriction induced by 5-HT or
leukotrienes. A therapeutically important property of
ipratropium and tiotropium is their minimal inhibitory
effect on mucociliary clearance relative to atropine.
Hence, the choice of these agents for use in patients
with airway disease minimizes the increased accumulation
of lower airway secretions encountered with
atropine.
Ipratropium appears to block all subtypes of muscarinic
receptors and accordingly also antagonizes the
inhibition of ACh release by presynaptic M 2
receptors
on parasympathetic postganglionic nerve terminals in
the lung; the resulting increase in ACh release may
counteract its blockade of M 3
receptor-mediated bronchoconstriction.
In contrast, tiotropium shows some
selectivity for M 1
and M 3
receptors; its lower affinity
for M 2
receptors minimizes its presynaptic effect to
enhance ACh release (Barnes, 2004; Disse et al., 1999)
Absorption, Distribution, and Elimination. The belladonna alkaloids
and the tertiary synthetic and semisynthetic derivatives are
absorbed rapidly from the GI tract. They also enter the circulation
when applied locally to the mucosal surfaces of the body. Absorption
from intact skin is limited, although efficient absorption does occur
in the postauricular region for some agents (e.g., scopolamine, allowing
delivery by transdermal patch). Systemic absorption of inhaled
or orally ingested quaternary muscarinic receptor antagonists is limited.
The quaternary ammonium derivatives of the belladonna alkaloids
also penetrate the conjunctiva of the eye less readily, and
central effects are lacking because the quaternary agents do not cross
the blood-brain barrier. Atropine has a t 1/2
of ~4 hours; hepatic
metabolism accounts for the elimination of about half of a dose; the
remainder is excreted unchanged in the urine.
Ipratropium is administered as an aerosol or solution for
inhalation whereas tiotropium is administered as a dry powder. As
with most drugs administered by inhalation, ~90% of the dose is
swallowed. Most of the swallowed drug appears in the feces. After
inhalation, maximal responses usually develop over 30-90 minutes,