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Chapter: Modern Pharmacology with Clinical Applications: Directly and Indirectly Acting Cholinomimetics

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Direct-Acting Parasympathomimetic Drugs

Acetylcholine is an ester of choline and acetic acid, the prototype for a small family of choline ester compounds.

DIRECT-ACTING PARASYMPATHOMIMETIC DRUGS

Acetylcholine

Acetylcholine is an ester of choline and acetic acid, the prototype for a small family of choline ester com-pounds. The choline moiety of ACh contains a quater-nary ammonium group that gives ACh a permanent positive charge, making it very hydrophilic and mem-brane impermeant.


ACh is degraded by a group of enzymes called cholinesterases. These enzymes catalyze the hydrolysis of ACh to choline and acetic acid (Fig. 12.1). The active center of cholinesterase has two areas that interact with ACh: the anionic site and the esteratic site. The anionic site contains a negatively charged amino acid that binds the positively charged quaternary ammonium group of ACh through coulombic forces. This probably serves to bring the ester linkage of ACh close to the esteratic site of the enzyme. The esteratic site contains a serine residue, which is made more reactive by hydrogen bonding to a nearby histidine residue. The nucleophilic oxygen of the serine reacts with the carbonyl carbon of ACh, thereby breaking the ester linkage. During this re-action, choline is liberated and an acetylated enzyme is formed. The latter intermediate is rapidly hydrolyzed to release acetic acid and regenerate the active enzyme. The entire process takes about 150 microseconds, one of the fastest enzymatic reactions known.

There are two major types of cholinesterases: acetylcholinesterase (AChE) and pseudocholinesterase (pseudo-ChE). AChE (also known as true, specific, or erythrocyte cholinesterase) is found at a number of sites in the body, the most important being the cholinergic neuroeffector junction. Here it is localized to the pre-junctional and postjunctional membranes, where it rap-idly terminates the action of synaptically released ACh. It is essential to recognize that the action of ACh is terminated only by its hydrolysis.  

There is no reuptake sys-tem in cholinergic nerve terminals to reduce the con-centration of ACh in a synaptic cleft, unlike the reup-take systems for other neurotransmitters such as dopamine, serotonin, and norepinephrine. Therefore, in-hibition of AChE can greatly prolong the activation of cholinoreceptors by ACh released at a synapse.

Pseudo-ChE (also known as butyryl-, plasma, and nonspecific cholinesterase) has a widespread distribu-tion, with enzyme especially abundant in the liver, where it is synthesized, and in the plasma. In spite of the abundance of pseudo-ChE, its physiological function has not been definitively identified. It does, however, play an important role in the metabolism of such clini-cally important compounds as succinylcholine, pro-caine, and numerous other esters.

Derivatives of ACh: Methacholine, Carbachol, and Bethanechol

The therapeutic usefulness of ACh is limited by (1) its lack of selectivity as an agonist for different types of choli-noreceptors and (2) its rapid degradation by cholin-esterases. These limitations have been circumvented in part by the development of three choline ester derivatives of ACh: methacholine (Provocholine), carbachol (Isopto Carbachol, Miostat) and bethanechol (Urecholine). Methacholine differs from ACh only in the addition of a methyl group at the -carbon of ACh. This modification greatly increases its selectivity for muscarinic receptors relative to nicotinic receptors, and it renders methacholine resistant to the pseudo-ChE in the plasma and decreases its susceptibility to AChE, thereby increasing its potency and duration of action compared to those of ACh. Carbachol differs from ACh only in the substitution of a carbamoyl group for the terminal methyl group of ACh. This substitution makes carbachol completely resistant to degradation by cholinesterases but does not improve its selectivity for muscarinic versus nicotinic receptors. Bethanechol combines the addition of the methyl group and the substitution of the terminal carbamoyl group, pro-ducing a drug that is a selective agonist of muscarinic re-ceptors and is resistant to degradation by cholinesterases.

All of these drugs are very hydrophilic and mem-brane impermeant because they retain the quaternary ammonium group of the choline moiety of ACh.

Pilocarpine is a naturally occurring cholinomimetic alkaloid that is structurally distinct from the choline es-ters. It is a tertiary amine that crosses membranes rela-tively easily. Therefore, it is rapidly absorbed by the cornea of the eye, and it can cross the blood-brain bar-rier. Pilocarpine is a pure muscarinic receptor agonist, and it is unaffected by cholinesterases. Muscarine is an alkaloid with no therapeutic use, but it can produce dangerous cholinomimetic stimulation following inges-tion of some types of mushrooms (e.g., Inocybes).

Basic Pharmacology of the Directly Acting Parasympathomimetic Drugs

Methacholine, bethanechol, and pilocarpine are selec-tive agonists of muscarinic receptors, whereas carbachol and ACh can activate both muscarinic and nicotinic re-ceptors. However, at usual therapeutic doses, the effects of carbachol and ACh are entirely due to the activation of muscarinic receptors. This apparent preference for muscarinic receptors can be attributed to the greater ac-cessibility and abundance of these cholinoreceptors compared with the nicotinic receptors.

Cardiovascular Effects

Low doses of muscarinic agonists given intravenously relax arterial smooth muscle and produce a fall in bloodpressure. These responses result from the stimulation of muscarinic receptors on vascular endothelial cells (Fig. 12.2). Activation of these receptors causes the endothe-lial cells to synthesize and release nitric oxide. Nitric ox-ide can diffuse into neighboring vascular smooth muscle cells, where it activates soluble guanylyl cyclase, thereby increasing the synthesis of cyclic guanosine monophos-phate (cGMP) and relaxing the muscle fibers. Most of the resistance vasculature is not innervated by choliner-gic neurons, and the physiological function of the en-dothelial muscarinic receptors is not known. However, activation of these receptors by directly acting choli-nomimetic drugs has major pharmacological signifi-cance, as the potentially dangerous hypotension pro-duced by their activation is an important limitation to the systemic administration of muscarinic agonists.


Although the release of ACh onto the heart by the vagus nerve slows the heart rate, a low dose of a mus-carinic agonist can sometimes increase the heart rate. This paradoxical effect is produced when the decrease in blood pressure produced by stimulation of endothe-lial muscarinic receptors, as described earlier, triggers the activation of a compensatory sympathetic reflex stimulation of the heart. Sympathetic stimulation in-creases heart rate and vasomotor tone, partially coun-teracting the direct vasodilator response. Therefore, the tachycardia produced by muscarinic agonists is indirect. At higher concentrations of a muscarinic agonist, the di-rect effects on cardiac muscarinic (M2) receptors in the SA node and A-V fibers become dominant. 

Activation of M2 receptors increases the potassium permeability and reduces cAMP levels, slowing the rate of depolar-ization and decreasing the excitability of SA node and A-V fiber cells. This results in marked bradycardia and a slowing of A-V conduction that can override the stim-ulation of the heart by catecholamines released during sympathetic stimulation. In fact, very high doses of a muscarinic agonist can produce lethal bradycardia and A-V block. Choline esters have relatively minor direct effects on ventricular function, but they can produce negative inotropy of the atria.

The Eye

When solutions of directly acting cholinomimetics are applied to the eye (i.e., conjunctival sac), they cause contraction of the smooth muscle in two important structures, the iris sphincter and the ciliary muscles (Fig. 12.3). Contraction of the iris sphincter decreases the di-ameter of the pupil (miosis). Contraction of the circular fibers of the ciliary muscle, which encircles the lens, re-duces the tension on the suspensory ligaments that nor-mally stretch and flatten the lens, allowing the highly elastic lens to spontaneously round up and focus for near vision (accommodation to near vision).


Other Organ Systems

Prominent effects within the digestive tract include stimulation of salivation and acid secretion, increased intestinal tone and peristaltic activity, and relaxation of most sphincters. Bronchoconstriction and stimulation of secretions are prominent effects in the respiratory sys-tem. Muscarinic agonists can also evoke secretion from nasopharyngeal glands. Urination is promoted by stim-ulation of the detrusor muscle of the bladder and is fa-cilitated by relaxation of the trigone and external sphincter muscles.

Clinical Uses

Glaucoma

Cholinomimetic drugs are useful for treating glaucoma because they can decrease the resistance to the move-ment of fluid (aqueous humor) out of the eye (Fig. 12.3), thereby reducing the intraocular pressure. It is useful to distinguish between open-angle glaucoma, a chronic condition in which the porosity of the trabecular mesh-work is insufficient to permit the movement of fluid into the canal of Schlemm, and angle-closure glaucoma, an emergency condition in which an abnormal position of the peripheral iris blocks the access of fluid to the tra-becular meshwork. Open-angle glaucoma can be effec-tively treated with cholinomimetics such as pilocarpine and carbachol, because contraction of the ciliary muscle stretches the trabecular network, increasing its porosity and permeability to the outflow of fluid. 

This beneficial effect, however, comes at the price of a spasm of ac-commodation and miosis, which seriously disturb vi-sion. Cholinomimetics, therefore, have been replaced by β-blockers and carbonic anhydrase inhibitors, both of which decrease the formation of aqueous humor with-out affecting vision. However, some patients simply do not respond to these treatments or do not tolerate the cardiovascular side effects of the β-blockers, and choli-nomimetics (most notably pilocarpine) remain as im-portant treatment alternatives.

Contraction of the iris sphincter (miosis) by choli-nomimetic stimulation is less important than contrac-tion of the ciliary muscle for treating angle-closure glau-coma, but it may be essential as emergency therapy for acute-angle glaucoma to reduce intraocular pressure prior to surgery (iridectomy). Contraction of the iris sphincter by pilocarpine pulls the peripheral iris away from the trabecular meshwork, thereby opening the path for aqueous outflow.

Pilocarpine is the first choice among cholinomimet-ics for the treatment of glaucoma. Pilocarpine can be applied to the eye as a gel (Pilopine HS Gel) or time-release system (Ocusert) for the chronic treatment of open-angle glaucoma, or as drops (Pilocar) for an acute reduction of intraocular pressure, as in the emergency management of angle-closure glaucoma. Carbachol is sometimes effective in treating cases of open-angle glaucoma that are resistant to pilocarpine.

Surgery of the Eye

Because ACh is rapidly inactivated by cholinesterases, its use is best suited for clinical applications requiring only a brief duration of action, such as when it is em-ployed to cause miosis during cataract surgery. Ach (Miochol) can produce a brief (10 minutes) miosis, and carbachol is used during eye surgery necessitating mio-sis of a longer duration.

Urinary Retention

Bethanechol is used to treat postsurgical bladder dys-function associated with the retention of urine. It is most commonly given orally for this purpose, although the subcutaneous route is also used. Effects are more rapid and intense after subcutaneous administration, but the duration of action is shorter.

Diagnosis of Bronchial Hyperreactivity

Methacholine is used to identify bronchial hyperreac-tivity in patients without clinically apparent asthma. For this indication, the drug is administered by inhalation, and patients who may be developing asthma usually produce an exaggerated airway contraction. Upon com-pletion of the test, a rapid-acting bronchodilator (e.g., inhaled β-adrenoceptor agonist) can be given to counter the bronchoconstrictor effect of methacholine and relieve the patient’s discomfort.

Adverse Effects

Potentially severe adverse effects can result from sys-temic administration of cholinomimetic drugs, and none should be administered by intramuscular or intra-venous injection. If significant amounts of these drugs enter the circulation, nausea, abdominal cramps, diar-rhea, salivation, hypotension with reflex tachycardia, cu-taneous vasodilation, sweating, and bronchoconstric-tion can result. Pilocarpine can cross the blood-brain barrier and affect cognitive function. Even the topical application of cholinomimetics to the eyes can present some risk, and the escape of cholinomimetics into the circulatory system following topical application to the eye can be minimized by pressure applied to the lacrimal duct. Within the eye, cholinomimetics elicit miosis and spasm of accommodation, both of which dis-turb vision.

Bethanechol is relatively selective in activating choli-noreceptors in the gastrointestinal and urinary tracts when taken orally, but it is less selective when given sub-cutaneously, and it is very dangerous when given intra-muscularly or intravenously, having the potential to pro-duce circulatory collapse and cardiac arrest. Systemic poisoning with cholinomimetics can be treated with the muscarinic receptor antagonist atropine.

Bethanechol should not be used in patients with pos-sible mechanical obstruction of the bladder or gastroin-testinal tract or when contraction of smooth muscles in these tissues may be harmful (e.g., recent intestinal re-section). It is also contraindicated in patients with bronchial asthma, peptic ulcer disease, coronary artery disease, gastrointestinal hypermotility or inflammatory disease, hypotension or marked bradycardia, hyperthy-roidism, parkinsonism, or epilepsy. Care should be exer-cised in administering pilocarpine to elderly patients be-cause it can enter the CNS and affect memory and cognition, even when applied topically to the eye. 

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