NSAIDs & PROSTAGLANDIN ANALOGS Simplified

Pharmacology of prostaglandin analogs

This post is going to cover pharmacology of non-steroidal anti-inflammatory drugs known as n set as well as pharmacology of prostaglandin analogs but before we do that let’s first discuss what happens during inflammatory response so following tissue injury or irritation enzyme called phospholipase a2 is released which converts phospholipids in the cell membrane into academic acid now our key tonic acid is a substrate for two major enzymes the cyclooxygenase abbreviated as cox and v lipo oxygenase abbreviated as five locks in this lecture we’re gonna focus just on the cyclooxygenase pathway now the Cox enzyme exists in different forms two of which are cox-1 and cox-2 the first one Cox one isoform if expressed constantly throughout the body and it’s primarily responsible for production of Traum boxing and prostaglandins which stimulate normal body functions such as secretion of protective gastric mucosa,
regulation of gastric acid,
promotion of platelet aggregation and maintenance of renal blood flow.

Now on the other hand Cox II isoform is not expressed constantly in most tissues but instead it is induced at sites of inflammation so unlike Cox one Cox two derived prostaglandins mediate mainly inflammation pain and fever now that we discussed the role of Cox enzymes in the inflammatory response let’s talk about mechanism of action of NSAIDs so ANSYS act primarily by inhibiting Cox enzymes which simply leads to decrease production of prostaglandins as a result and cells produced anti-inflammatory antipyretic and analgesic effects now based on their selectivity for Cox enzymes and sets can be divided into three broad categories:
First selective cox-1 inhibitors which include ketorolac flerbie profane ketoprofen in the medicine and low-dose aspirin in the second category we have relatively known selective Cox inhibitors which include naproxen proton pure oxygen and they flew us all and finally in the third category we have selective cox-2 inhibitors which include meloxicam diclofenac silicon chip and a $2 now this relative selectivity for the COTS enzymes explains some of the differences in efficacy and safety of these n sets so the most common adverse effects of answers occur in the gastrointestinal tract this is where it cox-1 mediated production of prostaglandin e2 t GE – for short and prostacyclin pgi2 for short plays

An important role in the synthesis of protective mucus as was regulating normal gastric blood flow this is why inhibition of coxswain increases risk for GI bleeding and peptic ulcers agents that are more selective for a coxswain are associated with the highest risk now the second major side effect of NSAIDs results from inhibition of coxswain mediated production of chum boxing a to TX a – for short as you may remember from boxing a – promotes platelet aggregation so decreasing its formation results in anti platelet effect and thus increased risk of bleeding this effect is particularly evident with the use of aspirin which unlike the rest of the end sets irreversibly inhibits coxswain enzyme in platelets moreover because platelets don’t have nucleus they can’t make new enzyme so aspirin induce anti platelet effect persist even after aspirin therapy stopped as it takes several days for the new platelets to replace the old ones.

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So again agents with higher selectivity for coxswain enzyme are also associated with prolonged bleeding time now let’s discuss the third major adverse effect of ances which results from their actions on the kidney so renal prostaglandins specifically e2 and I two types cause dilation of the reno efferent arteriole which is important for maintaining glomerular filtration rate that being said under normal conditions these prostaglandins have only minimal effect on renal perfusion however when kidney function becomes compromised for exam due to heart failure or old age the production of prostaglandins becomes a significant factor in preservation of the renal blood flow so because NSAIDs decrease production of renal prostaglandins they also may increase the risk of kidney injury in susceptible patients now the last major adverse effect of NSAIDs that I wanted to discuss results from their actions on cardiovascular system so our agents such as aspirin with high coxswain selectivity can have protective cardiovascular effect due to the antiplatelet properties

Agents with high cox-2 selectivity can have the opposite effect in order to understand where this adverse effect comes from let’s take a look at the blood vessel supplying blood to the heart so under normal conditions we have a balanced effect between cross recycling and from box in a 2 now prostacyclin is produced mainly by Cox do in the endothelium and it’s responsible for vasodilation and inhibition of platelet activation on the other hand from boxing a 2 is produced mainly by Cox 1 in platelets and it’s responsible for vasoconstriction and a promotion of platelet aggregation so now the problem arises when selective inhibition of Cox 2 tips the band’s in favor of term boxing a to formation this makes vasoconstriction and plate with aggregation more likely to occur this in turn leads to increased risk of cardiovascular events including myocardial infarction and Stroke now that we discuss NSAIDs let’s talk a little bit more about prostaglandins so even though prostaglandins can produce many unwanted effects such as inflammation they’re also responsible for many beneficial effects in order to harness those beneficial effects scientists developed prostaglandin analogs which simply mimic our endogenous prostaglandins now prostaglandins exert their effects by interacting with specific g-protein coupled prostaglandin receptor of which there are at least nine known subtypes.

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The effects of particular prostaglandin may vary widely depending on the tissue and express receptors so now let’s discuss some of the commonly used prostaglandin and starting with analogues of prostaglandin e1 example of agents that belong to this group are our possible lubiprostone and misoprostol although all these agents are derived from prostaglandin e1 they were designed for different therapeutic purposes so our pasta dough has two main therapeutic uses first is rectal dysfunction when our costa dough is applied into the urethra it acts via direct stimulation of cmp pathway to decrease intracellular calcium levels allowing for relaxation of trabecular smooth muscle and dilation of cavernosa arteries this ultimately leads to improved erectile function secondly our postural issues in neonates with congenital heart defects to temporarily maintain the patency of ductus arteriosus so for those of you who need a refresher doctors arteriosus is a blood vessel found in babies before birth that allows blood to bypass the pathway to the lungs although this blood vessel typically closes shortly after birth keeping it open in certain babies with heart defects may improve blood flow and oxygenation so infusion of our pasta dough relaxes the ductus arteriosus and supports its patency until surgery can be performed now let’s move on to the next prostaglandin e1 analog that is lubiprostone

so, lubiprostone is used in the treatment of chronic constipation it works by activating type 2 chloride channels in epithelial cells lining the intestine by stimulating these channels lubiprostone promotes secretion of chloride followed by passive secretion of sodium and water which increase the liquidity of the intestinal contents this secretion also stimulates intestinal smooth muscle contractions which facilitate the passage of stool now let’s move on to the next prostaglandin e1 analog that is misoprostol so misoprostol is another prostaglandin e1 analog and it is used to treat and prevent stomach ulcers particularly in patients taking In sets.

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It can also be used to induce labour misoprostol works by binding to the prostaglandin receptor on the gastric parietal cell and causing decrease in intracellular cmp leading to decreased activity of proton pump and thus modest inhibition of acid secretion furthermore my suppressor protects the stomach lining by increasing bicarbonate and mucus production lastly by interacting with prostaglandin receptors in the uterus misoprostol causes softening of cervix and urine contractions leading to the expulsion of the urine contents now let’s move on to prostaglandin F 2 alpha analogues example of agents that belong to this group are D’Amato Prost Latin approach and travel pros these agents are used optimally for treatment of open-angle glaucoma they work by increasing the outflow of ATS fluid from the eye and thus lowering intraocular pressure although Litella pros and charles accomplish that by interacting with prostaglandin f receptors located throughout the eye beam at approaches thought to have a different mechanism of action which is currently unknown.

Furthermore among the unique side effects of the matter process is elongation and darkening of the eyelashes which makes the net approach useful in treatment of eyelash hypertrichosis now let’s move on to the last group of analogues that is process cyclin analogues example of agents that belong to this group are isla post and repost in all these agents are used to treat pulmonary arterial hypertension they work by increasing production of CMP which leads to decreased levels of intracellular calcium in pulmonary vascular smooth muscle cells ultimately causing vasodilation this results in significant reduction in pulmonary vascular resistance and enhanced cardiac index and without I wanted to thank you for watching I hope you enjoyed this Post and as always stay tuned for more.

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