Page 141 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 8 Cholinoceptor-Blocking Drugs 127

TABLE 8–1 Muscarinic receptor subgroups important in peripheral tissues and their antagonists.

Subgroup
Property M 1 M 2 M 3
Primary locations Nerves Heart, nerves, smooth muscle Glands, smooth muscle,
endothelium
+
Dominant effector system ↑ IP 3 , ↑ DAG ↓ cAMP, ↑ K channel current ↑ IP 3 , ↑ DAG
4
3
Antagonists Pirenzepine, telenzepine, Gallamine, methoctramine, 4-DAMP, darifenacin, solifenacin,
1
dicyclomine, trihexyphenidyl 2 AF-DX 116 4 oxybutynin, tolterodine
Approximate dissociation constant 5
Atropine 1 1 1
Pirenzepine 25 300 500
AF-DX 116 2000 65 4000
Darifenacin 70 55 8
1 In clinical use as an intestinal antispasmodic agent.
2
In clinical use in the treatment of Parkinson’s disease.
3 In clinical use as a neuromuscular blocking agent (obsolete).
4
Compound used in research only.
5 Relative to atropine. Smaller numbers indicate higher affinity.
AF-DX 116, 11-({2-[(diethylamino)methyl]-1-piperidinyl}acetyl)-5,11-dihydro-6H-pyrido-[2,3-b](1,4)benzodiazepine-6-one; DAG, diacylglycerol; IP3, inositol trisphosphate;
4-DAMP, 4-diphenylacetoxy-N-methylpiperidine.

nonmuscarinic receptors. For example, some quaternary amine by topical atropine and other tertiary antimuscarinic drugs and
antimuscarinic agents have significant ganglion-blocking actions, results in unopposed sympathetic dilator activity and mydriasis
and others are potent histamine receptor blockers. The antimus- (Figure 8–4). Dilated pupils were considered cosmetically desir-
carinic effects of other agents, eg, antipsychotic and antidepressant able during the Renaissance and account for the name belladonna
drugs, have been mentioned. Their relative selectivity for musca- (Italian, “beautiful lady”) applied to the plant and its active extract
rinic receptor subtypes has not been defined. because of the use of the extract as eye drops during that time.
The second important ocular effect of antimuscarinic drugs
B. Organ System Effects is to weaken contraction of the ciliary muscle, or cycloplegia.
1. Central nervous system—In the doses usually used, atropine Cycloplegia results in loss of the ability to accommodate; the fully
has minimal stimulant effects on the CNS, especially the parasym- atropinized eye cannot focus for near vision (Figure 8–4).
pathetic medullary centers, and a slower, longer-lasting sedative Both mydriasis and cycloplegia are useful in ophthalmology.
effect on the brain. Scopolamine has more marked central effects, They are also potentially hazardous, since acute glaucoma may be
producing drowsiness when given in recommended dosages and induced in patients with a narrow anterior chamber angle.
amnesia in sensitive individuals. In toxic doses, scopolamine, A third ocular effect of antimuscarinic drugs is to reduce lac-
and to a lesser degree atropine, can cause excitement, agitation, rimal secretion. Patients occasionally complain of dry or “sandy”
hallucinations, and coma. eyes when receiving large doses of antimuscarinic drugs.
The tremor of Parkinson’s disease is reduced by centrally acting
antimuscarinic drugs, and atropine—in the form of belladonna 3. Cardiovascular system—The sinoatrial node is very sensi-
extract—was one of the first drugs used in the therapy of this dis- tive to muscarinic receptor blockade. Moderate to high thera-
ease. As discussed in Chapter 28, parkinsonian tremor and rigidity peutic doses of atropine cause tachycardia in the innervated
seem to result from a relative excess of cholinergic activity because and spontaneously beating heart by blockade of vagal slowing.
of a deficiency of dopaminergic activity in the basal ganglia-striatum However, lower doses often result in initial bradycardia before the
system. The combination of an antimuscarinic agent with a dopa- effects of peripheral vagal block become manifest (Figure 8–5).
mine precursor drug (levodopa) can sometimes provide more effec- This slowing may be due to block of prejunctional M 1 receptors
tive therapy than either drug alone. (autoreceptors, see Figures 6–3 and 7–4A) on vagal postgangli-
Vestibular disturbances, especially motion sickness, appear to onic fibers that normally limit acetylcholine release in the sinus
involve muscarinic cholinergic transmission. Scopolamine is often node and other tissues. The same mechanisms operate in the
effective in preventing or reversing these disturbances. atrioventricular node; in the presence of high vagal tone, atropine
can significantly reduce the PR interval of the electrocardiogram
2. Eye—The pupillary constrictor muscle (see Figure 6–9) depends by blocking muscarinic receptors in the atrioventricular node.
on muscarinic cholinoceptor activation. This activation is blocked Muscarinic effects on atrial muscle are similarly blocked, but these