Fun 2: 11:00-12:00 Scribe: Rylee Burt

Fun 2: 11:00-12:00 Scribe: Rylee Burt

Thursday, December 3, 2009 Proof: Kosha Shah

Dr. Arnold Inflammation, NSAIDs, and Gout Page 1 of 6

I. Inflammation, NSAIDS, and Gout [S1]:

a. Today we are going to be talking about inflammation, NSAIDs, and gout. Now I am just going to give a little bit of an overview of the stuff we are going to go over today. We are going to begin by going over the inflammation process. After that we are going to discuss a few of the agents used to treat inflammation, from the NSAIDs to acetaminophen. Finally we are going to finish by talking about an acute chronic inflammatory condition known as gout and some of the agents used to treat it and some of the potential interactions those drugs can have with other drugs.

II. Overview [S2]

a. Now let’s start with talking a little bit about inflammation. Inflammation is a process involved with many different diseases, either causative or symptoms of. That being the case, you are going to have a lot of medications used to treat inflammation in a variety of ways.

III. What is Inflammation? [S3]

a. Now, what is inflammation? Inflammation is essentially a vascular and cellular response to some sort of insult, injury, or trigger. It is characterized by the movement of white blood cells, fluid and so forth into the extravascular tissues.

IV. What is Inflammation? [S4]

a. There are many different triggers for inflammation. You see here bacteria, toxins, even auto-immune disease, but whatever the trigger is, the process is going to be essentially the same.

V. Inflammation [S5]

VI. Sequence of Events in Inflammation [S6]

a. We will have changes in blood flow mediated by different agents. Inflammation: the response will be redness and heat. Ultimately you will have permeability changes in endothelial cells that will result in swelling, pain, and what not. Finally in late stages we will have hemostasis and essentially loss of function.

VII. Inflammation [S7]

a. Now the 5, really 4, cardinal signs of inflammation. Verchow’s Triad is what it is known as. Redness, swelling, heat, and pain, and what has been recently been described as loss of function.

VIII. Mediators of Inflammation [S8]

a. One of the things I want to point out and remind you is that we often think of inflammation as bad. We think that inflammation is bad. Really, the inflammatory process serves a useful function. It helps to remove triggers, remove bacteria and what not, but when the inflammatory process goes awry, either through chronic conditions or what not, that is when we have to start worrying about ameliorating those symptoms with anti-inflammatory drugs. Now mediators of inflammation. Some of the ones that are the principle or chief precursor to all the mediators of inflammation is arachidonic acid. Arachidonic acid is a component of cell membranes and when we have damage we have release of arachidonic acid and ultimately conversion. Conversion by phospholipase, basically phospholipase conversion to arachidonic acid and that is ultimate conversion into other mediators of inflammation: leukotrienes, as well as prostacyclins, prostaglandins, and thromboxane.

IX. Mediators of Inflammation [S9]

a. Really the lipooxygenase pathway is a pathway that we won’t spend a lot of time talking about today. The leukotrienes are essentially produced during conditions such as asthma, those kinds of things. It can cause bronchoconstriction, so on and so forth.

b. What we will spend a lot of time talking about is the cyclooxygenases, COX-1 and COX-2. Now really as you see here, glucocorticoids are the Cadillac of anti-inflammatory drugs. They basically knock out inflammation from the top of the cascade. We can’t give glucocorticoids-if we could we would give them all the time-in inflammatory conditions. And a lot of times we still do. We can’t give glucocorticoids chronically because they have a lot of deleterious side effects that restrict their use. That being the case a lot of times we have to treat inflammation further down the cascade. We will talk a little more about that.

X. Non-steroidal Anti-Inflammatory Drugs (NSAIDS) [S10]

a. The non-steroidal anti-inflammatory drugs are one of the most popular and prevalent classes of anti-inflammatory drugs. There are about 70 million prescriptions written a year and 30 billion OTC medications purchased annually. As you can see, those are both nonprescription and prescription. This being the case, your patients are going to have access to the medications whether you write a prescription for them or they go to CVS and take them off the shelf. The first NSAID, salicylate, was isolated over 100 years ago. Folks found they could chew willow bark and it had beneficial properties in terms of reducing fever and pain. There is a lot of different compounds and one of the ways we actually which compound to use depends on side affect profile. I will talk a little more about that. One of the beautiful things about these compounds is that they have basically have no addictive potential, as opposed to using morphine, or some opioid where there is that chance for addiction. They lack the sedation respiratory depression that you might see with an opioid. At low doses, they tend to have analgesic properties, pain reducing properties. And as we begin to ramp up the dose we begin to see anti-inflammatory effects.

XI. NSAIDS Mechanism of Action [S11]

XII. Roles of COX-1 and COX-2 [S12]

a. The non-steroidal anti-inflammatory drugs mainly inhibit in the cascade at the COX-1 and COX-2 junction. So basically they can cause a decrease in the production of prostacyclins, prostaglandins, and thromboxanes. That can be important and we will talk specifically about what those mediators do in a moment. First, let’s consider the enzymes themselves. COX-1 is essentially thought of as a housekeeping enzyme. The prostaglandins that it produces function in things like GI cytoprotection, activation of platelets, as well as enhancing renal function. The COX-2 enzyme is thought of as more of an inducible enzyme. It has some housekeeping functions, some renal functions, but mainly it causes inflammation, pain, and fever. The prostaglandins it produces causes those things.

XIII. Effects of Prostanoids [S13]

a. So, different prostanoids and you can see the different functions that they have: vasodilation, pain sensitization, and bronchoconstriction. Two that are very interesting and will important later on are at the bottom there: prostacyclin and thromboxane. Prostacyclin essentially inhibits platelet aggregation. Thromboxane stimulates platelet aggregation. So there is sort of a yin, yang relationship between those two and later on in the lecture when we are talking about the COX-2 specific inhibitors, that’s going to be an important point.

XIV. Diagram [S14]

a. Because, as you can see from this slide COX-1 mainly produces thromboxanes. COX-2 mainly produces the prostacyclins, when you are talking about the yin-yang relationship.

XV. Clinical Effects of NSAIDS [S15]

a. Clinically we have already talked a little bit about some of the effects they have-the anti-inflammatory effects, the pain relieving effects, the anti-pyritic (the fever reducing effects), and then decreases in platelet aggregation.

XVI. Side-Effects of NSAIDS [S16]

a. We are all aware of some of the side affects of NSAIDS, especially some of the more celebrated ones like GI intolerance and ulceration. We will talk some more about that. There is a potential for increased bleeding, especially if you combine them with other anti-coagulant type drugs, say coumadin or warfarin. There are some relatively rare instances where you have hypersensitivities. When we have those hypersensitivities-bronchoconstriction, what not-these can be extremely serious, for a couple of reasons. We are talking about go to the ER type serious, but those are fairly rare. Also non-steroidals can cause dizziness, confusion, especially in our elderly patients.

XVII. Gastroprotective Role of PGE [S17]

a. Now prostaglandins and NSAIDs and GI intolerance. There are a couple of ways that NSAIDS can cause GI intolerance. One could be that the drug itself could be irritating to the lining of the stomach. So there can be a chemical intolerance from that standpoint. The prostaglandins actually have some systemic functions through COX-1. They enhance bicarbonate secretion. They enhance blood flow to the mucosal surfaces, which really are some of the important functions in the stomach. When we inhibit COX-1 with our NSAID those functions are taken away. This could be an extremely serious condition.

XVIII. Mortality from NSAID Induced GI Complications [S18]

a. You see from the slide here and I realize this data is pretty old, but I think it is probably not that far from what we see now. Mortality from NSAID induced GI complications-there is a higher death rate from these than from multiple myeloma, as well as asthma, and almost as many people die from GI complications from NSAIDs as people die from HIV and leukemia. So these can be some serious complications. This is something that we have to be careful with and monitor for.

XIX. Risk Factors for Serious NSAID GI Toxicity [S19]

a. Some risk factors for these serious NSAID GI toxicities: age. As I was saying, particularly in our elderly patients these medications can be tolerated relatively poorly. As we begin to use higher doses, the anti-inflammatory type doses, concurrent use of the glucocorticoids, the corticosteroids, previous history of ulcers and GI disease and just generally poor functional status.

XX. Renal Complications of NSAIDS [S20]

a. Some renal complications of NSAIDS. These medications can basically decrease renal blood flow by inhibiting some of those housekeeping prostaglandins. When we decrease the renal blood flow we are going to see sodium retention, hypertension, as well as high potassium and this is something that is applicable to the COX-2 selective agents that we will talk about. It is equally applicable to those agents because if you remember from the previous slide COX-2 actually has some housekeeping functions in renal function.

XXI. Nonselective COX Inhibitors [S21]

a. This is a listing of some of the nonselective COX inhibitors, probably ones that you are familiar with and some that you are less familiar with. One of the things that is important to look at and appreciate from this particular slide is that the NSAIDS are an extremely diverse group of compounds, a chemically diverse group of compounds.

XXII. Structures [S22]

a. They look quite different from each other. What does that mean for us? That means going back to the slide that we were talking about earlier. There is going to be different levels of inhibition of the different COXs, which means different levels of toxicities or side effects. This is the reason we pick which agent we want to use based on side effect profile. This is the reason because they are such a chemically diverse group of compounds.

XXIII. Properties of NSAIDS [S23]

a. Also another thing that influences which compound we use, which NSAID we use, is the half-life. A lot of the compounds at the top, aspirin, diclofenac, ibuprofen, are used more for analgesia and in some cases anti-inflammatory properties for more acute situations. The compounds near the bottom, particularly naproxen, is used for osteoarthritis because it has such a long half life and can be dosed once a day or twice a day.

XXIV. Aspirin (ASA) [S24]

a. Let’s talk about a few particular agents. One is aspirin, one of the oldest and most important NSAIDs. One thing that is important to remember about aspirin is that it is an irreversible inhibitor of the COX enzymes. That makes it unique in the NSAID family. None of those other drugs irreversibly inhibit those enzymes. It has been used to reduce pain, obviously of mild and moderate intensity, and also for the treatment of fever. It is a pretty good anti-pyretic.

XXV. Aspirin (ASA) [S25]

a. Aspirin itself can have anti platelet effects even at very, very low doses. If you look at its spectrum of activity, aspirin at low doses has anti-platelet activity. At slightly higher doses it has the anti-pyretic and analgesic properties. As we get much higher doses we begin to see anti-inflammatory activity. I imagine that some of our grandfathers take an aspirin a day, one of those chewable baby aspirins. The reason they do is to produce a slightly prolonged bleeding time and that is beneficial in patients who have cardiovascular problems. Now one thing that is important to remember if they are going to have a procedure where you would expect bleeding, they should probably discontinue their baby aspirin at least 8 to 10 days prior to that to minimize the chances of them having excess bleeding. Aspirin as we mentioned is an irreversible inhibitor and it takes a while for new COX enzymes to be produced. Higher doses of aspirin, not only does it have its anti-inflammatory properties, but it can also cause vomiting, tinnitus (ringing in the ears) and vertigo. There is conflicting data about the use of aspirin in children. if children have a fever of unknown etiology we probably don’t want to give them aspirin. There is a chance they could experience something known as Reye’s Syndrome. This is basically a hepatic encephalopathy that is basically irreversible. That is caused by giving children aspirin when they have a fever that is caused by a virus.

XXVI. Ibuprofen [S26]

a. This is the main ingredient in Advil or Motrin. Advil is usually the OTC preparation, 200 mg. The higher strengths- 400, 600, 800 mg are usually sold by prescription only and known as Motrin. Again, ibuprofen is a reversible inhibitor of the COX enzymes. The low doses (less than 2.4 grams a day) have the analgesic effects, not the anti-inflammatory effects. Ibuprofen generally has less GI irritation and bleeding problems than aspirin does, but there can be the same sort of renal problems we see with any NSAID. In rare cases there have been reports of interstitial nephritis, which is basically an inflammation of the kidneys. This is something that is usually drug induced and usually can be reversible upon discontinuation of the offending drug.