A 61-year-old man comes to the office for the evaluation of urinary incontinence. The patient has been waking up every morning with his underwear soaked in urine. He has noticed that if he does not take regular bathroom breaks at work, his underwear will have some urine in it. The patient urinates 8 to 11 times per day, with each episode producing small volumes of urine. Past medical history is significant for type II diabetes mellitus, hypertension, and hyperlipidemia. Current medications include lisinopril, metformin, and atorvastatin. Temperature is 36.8°C (98.2°F), pulse is 90/min, respirations are 15/min, and blood pressure is 167/108 mmHg. Physical examination reveals decreased pinprick sensation in the lower extremities. The patient is prescribed bethanechol. Which of the following complications is this patient most at risk of developing?

Cholinomimetics: Direct agonists

Chapters:

Introduction0:00–0:37

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.

Physiology0:37–2:10

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.

Mechanism of Action2:10–3:10

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.

Bethanechol3:10–4:06

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.

Pilocarpine4:06–5:25

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.

Pilocarpine also stimulates sweat glands, so it’s sometimes used for collecting sweat samples, which is used when screening a child for cystic fibrosis.

Methacholine5:25–6:07

Methacholine is another cholinomimetic that primarily acts on muscarinic receptors. Unlike the other medications in this class, It is susceptible to degradation by acetylcholinesterase.

Since it’s relatively short acting, methacholine is used as a screening tool for asthma. So say you’re suspecting someone may have asthma.

One of the ways you can confirm this is by asking them to inhale methacholine, which contracts the bronchial smooth muscles.

Patients with asthma often have hyperactive and overly sensitive bronchial smooth muscles, so their symptoms will worsen after giving them even a small amount of methacholine.

Contraindications6:07–6:27

There are no absolute contraindications for these medications. However, since they cause bronchospasms, they should be avoided in people with chronic obstructive pulmonary disease, or COPD and asthma.

They also increase gastric acid secretion so they should be avoided in peptic ulcer disease. Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts!

Memory Palace6:27–8:10

So let’s start with a tug of war between two bodybuilders representing the muscarinic receptors. Since acetylcholine is abbreviated as ACh, we’ll use the Greek hero Achilles to represent the neurotransmitter that acts on these receptors.

Next to one body builder, there’s a cola can with math problems on it for methacholine, and there’s an asthma inhaler sitting on top of the can since it’s used to screen for asthma.

Also on this side is Macbeth for bethanechol, and he’s cleaning a urinal and a toilet to promote intestinal and bladder motility.

For contraindications, there’s a gallstone and a kidney stone in the toilet and the urinal. Okay, moving on to the other bodybuilder.

We have a carp shaped pillow for pilocarpine that’s hanging from the rope. One of the eyes is popping out since it’s mainly used to treat glaucoma, and the pupil of the eye is constricted.

Let’s use an ogre to represent sjögren syndrome. He’s looking at the carp pillow and drooling since he mistook it for a real fish.

Finally at the midline, we have a crab holding a whisky bottle for carbachol. It’s smoking a giant cigar to help you remember it also acts on nicotinic receptors.

Review8:10–8:44

It’s eyes are popping out since it’s also used to treat glaucoma. For contraindications, let’s have a police officer for COPD, and he’s using an asthma inhaler.

If we look in his stomach, there’s also a large bleeding peptic ulcer. Alright, as a quick recap.

Direct cholinomimetics are medications that mimic the action of acetylcholine by directly acting at muscarinic or nicotinic receptors.

Clinical uses of these medications include ileus, urinary retention, and glaucoma. With the exception of methacholine, all of the cholinomimetics are resistant to degradation by acetylcholinesterase.

Mind Map8:44–9:15

Direct cholinomimetics should be used with caution in patients with COPD, asthma, or peptic ulcer disease. But wait, there’s more: Here’s a mind map with all of the mnemonics.

Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers after the credits.