The Problem with Deramaxx

This discussion is about a drug called Deramaxx,  a non-steroidal anti-inflammatory (NSAID) sold by Novartis Animal Health Products. If you haven't already, please read Side Effects of Deramaxx.

Deramaxx^® has been promoted as a miracle pain reliever, something every owner of a dog in pain wants. Novartis specifically terms Deramaxx^® a “smarter” drug and touts the benefits of the drug’s COX-2 (cyclooxygenase-2) specificity. It is a non-steroidal anti-inflammatory drug (NSAID) whose activity is similar to that of Celebrex^® , a widely used human NSAID. COX-2 is an enzyme involved in the body’s inflammatory response to injury which is a major source of pain.

Some dogs have benefited from Deramaxx®, perhaps the majority who have received it. For other dogs, the drug has been ineffective. And some dogs have become seriously ill or died after having been administered Deramaxx^®.

The drug is widely promoted by veterinarians for pain relief

The Problem

Pain relief is important. Most of us would rather suffer ourselves than see our animals in pain and many veterinarians feel the same way.

There are three choices available in the veterinary pharmacy for dealing with pain: steroids, NSAIDs and narcotics.

Steroids suppress pain because they suppress the body’s response to injury. They can have serious side effects, including diabetes mellitus. Several studies have indicated that as many as half of all diabetes cases in dogs are caused by long-term steroid use.

Narcotics are effective pain relievers, but so effective that they need to be managed carefully in a clinical setting.

That leaves NSAIDs. There are two types: COX-1 inhibitors and COX-2 inhibitors. COX is the abbreviation for the enzyme cyclooxygenase. There are two forms (isoforms) of this enzyme called isozymes. Both are involved in the body’s response to injury, particularly the inflammatory response which is largely responsible for pain.

COX-1 and COX-2 isozymes are versatile. They are also involved in other processes in the body, not just the inflammatory response. COX-1 helps the body protect the lining of the stomach from acids needed to digest food. COX-2 enzymes are involved in various kidney functions, particularly regulation of chemicals (electrolytes) in the body.

No drug is perfect. If a medicine could be developed that only targeted specific causes of pain, side effects theoretically would be minimized. But when the causes of pain, in this case the products of COX-2 enzymatic reactions, are involved in other vital bodily functions, there are side effects--side effects that include death.

It’s in the genes.

NSAIDs are widely taken and have been extensively studied. A key issue with any drug is how it is metabolized. To be effective, a certain level of the drug’s main ingredient(s) has to end up in the blood stream. Celebrex^®, a widely prescribed human COX-2 inhibitor similar to Deramaxx^®, is metabolized in the liver by a metabolic pathway known as CYP 450.

Because dogs are used extensively in clinical testing of human drugs, there has been considerable research into how dogs metabolize Celebrex^®. (While structurally different, the two drugs vary from each other by a single atom.)

Researchers have found that one of the key enzymes involved in the CYP 450 metabolic pathway determines how fast drugs such as Celebrex^® are metabolized. Variations (polymorphisms) in the gene that expresses this enzyme cause some dogs to be Fast Metabolizers and others Slow Metabolizers. About half the dogs fall into one category, half in the other.

Fast Metabolizers quickly metabolize Celebrex^® clearing it from the body in a few hours. In the case of Slow Metabolizers, the drug is broken down slowly; consequently, drug levels in the blood are elevated because the rate of excretion is reduced.

The Key Question

Fast Metabolizers are generally not at risk for adverse side effects. Since the drug is cleared quickly, the relief they receive may be limited to a few hours, but they are for the most part not in danger of adverse side effects.

The opposite is true for the Slow Metabolizers. The drug slowly builds up and can reach toxic levels. In some cases, there is a high level of the drug in the blood when the second dose is administered, sending the drug level even higher.

While this variation in metabolic rate is an issue with many of the NSAIDs, it is clearly not the only problem. Dogs with compromised kidneys, livers, heart problems or pre-existing gastro-intestinal ulceration are at risk, even if they are Fast Metabolizers.

Deramaxx^® Side Effects

When a COX-2 drug goes above a certain level in a dog’s system, three documented adverse reactions can occur:

1.      Kidney damage and secondary effects on the heart.

2.      Gastro-intestinal ulceration

3.      Liver damage

The degree of damage and danger varies, but can include death.

In the case of the kidneys, NSAIDs can upset the body’s ability to regulate electrolytes such as sodium and potassium, leading to sky-rocketing increases in blood pressure and the kidneys themselves can be damaged leading to other problems.

The table above shows that high levels of BUN and Creatinine are frequently associated with Deramaxx^®. Adverse event reports further suggest that Deramaxx^® can cause irreparable kidney damage. Many dogs continue to have abnormal blood values indicative of kidney damage long after Deramaxx^® has been discontinued.

Novartis has been less than straightforward when it comes to gastro-intestinal effects of Deramaxx^®. Veterinarians have been led to believe that COX-2 inhibitors spare the stomach, despite the fact that it has been documented that this is not the case when a COX-2 inhibitor drug reaches high levels.

Research into new drugs aimed at making them more COX-2 specific has shown that highly COX-2 specific drugs have gastro-intestinal effects that are not unlike those seen with traditional COX-1 inhibitors such as aspirin.

Just as COX-2 is involved in the basic functions of the kidneys, it is also involved in protecting the stomach from the body’s own digestive fluids. A review of reported adverse effects, including endoscopy and tissue biopsies indicates that Deramaxx^® can lead to massive gastric ulcerations as happened to Rudy. Signs and symptoms include vomiting, diarrhea and dark bloody stools.

Excessive levels of COX-2 inhibitors can be toxic to the liver as well as shown by the frequency of high levels of SGPT/ALT and ALK PHOS in the adverse event reports. In addition, the liver produces coagulation factors that are involved in wound healing, specifically the coagulation of blood. This can be a double whammy. Bleeding caused by ulceration of the stomach cannot be stopped because the liver is not producing coagulation factors necessary to stop the bleeding.

This appears to be what happened to Rudy who was on Deramaxx^® for only a single day.

Precisely how drugs like Deramaxx^® damage the liver is not well understood. However, we do know that the damage is caused by toxic levels of the drug in the blood and that this is common sign of dogs who have reacted badly to Deramaxx^®.

Some of the information on this page has been freely provided by Vetnsaids.com.

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