Page 143 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 8 Cholinoceptor-Blocking Drugs 129

The net cardiovascular effects of atropine in patients with nor-
mal hemodynamics are not dramatic: Tachycardia may occur, but 100
there is little effect on blood pressure. However, the cardiovascular
effects of administered direct-acting muscarinic agonists are easily
prevented. 80

4. Respiratory system—Both smooth muscle and secretory 60 Salivation
glands of the airway receive vagal innervation and contain Percent change
muscarinic receptors. Even in normal individuals, administra- 40 Heart rate
tion of atropine can cause some bronchodilation and reduce Micturition
secretion. The effect is more significant in patients with airway speed
disease, although the antimuscarinic drugs are not as useful 20 Accommodation
as the β-adrenoceptor stimulants in the treatment of asthma
(see Chapter 20). The effectiveness of nonselective antimusca- 0 0.5 1.0 2.0 mg
rinic drugs in treating chronic obstructive pulmonary disease
(COPD) is limited because block of autoinhibitory M receptors Atropine dose (log scale)
2
on postganglionic parasympathetic nerves can oppose the bron- FIGURE 8–6 Effects of subcutaneous injection of atropine on
chodilation caused by block of M receptors on airway smooth salivation, speed of micturition (voiding), heart rate, and accommo-
3
muscle. Nevertheless, antimuscarinic agents selective for M dation in normal adults. Note that salivation is the most sensitive of
3
receptors are valuable in some patients with asthma and in many these variables, accommodation the least. (Data from Herxheimer A: Br J
with COPD. Pharmacol 1958;13:184.)
Antimuscarinic drugs are frequently used before the admin-
istration of inhalant anesthetics to reduce the accumulation of
secretions in the trachea and the possibility of laryngospasm. regulation of gastric acid secretion likely involves multiple mus-
carinic receptor-dependent pathways. Pirenzepine and telenzepine
are investigational in the USA. Pancreatic and intestinal secretion
5. Gastrointestinal tract—Blockade of muscarinic recep- are little affected by atropine; these processes are primarily under
tors has dramatic effects on motility and some of the secre- hormonal rather than vagal control.
tory functions of the gut. However, even complete muscarinic Gastrointestinal smooth muscle motility is affected from the
block cannot abolish activity in this organ system, since local stomach to the colon. In general, antimuscarinic drugs diminish
hormones and noncholinergic neurons in the enteric nervous the tone and propulsive movements; the walls of the viscera are
system (see Chapters 6 and 62) also modulate gastrointestinal relaxed. Therefore, gastric emptying time is prolonged, and intes-
function. As in other tissues, exogenously administered mus- tinal transit time is lengthened. Diarrhea due to overdosage with
carinic stimulants are more effectively blocked than are the parasympathomimetic agents is readily stopped, and even diarrhea
effects of parasympathetic (vagal) nerve activity. The removal caused by nonautonomic agents can usually be temporarily con-
of autoinhibition, a negative feedback mechanism by which trolled. However, intestinal “paralysis” induced by antimuscarinic
neural acetylcholine suppresses its own release, might explain drugs is temporary; local mechanisms within the enteric nervous
the lower efficacy of antimuscarinic drugs against the effects of system usually reestablish at least some peristalsis after 1–3 days of
endogenous acetylcholine. antimuscarinic drug therapy.
Antimuscarinic drugs have marked effects on salivary secretion;
dry mouth occurs frequently in patients taking antimuscarinic 6. Genitourinary tract—The antimuscarinic action of atropine
drugs for Parkinson’s disease or urinary conditions (Figure 8–6). and its analogs relaxes smooth muscle of the ureters and bladder
Gastric secretion is blocked less effectively: the volume and wall and slows voiding (Figure 8–6). This action is useful in the
amount of acid, pepsin, and mucin are all reduced, but large doses treatment of spasm induced by mild inflammation, surgery, and
of atropine may be required. Basal secretion is blocked more effec- certain neurologic conditions, but it can precipitate urinary reten-
tively than that stimulated by food, nicotine, or alcohol. Pirenz- tion in men who have prostatic hyperplasia (see following section,
epine and a more potent analog, telenzepine, reduce gastric acid Clinical Pharmacology of the Muscarinic Receptor-Blocking
secretion with fewer adverse effects than atropine and other less Drugs). The antimuscarinic drugs have no significant effect on
selective agents. This was thought to result from a selective block- the uterus.
muscarinic receptors on vagal ganglion cells
ade of excitatory M 1
innervating the stomach, as suggested by their high ratio of M to 7. Sweat glands—Atropine suppresses thermoregulatory sweat-
1
M affinity (Table 8–1). However, carbachol was found to stimu- ing. Sympathetic cholinergic fibers innervate eccrine sweat glands,
3
late gastric acid secretion in animals with M receptors knocked and their muscarinic receptors are readily accessible to antimusca-
1
out; M receptors were implicated and pirenzepine opposed rinic drugs. In adults, body temperature is elevated by this effect
3
this effect of carbachol, an indication that pirenzepine is selec- only if large doses are administered, but in infants and children,
tive but not specific for M receptors. The mechanism of vagal even ordinary doses may cause “atropine fever.”
1