CHAPTER 8 Cholinergic Drugs
Cholinergic drugs are agents that mimic the actions of the endogenous neurotransmitter acetylcholine (ACh). As described in Chapter 5, ACh is the primary neurotransmitter released from the nerve terminals of the preganglionic fibers of the parasympathetic and sympathetic nervous systems, the postganglionic fibers of the parasympathetic nervous system (which include most of the postganglionic cholinergic neurons), and some postganglionic fibers of the sympathetic nervous system (mostly fibers to the sweat glands). ACh is also the primary neurotransmitter released from somatic efferents innervating skeletal muscle and from certain central nervous system (CNS) neurons.
Most cholinergic, or cholinomimetic, agonists produce parasympathetic responses by stimulating muscarinic receptors located on tissues innervated by the postganglionic fibers of the parasympathetic nervous system. These drugs are often referred to as muscarinic or parasympathomimetic agonists. Some cholinergic agonists produce a nonselective stimulation of the parasympathetic and sympathetic branches of the autonomic nervous system by activating ganglionic nicotinic receptors located on the cell bodies of postganglionic fibers. In addition, some cholinergic agonists excite skeletal muscle by activating a separate group of nicotinic receptors located on the motor end plate of the neuromuscular junction. The synapses in the CNS that contain nicotinic and muscarinic receptors can be stimulated by cholinomimetic agonists capable of penetrating the blood-brain barrier.
Drugs that inhibit the hydrolysis of ACh by the enzyme acetylcholinesterase (AChE) produce their cholinomimetic effects indirectly. These anticholinesterases prolong the effective life of ACh released at neuroeffector junctions. As a group, the anticholinesterases are less selective in effect than many direct-acting cholinomimetics, and they are largely without activity in denervated tissues. Nevertheless, their dependence on ACh release confers the potential advantage of retaining neural control over their effects.
The cholinomimetic agonists directly stimulate cholinergic receptors—muscarinic or nicotinic or both—to cause a pharmacologic response in an effector. These cholinergic drugs are classified into two groups on the basis of their origin and chemical composition: choline esters, which include ACh and its synthetic congeners, and the naturally occurring alkaloids and their congeners, including muscarine, pilocarpine, cevimeline, and nicotine. With few exceptions (e.g., nicotine), all these agents exert prominent parasympathomimetic effects.
The history of the discovery of ACh and its identification is described in Chapter 5. In 1909, Hunt synthesized the acetyl ester of choline, and earlier Hunt and Taveau16 reported on the pharmacology of many synthetic congeners of ACh. Interest in the choline esters arose partly out of the hope that some of these compounds would have a longer duration of action than ACh and, at the same time, a greater degree of selectivity. This goal has not been realized completely, and ACh and related drugs generally either are not used therapeutically or are used only in selected instances. The structures of ACh and the three principal synthetic esters of choline—methacholine, carbachol, and bethanechol—are shown in Figure 8-1. Succinylcholine, a diacetylcholine derivative with selective nicotinic receptor effects in skeletal muscle, is discussed in Chapter 10.
Several alkaloids obtained from various plants possess direct cholinomimetic activity. Muscarine, the prototype muscarinic agonist, is present during certain times of the year in the mushroom Amanita muscaria and is especially prominent in several Inocybe and Clitocybe species. Although a quaternary ammonium compound (Figure 8-2), muscarine has a rapid onset of action after oral ingestion and produces physiologic responses characteristic of profound parasympathetic nervous system stimulation. In severe poisoning, cardiovascular collapse may occur. Pilocarpine is found in the leaves of the South American shrub Pilocarpus jaborandi. It is also a selective muscarinic receptor agonist. Pilocarpine remains in the therapeutic armamentarium for a few specific indications and has a specific dental indication. Cevimeline, a synthetic agent, is similar in pharmacology to pilocarpine. Arecoline is the primary alkaloid of betel nuts. It is a euphoretic and stimulates muscarinic and ganglionic nicotinic receptors. Nicotine, an alkaloid found in tobacco leaves (Nicotiana tabacum), is important historically as the prototype nicotinic receptor agonist. In the form of cigarettes, nicotine is the most commonly used cholinergic agonist, and it is responsible for the physical dependence associated with smoking. This drug and other drugs selective for nicotinic receptors are discussed in Chapter 10.
Direct-acting cholinomimetic drugs produce their effects by binding to and stimulating muscarinic and nicotinic receptors. As noted previously, these receptors are located in junctional regions of the peripheral nervous system and the CNS. ACh is capable of stimulating muscarinic and nicotinic receptors when administered systemically; although muscarinic responses are produced by low doses of ACh, effects on ganglionic and somatomotor transmission require increasingly higher doses. The choline ester bethanechol and the plant alkaloid muscarine produce a relatively selective activation of muscarinic receptors located on autonomic effector tissues (especially in smooth muscle and glandular tissues) and on the cell bodies of unique populations of CNS neurons. Although these muscarinic agonists produce qualitatively similar responses in different organ systems, they vary in their relative potencies in evoking these reactions.
Parasympathomimetic responses to cholinergic drugs are mediated by the stimulation of several populations of muscarinic receptors. A total of five muscarinic receptor proteins (m1 through m5, corresponding to the pharmacologically identified receptors M1 through M5) have been produced from cloned muscarinic receptor genes, and it has been established that multiple receptor subtypes can coexist in the same organ or tissue. The exact distribution of these receptors and their functional properties are currently areas of active investigation, but a few general concepts have emerged. In the periphery, the M1 receptor seems to be localized in ganglia, some exocrine gland cells, and the enterochromaffin cells of the stomach (see Chapter 33). The M2 receptor is the primary subtype found in the heart and is present, along with the M4 receptor, in the lung. The M3 receptor is widely distributed and is most prominent in glandular tissue. Although a peripheral distribution of the M5 receptor has not been identified, it is expressed, as are the other subtypes, in discrete regions of the CNS.
Muscarinic receptors belong to a large family of plasma membrane receptors whose basic structure consists of seven helical segments spanning the membrane and joined by alternating intracellular and extracellular peptide bridges (see Chapter 1). Although the hydrophobic helical segments, which form the ligand-binding site, show considerable structural homology among the muscarinic receptor subtypes, the third intracellular loop, joining helices V and VI, is highly divergent. Biochemical studies suggest that this loop is of primary importance in the coupling between receptor binding and intracellular action.
Stimulation of muscarinic receptors initiates a cascade of intracellular events that ultimately leads to the observed pharmacologic effects. Evidence to date suggests that all muscarinic receptor subtypes regulate the activity of G proteins (see Chapter 5). The G proteins modulate intracellular processes by influencing “second messenger” systems. Agonist-induced activation of M1, M3, or M5 receptors stimulates the enzyme phospholipase C, which produces Ca++-dependent phosphorylation of specific cellular regulatory proteins. The stimulation of M2 or M4 receptors inhibits the activity of adenylyl cyclase, decreasing the intracellular concentration of cyclic adenosine 3′,5′-monophosphate. In the heart, this outcome of M2 receptor activation results in increased K+ efflux and reduced Ca++ influx, leading to characteristic muscarinic receptor–induced changes in cardiac function (see later). The activation of M2 receptors on the intact vascular endothelium produces a profound vasodilation by stimulating the production and release of nitric oxide, an important endothelium-derived relaxing factor (Figure 8-3).13,17 Nitric oxide stimulates guanylyl cyclase located in vascular smooth muscle, which catalyzes the formation of cyclic guanosine 3′,5′-monophosphate. This cyclic nucleotide reduces intracellular Ca++ concentrations, leading to vascular smooth muscle relaxation and vasodilation. The effect of agonists on the muscarinic receptors of endothelial cells accounts for the vasodilation when these drugs are administered systemically, especially intravenously. This vasodilation occurs despite the lack of nerve innervation to these receptors on endothelial cells.
FIGURE 8-3 Mechanism of vascular relaxation by muscarinic receptor agonists. The muscarinic agent acetylcholine (ACh) binds to its receptor (M3) on the intact vascular endothelium. Newly synthesized nitric oxide (NO) diffuses into the vascular smooth muscle, where it stimulates the formation of cyclic guanosine 3′,5′-monophosphate (cGMP) from guanosine triphosphate (GTP).
The systemic administration of high doses of ACh activates nicotinic receptors located on the cell bodies of postganglionic nerve fibers of the autonomic nervous system (NN receptors) and nicotinic receptors located in the neuromuscular junction (NM receptors). As described in Chapter 5, nicotinic receptors are composed of five glycoprotein subunits forming a rosette around a central channel spanning the plasma membrane. The α subunits (see also Figure 1-2) contain the ACh-binding sites. When stimulated by ACh, nicotine, or another nicotinic receptor agonist, a conformational change in the protein occurs, allowing Na+ and, to a lesser extent, Ca++ ions to move down their respective concentration gradients. The net ionic movement depolarizes the postganglionic cell body or muscle end plate. Prolonged stimulation of nicotinic receptors with ACh or nicotine results in a phenomenon referred to as “depolarization blockade,” in which responses to further stimulation are attenuated and then lost (see Chapter 10).
The pharmacologic effects produced by direct-acting cholinergic drugs vary according to the receptors they stimulate, their distribution throughout the body, and their mode of inactivation. The duration of action of ACh and its congeners is determined by their susceptibility to hydrolysis by AChE and pseudocholinesterase. Methacholine, with some susceptibility only to AChE, has a longer duration of action than ACh. Bethanechol, carbachol, cevimeline, and the natural alkaloids are not affected by the cholinesterases at all and also have longer durations of action than ACh.
Currently available agents exhibit significantly different affinities for muscarinic and nicotinic sites, so that carbachol has more pronounced nicotinic effects than ACh, and bethanechol, muscarine, pilocarpine, and cevimeline have very few nicotinic properties. Differences in effect are also noted regarding various target tissues. Bethanechol and carbachol are very effective stimulants of the gastrointestinal and urinary tracts, whereas ACh and methacholine exert more prominent cardiovascular effects. Some of the limitations of injected ACh arise because the drug is so quickly metabolized that it gains little access to tissues that are not well perfused.
Cholinergic agonists that stimulate muscarinic receptors produce end-organ responses that mimic parasympathetic nervous system stimulation. Table 5-1 outlines several of the physiologic responses produced by direct electric stimulation of parasympathetic nerves. The following discussion of the specific muscarinic effects of the cholinergic drugs is limited to actions that have some therapeutic application or toxicologic importance; not all of the cholinergic drugs possess all these actions.
Muscarinic receptor agonists activate the sphincter muscle of the iris and produce constriction of the pupil (miosis). At the same time, there is contraction of the ciliary muscle, so the eye is focused for near vision. Intraocular pressure is decreased, particularly if the tension was elevated initially. There may also be a transient hyperemia of the conjunctiva.
Direct cardiac effects are similar to the effects associated with vagal stimulation. The heart rate is decreased by drug-induced slowing of the spontaneous depolarization of the sinoatrial node (negative chronotropic effect). There is also a decrease in the force of contraction (negative inotropic effect) of atrial and, to a much lesser extent, ventricular muscle. Although the effective refractory period is shortened in atrial muscle, the refractory period in the atrioventricular node and conducting system of the heart is increased, and conduction is slowed.
These direct effects on the heart are subject to autonomic modification. A baroreceptor-mediated increase in sympathetic nervous system activity may occur if the muscarinic drug produces a significant decrease in blood pressure. In a patient receiving the muscarinic blocking drug atropine, a dose of a cholinergic drug great enough to activate nicotinic receptors in autonomic ganglia and the adrenal gland will promote the release of catecholamines and result in cardiac stimulation.
Muscarinic receptor agonists produce a generalized vasodilation that causes a decrease in blood pressure. All vascular beds are affected, which is consistent with pharmacologic evidence that all parts of the vasculature, including pulpal blood vessels, are supplied with muscarinic receptors. The physiologic significance of these receptors is still in doubt, however, partly because much of the vasculature receives no parasympathetic innervation. In the absence of an administered drug, it is likely that vasodilation in local tissues occurs most often in response to autoregulatory factors, such as high carbon dioxide concentrations, low oxygen concentrations, and an acidic pH, and not to stimulation of cholinergic nerves. ACh produced and released locally may facilitate vasodilation in response to local blood flow increases. As noted previously, muscarinic receptor agonists produce their vasodilatory effects by inducing the vascular endothelium to release nitric oxide into the surrounding vascular smooth muscle, where it produces muscle relaxation.13,17
All glands that are innervated by cholinergic fibers are potentially stimulated by cholinergic drugs, including the salivary, lacrimal, bronchial, sweat, gastric, intestinal, and pancreatic glands. The secretion by sweat glands is controlled by sympathetic nerves, which in this case have cholinergic postganglionic fibers.
Muscarinic receptor agonists stimulate contraction of the detrusor muscle, which results in decreased bladder capacity and opening of the urethral orifice in the fundus of the bladder. (Micturition is permitted by voluntary relaxation of the urethral sphincter.) Peristaltic activity in ureteral smooth muscle may also be stimulated.
Several cholinomimetic drugs can stimulate nicotinic receptors. Nicotinic receptor agonists have varying effects at different nicotinic sites; these effects are related to the structure of the molecule,3 the dosage of the drug, and the location and type of nicotinic receptor activated. As noted earlier, there are at least two major kinds of peripheral nicotinic receptors: those on ganglia (NN) and those in skeletal muscle (NM). Although exogenous ACh at low doses stimulates muscarinic receptors selectively, in substantially higher doses it stimulates NN receptors and, by close intra-arterial injection of high doses, NM receptors. Carbachol has substantial nicotinic properties at therapeutic doses. Its affinity for nicotinic receptors is higher than that for muscarinic receptors. There is evidence that carbachol not only occupies the postsynaptic cholinergic receptor but also causes the release of ACh from nerve terminals in certain locations by activating presynaptic nicotinic receptors. Muscarinic effects are obtained indirectly through increased ACh release at parasympathetic ganglia and muscarinic neuroeffector sites. Although pilocarpine is essentially muscarinic in action, it has been reported to produce ganglionic stimulation in high doses.
Stimulation of autonomic ganglia leads to a mixture of parasympathetic and sympathetic effects. Because these effects often oppose each other, the resultant outcome is often difficult to predict. In the case of ACh and carbachol, which also exert prominent muscarinic activity, parasympathetic effects predominate; this is likely due to the fact that these drugs have a more difficult time gaining access to nicotinic receptors. The pharmacology of nicotine, which is devoid of direct muscarinic properties, is reviewed in Chapter 10. None of these agents produces clinically useful skeletal muscle stimulation.
As previously mentioned, there are muscarinic and nicotinic receptors in the CNS. ACh, the choline esters, and the cholinomimetic alkaloids all are known to evoke CNS actions when applied directly to brain tissue. Central cholinergic systems have been implicated in central regulation of most physiologic systems (i.e., cardiovascular, respiratory, gastrointestinal, and somatomotor systems) and influence cognition and emotion. The observation that cholinergic agonists affect so many functions indicates that cholinergic receptors play an important role in central neurotransmission. In the intact individual, many cholinergic agents are excluded from the CNS, however, because of their quaternary ammonium constituents. The fact that these drugs may still produce behavioral arousal responses is probably the result of their peripheral influences, which lead to changes in sensory inputs conducted to the brain by visceral afferent fibers.
All the previously discussed cholinergic receptor agonists are absorbed after administration by oral and parenteral routes, although absorption of the quaternary ammonium compounds from the gastrointestinal tract is likely to be unpredictable. Parenteral administration of the choline esters must be done with extreme caution because of the profound effects they may have on cholinergic effectors. ACh is rapidly destroyed by AChE and pseudocholinesterase and exerts an effect measured in seconds if given by bolus intravenous injection. Methacholine, more slowly metabolized than ACh by AChE and immune to pseudocholinesterase, is longer in duration of action. For all practical purposes, carbachol and bethanechol are not affected by the cholinesterases, so they have a much longer duration of action and the potential for producing widespread and prolonged cholinergic effects.
Pilocarpine is well absorbed after oral, subcutaneous, or topical administration. It also gains ready access to the CNS, and it is well distributed through the tissues and organs of the body. A large fraction is excreted unchanged by the kidneys, with an elimination half-life of 0.75 to 1.5 hours. Cevimeline is also well absorbed after oral administration, with peak blood concentrations occurring in 1.5 to 2 hours. Most of the drug is metabolized to sulfoxides and glucuronic acid conjugates, with an elimination half-life of about 5 hours.
Generally, adverse reactions to the cholinomimetic drugs are predictable consequences of the stimulation of cholinergic receptors. Patients with increased risk of adverse responses include patients with asthma, cardiovascular disease, and peptic ulcer. Untoward reactions may include a response profile that many autonomic pharmacologists refer to as the SLUD response (salivation, lacrimation, urination, and defecation). In addition to the SLUD response, muscarinic receptor agonists can produce bronchospasm, hypotension, and arrhythmias. Hypertensive responses to pilocarpine and cevimeline may occur with parenteral injection of large doses; this seemingly atypical effect is the result of sympathetic ganglionic stimulation caused by activation of excitatory muscarinic receptors on postganglionic neurons. Intravenous and intramuscular injection is generally avoided because of the increased possibility for producing cardiopulmonary reactions; toxic reactions generally are reduced by the restricted and often topical use of these agents.
The mushrooms Amanita pantherina and Amanita muscaria contain muscarine but in amounts that are probably too small to account for the symptoms of poisoning that result from their ingestion. The mushroom Inocybe lateraria, with a much higher muscarine content, produces signs and symptoms of intoxication that resemble those produced by muscarine, including profuse salivation and sweating; miosis; bradycardia; severe abdominal pain with vomiting, cramps, and diarrhea; and respiratory difficulties arising from the constriction of bronchial muscle and increased secretion in the respiratory tract. The onset of poisoning is rapid, and treatment consists of the administration of atropine in large quantities, gastric lavage, and appropriate supportive measures. Recovery usually occurs in 1 or 2 days. In many cases of mushroom poisoning, there are delayed symptoms, including violent emesis and diarrhea and damage to parenchymatous organs (principally the liver), which are not amenable to atropine treatment and are produced by a group of cyclopeptide toxins from the mushroom that inhibit the synthesis of messenger ribonucleic acid.2
Anticholinesterases are drugs that stimulate cholinergic transmission indirectly by inhibiting the enzyme AChE, which hydrolyzes and inactivates ACh in the synaptic clefts of the autonomic nervous system, the CNS, and the neuromuscular junction of the somatic nervous system. Agents in this class derive their pharmacologic effects from their ability to prolong the life of ACh at receptor sites. These cholinesterase inhibitors are sometimes referred to as indirect-acting cholinergic drugs.
Anticholinesterases can be subclassified as either reversible or irreversible cholinesterase inhibitors. Reversible inhibitors (e.g., edrophonium, neostigmine, and physostigmine) temporarily inactivate the enzyme by forming noncovalent associations with the enzyme or covalent bonds that are readily hydrolyzed. Irreversible cholinesterase inhibitors (organophosphates) inactivate the enzyme by forming a permanent covalent bond with the enzyme.
Physostigmine, or eserine, the earliest known anticholinesterase, has a colorful history. An alkaloid, it is derived from a bean, or nut, known as the Calabar, ordeal, or Esére bean, and it was used in witchcraft trials by certain native tribes in West Africa. The bean was brought to England by a British medical officer stationed in Calabar in the mid-1800s, and its pharmacologic properties were investigated in numerous laboratories, including those of Fraser, who studied its toxicity in the 1860s and noted that its actions were antagonized by atropine. In 1877, physostigmine was used for the treatment of glaucoma, which remains one of its principal uses today. In 1914, noting the extreme brevity of the action of ACh, Dale8 suggested that an enzyme capable of destroying ACh must exist in the body, and in 1930 it was found that physostigmine could prevent the rapid destruction of ACh.
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