SPECTRUM OF ACTION OF
CHOLINOMIMETIC DRUGS
Early
studies of the parasympathetic nervous system showed that the alkaloid muscarine mimicked the effects of
parasympathetic nerve discharge; that is, the effects were parasympathomimetic. Application of muscarine to ganglia and to
autonomic effector tissues (smooth muscle, heart, exocrine glands) showed that
the parasympathomimetic action of the alkaloid occurred through an action on
receptors at effector cells, not those in ganglia. The effects of acetylcholine
itself and of other cholinomimetic drugs at autonomic neuroeffector junctions
are called parasympathomimeticeffects and
are mediated bymuscarinic receptors.In
contrast, low concentrations of the alkaloid nicotine stimulated autonomic ganglia and skeletal muscle
neuromuscular junctions but not auto-nomic effector cells. The ganglion and
skeletal muscle receptors were therefore labeled nicotinic. When acetylcholine
was later identified as the physiologic transmitter at both muscarinic and nicotinic receptors, both receptors
were recognized as cholinocep-tor subtypes.
Cholinoceptors
are members of either G protein–linked (muscarinic) or ion channel (nicotinic)
families on the basis of their transmembrane signaling mechanisms. Muscarinic
receptors contain seven transmembrane domains whose third cytoplasmic loop is
coupled to G proteins that function as transducers (see Figure 2–11). These
receptors regulate the production of intracel-lular second messengers and
modulate certain ion channels via their G proteins. Agonist selectivity is
determined by the subtypes of muscarinic receptors and G proteins that are
present in a given cell (Table 7–1). When expressed in cells, muscarinic
receptors form dimers or oligomers that are thought to function in receptor
movement between the endoplasmic reticulum and plasma mem-brane. Conceivably,
agonist or antagonist ligands could signal by changing the ratio of monomeric
to oligomeric receptors. Muscarinic receptors are located on plasma membranes
of cells in the central nervous system, in organs innervated by parasympathetic
nerves as well as on some tissues that are not innervated by these nerves, eg,
endothelial cells (Table 7–1), and on those tissues innervated by
postganglionic sympathetic cholinergic nerves.
Nicotinic
receptors are part of a transmembrane polypeptide whose subunits form
cation-selective ion channels (see Figure 2–9). These receptors are located on
plasma membranes of postgangli-onic cells in all autonomic ganglia, of muscles
innervated by somatic motor fibers, and of some central nervous system neurons
(see Figure 6–1).
Nonselective
cholinoceptor stimulants in sufficient dosage can produce very diffuse and
marked alterations in organ system function because acetylcholine has multiple
sites of action where it initiatesboth excitatory and inhibitory effects.
Fortunately, drugs are available that have a degree of selectivity, so that
desired effects can often be achieved while avoiding or minimizing adverse
effects.
Selectivity
of action is based on several factors. Some drugs stimulate either muscarinic
receptors or nicotinic receptors selec-tively. Some agents stimulate nicotinic
receptors at neuromuscular junctions preferentially and have less effect on
nicotinic receptors in ganglia. Organ selectivity can also be achieved by using
appro-priate routes of administration (“pharmacokinetic selectivity”). For
example, muscarinic stimulants can be administered topically to the surface of
the eye to modify ocular function while minimiz-ing systemic effects.
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