8 Rose M. McMurphy, Elizabeth G. Davis, Amy J. Rankin, Marjory A. Artzer, Barbara J. Lutjemeier, and Michael J. Kenney The authors thank HR Adams for the original chapter upon which this is based. Acetylcholine (ACh) is the primary neurotransmitter at autonomic ganglia, parasympathetic neuroeffector junctions, some sympathetic neuroeffector junctions, somatic neuromuscular junctions, the adrenal medulla (Figure 8.1 provides examples of each of these innervations), and certain regions of the central nervous system (CNS). In this chapter, drugs that influence postganglionic parasympathetic neuroeffector junctions and autonomic ganglia are examined. Figure 8.1 Schematic representation of the preganglionic and postganglionic anatomical relationships of nerves contained in the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS). The anatomical substrate of somatic motor nerves (SoNS) is also shown. Only the primary neurotransmitters are shown. Acetylcholine (ACh) is the neurotransmitter released at sympathetic and parasympathetic ganglia and at most parasympathetic neuroefffector junctions. “Visceral targets” refers to cardiac muscle, glands, and bladder smooth muscle. Note that some sympathetic postganglionic fibers release ACh. The adrenal medulla, a modified sympathetic ganglion, is innervated by sympathetic preganglionic fibers and releases epinephrine and NE into the blood. ACh, acetylcholine; EPI, epinephrine; M, muscarinic receptors; NN, nicotinic receptors; NE, norepinephrine. Cholinergic is used to describe nerve fibers that synthesize and release ACh without distinction as to anatomic site of action (Figure 8.2). Parasympathomimetic is used specifically to describe an ACh-like effect on effector cells innervated by postganglionic neurons of the parasympathetic nervous system (PSNS). The spectrum of responses to parasympathomimetic drugs is not entirely restricted to PSNS effects, and may include cholinergic actions throughout the body (Barnes and Hansel, 2004; Brown and Taylor, 2006; Westfall and Westfall, 2006). Figure 8.2 Schematic diagram depicting physiological processes at the site of a cholinergic nerve terminal innervating a target tissue. Processes have been described previously in Chapter 6. Cholinergic neurons synthesize and release ACh and this endogenous neurotransmitter binds to and activates nicotinic and muscarinic receptors. ACh, acetylcholine; AcCoA, acetyl-CoA; ChAT, choline acetyltransferase; CHT, choline transporter; SNAP, synaptosomal nerve-associated protein; VAT, vesicle-associated transporter; VAMP, vesicle-associated membrane protein. Based on mechanism of action, drugs that produce parasympathomimetic effects can be divided into two major groups (Figure 8.3): direct-acting agents, which like ACh activate cholinergic receptors located on effector cells; and cholinesterase inhibitors, which allow endogenous ACh to accumulate and thereby intensify and prolong its action (Brown and Taylor, 2006). Similar compounds are also used as antiparasitics and insecticides, and anesthetics, areas fully described in later chapters of this text. Figure 8.3 Schematic summarizing primary cholinergic receptor stimulants, muscarinic and nicotinic receptors, and target tissues. Acetylcholine is the principal endogenous agonist at two primary types of cholinergic receptors, nicotinic and muscarinic. Nicotinic neural (NN) receptors associated with the autonomic nervous system (ANS) are present on postganglionic neurons in autonomic ganglia and mediate neurotransmission from preganglionic to postganglionic neurons in both the sympathetic nervous system (SNS) and the PSNS. NN receptors are also present on adrenal medullary chromaffin cells and mediate neurotransmission from preganglionic SNS neurons to adrenal medullary chromaffin cells. Nicotinic muscle (NM) receptors are involved in mediating signal transmission at the neuromuscular junction and are an essential component of the somatic nervous system. Nicotinic receptors are ligand-gated ion channels and contain five homologous subunits organized around a central pore (Stokes et al., 2015). Activation of these receptors initiates: a rapid increase in cellular permeability to selective cations (Na+ and Ca2+); cell membrane depolarization; and excitation of postganglionic ANS neurons, adrenal medullary chromaffin cells, or skeletal muscle fibers (Stokes et al., 2015). Muscarinic receptors are located predominately at postsynaptic sites, such as the heart, gastrointestinal tract, glands, and urinary bladder, which are innervated by postganglionic parasympathetic nerves. Five subtypes of muscarinic receptors have been identified and many of the physiological functions associated with PSNS activation are mediated by muscarinic2 (M2) and muscarinic4 (M4) receptors. Muscarinic receptors are G protein-coupled receptors (GPCRs), and activation of these receptors may elicit an excitatory or inhibitory response (Calebiro et al., 2010; Jalink and Moolenaar, 2010; Ambrosio et al., 2011; Vischer et al., 2011; Latek et al., 2012; Duc et al., 2015). Direct-acting parasympathomimetic agonists consist of choline esters, including ACh and numerous synthetic esters, and cholinomimetic alkaloids. Methacholine, carbachol, and bethanecol are primary choline derivatives, whereas muscarine, pilocarpine, and arecoline are primary cholinomimetic alkaloids. Pharmacological effects of ACh and related choline esters and alkaloids are mediated by activation of cholinergic receptors located on cells innervated by cholinergic nerves and, in some cases, on cells that lack cholinergic innervation. Direct-acting agonists act directly on receptors and do not depend upon endogenous ACh for their effects. In general, the physiological responses of selected organs and effector tissues elicited by activation of efferent parasympathetic nerves, as well as direct-acting parasympathomimetic agonists, are similar (Table 8.1 ). However, the pharmacological characteristics of direct-acting parasympathomimetic agonists demonstrate nonuniform susceptibility to metabolism by cholinesterases, differential relative affinity for muscarinic and nicotinic receptors, and specificity in target organ effects (Table 8.2 ). Table 8.1 Effects of direct-acting cholinergic receptor stimulants Table 8.2 Scope of cholinergic receptor activating properties of some choline esters CV, cardiovascular; GI, gastrointestinal; UB, urinary bladder; E, eye. Direct-acting cholinergic agonists contain structural groupings that allow interaction of the agent with cholinergic receptors and result in similar membrane and cellular responses to those caused by ACh. Chemical structures of several choline esters and cholinomimetic alkaloids are shown in Figures 8.4 and 8.5. Figure 8.4 Molecular structures of primary choline esters. Figure 8.5 Molecular structures of several cholinomimetic alkaloids. Choline esters contain a quaternary nitrogen atom to which three methyl groups are attached. Except for some naturally occurring cholinomimetic alkaloids, a quaternary nitrogen moiety is usually required for a direct potent action on cholinergic receptors. The quaternary nitrogen group carries a positive charge and this cationic group electrostatically binds with a negatively charged (anionic) site of the cholinergic receptor. Receptive macromolecules (i.e., cholinergic receptors and cholinesterases) that recognize and bind ACh have, in addition to the anionic site, a region that combines with the ester component of ACh (Hucho et al., 1991). In cholinesterase, this region is called the esteratic site and its combination with the carboxyl group results in hydrolysis of the ester. Hydrolysis of ACh does not occur upon its interaction with a receptor, however, and the ester-attracting region of the receptor is called the esterophilic site (Inestrosa and Perelman, 1990; Taylor, 1991, 2006a; Massoulie et al., 1993). ACh is structurally arranged so that it combines with the esterophilic and anionic sites of both nicotinic and muscarinic receptors and acetylcholinesterases (Hucho et al., 1991). ACh is the prototypical cholinergic agent and activates both nicotinic and muscarinic receptors. Acetyl-β-methylcholine (methacholine) is identical in structure to ACh except for the substitution of a methyl group on the β-carbon atom of the choline group. This structural change yields a compound that is primarily a muscarinic receptor agonist lacking significant nicotinic effects when given in usual dosages. Further, it is more active on the cardiovascular system than on the GI tract. Duration of action of methacholine is considerably longer than that of ACh. Carbachol and bethanechol each have a carbamyl group substituted for the acetic moiety of ACh, and bethanechol also has a β-methyl group. Both of these agents are almost completely resistant to inactivation by the cholinesterases. Their duration of action is therefore considerably longer than that of ACh. Carbachol is active at both muscarinic and nicotinic receptor sites, whereas bethanechol is primarily a muscarinic agonist. Unlike methacholine, both these drugs are somewhat more active on smooth muscles of the GI tract and urinary bladder than on cardiovascular function. Pharmacological characteristics of these choline esters are presented in Table 8.2 . ACh is the prototypical cholinergic agonist and therefore provides a foundation for understanding the pharmacological effects of other cholinomimetic drugs. The biosynthesis, neuronal release, cellular activities, and inactivation of endogenous ACh were discussed in Chapter 6. Although an essential ANS neurotransmitter, ACh is not used therapeutically for at least two reasons. First, muscarinic and nicotinic receptors are located at numerous tissue sites and therefore no selective therapeutic response to ACh can be achieved. Second, its duration of action is quite brief because it is rapidly inactivated by the cholinesterases. Several derivatives of ACh are more resistant to hydrolysis by cholinesterase and have a somewhat greater selectivity in their sites of action (Table 8.2 ). Since ACh is a mixed nicotinic–muscarinic agonist, different physiological response profiles can be produced by administration of this agent, depending upon the relative dominance of muscarinic (parasympathomimetic) or nicotinic actions. These effects can be differentiated by use of small and large doses of ACh and by using selective cholinergic blocking drugs. In general, parasympathomimetic effects dominate with small doses, whereas with large doses nicotinic effects can be elicited. Use of cholinergic blocking drugs and small and large doses of ACh to differentiate muscarinic and nicotinic effects of ACh is shown in Figure 8.4. This figure is discussed in more detail in the following section regarding cardiovascular effects mediated by ACh administration. Intravenous (IV) administration of small amounts of ACh (5– 10 μg/kg) induces a brief but rapid fall in systolic and diastolic blood pressures, due to a decrease in peripheral resistance resulting from dilation of blood vessels. Most blood vessels receive little or no parasympathetic innervation, and muscarinic receptors located at these sites are noninnervated. Muscarinic receptors mediating dilation of blood vessels are located on the endothelium rather than on the smooth muscle, and the smooth muscle relaxation in response to ACh administration involves the production and release of nitric oxide (Furchgott and Zawadzki, 1980; Lowenstein et al., 1994). Somewhat larger doses of ACh (10–30 μg/kg) produce pronounced muscarinic effects; therefore, marked reductions in peripheral resistance, heart rate, and blood pressure are observed. Atrial myocardial cells contain muscarinic receptors associated with vagal fibers, and activation of these receptors by ACh produces negative chronotropic and inotropic effects. Generally, the chronotropic effects predominate. In addition to its pronounced slowing effect on heart rate, ACh exerts important effects on impulse conduction. With high doses (50–100 μg/kg) muscarinic effects of ACh on postganglionic effector cells are accentuated. Profound hypotensive and bradycardic responses are observed. Large doses of ACh produce, in addition to muscarinic (i.e., parasympathomimetic) effects, stimulation of the nicotinic receptors in autonomic ganglia (both parasympathetic and sympathetic) and the adrenal medulla. These effects are particularly evident when the muscarinic receptors of the parasympathetic neuroeffector junctions are blocked by atropine (nonselective muscarinic receptor antagonist). Under these circumstances large doses of ACh stimulate nicotinic receptors of both sympathetic and parasympathetic ganglia. However, because the muscarinic receptors of the parasympathetic neuroeffector junctions are blocked by atropine, the ACh released from postganglionic parasympathetic nerves does not bind to and activate the target organ muscarinic receptors. Under this condition, sympathomimetic responses will be evident, including increased arterial blood pressure, tachycardia, and other typical sympathetic-mediated effects. These effects can be blocked by use of appropriate adrenergic blocking drugs or by use of a ganglionic blocking agent (Figure 8.6). Figure 8.6 Muscarinic and nicotinic effects of acetylcholine (ACh) on blood pressure, heart rate, intestinal motility, and autonomic ganglionic action potentials in an anesthetized dog. Schematic reproductions: (1) A small dose of ACh (10 mg/kg) administered intravenously causes hypotension, bradycardia, and intestinal contractions caused by direct stimulation of muscarinic receptors of blood vessels, heart, and intestinal smooth muscle, respectively. These effects are brief because of rapid destruction of ACh by cholinesterase. (2) Atropine blocks the muscarinic receptors and thereby prevents the effects seen in (1). (3) Large doses of ACh (100 mg/kg) stimulate, in addition to muscarinic receptors, nicotinic receptors of parasympathetic and sympathetic ganglionic neurons, causing an increase in frequency and amplitude of ganglionic action potentials. Although all autonomic ganglia are activated, impulses arising from parasympathetic ganglia do not reach their effector cells because of blockade of parasympathetic postganglionic neuroeffector junctions by atropine. Sympathomimetic responses (pressor effect and tachycardia) result. (4) Impulses arising from sympathetic ganglia are prevented from reaching their effector cells by adrenergic blocking drugs; however, ganglionic nicotinic receptors are still activated by ACh. (5) Hexamethonium (hex) blocks nicotinic receptors of ganglia and thereby inhibits the nicotinic ganglionic stimulating effect of ACh and reduces ganglionic action potentials. AG, action potentials of autonomic ganglionic neuron; BP, systemic blood pressure; HR, heart rate; GI, intestinal peristaltic waves. ACh stimulates smooth muscle of the urinary bladder and uterus to contract (Chapple et al., 2002). Bronchiolar smooth muscle is also contracted by ACh, resulting in decreased airway diameter (Barnes and Hansel, 2004; Fisher et al., 2004). The smooth muscle effects of ACh are due to muscarinic receptor activation.
Cholinergic Pharmacology: Autonomic Drugs
Parasympathomimetic Agents
Cholinergic Receptors
Direct-acting Parasympathomimetic Agonists
General Characteristics
Organ
Tissue
Response
Eye
Sphincter muscle, iris
Pupillary constriction
Cillary muscle
Contraction
Glands
Salivary, lacrimal
↑↑ Secretion
Lung
Bronchial muscle
Contraction
Bronchial glands
Stimulation
Heart
Sinoatrial node
↓ Heart rate
Atria
↓ Contractility/conduction
Atrioventricular node
↓ Conduction
Ventricles
↓ Contractility (slight)
Blood vessels
Selected arteries
Dilation
Gastrointestinal tract
Motility
↑ GI Muscle Contraction
Sphincters
↓ Tone
Secretion
Stimulation
Urinary bladder
Detrusor muscle
Contraction
Sphincters
Relaxation
Agonistic properties
Susceptibility to
cholinesterase
Muscarinic receptors
True
Pseudo
CV
GI
UB
E
Nicotinic receptors
Acetylcholine
+ + +
+ + +
+ + +
+ + +
+ +
+
+ + +
Methacholine
+
–
+ + +
+ +
+ +
+
±
Carbachol
–
–
+
+ + +
+ + +
+ +
+ + +
Bethanechol
–
–
±
+ + +
+ + +
+ +
–
Structure–Activity Relationships
Acetylcholine: Prototypical Cholinergic Agonist
Pharmacological Mechanisms and Effects
Target Organ Effects of ACh
Cardiovascular:
Nonvascular smooth muscle:
Gastrointestinal system:
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