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ORGANIZATION OF CLASS

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Although I have titled this chapter “Cholinergic Agonists,” this chapter, in fact, considers all the drugs that increase activity in cholinergic neurons, sometimes called cholinomimetics (because they mimic the action of acetylcholine). There are two main targets of drug action: the postsynaptic receptor and the acetylcholinesterase enzyme, which breaks down acetylcholine.

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Cholinergic agonists have a direct action on the receptor for acetylcholine. Some drugs are specific for the muscarinic receptor; others are specific for the nicotinic receptor.

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First, remind yourself where the nicotinic and muscarinic receptors are found:

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  1. All autonomic ganglia have nicotinic receptors.

  2. All receptors at the neuromuscular junction are nicotinic receptors.

  3. All target organs of the parasympathetic nervous system have muscarinic receptors.

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Of course, there are other cholinergic receptors, such as those located in the central nervous system (CNS) and in sweat glands innervated by the sympathetic nervous system. Concentrate on learning the three types listed above for now and add the others later.

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The cholinesterase inhibitors act by blocking the metabolism of acetylcholine. These drugs effectively increase the concentration of acetylcholine at all cholinergic synapses.

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The enzyme that is specific for acetylcholine is called acetylcholinesterase, and it is found on both the pre- and postsynaptic membranes. There are other cholinesterases that also metabolize acetylcholine and drugs with related structures. These other cholinesterases are sometimes called pseudocholinesterases or nonspecific cholinesterases, and they are abundant in the liver. The structure and biochemistry of acetylcholinesterase is well studied and has an interesting story. Details can be found in most textbooks.

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Activation of Muscarinic Receptors Results in the Following Responses:

Eye

Cardiovascular

Respiratory

Gastrointestinal (GI)

Genitourinary (GU)

Glands

Miosis (constriction of pupil)

Decrease in heart rate

Bronchial constriction and increased secretions

Increased motility and relaxation of sphincters

Relaxation of sphincters and bladder wall contraction

Increased secretions

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Activation of nicotinic receptors results in muscle contraction (fasciculations and weakness).

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These effects can be predicted based on your knowledge of the effects of the parasympathetic nervous system. Therefore, this is a review and not a list of new things to learn. (We are trying to keep this simple.)

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CHOLINERGIC AGONISTS

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ESTERS Alkaloids

BETHANECHOL

carbachol

cevimeline

methacholine

arecoline

muscarine

pilocarpine

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These drugs are traditionally divided into two groups: esters of choline that are structurally related to acetylcholine (indicated by “-chol-” in their names), and alkaloids that are not related to acetylcholine and are generally plant derivatives. The only reason that this distinction is important is that the alkaloids, because of their complex structure, are not metabolized by cholinesterases.

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The effects of all of these agents are exclusively muscarinic.

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