Parasympathomimetic drugs

Muscarinic agonists mimic the effects of parasympathetic stimulation, so we expect a very profound effect on the various systems—one of which is vascular smooth muscle, in which you get dilation. This has always confounded students; how does an agent acting on a muscarinic receptor produce vascular smooth muscle dilation? Underneath this, stimulation of the parasympathetic nerves to bronchial smooth muscle leads to bronchoconstriction. This leads to a very important new strategy for treating asthma, which is characterized by bronchoconstriction, so we appreciate the role of the parasympathetic nervous system. The exocrine glands, we’ll always think of salivary glands, promote secretion. There are muscarinic receptors in the heart, the term negative inotropic is important… “inotropic” refers to the force of the heart, “negative inotropic” means a decreased force of contraction (decreased contractility means the same as negative inotropic). Negative chronotropic refers to vagus stimulation to the heart leads to a slowing of heart rate. And dromotropic is decreased conduction velocity within the myocardium. Clearly, drugs acting as agonists (parasympathomimetic drugs) can have a tremendous effect on a variety of organ systems. In patients who are on drugs that modify these receptors will show some consequences.

Less likely to be encountered in patients, are those taking acetylcholinesterase inhibitors. This is to inhibit the enzyme that specifically breaks down acetylcholine. When you see the term anticholinesterase, you’re inhibiting the enzyme that breaks down acetylcholine, therefore acetylcholine will accumulate and produce a rising of effects on smooth muscles, glands, the heart, and skeletal muscles (we’ll come back to this later).

These two groups of drugs (muscarinic agonists and acetylcholinesterase inhibitors) both mimic the action of the parasympathetic nervous system.

We’ll go into muscarinic receptor antagonists at a later date. Remember that there are 5 different muscarinic receptors, and that atropine (the prototypical muscarinic antagonist) will block all of them. We can see their effects on the eye, bladder, heart, brain etc.

We don’t have drugs that will affect the synthesis of acetylcholine. We do have drugs that influence the breakdown of acetylcholine (acetylcholinesterase) and the receptor sites-- depending on the organ system, either the muscarinic receptor (M) or the nicotinic receptor (N). You’ll notice on the figure that there is a pre-synaptic muscarinic receptor cartoon (M) but we don’t know the function of the pre-synaptic muscarinic receptor. It has probably greater significance when we talk about pre-synaptic adrenergic receptors.

The designations that appear in the text (M1-M5) are simplified here. But be careful! If you give atropine to a patient you’ll get xerostomia and other effects, but you probably do NOT effect nerve conduction. So when M1 refers to nerves, they should perhaps instead be referring to neurons. Atropine and other analogs do not affect nerve conduction like lidocaine does. The M2 receptor appears to be predominant on the heart and on smooth muscle. For the moment, we’re not talking about intracellular transduction, but we’re going to focus on the physiology. So there are some M1 and M2 in the CNS. M3 receptors are in smooth muscle and exocrine glands, including the SALIVARY GLANDS. “Over and over again, students don’t know about the regulating autonomic factors controlling salivary function—its much more complicated than just bicarbonate secretion and keeping the mouth moist!” ** M4 and M5 are probably in the CNS, these are less well characterized. M1-M3 have the most clinical significance.

This is a table listing some agonists, obviously the natural neurotransmitter is acetylcholine. Does acetylcholine have any therapeutic use? No, we don’t inject acetylcholine for any therapeutic reasons. HOWEVER, we can mimic the effects of acetylcholine by using drugs such as methacholine, carbachol, bethanechol… and those are used in medicine. For example, a physician who wants to stimulate smooth muscle in the gut can use carbachol, there’s lots of cholinergic muscarinic receptors in the gut. So these analogs are used instead of acetylcholine. Bethanechol can be used in pulmonary medicine as a provocative test to see some of the pathophysiology of asthma, because bethanechol can constrict the smooth muscle of the bronchioles and this can tell the MD about the bronchial reactivity and help him to select the correct anti-asthmatic drug. Muscarine comes from the poisonous mushroom and has no therapeutic use, only in the laboratory. (The problem with eating these poisonous mushrooms is that you get all the problems associated with a cholinergic crisis). Pilocarpine, finally, does have significance in medicine and dentistry… lets explore those now…

There are conditions where a diminished salivary flow exists. The question arises in dentistry how to improve this function—artificial saliva may be palliative, but doesn’t get to the root cause of salivary dysfunction. It turns out that because salivary glands are innervated by parasympathetic nerves and muscarinic receptors, it would be important to consider giving a muscarinic agonist, like pilocarpine. Officially the use of Pilocarpine in dentistry is limited to treating the effects of radiation therapy to the head and neck.. Typically this radiation therapy markedly affects the acinar cells and the patient gets severe xerostomia with rampant caries. Often, the dentist is called in by the oncologist to help out. So Pilocarpine is a valid tool for treating xerostomia caused by radiation therapy, but that doesn’t mean that you cant use Pilocarpine to treat other hyposalivating conditions where you have xerostomia. Yes, you can prescribe Pilocarpine for chronic xerostomia (5mg tablets, 90 tabs, 1 tab taken t.i.d. = three times/ day).

Remember, Pilocarpine is a muscarinic agonist. Pilocarpine is a very old drug; in dental journals you’ll see the brand name Salagen.

There will of course be a price to pay; CONTRAINDICATIONS!!!

The patient cannot be an asthmatic, either controlled or uncontrolled. Why? Because in the bronchial smooth muscle, one of the things controlling bronchial tone is parasympathetic innervation and muscarinic receptors. Obviously, if an asthmatic is given a muscarinic agonist like pilocarpine, it will stimulate those muscarinic receptors, stimulate contraction of the bronchial smooth muscle, and this leads to bronchospasm, and can be life-threatening! COPD (Chronic Obstructive Pulmonary Disease), which includes emphysema, and Chronic Bronchitis are also contraindications for prescribing Pilocarpine because of this problem with the bronchial smooth muscle.

In the biliary tract, smooth muscle contractions lead to severe abdominal pain, patient thinks that they are having an appendicitis. In the heart there are muscarinic receptors, so with cardiac disease the effect of Pilocarpine might be variable depending on a number of things—this is a “relative” contraindication. Since there is an effect on the muscarinic receptors, those in they eye can cause myosis (pupillary constriction) so there’s a contraindication there. The same with Renal Colic which is due to the contraction of the ureteral smooth muscle.

For many years, Pilocarpine was the only agent available in dentistry and medicine to stimulate salivary function. Then a more specific agent, Cevimeline (Evoxac) was introduced. It is a muscarinic agonist indicated for the treatment of xerostomia, particularly for Sjogren’s syndrome (an autoimmune disease, characterized by severe dry mouth, dry eyes (lack of lacrimal flow), all the exocrine and mucous systems are diminished, in dentistry the most significant effect is severe xerostomia with rampant caries). Cevimeline would be contraindicated again in asthmatic patients for the same reasons as outlined above (bronchospasms), and can also affect the muscarinic effector in the eye and is contraindicated in iritis.

Apparently, Cevimeline binds and activates the muscarinic M3 receptor (although this isn’t certain). So although this drug has a pretty good affinity for the M3 receptor to promote salivary secretion, there are some side effects on the heart and eye (M2 receptor). So we don’t have an absolute M3 agonist, maybe someday we will.

Major side effects of Cevimeline (Evoxac) include sweating (19%), nausea (14%), and diarrhea (10%). The diarrhea is due to stimulation of the muscarinic receptors in the gut smooth muscle causing increased motility, leading to diarrhea. There may be some cardiac arrhythmias, eye pain, decreased visual acuity as well.

Cevimeline (Evoxac) is metabolized in the liver, by the hepatic P450 cytochrome system. So if you were to use such a drug, a lot of common dental drugs such as ketoconazole (used to combat candidiasis and other fungal infections), the metabolism can be affected so that the drugs effects will be altered. Effects are decreased when used with drugs with anticholinergic action (e.g., atropine or other anticholinergic drugs—BENEDRIL has anticholinergic side effects, as if the patient were taking atropine… so the antagonistic actions of benedril will block the effects of the cholinergic agonist).

Half live of Cevimeline (Evoxac) is about 5 hours, and is given 30mg orally three times per day.

It’s important to remember that the incidence of Sjogren’s disease is very low—you won’t see if very often so don’t jump to conclusions if you see dry mouth. Sjogren’s disease is seen in only 1% of the population, and is highly female predominated (9:1).

Category: Pharmacology Notes