The Threat of Common Anticoagulants

Warfarin and Heparin are two common anticoagulants used to prevent thrombosis. They are both very effective at what they do, but come with some serious risks. Warfarin (market brand Coumadin) is a natural chemical found in plants that was originally marketed as a rat pesticide. Research uncovered Warfarin’s relatively safe and effective use as an anticoagulant not long after. If used at a safe dosage, Warfarin can prevent both thrombosis and embolism. The way Warfarin works is by inhibiting Vitamin K epoxide reducatase, therefore diminishing the amount of Vitamin K available in tissues and inhibiting the Vitamin K synthesis of many calcium dependent and regulator factors. This inhibition prevents the carboxylation activity necessary for coagulation factors to bind to blood vessel surfaces. The primary side effect of this effective clot-preventing drug is hemorrhage. Although the risk for hemorrhage is small, it is definite, which means that Warfarin derivatives should only be used if absolutely necessary.

Heparin (market brand Calciparine or Hep-lock) is an injectable anticoagulant, which makes it a much faster acting prevention for thrombosis than Warfarin. Heparin is derived from the mucosal tissues of slaughtered meat such as pigs and cows. It is a naturally occurring anticoagulant that is produced in basophils and mast cells. Heparin prevents clot formation and extension by binding to antithrombin 3 inhibitor, which then inactivates the body’s blood clotting response. The major side effect of this drug is known as Heparin-Induced Thrombocytopenia Syndrome, or HITS. This side effect makes the body’s blood platelets an immunological target, leading to the degradation of platelets.

Due to the considerable effectiveness of these two drugs, they are some of the most commonly used anticoagulants. Warfarin is typically administered as a prescription drug to patients who have already formed a blood clot. Because of its strong side effects, patients are required to submit a blood sample as often as once a day to ensure a proper dosage level is maintained. Heparin is restricted primarily to hospital use because it must be administered as a continuous infusion or as frequently as every half hour. Both of these treatments are very effective at preventing blood clots, but with side effects as severe as these, any patient considering starting Warfarin or Heparin should be cautious!

Acetaminophen vs. Ibuprofen

Acetaminophen and Ibuprofen, the active ingredients contained in Tylenol and Advil respectively, are two of the most common over the counter pain analgesics. As with any medication, the side effects are dose-dependent, and may be elevated in conjunction with alcohol consumption. In a society that demands a disclaimer on our fast food coffee, it seems appropriate that these drugs should carry a warning label as well.

In large quantities, acetaminophen can induce acute hepatoxicity. The liver is an essential organ in digestive metabolism via the hepatic portal system, to reduce contaminants entering systemic circulation. For this reason, the combination of alcohol and Tylenol should be avoided, due to the extra stress placed on the liver.

In contrast, ibuprofen can induce gastric bleeding with inappropriate use. The mechanism of this drug inhibits the constitutively expressed COX-1 in the stomach, which may have protective effects on the stomach lining. Ibuprofen also has blood thinning effects, which also increases the chance of gastric bleeding.

The moral of the story? Ibuprofen and acetaminophen are effective analgesics when taken in moderation. Anything can be toxic to the body in large doses, so following dosage instructions is important in reducing the risk of developing side effects.

Use of NSAIDs--An Update

The articles for this week deal with the positive and negative actions of NSAIDs. This particular article primarily addressed a popular news topic: the increase in risk for cardiovascular and cerebrovascular events due to selective COX-2 inhibitors. These drugs looked promising for pain relief without the unwanted side affect of GI bleeding that occurs with COX-1 inhibition. However, in September 2004, Merck withdrew its product, Vioxx, from the market and the concerns for COX-2 inhibitors increased significantly.

The American Heart Association released this article as an update on the safety of using NSAIDs. An FDA joint meeting came to the conclusion that celecoxib (Celebrex), valdecoxib (Bextra) and rofecoxib (Vioxx), all selective COX-2 inhibitors, “significantly increase the risk of cardiovascular events in a dose-dependent manner.” Although celecoxib is still on the U.S. market, it comes with a strict “black box” warning.

The article by Antman et al. stated the hypothesis that the increased risk for CV events is due to a shift in the prothrombotic/antithrombotic balance on endothelial cells. The shift leans toward thrombosis. It is believed this occurs because platelet aggregation is COX-1-dependent and so this mechanism would still work. In addition, COX enzymes catalyze the production of prostacyclin in endothelial cells which can disrupt platelet aggregation. So selective COX-2 inhibition would keep COX-1 activated while decreasing prostacyclin production and thus decreasing antithrombotic activity. The hypothesis also includes the fact that COX-2 inhibition increases sodium and thus water reabsorption (which can cause edema) and can increase risk for heart failure and hypertension (since activation of COX ultimately causes “local smooth muscle cell relaxation and vasodilation” and this would be inhibited).

The article concludes basically by saying that patients who must have NSAID treatment should first try acetaminophen or aspirin, the least risky NSAIDs. If this doesn’t work, then they should be prescribed nonselective NSAIDs. Selective COX-2 inhibitors should only be prescribed if absolutely necessary, and in the lowest dose and for the shortest duration possible. Any patients with a medical history of CV problems should seriously weigh the risks and benefits.

Warfarin or the generic form Coumadin is a commonly used prescription drug that is used to prevent stroke in patient suffering from chronic atrial fibrillation, a heart valve replacement, and/or a recent heart attack. Warfarin is usually referred to as a "blood thinner" or anticoagulant because it keeps blood flowing smoothly throughout the body by decreasing the amount of clotting proteins in the blood. This medication is classified has having a low therapeutic index(i.e. there is a small margin between a normal recommended dose and a potentially lethal dose).
Since the topic this week is Anti-inflammatories and warfarin has a extremely high level of protein binding, there is a possibility that Warfarin may interact with NSAIDs. Along with the affinity for protein binding, it also can cause partial metabolic inactivation by prehepatic and hepatic CYP2C9. The medications that can cause adverse reactions include aspirin, ibuprofen, naproxen, and celecoxib(Celebrex). The complications start because the NSAID's and the COX-2 inhibitor are also extremely prone to bind to proteins in the blood(~99%) and can therefore displace the protein binding for warfarin. This can then lead to free blood levels of non-binded warfarin which can lead to the increased risk of GI or other types of hemorrhagic diseases.
Another factor that could lead to the increased GI bleeding is that each of these drugs can have an effect of the clotting profile of the blood such as inhibition of potassium dependent clotting factors suppressed by the Warfarin and the inhibition of the COX-1 in the platelets and GI mucosa caused by the NSAID's. It could be recommended then that NSAIDs should be avoided while taking anticoagulants such as Warfarin and Coumadin and to use a mild pain reliever such as Acetaminophen or Tramadol as the alternative.