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

Muscarinic Receptor Agonists
and Antagonists
Joan Heller Brown and
Nora Laiken
ACETYLCHOLINE AND ITS
MUSCARINIC RECEPTOR TARGET
Muscarinic acetylcholine receptors in the peripheral
nervous system occur primarily on autonomic effector
cells innervated by postganglionic parasympathetic
nerves. Muscarinic receptors are also present in autonomic
ganglia and on some cells (e.g., vascular
endothelial cells) that, paradoxically, receive little or no
cholinergic innervation. Within the central nervous
system (CNS), the hippocampus, cortex, and thalamus
have high densities of muscarinic receptors.
Acetylcholine (ACh), the naturally occurring
neurotransmitter for these receptors, has virtually no
systemic therapeutic applications because its actions
are diffuse, and its hydrolysis, catalyzed by both
acetylcholinesterase (AChE) and plasma butyrylcholinesterase,
is rapid. Muscarinic agonists mimic the
effects of ACh at these sites. These agonists typically
are longer-acting congeners of ACh or natural alkaloids,
some of which stimulate nicotinic as well as muscarinic
receptors.
The mechanisms of action of endogenous ACh at
the postjunctional membranes of the effector cells and
neurons that represent different types of cholinergic
synapses are discussed in Chapter 8. To recapitulate,
these synapses are found at: 1) autonomic effector sites
innervated by postganglionic parasympathetic nerves
(or, in the sweat glands, by postganglionic sympathetic
nerves); 2) sympathetic and parasympathetic ganglia
and the adrenal medulla, innervated by preganglionic autonomic
nerves; 3) motor end plates on skeletal muscle,
innervated by somatic motor nerves; and 4) certain
synapses in the CNS (Krnjevic, 2004), where ACh can
have either pre- or postsynaptic actions. When ACh is
administered systemically, it can potentially act at all
of these sites; however, as a quaternary ammonium
compound, its penetration to the CNS is limited, and
the amount of ACh that reaches peripheral areas with
low blood flow is limited due to hydrolysis by plasma
butyrylcholinesterase.
The actions of ACh and related drugs at autonomic
effector sites are referred to as muscarinic, based
on the observation that the alkaloid muscarine acts
selectively at those sites and produces the same qualitative
effects as ACh. The muscarinic, or parasympathomimetic,
actions of the drugs considered in this
chapter are practically equivalent to the parasympathetic
effects of ACh listed in Table 8–1. Muscarinic
receptors are present in autonomic ganglia and the adrenal
medulla but primarily function to modulate the
nicotinic actions of ACh at these sites (Chapter 11). In
the CNS, muscarinic receptors are widely distributed
and have a role in mediating many important responses.
The differences between the actions of ACh and other
muscarinic agonists are largely quantitative, with limited
selectivity for one organ system or another. All of
the actions of ACh and its congeners at muscarinic
receptors can be blocked by atropine.
Properties and Subtypes
of Muscarinic Receptors
Muscarinic receptors were characterized initially by
analysis of the responses of cells and organ systems in
the periphery and the CNS. For example, differential
effects of two muscarinic agonists, bethanechol and
McN-A-343, on the tone of the lower esophageal
sphincter led to the initial designation of muscarinic
receptors as M 1
(ganglionic) and M 2
(effector cell)
(Goyal and Rattan, 1978). The cloning of the cDNAs
that encode muscarinic receptors identified five distinct
gene products (Bonner et al., 1987), now designated as