Cholinomimetic Activators and Effects

by Pravin Shukle, MD

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    00:00 Hi. I'm Dr. PJ Shukle, we're going to continue the discussions about the pharmacology of the autonomic nervous system. Now we have many different types of cholinomimetics that act as direct activators. There are those that act on the muscarinic cholinergic receptors and those that act on the nicotinic cholinergic receptors. So there are cholinesterase like acetylcholine that act on both, there is methacholine and there is also carbachol and bethanechol which act on the muscarinic cholinergic receptors. In the nicotinic cholinergic column, we just have carbachol. We also have some alkaloids that can work on the muscarinic cholinergic receptors including pilocarpine. Now let's take a quick look at the synaptic cleft in the autonomic nervous system. So specifically this is a cholinergic synaptic cleft and you can see that there is acetylcholine that is being released by the vesicle into the synaptic cleft.

    01:05 So you see ACH there, that's acetylcholine. It would normally interact with a cholinoreceptor.

    01:11 Now, if that acetylcholine is in the synaptic cleft for too long, it will get broken down by acetylcholinesterase or ACHE into choline and acetate. If we block acetylcholinesterase, we increase the levels of acetylcholine in the synaptic cleft and you have more excitation of the cholinoreceptors. We can have indirect activators of the system through this acetylcholinesterase inhibitor. Edrophonium is a good example of a short-acting agent that lasts between 5 and 15 minutes. Intermediate-acting agents can include neostigmine and physostigmine and this is often used in the treatment of myasthenia gravis and long-acting agents are often thought of as poisons or toxins and we see that with a lot of organophosphate such as malathion, parathion, and others that are used as pesticides. Now there is another long-acting agent that I just want to quickly mention. Sarin was used in the 1995 Tokyo attacks and it had devastating effects. So let's go to 1995 in Tokyo. What happened was was that this organophosphate was released into a subway system and patients ended up having death within minutes. They developed asphyxia. There is significant persistent neurological damage in those survivors. Now, why did some of these patients leave? Because there is some particularly astute doctors who are working in the emergency departments nearby the subway stations that immediately recognized what was going on, not because they had ever experienced this particular toxin or terrorist agent before but because they recognize the neurological symptoms of acetylcholinesterase and so they knew that the antidote to this would be atropine. So it's one of the least used drugs in our crash carts but it can save lives in the event of this kind of terrorist attack. So what was it that these astute emergency room physicians noticed about their patients? Well, they knew that these syndromes that these patients were experiencing were very similar to exposures, toxic exposures to some of the organophosphate pesticides like malathion and parathion. They also noticed that they had physiological effects similar to the administration of medicines like pyridostigmine, neostigmine, or physostigmine. And what were those clinical findings? Well, in the eye they notice that patients had a contraction of the circular or sphincter muscle of the iris. This causes pupillary contraction or what we call myosis. This is used in near vision accommodation so this is why they were able to tell just by looking at the pupils that these patients had been poisoned with some kind of acetylcholinesterase. In terms of the heart, there is sinoatrial node suppression. So patients often presented with a decreased heart rate or what we call negative chronotropy and remember that Chronos was the God of time so decreased time means that these patients had a slower heart rate. In terms of the atria, there is decreased contractile force or negative inotropy. Inos was the Greek God of strength so there is less strength. In terms of the AV node, there is decreased conduction velocity of each impulse or negative dromotropy. Dromos was the Greek God of the racist. So things were going slower down a pathway. Other effects on the AV node, an increased refractory period and in terms of the effect on the ventricles, there is decreased contractile force or negative inotropy. What are the cholinomimetic effects on the brain? So for example if you have a lot of nicotine, patients will have an elevated mood particularly alert and sometimes there is an addictive potential but if you're overdosing or if you're having toxic levels like in the sarin gas attack, patients would have a lot of nausea, a lot of vomiting, convulsions and even a coma. What about the effects on the circulatory system? You will generally get dilation of blood vessels so there is a release of endothelial-derived relaxing factor or EDRF that dilates the blood vessels. In terms of the lungs, you have the opposite which is bronchoconstriction. Remember that because generally speaking what the lungs are doing, the body does the opposite because of the way that the nervous system is set up. So you have dilation of the peripheral circulation and constriction in the respiratory circulation. In terms of the gut, you would have smooth muscle contraction so you would have increased peristalsis. In terms of the sphincters, you would have a contraction of the GE sphincter and a relaxation of the pyloric sphincter. So that's kind of a hard thing to recognize until you realize what we're talking about here is moving things through quickly. So, the GE sphincter should contract because you don't want food to go back up into the stomach when the intestines contract. That's how it's easy to remember. In terms of the urinary tract, it's quite similar. The detrusor muscle will contract whereas the trigone will relax. That ends up causing the bladder to open up its sphincter, contract, and push out urine. What's the effect on skeletal muscle? Generally speaking on the neuromuscular endplates, you have activation so patients tend to be depolarized and a good example of that is succinylcholine because it is what we call a depolarizing paralytic. Edrophonium is an antidote to the non-depolarizing paralytics. So that's something that's important to remember. In terms of the exocrine glands, the sweat glands will increase their production and release so you have more sweating, you have salivary gland hyperexcitation so you have more salivation, mouth is wet. The tear ducts are more stimulated so you have more lacrimation. And in terms of the GI and lung mucous glands, you have more secretion. So it's a hard thing to remember but just remember that what we're trying to do here is we're trying to make things wet. So patients are wet with cholinomimetics so therefore there is more sweat, more saliva, more tears, and more mucous from the mucous membranes. So, I have a mnemonic for you called DUMBELLS which is good for cholinomimetic. So D is diarrhea, urination, myosis, bronchoconstriction, bradycardia, excitation of skeletal muscle and central nervous system, lacrimation, salivation, and sweating.

    About the Lecture

    The lecture Cholinomimetic Activators and Effects by Pravin Shukle, MD is from the course ANS - Pharmacology.

    Included Quiz Questions

    1. Pilocarpine
    2. Acetylcholine
    3. Carbachol
    4. Methacholine
    5. All options provided can activate both types of receptors.
    1. Neostigmine
    2. Malathion
    3. Parathion
    4. Edrophonium
    5. Sarin
    1. Muscle relaxant
    2. Pesticide
    3. Diagnosis of neuromuscular junction disease
    4. Chemical weapon
    5. Treatment for myasthenia gravis

    Author of lecture Cholinomimetic Activators and Effects

     Pravin Shukle, MD

    Pravin Shukle, MD

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