Muscarinic agonists and antagonists

CHAPTER 14


Muscarinic agonists and antagonists


The muscarinic agonists and antagonists produce their effects through direct interaction with muscarinic receptors. The muscarinic agonists cause receptor activation; the antagonists produce receptor blockade. Like the muscarinic agonists, another group of drugs—the cholinesterase inhibitors—can also cause receptor activation, but they do so by an indirect mechanism. These drugs are discussed separately in Chapter 15.




Muscarinic agonists


The muscarinic agonists bind to muscarinic receptors and thereby cause receptor activation. Since nearly all muscarinic receptors are associated with the parasympathetic nervous system, responses to muscarinic agonists closely resemble those produced by stimulation of parasympathetic nerves. Accordingly, muscarinic agonists are also known as parasympathomimetic agents.



Bethanechol


Bethanechol [Urecholine, Duvoidimage] embodies the properties that typify all muscarinic agonists, and hence will serve as our prototype for the group.




Pharmacologic effects

Bethanechol can elicit all of the responses typical of muscarinic receptor activation. Accordingly, we can readily predict the effects of bethanechol by knowing the information on muscarinic responses summarized in Table 13–2.


The principal structures affected by muscarinic activation are the heart, exocrine glands, smooth muscles, and eye. Muscarinic agonists act on the heart to cause bradycardia (decreased heart rate) and on exocrine glands to increase sweating, salivation, bronchial secretions, and secretion of gastric acid. In smooth muscles of the lung and GI tract, muscarinic agonists promote contraction. The result is constriction of the bronchi and increased tone and motility of GI smooth muscle. In the bladder, muscarinic activation causes contraction of the detrusor muscle and relaxation of the trigone and sphincter; the result is bladder emptying. In vascular smooth muscle, these drugs cause relaxation; the resultant vasodilation can produce hypotension. Activation of muscarinic receptors in the eye has two effects: (1) miosis (pupillary constriction); and (2) contraction of the ciliary muscle, resulting in accommodation for near vision. (The ciliary muscle, which is attached to the lens, focuses the eye for near vision by altering lens curvature.)






Therapeutic uses

Although bethanechol can produce a broad spectrum of pharmacologic effects, the drug is approved only for urinary retention.



Urinary retention.

Bethanechol relieves urinary retention by activating muscarinic receptors of the urinary tract. Muscarinic activation relaxes the trigone and sphincter muscles and increases voiding pressure (by contracting the detrusor muscle, which composes the bladder wall). Bethanechol is used to treat urinary retention in postoperative and postpartum patients. The drug should not be used to treat urinary retention caused by physical obstruction of the urinary tract. Why? Because increased pressure in the tract in the presence of blockage could cause injury. When patients are treated with bethanechol, a bedpan or urinal should be readily available.






Adverse effects

In theory, bethanechol can produce the full range of muscarinic responses as side effects. However, with oral dosing, side effects are relatively rare. (When the drug was available for subQ administration, side effects were much more common.)







Dysrhythmias in hyperthyroid patients.

Bethanechol can cause dysrhythmias in hyperthyroid patients, and hence is contraindicated for these people. The mechanism of dysrhythmia induction is explained below.



If given to hyperthyroid patients, bethanechol may increase heart rate to the point of initiating a dysrhythmia. (Note that increased heart rate is opposite to the effect that muscarinic agonists have in most patients.) When hyperthyroid patients are given bethanechol, their initial cardiovascular responses are like those of anyone else: bradycardia and hypotension. In reaction to hypotension, the baroreceptor reflex attempts to return blood pressure to normal. Part of this reflex involves the release of norepinephrine from sympathetic nerves that regulate heart rate. In patients who are not hyperthyroid, norepinephrine release serves to increase cardiac output, and thereby helps restore blood pressure. However, in hyperthyroid patients, norepinephrine can induce cardiac dysrhythmias. The reason for this unusual response is that, in hyperthyroid patients, the heart is exquisitely sensitive to the effects of norepinephrine, and hence relatively small amounts can cause stimulation sufficient to elicit a dysrhythmia.






Other muscarinic agonists



Cevimeline



Actions and uses.


Cevimeline [Evoxac] is a derivative of acetylcholine with actions much like those of bethanechol. The drug is indicated for relief of xerostomia (dry mouth) in patients with Sjögren’s syndrome, an autoimmune disorder characterized by xerostomia, keratoconjunctivitis sicca (inflammation of the cornea and conjunctiva), and connective tissue disease (typically rheumatoid arthritis). Dry mouth results from extensive damage to salivary glands. Left untreated, dry mouth can lead to multiple complications, including periodontal disease, dental caries, altered taste, oral ulcers and candidiasis, and difficulty eating and speaking. Cevimeline relieves dry mouth by activating muscarinic receptors on residual healthy tissue in salivary glands, thereby promoting salivation. The drug also increases tear production, which can help relieve keratoconjunctivitis. Because it stimulates salivation, cevimeline may also benefit patients with xerostomia induced by radiation therapy for head and neck cancer, although the drug is not approved for this use.



Adverse effects.


Adverse effects result from activating muscarinic receptors, and hence are similar to those of bethanechol. The most common effects are excessive sweating (18.9%), nausea (13.8%), rhinitis (11.2%), and diarrhea (10.3%). To compensate for fluid loss caused by sweating and diarrhea, patients should increase fluid intake. Like bethanechol, cevimeline promotes miosis (constriction of the pupil) and may also cause blurred vision. Both actions can make driving dangerous, especially at night.


Activation of cardiac muscarinic receptors can reduce heart rate and slow cardiac conduction. Accordingly, cevimeline should be used with caution in patients with a history of heart disease.


Because muscarinic activation increases airway resistance, cevimeline is contraindicated for patients with uncontrolled asthma, and should be used with caution in patients with controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease.


Because miosis can exacerbate symptoms of both narrow-angle glaucoma and iritis (inflammation of the iris), cevimeline is contraindicated for people with these disorders.





Pilocarpine


Pilocarpine is a muscarinic agonist used mainly for topical therapy of glaucoma, an ophthalmic disorder characterized by elevated intraocular pressure with subsequent injury to the optic nerve. The basic pharmacology of pilocarpine and its use in glaucoma are discussed in Chapter 104 (Drugs for the Eye).


In addition to its use in glaucoma, pilocarpine is approved for oral therapy of dry mouth resulting from Sjögren’s syndrome or from salivary gland damage caused by radiation therapy of head and neck cancer. For these applications, pilocarpine is available in 5-mg tablets under the trade name Salagen. The recommended dosage is 5 mg 3 or 4 times a day. At this dosage, the principal adverse effect is sweating, which occurs in 29% of patients. However, if dosage is excessive, pilocarpine can produce the full spectrum of muscarinic effects.





Toxicology of muscarinic agonists







Muscarinic antagonists (anticholinergic drugs)


Muscarinic antagonists competitively block the actions of acetylcholine at muscarinic receptors. Because the majority of muscarinic receptors are located on structures innervated by parasympathetic nerves, the muscarinic antagonists are also known as parasympatholytic drugs. Additional names for these agents are antimuscarinic drugs, muscarinic blockers, and anticholinergic drugs.


The term anticholinergic can be a source of confusion and requires comment. This term is unfortunate in that it implies blockade at all cholinergic receptors. However, as normally used, the term anticholinergic only denotes blockade of muscarinic receptors. Therefore, when a drug is characterized as being anticholinergic, you can take this to mean that it produces selective muscarinic blockade—and not blockade of all cholinergic receptors. In this chapter, I use the terms muscarinic antagonist and anticholinergic agent interchangeably.



Atropine


Atropine [Sal-Tropine, AtroPen, others] is the best-known muscarinic antagonist and will serve as our prototype for the group. The actions of all other muscarinic blockers are much like those of this drug.


Atropine is found naturally in a variety of plants, including Atropa belladonna (deadly nightshade) and Datura stramonium (aka Jimson weed, stinkweed, and devil’s apple). Because of its presence in Atropa belladonna, atropine is referred to as a belladonna alkaloid.




Pharmacologic effects

Since atropine acts by causing muscarinic receptor blockade, its effects are opposite to those caused by muscarinic activation. Accordingly, we can readily predict the effects of atropine by knowing the normal responses to muscarinic receptor activation (see Table 13–2) and by knowing that atropine will reverse those responses. Like the muscarinic agonists, the muscarinic antagonists exert their influence primarily on the heart, exocrine glands, smooth muscles, and eye.








Dose dependency of muscarinic blockade.

It is important to note that not all muscarinic receptors are equally sensitive to blockade by atropine and most other anticholinergic drugs: At some sites, muscarinic receptors can be blocked with relatively low doses, whereas at other sites much higher doses are needed. Table 14–1 indicates the sequence in which specific muscarinic receptors are blocked as the dose of atropine is increased.



Differences in receptor sensitivity to muscarinic blockers are of clinical significance. As indicated in Table 14–1, the doses needed to block muscarinic receptors in the stomach and bronchial smooth muscle are higher than the doses needed to block muscarinic receptors at all other locations. Accordingly, if we want to use atropine to treat peptic ulcer disease (by suppressing gastric acid secretion) or asthma (by dilating the bronchi), we cannot do so without also affecting the heart, exocrine glands, many smooth muscles, and the eye. Because of these obligatory side effects, atropine and most other muscarinic antagonists are not preferred drugs for treating peptic ulcers or asthma.






Therapeutic uses


Preanesthetic medication.

The cardiac effects of atropine can help during surgery. Procedures that stimulate baroreceptors of the carotid body can initiate reflex slowing of the heart, resulting in profound bradycardia. Since this reflex is mediated by muscarinic receptors on the heart, pretreatment with atropine can prevent a dangerous reduction in heart rate.


Certain anesthetics—especially ether, which is obsolete—irritate the respiratory tract, and thereby stimulate secretion from salivary, nasal, pharyngeal, and bronchial glands. If these secretions are sufficiently profuse, they can interfere with respiration. By blocking muscarinic receptors on secretory glands, atropine can help prevent excessive secretions. Fortunately, modern anesthetics are much less irritating than ether. The availability of these new anesthetics has greatly reduced the use of atropine as an antisecretagogue during anesthesia.






Muscarinic agonist poisoning.

Atropine is a specific antidote to poisoning by agents that activate muscarinic receptors. By blocking muscarinic receptors, atropine can reverse all signs of muscarinic poisoning. As discussed above, muscarinic poisoning can result from an overdose with medications that promote muscarinic activation (eg, bethanechol, cholinesterase inhibitors) or from ingestion of certain mushrooms.








< div class='tao-gold-member'>

Related posts:

  1. Orientation to pharmacology
  2. Drug therapy of infertility
  3. Drug abuse III: nicotine and smoking
  4. Review of the immune system

Stay updated, free articles. Join our Telegram channel
Tags:
Jul 24, 2016 | Posted by in NURSING | Comments Off on Muscarinic agonists and antagonists

Full access? Get Clinical Tree
Get Clinical Tree app for offline access