How Some Pain Relievers Induce Heart Attack

Some pain relievers (COX-2 inhibitors) do not reduce blood clotting resulting in heart attack

We have two concerns: One, how does cyclooxygenase (COX) contribute to heart attack? Two, how do some painkillers (COX-2 inhibitors) inhibit pain but contribute to stroke and heart attack?

COX is an enzyme. “... There are two forms of the COX enzyme, COX-1 and COX-2. COX-1 is found in most normal tissues, while COX-2 is induced in the presence of inflammation. Because COX-2 is not normally expressed in the stomach, the use of COX-2 inhibitors (e.g., rofecoxib, celecoxib) seems to result in less gastric ulceration than occurs with other anti-inflammatory analgesics. However, COX-2 inhibitors do not reduce the ability of platelets to form clots” (Encyclopedia Britannica 2009).

Blood clot can block blood flow in arteries that can lead to heart attack.

Superoxide

Cyclooxygenase (COX) produces superoxide (Spieker, L. E. , A. J. Flammer and T. F. Luscher. “The Vascular Endothelium in Hypertension.” The Vascular Endothelium II.2006.249-283).

Superoxide is a molecule with two atoms of oxygen bound together by six electrons with one free unpaired electron that makes it a free radical. It is indicated as O2-. It was formerly a molecular oxygen (O22-) that had grabbed one electron.

O2- reacts with nitric oxide (NO) resulting in peroxynitrite indicated as ONOO- with one free unpaired electron. O2- oxidizes (destroys) L-arginine, the precursor of NO resulting in reduced supply of NO.

NO has two forms: NO- and NO+ (respectively, a grabber of electron and a donor of electron) that account for its being harmful or beneficial.

Other sources of superoxide

Other producers of superoxide are: (1) adenine dinucleotide dehydrogenase (NADH) an enzyme in the mitochondria, (2) xanthine oxidase, (3) nitric oxide synthase (NOS), and (4) cytotochrome P450 monooxygenase, a by-product in the production of energy called adenosine triphosphate (ATP).

We will highlight COX because it was the basis of the formulation of a painkiller that had a side effect of heart attack among long-time users.

Remember Vioxx?

“On September 30, 2004, Vioxx (rofecoxib), a drug used to quiet the inflammation of arthritis and relieve pain, was withdrawn from the market by its maker, Merck. The reason for the withdrawal was the occurrence of side effects noted in a study that Merck was conducting to see if Vioxx could prevent polyps of the colon and rectum. During this trial, it was noted that there was an increased risk for heart attack and stroke in patients continuing to take Vioxx longer than 18 months.

“The risk of heart attack or stroke from taking Vioxx was small, but real. Of note, there has been no indication that any long term damage occurs once the drug is discontinued” (William C. Shiel, Jr., MD, FACP, FACR. Doctor’s View Archive,COX-2 Inhibitors Dilemma Vioxx, Celebrex, Bextra. Yahoo. January 22,2012).

Vioxx was withdrawn from the market in September 2004 “because the drug has been shown to double the risk of heart attacks and strokes in long-term users” It had sales of US $ 2.5 billion a year and about 20 million people around the world had taken it (Simons, J and D. Stipp. “Will Merck Survive Vioxx? “ Fortune. 2004. Nov.:91-104).

Vioxx is a COX-2 inhibitor. In other words, it inhibits inflammation in arthritis whose felt symptom is pain. Inflammation is caused by free radicals that attack the synovial fluid of joints.

Biomedicine or conventional medicine ignores free radicals as causes of disease that is why it cannot explain satisfactorily how COX contributes to heart attack.

Some effects of nitric oxide

Nitric oxide (NO) is a free radical in the form of gas produced and released by the inner lining of arteries called endothelium. NO is a messenger that signals the artery to dilate in response to shear stress, or blood pumped by the heart.

Systemic inhibition of NO increases high blood pressure. Inhibition also consists of peroxynitrite catching NO such that the population of NO is reduced. This results in reduced performance of NO population overall. The effect of peroxynitrite in high blood pressure is that NO becomes inadequate to dilate arteries thus blood exerts more pressure on the wall of the artery to pass through.

Inhibition of NO decreases cardiac output or amount of blood that the heart pumps out.

“NO prevents leucocyte adhesion and migration into the arterial wall, smooth muscle cell proliferation, and platelet, and aggregation; i.e. key events in the development of atherosclerosis....” (Spieker, L. E. , A. J. Flammer and T. F. Luscher. “The Vascular Endothelium in Hypertension.” The Vascular Endothelium II.2006.249-283). Inadequacy of NO contributes to atherosclerosis or plaque in heart artery.

NO could alleviate death of cells due to infection. NO is used by the macrophage, a component of the immune system, like bullets to shoot and kill bacteria causing infection (Cranton, D. MD and A. Brecher. Bypassing Bypass. 1984)..

Earlier on, nitric oxide was loosely called endothelium-derived relaxation factor (EDRF) by Robert Furchgott. Ferid Murad found that nitroglycerin produces NO. Louis Ignarro found that EDRF and NO are the same. The three shared the Nobel Prize in Medicine in 1998 (Encyclopedia Britannica 2009). Their work explain how nitroglycerin alleviates angina pectoris which could not be explained in the long time that nitroglycerin had been in use. Their work spurred a lot of medical research on NO, and free radicals for that matter, and how it can treat or cure heart disease, hypertension, stroke, diabetes, emphysema, arthritis, Crohn's disease, multiple sclerosis, osteoporosis, cancer and other free radical diseases.

Effects of peroxynitrite

Peroxynitrite (ONOO-) reduces the anti-inflammatory effect of NO. ONOO- impairs other vasodilators like acetylcholine that improves circulation and reduces shear stress in arteries.

ONOO- also oxidizes L-arginine, worse it is a more potent oxidant than O2- (three times over) resulting in reduced supply of NO. ONOO- reduces the bioavailability of NO that results in disease owing to lack of NO, like hypertension, atherosclerosis and spasm.

Spasm, even without atherosclerosis, can lead to sudden death from heart attack (Pierce, J. Heart Healthy Magnesium. 1984). Spasm is like a soft drinks straw that is clamped such that the fluid cannot pass through. In the same way, spasm prevents blood flow in an artery to the heart. The blood carries oxygen. No blood to the heart means no oxygen for the heart. Heart muscles starved for oxygen die. If several heart muscles die, heart attack occurs.

To summarize: COX produces superoxide that reacts with nitric oxide resulting in peroxynitrite. Both superoxide and peroxynitrite catch and disable nitric oxide. Gross inadequacy of nitric oxide leads to spasm. Blood clot compromised by spasm exacerbates thrombosis that can lead to heart attack. Spasm alone can lead to heart attack.

Superoxide and nitric oxide are free radicals; peroxynitrite is a reactive oxygen species (ROS) that acts like a free radical. ROS is also called reactive oxygen intermediate (ROI). A free radical and a ROS have very short life span. Hydrogen peroxide, a ROS, for example, has a life span of 0.00000001 seconds. They can be detected with electron spin resonance spectroscopy.

COX adds to the population of free radicals and ROS that, if not counterbalanced, eventually cause stroke and heart attack. We have now tackled our first concern of how COX contributes to heart attack.

New entries as of January 27,2012

How COX-2 inhibitors work

To start with, stroke and heart attack have several things in common. Both involve the cardiovascular system consisting of the heart, arteries, veins, and capillaries. Stroke, in addition, involves the brain.

Heart disease, that leads to heart attack, and stroke involve atherosclerosis consisting of hardening and occlusion of arteries. In heart disease, plaque in heart arteries block blood flow starving heart muscles of oxygen, killing a lot of heart muscles resulting in heart attack.

There are two kinds of stroke: ischemic and hemorrhagic. In ischemic, arteries that feed blood to the brain, like the aorta, sustain occlusion or plaque that limit or block blood flow to the brain. Part of the brain starved for oxygen cannot do its work and the part of the body that it controls do not work either, for example arm or leg.

Hemorrhagic stroke consists in bursting of artery and bleeding into brain cells. Bleeding must be stopped, injury of artery must be healed, blood clot must be dissolved and drained, and damaged brain cells must be revived. Sometimes, the skull must be opened to remove blood clot. Ischemic stroke is easier to treat than hemorrhagic stroke.

Both stroke and heart disease are started by free radicals and ROS by grabbing electrons from the endothelium resulting in injury. That injury results in a mutation consisting of atheroma, a non-malignant tumor. The body attempts to repair this injury with collagen, elastin, fibrin, and cholesterol. Calcium comes in later as a cementing agent. But this attempt at repair turns awry. Their combination grows as a mound, an occlusion, eventually a plaque that blocks blood flow to the heart or to the brain (Cranton, E. MD and A. Brecher. Bypassing Bypass. 1984). Free radicals and ROS also weaken arteries that may burst from shear stress, or pressure from rushing blood resulting in hemorrhagic stroke.

COX catalyzes the production of superoxide radical out of arachidonic acid (Sears, B. Ph.. "Aspirin:The Wonder Drug." The Zone. 1995:113-118). Aspirin and non-steroidal anti-inflammatory drugs (NSAID) inhibit COX which consists of COX-1 and COX-2. COX-2 is accompanied by inflammation, especially in arthritis.

However, NSAIDs induce ulcer, among others. That is why there had been a search for COX-2 inhibitors that remedy pain from arthritis with negligible side effects on the stomach. These inhibitors fall in the class of celecoxib and rofecoxib like Vioxx that had been withdrawn from the market in 2004.

In year 2000 yet, there had been reports of the possible effect of COX-2 inhibitors on the cardiovascular system, to wit:

"...In addition, COX-2 inhibitors do not inhibit platelet COX-1, so they may unfavorably alter the thromboxane/prostacyclin balance by inhibiting COX-2-dependent prostacyclin formation in vascular endothelial cells (McAdam et al. 1999). Individuals with severe thrombotic disorders may be more sensitive to COX-2 inhibitors...." (Serhan, C.N. and H.D. Perez, editors. Advances in Eicosanoid Research. Marnett, L.J. " Structure, Function and Inhibition of Cyclo-oxygenases." 2000:65-83).

It seems that the smoking gun is the inhibition of the formation of prostacyclin. Vane hinted as much, to wit:

"Finally, the suppression of prostacyclin release from endothelial cells by specific COX-2 inhibitors suggests the possibility of interference with the cardiovascular system...." (Serhan, C.N. and H.D. Perez, editors. Advances in Eicosanoid Research. Vane, J.R. "The Mechanism of Action of Anti-inflammatory Drugs." 2000:1-23). Vane shared with Bengt Samuelsson and Sune Bergstrom the Nobel Prize in Medicine in 1982 for their research on eicosanoids, according to Sears.

"Thrombotic disorders" mean presence of risks for stroke and heart disease. Prostacyclin counterbalances thromboxane. Prostacyclin is a dilator of arteries; thromboxane is a constrictor. However, thromboxane can tolerate free radicals and ROS; prostacyclin in their vicinity switches off.

"...Prostacyclin reduces the adhesiveness of platelets, allowing free flow of blood cells and plasma, reducing the tendency to fibrin deposition and thrombi....Thromboxane does the opposite. It causes intense spasm in blood vessel walls and it stimulates platelets to adhere...

"Synthesis of prostacyclin is completely blocked by the presence of lipid peroxides (LDL-oxy) and free radicals while thromboxane remains unaffected...." (Cranton, E. MD and A. Brecher. Bypassing Bypass, updated edition. 1984:215, parenthetical mine). More on LDL-oxy below.

We have just assembled an answer to the question: How do some painkillers (COX-2 inhibitors) inhibit pain but contribute to stroke and heart attack?

Painkillers that block prostacyclin lead to stroke and heart attack.

What makes aspirin different from other COX-inhibitors?

"Aspirin is the only COX inhibitor that covalently modifies COX enzymes, but is more potent against COX-1 than against COX-2 (Roth et al. 1975) This feature accounts for its anti-platelet/cardiovascular effects and its ulcerogenic side effects...." (Serhan, C.N. and H.D. Perez, editors. Advances in Eicosanoid Research. Marnett, L.J. "Structure, Function and Inhibition of Cyclo-oxygenases." 2000:65-83). So, aspirin takes care of thromboxane A2 in COX-1 that COX-2 inhibitors neglect. End of new entries.

Some COX-2 inhibitors, like Vioxx, are unlike aspirin that is also a pain killer. Aspirin blocks the formation of superoxide from arachidonic acid, the precursor of prostaglandins consisting of prostacyclin and thromboxane A2. A potent constrictor of arteries, thromboxane A2 also promotes aggregation of blood platelets. Such aggregation can grow big that it can block an artery which can lead to heart attack (Sears, B., Ph.D. The Zone. 1995:113-118). Its ability to block thromboxane A2 is the reason why aspirin is part of a medication against heart disease. Completely blocking thromboxane is not desirable; blood clotting is needed in healing injury and during surgery and amputation.

The blocking of prostacyclin formation done in concert by COX-2 inhibitors and by free radicals and ROS lead to stroke and heart attack.

What is desired is a balance between thromboxane and prostacyclin, according to Dr. Cranton. Both are eicosanoids, thromboxane is the "bad" one; prostacyclin is the "good" one. Still, both are needed; they should be in proper balance (Sears, B., Ph.D. The Zone. 1995).

Counteractions

The enzyme superoxide dismutase dismantles superoxide to form hydrogen peroxide, a ROS. Glutathione peroxidase dismantles hydrogen peroxide into safe water. However, the formation of peroxynitrite is three times faster than the dismantling of superoxide so that there is always extra amount of peroxynitrite to inhibit the bioavailability of NO. The desired situation is that the dismantling of superoxide is fast enough so that superoxide could not combine with NO and form peroxynitrite. Of course, the total elimination of superoxide is impossible. It is not even desirable. The metabolism of glucose to produce energy has superoxide as a by-product. Energy production without superoxide as by-product (fermentation that is anaerobic) cannot sustain the life of man.

Fermentation occurs before the splitting of glucose in citric acid cycle in energy production. This produces a measly 2 molecules of adenosine triphosphate (ATP), the currency of energy. After the split of the citric acid cycle into two pathways and entrance of both pathways to the cytochrome system, each pathway produces 13 ATPs pulled, as it were, by molecular oxygen at the bottom of the pathway. [Without molecular oxygen, the process would back up, leading to 2 ATPs produced, eventually to death of the person.] Overall, one glucose molecule produces 38 ATPs. By-products are water, carbon dioxide and superoxide. We consume a lot of ATPs: one brain cell consumes 10 million ATPs per second (Microsoft Encarta Encyclopedia 2009); other cells consume 7.5 times less.

Superoxide produces other ROS like alkoxy radical, hydroxyl and singlet oxygen (Sharma, H. MD. Freedom from Disease. 1993). Superoxide oxidizes low-density lipoprotein (LDL), a component of fats, and turns it into bad cholesterol: LDL-oxy which is also a ROS that contributes to the plaque in arteries. LDL-oxy is a very potent oxidant: LDL-oxy engulfs a whole molecular oxygen with its two unpaired electrons intact, that is why LDL-oxy can oxidize two molecules of other tissues.

Occlusion that threatens to cause ischemic stroke can be treated with infusion chelation therapy whose main ingredient is ethylene diamine tetra acetate (EDTA). Chelation removes minerals like copper and iron that catalyze the formation of ROS; removes calcium apatite that serves as cementing agent of occlusions; and catches free radicals and ROS. In other words, chelation dissolves plaque.

Hemorrhagic stroke can be treated with streptokinase or recombinant tissue plasmonigen activator (t-Pase) both of which dissolve blood clot, and infusion chelation therapy. Dr. Arturo V. Estuita, MD, a cardiologist and chelationist administering my chelation therapy, related about his friend who had hemorrhagic stroke and comatose for six hours. He administered neither streptokinase nor t-Pase (more potent than streptokinase by 2%) but infusion chelation therapy. His friend rebounded and now can play tennis.

Heart attack can be prevented with infusion chelation therapy, especially in one with artery blockage. Prevention of heart attack is the best option for one with a risk for it. Usually the warning for risk of heart attack is angina pectoris or chest pain that is a symptom of an advanced stage of heart disease. Chest pain is felt, upon exertion or even at rest, when about half or more of the diameter of at least one artery of the heart is blocked. Chelation, administered like dextrose, can prevent a second or a third heart attack (if you already had a second one).

Proper balance

It is enough that a balance between oxidants (free radicals and ROS) and antioxidants is achieved. Some antioxidants are built-in to the body, like superoxide dismutase, lactase, glutathione enzyme system (glutathione peroxidase, glutathione reductase, glutathione synthase). Glutathione reductase recycles glutathione peroxidase; glutathione synthase makes glutathione out of nutrition with building blocks glutamate, cystine, cysteine, and cofactors lipoic acid, selenium, zinc and vitamin B-2. Other antioxidants are supplemented, like vitamins A, C, E, coenzyme Q10 and B complex.

Likewise, there should be balance among eicosanoids.

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