Cholinergic drugs 1

Cholinergic Drugs

Cholinomimetic Choline Esters and Natural Alkaloids

Muscarinic cholinergic receptor agonists can be divided into two groups: (1) ACh and several synthetic choline esters, and (2) the naturally occurring cholinomimetic alkaloids (particularly pilocarpine, muscarine, and arecoline) and their synthetic congeners.

Methacholine (acetyl--methylcholine) differs from ACh chiefly in its greater duration and selectivity of action. Its action is more prolonged because the added methyl group increases its resistance to hydrolysis by cholinesterases. Its selectivity is manifested by slight nicotinic and a predominance of muscarinic actions, the latter being manifest in the cardiovascular system (Table 7–1).

Table 7–1 Some Pharmacological Properties of Choline Esters and Natural Alkaloids



MUSCARINIC ACTIVITY
MUSCARINIC AGONIST SUSCEPTIBILITY TO CHOLINESTERASES Cardiovascular Gastrointestinal Urinary Bladder Eye (Topical) Antagonism by Atropine NICOTINIC ACTIVITY
Acetylcholine +++ ++ ++ ++ + +++ ++
Methacholine + +++ ++ ++ + +++ +
Carbachol – + +++ +++ ++ + +++
Bethanechol – ± +++ +++ ++ +++ –
Muscarine – ++ +++ +++ ++ +++ –
Pilocarpine – + +++ +++ ++ +++ –




Carbachol and bethanechol, which are unsubstituted carbamoyl esters, are completely resistant to hydrolysis by cholinesterases; their half-lives are thus sufficiently long that they become distributed to areas of low blood flow. Bethanechol has mainly muscarinic actions, showing some selectivity on gastrointestinal tract and urinary bladder motility. Carbachol retains substantial nicotinic activity, particularly on autonomic ganglia. It is likely that both its peripheral and its ganglionic actions are due, at least in part, to the release of endogenous ACh from the terminals of cholinergic fibers.

The three major natural alkaloids in this group—pilocarpine, muscarine, and arecoline—have the same principal sites of action as the choline esters discussed above. Muscarine acts almost exclusively at muscarinic receptor sites, and the classification of the receptors as such is derived from this fact. Arecoline also acts at nicotinic receptors. Pilocarpine has a dominant muscarinic action, but it causes anomalous cardiovascular responses; the sweat glands are particularly sensitive to the drug. Although these naturally occurring alkaloids are of great value as pharmacological tools, present clinical use is restricted largely to the employment of pilocarpine as a sialagogue and miotic agent


Pharmacological Properties

Gastrointestinal Tract

All muscarinic agonists are capable of stimulating smooth muscle of the gastrointestinal tract, thereby increasing tone and motility; large doses will cause spasm and tenesmus. Unlike methacholine, carbachol, bethanechol, and pilocarpine stimulate the GI tract without significant cardiovascular effects.

Urinary Tract

The choline esters and pilocarpine contract the detrusor muscle of the bladder, increase voiding pressure, decrease bladder capacity, and increase ureteral peristalsis. In addition, the trigone and external sphincter muscles relax. Selectivity for bladder stimulation relative to cardiovascular activity is evident for bethanechol. In animals with experimental spinal cord lesions, muscarinic agonists promote evacuation of the bladder (Yoshimura et al., 2000).

Exocrine Glands

The choline esters and muscarinic alkaloids stimulate secretion of glands that receive parasympathetic or sympathetic cholinergic innervation, including the lacrimal, salivary, digestive, tracheobronchial, and sweat glands. Pilocarpine in particular causes marked diaphoresis in human beings; 2 to 3 liters of sweat may be secreted. Salivation also is increased markedly. Oral administration of pilocarpine causes a more continuous production of saliva. Muscarine and arecoline also are potent diaphoretic agents. Accompanying side effects may include hiccough, salivation, nausea, vomiting, weakness, and occasionally collapse. These alkaloids also stimulate the lacrimal, gastric, pancreatic, and intestinal glands, and the mucous cells of the respiratory tract.

Respiratory System

In addition to tracheobronchial secretions, bronchial smooth muscle is stimulated by the muscarinic agonists. Asthmatic patients respond with intense bronchoconstriction, secretions, and a reduction in vital capacity. These actions form the basis of the methacholine challenge test used to diagnose airway hyperreactivity.

Cardiovascular System

Continuous intravenous infusion of methacholine elicits hypotension and bradycardia, just as ACh does but at 1/200 the dose. Muscarine, at small doses, also leads to a marked fall in blood pressure and a slowing or temporary cessation of the heartbeat. In contrast, carbachol and bethanechol generally cause only a transient fall in blood pressure at doses that affect the gastrointestinal and urinary tracts. Likewise, pilocarpine produces only a brief fall in blood pressure. However, if this is preceded by an appropriate dose of a nicotinic receptor antagonist, pilocarpine produces a marked rise in pressure. Both the vasodepressor and pressor responses are prevented by atropine; the latter effect also is abolished by adrenergic receptor antagonists. These actions of pilocarpine have not been fully explained, but may arise from ganglionic and adrenomedullary stimulation.

Eye

Muscarinic agonists stimulate the pupillary constrictor and ciliary muscles when applied locally to the eye, causing pupil constriction and a loss of ability to accommodate to far vision.

Central Nervous System

The intravenous injection of relatively small doses of pilocarpine, muscarine, or arecoline evokes a characteristic cortical arousal or activation response in cats, similar to that produced by injection of anticholinesterase agents or by electrical stimulation of the brainstem reticular formation. The arousal response to all of these drugs is reduced or blocked by atropine and related agents (Krnjev?c, 1974). Being quaternary, the choline esters do not cross the blood–brain barrier.

Therapeutic Uses

Acetylcholine (MIOCHOL-E) is available as an ophthalmic surgical aid for the rapid production of miosis. Bethanechol chloride (carbamyl--methylcholine chloride; URECHOLINE , others) is available in tablets and as an injection and is used as a stimulant of the smooth muscle of the gastrointestinal tract, and in particular, the urinary bladder. Pilocarpine hydrochloride (SALAGEN) is available as 5- or 7.5-mg oral doses for treatment of xerostomia or as ophthalmic solutions (PILOCAR, others) of varying strength. Methacholine chloride (acetyl--methylcholine chloride; PROVOCHOLINE) may be administered for diagnosis of bronchial hyperreactivity. The unpredictability of absorption and intensity of response has precluded its use as a vasodilator or cardiac vagomimetic agent. Cevimeline (EVOXAC) is a newer muscarinic agonist available orally for use in treatment of xerostomia.

Gastrointestinal Disorders

Bethanechol can be of value in certain cases of postoperative abdominal distention and in gastric atony or gastroparesis. The oral route is preferred; the usual dosage is 10 to 20 mg, three or four times daily. Bethanechol is given by mouth before each main meal in cases without complete retention; when gastric retention is complete and nothing passes into the duodenum, the subcutaneous route is necessary because of poor stomach absorption. Bethanechol likewise has been used to advantage in certain patients with congenital megacolon and with adynamic ileus secondary to toxic states. Prokinetic agents with combined cholinergic-agonist and dopamine-antagonist activity (e.g., metoclopramide) or serotonin-antagonist activity (see Chapter 37) have largely replaced bethanechol in gastroparesis or esophageal reflux disorders.

Urinary Bladder Disorders

Bethanechol may be useful in treating urinary retention and inadequate emptying of the bladder when organic obstruction is absent, as in postoperative and postpartum urinary retention and in certain cases of chronic hypotonic, myogenic, or neurogenic bladder (Wein, 1991). Adrenergic receptor antagonists are useful adjuncts in reducing outlet resistance of the internal sphincter (see Chapter 10). Bethanechol may enhance contractions of the detrusor muscle after spinal injury if the vesical reflex is intact, and some benefit has been noted in partial sensory or motor paralysis of the bladder. Catheterization thus can be avoided. For acute retention, multiple subcutaneous doses of 2.5 mg of bethanechol may be administered. The stomach should be empty at the time the drug is injected. In chronic cases, 10 to 50 mg of the drug may be given orally two to four times daily with meals to avoid nausea and vomiting. When voluntary or spontaneous voiding begins, bethanechol is then slowly withdrawn.

Xerostomia

Pilocarpine is administered orally in 5- to 10-mg doses given three times daily for the treatment of xerostomia that follows head and neck radiation treatments or that is associated with Sj?gren s syndrome (Wiseman and Faulds, 1995; Porter et al., 2004). The latter is an autoimmune disorder occurring primarily in women in whom secretions, particularly salivary and lacrimal, are compromised (Anaya and Talal, 1999; Nusair and Rubinow, 1999). Provided salivary parenchyma maintains residual function, enhanced salivary secretion, ease of swallowing, and subjective improvement in hydration of the oral cavity are achieved. Side effects typify cholinergic stimulation, with sweating being the most common complaint. Bethanechol is an oral alternative that produces less diaphoresis (Epstein et al., 1994). Cevimeline (EVOXAC) is a newer agonist with activity at M3 muscarinic receptors. These receptors are found on lacrimal and salivary gland epithelia. Cevimeline has a long-lasting sialogogic action and may have fewer side effects than pilocarpine (Anaya and Talal, 1999). It also enhances lacrimal secretions in Sj?gren s syndrome (Ono et al., 2004).

Ophthalmological

Pilocarpine also is used in the treatment of glaucoma, where it is instilled into the eye usually as a 0.5% to 4% solution. An ocular insert (OCUSERT PILO-20) that releases 20 g of pilocarpine per hour over 7 days also is marketed for the control of elevated intraocular pressure. Pilocarpine usually is better tolerated than are the anticholinesterases, and pilocarpine is the standard cholinergic agent in the treatment of open-angle glaucoma. Reduction of intraocular pressure occurs within a few minutes and lasts 4 to 8 hours. The ophthalmic use of pilocarpine alone and in combination with other agents is discussed in Chapter 63. The miotic action of pilocarpine is useful in reversing a narrow-angle glaucoma attack and overcoming the mydriasis produced by atropine; alternated with mydriatics, pilocarpine is employed to break adhesions between the iris and the lens.

CNS

Agonists that show functional selectivity for M1 and M2 receptors have been targets for drug development, and some have been in clinical trial for use in treating the cognitive impairment associated with Alzheimer s disease. The potential advantage of such agonists would arise from stimulating postsynaptic M1 receptors in the CNS without concomitantly stimulating the presynaptic M2 receptors that inhibit release of endogenous ACh. However, lack of efficacy in improvement of cognitive function has diminished enthusiasm for this approach