1.0 0.5 0 0.1 1 10 100 Effect * * * * Receptor occupancy 1.6 1.2 0.5 0.8 0.4 1.0 0 0.1 1 10 100 Atropine dose (µg/kg) Atropine dose (µg/kg)
FIGURE 8–5 Effects of increasing doses of atropine on heart rate (A) and salivary flow (B) compared with muscarinic receptor occupancy in humans. The parasympathomimetic effect of low-dose atropine is attributed to blockade of prejunctional muscarinic receptors that suppress acetylcholine release. (Adapted, with permission, from Wellstein A, Pitschner HF: Complex dose-response curves of atropine in man explained by different functions of M1 and M2 cholinoceptors. Naunyn Schmiedebergs Arch Pharmacol 1988;338:19. Copyright © 1988 Springer-Verlag.)
The net cardiovascular effects of atropine in patients with normal hemodynamics are not dramatic: Tachycardia may occur, but there is little effect on blood pressure. However, the cardiovascular effects of administered direct-acting muscarinic agonists are easily prevented.
4.
Respiratory system—Both smooth muscle and secretory glands of the airway receive vagal innervation and contain muscarinic receptors. Even in normal individuals, administration of atropine can cause some bronchodilation and reduce secretion. The effect is more significant in patients with airway disease, although the antimuscarinic drugs are not as useful as the β-adrenoceptor stimulants in the treatment of asthma (see Chapter 20). The effectiveness of nonselective antimuscarinic drugs in treating chronic obstructive pulmonary disease (COPD) is limited because block of autoinhibitory M2 receptors on postganglionic parasympathetic nerves can oppose the bronchodilation caused by block of M3 receptors on airway smooth muscle. Nevertheless, antimuscarinic agents selective for M3 receptors are valuable in some patients with asthma and in many with COPD.
Antimuscarinic drugs are frequently used before the administration of inhalant anesthetics to reduce the accumulation of secretions in the trachea and the possibility of laryngospasm.
5.
Gastrointestinal tract—Blockade of muscarinic receptors has dramatic effects on motility and some of the secretory functions of the gut. However, even complete muscarinic block cannot abolish activity in this organ system, since local hormones and noncholinergic neurons in the enteric nervous system (see Chapters 6 and 62) also modulate gastrointestinal function. As in other tissues, exogenously administered muscarinic stimulants are more effectively blocked than are the effects of parasympathetic (vagal) nerve activity. The removal of autoinhibition, a negative feedback mechanism by which neural acetylcholine suppresses its own release, might explain the lower efficacy of antimuscarinic drugs against the effects of endogenous acetylcholine.