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Cholinoceptor-Blocking Drugs - Achilles J. Pappano, PhD

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INTRODUCTION

Cholinoceptor antagonists, like agonists, are divided into muscarinic and nicotinic subgroups on the basis of their specific receptor affinities. Ganglion-blockers and neuromuscular junction blockers comprise the antinicotinic drugs. The ganglion-blocking drugs have little clinical use and are discussed at the end of this chapter. The neuromuscular blockers are discussed in Chapter 27. This chapter emphasizes drugs that block muscarinic cholinoceptors.

Five subtypes of muscarinic receptors have been identified, primarily on the basis of data from ligand binding and cDNA-cloning experiments (see Chapters 6 and 7). A standard terminology (M1 through M5) for these subtypes is now in common use, and evidence, based mostly on selective agonists and antagonists, indicates that functional differences exist between several of these subtypes.

As suggested in Chapter 6, the M1 receptor subtype is located on central nervous system neurons, sympathetic postganglionic cell bodies, and many presynaptic sites. M2 receptors are located in the myocardium, smooth muscle organs, and some neuronal sites. M3 receptors are most common on effector cell membranes, especially glandular and smooth muscle cells.

I. BASIC PHARMACOLOGY OF THE MUSCARINIC RECEPTOR-BLOCKING DRUGS

Introduction

Muscarinic antagonists are sometimes called parasympatholytic because they block the effects of parasympathetic autonomic discharge. However, they do not "lyse" parasympathetic nerves, and they have some effects that are not predictable from block of the parasympathetic nervous system. For these reasons, the term "antimuscarinic" is preferable.

Naturally occurring compounds with antimuscarinic effects have been known and used for millennia as medicines, poisons, and cosmetics. Atropine is the prototype of these drugs. Many similar plant alkaloids are known, and hundreds of synthetic antimuscarinic compounds have been prepared.

Chemistry & Pharmacokinetics

A. SOURCE AND CHEMISTRY
Atropine and its naturally occurring congeners are tertiary amine alkaloid esters of tropic acid (Figure 8-1). Atropine (hyoscyamine) is found in the plant Atropa belladonna, or deadly nightshade, and in Datura stramonium, also known as jimsonweed (Jamestown weed), sacred Datura, or thorn apple. Scopolamine (hyoscine) occurs in Hyoscyamus niger, or henbane, as the l(-) stereoisomer. Naturally occurring atropine is l(-)-hyoscyamine, but the compound readily racemizes, so the commercial material is racemic d,l-hyoscyamine. The l(-) isomers of both alkaloids are at least 100 times more potent than the d(+) isomers.

A variety of semisynthetic and fully synthetic molecules have antimuscarinic effects.

The tertiary members of these classes (Figure 8-2) are often used for their effects on the eye or the central nervous system. Many antihistaminic (see Chapter 16), antipsychotic (see Chapter 29), and antidepressant (see Chapter 30) drugs have similar structures and, predictably, significant antimuscarinic effects.

Quaternary amine antimuscarinic agents (Figure 8-2) have been developed to produce more peripheral effects with reduced central nervous system effects.

B. ABSORPTION
The natural alkaloids and most tertiary antimuscarinic drugs are well absorbed from the gut and conjunctival membranes. When applied in a suitable vehicle, some (eg, scopolamine) are even absorbed across the skin (transdermal route). In contrast, only 10-30% of a dose of a quaternary antimuscarinic drug is absorbed after oral administration, reflecting the decreased lipid solubility of the charged molecule.

C. DISTRIBUTION
Atropine and the other tertiary agents are widely distributed in the body. Significant levels are achieved in the central nervous system within 30 minutes to 1 hour, and this can limit the dose tolerated when the drug is taken for its peripheral effects. Scopolamine is rapidly and fully distributed into the central nervous system where it has greater effects than most other antimuscarinic drugs. In contrast, the quaternary derivatives are poorly taken up by the brain and therefore are relatively free¾at low doses¾of central nervous system effects.

D. METABOLISM AND EXCRETION
After administration, atropine disappears rapidly from the blood with a half-life of 2 hours. About 60% of the dose is excreted unchanged in the urine. Most of the rest appears in the urine as hydrolysis and conjugation products. The drug's effect on parasympathetic function declines rapidly in all organs except the eye. Effects on the iris and ciliary muscle persist for ³ 72 hours.

 Figure 8-1. The structure of atropine (oxygen at [1] is missing) or scopolamine (oxygen present). In homatropine, the hydroxymethyl at [2] is replaced by a hydroxyl group, and the oxygen at [1] is absent. 0 
 Figure 8-2. Structures of some semisynthetic and synthetic antimuscarinic drugs. 0 

Pharmacodynamics

A. MECHANISM OF ACTION
Atropine causes reversible (surmountable) blockade (see Chapter 2) of cholinomimetic actions at muscarinic receptors¾ie, blockade by a small dose of atropine can be overcome by a larger concentration of acetylcholine or equivalent muscarinic agonist. Mutation experiments suggest that aspartate in the receptor forms the characteristic bond with the nitrogen atom of acetylcholine; this amino acid is also required for binding of antimuscarinic drugs. When atropine binds to the muscarinic receptor, it prevents actions such as the release of inositol trisphosphate (IP3) and the inhibition of adenylyl cyclase that are caused by muscarinic agonists (see Chapter 7).

The effectiveness of antimuscarinic drugs varies with the tissue and with the source of agonist. Tissues most sensitive to atropine are the salivary, bronchial, and sweat glands. Secretion of acid by the gastric parietal cells is the least sensitive. In most tissues, antimuscarinic agents block exogenously administered cholinoceptor agonists more effectively than endogenously released acetylcholine.

Atropine is highly selective for muscarinic receptors. Its potency at nicotinic receptors is much lower, and actions at nonmuscarinic receptors are generally undetectable clinically.

Atropine does not distinguish between the M1, M2, and M3 subgroups of muscarinic receptors. In contrast, other antimuscarinic drugs are moderately selective for one or another of these subgroups (Table 8-1). Most synthetic antimuscarinic drugs are considerably less selective than atropine in interactions with nonmuscarinic receptors. For example, some quaternary amine antimuscarinic agents have significant ganglion-blocking actions, and others are potent histamine receptor blockers. The antimuscarinic effects of other agents, eg, antipsychotic and antidepressant drugs, have been mentioned. Their relative selectivity for muscarinic receptor subtypes has not been defined.

B. ORGAN SYSTEM EFFECTS

1. Central nervous system¾ In the doses usually used, atropine has minimal stimulant effects on the central nervous system, especially the parasympathetic medullary centers, and a slower, longer-lasting sedative effect on the brain. Scopolamine has more marked central effects, producing drowsiness when given in recommended dosages and amnesia in sensitive individuals. In toxic doses, scopolamine and to a lesser degree atropine can cause excitement, agitation, hallucinations, and coma.

The tremor of Parkinson's disease is reduced by centrally acting antimuscarinic drugs, and atropine¾in the form of belladonna extract¾was one of the first drugs used in the therapy of this disease. As discussed in Chapter 28, parkinsonian tremor and rigidity seem to result from a relative excess of cholinergic activity because of a deficiency of dopaminergic activity in the basal ganglia-striatum system. The combination of an antimuscarinic agent with a dopamine precursor drug (levodopa) can sometimes provide more effective therapy than either drug alone.

Vestibular disturbances, especially motion sickness, appear to involve muscarinic cholinergic transmission. Scopolamine is often effective in preventing or reversing these disturbances.

2. Eye¾ The pupillary constrictor muscle (see Figure 6-9) depends on muscarinic cholinoceptor activation. This activation is blocked by topical atropine and other tertiary antimuscarinic drugs and results in unopposed sympathetic dilator activity and mydriasis (Figure 8-3). Dilated pupils were considered cosmetically desirable during the Renaissance and account for the name belladonna (Italian, "beautiful lady") applied to the plant and its active extract because of the use of the extract as eye drops during that time.

The second important ocular effect of antimuscarinic drugs is to weaken contraction of the ciliary muscle, or cycloplegia. Cycloplegia results in loss of the ability to accommodate; the fully atropinized eye cannot focus for near vision (Figure 8-3).

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