this is Dr busty and we're going to be doing our focus session on neurology on the topic of nonopioid um analesics it is a drug class review uh we'll incorporate some clinical pearls and integration of clinical um things that are important to monitor and and consider when you're taking care of patients so we'll start off talking about a Tylenol and then we'll go into O NSAIDs and NSAID nonol related mechanisms of action side effects monitoring parameters and then we'll finish off with some topical capsation um which would be another um nonopioid analesic that we use um in clinical practice so um acetaminophen has been around for obviously a long time it comes in a number of different dosage forms many of which are listed on this slide um that's just to demonstrate all the different products that are out there it's constantly changing and it's constantly it's more um involved than even what is listed here but the point is to show you that there are a number of products that are available um on the market and that contribute to its use um and I think it's important to realize um these formulations because as it relates to toxicity profile concerns that's where this comes from and we're going to come back to this in just a second we do have an IV formulation here that is usually restricted um of that is um restricted most by institutions mainly due to the cost um issues but it can be useful in some patients who have nausea um and or vomiting and need antipotic and don't qualify for anal now the mechanism of action has changed over time and depending on what you read uh you may get variations in that um there are different cs oxygenase enzymes that are present throughout the body and cycllox oxygenase is an important enzyme for metabolism of arachidonic acid and there's different there's different subtypes do different things and one of the um products that and mechanisms for which Tylenol uh seems to work on is in cycllo oxygenase 3 which is in the central nervous system that may have an impact on prostaglandins that mediate and control some of the um within the central nervous system thermmorreulatory center uh it has no anti-inflammatory properties and I think that's an important difference between the NSAIDs non-steral non-steroidal anti-inflammatory drugs versus um acetaminophen so which really an antipietic and mild analesic um type of medication uh the dose is limited usually uh there is a ceiling effect and that usually is around 4,000 milligrams historically per day from all sources um some manufacturers have reduced that or limit it uh mainly due to um concerns for legal legal issues um and error on the side of precaution um now there's a number of reasons for some of the warnings and the concerns um we even now have differences in um from the FDA as far as requirements for unit doses in the amount of Tylenol that is um formulated with in a particular dosage formulation and the reason for that has to do with a lot of even accidental overdoses that has contributed to a large amount of hospitalizations as well as um impacts on mortality um and so we'll we'll come back to the toxicity profile issues here in a second now within the IV uh formulation um these are approved uh for use in 2 years and above and again it's based on the weight of the patient um so that we don't overdose uh that patient but the onset of analesia has been reported to be as early as uh five to 10 minutes and antipetic effects are within um 30 minutes now our concern with overdose and and consuming too much of acetaminophen is is the toxicity with specifically not just only liver toxicity but renal toxicity and acidbased um disturbances and this comes from the way that Tylenol is uh metabolized and I'm going to cover that here in just a second but it it comes when we oversaturate the phase 2 metabolic pathway remember there's phase one phase two pathways of metabolism and elimination for various medications and phase 2 tends to be a conjugative pathway um and is its primary route of elimination but when you saturate that then you shunt the drug down the 2E1 pathway which is part of phase one metabolism that generates a toxic metabolite that requires further conjugation with glutathione and if it's not glutathione is not present then it causes damage to the cells and the surrounding area and so the antidote in that situation for those also thinking about their toxicology sort of topics is an acetylcyine and giving it usually within 8 to 10 hours of the ingestion especially when the ingestion is considered to be toxic or an intentional overdose so this diagram helps to understand what the issue is so if you look up here you see acetaminophen and like I said it preferentially wants to go down through phase 2 metabolic pathways well that's UGT is one of the more common ones and then soful transferase so you can see that the majority of it wants to go down the UGT pathway to get glucaronidated about 40 to 60% 20 to 40% go gets sulfated um and gets eliminated makes it more water soluble that is the intention and the purpose of phase 2 pathways is to make the molecule more water soluble well if you saturate this because you've ingested too much and you brought too much in quickly then some of that is going to get shunted down the 2E1 pathway remember which is a phase one metabolic pathway which underos oxidative reductant pathways and it forms this metabolite called napki and napki is a toxic metabolite that requires glutathione conjugation in order for it to be um inactive and made to be water- soluble for elimination in the kidneys however if you deplete all the glutathione that has nowhere else to go so therefore it it attacks and binds to surrounding cellular proteins and structures and that's what causes the cellular damage now in patients who consume acetaminophen and have enzymes that are induced or upregulated like with patients drinking alcohol so alcohol is known to be an inducer of 2E1 so therefore we are going to shunt more of the acetaminophen down this pathway and as a result of that generate even more napki in patients with known chronic li uh alcohol abuse um and so patients with uh who are chronic alcoholics and who have liver damage to begin with where there's likely to be lower amounts of glutathione they tend penny many clinicians tend to error on the side of reducing the amount of overall exposure of acetaminophen some say 3,000 some say 3500 um and you know who knows the exact level because I think it does vary based on a number of other confounders including nutritional status and the degree of enzyme induction that is present uh and so these are important parameters because we need to think about how to prevent this toxicity from happening and that's where we give the antidote an acetylcysteine which replenishes the glutathione to shunt the reaction this way so that the metabolite becomes um conjugated and made inactive and more water soluble for elimination in the kidneys when we start to think about who gets an acettocysteine has to do with the levels in the amount ingested uh this uh nomogram is is historically what is used to plot the levels based on the time frame if you know it of when the ingestion occurred so when you look at this let me orient you to here this is the hours after ingestion on the x axis and the yaxis are the Tylenol levels that you've actually ordered and measured you will see that the recommended way that this nomogram works is at the first point being 4 hours after known ingestion so the underlying assumption is that you know when the ingestion occurred if someone overdosed and used multiple medications where they have altered mental status or um have been partially successful in certain overdoses and are unresponsive you're not going to be able to adequately determine when that 4hour point is done and so that's why patients when they first come in will immediately get labs drawn to determine because if the level already comes above you know 200 then you know you're in a problem okay you just don't know what direction the problem is going is it going up or down and so you repeat it again and you see the trajectory that's that's going but the 4hour mark is the important point as it relates to the nomogram for proper interpretation and any level above 150 is concerning and if you you initially get that you probably should start in acettocysteine in these patients and that's where you have possible risk for liver damage anything above 200 then you probably are going to have hippatic toxpattocellular toxicity and liver destruction and or damage and you should go ahead and start therapy and then repeat the levels to see where they're going um as it relates to that so there's two different dosage formulations of an acetylcysteine historically um the oral formulation is what is most commonly known and has been taught um but now we do have an IV formulation they are different in their dosing and the um rate of administration to complete the total amount of medication to be administered and that's important differentiation it also they differentiate on their side effects oral is cheap smells very nasty but overall has really no major side effects however the IV formulation can be given quicker and over a shorter period of time but it runs the risk of anaphylactoid type reactions as well as increasing risk of bronco spasms especially in patients with more moderate to severe um hyperactive airway disease or asthma so let's look at that so we have an acetylcysteine in the oral formulation and then we have um acetone which is your IV formulation when we look at the oral an acetylcysteine as I mentioned it smells nasty smells like sulfur um and it's it it's putrid is very difficult to uh ingest and so this is why clinicians will co-administer it with some sort of drink or beverage that has something to kind of mask or cloud some of that um nasty smell um it is best to use within 24 hours of the overdose if possible the initial dose is 140 milligrams per kilo so if you think about that line of discrimination on the nomogram anything over 150 you get kind of ways to try to remember things 140 milligs per kilo is the total amount of loading dose okay that's given up front and then four hours later you give start giving these patients 70 mg per kilo and you do that every four hours for 17 doses so it will take a total of 72 hours to complete the entire regimen so that's very hard to do and requires some degree of cooperation and compliance from the patient um and as I mentioned we dilute it with soda because of the bad taste it takes a long time to get finished 72 hours um but it is cheap and very well overall tolerated now let's look at the IV formulation and it's best if and you look at the manufacturing recommendations to give within 8 to 10 hours okay the obviously the earlier and the sooner that you can administer the medication the better that's the take-home point the dose is a little bit different the total dose is going to be 300 milligs per kilogram but it's administered over a total of 21 hours at minimum all right at minimum i'm going to come back to that in a minute so the initial dose is 150 mg per kilo over 1 hour and then you get 50 mg per kilo in 500 cc's now we use a larger volume to help dilute the medication to reduce this chance of these anaphylacttoid like reactions that can also then exacerbate hyperactive airway disease and we do that um uh every four hours and then we move for the last 16 hours giving 100 milligrams per kilogram so we're slowly tapering it down and we're keeping it more dilute as we administer it so the high dose early on is the one that you're most concerned about um and the greatest risk of what we call flushing athemma in that first 30 to 60 minutes of that initial um infusion from the loading dose itself as I mentioned the anaphilacttoid reaction tends to occur early because of the dose but also more commonly in pediatric patients uh when you look at the overall incident that probably has to do with the degree of concentration of the fluids because of the size of the patient um but we tend to dilute more and give it slower to minimize that risk especially in the United States but if somebody has an underlying history of more moderate to severe hyperactive airway disease especially that requires multiple medications to maintain control this is considered a relatively contraindication to its use unless you have no other way of administering the medication if you do then just administer it much slower all right so that's Tylenol uh pretty straightforward pretty easy overall um issues to consider okay NSAIDs now NSAIDs are nonsteroidal anti-inflammatory drugs which are largely considered weak acids okay the exception to that rule is nebumatone okay um the uh well I'm sorry numatone is a weak acid but all of the uh NSAIDs are weak or being weak acids undergo varying degrees of eneropatic recirculation the exception is nebumatone okay the relevance of of this comes in as it relates to the amount of toxicity um to the gastric mucosa okay from chronic exposure so there's a topical direct irritation to the muscle uh mucosa but there's also the a systemic or indirect effect from the side of the on the blood once it gets absorbed and we're going to come back to that here in just a minute but being a weak acid is very important because in the presence of an acid a strong acid it stays in a nonionized state remember weak acids generally don't release their hydrogen ions in the presence of a strong acid and that becomes relevant um in the context of topical gastritis and why we administer the drugs with food to minimize that okay all right now all NSAIDs are considered to be equally efficacious at equal potent doses basically if you give the one NSAID compared to another in NSID at equal potent doses then they basically exert the same you know effect in patients from an efficacy standpoint there are some variations um based on the drugs route of administration okay there are parental agents as and topical agents as well as what indication you're using it for and we're going to come back to some of these so the more common one is oral but we do have IV formulations and then topical and even opthalmic eye drops okay there's a large number of indications and this is not the only you know exhaustive list but it's the more common list that is used and and recognized the common uses right osteoarthritis rheumatoid arthritis um analesia from acute pain assuming that the patient isn't at bleeding headaches and assuming they're not the headache isn't from a subacoid hemorrhage right pyrexia which is a fever uh acute gouty arthritis ankylosing spondilitis menstrual cramps and pains because those are prostaglandin mediated problems and contractions of the uterus and we'll see that NSAIDs block prostaglandins here in a minute kidney stones uh pericarditis another very common one post-operative pain especially to minimize the amount of opioids so that the patient can actually get out of the um pre post-operative area and even go home potentially earlier pda closure in in in newborns where the patent ductus arteriosis is still open and we need to get it closed and then it's also used in in a more non FDA approved indication for familial adenomus uh polyposis which is a a bunch of polyps that grow inside the colon and so they can be precancerous and so trying to get them under control um can be helpful and there's two drugs in particular that have been used for that saloxib and Solandac thealmic NSAIDs tend to occur for more ocular itching secondary to usually allergic conjunctivitis or pain and inflammation associated with postcataract uh removal okay now some patients especially now with refractive um cornea uh laser therapies for trying to get you know patients that don't want to wear glasses anymore this is for analesia post um procedure so how do they work well it's important to recognize that arachidonic acid is a omega-6 fatty fatty acid that comes out of the cell membrane of of cells and cells are made up of bipid cell membrane and so these are omega-3 and omega6 fatty acids make up components of the cell membrane and it's released by phospholipase A2 which is normally regulated by the presence of gluccocorticoids or corticosteroids arachidonic acid then can go down one of two pathways it can go down the five lipoxygenase pathway and form lucotrines which are pro-inflammatory mediators cytoines can cause a lot of inflammation as well or they can go down the cycle oxygenase pathway to form prostaglandins and then those prostaglandins can then go on to be further metabolized to other types of prostaglandins or can go through thromboxane synthetase to form throane A2 which is known to have um uh platelet um aggregating properties and so when we look at cycle oxygenase and we compare NSAIDs which I'm using the prototype ibuprofen in this situation right but all NSAIDs competitively inhibit cycle oxygenase not irreversible like aspirin so aspirin which is up here as well is not an NSAID but is linked up here to show you and to demonstrate a difference in mechanism they both work on cycle oxygenase but they work on different types of cycle oxygenase as you remember as I was talking about acetaminophen there's cycle oxygenase 3 that Tylenol may be working on in the central nervous system whereas NSAIDs and aspirin are working on COX 2 COX one predominantly COX one for aspirin and more COX 2 depending on and COX ones for NSAIDs okay and that's what makes them different but the big difference in how they inhibit cyclloyn is important nsaids competitively inhibit aspirin irreversible inhibition for the life of that enzyme okay and this has impact not only on local vasoddilatory properties okay because prostaglandins are vasoddilatory when they're present but also have platelet effects that we've been talking about okay and this sets up the risk for side effects which I'll come back to both in the kidneys and in the gut and your risk for bleeding all the stuff smart making sense when you understand the mechanism of action which is why I'm trying to spend a little bit more time making sure that mechanism is clear now anti-inflammatory properties okay nonsteroidal anti-inflammatory drugs comes from the inhibition of the immune systems chemotaxis these are white blood cells that move to areas of inflammation it blocks some of that it also downregulates interlucans which is the antipyuretic effect that is seen not only in chronic inflammatory states but also in infectious disease states it also decreases free radicals and superoxides um that create more tissue damage and problems so how do you make or how are the NSAIDs different they differ in their mechanism on what type of cycle oxygenase they predominantly inhibit they also differ in their halflife which then confers their effects on platelets and the risk of bleeding okay remember I said at the beginning all NSAIDs at equal potent doses pretty much are equal okay now you'll see here that aspirin as I mentioned is not an NSAID is an irreversible inhibitor okay permanent inhibitor of cycle oxygenase and specifically cycle oxygenase one whereas all the NSAIDs which is everything down below um aspirin are differ in the amount of COX one to COX 2 that they inhibit so some of the NSAIDs are more COX 2 selective whereas some are more COX one right as Aspirin being predominantly COX one and it what's important to note is that COX one is a normally constitutively expressed enzyme throughout the body in various organs that means it's part of the normal physiology and function of our body whereas COX 2 expression in the amount that's present is influenced by uh acute and chronic inflammatory conditions okay so if you really want to affect anti-inflammatory have anti-inflammatory properties you really want to be affecting COX 2 because COX one does a lot of things that is normal for our normal physiology that's helpful things like gut profusion things like platelet effects things on the blood vessel diameter we want to be careful about inhibiting too much COX one and so COX 2 selective agents tend to be a little bit better in their re because they have less risk of GI ulceration risk as well as the risk of bleeding and we're going to come back to that again i'm going to keep building on this but that's what makes them different so you can see like celoxib is a very strong or more selective COX 2 inhibitor dicloanac is more COX 2 selective etotilac or loadine is more COX2 selective the other thing that I mention is their difference in their half-life you can see that a lot of these agents are fairly short but we have a few that are longer like celoxib dlunisol right we have a total act which is decent right um so we have some that are longer we'll see here on the next slide that neproxin is also a longer acting agent the relevance of that even though they're competitive inhibition they do um cause some degree of antiplatlet effects and so you can see those listed here these are not things that you have to memorize Nice but the important relevant point is that somebody's going into surgery where they're at higher risk for bleeding right you want to avoid and know when know when to stop these medications and counsel patients of when to stop them whereas with aspirin you could you see that you have to sometimes stop a week to two weeks in advance of a surgery especially if that surgery is at high risk for significant bleeding because of the irreversible impact but due to the fact that a lot of these are these are NSAIDs are competitive inhibitors usually within one day to two days most of these drugs are completely gone now I have a few clinical notes here in this last column that just little pearls that make them a little bit different really there's nothing significant in here that really is that important and I'm not going to be picky or I don't think any board exams going to be picky about this on on a test okay as I've mentioned ketorofen here a little bit more COX 2 selective and you can see that really there's no known either CO2 selectivity or it varies depending on the assay now you can read papers that will vary in their opinion based on the assay and the model that is used um I did want to point out an approxim um present in um a leave which is available over the counter without a prescription you can see that it has a much longer halflife compared to a lot of um insaids and so it can be administered twice a day with good relief it also has pretty good penetration in the central nervous system which can be helpful in patients with migraines so if you think about patients struggling with headaches you want to get drug present into the site of where it's going to predominantly work and so this is an advantage to neproxin um especially given the fact that it is available over the counter you can see that peroxyam has a very long halflife as well as oxiproin or day pro as well okay and so that makes it easier for dosing okay you see that dosing once a day whereas neproxin is every 12 hours so linking the pharmacocinetic profile influences the way that the drug is prescribed and that's an important point we have parental NSAIDs uh we have dicloanac dyloect ibuprofen calorac which is probably the most common used in practice mainly because of its availability and cost is toridol and then we have endomethasin which we historically and predominantly reserved for specifically closure of the patent ductus arteriosis if it is open in a newborn okay again all these are given IV the exception uh is that we give um ctorillac you can also give it I am okay now what makes them a little bit different well part of it is their dosing okay you can see the ibuprofen dicloanac every six hours you can also do that with ctorillac you but the problem with ctorillac is it tends to be a little bit more cox 2 I'm sorry cox one selective and unfortunately uh is dosed based on the weight of the patient and the route of administration so for example you'll see with patients who are younger and over 50 kilos we can get away with larger doses and the IV and IM basically the IM is twice the amount of the IV when you get to be older where your risk of renal impairment is higher and they're on other medications um and or they are smaller and more kekctic then our doses are basically cut in half okay further and that's important now you'll also see that many hospitals um and agencies will limit institutions will limit the use to less than 10 uh five days and the reason for that is because of the risk of renal damage nephrotoxicity risk of GI bleed increased risk of bleeding and increased risk of cardiovascular related events now a lot of times couturlac is used around procedures or post-operatively to try to reduce the amount of opioids that patients need again it's been highly available it's generic it's cost-effective and it works but you should be using it more intermittently and not repetitively another place that I see it used a lot is in cickle cell disease uh patients now there's problems with giving cickle cell patients parental NSAIDs and it mainly comes down to the increased nephrotoxicity effect because they're sickling these cells and causing olusive uh uh crisis even into the blood vessels of the kidneys and so they have higher risk of developing especially chronic kidney disease earlier than other patients so we have to be very careful with their use we do have some topical NSAIDs mainly dicloanac that comes as a solution sorry solution here uh but we also have gel and a transdermal patch can be used for acute sprains or osteoarthritis the idea behind topical to minimize the systemic exposure specifically the risk of GI toxicity and the risk of of um uh bleeding but you we need to realize that it's not zero it does reduce the risk though okay all right opthalmic agents like I mentioned before for pain inflammation after procedures so cataract surgery see here coral refractive surgery very common you'll see that couttorac is available um for use for seasonal allergic conjunctivitis um and so the they differ in the number of drops that they have to apply and the frequency you can see some of these one drop every 30 minutes okay one drop four times a day so it just depends on the agent now if you have a suspension which is kind of nice you can get away with once a day starting prior to surgery uh in in that situation if your opthalmologist prescribes it um to you that way now some of the issues uh with this is that it can increase the lacrimmation so that's forming tears it can also cause corneial irritation so keratitis and it has also been shown to increase uh intraocular pressures and if you think about drugs that are used to treat glaucoma from that cause that's as a result of increased intercular pressure those are prostaglandon analoges so remember NSAIDs are reducing prostaglandins will therefore increase intraocular pressure which would be problematic in a glaucoma patient okay so here's all the different side effects so I've been mentioning bleeds GI irritation ulcers there's also increased risk of hypertension you due to increased plasma volume which can lead to heart attacks and stroke there's also nephrotoxicity effects and um even seizures with an older drug that we don't really use anymore okay most of these side effects go back to prostaglandins in particular some of them have to do with thromboxin A2 as it relates to the bleeding okay okay so I'd like to go through some of these side effects with you okay but as a reminder that arachidonic acid that would normally go through cycllo oxygenase to form these prostaglandins right see all these prostaglandins those are helpful to have local vasodilatory properties on the blood vessel so they're vasodilatory when they're present and they have anti-platlet properties antiplatlet properties so therefore if we block them then we're going to cause vasoc constriction which is going to reduce profusion to tissue it's also going to reduce the antiplatelet properties and make it more prothrombotic state however you're also blocking thromboxane formation in these situations so that increases your risk for bleeding so there's a net increased risk of bleeding and a net effect of vasoc constriction when we block these uh with this enzyme again ibuprofen being uh and NSAIDs being competitive inhibi inhibitors based on the half-life depends on how much inhibition you get whereas aspirin is an irreversible inh inhibitor so therefore let's go through some of these adverse events so what's happening with NSAIDs as it impacts vasom motor tone so we thought about the side effects earlier what I said hypertension which can then increase your risk for MIS and stroke so how does it do that well remember the blood vessels are made up of smooth muscle and they're always dilating and contracting dilating and contracting and there's a number of mediators that cause those to dilate and contract right we have calcium we have alpha 1 receptors we have beta 2 receptors but they also in respond to prost prostaglandins in particular pro prosttoycline or PGI2 so PGI2 is known to have vasoddilatory properties but if you block it you then shift the vessel to a smaller vessel so it's constricted that means the blood flow to the tissue distal to that vessel that's being spasmed shut is going to be decreased and that's not a good thing it also will increase the blood pressure but it also decreases profusion to things like the kidney kidney doesn't like that and so the kidney sees decreased oxygenation being delivered to the renal parinma or tissue that can cause death to that cell which is why NSAIDs are nephrotoxic at some level they also then turn on RAS right renin angotensin aldoststerone system because the jxular glomeular cells in the nephron sense a decreased perfusion as a result of the decreased profusion they release RAS or renin sorry which ra activates RAS and the end result of RAS is aldoststerone release that causes sodium water retention and that increases plasma volume which raises our blood pressure that hopefully turns around and increases perusion back to the kidney so it has an impact on vasom motor tone of to tissues all over the place the heart the GI tract the kidneys your eyes your brain it doesn't matter okay now what are NSAIDs doing to platelets well remember platelets are these fragments and the uh components that make up sort of part of the thrombus that's forming to prevent you from bleeding out now remember platelets only express COX one so therefore aspirin predominantly works on COX one it's an irreversible inhibitor so for the life of that platelet it's affected whereas NSAIDs are competitive inhibitors but also have a different ratio of COX one to COX 2 so some NSAIDs are going to affect platelets more than other NSAIDs more COX2 selective NSAIDs have less effects on the platelets and less risk for bleeding that's one of the reasons why Celoxiv or or Celre is used in patients with chronic need for anti-inflammatory drugs to reduce the risk of not only ulcers but also the risk of bleeding but if you have a COX 2 selective agent it won't decrease platelet aggregation and if you have a patient with vascular disease that actually could be bad okay now what impact is it having on blood volume remember we just talked about RAS well this is that blood vessel aerant arterial coming into the nephron here's your glomemeilus and here's the bow and space of the nephron right and blood flow comes in and blood flow leads out and then it puts pressure on the basement membrane and it filters things out right but if I give a prostaglandon uh inhibitor like NSAIDs then I constrict this blood vessel right if I constrict this blood vessel then I take away some of the profusion pressure because there's less flowing in i also decrease the amount of profusion distal to that point so all of this tissue over here is going to be compromised and that's what causes acute tubular necrosis cell death the the tubule dies because it lost blood flow to it and that's what can happen by giving somebody especially if they're dehydrated or they have vascular disease or in cickle cell patients who have a vasoclusive crisis where they're oluding the blood vessels now you constrict the blood vessels further now you're going to decrease profusion even more so and that causes renal damage okay now the cells in this area right here that sense that reduce profusion those are the JG cells okay jcular glomemeular cells that are known to increase the release of renin renin is important because it helps to convert angotensinogen to angotensin 1 angotensin one gets converted via ACE to angotensin 2 angotensin 2 then goes to the adrenal gland and binds to the angotensin 2 subtype one receptor that increases the release of aldoststerone aldoststerone then goes to the distal convoluted tubule of your kidney to facilitate sodium and water reabsorption as a result of reabsorbing sodium and water we increase plasma volume as an increase in plasma volume that increases the profusion so going back here that increases the blood flow back through the renal aerant arterial and these JG cells then sense that increased profusion and reduce the amount of renin that is being released but that raises your blood pressure when they do that okay now what about ulcers in the GI tract we know that um one and to 3% of users will end up having a GI bleed that's a deadinal ulcer or a gastric ulcer okay again the one dadinal ulcers are the ones you get most concerned about because there's a lot of blood vessels there that we'll see here in a minute that are close to the vasculature so here's the aorta a very important large blood vessel in the body and you can see that the blood vessels coming off peruse the GI tract okay now these blood vessels coming off of a large blood vessel there's one back here in particular that we're most concerned about and that's the um gastrodinal artery here okay this one right here and if you get an ulcer in this area of the deadum uh then they these patients can have life-threatening bleeds obviously there's other blood vessels around there that can bleed profusely and this is what causes patients to either vomit bright red blood or if they end up digesting this blood it turns their stools black and that's what we term melanina uh in the stool right that's their black thick tarry stools from blood that is bleaking out here up in the upper GI tract and over time gets digested down and turns the stool black what are the risk factors well patients with a previous risk of um peptic ulcer disease and this would be a reason why you may want to avoid using NSAIDs in these patients older patients over the age of 65 and the reason for that is this these patients already have known vascular disease usually over time they end up also being on multiple medications some of those medications can include anti-platelet drugs and anti-coagulants which increase the risk for bleeds already right and so they have a lot of medications they have a lot of risk factors and their ability to handle bleeding is less than somebody who's younger without other coorbidities especially if they have vascular disease and you start leaking a lot of blood out you lose the oxygen carrying capacity to the to the tissue of your heart and then you can start having chest pain so this is where a patient can have a GI bleed that leads to a heart attack because of lack of oxygen carrying capacity to the myioardium all right patients with systemic vascular disorders like CVD peripheral vascular disease already concominant cortosteroids aspirin use anticoagulants antiplatlets again we again we see this more commonly in our older patients and then having a known presence of H pylori helicoacttor pylori is something that a lot of people get colonized with and we get exposed to but when it's present um it does increase the risk of GI bleeds and if you don't adequately treat H pylori it causes recurrent GI bleeds in patients and so this is one of the reasons why we have to look for this and why patients need an EGD um and basically in a um uh endoscopy where they we look into their stomach and we biopsy the actual tissue to see if they have H pylori present or we do the ura breath test to discern if it's present because if it's it is when we need to treat it now what causes these ulcers what is the pathophysiology well there's something called initially direct or topical irritation so when you administer one of these NSAIDs by mouth in particular right they're weak acids being a weak acid okay that means the pKa is pretty high so that means that in the presence of a strong acid it is not going to release its hydrogen ion that means it's going to be a nonionized or noncharged state the relevance of that is nonionized and non-charged molecules tend to be more lipopilic or fatloving and that would allow them to penetrate through cell membranes more effectively and efficiently and when you administer an insaid on an empty stomach in the presence of a strong acid like hydrochloric acid that's there what h ends up happening is that molecule diffuses into the cells of the lining of the GI tract and then it gets inside of those cells where the cytoplasm is at a pH that's much higher than that of hydrochloric acid now it's in the presence of a more alkaline or neutral environment where it can release its hydrogen ion and become charged once it gets charged it's also trapped in that environment okay which is problematic but that facilitates something called hydrogen ion back diffusion where the the drug molecule diffuses through the cell it releases its hydrogen ion backwards onto that cell's lining and that increases the breakdown of the gastric protection so that's gastric mucus it also affects the hydrophob uh uh phobic areas of that tissue and compromises its protection okay drugs that undergo bilary excretion and eneropatic recirculation where it's being kicked out in the bile back into the intestine back into the bile back out in the intestine that pro that is problematic because you're chronically exposing the tissue but the reason we tell patients to take it with food is to create a barrier so that that nonionized or non-charged molecule has no way of penetrating through that cell membrane so that's why we tell patients to take it with food once it gets absorbed it doesn't matter at that point food or no food it's going to inhibit prostaglandins and in prostaglandon inhibition does a number of things we not only talked about what it does to blood vessels so it will decrease blood flow to the mucosa of the intestine and the GI tract which is not good because it doesn't then bring oxygen and the nutrients and the precursors to make by carb mucus and all these other things that protect the gastric lining so then what ends up happening is we compromise epithelial mucus production we compromise bicarbonate secretion we decrease blood flow and profusion to the GI tract we affect epithelial cells to be able to replicate which is a highly dependent area for replication that increases our overall uh chance of uh res uh mucosal injury because we lose the resistance in protection of that GI tract okay now NSAIDs that more COX 2 selective okay historically Vio which was pulled off the market Beckra which was also pulled off the market uh many years back because of their risk of cardiovascular disease now Celoxib is still present on the market but why did they worsen and increase vascular disease and events well it's mainly because again platelets only express COX one so if you have a very COX 2 selective agent you're not getting any uh antiplatlet properties and in patients with vascular disease we know that that's not a good thing okay on top of that when you do have vascular disease and you wipe out the prostaglandins that are normally causing a local vasodilatory property and you wipe those out you then cause vasoc constriction well if you already have a vessel that's got a bunch of plaque in it that is now more likely to constrict you're going to reduce profusion even more so and so patients taking long-term NSAIDs or more COX2 selective agents and patients not taking aspirin then are at higher risk for vascular disease well the problem is if you take aspirin on top of an NSAID now you have two drugs that are affecting cyclloxygenase that affect constituentase that increases your risk of toxicity including GI bleed so you basically lose the GI protective benefits of COX2 inhibitors when you co-administer it with aspirin but at the same time you reduce that chance of vascular uh events but this is the reason that the FDA over the years has increased its warnings about NSAIDs and the greater risk of heart attacks strokes and heart failure and the reasons for that is not only due to increases in plasma volume that raises your blood pressure but if it raises your blood pressure and plasma volume it can certainly exacerbate heart failure because too much fluid exacerbates systolic dysfunction and so this is really really important to recognize but it's also when you think about the mechanism of being a competitive antagonist or inhibitor of psychoynase versus aspirin being an irreversible inhibitor this is one of the reasons why aspirin offers or confers a cardioprotective benefit specifically because they're working on platelets more so than um the NSAIDs okay so NSAIDs do not confer any mortality benefit and should not be used as a replacement of aspirin in patients with cardiovascular disease i describe that in detail here on this particular slide for those of you that need additional you know notes or you want to read about it in more detail but that is the risk factors and that is the mechanism or the pathophysiology that I just described this is also the mechanisms for the renal complications as a result of decreased profusion so we reduce renal blood flow that reduces our GFR this can lead to decreased oxygenation to the tissue that causes necrosis so we get acute tubular necrosis or ATN we can also see renal papillary necrosis interstitial nefritis okay and then we know that this worsens blood pressure and it can also then cause dysfunction I'm sorry interaction with other drugs like ACE inhibitors andotensin receptor blockers and even diuretics because if you think about all those drugs they're all trying to reduce plasma volume so how does that happen well if you think about the cross-section of a kidney right these are where all the nefrons are located and you see all those blood vessels coming in and going out if we zoom in again we're here in that renal aerant arterial but if you decrease the blood flow coming in remember those JG cells are going to increase the release of renin which is going to increase RAS which if you're on ACES and ARBs or renin inhibitors you're trying to block RAS so what ends up happening is the NSAIDs sort of rev up RAS that is partially being inhibited by these drugs and so therefore you lose not all the efficacy you lose some of the efficacy of ACE inhibitors antidotensor receptor blockers renin inhibitor use right now diuretics are problematic because they reduce plasma volume and when you reduce plasma volume and you reduce that blood flow because of prostaglandin inhibition now you got some decreased profusion that's important and very relevant but at the same time NSAIDs are going to known to rev up RAS which the end result is to increase plasma volume so you got a drug over here that's trying to decrease it you got another drug over here that ends up increasing it indirectly and that's why there's drug interactions with these medications and that should hopefully make sense okay all right uh so this is just a summary slide you know for again to summarize it nsaids are all equally efficacious at equal potent doses they differ in their cost their dosage formulation root of ad uh root of administration okay okay if one isn't working switch to another agent some people respond better remember they differ in their COX 2 to COX one ratios um do not um these drugs when they're being used for rheumatoid arthritis they do not work as demarge they only slow down the the or reduce the pain associated with these um drugs you have to really use demarge and rheumatoid arthritis to actually prevent some of the destruction of the um joints we talked about the renal and vascular related events with these drugs all right what about capsation to finish this off now capsation has been available over the counter historically in mainly topical administration right as a cream now there's also a a patch that's called and it's a they differ in their formulations by the concentration of capsation capsation is like eating chili pepper basically it burns like crazy the reason that it burns is because it actually stimulates initially the nerve endings and activates nerve pathways to your spinal cord and eventually to your brain and the way that it does that is it activates this uh u receptor called the transient potential vanilloid one receptor okay so on these nerve endings that are sitting out on your skin or on your tongue or in your mouth or in your eyes wherever they get turned on and it stimulates those and you start shooting all these nerve conductions to your spinal cord into your brain so your brain perceives ow that hurts that burns now what happens when people eat red hot chili peppers day and day and day after they they can eventually start to eat those peppers without any burning um they develop sort of a tolerance to that and what happens is you continue to activate this this transient vinyl or potential vinyl one receptor it causes a down reggulation and decreases that nerve stimulation over time but you got to continue to expose the nerve to it that's the number one problem with this drug it requires continuous exposure with the topical cream but the topical high concentrated patch you'll see here in a minute the dosage is so high in concentration that you can get away with a one-time dose every three months now let's talk about the cream first so they differ in over-the-counter formulations by their concentration you can see this concentration of up to 0.1 i've not really seen formulations of 0.15% although they I've technically available um but this is much different and lower potency compared to which is 8.0% very big different concentration now when we use the topical creams these patients are going to start to have burning right I just told you you're going to activate the receptor so you have to counsel the patient and warn them ahead of time this causes initial burning you have to use it three to four times a day and over the next 10 to 14 days that burning will go away and then you'll get pain relief and the benefit of this pain relief is that it doesn't cause systemic side effects or toxicities it doesn't interact with medications and it can provide you pain relief that's something you don't even need a prescription for but you've got to take it on a scheduled basis day in day out and even when the pain goes away you have to continue to use it every day even though the pain is not there because it's the constant exposure so this drug should never be prescribed or administered as a PRN or as needed basis it will never work for pain management and anybody who prescribes it or administers it in that fashion doesn't have a clue what they're doing and should stop and quit now the capsation patch is a transdermal patch uh it is a one-time patch that's applied for 1 hour now because of the high concentration you're taking those nerve receptors and you are really revving them up okay and so you have to actually premedicate these patients with lidocaine you need to give them some analesics like hydrocodone and and Tylenol to try to minimize the pain then you apply this uh patch on for an hour you then remove it and you wash the area for about a minute and yes they're going to burn for about 24 to 48 hours but then they get up to three months of pain relief and they don't need any more medication now they have to come back to get another repeat dose okay but it's only administered and applied in the clinic this is not something that we prescribe and dispense to patients to use at home it is it is cut out and applied to the area of concern um in pain relief and it that is nice to get a one-time application yes you you have to go through a little bit of burning but you get three months of continuous pain relief without having to apply the medication on a daily basis that's pretty cool in my opinion so it does have utility although it can't be dispensed as I mentioned or prescribed to patients