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Prokinetic Drugs

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In this episode, Dr. Dan Sadowski reviews the mechanism of action of prokinetic drugs for the gastrointestinal tract.

Hello and welcome back to gi 101 my name is dr. adriana la cerva schoo and i am your host for this episode with me in the studio today is dr. dan sadowski dan last episode we began our discussion on prokinetic drugs and started with an overview of the enteric nervous system what are we discussing today right so today i’d like to demonstrate how various prokinetic

Drugs actually interact with the enteric nervous system to improve gut motility it would be good to refer our listeners to the previous episode on the enteric nervous system yeah i think that’s a good idea and just by way of brief review remember that the peristaltic reflex is the basis for all gut motility distension of the gut wall initiate sadhu reflex arc that

Produces a contraction of smooth muscle behind the bolus mediated by ach and relaxation ahead of the bolus mediated by inhibitory neurotransmitters such as vip nitric oxide and atp you also mention that several important systems regulate this neuro reflex system in the gut why don’t we start talking about the serotonin system first so serotonin is released from

The intro chromaffin cells in the gut in response to a variety of chemical and mechanical stimuli and remember that serotonin has a number of receptors that it can bind to for example when it binds to the five ht4 receptor it greatly enhances ach released from the cholinergic nerves thereby increasing smooth muscle contraction conversely when serotonin binds to

The five hd3 receptor it works more on the relaxation side of the reflex arc so is it possible to influence the gut serotonin system or pharmacologically yes it is for example let’s take a look at the drug percolo pride percolo pride is a molecule that is a five ht4 receptor agonist in human studies it has been shown to speed up colonic transit time and has been

Approved for use in canada for the treatment of idiopathic chronic constipation its usual dose is 2 milligrams once daily and percolo pride is the only drug that we currently have available that is a pure 5-ht for receptor agonist there used to be a drug called cisapride how did that work so cisapride as well did work on the 5h d4 receptor and was available for many

Years and was used to treat diabetic gastroparesis and slow transit constipation however it has been taken off the market because of cardiac arrhythmias so are there any drugs that work on the v h g3 system so when serotonin binds to the v ht 3 receptor several things happen gut relaxation occurs resulting in increased forward flow there is increased secretion of

Water in the gut and there is increased visceral pain signal sensation to the cns so in gut motility disorders like diarrhea predominant irritable bowel syndrome you can see why blocking the v hd3 receptor might be a good thing what are some examples of 5-ht 3 antagonists so currently we have aloe citron and ondansetron let’s talk about a lawsuit ron so this drug

Is an example of a 5 ht 3 receptor antagonist it reduces gut contractility particularly in the colon and also stimulates fluid absorption and because of this it’s useful in the treatment of diarrhea predominant irritable bowel syndrome a lawsuit ron however is not available in canada and in the u.s. it was found to be associated with the development of ischemic

Colitis in some patients and thus is only available under a special access program what about ondansetron so ondansetron as many of our listeners know is a good drug for nausea and vomiting particularly for vomiting occurring in the setting of chemotherapy it turns out that chemo therapeutic drugs especially cisplatin caused a large release of serotonin from the

Gut this serotonin can go to the brain and interact with the five ht3 receptor in the chemoreceptor trigger zone thus resulting in vomiting ondansetron has a high affinity for these 5-ht 3 receptors in the chemoreceptor trigger zone and thus block the vomiting response there are several other drugs commonly used in gi such as domperidone and metoclopramide how do

They work both of these drugs work on the dopaminergic system in the gut dopamine is released in the gut by sympathetic nerves dopamine binds mainly to the d2 receptor and it acts as a brake on the entire peristaltic reflex decreasing ach secretion as well as decreasing nitric oxide vip and atp release is it possible to influence the dopamine system with medication

Yes so don’t perdón for example is a d2 receptor antagonist it stimulates gut motility mainly in the upper gi tract and it has virtually no colonic activity it does result in increased le s tone it increases antral and small intestinal contractions it is used mainly in patients who have symptoms of delayed gastric emptying and dyspepsia and the usual dose is 10

Milligrams taken 30 minutes before meals what about metoclopramide so medical permit has been around a lot longer than domperidone and it essentially has the same effects mainly upper gut activity however it’s not as clean a druggist on perdón while it is a d2 receptor antagonist it also binds to several other receptors for example it is actually a weak 5 h t4

Agonist like domperidone it is mainly used in patients who have symptoms arising from delayed gastric emptying and again the usual dose is 10 milligrams 30 minutes before meals metoclopramide also has some ability to bind to the d2 receptors in the chemoreceptor trigger zone making it useful as an antiemetic agent as well there is a parental preparation which is

Available for intravenous or intramuscular administration perhaps you should mention some of the key safety issues with metoclopramide and don para don right so while safety issues with these drugs are rare it is important that the prescriber be aware of the important adverse events for example medical provide does have some ability to cross the blood-brain barrier

And can cause extrapyramidal effects such as acute dystonia usually in the setting of intravenous administration it can also cause parkinsonian like symptoms that may occur several weeks after initiation of therapy these side effects usually reverse upon discontinuation of the medication medical provide as well can cause collect area in women by blocking the

Inhibitory effect of dopamine on prolactin release with domperidone there is a slightly increased risk of ventricular arrhythmias particularly in the setting of prolonged qt interval the risk is especially elevated in individuals who are greater than 60 years of age and at doses above 30 milligrams per day like metoclopramide domperidone can also elevate serum

Prolactin levels which can lead to collect area gynecomastia amenorrhea and impotence and again i should point out that these side effects are rare and that these drugs can be an effective treatment for patients with upper gi motility disorders thanks down that’s the end of our podcast today you discussed how we can influence the serotonin and dopamine systems

With medications to enhance gut motility perhaps in our next episode we can talk about the endogenous opiates okay let’s do that see you next time you

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Prokinetic Drugs By Gastroenterology 101