Page 138 - Basic _ Clinical Pharmacology ( PDFDrive )

8 Cholinoceptor-Blocking
C H A P T E R

Drugs

Achilles J. Pappano, PhD

C ASE STUD Y

JH, a 63-year-old architect, complains of urinary symptoms prostatectomy to relieve symptoms. He now complains that
to his family physician. He has hypertension, and during he has an increased urge to urinate as well as urinary fre-
the last 8 years, he has been adequately managed with a quency, and this has disrupted the pattern of his daily life.
thiazide diuretic and an angiotensin-converting enzyme What do you suspect is the cause of JH’s problem? What
inhibitor. During the same period, JH developed the signs information would you gather to confirm your diagnosis?
of benign prostatic hypertrophy, which eventually required What treatment steps would you initiate?

Cholinoceptor antagonists, like the agonists, are divided into allosteric ligands is the extracellular vestibule. Among the recep-
muscarinic and nicotinic subgroups on the basis of their specific tor subtypes, the extracellular vestibule is comprised of different
receptor affinities. Ganglion blockers and neuromuscular junction amino acids that provide distinctive sites for binding by selective
blockers make up the antinicotinic drugs. The ganglion-blocking allosteric modulators. The M receptor subtype is located on
1
drugs have little clinical use and are discussed at the end of this central nervous system (CNS) neurons, autonomic postganglionic
chapter. Neuromuscular blockers are heavily used and are discussed cell bodies, and many presynaptic sites. M receptors are located
2
in Chapter 27. This chapter emphasizes drugs that block musca- in the myocardium, smooth muscle organs, and some neuronal
rinic cholinoceptors. sites. M receptors are most common on effector cell membranes,
3
Five subtypes of muscarinic receptors have been identified, pri- especially glandular and smooth muscle cells. M and M recep-
5
4
marily on the basis of data from ligand-binding and cDNA-cloning tors are less prominent and appear to play a greater role in the
experiments (see Chapters 6 and 7). A standard terminology CNS than in the periphery.
through M ) for these subtypes is now in common use, and
(M 1 5
evidence—based mostly on selective agonists and antagonists—
indicates that functional differences exist between several of these ■ BASIC PHARMACOLOGY OF
subtypes. The X-ray crystallographic structures of the M sub- THE MUSCARINIC RECEPTOR-
1–4
types of muscarinic receptors have been reported. The structures of
the M receptors are very similar in the inactive state with inverse BLOCKING DRUGS
1–4
agonist or antagonist bound to the receptor. The binding pocket
for orthosteric ligands lies well within the plane of the plasma Muscarinic antagonists are sometimes called parasympatholytic
membrane, and the amino acids composing the site are conserved because they block the effects of parasympathetic autonomic
among muscarinic receptor subtypes. This observation underscores discharge. However, the term “antimuscarinic” is preferable.
the difficulty in identifying subtype-selective ligands. A structure Naturally occurring compounds with antimuscarinic effects
forming a “lid” separates the orthosteric binding site from an upper have been known and used for millennia as medicines, poisons, and
cavity termed the “vestibule” (Figure 8–1). The binding site for cosmetics. Atropine is the prototype of these drugs. Many similar

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