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Cholinomimetics: Direct agonists



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Cholinomimetics: Direct agonists


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Cholinomimetics: Direct agonists

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Content Reviewers:

Yifan Xiao, MD

The nervous system is divided into the central nervous system, that is the brain and spinal cord, and the peripheral nervous system, which includes all the nerves that connect the central nervous system to the muscles and organs.

The peripheral nervous system can be divided into the somatic nervous system, which controls voluntary movement of our skeletal muscles, and the autonomic nervous system, which controls the involuntary activity of the smooth muscles and glands of our organs, and is further divided into the sympathetic and the parasympathetic nervous systems.

Parasympathetic neurons in the central nervous system project preganglionic fibers towards parasympathetic ganglia, which are collections of neurons near the organ they are supposed to affect.From there, postganglionic fibers project towards the target cell.

Both the preganglionic and postganglionic neurons release the neurotransmitter acetylcholine.

Acetylcholine released from preganglionic fibers acts on nicotinic receptors on the postganglionic neurons.

And acetylcholine released from postganglionic neurons acts on muscarinic and nicotinic receptors on target organs.

Nicotinic receptors are coupled to ion channels that let sodium in and potassium out, causing depolarization.

Muscarinic receptors are G-protein coupled receptors, which means they trigger secondary messenger proteins that activate a cascade of enzymes inside the cell.

The physiologic effects of the muscarinic and nicotinic stimulation can be remembered with the mnemonic: DUMB HAVES, so defecation; urination; muscle excitation; bronchospasm; heart bradycardia; autonomic ganglia stimulation; vasodilation; eye miosis, which is constriction of the pupil, and eye accommodation, which is contraction of the ciliary muscles of the iris to facilitate looking at near objects; and secretions from the lacrimal, salivary and sweat glands as well as glands in the GI tract.

Now, medications that directly act on muscarinic or nicotinic receptors are called direct cholinomimetics, because they mimic acetylcholine. Examples of these medications include bethanechol, carbachol, methacholine, and pilocarpine.

But they’re not exactly like acetylcholine. That’s because unlike acetylcholine, direct cholinomimetics don’t bind to the muscarinic and nicotinic receptors equally. Instead, some of them are relatively selective for one receptor or the other.

Another thing is, normally, acetylcholine is degraded in the synaptic cleft by acetylcholinesterases. On the other hand, some of these medications are resistant to that degradation, and have a long lasting or more potent effect.

By knowing the physiological effects of muscarinic and nicotinic stimulation, we can logically figure out when someone might need these medications, as well as their potential side effects.

First off, bethanechol is a direct cholinomimetic that acts only on muscarinic receptors, with no nicotinic activity. Although seldom used clinically, it can be given to stimulate intestinal motility in people with ileus, which is failure of intestinal motility.

Bethanechol can also be given to stimulate bladder contractility and emptying in people retaining urine in their bladder.

Both ileus and urinary retention can happen after long surgical procedures as a side effect of general anesthetic medications, or as a complication of diseases that affect the autonomic nervous system, such as diabetes mellitus.

However, before giving these medications, one must make sure that the person’s urinary retention or ileus is not due to a physical obstruction, since severe pain can result as the muscles push against the obstruction.

Pilocarpine is a widely used cholinomimetic that primarily acts on muscarinic receptors. It’s one of the medications of choice in glaucoma, or an increased pressure within the anterior chamber of the eye.

When given topically on the eye, pilocarpine stimulates the contraction of the ciliary muscle in the eye, increasing the outflow of aqueous humor, which is the fluid in the anterior chamber of the eye. Therefore, pilocarpine decreases the intraocular pressure.

Carbachol is another medication that’s used to treat glaucoma. It acts on both muscarinic and nicotinic receptors and is more potent, but is less frequently used due to more severe side effects.

A less common use for pilocarpine is to stimulate tear and salivary glands in people with sjögren syndrome, which is a disease in which the person’s own immune system destroys these glands.

People with sjögren syndrome often complain of dry eyes and a dry mouth. So pilocarpine can help enhance the secretion of tears and saliva.

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