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Chapter: Basic & Clinical Pharmacology : Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs

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.

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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Basic & Clinical Pharmacology : Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs : Spectrum of Action of Cholinomimetic Drugs |


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