NSAIDs

Part 1
The nonsteroidal anti-inflammatory drugs (NSAIDs) Celebrex and Vioxx have recently come under fire when it was admitted that these drugs could significantly increase the risk of heart attack and stroke. Are these the only NSAIDs capable of increasing this risk though?

Many heart disturbances, including heart attack, result from decreased blood flow to the heart. Common causes of decreased blood flow include arterial plaque formation, blood clots, and narrowing of the arteries from muscular contraction of the blood vessels.

Arterial plaque formation starts with damage to the blood vessel walls. This leads to depositing of cholesterol and calcium on the arterial walls. One of the most common causes of the arterial damage is high blood pressure caused from constriction of blood vessels. Various factors may lead to blood vessel constriction. These include elevated serum calcium, elevated insulin levels in type 2 diabetes, and epinephrine (adrenaline) induced constriction. NSAIDs constrict blood vessels as well, which leads to an elevation of blood pressure. Increased blood pressure may result in narrowing of the arteries from plaque due to resulting arterial damage. This narrowing of the arteries not only increases the risk of heart attack, but also of thrombic and embolytic stroke.

Because NSAIDs constrict blood vessels, these drugs increase the risk of angina, heart arrhythmias, and heart attack in people with already impaired perfusion to the heart. These include individuals with previous angina, or heart attacks, history of congestive heart failure, diabetics, and individuals who tend to put out too much epinephrine, etc.

Further risk comes from the fact that NSAIDs inhibit prostaglandins, including prostacyclin, also known as prostaglandin I2 (PGI2). PGI2 is produced by healthy endothelial cells of blood vessels. The roles of PGI2 are to dilate blood vessels, to increase blood flow, and to inhibit platelet formation and blood clot formation. By dilating blood vessels, blood pressure is reduced, and more blood reaches critical areas, such as the brain and heart. This also lowers the risk of heart disease by reducing arterial damage, which would otherwise lead to plaque formation. By reducing blood clot formation, the risk of heart attack and thrombic stroke are reduced. Both damage to endothelial cells and the use of NSAIDs inhibit PGI2 production, which increases blood clot formation and reduces blood flow. Production of blood clots and reduction of blood flow increase the risk of angina, arrhythmias, and heart attack, as well as transient ishemic attacks, and thrombic stroke.

As we can see, the increased risk of heart attack and stroke are not limited to certain NSAIDs, but rather can occur with all pharmaceutical NSAIDs. And the problem is not a new finding. The blood vessel constricting effects of NSAIDs have been known for decades. Part of the drug approval process includes knowing how the drug works. NSAIDs are known, and have been known, to work by consticting blood vessels. When blood vessels are overdilated by inflamamtory prostaglandins, they become permeable, which leads to leakage of fluids in to the surounding tissues, and resulting inflammation. By consticting blood vessels, NSAIDs prevent blood vessels from leaking. It is well known that the adverse effects of liver and kidney failure by NSAIDs is due to impeded blood flow to these organs due to this constiction of the blood vessels. Other organs, such as the heart, as well as glands are adversely affected by the impeded blood flow in the same manner. Therefore, the only explanation for the increased risk of heart attack and stroke being "discovered" recently would be that the drug companies and FDA knew about the problem all along and just recently decided to make this known fact public.

Part 2

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used as pain relievers for inflammatory conditions. These drugs include ibuprofen (Advil, Motrin, Nuprin), naproxen, (Aleve), aspirin, rofecoxib (Vioxx), and celecoxib (Celebrex). Although, the pain relieving effects come with some potentially dangerous, and possibly deadly side effects.

NSAIDs work by inhibiting hormones, known as prostaglandins. Prostaglandins serve numerous functions within the body including regulating blood pressure, antidepressant, protecting the stomach from acid, etc. Inflammatory prostaglandins are essential for increasing blood flow to injured areas, which promotes healing by increasing oxygen and nutrient levels to the injured site. Prostaglandins do this by dilating the blood vessels. The inflammation occurs when the blood vessels are dilated, which causes the blood vessels to become permeable. This permeability causes the small blood vessels to leak fluid in to the surrounding tissues, which leads to the swelling. NSAIDs decrease the pain and swelling by countering these inflammatory prostaglandins. This causes the blood vessels to constrict, thereby reducing leakage of capillaries.

By reducing blood flow, NSAIDs actually inhibit the healing process. Although this is one of the more mild side effects of these drugs. Other side effects of NSAIDs include, but are not limited to, liver failure, kidney failure, aseptic meningitis, loss of vision, tinnitus (ringing in the ears), high blood pressure, depression, and bleeding ulcers.

The most common side effect is bleeding ulcers, which leads to the majority of the over 16,000 deaths annually from these drugs. These ulcerations occur from the inhibition of another prostaglandin required to form the protective mucous lining of the stomach. This mucous coating protects the stomach wall from stomach acid. By inhibiting the formation of the protective stomach lining, the stomach wall is prone to direct attack from the stomach acid, leading to ulceration of the stomach wall and internal bleeding.

Constriction of blood flow leads to elevation of blood pressure. Loss of vision and tinnitus occur from reduced blood flow to the eye and in the area of the neck, due to the blood vessel constriction.

Prostaglandins play a major role in mood. By countering prostaglandins, the use of NSAIDs will cause depression.

Kidney and liver failure occur from a lack of blood flow to these organs. In fact, 2 dozen people died from ibuprofen induced hepatitis during clinical trials. People with poor perfusion to the organs, such as those with congestive heart failure, diabetes, Raynaud's, etc. are at a higher risk for the damage or organ failure since blood flow is already reduced in these individuals. Further constriction of the blood vessels by NSAIDs may completely cut off the blood supply to organs and glands leading to damage or complete failure.

Contrary to popular belief, it does not take long term use or overdose to cause organ failure. In fact a single, recommended, dose can cause sufficient constriction of the blood vessels to cause damage. I know of 4 people that developed kidney failure after taking a single recommended dose of ibuprofen. And the number of cases is most likely heavily underreported since adverse effects of drugs are commonly attributed to other disorders.

The NSAID Bextra, manufactured by the pharmaceutical company Pfizer, was approved by the FDA in November of 2001. Bextra was later recalled after it was revealed that the drug could cause potentially deadly allergic reactions, and the disorders Steven's-Johnson syndrome, and toxic epidermal necrolysis.

The new proposals for warning labels on these drugs need to include the risk of adverse effects from recommended use as well. Not only long term use and overdose as is currently being recommended.

A few other recommendations that I feel should be implemented include:

• Pulling NSAIDs off the market as was done with Bextra since the safety studies were either never done, or were suppressed by the drug companies, or ignored by the FDA, to get approval.
• Requiring more evidence of safety before approving these drugs.
• Charging pharmaceutical drug company executives, and FDA officials, with manslaughter when it is shown that side effects were hidden to gain approval, and it has resulted in deaths. Right now only pharmaceutical companies are held liable. Although only by civil liability, not criminal. Fines are sometimes imposed against pharmaceutical companies, although they are hardly punishment. Fines are generally around a million dollars, or slightly higher when the drug companies have made hundreds of millions or even billons of dollars in profits. This is hardly punishment, and encourages the drug companies to hide adverse effects since profits will far outweigh any liabilities.
• Heavier civil penalties against the drug companies to actually punish them for deliberately hiding known side effects, and for manipulating research to make their drugs appear safe and effective
• Civil lawsuits should not only include the drug companies, but also the FDA officials who receive gifts, payoffs, and jobs to push the drugs through the approval process.
• Cracking down on illegal investments by FDA officials in to the drug companies they regulate. This is a violation of insider trading laws. Despite this, nothing has been done to correct this illegal activity within the FDA despite the illegal investments being reported for nearly 3 decades.
• Faster action on pulling drugs from the market suspected of causing harm until safety of the drugs can be established.
• Testing of drugs by independent testing agencies. Currently the FDA requires the drug companies to provide their own safety data to obtain approval. If the drug company has already invested millions of dollars in to the drug, and a safety issue appears the drug company is not going to reveal the safety issue and risk approval being denied. This is a major reason drugs are being approved, then being pulled several years later, after the drug companies have not only paid for the cost of approval, but have also paid stockholders and made millions of dollars or more in profits.
• Drugs requiring a prescription when they are originally approved should remain only available by prescription. They should not be made available over the counter when the drug's patent expires. The chemistry, or dangers, of the drug do not change just because the patent has expired on the drug.