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Warfarin and what affects It.

Warfarin: Do we have options?

Do you know how warfarin was made?   In the 1950s, some ranchers in Wisconsin were upset  that their cattle were bleeding to death. The ranchers sought help at the University of Wisconsin. Researchers discovered that the cattle were bleeding to death as a result of eating spoiled sweet clover. They were able to identify and isolate the substance in the spoiled sweet clover that was causing the excessive bleeding. This substance was a derivative warfarin. It has been modified and standardised in a laboratory to make it safe for use by patients.

Warfarin or coumadin has a half life of between 20-60 hours.  The response of oral anticoagulation is very varied, it may be enhanced in obstructive jaundice, hepatitis and cirrhosis due to reduced vitamin K absorption, while foods high in Vitamin K (Beef, pork, green leafy vegetables) will decrease the efficacy of warfarin. Additionally, many medications can decrease the risk of anticoagulation (anti-thyroid drugs, barbiturates, estrogens) and others increase the risk of hemorrhage. Inhibition of coagulation factors occurs 12 to 24 hours after oral administration, but antithrombotic effects may not occur until 2 to 7 days after initiation of therapy.

Coumadin has been the only option for oral anticoagulation.  This is a long term or life time therapy that is problematic for many people.  It is easy to monitor, but most people do not fall into the therapeutic range, requiring constant dose adjustments.  The International Normalized Ratio (INR) helped to standardize results regardless of the laboratory instrument reagent combination, helping to achieve the target range of 2-3.

• Warfarin has a narrow therapeutic range
• Accounts for 15% of all severe adverse effects
• Doses from 1-10 mg/daily
• Different ethnicities display varying sensitivity, about 35% of population have genetic variants
• Cause warfarin to be metabolized less efficiently
• The FDA has labeled warfarin concerning role of genetics in dosing
• Genes identified as CYP450 2C9 and VKORC1 (RUO)

One of the downsides of this medication is that it interacts with many different foods and beverages. While there is no specific diet for people taking Coumadin, there are general guidelines that should be followed to help improve the safety of the medication.
 

The foods that you eat can also affect the way this medicine affects your body. This is a result of the effects of the anticoagulant which depend on the amount of vitamin K in your body. It is best to have the same amount of vitamin K in your body every day. Some multiple vitamins and some nutrition supplements contain vitamin K. Vitamin K is also present in green, leafy vegetables (such as broccoli, cabbage, collard greens, kale, lettuce, and spinach) and some vegetable oils.

There are 4 food and lifestyle interactions with warfarin which include:

Coumadin and Alcohol (Ethanol)

Enhanced hypoprothrombinemic response to warfarin has been reported in patients with acute alcohol intoxication and/or liver disease. The proposed mechanisms are inhibition of warfarin metabolism and decreased synthesis of clotting factors. Binge drinking may exacerbate liver impairment and its metabolic ability in patients with liver dysfunction. The risk of bleeding may be increased. Conversely, reductions in INR/PT have also been reported in chronic alcoholics with liver disease. The proposed mechanism is that continual drinking of large amounts of alcohol induces the hepatic metabolism of anticoagulants. Effects are highly variable and significant INR/PT fluctuations are possible.

Moderate Food Interaction

Vitamin K may antagonize the hypoprothrombinemic effect of oral anticoagulants. The intake of vitamin K through supplements or diet can reverse the action of oral anticoagulants. Resistance to oral anticoagulants has been associated with consumption of foods high in vitamin K content which include green, leafy vegetables, avocados, soy beans, and green tea. Lesser amounts are found in liver, bacon, cheese, butter, cauliflower, and coffee. Snack foods containing the fat substitute, olestra, are fortified with 80 mcg of vitamin K per each one ounce serving so as to offset any depletion of vitamin K that may occur due to olestra interference with its absorption.  Large amounts of mango has been associated with enhanced effects of warfarin. The mechanism of interaction is unknown but may be related to the vitamin A content, which may inhibit metabolism of warfarin. discontinuation of mango ingestion for 2 weeks.
Warfarin and cranberry juice can result in changes in the INR and/or bleeding complications. The mechanism is unknown but may involve alterations in warfarin metabolism induced by flavonoids contained in cranberry juice. It is not known if variations in the constituents of different brands of cranberry juice may affect the potential for drug interactions.

Soy protein in the form of soy milk was thought to be responsible for a case of possible warfarin antagonism in an elderly male stabilized on warfarin. The exact mechanism of interaction is unknown, as soy milk contains only trace amounts of vitamin K. Subtherapeutic INR values were observed approximately 4 weeks after the patient began consuming soy milk daily for the treatment of hypertriglyceridemia. No other changes in diet or medications were noted during this time. The patient's INR returned to normal following discontinuation of the soy milk with no other intervention.

An interaction with chewing tobacco was suspected in a case of warfarin therapy failure in a young male who was treated with up to 25 to 30 mg/day for 4.5 years. The inability to achieve adequate INR values led to eventual discontinuation of the chewing tobacco, which resulted in an INR increase from 1.1 to 2.3 in six days. The authors attributed the interaction to the relatively high vitamin K content in smokeless tobacco.

DRUGS:

A total of 680 drugs (3290 brand and generic names) are known to interact with Coumadin (warfarin).

• 187 major drug interactions
• 313 moderate drug interactions
• 180 minor drug interactions 

High Blood Pressure (Hypertension)
The use of OAC is contraindicated in patients with malignant or severe, uncontrolled hypertension since they may be at increased risk for cerebral hemorrhage. Therapy with oral anticoagulants should be administered cautiously in patients with moderate hypertension.

High Cholesterol (Hyperlipoproteinemia, Hypertriglyceridemia, Sitosterolemia)

A decreased OAC response may be seen in patients  with edema, hereditary coumarin resistance, hyperlipidemia, hypothyroidism, or nephrotic syndrome may exhibit lower than expected hypoprothrombinemic response. Thus, more frequent laboratory (PT/INR) monitoring and dosage adjustment of anticoagulant may be required based on changes in the patient's condition.

Potentiating the Effect of Warfarin

Many antibiotics are reported to potentiate the effect of warfarin. Some examples include: cotrimoxazole, erythromycin, isoniazid, fluconazole, miconazole, and metronidazole.  Antibiotics  with a lower risk of enhancing warfarin are:mciprofloxacin, itraconazole, and tetracycline  Several cardiac drugs had highly probable evidence that they potentiated the effect of warfarin: These included amiodarone, clofibrate, propafenone, propranolol, and sulfinpyrazone. Sulfinpyrazone's effect was biphasic, which means that an initial potentiation of the warfarin anticoagulant effect was noted, followed by inhibition of the effect. Quinidine, simvastatin, and acetylsalicylic acid had probable evidence that they potentiated warfarin Among the anti-inflammatory or analgesic drugs, phenylbutazone, piroxicam, acetylsalicylic acid, acetaminophen, and dextropropoxyphene had highly probable or probable evidence ..
Drugs Inhibiting the Effect of Warfarin
Fewer drugs inhibited the effect of warfarin,  Highly probable evidence was reported for nafcillin, rifampin, griseofulvin, cholestyramine, barbiturates, carbamazepine, chlordiazepoxide, sucralfate, high vitamn K content in enteral feeds or in the diet, and large amounts of avocado.. Probable evidence was reported with dicloxacillin. The reported interactions of four other drugs in addition to the consumption of large amounts of broccoli were considered possible evidence 
New Oral anticoagulants on the horizon:

The new class of oral anticoagulants has been developed to pinpoint a specific target for controlling the clotting cascade with maximum efficacy and minimum inconvenience.
Nattokinase is a soybean food content, produced by the bacterium Bacillus subtilis (natto) during fermentation of soybeans. It is a 275 amino acid peptide. It is also called "Subtilisin NAT". It is said to have similar clot-dissolving abilities as does plasmin. Nattokinase may have some potential to protect from blood clots. However, it has not been appropriately studied in humans. Nattokinase is not a substitute for warfarin. The FDA concluded in 2002 that there is no "adequate basis to conclude that NKCP [Natto extract] containing 0.01 % of Nattokinase enzyme is reasonably expected to be safe" and that "there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury". Furthermore, the FDA has warned that unsubstantiated and illegal claims are being published about the effectiveness of NSK-SD Nattokinase .
PRADAX™ (dabigatran etexilate), is a novel oral direct thrombin inhibitor (DTI) for the prevention of venous thromboembolism (VTE) in adult patients who have undergone elective total hip or total knee replacement surgery. Oral direct thrombin inhibitor binds directly to thrombin, blocking interaction with its substrates, thereby preventing the conversion of fibrinogen to fibrin and forming a crosslinked blood clot or preventing thrombin generation, and thus producing a state of anticoagulation. It is given once-daily and does not require extensive anticoagulation monitoring. PRADAX™ is taken orally and no injections are needed. PRADAX™ does not interact with food and has a low potential for drug-drug interactions. They offer the advantages of fixed dosing and preclude the need for routine blood monitoring, making them very attractive alternatives to warfarin
Trials are ongoing to establish the efficacy and safety of dibigatran versus warfarin.
Another agent close to approval is the Factor Xa inhibitor apixaban.  Apixaban suffered a setback last year when results of the ADVANCE-1 trial were reported. Apixaban did not meet its noninferiority goal, because of an unexpectedly low rate of events in the trial of 3,195 patients.
Despite the promising outlook for the Factor Xa and thrombin inhibitors in the coming years, the drugs are not without limitations. They do not require the INR monitoring that limits warfarin use, but patients with severe renal insufficiencies will most likely not be candidates for the new agents. There are other potential problems as well. Cost may be a factor, warfarin is a cheap drug.
These new oral thrombin and factor Xa inhibitors have demonstrated rapid onset of action and predictable pharmacokinetics.. These anticoagulants also have a low propensity to clinically relevant drug-drug interactions. They potentially eliminate the need to provide additional follow up services to those on extended prophylaxis who are either unable or reluctant to self inject their low molecular weight heparin prophylaxis. US Food and Drug Administration approval of dabigatran is pending.

Donna Castellone

About the Author

Donna Castellone,
MS, MT(ASCP)SH
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