CHAPTER 9 Antimuscarinic Drugs
Various drugs can interfere with the transmission of nerve impulses at cholinergic junctions. As shown in Table 5-2, some drugs prevent the uptake of choline by the nerve terminal or the release of acetylcholine (ACh) from the terminal; other drugs block at ganglia or, by a competitive or depolarizing form of blockade, at neuromuscular junctions. The drugs presented in this chapter block responses in muscarinic receptors and are essentially without effect except at inordinately high doses at nicotinic receptors. These drugs are known as antimuscarinic or muscarinic receptor–blocking drugs; the term anticholinergic, although often used for this class of drugs, is inaccurate because these drugs, for the most part, are selective for muscarinic receptors but not nicotinic receptors. They are also termed atropine-like because of their derivation from or relation to the oldest and best-known member of the group. Because peripheral muscarinic receptors are the primary targets of ACh released by postganglionic cholinergic neurons, the effects achieved by the antimuscarinic drugs are chiefly on smooth muscle, cardiac muscle, and glands that are innervated by these neurons.
The natural alkaloids are derived from numerous plants, including Atropa belladonna (deadly nightshade); Datura stramonium, also known as jimsonweed or Jamestown weed; Hyoscyamus niger (henbane); and mandragora, among others. Datura was used in India in ancient times—its name comes from the Sanskrit. These drugs are mentioned in the Ebers papyrus (circa 1550 bc), in the Greek herbal of Dioscorides, and by Galen. In Western civilization, the drugs were used by professional poisoners in the Middle Ages for slow poisoning because of the obscure symptoms and the slow course of illness. The Swedish botanist Linné named the shrub Atropa belladonna after Atropos, one of the three Fates, who cuts the thread of life. The term belladonna comes from the Italian and means “beautiful woman”; this term was used because instillation of one of these drugs into the eyes was said to make women more attractive. Atropine, scopolamine, and related natural chemicals are also referred to as belladonna alkaloids.
A prototypic chemical structure of each of these types is shown in Table 9-1, and a more extensive list is at the end of the chapter.
|TYPE OF COMPOUND||EXAMPLE||CHEMICAL STRUCTURE|
|Naturally occurring alkaloid||Atropine|
|Semisynthetic derivative of alkaloid||Methscopolamine|
|Synthetic quaternary ammonium compound||Propantheline|
|Synthetic but not quaternary ammonium compound||Benztropine|
The antimuscarinic drugs—whether the naturally occurring alkaloids or the semisynthetic or synthetic derivatives—are competitive antagonists of ACh at muscarinic receptors. (Review Figure 5-1 for the principal location of muscarinic receptors.) They have an affinity for muscarinic receptor sites but lack intrinsic activity.1 They occupy the receptor sites and prevent access of ACh, creating a blockade that is generally reversible by increasing the amount of ACh in the area of the receptor, as would occur after the administration of an anticholinesterase drug. Because atropine can antagonize the muscarinic effects of the anticholinesterases and vice versa, each drug can be used as an antidote for the other in case of poisoning. The antimuscarinic drugs are capable of blocking responses to parasympathetic nerve stimulation, to sympathetic nerve stimulation of thermoregulatory sweat glands, to ACh protected from hydrolysis by anticholinesterases, and to direct-acting muscarinic agents, although their capability for inhibiting the latter two is greater than for the first two.
Several explanations have been offered for why atropine is more effective in blocking the pharmacologic effects produced by muscarinic receptor agonists than in blocking physiologic responses evoked by parasympathetic nervous system stimulation. One possibility is that ACh released into the restricted environs of a junctional cleft may overwhelm the antagonist by the high, although temporary, concentrations achieved. A second possibility is that the antimuscarinic drugs facilitate ACh release from cholinergic neurons by blocking presynaptic muscarinic receptors that limit evoked ACh release. A third explanation arises from the fact that physiologic responses to parasympathetic nervous system stimulation are mediated by several neurotransmitters in addition to ACh. Direct electrical stimulation of the parasympathetic nervous system causes the release of ACh and several other neurotransmitters from the postganglionic nerve terminal.7 ACh and adenosine triphosphate (ATP) are released from postganglionic parasympathetic nerves. In this setting, ATP, acting on nucleotide receptors, functions as a cotransmitter with ACh.9
Although atropine is a highly effective antagonist at all muscarinic receptors, evidence has accumulated that there are five muscarinic subtypes, M1 to M5, each with different affinities for certain muscarinic agonists and antagonists, different anatomic distributions, and different second messenger signaling mechanisms (see Chapters 5 and 8). The relatively selective affinity of the tricyclic benzodiazepine pirenzepine for M1 receptors versus M2 and M3 receptors gives it stronger antimuscarinic properties in certain sites (e.g., corpus striatum, cerebral cortex, and enterochromaffin cells) compared with others (e.g., heart and ileum). Pirenzepine, which is available outside of the United States, was the first clinically useful selective muscarinic receptor antagonist. Darifenacin is a selective antagonist at the M3 receptor and is available for treatment of overactive bladder.14 The characterization of different muscarinic receptor subtypes continues to provide an impetus for development of selective antagonists.
Therapeutic doses of antimuscarinic drugs produce effects attributable to the blockade of peripheral muscarinic receptors and similar receptors in the central nervous system (CNS) located within the medulla and higher cerebral centers. In the following discussion, atropine and scopolamine, which have always been considered the prototypes for this class of drugs, are principally reviewed, but (1) atropine and scopolamine differ in the relative intensity of their antimuscarinic effects on specific organs (Table 9-2); (2) there is a difference in the susceptibility of various effectors to antimuscarinic agents in general (Table 9-3); (3) because of differences in chemical structure, some antimuscarinic drugs pass readily into the CNS, whereas others do not; (4) there are some major differences among antimuscarinic drugs in the onset and duration of their actions (Table 9-4); and (5) muscarinic receptor subtypes have differing affinities for specific antimuscarinic drugs.
|Secretion (saliva, sweat, bronchial)||Low|
|Mydriasis, cycloplegia, tachycardia||↓|
|Loss of parasympathetic control of urinary bladder and gastrointestinal smooth muscle|
|Inhibition of gastric secretion||High|
The antimuscarinic drugs possess peripheral nervous system and CNS actions, but the nature and intensity of these vary with the individual drug and the dose administered. Most peripheral nervous system effects are caused by an interruption of parasympathetic impulses to a given effector. This interruption results in control of the tissue or organ by the sympathetic nervous system, which often exerts effects opposite to those of the parasympathetic nervous system. An important exception is where the sympathetic effect acts through muscarinic receptors, most notably in the sweat glands. The sympathetic effect of sweating is inhibited by antimuscarinic drugs. The pharmacologic effects observed depend largely on the existing activity of postganglionic cholinergic neurons. Inhibition of sweating and hyperthermia are likely to be observed on a hot day, but no effect on thermoregulation is apparent in a cold environment. Generally, atropine-like drugs block the salivation, lacrimation, urination, and defecation response to cholinergic drugs described in Chapter 8 and the hypotensive and bradycardic effects of muscarinic receptor stimulation. The effects of antimuscarinic agents on specific tissues are described next.
Atropine-like drugs block muscarinic receptors in the sphincter of the iris and in the ciliary muscle, leading to dilation of the pupil (mydriasis) and paralysis of accommodation (cycloplegia). Photophobia and fixation of the lens occurs for far vision, and vision for near objects is blurred. Intraocular pressure is not significantly affected except in the case of narrow-angle (or angle-closure) glaucoma, for which administration of these drugs may cause a dangerous increase in intraocular pressure. The onset and duration of the mydriatic and cycloplegic effects differ, as shown for cycloplegia in Table 9-4, and to some extent the choice of an agent for an ophthalmologic procedure is influenced by these differences.
After administration of antimuscarinic drugs, the bronchial smooth muscle is left under the sole control of the sympathetic nervous system and is relaxed. This relaxation of the smooth muscle decreases airway resistance. Sometimes there is an increase in respiratory minute volume resulting from an increase in the physiologic dead space and medullary stimulation. The bronchoconstriction caused by muscarinic agonists, sulfur dioxide, and certain other bronchial spasmogens is easily reversed by atropine, but bronchoconstriction caused by histamine, 5-hydroxytryptamine, and the leukotrienes is resistant.
Secretion of all glands in the nose, mouth, pharynx, and respiratory tree is inhibited. This suppression of secretory activity in the respiratory tract is the underlying reason for the effectiveness of antimuscarinic drugs in preventing laryngospasm during general anesthesia; these agents are incapable of directly blocking contraction of the laryngeal muscle.
Parasympathetically mediated salivary secretion is abolished in a dose-dependent manner, whereas salivary gland vasodilation is much less affected. The mouth and throat become unpleasantly dry, to the point that speech and swallowing may become difficult. Dry mouth or xerostomia can lead to numerous adverse effects on the oral cavity (see Chapter 8).
Although antimuscarinic drugs are quite effective in preventing the expected motor and secretory responses of the gastrointestinal tract to administered cholinergic drugs, their effects on vagal stimulation are more ambiguous. Antimuscarinic drugs have a marked inhibitory effect on motility throughout the gastrointestinal tract. Interference with the normal parasympathetic impulses to the gastrointestinal tract, as would occur with antimuscarinic drugs and ganglionic blocking agents, causes a profound decrease in the tone of gastrointestinal smooth muscle and in the frequency and amplitude of peristaltic contractions. Regarding secretion, gastric secretory activity in humans is inhibited only at very high doses of belladonna alkaloids, when essentially all other parasympathetic function has been blocked and the patient has an extremely dry mouth, blurred vision, an increased heart rate, and marked inhibition of gastrointestinal motility. At these high doses, atropine reduces gastric acidity, pepsin secretion, and total gastric secretion.
The fact that the gastrointestinal tract, particularly the secretory apparatus, is resistant to belladonna alkaloids and the fact that the therapeutic use of these drugs as antiulcer and antispasmodic agents has been disappointing underscore the finding that transmitters in addition to ACh are involved in the regulation of secretion and motor activity in the gas/>