Pharmacology_Katzung

Pharmacology_Katzung. The direct-acting cholinomimetic drugs can be divided on the basis of chemical structure into esters of choline (including acetylcholine) and alkaloids (such as muscarine and nicotine). Many of these drugs have effects on both receptors; acetylcholine is typical. A few of them are highly selective for the muscarinic or nicotinic receptor. However, none of the clinically useful drugs is selective for receptor subtypes within either class. Development of subtype-selective allosteric modulators could be clinically useful. A. Structure


Pharmacology_Katzung

Pharmacology_Katzung. A. Structure Four important choline esters that have been studied extensively are shown in Figure 7–2. Their permanently charged quaternary ammonium group renders them relatively insoluble in lipids. Many naturally occurring and synthetic cholinomimetic drugs that are not choline esters have been identified; a few of these are shown in Figure 7–3. The muscarinic receptor is strongly stereoselective: (S)-bethanechol is almost 1000 times more potent than (R)-bethanechol. B. Absorption, Distribution, and Metabolism Choline esters are poorly absorbed and poorly distributed into the central nervous system because they are hydrophilic. Although all are hydrolyzed in the gastrointestinal tract (and less active by the FIGURE 7–2 Molecular structures of four choline esters. Acetylcholine and methacholine are acetic acid esters of choline and β-methylcholine, respectively. Carbachol and bethanechol are carbamic acid esters of the same alcohols.


Pharmacology_Katzung

Pharmacology_Katzung. oral route), they differ markedly in their susceptibility to hydrolysis by cholinesterase. Acetylcholine is very rapidly hydrolyzed (see Chapter 6); large amounts must be infused intravenously to achieve concentrations sufficient to produce detectable effects. A large intravenous bolus injection has a brief effect, typically 5–20 seconds, whereas intramuscular and subcutaneous injections produce only local effects. Methacholine is more resistant to hydrolysis, and the carbamic acid esters carbachol and bethanechol are still more resistant to hydrolysis by cholinesterase and have correspondingly longer durations of action. The β-methyl group (methacholine, bethanechol) reduces the potency of these drugs at nicotinic receptors (Table 7–2).


Pharmacology_Katzung

Pharmacology_Katzung. The tertiary natural cholinomimetic alkaloids (pilocarpine, nicotine, lobeline) are well absorbed from most sites of administration. Nicotine, a liquid, is sufficiently lipid-soluble to be absorbed across the skin. Muscarine, a quaternary amine, is less completely absorbed from the gastrointestinal tract than the tertiary amines but is nevertheless toxic when ingested—eg, in certain mushrooms—and it even enters the brain. Lobeline is a plant derivative similar to nicotine. These amines are excreted chiefly by the kidneys. Acidification of the urine accelerates clearance of the tertiary amines (see Chapter 1). FIGURE 7–3 Structures of some cholinomimetic alkaloids. A. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 7–3 Structures of some cholinomimetic alkaloids. A. Mechanism of Action Activation of the parasympathetic nervous system modifies organ function by two major mechanisms. First, acetylcholine released from parasympathetic nerves activates muscarinic receptors on effector cells to alter organ function directly. Second, acetylcholine released from parasympathetic nerves interacts with muscarinic receptors on nerve terminals to inhibit the release of their neurotransmitter. By this mechanism, acetylcholine release and circulating muscarinic agonists indirectly alter organ function by modulating the effects of the parasympathetic and sympathetic nervous systems and perhaps nonadrenergic, noncholinergic (NANC) systems.


Pharmacology_Katzung

Pharmacology_Katzung. As indicated in Chapter 6, muscarinic receptor subtypes have been characterized by binding studies and cloned. Several cellular events occur when muscarinic receptors are activated, one or more of which might serve as second messengers for muscarinic activation. All muscarinic receptors appear to be of the G protein-coupled type (see Chapter 2 and Table 7–1). Muscarinic agonist TABLE 7–2 Properties of choline esters.


Pharmacology_Katzung

Pharmacology_Katzung. binding to M1, M3, and M5 receptors activates the inositol trisphosphate (IP3), diacylglycerol (DAG) cascade. Some evidence implicates DAG in the opening of smooth muscle calcium channels; IP3 releases calcium from endoplasmic and sarcoplasmic reticulum. Muscarinic agonists also increase cellular cGMP concentrations. Activation of muscarinic receptors also increases potassium flux across cardiac cell membranes (Figure 7–4A) and decreases it in ganglion and smooth muscle cells. This effect is mediated by the binding of an activated G protein βγ subunit directly to the channel. Finally, activation of M2 and M4 muscarinic receptors inhibits adenylyl cyclase activity in tissues (eg, heart, intestine). Moreover, muscarinic agonists attenuate the activation of adenylyl cyclase and modulate the increase in cAMP levels induced by hormones such as catecholamines. These muscarinic effects on cAMP generation reduce the physiologic response of the organ to stimulatory hormones.


Pharmacology_Katzung

Pharmacology_Katzung. The mechanism of nicotinic receptor activation has been studied in great detail, taking advantage of three factors: (1) the receptor is present in extremely high concentration in the membranes of the electric organs of electric fish; (2) α-bungarotoxin, a component of certain snake venoms, binds tightly to the receptors and is readily labeled as a marker for isolation procedures; and (3) receptor activation results in easily measured electrical and ionic changes in the cells involved. The nicotinic receptor in muscle tissues (Figure 7–4B) is a pentamer of four types of glycoprotein subunits (one monomer occurs twice) with a total molecular weight of about 250,000. The neuronal nicotinic receptor consists of α and β subunits only (Table 7–1). Each subunit has four transmembrane segments. The nicotinic receptor has two agonist binding sites at the interfaces formed by the two α subunits and two adjacent subunits (β, γ, ε). Agonist binding to the receptor sites causes a conformational


Pharmacology_Katzung

Pharmacology_Katzung. The nicotinic receptor has two agonist binding sites at the interfaces formed by the two α subunits and two adjacent subunits (β, γ, ε). Agonist binding to the receptor sites causes a conformational change in the protein (channel opening) that allows sodium and potassium ions to diffuse rapidly down their concentration gradients (calcium ions may also carry ––+˜°˛ACh ACh Vagus nerve varicosity Acetylcholine autoreceptor ACh M2R Sinoatrial nodal cell AC IK, ACh If ICa ATP cAMP PKA˝ATP Channel ˜˛°Gi/o


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 7–4 Muscarinic and nicotinic signaling. A: Muscarinic transmission to the sinoatrial node in heart. Acetylcholine (ACh) released from a varicosity of a postganglionic cholinergic axon interacts with a sinoatrial node cell muscarinic receptor (M2R) linked via Gi/o to K+ channel opening, which causes hyperpolarization, and to inhibition of cAMP synthesis. Reduced cAMP shifts the voltage-dependent opening of pacemaker channels (If) to more negative potentials, and reduces the phosphorylation and availability of L-type Ca2+ channels (ICa). Released ACh also acts on an axonal muscarinic receptor (autoreceptor; see Figure 6–3) to cause inhibition of ACh release (autoinhibition). B: Nicotinic transmission at the skeletal neuromuscular junction. ACh released from the motor nerve terminal interacts with subunits of the pentameric nicotinic receptor to open it, allowing Na+ influx to produce an excitatory postsynaptic potential (EPSP). The EPSP depolarizes the muscle membrane, generating


Pharmacology_Katzung

Pharmacology_Katzung. with subunits of the pentameric nicotinic receptor to open it, allowing Na+ influx to produce an excitatory postsynaptic potential (EPSP). The EPSP depolarizes the muscle membrane, generating an action potential, and triggering contraction. Acetylcholinesterase (AChE) in the extracellular matrix hydrolyzes ACh.


Pharmacology_Katzung

Pharmacology_Katzung. charge through the nicotinic receptor ion channel). Binding of an agonist molecule by one of the two receptor sites only modestly increases the probability of channel opening; simultaneous binding of agonist by both of the receptor sites greatly enhances opening probability. Nicotinic receptor activation causes depolarization of the nerve cell or neuromuscular end plate membrane. In skeletal muscle, the depolarization initiates an action potential that propagates across the muscle membrane and causes contraction (Figure 7–4B).


Pharmacology_Katzung

Pharmacology_Katzung. Prolonged agonist occupancy of the nicotinic receptor abolishes the effector response; that is, the postganglionic neuron stops firing (ganglionic effect), and the skeletal muscle cell relaxes (neuromuscular end plate effect). Furthermore, the continued presence of the nicotinic agonist prevents electrical recovery of the postjunctional membrane. Thus, a state of “depolarizing blockade” occurs initially during persistent agonist occupancy of the receptor. Continued agonist occupancy is associated with return of membrane voltage to the resting level. The receptor becomes desensitized to agonist, and this state is refractory to reversal by other agonists. As described in Chapter 27, this effect can be exploited to produce muscle paralysis. B. Organ System Effects


Pharmacology_Katzung

Pharmacology_Katzung. B. Organ System Effects Most of the direct organ system effects of muscarinic cholinoceptor stimulants are readily predicted from knowledge of the effects of parasympathetic nerve stimulation (see Table 6–3) and the distribution of muscarinic receptors. Effects of a typical agent such as acetylcholine are listed in Table 7–3. The effects of nicotinic agonists are similarly predictable from knowledge of the physiology of the autonomic ganglia and skeletal muscle motor end plate. 1. Eye—Muscarinic agonists instilled into the conjunctival sac cause contraction of the smooth muscle of the iris sphincter (resulting in miosis) and of the ciliary muscle (resulting in accommodation). As a result, the iris is pulled away from the angle of the anterior chamber, and the trabecular meshwork at the base of the ciliary muscle is opened. Both effects facilitate aqueous humor outflow into the canal of Schlemm, which drains the anterior chamber. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Cardiovascular system—The primary cardiovascular effects of muscarinic agonists are reduction in peripheral vascular resistance and changes in heart rate. The direct effects listed in Table 7–3 are modified by important homeostatic reflexes, as described in Chapter 6 and depicted in Figure 6–7. Intravenous infusions of minimally effective doses of acetylcholine in humans (eg, 20–50 mcg/min) cause vasodilation, resulting in a reduction in blood pressure, often accompanied by a reflex increase in heart rate. Larger doses of acetylcholine produce bradycardia and decrease atrioventricular node conduction velocity in addition to causing hypotension. The direct cardiac actions of muscarinic stimulants include the following: (1) an increase in a potassium current (IK(ACh)) in the cells of the sinoatrial and atrioventricular nodes, in Purkinje cells,


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 7–3 Effects of direct-acting cholinoceptor stimulants.1 1Only the direct effects are indicated; homeostatic responses to these direct actions may be important (see text). EDRF, endothelium-derived relaxing factor. and also in atrial and ventricular muscle cells; (2) a decrease in the slow inward calcium current (ICa) in heart cells; and (3) a reduction in the hyperpolarization-activated current (If) that underlies diastolic depolarization (Figure 7–4A). All these actions are mediated by M2 receptors and contribute to slowing the pacemaker rate. Effects (1) and (2) cause hyperpolarization, reduce action potential duration, and decrease the contractility of atrial and ventricular cells. Predictably, knockout of M2 receptors eliminates the bradycardic effect of vagal stimulation and the negative chronotropic effect of carbachol on sinoatrial rate.


Pharmacology_Katzung

Pharmacology_Katzung. The direct slowing of sinoatrial rate and atrioventricular conduction that is produced by muscarinic agonists is often opposed by reflex sympathetic discharge, elicited by the decrease in blood pressure (see Figure 6–7). The resultant sympathetic-parasympathetic interaction is complex because muscarinic modulation of sympathetic influences occurs by inhibition of norepinephrine release and by postjunctional cellular effects. Muscarinic receptors that are present on post-ganglionic parasympathetic nerve terminals allow neurally released acetylcholine to inhibit its own secretion. The neuronal muscarinic receptors need not be the same subtype as found on effector cells. Therefore, the net effect on heart rate depends on local concentrations of the agonist in the heart and in the vessels and on the level of reflex responsiveness.


Pharmacology_Katzung

Pharmacology_Katzung. Parasympathetic innervation of the ventricles is much less extensive than that of the atria; activation of ventricular muscarinic receptors causes much less direct physiologic effect than that seen in atria. However, the indirect effects of muscarinic agonists on ventricular function are clearly evident during sympathetic nerve stimulation because of muscarinic modulation of sympathetic effects (“accentuated antagonism”).


Pharmacology_Katzung

Pharmacology_Katzung. In the intact organism, intravascular injection of muscarinic agonists produces marked vasodilation. However, earlier studies of isolated blood vessels often showed a contractile response to these agents. It is now known that acetylcholine-induced vasodilation arises from activation of M3 receptors and requires the presence of intact endothelium (Figure 7–5). Muscarinic agonists release endothelium-derived relaxing factor (EDRF), identified as nitric oxide (NO), from the endothelial cells. The NO diffuses to adjacent vascular smooth muscle, where it activates guanylyl cyclase and increases cGMP, resulting in relaxation (see Figure 12–2). Isolated vessels prepared with the endothelium preserved consistently reproduce the vasodilation seen in the intact organism. The relaxing effect of acetylcholine was maximal at 3 × 10−7 M (Figure 7–5). This effect was eliminated in the absence of endothelium, and acetylcholine, at concentrations greater than 10−7 M, then caused contraction. This


Pharmacology_Katzung

Pharmacology_Katzung. acetylcholine was maximal at 3 × 10−7 M (Figure 7–5). This effect was eliminated in the absence of endothelium, and acetylcholine, at concentrations greater than 10−7 M, then caused contraction. This results from a direct effect of acetylcholine on vascular smooth muscle in which activation of M3 receptors stimulates IP3 production and releases intracellular calcium.


Pharmacology_Katzung

Pharmacology_Katzung. Parasympathetic nerves can regulate arteriolar tone in vascular beds in thoracic and abdominal visceral organs. Acetylcholine released from postganglionic parasympathetic nerves relaxes coronary arteriolar smooth muscle via the NO/cGMP pathway in humans as described above. Damage to the endothelium, as occurs with atherosclerosis, eliminates this action, and acetylcholine is then able to contract arterial smooth muscle and produce vasoconstriction. Parasympathetic nerve stimulation also causes vasodilation in cerebral blood vessels; however, the effect often appears as a result of NO released either from NANC (nitrergic) neurons or as a cotransmitter from cholinergic nerves. The relative contributions of cholinergic and NANC neurons to the vascular effects of parasympathetic nerve stimulation are not known for most viscera. Skeletal muscle receives sympathetic cholinergic vasodilator nerves, but the view that acetylcholine causes vasodilation in this vascular bed has not been verified


Pharmacology_Katzung

Pharmacology_Katzung. are not known for most viscera. Skeletal muscle receives sympathetic cholinergic vasodilator nerves, but the view that acetylcholine causes vasodilation in this vascular bed has not been verified experimentally. Nitric oxide, rather than acetylcholine, may be released from these neurons. However, this vascular bed responds to exogenous choline esters because of the presence of M3 receptors on endothelial and smooth muscle cells.


Pharmacology_Katzung

Pharmacology_Katzung. The cardiovascular effects of all the choline esters are similar to those of acetylcholine—the main difference being in their potency and duration of action. Because of the resistance of methacholine, carbachol, and bethanechol to acetylcholinesterase, lower doses given intravenously are sufficient to produce effects similar to those of acetylcholine, and the duration of action of these synthetic choline esters is longer. The cardiovascular effects of most of the cholinomimetic natural alkaloids and the synthetic analogs are also generally similar to those of acetylcholine.


Pharmacology_Katzung

Pharmacology_Katzung. Pilocarpine is an interesting exception to the above statement. If given intravenously (an experimental exercise), it may produce hypertension after a brief initial hypotensive response. The longer-lasting hypertensive effect can be traced to sympathetic ganglionic discharge caused by activation of postganglionic cell membrane M1 receptors, which close K+ channels and elicit slow excitatory (depolarizing) postsynaptic potentials (Figure 6–8). This effect, like the hypotensive effect, can be blocked by atropine, an antimuscarinic drug.


Pharmacology_Katzung

Pharmacology_Katzung. NA –8 NA –8 –8 –7.5 –7 –6.5 –6 W ACh –8 –7.5 –7–6.5 UnrubbedRubbed–6 W ACh Tension Time FIGURE 7–5 Activation of endothelial cell muscarinic receptors by acetylcholine (ACh) releases endothelium-derived relaxing factor (nitric oxide), which causes relaxation of vascular smooth muscle precontracted with norepinephrine, 10−8 M. Removal of the endothelium by rubbing eliminates the relaxant effect and reveals contraction caused by direct action of ACh on vascular smooth muscle. (NA, noradrenaline [norepi-nephrine]; W, wash. Numbers indicate the log molar concentration applied at the time indicated.) (Adapted, with permission, from Furchgott RF, Zawadzki JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373. Copyright 1980 Macmillan Publishers Ltd.) 3.


Pharmacology_Katzung

Pharmacology_Katzung. Respiratory system—Muscarinic stimulants contract the smooth muscle of the bronchial tree. In addition, the glands of the tracheobronchial mucosa are stimulated to secrete. This combination of effects can occasionally cause symptoms, especially in individuals with asthma. The bronchoconstriction caused by muscarinic agonists is eliminated in knockout animals in which the M3 receptor has been mutated. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Gastrointestinal tract—Administration of muscarinic agonists, as in parasympathetic nervous system stimulation, increases the secretory and motor activity of the gut. The salivary and gastric glands are strongly stimulated; the pancreas and small intestinal glands are stimulated less so. Peristaltic activity is increased throughout the gut, and most sphincters are relaxed. Stimulation of contraction in this organ system involves depolarization of the smooth muscle cell membrane and increased calcium influx. Muscarinic agonists do not cause contraction of the ileum in mutant mice lacking M2 and M3 receptors. The M3 receptor is required for direct activation of smooth muscle contraction, whereas the M2 receptor reduces cAMP formation and relaxation caused by sympathomimetic drugs. 5.


Pharmacology_Katzung

Pharmacology_Katzung. 5. Genitourinary tract—Muscarinic agonists stimulate the detrusor muscle and relax the trigone and sphincter muscles of the bladder, thus promoting voiding. The function of M2 and M3 receptors in the urinary bladder appears to be the same as in intestinal smooth muscle. The human uterus is not notably sensitive to muscarinic agonists. 6. Miscellaneous secretory glands—Muscarinic agonists stimulate secretion by thermoregulatory sweat, lacrimal, and nasopharyngeal glands. 7. Central nervous system—The central nervous system contains both muscarinic and nicotinic receptors, the brain being relatively richer in muscarinic sites and the spinal cord containing a preponderance of nicotinic sites. The physiologic roles of these receptors are discussed in Chapter 21.


Pharmacology_Katzung

Pharmacology_Katzung. All five muscarinic receptor subtypes have been detected in the central nervous system. The roles of M1 through M3 have been analyzed by means of experiments in knockout mice. The M1 subtype is richly expressed in brain areas involved in cognition. Knockout of M1 receptors was associated with impaired neuronal plasticity in the forebrain, and pilocarpine did not induce seizures in M1 mutant mice. The central nervous system effects of the synthetic muscarinic agonist oxotremorine (tremor, hypothermia, and antinociception) were lacking in mice with homozygously mutated M2 receptors. Animals lacking M3 receptors, especially those in the hypothalamus, had reduced appetite and diminished body fat mass.


Pharmacology_Katzung

Pharmacology_Katzung. Despite the smaller ratio of nicotinic to muscarinic receptors, nicotine and lobeline (Figure 7–3) have important effects on the brain stem and cortex. Activation of nicotinic receptors occurs at presynaptic and postsynaptic loci. Presynaptic nicotinic receptors allow acetylcholine and nicotine to regulate the release of several neurotransmitters (glutamate, serotonin, GABA, dopamine, and norepinephrine). Acetylcholine regulates norepinephrine release via α3β4 nicotinic receptors in the hippocampus and inhibits acetylcholine release from neurons in the hippocampus and cortex. The α4β2 oligomer is the most abundant nicotinic receptor in the brain. Chronic exposure to nicotine has a dual effect at nicotinic receptors: activation (depolarization) followed by desensitization. The former effect is associated with greater release of dopamine in the mesolimbic system of humans. This effect is thought to contribute to the mild alerting action and the addictive property of nicotine absorbed


Pharmacology_Katzung

Pharmacology_Katzung. is associated with greater release of dopamine in the mesolimbic system of humans. This effect is thought to contribute to the mild alerting action and the addictive property of nicotine absorbed from tobacco. When the β2 subunits are deleted in reconstitution experiments, acetylcholine binding is reduced, as is the release of dopamine. The later desensitization of the nicotinic receptor is accompanied by increased high-affinity agonist binding and an upregulation of nicotinic binding sites, especially those of the α4β2 oligomer. Sustained desensitization may contribute to the benefits of nicotine replacement therapy in smoking cessation regimens. In high concentrations, nicotine induces tremor, emesis, and stimulation of the respiratory center. At still higher levels, nicotine causes convulsions, which may terminate in fatal coma. The lethal effects on the central nervous system and the fact that nicotine is readily absorbed form the basis for the use of nicotine and derivatives


Pharmacology_Katzung

Pharmacology_Katzung. convulsions, which may terminate in fatal coma. The lethal effects on the central nervous system and the fact that nicotine is readily absorbed form the basis for the use of nicotine and derivatives (neonicotinoids) as insecticides.


Pharmacology_Katzung

Pharmacology_Katzung. The α7 subtype of nicotinic receptors (α7 nAChR) is detected in the central and peripheral nervous systems where it may function in cognition and pain perception. This nicotinic receptor subtype is a homomeric pentamer (α7)5 having five agonist binding sites at the interfaces of the subunits. Positive allosteric modulators (see Chapter 1) of the α7 receptor are being developed with a view to improving cognitive function in the treatment of schizophrenia. The presence of α7 nAChR on nonneuronal cells of the immune system has been suggested as a basis of anti-inflammatory actions. Acetylcholine or nicotine reduces the release of inflammatory cytokines via α7 nAChR on macrophages and other cytokine-producing cells. In human volunteers, transdermal nicotine reduced markers of inflammation caused by lipopolysaccharide. The anti-inflammatory role of α7 nAChR has gained support from such data.


Pharmacology_Katzung

Pharmacology_Katzung. 8. Peripheral nervous system—Autonomic ganglia are important sites of nicotinic synaptic action. The α3 subtype is found in autonomic ganglia and is responsible for fast excitatory transmission. Beta2 and β4 subunits are usually present with the α3 subunit to form heteromeric subtypes in parasympathetic and sympathetic ganglia and in the adrenal medulla. Nicotinic agents cause marked activation of these nicotinic receptors and initiate action potentials in postganglionic neurons (see Figure 6–8). Nicotine itself has a somewhat greater affinity for neuronal than for skeletal muscle nicotinic receptors.


Pharmacology_Katzung

Pharmacology_Katzung. Nicotine action is the same on both parasympathetic and sympathetic ganglia. Therefore, the initial response often resembles simultaneous discharge of both the parasympathetic and sympathetic nervous systems. In the case of the cardiovascular system, the effects of nicotine are chiefly sympathomimetic. Dramatic hypertension is produced by parenteral injection of nicotine; sympathetic tachycardia may alternate with a bradycardia mediated by vagal discharge. In the gastrointestinal and urinary tracts, the effects are largely parasympathomimetic: nausea, vomiting, diarrhea, and voiding of urine are commonly observed. Prolonged exposure may result in depolarizing blockade of the ganglia.


Pharmacology_Katzung

Pharmacology_Katzung. Primary autoimmune autonomic failure provides a pathophysiologic example of the effects of suppression of nicotinic receptor function at autonomic ganglia. In some patients, neither diabetic neuropathy nor amyloidosis can account for the autonomic failure. In those individuals, circulating auto-antibodies selective for the α3β4 nicotinic receptor subtype are present and cause orthostatic hypotension, reduced sweating, dry mouth and eyes, reduced baroreflex function, urinary retention, constipation, and erectile dysfunction. These signs of autonomic failure can be ameliorated by plasmapheresis, which also reduces the concentration of autoantibodies to the α3β4 nicotinic receptor.


Pharmacology_Katzung

Pharmacology_Katzung. Deletion of either the α3 or the β2 and β4 subunits causes widespread autonomic dysfunction and blocks the action of nicotine in experimental animals. Humans deficient in α3 subunits are afflicted with microcystis (inadequate development of the urinary bladder), microcolon, intestinal hypo-peristalsis syndrome; urinary incontinence, urinary bladder distention and mydriasis also occur. Neuronal nicotinic receptors are present on sensory nerve endings, especially afferent nerves in coronary arteries and the carotid and aortic bodies as well as on the glomus cells of the latter. Activation of these receptors by nicotinic stimulants and of muscarinic receptors on glomus cells by muscarinic stimulants elicits complex medullary responses, including respiratory alterations and vagal discharge.


Pharmacology_Katzung

Pharmacology_Katzung. 9. Neuromuscular junction—The nicotinic receptors on the neuromuscular end plate apparatus are similar but not identical to the receptors in the autonomic ganglia (Table 7–1). Both types respond to acetylcholine and nicotine. (However, as noted in Chapter 8, the receptors differ in their structural requirements for nicotinic blocking drugs.) When a nicotinic agonist is applied directly (by iontophoresis or by intra-arterial injection), an immediate depolarization of the end plate results, caused by an increase in permeability to sodium and potassium ions (Figure 7–4B). The contractile response varies from disorganized fasciculations of independent motor units to a strong contraction of the entire muscle depending on the synchronization of depolarization of end plates throughout the muscle. Depolarizing nicotinic agents that are not rapidly hydrolyzed (like nicotine itself) cause rapid development of depolarization blockade; transmission blockade persists even when the membrane has


Pharmacology_Katzung

Pharmacology_Katzung. Depolarizing nicotinic agents that are not rapidly hydrolyzed (like nicotine itself) cause rapid development of depolarization blockade; transmission blockade persists even when the membrane has repolarized (discussed further in Chapters 8 and 27). This latter phase of block is manifested as flaccid paralysis in the case of skeletal muscle.


Pharmacology_Katzung

Pharmacology_Katzung. The actions of acetylcholine released from autonomic and somatic motor nerves are terminated by enzymatic hydrolysis of the molecule. Hydrolysis is accomplished by the action of acetylcholinesterase, which is present in high concentrations in cholinergic synapses. The indirect-acting cholinomimetics have their primary effect at the active site of this enzyme, although some also have direct actions at nicotinic receptors. The chief differences between members of the group are chemical and pharmacokinetic—their pharmacodynamic properties are almost identical. A. Structure


Pharmacology_Katzung

Pharmacology_Katzung. A. Structure There are three chemical groups of cholinesterase inhibitors: (1) simple alcohols bearing a quaternary ammonium group, eg, edrophonium; (2) carbamic acid esters of alcohols having quaternary or tertiary ammonium groups (carbamates, eg, neostigmine); and (3) organic derivatives of phosphoric acid (organophosphates, eg, echothiophate). Examples of the first two groups are shown in Figure 7–6. Edrophonium, neostigmine, and pyridostigmine are synthetic quaternary ammonium agents used in medicine. Physostigmine (eserine) is a naturally occurring tertiary amine of greater lipid solubility that is also used in therapeutics. Carbaryl (carbaril) is typical of a large group of carbamate insecticides designed for very high lipid solubility, so that absorption into the insect and distribution to its central nervous system are very rapid.


Pharmacology_Katzung

Pharmacology_Katzung. A few of the estimated 50,000 organophosphates are shown in Figure 7–7. Many of the organophosphates (echothiophate is an exception) are highly lipid-soluble liquids. Echothiophate, a thiocholine derivative, is of clinical value because it retains the very long duration of action of other organophosphates but is more stable in aqueous solution. Sarin is an extremely potent “nerve gas.” Parathion and malathion are thiophosphate (sulfurcontaining phosphate) prodrugs that are inactive as such; they are converted to the phosphate derivatives in animals and plants and are used as insecticides. B. Absorption, Distribution, and Metabolism


Pharmacology_Katzung

Pharmacology_Katzung. B. Absorption, Distribution, and Metabolism Absorption of the quaternary carbamates from the conjunctiva, skin, gut, and lungs is predictably poor, since their permanent charge renders them relatively insoluble in lipids. Thus, much larger doses are required for oral administration than for parenteral injection. Distribution into the central nervous system is negligible. Physostigmine, in contrast, is well absorbed from all sites and can be used topically in the eye (Table 7–4). It is distributed into the central nervous system and is more toxic than the more polar quaternary carbamates. The carbamates are relatively stable in aqueous solution but can be metabolized by nonspecific esterases in the body as well as by cholinesterase. However, the duration of their effect is determined chiefly by the stability of


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 7–6 Cholinesterase inhibitors. Neostigmine exemplifies the typical ester composed of carbamic acid ([1]) and a phenol bearing a quaternary ammonium group ([2]). Physostigmine, a naturally occurring carbamate, is a tertiary amine. Edrophonium is not an ester but binds to the active site of the enzyme. Carbaryl is used as an insecticide. the inhibitor-enzyme complex (see later Mechanism of Action highly effective as insecticides. They are relatively less stable section), not by metabolism or excretion. than the carbamates when dissolved in water and thus have a The organophosphate cholinesterase inhibitors (except for limited half-life in the environment (compared with another echothiophate) are well absorbed from the skin, lung, gut, and major class of insecticides, the halogenated hydrocarbons, eg, conjunctiva—thereby making them dangerous to humans and DDT). Echothiophate is highly polar and more stable than most


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 7–7 Structures of some organophosphate cholinesterase inhibitors. The dashed lines indicate the bond that is hydrolyzed in binding to the enzyme. The shaded ester bonds in malathion represent the points of detoxification of the molecule in mammals and birds. TABLE 7–4 Therapeutic uses and durations of action of cholinesterase inhibitors. other organophosphates. When prepared in aqueous solution for ophthalmic use, it retains activity for weeks.


Pharmacology_Katzung

Pharmacology_Katzung. other organophosphates. When prepared in aqueous solution for ophthalmic use, it retains activity for weeks. The thiophosphate insecticides (parathion, malathion, and related compounds) are quite lipid-soluble and are rapidly absorbed by all routes. They must be activated in the body by conversion to the oxygen analogs (Figure 7–7), a process that occurs rapidly in both insects and vertebrates. Malathion and a few other organophosphate insecticides are also rapidly metabolized by other pathways to inactive products in birds and mammals but not in insects; these agents are therefore considered safe enough for sale to the general public. Unfortunately, fish cannot detoxify malathion, and significant numbers of fish have died from the heavy use of this agent on and near waterways. Parathion is not detoxified effectively in vertebrates; thus, it is considerably more dangerous than malathion to humans and livestock and is not available for general public use in the USA.


Pharmacology_Katzung

Pharmacology_Katzung. All the organophosphates except echothiophate are distributed to all parts of the body, including the central nervous system. Therefore, central nervous system toxicity is an important component of poisoning with these agents. A. Mechanism of Action Acetylcholinesterase is the primary target of these drugs, but butyrylcholinesterase is also inhibited. Acetylcholinesterase is an extremely active enzyme. In the initial catalytic step, acetylcholine binds to the enzyme’s active site and is hydrolyzed, yielding free choline and the acetylated enzyme. In the second step, the covalent acetyl-enzyme bond is split, with the addition of water (hydration). The entire process occurs in approximately 150 microseconds. All the cholinesterase inhibitors increase the concentration of endogenous acetylcholine at cholinoceptors by inhibiting acetylcholinesterase. However, the molecular details of their interaction with the enzyme vary according to the three chemical subgroups mentioned above.


Pharmacology_Katzung

Pharmacology_Katzung. The first group, of which edrophonium is the example, consists of quaternary alcohols. These agents reversibly bind electrostatically and by hydrogen bonds to the active site, thus preventing access of acetylcholine. The enzyme-inhibitor complex does not involve a covalent bond and is correspondingly short-lived (on the order of 2–10 minutes). The second group consists of carbamate esters, eg, neostigmine and physostigmine. These agents undergo a two-step hydrolysis sequence analogous to that described for acetylcholine. However, the covalent bond of the carbamoylated enzyme is considerably more resistant to the second (hydration) process, and this step is correspondingly prolonged (on the order of 30 minutes to 6 hours). The third group consists of the organophosphates. These agents also undergo initial binding and hydrolysis by the enzyme, resulting in a phosphorylated active site. The covalent phosphorus-enzyme bond is extremely stable and hydrolyzes in water at a very slow rate


Pharmacology_Katzung

Pharmacology_Katzung. undergo initial binding and hydrolysis by the enzyme, resulting in a phosphorylated active site. The covalent phosphorus-enzyme bond is extremely stable and hydrolyzes in water at a very slow rate (hundreds of hours). After the initial binding-hydrolysis step, the phosphorylated enzyme complex may undergo a process called aging. This process apparently involves the breaking of one of the oxygen-phosphorus bonds of the inhibitor and further strengthens the phosphorus-enzyme bond. The rate of aging varies with the particular organophosphate compound. For example, aging occurs within 10 minutes with the chemical warfare agent soman, but as much as 48 hours later with the drug VX. If given before aging has occurred, strong nucleophiles like pralidoxime are able to break the phosphorus-enzyme bond and can be used as “cholinesterase regenerator” drugs for organophosphate insecticide poisoning (see Chapter 8). Once aging has occurred, the enzyme-inhibitor complex is even more stable and is


Pharmacology_Katzung

Pharmacology_Katzung. bond and can be used as “cholinesterase regenerator” drugs for organophosphate insecticide poisoning (see Chapter 8). Once aging has occurred, the enzyme-inhibitor complex is even more stable and is more difficult to break, even with oxime regenerator compounds.


Pharmacology_Katzung

Pharmacology_Katzung. The organophosphate inhibitors are sometimes referred to as “irreversible” cholinesterase inhibitors, and edrophonium and the carbamates are considered “reversible” inhibitors because of the marked differences in duration of action. However, the molecular mechanisms of action of the three groups do not support this simplistic description. B. Organ System Effects The most prominent pharmacologic effects of cholinesterase inhibitors are on the cardiovascular and gastrointestinal systems, the eye, and the skeletal muscle neuromuscular junction (as described in the Case Study). Because the primary action is to amplify the actions of endogenous acetylcholine, the effects are similar (but not always identical) to the effects of the direct-acting cholinomimetic agonists. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Central nervous system—In low concentrations, the lipid-soluble cholinesterase inhibitors cause diffuse activation on the electroencephalogram and a subjective alerting response. In higher concentrations, they cause generalized convulsions, which may be followed by coma and respiratory arrest. 2. Eye, respiratory tract, gastrointestinal tract, urinary tract—The effects of the cholinesterase inhibitors on these organ systems, all of which are well innervated by the parasympathetic nervous system, are qualitatively quite similar to the effects of the direct-acting cholinomimetics (Table 7–3). 3. Cardiovascular system—The cholinesterase inhibitors can increase activity in both sympathetic and parasympathetic ganglia supplying the heart and at the acetylcholine receptors on neuroeffector cells (cardiac and vascular smooth muscles) that receive cholinergic innervation.


Pharmacology_Katzung

Pharmacology_Katzung. In the heart, the effects on the parasympathetic limb predominate. Thus, cholinesterase inhibitors such as edrophonium, physostigmine, or neostigmine mimic the effects of vagal nerve activation on the heart. Negative chronotropic, dromotropic, and inotropic effects are produced, and cardiac output falls. The fall in cardiac output is attributable to bradycardia, decreased atrial contractility, and some reduction in ventricular contractility. The latter effect occurs as a result of prejunctional inhibition of nor-epinephrine release as well as inhibition of postjunctional cellular sympathetic effects.


Pharmacology_Katzung

Pharmacology_Katzung. Cholinesterase inhibitors have minimal effects by direct action on vascular smooth muscle because most vascular beds lack cholinergic innervation (coronary vasculature is an exception). At moderate doses, cholinesterase inhibitors cause an increase in systemic vascular resistance and blood pressure that is initiated at sympathetic ganglia in the case of quaternary nitrogen compounds and also at central sympathetic centers in the case of lipid-soluble agents. Atropine, acting in the central and peripheral nervous systems, can prevent the increase of blood pressure and the increased plasma norepinephrine.


Pharmacology_Katzung

Pharmacology_Katzung. The net cardiovascular effects of moderate doses of cholinesterase inhibitors therefore consist of modest bradycardia, a fall in cardiac output, and an increased vascular resistance that results in a rise in blood pressure. (Thus, in patients with Alzheimer’s disease who have hypertension, treatment with cholinesterase inhibitors requires that blood pressure be monitored to adjust antihypertensive therapy.) At high (toxic) doses of cholinesterase inhibitors, marked bradycardia occurs, cardiac output decreases significantly, and hypotension supervenes.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Neuromuscular junction—The cholinesterase inhibitors have important therapeutic and toxic effects at the skeletal muscle neuromuscular junction. Low (therapeutic) concentrations moderately prolong and intensify the actions of physiologically released acetylcholine. This increases the strength of contraction, especially in muscles weakened by curare-like neuromuscular blocking agents or by myasthenia gravis. At higher concentrations, the accumulation of acetylcholine may result in fibrillation of muscle fibers. Antidromic firing of the motor neuron may also occur, resulting in fasciculations that involve an entire motor unit. With marked inhibition of acetylcholinesterase, depolarizing neuromuscular blockade occurs and that may be followed by a phase of nondepolarizing blockade as seen with succinylcholine (see Table 27–2 and Figure 27–7).


Pharmacology_Katzung

Pharmacology_Katzung. Some quaternary carbamate cholinesterase inhibitors, eg, neostigmine and pyridostigmine, have an additional direct nicotinic agonist effect at the neuromuscular junction. This may contribute to the effectiveness of these agents as therapy for myasthenia. The major therapeutic uses of the cholinomimetics are to treat diseases of the eye (glaucoma, accommodative esotropia), the gastrointestinal and urinary tracts (postoperative atony, neurogenic bladder), and the neuromuscular junction (myasthenia gravis, curare-induced neuromuscular paralysis), and to treat patients with Alzheimer’s disease. Cholinesterase inhibitors are occasionally used in the treatment of atropine overdosage and, very rarely, in the therapy of certain atrial arrhythmias. A. The Eye


Pharmacology_Katzung

Pharmacology_Katzung. A. The Eye Glaucoma is a disease characterized by increased intraocular pressure. Muscarinic stimulants and cholinesterase inhibitors reduce intraocular pressure by causing contraction of the ciliary body so as to facilitate outflow of aqueous humor and perhaps also by diminishing the rate of its secretion (see Figure 6–9). In the past, glaucoma was treated with either direct agonists (pilocarpine, methacholine, carbachol) or cholinesterase inhibitors (physostigmine, demecarium, echothiophate, isoflurophate). For chronic glaucoma, these drugs have been largely replaced by prostaglandin derivatives and topical β-adrenoceptor antagonists.


Pharmacology_Katzung

Pharmacology_Katzung. Acute angle-closure glaucoma is a medical emergency that is frequently treated initially with drugs but usually requires surgery for permanent correction. Initial therapy often consists of a combination of a direct muscarinic agonist (eg, pilocarpine) and other drugs. Once the intraocular pressure is controlled and the danger of vision loss is diminished, the patient can be prepared for corrective surgery (laser iridotomy). Open-angle glaucoma and some cases of secondary glaucoma are chronic diseases that are not amenable to traditional surgical correction, although newer laser techniques appear to be useful. Other treatments for glaucoma are described in the Box: The Treatment of Glaucoma in Chapter 10. Accommodative esotropia (strabismus caused by hypermetropic accommodative error) in young children is sometimes diagnosed and treated with cholinomimetic agonists. Dosage is similar to or higher than that used for glaucoma. B. Gastrointestinal and Urinary Tracts


Pharmacology_Katzung

Pharmacology_Katzung. In clinical disorders that involve depression of smooth muscle activity without obstruction, cholinomimetic drugs with direct or indirect muscarinic effects may be helpful. These disorders include postoperative ileus (atony or paralysis of the stomach or bowel following surgical manipulation) and congenital megacolon. Urinary retention may occur postoperatively or postpartum or may be secondary to spinal cord injury or disease (neurogenic bladder). Cholinomimetics were also sometimes used to increase the tone of the lower esophageal sphincter in patients with reflux esophagitis but proton pump inhibitors are usually indicated (see Chapter 62). Of the choline esters, bethanechol is the most widely used for these disorders. For gastrointestinal problems, it is usually administered orally in a dose of 10–25 mg three or four times daily. In patients with urinary retention, bethanechol can be given subcutaneously in a dose of 5 mg and repeated in 30 minutes if necessary. Of the


Pharmacology_Katzung

Pharmacology_Katzung. orally in a dose of 10–25 mg three or four times daily. In patients with urinary retention, bethanechol can be given subcutaneously in a dose of 5 mg and repeated in 30 minutes if necessary. Of the cholinesterase inhibitors, neostigmine is the most widely used for these applications. For paralytic ileus or atony of the urinary bladder, neostigmine can be given subcutaneously in a dose of 0.5–1 mg. If patients are able to take the drug by mouth, neostigmine can be given orally in a dose of 15 mg. In all of these situations, the clinician must be certain that there is no mechanical obstruction to outflow before using the cholinomimetic. Otherwise, the drug may exacerbate the problem and may even cause perforation as a result of increased pressure.


Pharmacology_Katzung

Pharmacology_Katzung. Pilocarpine has long been used to increase salivary secretion. Cevimeline, a quinuclidine derivative of acetylcholine, is a newer direct-acting muscarinic agonist used for the treatment of dry mouth associated with Sjögren’s syndrome or caused by radiation damage of the salivary glands. C. Neuromuscular Junction


Pharmacology_Katzung

Pharmacology_Katzung. Myasthenia gravis is an autoimmune disease affecting skeletal muscle neuromuscular junctions. In this disease, antibodies are produced against the main immunogenic region found on α1 subunits of the nicotinic receptor-channel complex. Antibodies are detected in 85% of myasthenic patients. The antibodies reduce nicotinic receptor function by (1) cross-linking receptors, a process that stimulates their internalization and degradation; (2) causing lysis of the postsynaptic membrane; and (3) binding to the nicotinic receptor and inhibiting function. Frequent findings are ptosis, diplopia, difficulty in speaking and swallowing, and extremity weakness. Severe disease may affect all the muscles, including those necessary for respiration. The disease resembles the neuromuscular paralysis produced by d-tubocurarine and similar nondepolarizing neuromuscular blocking drugs (see Chapter 27). Patients with myasthenia are exquisitely sensitive to the action of curariform drugs and other drugs that


Pharmacology_Katzung

Pharmacology_Katzung. by d-tubocurarine and similar nondepolarizing neuromuscular blocking drugs (see Chapter 27). Patients with myasthenia are exquisitely sensitive to the action of curariform drugs and other drugs that interfere with neuromuscular transmission, eg, aminoglycoside antibiotics.


Pharmacology_Katzung

Pharmacology_Katzung. Cholinesterase inhibitors—but not direct-acting acetylcholine receptor agonists—are extremely valuable as therapy for myasthenia. Patients with ocular myasthenia may be treated with cholinesterase inhibitors alone (Figure 7–4B). Patients having more widespread muscle weakness are also treated with immunosuppressant drugs (steroids, cyclosporine, and azathioprine). In some patients, the thymus gland is removed; very severely affected patients may benefit from administration of immunoglobulins and from plasmapheresis. Edrophonium is sometimes used as a diagnostic test for myasthenia. A 2 mg dose is injected intravenously after baseline muscle strength has been measured. If no reaction occurs after 45 seconds, an additional 8 mg may be injected. If the patient has myasthenia gravis, an improvement in muscle strength that lasts about 5 minutes can usually be observed.


Pharmacology_Katzung

Pharmacology_Katzung. Clinical situations in which severe myasthenia (myasthenic crisis) must be distinguished from excessive drug therapy (cholinergic crisis) usually occur in very ill myasthenic patients and must be managed in hospital with adequate emergency support systems (eg, mechanical ventilators) available. Edrophonium can be used to assess the adequacy of treatment with the longer-acting cholinesterase inhibitors usually prescribed in patients with myasthenia gravis. If excessive amounts of cholinesterase inhibitor have been used, patients may become paradoxically weak because of nicotinic depolarizing blockade of the motor end plate. These patients may also exhibit symptoms of excessive stimulation of muscarinic receptors (abdominal cramps, diarrhea, increased salivation, excessive bronchial secretions, miosis, bradycardia). Small doses of edrophonium (1–2 mg intravenously) will produce no relief or even worsen weakness if the patient is receiving excessive cholinesterase inhibitor therapy. On


Pharmacology_Katzung

Pharmacology_Katzung. miosis, bradycardia). Small doses of edrophonium (1–2 mg intravenously) will produce no relief or even worsen weakness if the patient is receiving excessive cholinesterase inhibitor therapy. On the other hand, if the patient improves with edrophonium, an increase in cholinesterase inhibitor dosage may be indicated.


Pharmacology_Katzung

Pharmacology_Katzung. Long-term therapy for myasthenia gravis is usually accomplished with pyridostigmine; neostigmine is an alternative. The doses are titrated to optimum levels based on changes in muscle strength. These drugs are relatively short-acting and therefore require frequent dosing (every 6 hours for pyridostigmine and every 4 hours for neostigmine; Table 7–4). Sustained-release preparations are available but should be used only at night and if needed. Longer-acting cholinesterase inhibitors such as the organophosphate agents are not used, because the dose requirement in this disease changes too rapidly to permit smooth control of symptoms with long-acting drugs. If muscarinic effects of such therapy are prominent, they can be controlled by the administration of antimuscarinic drugs such as atropine. Frequently, tolerance to the muscarinic effects of the cholinesterase inhibitors develops, so atropine treatment is not required.


Pharmacology_Katzung

Pharmacology_Katzung. Neuromuscular blockade is frequently produced as an adjunct to surgical anesthesia, using nondepolarizing neuromuscular relaxants such as pancuronium and newer agents (see Chapter 27). After surgery, it is usually desirable to reverse this pharmacologic paralysis promptly. This can be easily accomplished with cholinesterase inhibitors; neostigmine and edrophonium are the drugs of choice. They are given intravenously or intramuscularly for prompt effect. Some snake venoms have curare-like effects, and the use of neostigmine as a nasal spray is under study to prevent respiratory arrest. D. Heart The short-acting cholinesterase inhibitor edrophonium was used to treat supraventricular tachyarrhythmias, particularly paroxysmal supraventricular tachycardia. In this application, edrophonium has been replaced by newer drugs with different mechanisms (adenosine and the calcium channel blockers verapamil and diltiazem, see Chapter 14). E. Antimuscarinic Drug Intoxication


Pharmacology_Katzung

Pharmacology_Katzung. Atropine intoxication is potentially lethal in children (see Chapter 8) and may cause prolonged severe behavioral disturbances and arrhythmias in adults. The tricyclic antidepressants, when taken in overdosage (often with suicidal intent), also cause severe muscarinic blockade (see Chapter 30). The muscarinic receptor blockade produced by all these agents is competitive in nature and can be overcome by increasing the amount of endogenous acetylcholine at the neuroeffector junctions. Theoretically, a cholinesterase inhibitor could be used to reverse these effects. Physostigmine has been used for this application because it enters the central nervous system and reverses the central as well as the peripheral signs of muscarinic blockade. However, as described below, physostigmine itself can produce dangerous central nervous system effects, and such therapy is therefore used only in patients with dangerous elevation of body temperature or very rapid supraventricular tachycardia (see also


Pharmacology_Katzung

Pharmacology_Katzung. produce dangerous central nervous system effects, and such therapy is therefore used only in patients with dangerous elevation of body temperature or very rapid supraventricular tachycardia (see also Chapter 58).


Pharmacology_Katzung

Pharmacology_Katzung. F. Central Nervous System Tacrine was the first drug with anticholinesterase and other cholinomimetic actions used for the treatment of mild to moderate Alzheimer’s disease. Tacrine’s efficacy is slight, and hepatic toxicity is significant. Donepezil, galantamine, and rivastigmine are newer, more selective acetylcholinesterase inhibitors that appear to have the same marginal clinical benefit as tacrine but with less toxicity in treatment of cognitive dysfunction in Alzheimer’s patients. Donepezil may be given once daily because of its long half-life, and it lacks the hepatotoxic effect of tacrine. However, no trials comparing these newer drugs with tacrine have been reported. These drugs are discussed in Chapter 60. The toxic potential of the cholinoceptor stimulants varies markedly depending on their absorption, access to the central nervous system, and metabolism. A. Direct-Acting Muscarinic Stimulants


Pharmacology_Katzung

Pharmacology_Katzung. The toxic potential of the cholinoceptor stimulants varies markedly depending on their absorption, access to the central nervous system, and metabolism. A. Direct-Acting Muscarinic Stimulants Drugs such as pilocarpine and the choline esters cause predictable signs of muscarinic excess when given in overdosage. These effects include nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, cutaneous vasodilation, and bronchial constriction. The effects are all blocked competitively by atropine and its congeners. Certain mushrooms, especially those of the genus Inocybe, contain muscarinic alkaloids. Ingestion of these mushrooms causes typical signs of muscarinic excess within 15–30 minutes. These effects can be very uncomfortable but are rarely fatal. Treatment is with atropine, 1–2 mg parenterally. (Amanita muscaria, the first source of muscarine, contains very low concentrations of the alkaloid.) B. Direct-Acting Nicotinic Stimulants


Pharmacology_Katzung

Pharmacology_Katzung. B. Direct-Acting Nicotinic Stimulants Nicotine itself is the only common cause of this type of poisoning. (Varenicline toxicity is discussed elsewhere in this chapter.) The acute toxicity of the alkaloid is well defined but much less important than the chronic effects associated with smoking. Nicotine was also used in insecticides but has been replaced by neonicotinoids, synthetic compounds that resemble nicotine only partially in structure. As nicotinic receptor agonists, neonicotinoids are more toxic for insects than for vertebrates. This advantage led to their widespread agricultural use to protect crops. However, there is concern about the role of neonicotinoids in the collapse of bee colonies.


Pharmacology_Katzung

Pharmacology_Katzung. The European Commission imposed a 2-year ban on certain neonicotinoids (clothianidin, imidacloprid, thiamethoxam) in 2013. Their use remains restricted in the European Union until a review of this policy’s effects is completed in January 2017. As of January 2016, the US Fish and Wildlife Service banned neonicotinoid use in wildlife refuges. Neonicotinoids are suspected to contribute to colony collapse disorder because they suppress immunity against bee pathogens including the mite (Varroa destructor) that also serves as a vector for viruses and the Nosema species of fungi that parasitize the gut of bees. Research to ascertain the effect of neonicotinoids on pollinators such as bees and butterflies requires carefully controlled conditions. Neonicotinoid residues have a long half-life (5 months to 3 years) in the soil, and because they are systemic and enter the plant stem, leaves, and flowers, they can present a long-lasting hazard to pollinators. The Australian government’s report on


Pharmacology_Katzung

Pharmacology_Katzung. to 3 years) in the soil, and because they are systemic and enter the plant stem, leaves, and flowers, they can present a long-lasting hazard to pollinators. The Australian government’s report on neonicotinoids and honey bees recounts that Australia is one of a few countries that lack Varroa, which therefore provides an opportunity to test neonicotinoids in the absence of compounds used to treat this mite that contributes to bee pathology.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Acute toxicity—The fatal dose of nicotine is approximately 40 mg, or 1 drop of the pure liquid. This is the amount of nicotine in two regular cigarettes. Fortunately, most of the nicotine in cigarettes is destroyed by burning or escapes via the “sidestream” smoke. Ingestion of nicotine insecticides or of tobacco by infants and children is usually followed by vomiting, limiting the amount of the alkaloid absorbed. The toxic effects of a large dose of nicotine are simple extensions of the effects described previously. The most dangerous are (1) central stimulant actions, which cause convulsions and may progress to coma and respiratory arrest; (2) skeletal muscle end plate depolarization, which may lead to depolarization blockade and respiratory paralysis; and (3) hypertension and cardiac arrhythmias.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment of acute nicotine poisoning is largely symptom-directed. Muscarinic excess resulting from parasympathetic ganglion stimulation can be controlled with atropine. Central stimulation is usually treated with parenteral anticonvulsants such as diazepam. Neuromuscular blockade is not responsive to pharmacologic treatment and may require mechanical ventilation. Fortunately, nicotine is metabolized and excreted relatively rapidly. Patients who survive the first 4 hours usually recover completely if hypoxia and brain damage have not occurred.


Pharmacology_Katzung

Pharmacology_Katzung. Fortunately, nicotine is metabolized and excreted relatively rapidly. Patients who survive the first 4 hours usually recover completely if hypoxia and brain damage have not occurred. 2. Chronic nicotine toxicity—The health costs of tobacco smoking to the smoker and its socioeconomic costs to the general public are still incompletely understood. However, the 1979 Surgeon General’s Report on Health Promotion and Disease Prevention stated that “cigarette smoking is clearly the largest single preventable cause of illness and premature death in the United States.” This statement has been supported by numerous subsequent studies. Unfortunately, the fact that the most important of the tobacco-associated diseases are delayed in onset reduces the health incentive to stop smoking.


Pharmacology_Katzung

Pharmacology_Katzung. Clearly, the addictive power of cigarettes is directly related to their nicotine content. It is not known to what extent nicotine per se contributes to the other well-documented adverse effects of chronic tobacco use. It is highly probable that nicotine contributes to the increased risk of vascular disease and sudden coronary death associated with smoking. In addition, nicotine probably contributes to the high incidence of ulcer recurrences in smokers with peptic ulcer. These effects of smoking are not avoided by the use of electronic cigarettes (“vaping”) since only the nonnicotine components (“tars”) of tobacco are eliminated.


Pharmacology_Katzung

Pharmacology_Katzung. There are several approaches to help patients stop smoking. One approach is replacement therapy with nicotine in the form of gum, transdermal patch, nasal spray, or inhaler. All these forms have low abuse potential and are effective in patients motivated to stop smoking. Their action derives from slow absorption of nicotine that occupies α4β2 receptors in the central nervous system and reduces the desire to smoke and the pleasurable feelings of smoking.


Pharmacology_Katzung

Pharmacology_Katzung. Another quite effective agent for smoking cessation is varenicline, a synthetic drug with partial agonist action at α4β2 nicotinic receptors. Varenicline also has antagonist properties that persist because of its long half-life and high affinity for the receptor; this prevents the stimulant effect of nicotine at presynaptic α4β2 receptors that causes release of dopamine. However, its use is limited by nausea and insomnia and also by exacerbation of psychiatric illnesses, including anxiety and depression. The incidence of adverse neuropsychiatric and cardiovascular events is reportedly low yet post-marketing surveillance continues. The efficacy of varenicline is superior to that of bupropion, an antidepressant (see Chapter 30). Some of bupropion’s efficacy in smoking cessation therapy stems from its noncompetitive antagonism (see Chapter 2) of nicotinic receptors where it displays some selectivity among neuronal subtypes. C. Cholinesterase Inhibitors


Pharmacology_Katzung

Pharmacology_Katzung. C. Cholinesterase Inhibitors The acute toxic effects of the cholinesterase inhibitors, like those of the direct-acting agents, are direct extensions of their pharmacologic actions. The major source of such intoxications is pesticide use in agriculture and in the home. Approximately 100 organophosphate and 20 carbamate cholinesterase inhibitors are available in pesticides and veterinary vermifuges used in the USA. Cholinesterase inhibitors used in agriculture can cause slowly or rapidly developing symptoms, as described in the Case Study, which persist for days. The cholinesterase inhibitors used as chemical warfare agents (soman, sarin, VX) induce effects rapidly because of the large concentrations present.


Pharmacology_Katzung

Pharmacology_Katzung. Acute intoxication must be recognized and treated promptly in patients with heavy exposure. The dominant initial signs are those of muscarinic excess: miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea. Central nervous system involvement (cognitive disturbances, convulsions, and coma) usually follows rapidly, accompanied by peripheral nicotinic effects, especially depolarizing neuromuscular blockade. Therapy always includes (1) maintenance of vital signs—respiration in particular may be impaired; (2) decontamination to prevent further absorption—this may require removal of all clothing and washing of the skin in cases of exposure to dusts and sprays; and (3) atropine parenterally in large doses, given as often as required to control signs of muscarinic excess. Therapy often also includes treatment with pralidoxime, as described in Chapter 8, and administration of benzodiazepines for seizures.


Pharmacology_Katzung

Pharmacology_Katzung. Preventive therapy for cholinesterase inhibitors used as chemical warfare agents has been developed to protect soldiers and civilians. Personnel are given autoinjection syringes containing a carbamate, pyridostigmine, and atropine. Protection is provided by pyridostigmine, which, by prior binding to the enzyme, impedes binding of organophosphate agents and thereby prevents prolonged inhibition of cholinesterase. The protection is limited to the peripheral nervous system because pyridostigmine does not readily enter the central nervous system. Enzyme inhibition by pyridostigmine dissipates within hours (Table 7–4), a duration of time that allows clearance of the organophosphate agent from the body.


Pharmacology_Katzung

Pharmacology_Katzung. Chronic exposure to certain organophosphate compounds, including some organophosphate cholinesterase inhibitors, causes delayed neuropathy associated with demyelination of axons. Triorthocresyl phosphate, an additive in lubricating oils, is the prototype agent of this class. The effects are not caused by cholinesterase inhibition but rather by inhibition of neuropathy target esterase (NTE) whose symptoms (weakness of upper and lower extremities, unsteady gait) appear 1–2 weeks after exposure. Another nerve toxicity called intermediate syndrome occurs 1–4 days after exposure to organophosphate insecticides. This syndrome is also characterized by muscle weakness; its origin is not known but it appears to be related to cholinesterase inhibition. Activates M1, M2, and M3 receptors in all peripheral secretion, smooth muscle contraction (except vascular smooth muscle relaxes), and changes in heart rate Postoperative and neurogenic ileus and urinary retention


Pharmacology_Katzung

Pharmacology_Katzung. Oral and parenteral, duration ~30 min • does not enter central nervous system (CNS) • Toxicity: Excessive parasympathomimetic effects, especially bronchospasm in asthmatics • Interactions: Additive with other parasympathomimetics • Carbachol: Nonselective muscarinic and nicotinic agonist; otherwise similar to bethanechol; used topically almost exclusively for glaucoma DIRECT-ACTING MUSCARINIC ALKALOIDS OR SYNTHETICS •PilocarpineLike bethanechol, partial agonist Like bethanechol Glaucoma; Sjögren’s syndrome Orallozengeandtopical•Toxicity & interactions: Like bethanechol •Cevimeline: Synthetic M3-selective; similar to pilocarpine DIRECT-ACTING NICOTINIC AGONISTS •NicotineAgonist at both NN and NM receptors cessation • nonmedical Oral gum, patch for smoking cessation • Toxicity:


Pharmacology_Katzung

Pharmacology_Katzung. Acutely increased gastrointestinal (GI) activity, • Varenicline: Selective partial agonist at α4β2 nicotinic receptors; used exclusively for smoking cessation •NeostigmineForms covalent bond with AChE, but hydrolyzed and released Like edrophonium, but longer-acting Myasthenia gravis •postoperativeandneurogenic ileus and urinary retention Oral and parenteral; quaternary amine, does not enterCNS.Duration2–4h•Toxicity & interactions: Like edrophonium Pyridostigmine: Like neostigmine, but longer-acting (4–6 h); used in myasthenia Physostigmine: Like neostigmine, but natural alkaloid tertiary amine; enters CNS Like neostigmine, but Like neostigmine, but Topical only • Toxicity: Brow ache, uveitis, blurred Malathion: Insecticide, relatively safe for mammals and birds because metabolized by other enzymes to inactive products; some medical use as ectoparasiticide


Pharmacology_Katzung

Pharmacology_Katzung. Malathion: Insecticide, relatively safe for mammals and birds because metabolized by other enzymes to inactive products; some medical use as ectoparasiticide Parathion, others: Insecticide, dangerous for all animals; toxicity important because of agricultural use and exposure of farm workers (see text) Sarin, others: “Nerve gas,” used exclusively in warfare and terrorism Bethanechol Generic, Urecholine Ophthalmic (topical) Isopto Carbachol, Carboptic Ophthalmic (intraocular) Miostat, Carbastat Cevimeline Generic, Evoxac Transdermal Generic, Nicoderm CQ, Nicotrol Inhalation Nicotrol Inhaler, Nicotrol NS Gum Generic, Commit, Nicorette Ophthalmic (drops)1, 2, 4, 6 Generic, Isopto Carpine Ophthalmic sustained-release Ocusert Pilo-20, Ocusert Pilo-40 inserts CHOLINESTERASE INHIBITORS Donepezil Generic, Aricept Edrophonium Generic, Tensilon Galantamine Generic, Reminyl, Razadyne Neostigmine Generic, Prostigmin Physostigmine Generic, Eserine


Pharmacology_Katzung

Pharmacology_Katzung. CHOLINESTERASE INHIBITORS Donepezil Generic, Aricept Edrophonium Generic, Tensilon Galantamine Generic, Reminyl, Razadyne Neostigmine Generic, Prostigmin Physostigmine Generic, Eserine Pyridostigmine Generic, Mestinon, Regonol Aaron CK: Organophosphates and carbamates. In: Shannon MW, Borron SW, Burns MJ (editors): Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose, 4th ed. Philadelphia: Saunders, 2007:1171. Australian Pesticides and Veterinary Medicines Authority: Overview report: Neonicotinoids and the health of honey bees in Australia. 2014. https:// archive.apvma.gov.au/news_media/chemicals/bee_and_neonicotinoids.php. Benowitz N: Nicotine addiction. N Engl J Med 2010;362:2295. Brito-Zerón P et al: Primary Sjögren syndrome: An update on current pharmacotherapy options and future directions. Expert Opin Pharmacother 2013;14:279.


Pharmacology_Katzung

Pharmacology_Katzung. Brito-Zerón P et al: Primary Sjögren syndrome: An update on current pharmacotherapy options and future directions. Expert Opin Pharmacother 2013;14:279. Cahill K et al: Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Chen L: In pursuit of the high-resolution structure of nicotinic acetylcholine receptors. J Physiol 2010;588:557. Corradi J, Bourzat C: Understanding the bases of function and modulation of α7 nicotinic receptors: Implications for drug discovery. Mol Pharmacol 2016;90:288. Dineley KT, et al: Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol Sci 2015;36:96. Ehlert FJ: Contractile role of M2 and M3 muscarinic receptors in gastrointestinal, airway and urinary bladder smooth muscle. Life Sci 2003;74:355.


Pharmacology_Katzung

Pharmacology_Katzung. Ehlert FJ: Contractile role of M2 and M3 muscarinic receptors in gastrointestinal, airway and urinary bladder smooth muscle. Life Sci 2003;74:355. Ferré S et al: G protein-coupled receptor oligomerization revisited: Functional and pharmacological perspectives. Pharmacol Rev 2014;66:413. Giacobini E (editor): Cholinesterases and Cholinesterase Inhibitors. London: Martin Dunitz, 2000. Gilhus NE: Myasthenia gravis. N Engl J Med 2016;375:2570. Harvey RD, Belevych AE: Muscarinic regulation of cardiac ion channels. Br J Pharmacol 2003;139:1074. Lamping KG et al: Muscarinic (M) receptors in coronary circulation. Arterioscler Thromb Vasc Biol 2004;24:1253. Lazartigues E et al: Spontaneously hypertensive rats cholinergic hyper-responsiveness: Central and peripheral pharmacological mechanisms. Br J Pharmacol 1999;127:1657.


Pharmacology_Katzung

Pharmacology_Katzung. Lazartigues E et al: Spontaneously hypertensive rats cholinergic hyper-responsiveness: Central and peripheral pharmacological mechanisms. Br J Pharmacol 1999;127:1657. Picciotto MR et al: It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Prog Neurobiol 2008;84:329. Richardson CE et al: Megacystis-microcolon-intestinal hypoperistalsis syndrome and the absence of the α3 nicotinic acetylcholine receptor subunit. Gastroenterology 2001;121:350. Sánchez-Bayo F et al: Are bee diseases linked to pesticides?—A brief review. Environ Int 2016;89-90:7. Schroeder C et al: Plasma exchange for primary autoimmune autonomic failure. N Engl J Med 2005;353:1585. The Surgeon General: Smoking and Health. US Department of Health and Human Services, 1979. Tomizawa M, Casida JE: Neonicotinoid insecticide toxicology: Mechanisms of selective action. Annu Rev Pharmacol Toxicol 2005;45:247.


Pharmacology_Katzung

Pharmacology_Katzung. Tomizawa M, Casida JE: Neonicotinoid insecticide toxicology: Mechanisms of selective action. Annu Rev Pharmacol Toxicol 2005;45:247. Wess J et al: Muscarinic acetylcholine receptors: Mutant mice provide new insights for drug development. Nat Rev Drug Discov 2007;6:721. Wing VC et al: Measuring cigarette smoking-induced cortical dopamine release: A [11C]FLB-457 PET study. Neuropsychopharmacology 2015;40:1417.


Pharmacology_Katzung

Pharmacology_Katzung. Wing VC et al: Measuring cigarette smoking-induced cortical dopamine release: A [11C]FLB-457 PET study. Neuropsychopharmacology 2015;40:1417. The patient’s presentation is characteristic of poisoning by organophosphate cholinesterase inhibitors (see Chapter 58). Ask the coworker if he can identify the agent used. Decontami-nate the patient by removal of clothing and washing affected areas. Ensure an open airway and ventilate with oxygen. For muscarinic effects, administer atropine (0.5–5 mg) intrave-nously until signs of muscarinic excess (dyspnea, lacrimation, confusion) subside. To treat nicotinic excess, infuse 2-PAM (initially a 1–2% solution in 15–30 minutes) followed by infu-sion of 1% solution (200–500 mg/h) until muscle fasciculations cease. Respiratory support is required because 2-PAM does not enter the central nervous system and may not reactivate “aged” organophosphate-cholinesterase complex. If needed, decon-taminate the coworker and isolate all contaminated clothing.


Pharmacology_Katzung

Pharmacology_Katzung. Achilles J. Pappano, PhD JH, a 63-year-old architect, complains of urinary symptoms to his family physician. He has hypertension, and during the last 8 years, he has been adequately managed with a thiazide diuretic and an angiotensin-converting enzyme inhibitor. During the same period, JH developed the signs of benign prostatic hypertrophy, which eventually required prostatectomy to relieve symptoms. He now complains that he has an increased urge to urinate as well as urinary fre-quency, and this has disrupted the pattern of his daily life. What do you suspect is the cause of JH’s problem? What information would you gather to confirm your diagnosis? What treatment steps would you initiate?


Pharmacology_Katzung

Pharmacology_Katzung. Cholinoceptor antagonists, like the agonists, are divided into muscarinic and nicotinic subgroups on the basis of their specific receptor affinities. Ganglion blockers and neuromuscular junction blockers make up the antinicotinic drugs. The ganglion-blocking drugs have little clinical use and are discussed at the end of this chapter. Neuromuscular blockers are heavily used and are discussed in Chapter 27. This chapter emphasizes drugs that block muscarinic cholinoceptors.


Pharmacology_Katzung

Pharmacology_Katzung. Five subtypes of muscarinic receptors have been identified, primarily on the basis of data from ligand-binding and cDNA-cloning experiments (see Chapters 6 and 7). A standard terminology (M1 through M5) for these subtypes is now in common use, and evidence—based mostly on selective agonists and antagonists— indicates that functional differences exist between several of these subtypes. The X-ray crystallographic structures of the M1–4 subtypes of muscarinic receptors have been reported. The structures of the M1–4 receptors are very similar in the inactive state with inverse agonist or antagonist bound to the receptor. The binding pocket for orthosteric ligands lies well within the plane of the plasma membrane, and the amino acids composing the site are conserved among muscarinic receptor subtypes. This observation underscores the difficulty in identifying subtype-selective ligands. A structure forming a “lid” separates the orthosteric binding site from an upper cavity termed the


Pharmacology_Katzung

Pharmacology_Katzung. subtypes. This observation underscores the difficulty in identifying subtype-selective ligands. A structure forming a “lid” separates the orthosteric binding site from an upper cavity termed the “vestibule” (Figure 8–1). The binding site for allosteric ligands is the extracellular vestibule. Among the receptor subtypes, the extracellular vestibule is comprised of different amino acids that provide distinctive sites for binding by selective allosteric modulators. The M1 receptor subtype is located on central nervous system (CNS) neurons, autonomic postganglionic cell bodies, and many presynaptic sites. M2 receptors are located in the myocardium, smooth muscle organs, and some neuronal sites. M3 receptors are most common on effector cell membranes, especially glandular and smooth muscle cells. M4 and M5 receptors are less prominent and appear to play a greater role in the CNS than in the periphery.


Pharmacology_Katzung

Pharmacology_Katzung. Muscarinic antagonists are sometimes called parasympatholytic because they block the effects of parasympathetic autonomic discharge. However, the term “antimuscarinic” is preferable. Naturally occurring compounds with antimuscarinic effects have been known and used for millennia as medicines, poisons, and cosmetics. Atropine is the prototype of these drugs. Many similar FIGURE 8–1 Upper portion of the M3 receptor with a “lid” formed by tyrosine (Tyr) residues separating the cavity into an upper portion called the vestibule from the lower portion, with the orthosteric binding site depicted as occupied by tiotropium. The receptor is in black, tiotropium is in yellow, and the receptor surface is in green. (Adapted, with permission, from Kruse AC et al: Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature 2012;482:552. Copyright © 2012 Macmillan Publishers Ltd.) plant alkaloids are known, and hundreds of synthetic antimuscarinic compounds have been prepared.


Pharmacology_Katzung

Pharmacology_Katzung. A. Source and Chemistry Atropine and its naturally occurring congeners are tertiary amine alkaloid esters of tropic acid (Figure 8–2). Atropine (hyoscyamine) is found in the plant Atropa belladonna, or deadly nightshade, and in Datura stramonium, also known as jimson-weed (Jamestown weed), sacred Datura, or thorn apple. Scopolamine (hyoscine) occurs in Hyoscyamus niger, or henbane, as the l(−) stereoisomer. FIGURE 8–2 The structure of atropine (oxygen [red] at [1] is missing) or scopolamine (oxygen present). In homatropine, the hydroxymethyl at [2] is replaced by a hydroxyl group, and the oxygen at [1] is absent. Naturally occurring atropine is l(−)-hyoscyamine, but the compound readily racemizes, so the commercial material is racemic d,l-hyoscyamine. The l(−) isomers of both alkaloids are at least 100 times more potent than the d(+) isomers.


Pharmacology_Katzung

Pharmacology_Katzung. A variety of semisynthetic and fully synthetic molecules have antimuscarinic effects. The tertiary members of these classes (Figure 8–3) are often used for their effects on the eye or the CNS. Many antihistaminic (see Chapter 16), antipsychotic (see Chapter 29), and antidepressant (see Chapter 30) drugs have similar structures and, predictably, significant antimuscarinic effects. Quaternary amine antimuscarinic agents (Figure 8–3) have been developed to produce more peripheral effects and reduced CNS effects. B. Absorption Natural alkaloids and most tertiary antimuscarinic drugs are well absorbed from the gut and conjunctival membranes. When applied in a suitable vehicle, some (eg, scopolamine) are even absorbed across the skin (transdermal route). In contrast, only 10–30% of a dose of a quaternary antimuscarinic drug is absorbed after oral administration, reflecting the decreased lipid solubility of the charged molecule. C. Distribution


Pharmacology_Katzung

Pharmacology_Katzung. C. Distribution Atropine and the other tertiary agents are widely distributed in the body. Significant levels are achieved in the CNS within 30 minutes to 1 hour, and this can limit the dose tolerated when the drug is taken for its peripheral effects. Scopolamine is rapidly and fully distributed into the CNS where it has greater effects than most other antimuscarinic drugs. In contrast, the quaternary derivatives are poorly taken up by the brain and therefore are relatively free—at low doses—of CNS effects. D. Metabolism and Excretion


Pharmacology_Katzung

Pharmacology_Katzung. D. Metabolism and Excretion After administration, the elimination of atropine from the blood occurs in two phases: the half-life (t1/2) of the rapid phase is 2 hours and that of the slow phase is approximately 13 hours. About 50% of the dose is excreted unchanged in the urine. Most of the rest appears in the urine as hydrolysis and conjugation products. The drug’s effect on parasympathetic function declines rapidly in all organs except the eye. Effects on the iris and ciliary muscle persist for ≥ 72 hours. A. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. A. Mechanism of Action Atropine causes reversible (surmountable) blockade (see Chapter 2) of cholinomimetic actions at muscarinic receptors; that is, blockade by a small dose of atropine can be overcome by a larger concentration of acetylcholine or equivalent muscarinic agonist. Mutation experiments suggest that aspartate in the third trans-membrane segment of the heptahelical receptor forms an ionic bond with the nitrogen atom of acetylcholine; this amino acid is also required for binding of antimuscarinic drugs. When atropine binds to the muscarinic receptor, it prevents actions such as the Quaternary amines for gastrointestinal and pulmonary applications (peptic disease, COPD): Tropicamide Dicyclomine (mydriatric, cycloplegic) (peptic disease, hypermotility) Quaternary amine for use in asthma: Tertiary amine for Parkinson’s disease: FIGURE 8–3 Structures of some semisynthetic and synthetic antimuscarinic drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Quaternary amine for use in asthma: Tertiary amine for Parkinson’s disease: FIGURE 8–3 Structures of some semisynthetic and synthetic antimuscarinic drugs. release of inositol trisphosphate (IP3) and the inhibition of adenylyl cyclase that are caused by muscarinic agonists (see Chapter 7). Muscarinic antagonists were traditionally viewed as neutral compounds that occupied the receptor and prevented agonist binding. Recent evidence indicates that muscarinic receptors are constitutively active, and most drugs that block the actions of acetylcholine are inverse agonists (see Chapter 1) that shift the equilibrium to the inactive state of the receptor. Muscarinic blocking drugs that are inverse agonists include atropine, pirenzepine, trihexyphenidyl, AF-DX 116, 4-DAMP, ipratropium, glycopyrrolate, and a methyl derivative of scopolamine (Table 8–1).


Pharmacology_Katzung

Pharmacology_Katzung. The effectiveness of antimuscarinic drugs varies with the tissue and with the source of agonist. Tissues most sensitive to atropine are the salivary, bronchial, and sweat glands. Secretion of acid by the gastric parietal cells is the least sensitive. In most tissues, antimuscarinic agents block exogenously administered cholinoceptor agonists more effectively than endogenously released acetylcholine. Atropine is highly selective for muscarinic receptors. Its potency at nicotinic receptors is much lower, and actions at nonmuscarinic receptors are generally undetectable clinically. Atropine does not distinguish among the M1, M2, and M3 subgroups of muscarinic receptors. In contrast, other antimuscarinic drugs are moderately selective for one or another of these subgroups (Table 8–1). Most synthetic antimuscarinic drugs are considerably less selective than atropine in interactions with TABLE 8–1 Muscarinic receptor subgroups important in peripheral tissues and their antagonists.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 8–1 Muscarinic receptor subgroups important in peripheral tissues and their antagonists. 1In clinical use as an intestinal antispasmodic agent. 2In clinical use in the treatment of Parkinson’s disease. 3In clinical use as a neuromuscular blocking agent (obsolete). 4Compound used in research only. 5Relative to atropine. Smaller numbers indicate higher affinity. AF-DX 116, 11-({2-[(diethylamino)methyl]-1-piperidinyl}acetyl)-5,11-dihydro-6H-pyrido-[2,3-b](1,4)benzodiazepine-6-one; DAG, diacylglycerol; IP3, inositol trisphosphate; 4-DAMP, 4-diphenylacetoxy-N-methylpiperidine. nonmuscarinic receptors. For example, some quaternary amine antimuscarinic agents have significant ganglion-blocking actions, and others are potent histamine receptor blockers. The antimuscarinic effects of other agents, eg, antipsychotic and antidepressant drugs, have been mentioned. Their relative selectivity for muscarinic receptor subtypes has not been defined.


Pharmacology_Katzung

Pharmacology_Katzung. B. Organ System Effects 1. Central nervous system—In the doses usually used, atropine has minimal stimulant effects on the CNS, especially the parasympathetic medullary centers, and a slower, longer-lasting sedative effect on the brain. Scopolamine has more marked central effects, producing drowsiness when given in recommended dosages and amnesia in sensitive individuals. In toxic doses, scopolamine, and to a lesser degree atropine, can cause excitement, agitation, hallucinations, and coma.


Pharmacology_Katzung

Pharmacology_Katzung. The tremor of Parkinson’s disease is reduced by centrally acting antimuscarinic drugs, and atropine—in the form of belladonna extract—was one of the first drugs used in the therapy of this disease. As discussed in Chapter 28, parkinsonian tremor and rigidity seem to result from a relative excess of cholinergic activity because of a deficiency of dopaminergic activity in the basal ganglia-striatum system. The combination of an antimuscarinic agent with a dopamine precursor drug (levodopa) can sometimes provide more effective therapy than either drug alone. Vestibular disturbances, especially motion sickness, appear to involve muscarinic cholinergic transmission. Scopolamine is often effective in preventing or reversing these disturbances.


Pharmacology_Katzung

Pharmacology_Katzung. Vestibular disturbances, especially motion sickness, appear to involve muscarinic cholinergic transmission. Scopolamine is often effective in preventing or reversing these disturbances. 2. Eye—The pupillary constrictor muscle (see Figure 6–9) depends on muscarinic cholinoceptor activation. This activation is blocked by topical atropine and other tertiary antimuscarinic drugs and results in unopposed sympathetic dilator activity and mydriasis (Figure 8–4). Dilated pupils were considered cosmetically desirable during the Renaissance and account for the name belladonna (Italian, “beautiful lady”) applied to the plant and its active extract because of the use of the extract as eye drops during that time. The second important ocular effect of antimuscarinic drugs is to weaken contraction of the ciliary muscle, or cycloplegia. Cycloplegia results in loss of the ability to accommodate; the fully atropinized eye cannot focus for near vision (Figure 8–4).


Pharmacology_Katzung

Pharmacology_Katzung. Both mydriasis and cycloplegia are useful in ophthalmology. They are also potentially hazardous, since acute glaucoma may be induced in patients with a narrow anterior chamber angle. A third ocular effect of antimuscarinic drugs is to reduce lacrimal secretion. Patients occasionally complain of dry or “sandy” eyes when receiving large doses of antimuscarinic drugs.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Cardiovascular system—The sinoatrial node is very sensitive to muscarinic receptor blockade. Moderate to high therapeutic doses of atropine cause tachycardia in the innervated and spontaneously beating heart by blockade of vagal slowing. However, lower doses often result in initial bradycardia before the effects of peripheral vagal block become manifest (Figure 8–5). This slowing may be due to block of prejunctional M1 receptors (autoreceptors, see Figures 6–3 and 7–4A) on vagal postganglionic fibers that normally limit acetylcholine release in the sinus node and other tissues. The same mechanisms operate in the atrioventricular node; in the presence of high vagal tone, atropine can significantly reduce the PR interval of the electrocardiogram by blocking muscarinic receptors in the atrioventricular node. Muscarinic effects on atrial muscle are similarly blocked, but these


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 8–4 Effects of topical scopolamine drops on pupil diameter (mm) and accommodation (diopters) in the normal human eye. One drop of 0.5% solution of drug was applied at zero time, and a second drop was administered at 30 minutes (arrows). The responses of 42 eyes were averaged. Note the extremely slow recovery. (Reproduced, with permission, from Marron J: Cycloplegia and mydriasis by use of atropine, scopolamine, and homatropine-paredrine. Arch Ophthalmol 1940;23:340. Copyright © 1940 American Medical Association. All rights reserved.) effects are of no clinical significance except in atrial flutter and arteries, and sympathetic cholinergic nerves cause vasodilation in fibrillation. The ventricles are less affected by antimuscarinic drugs the skeletal muscle vascular bed (see Chapter 6). Atropine can at therapeutic levels because of a lesser degree of vagal control. In block this vasodilation. Furthermore, almost all vessels contain toxic concentrations, the drugs can cause


Pharmacology_Katzung

Pharmacology_Katzung. 6). Atropine can at therapeutic levels because of a lesser degree of vagal control. In block this vasodilation. Furthermore, almost all vessels contain toxic concentrations, the drugs can cause intraventricular conduc-endothelial muscarinic receptors that mediate vasodilation (see tion block that has been attributed to a local anesthetic action. Chapter 7). These receptors are readily blocked by antimuscarinic


Pharmacology_Katzung

Pharmacology_Katzung. Most blood vessels, except those in thoracic and abdominal vis-drugs. At toxic doses, and in some individuals at normal doses, cera, receive no direct innervation from the parasympathetic sys-antimuscarinic agents cause cutaneous vasodilation, especially in tem. However, parasympathetic nerve stimulation dilates coronary the upper portion of the body. The mechanism is unknown. 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)


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. Antimuscarinic drugs have marked effects on salivary secretion; dry mouth occurs frequently in patients taking antimuscarinic drugs for Parkinson’s disease or urinary conditions (Figure 8–6). Gastric secretion is blocked less effectively: the volume and amount of acid, pepsin, and mucin are all reduced, but large doses of atropine may be required. Basal secretion is blocked more effectively than that stimulated by food, nicotine, or alcohol. Pirenzepine and a more potent analog, telenzepine, reduce gastric acid secretion with fewer adverse effects than atropine and other less selective agents. This was thought to result from a selective blockade of excitatory M1 muscarinic receptors on vagal ganglion cells innervating the stomach, as suggested by their high ratio of M1 to M3 affinity (Table 8–1). However, carbachol was found to stimulate gastric acid secretion in animals with M1 receptors knocked out; M3 receptors were implicated and pirenzepine opposed this effect of carbachol, an


Pharmacology_Katzung

Pharmacology_Katzung. 8–1). However, carbachol was found to stimulate gastric acid secretion in animals with M1 receptors knocked out; M3 receptors were implicated and pirenzepine opposed this effect of carbachol, an indication that pirenzepine is selective but not specific for M1 receptors. The mechanism of vagal 0.5 1.0 2.0 mg


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 8–6 Effects of subcutaneous injection of atropine on salivation, speed of micturition (voiding), heart rate, and accommodation in normal adults. Note that salivation is the most sensitive of these variables, accommodation the least. (Data from Herxheimer A: Br J Pharmacol 1958;13:184.) regulation of gastric acid secretion likely involves multiple muscarinic receptor-dependent pathways. Pirenzepine and telenzepine are investigational in the USA. Pancreatic and intestinal secretion are little affected by atropine; these processes are primarily under hormonal rather than vagal control.


Pharmacology_Katzung

Pharmacology_Katzung. Gastrointestinal smooth muscle motility is affected from the stomach to the colon. In general, antimuscarinic drugs diminish the tone and propulsive movements; the walls of the viscera are relaxed. Therefore, gastric emptying time is prolonged, and intestinal transit time is lengthened. Diarrhea due to overdosage with parasympathomimetic agents is readily stopped, and even diarrhea caused by nonautonomic agents can usually be temporarily controlled. However, intestinal “paralysis” induced by antimuscarinic drugs is temporary; local mechanisms within the enteric nervous system usually reestablish at least some peristalsis after 1–3 days of antimuscarinic drug therapy. 6.


Pharmacology_Katzung

Pharmacology_Katzung. 6. Genitourinary tract—The antimuscarinic action of atropine and its analogs relaxes smooth muscle of the ureters and bladder wall and slows voiding (Figure 8–6). This action is useful in the treatment of spasm induced by mild inflammation, surgery, and certain neurologic conditions, but it can precipitate urinary retention in men who have prostatic hyperplasia (see following section, Clinical Pharmacology of the Muscarinic Receptor-Blocking Drugs). The antimuscarinic drugs have no significant effect on the uterus. 7. Sweat glands—Atropine suppresses thermoregulatory sweating. Sympathetic cholinergic fibers innervate eccrine sweat glands, and their muscarinic receptors are readily accessible to antimuscarinic drugs. In adults, body temperature is elevated by this effect only if large doses are administered, but in infants and children, even ordinary doses may cause “atropine fever.”


Pharmacology_Katzung

Pharmacology_Katzung. The antimuscarinic drugs have applications in several of the major organ systems and in the treatment of poisoning by muscarinic agonists. A. Central Nervous System Disorders 1. Parkinson’s disease—The treatment of Parkinson’s disease (see Chapter 28) is often an exercise in polypharmacy, since no single agent is fully effective over the course of the disease. Most antimuscarinic drugs promoted for this application (see Table 28–1) were developed before levodopa became available. Their use is accompanied by all of the adverse effects described below, but the drugs remain useful as adjunctive therapy in some patients. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Motion sickness—Certain vestibular disorders respond to antimuscarinic drugs (and to antihistaminic agents with antimuscarinic effects). Scopolamine is one of the oldest remedies for seasickness and is as effective as any more recently introduced agent. It can be given by injection or by mouth or as a transdermal patch. The patch formulation produces significant blood levels over 48–72 hours. Useful doses by any route usually cause significant sedation and dry mouth. B. Ophthalmologic Disorders