Muscarinic pharmacology: No need to memorize

American Journal of Pharmaceutical Education, Summer 1999 by Bazil, Michelle K

PROLOGUE

The following is a summary of a one hour lecture on muscarinic receptor agonists provided to pharmacy students in their second semester of professional study. During the previous semester students complete prerequisite courses in physiology and biochemistry. The lecture is preceded by lectures covering pharmacokinetics, pharmacodynamics, receptor theory, and the autonomic nervous system (ANS). The lecture represents the students' first exposure to a pharmacologic class of agents. In conjunction with the pharmacology course, students are enrolled in a medicinal chemistry course. The objectives of the lecture are to present the pharmacology of direct muscarinic receptor agonists, and to assist the students develop an approach to the application of prerequisite knowledge to the study of pharmacology.

Muscarinic pharmacology is frequently one of the first topics covered in entry-level pharmacology courses. As a result, it is important that students apply prerequisite knowledge (e.g., physiology, biochemistry, pharmacodynamics, and receptor theory) to the comprehension of pharmacology. If students attempt to understand pharmacology, the quantity of memorization decreases. Although muscarinic agonists are generally not found among lists of the "Top 200" prescription medications they serve as a useful model class. Prior to the lecture students are provided a few scenarios and exercises to prepare them for the study of muscarinic pharmacology (Appendix).

The pharmacology of muscarinic agonists is presented using an organ system approach. The major target organs of muscarinic agonists include: blood vessels, heart, eyes, lungs, and gastrointestinal and urinary smooth muscle(1). For each organ system the effect of stimulation of muscarinic receptors is presented with emphasis on correlation to the activities of the parasympathetic nervous system. Based upon the effect on organ function, potential therapeutic uses and adverse effects are discussed. Examples of agents are provided and distinguishing features presented. It is hoped that at the conclusion of the lecture students will be able to apply knowledge of the ANS to muscarinic pharmacology and the only information requiring memorization is the names of the pharmacologic agents.

DIRECT MUSCARINIC AGONISTS

Agents that mimic the effects of acetylcholine include direct receptor agonists and indirect agonists(1). An example of an indirect cholinergic agonist would be an agent that inhibits the breakdown of acetylcholine by acetylcholinesterase. The indirect agonists will not be discussed during this lecture.

The study of cholinergic pharmacology begins with the neurotransmitter acetylcholine. Acetylcholine activates muscarinic and nicotinic receptors(2). Pharmacologically, it is generally desirable to develop agents that are "selective" for one receptor type. With regard to cholinergic pharmacology, agents that are relatively selective for muscarinic receptors have been developed. These selective muscarinic agonists offer the advantage of lack of nicotinic effects (e.g., stimulation of skeletal muscle contraction).

The clinically available direct muscarinic agonists are divided into two classes. The choline esters are structural analogs of acetylcholine and the alkaloids are analogs of naturally occurring substances(l). With the exception of acetylcholine, agents are selective for muscarinic receptors as compared to nicotinic receptors, but do not distinguish between the subtypes of muscarinic receptors(l). That is, they activate M^sub 1^, M^sub 2^, M^sub 3^, M^sub 4^, and M^sub 5^ receptors. Muscarinic receptors are classified as Ml- Ms based upon the results of cloning and pharmacologic experimentation(3). All muscarinic receptors are Gprotein linked receptors. The second messenger systems of the muscarinic receptors are generally thought to be inhibition of adenylate cyclase for the M^sub 2^ and M^sub 4^ subtypes and activation of phospholipase C for the M^sub 1^, M^sub 3^, and M^sub 5^ subtypes(3). Additional second messenger systems probably exist for some subtypes(3).

Muscarinic receptors are located in many areas of the body (Table I). As a result of the lack of selectivity, muscarinic agonists have diverse and far reaching effects. Nevertheless due to their inability to activate nicotinic receptors, as compared to acetylcholine, the muscarinic agonists are pharmacologically preferred. In theory, development of an agent selective for one of the subtypes of muscarinic receptors would possess enhanced efficacy and decreased adverse effects. A few experimental agents exist, but no selective agents are currently approved for use in the United States (1,3).

Understanding the pharmacology of muscarinic agonists relies upon knowledge of the parasympathetic nervous system. The parasympathetic nervous system is active mainly at rest and is responsible for maintaining homeostasis and conserving energy(2). The effect of stimulation of muscarinic receptors on the function of various organ systems will in general mimic parasympathetic stimulation. Based upon the effects of parasympathetic stimulation, it is easy to predict therapeutic uses and adverse effects of the muscarinic receptor agonists.