Fundamentals II: 11:00 - 11:50 Scribe: David Davis

Fundamentals II: 11:00 - 11:50 Scribe: David Davis

Friday, December 4, 2009 Proof: Brittany Paugh

Dr. Pillion Case Studies and Histamines Page 7 of 7

I. S1]: Case 29 - *Starts with slide 14*

a. A 58 year old man with gout comes in. What is gout characterized by? When you hear the word gout, one chemical should come to mind.

i. Uric Acid. Uric acid is a normal component of our metabolism. We need it and we use it to break down product of DNA and RNA, but if we have too much of it, it will precipitate and it usually chooses to precipitate in our joints. When it precipitates in the joints, we get a little crystal there and it hurts like “all get out”.

b. When you are afflicted by a “gouty” toe, you want relief. So, this is a 58 year old guy who came in who had elevated levels of uric acid. He had normal levels of uric acid in his urine. Now, some people with gout – usually, you can take gouty folks and divide them up into two categories – those who do and those who do not urinate uric acid at high levels. You would think that if your serum level of uric acid is high your urine level of uric acid should also be high. There are some people who have a high level of uric acid in their serum yet the level of uric acid in the urine is very low. That is not good. It indicates some type of a problem with uric acid excretion. We think that the uric acid excretion problem in some people is what causes the increase of uric acid in the bloodstream and therefore it predisposes them to having a gouty attack. In some people, we test the uric acid level in the urine and if it is extremely low and they are having gouty attacks, we give them a drug that promotes the excretion of uric acid in the urine. It often times gives them relief. This guy does not fall in that group. He had elevated serum uric acid levels but he did excrete plenty of uric acid.

c. We are left with a different approach

II. [S2] Gout Medications

a. We can give him Colchicine, Allopurinol, NSAIDS, or Probenecid. Which one among you think that we should give this guy, if he isn’t having an acute attack, we should give him which of these drugs? The correct answer was Colchicine.

b. NSAIDS was the other correct answer.

c. So, Colchicine, Allopurinol, NSAIDS, and Probenecid – four different types of drugs with four different mechanisms of action all are used to treat gout. You need to know which is which and why you use one for the other. For an acute attack, which one is favored? Colchicine…excellent. NSAIDS, that is the other correct choice.

d. The correct one to go with here, Colchicine, what kind of drug is Colchicine? It binds to microtubules and it prevents cells from changing their shape. What does that have to do with gout? We don’t really know, but we do know if we give Colchicine to people, the migration of cells to the location of where the gouty attack is taking place is compromised. In other words, usually your body mounts an attack against a uric acid crystal. If you give your body Colchicine, the cells that move to the site of attack and do their thing which is to open up and dump out their cytokines and then attract other cells and cause vasodilation and to cause your toe to get red and inflamed – those cells don’t work as good. Really, you are giving the body a poison. Colchicine can be used as an anti-cancer drug. It poisons cells. You are giving your body a poison to slow down the inflammatory response to a uric acid crystal in your big toe.

i. It turns out that this is about the best thing that we can do. It is not a very specific and it isn’t a very curative way to go. What it does is that it is blocking inflammation. It is doing it in a strange way. It is blocking cells being able to change their shapes and dump out their contents.

ii. You don’t want to do this all of the time because all of your cells get hit with this drug at the same time. They all have this problem. It is a pretty toxic way to go. You only use it during the first 24 hours of a gout attack. You don’t do it on a regular prophylactic basis. That’s always a good test question.

1. Summary – Colchicine – acute attack, first 24 hours only. That is the only time that you use it. Most people that get gout attacks get them once every four years or so, so you can afford to give someone a poison every four years. They will be fine. You wouldn’t want to give it to them everyday.

e. What about the use of the NSAIDS in this situation? It is a prompt, temporary relief of pain. They are getting pain and inflammation, so you give them a nice high dose of a NSAID to make them feel less pain. You did not cure the disease and you did not cure the uric acid crystal in any way, shape or form. All you did was relieve some pain.

f. What about Allopurinol? It is different. It is an analog of Xanthine. Xanthine is the molecule that gets broken down when we hydrolyze purines and pyrimidines. We end up producing Xanthine and then Xanthine ends up being converted into uric acid by the enzyme xanthine oxidase. Allopurinol is a competitive inhibitor. It looks like the substrate, inhibits the enzyme, it lowers the production of uric acid. It is the preferred therapy for prophylactic treatment. After this 58 year old man has had the attack leaves the office and he goes home, for the rest of his life, you want to put him on allopurinol. That is the drug of choice most of the time. However, If he falls in the subset of people who don’t excrete uric acid, he has probably not a problem with making too much uric acid, but rather, not getting rid of the uric acid that he makes. You give him a drug that helps him eliminate the uric acid in his body by urination. That drug is Probenecid.

i. Probenecid is a funky little drug that has two different actions. It is always confusing to both me and the students. I’m going to go ahead and move to the probenecid case.

III. [S3] (Slide 20 of PPT) Case 8

a. Case 8 is a 50 year old man that has gout and arthritis. He has elevated serum uric acid levels but he has very low levels of uric acid in his urine. In a test question, you might see this in the beginning of the questions before I say which drug would you use to treat this patient. It might say his urine level of uric acid is low or it might say his urine level of uric acid is normal or high. That would impact what the right answer is to the question.

b. This drug that we are going to talk about with probenecid is the drug that we would use if he had low levels of uric acid in his urine because this probenecid drug is going to goose up the amount of uric acid that he urinates out. If he is already putting out uric acid, there is no sense of giving him this drug because his kidneys are already getting rid of uric acid as it is presented to them.

IV. [S4] (Slide 22) Probenecid

a. What drugs are indicated for him? Probenecid. It inhibits two sites of anion movement. The transfer of organic acids from the serum to the urine across the renal tubule cells and there, it is competing for an organic ion – or an organic acid- channel. This organic molecule takes stuff from the bloodstream, brings it across the kidney, and into the urine – into the lumen of the tubule.

b. We have stuff in our bloodstream that we want to get rid of in the urine. Most of what we get rid of in the urine, how does it get into the urine? When it enters the glomerulus of the kidney, there is a filter there. About a third of the blood goes through the filter and goes into the urine. Anything that is small goes across that filter and goes into the lumen of the kidney tubules and there it goes down the tubule and if it doesn’t get reabsorbed, it will go out into the urine. Our kidney tubules have ways to reabsorb a lot of stuff so that our urine does not contain sodium and does not contain glucose and does not contain ATP and does not contain amino acids and does not contain protein because all of that stuff is reabsorbed from the lumen before it goes out into the urine. That is what our kidney does. It reabsorbs stuff that we want to keep. The stuff that we don’t want to keep is stuff like urea and uric acid. That is stuff that we do want to put out into the urine. That is when our kidney is happy and is doing its normal job.

c. There are some drugs like penicillin that when we take it, we lose it into the urine. In the case of penicillin when it first came along, it was very hard to isolate so we wanted to keep it into the body longer. We could give someone a penicillin pill and give them probenecid, and they would keep the penicillin in their body longer. The penicillin would be twice as effective. That is because it competed with the penicillin for getting secreted into the urine. Secretion into the urine is different from filtering into the urine.

i. Filtering into the urine is what happens at the glomerulus. Your blood comes into the glomerulus, there is a filter there, and it goes through that net and goes into the lumen of the kidney and then goes down eventually into the bladder.

ii. Additionally, the kidney tubule can take stuff from the blood side into the kidney cells and secrete it into the urine and it does that. That is an important process for getting rid of a lot of things like urea and some other chemicals. Penicillin was one that is an artificial drug that goes that way and uric acid is another. Those chemicals get secreted into the urine. Probenecid competes with organic acids for secretion into the urine. If you have a drug like penicillin, you add probenecid – less of it gets secreted.

iii. You are trying to get rid of uric acid, uric acid is also going down that pathway and probenecid is going down that pathway and they are competing with each other. That isn’t good. We are trying to get rid of uric acid. Probenecid would actually slow down the uric acid that gets secreted because it would compete with it. The key thing is that once probenecid does get out into the lumen of the kidney tubule. In there, it competes with uric acid from getting reabsorbed. Uric acid can get into the lumen by this filtration up at the top of the kidney tubule – right at the glomerulus, uric acid is going to get filtered and go into the lumen that way. Probenecid is going to get secreted into the urine and it is going to prevent the reabsorption of uric acid. It is competing with uric acid for reabsorption. Let’s say that I had a hundred molecules of uric acid and under normal circumstances, I would reabsorb 50 of them and I would put 50 out in my urine. If I add probenecid, I still have 100 molecules of uric acid there; I don’t reabsorb any of the uric acid. Now, I put out 100 in my urine. So, I have doubled the amount of uric acid I have put out. It increases the amount of uric acid that goes out into the urine because it competes for the reuptake in the kidney of uric acid.

iv. Student Questions: Someone has this kind of gout and they have an acute attack, what do you do? Do you give them Colchicines, probenecid, or do you give them both?

1. Why not give them both for the first twenty-four hours? After that, keep them on the probenecid. In real world, if that happens, you might say if the person has been on probenecid and they still have an attack, I might have to goose up the concentration of the dose of the probenecid that I give him.

v. Unfortunately, people on probenecid therapy are not cured of their gout so they do still have attacks. So, you kind of ramp up the dose until you don’t see an attack for a while and then typically, you see an attack and then you kind of goose up the concentration of probenecid again and then you might try to taper it down. You kind of yin and yang it until attacks become too frequent. When they become too frequent, you get the dose up higher again. Like every drug in the world, probenecid has its bad side effects. Does the probenecid story make sense? It can be confusing because it actually blocks two different processes.

vi. The other thing that is weird about it or that makes – if you want to get to the next level of questions, is what happens when you add aspirin to a person who has gout and takes probenecid? Aspirin is also an organic acid and acid competes with probenecid for binding to the kidney transporter that secretes the stuff into the urine.

vii. You have a guy with gout. He isn’t feeling good. His toe hurts. You have him on probenecid and you have him on aspirin. The aspirin will actually compete with the probenecid for getting into the urine. Because of the aspirin, less of the probenecid gets into his urine and what do you think that will do to his uric acid output?

1. It blocks the effects of the probenecid. If it isn’t getting to the urine, it isn’t preventing uric acid uptake. So, uric acid will get taken back up again and it will have the effect of increasing his uric acid levels which will make his gout get worse which is not what you want. That is one thing they noticed in people who had gouty attacks on probenecid that took aspirin for pain relief and their uric acid level went up. The two drugs compete with each other for this organic ion transport channel.

2. That is the kind of level that I wouldn’t ask you. It is kind of an upper level question. A national board guy might ask.

viii. Going to move on to antihistamines.

V. *New PPT Lecture *[S5] Antihistamines

a. These drugs are a little bit less intense. They are taken over the counter. They are taken for the relief of irritation, runny nose, red eye and things like that. A lot of patients will use them for comfort purposes but they are certainly a lot less toxic than the NSAIDS. The big thing to remember about antihistamines is that you need to remember what histamine is, where it is found, and what it does.

VI. [S6] Mast Cells Contain Mediators: