NSAIDs & Asthma

I thought it was very interesting that Kerry brought up the adverse effects of NSAIDs on asthmatic people, so I did some research to see if a mechanism had been found.

I came across an article from the June 2007 edition of the journal Allergy (vol. 62). Wang, X.S. et al were able to culture mast cells (cells that are like basophil granulocytes and are involved in allergies) from peripheral blood progenitors into mature cells that resembled human lung mast cells. They cultured these cells from 3 groups of patients: normal/healthy patients, patients with aspirin tolerant asthma (ATA) and patients with aspirin exacerbated respiratory disease (AERD)--these are the ones at risk for increased bronchospasms due to NSAIDs.

Basically, the research group found that AERD patient mast cells are different from mast cells of the other 2 groups. AERD mast cells, when activated, can produce much more cysteinyl-leucotrienes (cys-LTs), which are chemical messengers involved in inflammation. cys-LTs help regulate the state of blood vessels and airways.

In addition, PGE2 decreases this overproduction of cys-LTs. So when AERD patients take NSAIDs and inhibit COX as well as PGE2 synthesis, this enables the increase in cys-LTs. More specifically, cys-LTs cause asthma attacks by allowing for bronchoconstriction, increased mucus secretion in the airway and infiltration of leukocytes in the airway. In fact, leucotriene receptor antagonists are used to treat asthma.

So...there you have it. =)

Most Recent Celebrex Side Effect

Celecoxib, marketed as Celebrex, is an NSAID commonly used in the treatment of rheumatoid arthritis. Celebrex hit the market just under 10 years ago as an “alternative” NSAID with the same pain relief but fewer adverse gastrointestinal effects than “conventional” NSAIDS like ibuprophen and naproxen. As an “alternative” NSAID, Celebrex is a highly selective COX 2 inhibitor, whereas the “conventional” NSAIDs inhibit both COX 1 and COX 2. Because Celebrex is a relatively new NSAID, the side effects, risks, and suggested dosages seem to be changing rather frequently. The most recent and detrimental risk that has been identified for Celebrex is heart attack and stroke. As recent as 2007, Celebrex was deemed a drug that should be used as a last result anti-inflammatory medication for those who are at risk of heart attack or related cardiovascular disease. It seems like every year that changes to the Celebrex label have to be made to add more side effects and risk factors. I don’t know how the typical FDA approval and initial marketing of new drugs usually plays out, but it seems like there have been a lot of detrimental effects caused by Celebrex, and the Pfizer company who markets the drug is trying to focus solely on the fact that it has decreased gastrointestinal risks. So until their large scale clinical trials are complete in 2010, my suggestion would be to steer clear of Celebrex and find another NSAID that has been around long enough to have all of its risks and benefits ironed out.

The Bad and The Ugly of NSAIDs

In this week’s reading, “Comparison of the Intestinal Toxicity of Celecoxib, a Selective COX-2 Inhibitor, and Indomethacin in the Experimental Rat,” it mentions that non-steroid anti-inflammatories or NSAIDs are implicated in gastrointestinal and small bowel side effects. To put this into context, I looked up what exactly these side effects include, and found that NSAIDs can cause ulcers, diarrhea or constipation, loss of appetite, liver failure, kidney failure, and hemorrhaging. People with asthma can experience more exacerbated side effects, which can even lead to death because NSAIDs can induce bronchospasms. However, like with most things in science, it is not well understood why NSAIDs cause a more severe effects in asthmatic people. Maybe someone in our class has a guess as to why?

Comparison of Toxicity of Celecoxib vs. Indomethacin

There have been several factors that can lead to the damage of the gastrointestinal tract from NSAID's. There are two main mechanisms for the damage, one involves a the uncoupling of mitochondrial oxidative phosphorylation while the other is the inhibition of COX-1. For the peer review articles this week, it was suggested that the inhibition of COX-2 would suppress the prostaglandin synthesis at the sites of inflammation. To research this, the study used selective COX-2 inhibitors such as Celecoxib and Refecoxib while using Indomethiacin as the positive control in experimental rats.
The rats were treated with the drugs and such factors that were observed were in vitro which measured the liver mitochondria, in vivo which was measured through electron microscopy, intestinal permeability which was measured in urine excretion, the granulocyte marker protein which was taken by faecal samples, Intestinal prostaglandin determination which was taken by freezing the small bowel of the rat in liquid nitrogen and the prostaglandin was extracted from the sample and measured, and finally macroscopic damage which was done by performing a laparotomy on the rats and recording the amount of ulcers that were present upon dissection.
The results after gathering and assessing all the data was that the selective COX-2 inhibitor (Celecoxib) had no significant damage on the small intestine mucosa when compared to Indomethacin. This was probably due to the significantly less reduction that Celecoxib had on PGE levels when compared to Indomethacin which had a 90% reduction in PGE levels. Also to note is that Celecoxib did not lead to physiologic changes which is common with uncouplers of oxidative phosphorylation while Indomethacin showed all parameters of pathophysiologic changes and also caused intestinal ulcers which were present during the laparotomy. To summarize, when compared to Indomethacin, the Celecoxib showed no association with intestinal toxicity in the given study models.

One for the Ages???

After reading this lay article I found several points that left a bad taste in my mouth. One of the key problems I found was the author's lack of significant proof. When he finally mentioned some numbers to back up the suggestions they were scarce and prove nothing. Out of the original 76 rhesus monkeys only 50 are still alive. There is no mention here about how many were from the experimental group and how many are from the control group. The difference in cancer of 5 to 3 (control vs. esperimental groups respectively) is not a significant difference. In addition the causes of cancer are still not fully understood so this is quite possibly due to the randomness of the disease.
The author also wrote about the "lower insulin levels". If we think back to PSIO 202 we can recall insulin is released by the pancreas in response to sugar levels. Now, if you are taking in less calories you are most likely taking in less sugar.
Another point that is not mentioned here is the quality of the diet. If someone were to reduce their caloric intake it would be necessary for them to maximize the amount of nutrients in their diet. To put it another way if you are going to eat less than a normal diet, that limited amount must be of a higher quality. With that in mind how much of the longevity observed is due to less calories and how much is due to a better quality diet.
Sorry to sound like a skeptic here but there just seemed to be too many gaps in the information to convince me.

Possible Deaths due to Heparin

In class last week it was discussed about the safety of warfarin compared to heparin. I've recently looked up a article from the FDA stating that possible deaths related to heparin use could be higher than expected. I posted the link below and there is another link within the article that shows figures from Jan. '07 to March '08. My personal view of the article is probably the same as any other lay article, I cant say much on the accuracy and credibility, but could still be considered an interesting read.


http://www.medscape.com/viewarticle/572751

The Threat of Common Anticoagulants

Warfarin and Heparin are two common anticoagulants used to prevent thrombosis. They are both very effective at what they do, but come with some serious risks. Warfarin (market brand Coumadin) is a natural chemical found in plants that was originally marketed as a rat pesticide. Research uncovered Warfarin’s relatively safe and effective use as an anticoagulant not long after. If used at a safe dosage, Warfarin can prevent both thrombosis and embolism. The way Warfarin works is by inhibiting Vitamin K epoxide reducatase, therefore diminishing the amount of Vitamin K available in tissues and inhibiting the Vitamin K synthesis of many calcium dependent and regulator factors. This inhibition prevents the carboxylation activity necessary for coagulation factors to bind to blood vessel surfaces. The primary side effect of this effective clot-preventing drug is hemorrhage. Although the risk for hemorrhage is small, it is definite, which means that Warfarin derivatives should only be used if absolutely necessary.

Heparin (market brand Calciparine or Hep-lock) is an injectable anticoagulant, which makes it a much faster acting prevention for thrombosis than Warfarin. Heparin is derived from the mucosal tissues of slaughtered meat such as pigs and cows. It is a naturally occurring anticoagulant that is produced in basophils and mast cells. Heparin prevents clot formation and extension by binding to antithrombin 3 inhibitor, which then inactivates the body’s blood clotting response. The major side effect of this drug is known as Heparin-Induced Thrombocytopenia Syndrome, or HITS. This side effect makes the body’s blood platelets an immunological target, leading to the degradation of platelets.

Due to the considerable effectiveness of these two drugs, they are some of the most commonly used anticoagulants. Warfarin is typically administered as a prescription drug to patients who have already formed a blood clot. Because of its strong side effects, patients are required to submit a blood sample as often as once a day to ensure a proper dosage level is maintained. Heparin is restricted primarily to hospital use because it must be administered as a continuous infusion or as frequently as every half hour. Both of these treatments are very effective at preventing blood clots, but with side effects as severe as these, any patient considering starting Warfarin or Heparin should be cautious!

Acetaminophen vs. Ibuprofen

Acetaminophen and Ibuprofen, the active ingredients contained in Tylenol and Advil respectively, are two of the most common over the counter pain analgesics. As with any medication, the side effects are dose-dependent, and may be elevated in conjunction with alcohol consumption. In a society that demands a disclaimer on our fast food coffee, it seems appropriate that these drugs should carry a warning label as well.

In large quantities, acetaminophen can induce acute hepatoxicity. The liver is an essential organ in digestive metabolism via the hepatic portal system, to reduce contaminants entering systemic circulation. For this reason, the combination of alcohol and Tylenol should be avoided, due to the extra stress placed on the liver.

In contrast, ibuprofen can induce gastric bleeding with inappropriate use. The mechanism of this drug inhibits the constitutively expressed COX-1 in the stomach, which may have protective effects on the stomach lining. Ibuprofen also has blood thinning effects, which also increases the chance of gastric bleeding.

The moral of the story? Ibuprofen and acetaminophen are effective analgesics when taken in moderation. Anything can be toxic to the body in large doses, so following dosage instructions is important in reducing the risk of developing side effects.

Use of NSAIDs--An Update

The articles for this week deal with the positive and negative actions of NSAIDs. This particular article primarily addressed a popular news topic: the increase in risk for cardiovascular and cerebrovascular events due to selective COX-2 inhibitors. These drugs looked promising for pain relief without the unwanted side affect of GI bleeding that occurs with COX-1 inhibition. However, in September 2004, Merck withdrew its product, Vioxx, from the market and the concerns for COX-2 inhibitors increased significantly.

The American Heart Association released this article as an update on the safety of using NSAIDs. An FDA joint meeting came to the conclusion that celecoxib (Celebrex), valdecoxib (Bextra) and rofecoxib (Vioxx), all selective COX-2 inhibitors, “significantly increase the risk of cardiovascular events in a dose-dependent manner.” Although celecoxib is still on the U.S. market, it comes with a strict “black box” warning.

The article by Antman et al. stated the hypothesis that the increased risk for CV events is due to a shift in the prothrombotic/antithrombotic balance on endothelial cells. The shift leans toward thrombosis. It is believed this occurs because platelet aggregation is COX-1-dependent and so this mechanism would still work. In addition, COX enzymes catalyze the production of prostacyclin in endothelial cells which can disrupt platelet aggregation. So selective COX-2 inhibition would keep COX-1 activated while decreasing prostacyclin production and thus decreasing antithrombotic activity. The hypothesis also includes the fact that COX-2 inhibition increases sodium and thus water reabsorption (which can cause edema) and can increase risk for heart failure and hypertension (since activation of COX ultimately causes “local smooth muscle cell relaxation and vasodilation” and this would be inhibited).

The article concludes basically by saying that patients who must have NSAID treatment should first try acetaminophen or aspirin, the least risky NSAIDs. If this doesn’t work, then they should be prescribed nonselective NSAIDs. Selective COX-2 inhibitors should only be prescribed if absolutely necessary, and in the lowest dose and for the shortest duration possible. Any patients with a medical history of CV problems should seriously weigh the risks and benefits.

Warfarin or the generic form Coumadin is a commonly used prescription drug that is used to prevent stroke in patient suffering from chronic atrial fibrillation, a heart valve replacement, and/or a recent heart attack. Warfarin is usually referred to as a "blood thinner" or anticoagulant because it keeps blood flowing smoothly throughout the body by decreasing the amount of clotting proteins in the blood. This medication is classified has having a low therapeutic index(i.e. there is a small margin between a normal recommended dose and a potentially lethal dose).
Since the topic this week is Anti-inflammatories and warfarin has a extremely high level of protein binding, there is a possibility that Warfarin may interact with NSAIDs. Along with the affinity for protein binding, it also can cause partial metabolic inactivation by prehepatic and hepatic CYP2C9. The medications that can cause adverse reactions include aspirin, ibuprofen, naproxen, and celecoxib(Celebrex). The complications start because the NSAID's and the COX-2 inhibitor are also extremely prone to bind to proteins in the blood(~99%) and can therefore displace the protein binding for warfarin. This can then lead to free blood levels of non-binded warfarin which can lead to the increased risk of GI or other types of hemorrhagic diseases.
Another factor that could lead to the increased GI bleeding is that each of these drugs can have an effect of the clotting profile of the blood such as inhibition of potassium dependent clotting factors suppressed by the Warfarin and the inhibition of the COX-1 in the platelets and GI mucosa caused by the NSAID's. It could be recommended then that NSAIDs should be avoided while taking anticoagulants such as Warfarin and Coumadin and to use a mild pain reliever such as Acetaminophen or Tramadol as the alternative.