A Short History and Useful Factoids about Warfarin (Coumadin®)
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A Short History and Useful Factoids about Warfarin (Coumadin®) |
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Warning: I am not a physician, and anything in here that might lead you to suspect that you can engage in any activities with respect to anticoagulant treatment other than those countenanced by your physician is a misinterpretation of the information contained herein. This is not a medical treatise, and should not be considered as one. Consult your physician before doing anything that could affect your anticoagulant treatment.
In 1921, ranchers were dismayed at the sudden onset of lossage in their herds due to a strange condition: the animals bled to death. Small cuts failed to heal. The roughage cows eat will scratch their digestive systems, but unlike the normal case where such scratches are minor and readily heal, these scratches failed to heal and the animals died from internal hemorrhaging. What seemed odd was that the animals were being fed hay from fields that appeared not dissimilar from that of previous years. No sudden invasive plants of a poisonous nature had been found.
A researcher by the name of Karl Paul Link, working under the aegis of the Wisconsin Alumni Research Fund (WARF), did a careful analysis of the ensilage from ranches that suffered losses and those that did not. He discovered that a chemical, dicoumorin, found in the ensilage of sweetclover hay from those ranches suffering the losses, was a powerful anticoagulant. Dicoumarin is the result of a substance called coumarin, which is the chemical which gives new-mown hay its characteristic smell, being subjected to the heat and mold in a silo, and forming a double molecule. The year of the serious losses had been an unusually warm one after the ensilage was created. [This information is from Kingsley's book "Poisonous Plants", which is one of the first serious studies of the biology of plant toxins].
Link named this substance after the organization that supported his research. Hence the name warfarin.
In the mid-1940s, this substance was used as a rodenticide. Rats are quite intelligent, and when rats would see a number of dead rats around a poisoned bait (usually some fast-acting poison like arsenic or strychnine was used), they would say "This is a dangerous substance. Avoid it". This is known in the pest control trade as becoming "bait-shy".
However, rats are not all that intelligent. They are not, what is called in the perception trade, "time-binding". That is, a rat seeing another dead rat near some poison-laced bait concludes "This is trouble, avoid it". But a rat that dies three days later from internal hemorrhaging does not communicate "This is the consequence of that great meal I had on Tuesday". So as two rats are munching on warfarin-laced bait, they are talking about poor old Charley who died last week. "Stress, probably. That cat" or "These things just happen. And so young, too", but the association with the fact that he dined on the same bait they are eating is lost on them. So for decades, warfarin has been used as a rodenticide. One advantage of warfarin is that its effectiveness is based on proportion-to-body-weight. A 1kg rat or a 200mg mouse get a fatal dosage that might not be fatal to, and perhaps not even dangerous to, a 15kg dog or 30kg small child.
One of the problems of warfarin is the process that manufactures it tends to leave a number of deleterious impurities in the resulting product. When used as a rodenticide, this is not a major consideration. And these are only dangerous over a sustained period of time. But it was also determined that a good anticoagulant for human beings would be a Good Thing. The product trademarked Coumadin is a form of crystalline sodium warfarin that is created by a process that leaves no such impurities, and therefore is safe for long-term human consumption. Of course, since the patents on Coumadin have expired, many other firms now synthesize the medication, and call it by its generic name, "sodium warfarin". However, do not think that if you are on Coumadin/warfarin therapy that you can substitute rat poison; besides the impurities found in the warfarin used for that purpose, many other potentially fatal ingredients are used to enhance the effectiveness of the rodenticide, and none of these would be healthy to consume.
Warfarin was used in the 1950s as an anticoagulant for victims of heart attacks and strokes, but gained fame when it was used to treat President Dwight D. Eisenhower after his 1956 coronary (while in office).
Therapeutic doses of warfarin are minuscule: 2mg to 10mg for a 100kg person. The actual dosage depends upon an individual's diet and metabolism, as well as body weight. In fact, body weight is not a major factor. A 150kg person may require 2mg while a 75kg person may require 10mg for the same therapeutic effect.
There are very few good alternatives to sodium warfarin treatment. In some cases, a doctor may prescribe low-molecular-weight heparin (LMWH). I do not know the issues about long-term effectiveness of LMWH, but the fact that it requires two injections per day, subcutaneous, at fairly precise 12-hour intervals, precludes its use for most people. I've done it in the short-term (post-surgical recovery while the warfarin is "ramping up"). I wouldn't want to have to do it every day.
Warfarin impairs the creation of one of the significant blood clotting factors, prothrombin. Vitamin K is an important factor in the synthesis of prothrombin clotting factors in the blood. Because of this, Vitamin K is considered an "antidote" for warfarin overdose. If a child or pet inadvertently consumes a warfarin-based rodenticide, the usual treatment is injections of Vitamin K. This is simplified greatly because the actual effects of the warfarin can be measured fairly accurately by measuring the blood clotting rate. This "prothrombin clotting time" or "protime" measurement is necessary for anyone on warfarin prophylaxis therapy. Tests may be done as frequently as daily to as infrequently as monthly.
The complementary problem for people on warfarin therapy is that it is necessary to keep a balanced intake of Vitamin K. Many foods are high in Vitamin K, including shrimp and spinach, and an unbalanced intake of Vitamin K will cause the prothrombin times to vary wildly. This is not to say that foods containing Vitamin K must be avoided; merely that the intake should be reasonably constant, so the warfarin dosage can be adjusted to compensate for it. For example, an occasional spinach salad is not considered dangerous, but a spinach salad every night for two weeks would not be a good idea, particularly if there was a prothrombin-clotting-time test taken just at the end of those two weeks. Besides the risk that the sustained Vitamin K intake would cause (due to lowered clotting time), an adjustment made to the dosage followed by a discontinuance of the intake would result in a significantly raised clotting time. So the key is to maintain a reasonably constant Vitamin K intake.
When my prothrombin clotting factor (measured in units expressed as the "INR", an acronym for the International Normalized Ratio) goes above a number my doctor and I have agreed upon, I can pig out on shrimp. Below that value, it is not a good idea, and if I drop below another level, it could be seriously dangerous to pig out on shrimp. Note that my physician and I have agreed upon certain values, based upon my medical condition. If you are on, or are using this for someone who is on, anticoagulant therapy, you must consult your physician regarding which values are appropriate. For someone on prophylactic anti-stroke therapy these numbers would be quite different, for example. Consult your physician for your particular case.
It is extremely important that you maintain your protime tests at the frequency your doctor requires. Going for too long a time with a too-low or too-high protime puts you at risk for blood clots or bleeding. Do not put it off, delay it for "good" reasons, or avoid it. Yes, it hurts. For a fraction of a second. Deal with it. Dying is a lot worse. In twenty years of warfarin therapy, I've gone for tests as often as three times a week, had them two or three times daily when I'm in the hospital for surgery, and had them as infrequently as monthly. This is a difficult drug to control. Be careful of "herbal remedies". Watch your diet. But no matter what you do, you may still have problems regulating your INR. I know the blood labs in many major cities. If you're traveling, make sure you have a current prescription in case your doctor calls you and says "and have it checked in a week" but you won't return home for two or three. Personally, I find Quest Diagnostics to be a good place to go, and they are all over the country, but you probably should check that they accept your health insurance.
Note that under FDA regulations, a prescription drug can vary, on a per-tablet basis, as much as ±20%. This means that if you are taking a 5mg generic sodium warfarin tablet, on different prescription refills you might find you are in effect taking a 4mg dosage or a 6mg dosage. One reason many physicians insist on "no brand substitution" and insist on the Coumadin brand name is that the brand name is regulated to a much higher precision (I have been told, but have been unable to verify, that the control is ±5%), making it more predictable from refill to refill (this was my experience; if you are having problems keeping INR well-regulated, having it go very high under some conditions and go very low under others which appear to be the same, from month to month, it might be the dosage change caused by batch variation or the fact that for different refills the generic form supplied to the pharmacist has come from different manufacturers. The cost of the brand name Coumadin is not that much higher than the generic sodium warfarin, so if it is at all affordable, this is often a better alternative as far as regulating the INR is concerned).
For more details, you may consult the Coumadin brand Web site at www.coumadin.com.
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