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

222 difficult to observe with administered ACh because CNS Effects. While systemically administered ACh has limited CNS
penetration, muscarinic agonists that can cross the blood-brain barrier
evoke a characteristic cortical arousal or activation response,
similar to that produced by injection of anticholinesterase agents or
by electrical stimulation of the brainstem reticular formation. All
five muscarinic receptor subtypes are found in the brain (Volpicelli
and Levey, 2004), and recent studies suggest that muscarinic receptorregulated
pathways may have an important role in cognitive function,
motor control, appetite regulation, nociception, and other
processes (Wess et al., 2007).
SECTION II
NEUROPHARMACOLOGY
poor perfusion of visceral organs and rapid hydrolysis
by plasma butyrylcholinesterase limit access of systemically
administered ACh to visceral muscarinic receptors.
Control of bladder contraction apparently is
mediated by multiple muscarinic receptor subtypes.
Receptors of the M 2
subtype appear most prevalent in
the bladder, yet studies with selective antagonists and
M 3
knockout mice suggest that the M 3
receptor mediates
detrusor muscle contraction (Matsui et al., 2000). The
M 2
receptor may act to inhibit β adrenergic receptor–
mediated relaxation of the bladder and may be involved
primarily in the filling stages to diminish urge incontinence
(Chapple, 2000; Hegde and Eglen, 1999).
GI Tract. Although stimulation of vagal input to the GI
tract increases tone, amplitude of contractions, and
secretory activity of the stomach and intestine, such
responses are inconsistently seen with administered
ACh for the same reasons that urinary tract responses
are difficult to observe. As in the urinary tract, muscarinic
receptors of the M 2
subtype are most prevalent,
but M 3
muscarinic receptors appear to be primarily
responsible for mediating the cholinergic control of GI
motility (Matsui et al., 2002).
Miscellaneous Peripheral Effects. In addition to its above-mentioned
stimulatory effects on the tracheobronchial and GI secretions, ACh
stimulates secretion from other glands that receive parasympathetic
or sympathetic cholinergic innervation, including the lacrimal,
nasopharyngeal, salivary, and sweat glands. All of these effects are
mediated primarily by M 3
muscarinic receptors (Caulfield and
Birdsall, 1998); M 1
receptors also contribute significantly to the
cholinergic stimulation of salivary secretion (Gautam et al., 2004).
When instilled into the eye, ACh produces miosis by contracting the
pupillary sphincter muscle and accommodation for near vision by
contracting the ciliary muscle (Chapter 64); both of these effects are
mediated primarily by M 3
muscarinic receptors, but other subtypes
may contribute to the ocular effects of cholinergic stimulation.
MUSCARINIC RECEPTOR AGONISTS
Muscarinic cholinergic receptor agonists can be divided
into two groups: 1) choline esters, including ACh and several
synthetic esters; and 2) the naturally occurring cholinomimetic
alkaloids (particularly pilocarpine, muscarine,
and arecoline) and their synthetic congeners.
Of several hundred synthetic choline derivatives
investigated, only methacholine, carbachol, and
bethanechol (Figure 9–1) have had clinical applications.
Methacholine (acetyl-β-methylcholine), the β-methyl
analog of ACh, is a synthetic choline ester that differs
from ACh chiefly in its greater duration and selectivity
of action. Its action is more prolonged because the
added methyl group increases its resistance to hydrolysis
by cholinesterases. Its selectivity is reflected in a
predominance of muscarinic with only minor nicotinic
actions, the former manifest most clearly in the cardiovascular
system (Table 9–1).
Carbachol, and its β-methyl analog, bethanechol,
are unsubstituted carbamoyl esters that are almost completely
resistant to hydrolysis by cholinesterases; their
t 1/2
are thus sufficiently long that they become distributed
to areas of low blood flow. Carbachol retains substantial
nicotinic activity, particularly on autonomic
ganglia. Bethanechol has mainly muscarinic actions,
with prominent effects on motility of the GI tract and
urinary bladder.
ACETYLCHOLINE METHACHOLINE CARBACHOL BETHANECHOL
ARECOLINE
PILOCARPINE
MUSCARINE
Figure 9–1. Structural formulas of acetylcholine, choline esters, and natural alkaloids that stimulate muscarinic receptors.