Sunday, December 23, 2012


     There have been many articles written about the uses and benefits of aspirin, and I thought I would review them here. Without clouding the discussion, it is important to understand the distinction between primary and secondary benefits from taking a drug. If the drug has a primary benefit, then it prevents the disease or condition from occurring, and everyone might benefit from taking it. If the drug has a secondary benefit, then it is given to patients who already have had an attack of the disease, to prevent a second attack. It is always easier to demonstrate the existence or non-existence of a secondary effect, because the greatest risk factor for an attack of any disease (especially a heart attack) is having had a previous attack of the disease. One example of primary benefit would be in taking medicine as malaria prophylaxis when traveling to a malarious region of the world. Another example would be yellow fever vaccine. One example of a secondary benefit is giving all survivors of a heart attack a daily dose of a statin, which decreases the chance  of having a second heart attack.

     Aspirin, abbreviated ASA, is acetylsalicylic acid. Hippocrates knew that the bark of the willow plant could reduce fever, reduce pain, and reduce inflammation. The active ingredient was salicylic acid, which is an extreme irritant to the stomach. Most people are unaware that not only do we ingest salicylic acid in our diets, but that our bodies synthesize it from benzoic acid.  In 1897 a German chemist working for Bayer, (Felix Hoffman) was able to synthesize ASA by acetylizing salicylic acid, thereby making it much less injurious to the mucosal lining of the human stomach. Although he was not the first to create ASA in the lab, Bayer successfully patented ASA and initially made it available only through a doctor's prescription. Interestingly enough, about the same time Bayer chemists synthesized heroin which is diacetyl morphine, and it was sold  over-the-counter as a non-addictive(!) form of morphine.

     The precise mechanism of the action of aspirin in inhibiting the formation of prostaglandins  (by inhibiting the action of cyclo-oxygenase enzymes) and thromboxanes  is unimportant for the purposes of our discussion, except to note that the inhibition is irreversible and the effects of a single dose of aspirin on the bleeding time can last for 10 days, unlike the other Non-Steroidal Anti-Inflammatory Drugs (NSAID's) such as Advil whose effect is reversible. Since aspirin binds irreversibly to platelets, patients about to undergo surgery are advised to avoid all aspirin and aspirin-containing products for 10 days before surgery, since that is the length of time for which an extension of the bleeding time due to aspirin can be measured. The aspirin achieves this effect through its binding to platelets, which normally can clump together to form a clot and stop bleeding, and platelets bound to aspirin do not clump together.

     Let me list a few known facts. Aspirin is 99% cleared by metabolism in the liver, but if too large a dose is taken the hepatic clearance mechanism is saturated, renal clearance is needed, and the clearance kinetics shift from first order to zero order.  Thus the half-life of a 325 mg pill is 3 hrs, but a 2000 mg dose has a half-life of 9 hours.
In the United states, the basic strength of an adult ASA tablet is 325 mg, and that of a children's tablet 81mg. In Europe the strengths are 300mg and 75 mg respectively, but it makes no apparent clinical difference. Adding caffeine to an aspirin pill increases its pain-reducing strength, hence the popularity of APC's or Excedrin migraine compounds (aspirin, phenaciten or Tylenol, and caffeine). ASA in an effervescent solution is absorbed faster, hence the popularity of Alka-Seltzer. The bleeding effect of aspirin on the stomach can be reduced by taking ASA along with 500 mg of Vitamin C, or 500 mg of SAMe, or 350 mg of deglycyrrhizinated licorice. Many  people who take aspirin on a daily basis develop an iron-deficiency anemia from microscopic bleeding somewhere in the GI tract, and buffering the aspirin seems to make no difference. But buffered ASA is absorbed more slowly, and some recent studies suggest that this is the cause of apparent "aspirin resistance". I should mention here that aspirin given intravenously causes absolutely no GI irritation.

     There are studies showing that taking a daily aspirin (check with your doctor for the suggested dose) can lower the risk of a second heart attack, a stroke following a TIA, a cardiac embolus if you have atrial fibrillation, and cancer of the colon; the first two are examples of secondary prevention, and the last two of primary prevention. It is extremely dangerous to give aspirin to febrile children up to the age of 16  because ASA in a febrile child can trigger a sometimes fatal condition known as Reye's syndrome, which is swelling of the brain compounded by liver failure. A few people develop an acute allergic reaction to aspirin with angioedema. Aspirin exposed to water decomposes back into acetic acid (vinegar) and salicylic acid, hence the vinegary smell when you open a large bottle of aspirin that you  have had for some time.

     There are many drug interactions with ASA; for instance Diamox (acetazolamide) enhances the likelihood of salicylate poisoning, and alcohol increases the risk of gastric bleeding, as does taking Advil or any other NSAID along with aspirin. Because aspirin is  bound to protein in the blood, it can displace other drugs that are bound to protein, thereby raising their plasma concentration to dangerous levels. Some of these drugs are tolbutamide, methotrexate, Dilantin, valproic acid, and probenecid. Taking ASA can  raise the blood level of uric acid. Very rarely through a kidney-based mechanism, aspirin can cause elevated potassium in your blood; this is especially true for diabetics (hyporenin hypoaldosteronism).Aspirin can also inhibit the renal clearance of penicillin G if either drug is given in very high dose. And paradoxically, very high doses of aspirin can cause fever rather than alleviate it.  So whenever you get a prescription for any drug, it would be wise to ask your doctor about possible interactions with ASA.

     And please never forget that unless your doctor gives you permission, never take aspirin with any drug that can cause bleeding, such as Advil, Alleve, Coumadin, Xarelto, and, sometimes, alcohol.



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