The Impact of Vitamin E, Fish Oil, and Protein Supplements

Abstract

The warfarin therapy of the patients and their nutrients in the form of vitamin E and various doses of the supplements of fish oil has been on the determinants of INR (International Normalized Ratio) in patients who are recipients of chronic warfarin therapy. The INR determinants and the adverse reactions of the warfarin are also discussed. The efficacy of the nutrients in relation to the clinical practice of warfarin has been part of the study. The usage of drugs and various nutrients such as vitamin E, fish oil and various fruits containing high protein has been compared.

1.0. Introduction

The chosen drug for this study is warfarin. The anticoagulant therapy’s goal with warfarin is administering the drug’s lowest effective dose in maintaining the target INR (international normalized ratio). Warfarin is antagonist of vitamin K, which is an oral anticoagulant that treats and prevents the venous thrombosis and its treatment and prevention and extension of the thromboembolic complications that has association with atrial fibrillation. The usage of warfarin has been for the prevention of ischemic attacks that are recurrent transient and for the reduction of the risk pertaining to recurrent myocardial infarction. However, the data that supports these indications cannot be conclusive at this time. The usage of omega-3 fatty acids for the benefits of health is well established worldwide (Kris-Etherton 2002). A number of international and national health authorities have recommended its intake.

2.0. Drug

The acts of Warfarin are by inhibiting the clotting factors synthesis that is vitamin K-dependent. This is inclusive of anticoagulant proteins S and C and Factors II, VII, IX, and X. The Vitamin K is the cofactor that is essential for the vitamin K-dependent clotting factors’ post ribosomal synthesis. The promotion is done by the Vitamin K for γ-carboxyglutamic acid’s biosynthesis in the residues of the proteins that has essentiality for the biological activity. Warfarin is supposed to be interfering with the synthesis of the clotting factor by the inhibiting of the VKORC1 (vitamin K epoxide reductase) enzyme complex’s C1 subunit. This reduces vitamin K1 epoxide’s regeneration (Horton and Bushwick 1999).

3.0. Pharmacodynamics

The effect of the anticoagulation usually occurs within a day after the administration of warfarin. Nonetheless, the anticoagulant effect may be peaking at a delayed time between 72 to 96 hours. The action’s duration of racemic warfarin’s single dose is between 2 to 5 days. The COUMADIN’s effect may be becoming more pronounced as there is overlapping of the effects of daily maintenance. This has consistency with half lives of the affected vitamin K-depenedent anticoagulation proteins and clotting factors: Factor X - 48 to 72 hours, IX - 24 hours, VII - 4 to 6 hours, II - 60 hours, and proteins S and C are around 30 hours and 8 hours respectively (Lamb 1997).

4.0. Pharmacokinetics

The warfarin’s racemic mixture of S- and R- enantiomers is COUMADIN. There is exhibition of the S-enantiomer to the tune of 2-5 times greater of anticoagulant activity compared to the human’s R-enantiomer, although in general having more rapid clearance (Gage and Milligan 2005).

4.1. Absorption

After the oral administration, there is complete absorption of warfarin, peaking the concentration within the initial four hours (Gage and Milligan 2005).

4.2. Distribution

The distribution of warfarin has been in way of distribution’s relatively small volume of approximately 0.14 L/kg. The lasting of the distribution phase is between 6-12 hours that can be distinguished after oral or intravenous administration of an aqueous solution. Around 99 percent of the drug has been bound towards plasma protein (Gage and Milligan 2005).

4.3. Metabolism

The warfarin’s elimination is totally by metabolism. Warfarin is metabolized stereoselectively by microsomal enzymes, hepatic cytochrome P-450 (CYP450) in inactivating hydroxylated metabolites and by reductases in reducing matabolites, which are warfarin alcohols with minimal anticoagulant activity. The metabolite that is identified of warfarin is inclusive of a couple of diastereoisomer alcohols, dehydrowarfarin, and 10-, 8-, 7-, 6-, and 4- hydroxywarfarin (Margaglione et al. 2000).

4.4. Excretion

The warfarin’s terminal half life after one dose is around one week. However, the range of the effective half life is between 20-60 hours with the average of approximately 40 hours. The R-warfarin’s clearance is usually 50 percent that of S-warfarin. Therefore, the distribution volume has been identical and the R-warfarin’s half life is longer compared to S-warfarin. The range of the R-warfarin’s half life is between 37-89 hours, while the range of S-warfarin is between 21-43 hours. The studies pertaining to the radiolabeled drug have shown that up to 92 percent of the doses administered orally are recoverable in urine. There is very small quantity of warfarin that has been unchanged in the excretion through urine. The excretion of the urine has been in the metabolites form (Margaglione et al. 2000).

4.5. Geriatric Patients

The patients having age of 60 years or older have been seen to be exhibiting INR response that is greater than expected to the warfarin’s anticoagulant effects. In this age group, the cause of the anticoagulant effects’ increased sensitivity is not known. However, it can be because of combination of pharmacodynamic and pharmacokinetic factors. The information is limited that is suggestive of having no difference in the S-warfarin’s clearance. Nonetheless, there can be small decrease in the R-warfarin’s clearance in the elderly than the young. Thus, with the increase of the age of the patient, a warfarin’s lower dose is generally required in producing anticoagulation’s therapeutic level (Margaglione et al. 2000).

5.0. Efficacy

The efficacy and the safety of the warfarin theory have the dependency on the maintenance of the INR within the range of the target. When the patient starts an oral anticoagulant, the monitoring of the INR should be daily performed till the INR for the minimum of two consecutive days is within the therapeutic range (Loebstein et al. 2001). The INR if fluctuate unexpectedly in a patient who is otherwise stable can be because of alcohol consumption, drug use that is undisclosed, poor compliance, diet change, or self medication.

6.0. Side Effects

When warfarin is taken, there would be blood clotting of the patient so easily. However, while the warfarin is taken, and there is an accidental cut, it may heavily bleed. Nonetheless, there is low risk related to the major bleeding event. There is likelihood of having bleeding problems if the patient’s age is 75 years or older or if the patient takes other medications related to the blood thinning that can be increasing further the risk of bleeding.

The risk of bleeding problems is higher in the following conditions:

• Liver disease
• Alcoholism
• Cancer
• Kidney problems
• Stroke history
• High blood pressure (hypertension) (Kaminsky and Zhang 1997)

7.0. Efficacy of nutrients in relation to the Warfarin’s clinical applications

Since warfarin and vitamin K work against one another, the vitamin K’s amount in the diet can change the effects of warfarin. It is very important in keeping the dietary intake in the form of vitamin K as consistent. Foods such as vegetables that are green and leafy and that are containing certain oils have higher vitamin K contents. If the vitamin K intake is reduced with the consumption of lower levels of foods that contain vitamin K, the warfarin dose can be required to be lowered in preventing bleeding. If vitamin Kintake is increased, the warfarin’s dose may be required to be increased in preventing blood clots. If the intake of the vitamin K is changed majorly, it can affect the patient’s PT/INR. However, the variations that are normal and daily in foods consumed are okay. The avoidance of the food high on vitamin K is not required (Beatty et al. 2005). The patient needs to keep the diet consistent.

There are several people on special diets, such as South Beach or Atkin’s diets for losing weight. These are diets of high protein that can also be affecting the way warfarin has been working in the body. Once the warfarin dose is taken, some of it binds to the bloodstream’s protein. While this protein is attached to the warfarin, it seizes to have effect on the body. It is supposed that diets of high protein may be increasing the protein amounts in the body and may be causing greater amount of warfarin to have bindings to the protein. This may be causing the decreasing of the warfarin available for the prevention of clots, so that there is need for the warfarin dose to be increased (Beatty et al. 2005).

There are some foods that can be affecting the way liver can be clearing warfarin from the body that causes the levels of warfarin to be decreasing or increasing. The examples of it are the cranberry products (such as supplements and juice), alcohol and also possibly grapefruit juice or grapefruit (Beatty et al. 2005). However, high quantity of grapefruit products, cranberry products, or alcohol may increase the effect of warfarin and increase the risk of bleeding.

7.1. Vitamin E

The Vitamin E can be explained as an antioxidant agent having been tested in clinical trials in assessing the potential efficacy to prevent complications of cardiovascular in nature that has been secondary to the processes of atherosclerotic. Such therapy’s rationale has been on the basis of the assumption that a pivotal role is played by the oxidant stress in the atherosclerotic lesions’ progression. The experimental studies have revealed that vitamin E is responsible for the reduction of oxidant of LDL (low density lipoproteins) that is seemingly critical in the macrophages’ recruitment and foam cells’ production. However, it has been observed that there exist no relationship between the experimental atherosclerosis’ prevention and LDL oxidation inhibition. It is demonstrated previously that there is interference of vitamin E with platelet activation that is collagen induced on the strength of its capability in quenching the production of H2O2 in the platelets of the humans (Pignatelli et al. 1999).

7.2. Fish Oils/Omega-3 Fatty Acids Cardiovascular Drugs Alone versus Plus Cardiovascular Drugs

The outcomes are graft occlusion, coronary vasospasm, restenosis, cardiovascular procedures, myocardial infarction, and mortality. The assessment of these outcomes has been with various cardiovascular drugs such as warfarin. The evidences have been insufficient from the trials of single efficacy with sparse events that failed in demonstrating a difference that lies in the all cause mortality outcome (Nestel et al. 2002).

8.0. Modes of use of drugs and nutrients

Additionally to food, many over the counter drugs and prescriptions that include herbal supplements and vitamins can be affecting the level of warfarin (Hirsh 1995). The patient should not be changing, stopping, and starting the doses of any supplements or drugs without the consultation of the physicians.

The patient should be trying in keeping well balanced and healthy diet and also keeping the intake of the vitamin consistent. The warfarin dose should be taken in each day around the same time (Hirsh 1995). If a dose is missed, it should be taken at the earliest. The doubling up of the doses should not be done with consultation of the healthcare professional.

8.1. Warfarin Food Interactions

The interaction between vitamin E containing foods and warfarin is well documented. The patients who are involved in warfarin therapy are supposed to report the changes that are significant in the intake of dietary vitamin K in trying to maintain a therapeutic INR (international normalized ratio) (Heck et al. 2000) However, the interactions between the antiplatelet effects, foods and high protein diets and the warfarin, or the foods affecting the cytochrome P450 enzyme system have not been documented well.

8.2. High Protein Diets

The popularity of low carbohydrates and high protein diets has soared in last few years. The medication of the warfarin is highly protein bound. The INR decreases in patients after the diet of low carbohydrate and high protein initiation may be related to the albumin level protein intake. The albumin level increase appears to be occurring within ten days of the initiation of low carbohydrate and high protein diet. The albumin level increase causes the binding of the warfarin to the albumin that makes the availability of warfarin less free for anticoagulant effect.

8.3. Cranberry Juice

Safety of Medicine (CSM), which is a committee based in United Kingdom, issued a warning in 2003 regarding a possibility of interaction between warfarin and cranberry. The potentiality of the interaction is probably because of flavonoids found in cranberry (Shields 2003). The theory states that flavonoids found in cranberry might be inhibiting warfarin’s CYP2C9 metabolism and thereby increasing INR.

8.4. Grapevine Juice

The grapefruit juice is contained with flavonoids that can be inhibiting CYP1A2, CYP2C19, CYP2C9, and CYP3A4, isoenzymes. The grapefruit juice’s effect on drugs is hard to predict as there can be varying amount of flavoniods with respect to product to product and the flavnoid’s uptake may also be varying amongst the individuals. In theory, the grapefruit and the grapefruit juice itself may be increasing the effect of warfarin by the comparison of S-warfarin and R-warfarin metabolism.

8.5. Fish Oils

The cellular membrane’s integral component is the fatty acids. They have interactions with membrane proteins affecting membrane excitability, signal transduction, enzyme activity, and receptor function. The evidences found recently which are derivatives of omega-3 polyunsaturated fatty acids also called as fish oil or n-3 fatty acids have shown in having effect to decrease leukocyte and platelet and triglycerides reactivity and possibly can be decreasing blood pressure in subjects that is hypersensitive. The epidemiologic studies have indicated the consumption increase of the cold water fish or oil of those fishes can be reducing the mortality risk by 44 percent from the cardiovascular disease (Blasbalg et al. 2011).

8.6. Vitamin E

The adverse vitaminK-vitamin E interaction has been observed amongst patients that take oral anticoagulants that are coumarin based, such as warfarin. The mechanism related to the apparent vitamin E enhancement of coumarin action is unknown. The antagonism of vitamin E of vitamin K–dependent coagulation might be increasing the hemorrhagic disorders risks in patients who take oral anticoagulants. This makes the vitamin E antagonism of vitamin K in adults who are healthy be a mechanism with which the effect of putative mild anticoagulant is exerted by vitamin E and having association with coronary artery disease’s reduced risk (Dowd and Zheng 1995).

9.0. Concomitant use and contraindications Warfarin with nutrients

This medication is taken by mouth, usually once daily with or without food. The basis of the dosage is dependent on response to treatment, laboratory tests like INR, and the patient’s medical condition. The medication is used regularly in getting most benefits from it. It should also be taken each day at the same time. It is very important that while the warfarin is taken, the diet should be consistent and balanced. There are certain foods that can be affecting the way warfarin works in the body and can be affecting the patient’s dose and treatment. The large and sudden decrease and increase of the patient’s food intake should be avoided (Wadelius and Pirmohamed 2007). The food intake should include high in vitamin K such, green tea, liver, spinach and other vegetables that are leafy, kale, brussel sprouts, cabbage, cauliflower, broccoli, and other vitamin supplements.

This drug can have absorption through the lungs and skin that can be harming pregnant women and unborn baby or women who may become pregnant. Therefore, these kinds of people should not be handling this medication or should not be breathing the tablets’ dust (Wadelius and Pirmohamed 2007).

Warfarin is a drug that is one of most widely used worldwide for various indications that involves the treatment and prevention of thromboembolic phenomena. It is the toxicity’s narrow threshold. Its many factors that includes dose response ratio are the determining factors of how well it works. Even after 60 years since the starting of this use of drugs, it is still under research of establishing the range of the safest dosage (Wadelius and Pirmohamed 2007).

The fish oil effect on the risk factors pertaining to cardiovascular disease has been in search of action’s mechanism to reduce cardiovascular mortality. Nonetheless, the studies mostly encompassed relatively few patients and duration and doses of fish oil that has been used varied (Schmidt and Dyerberg 1994).

The primary consideration is this drug use is whether any contraindications exist in its use. There can be forbidding of its usage under any circumstances or relative, in case of which, physicians may require in balancing the bleeding risks complications under the thromboembolism risk posed by the condition of the disease that requires warfarin therapy.

9.1. Absolute contraindications

Warfarin’s absolute contraindications include:

• Decomposed liver disease
• Coagulation baseline defects that makes INR over 1.5
• Pregnancy and within delivery’s 48 hours because of teratogenicity known and capacity of inducing fetal/perinatal bleeding and spontaneous absorption
• Bleeding condition that is significant clinically and thereby reassessing risks after three months
• Drugs’ hypersensitivity, such as priapism or skin ischemic necrosis
• The count of platelets less than 50 x 109/cu.mm constituting thrombocytopenia significantly
• After a major surgery, within 72 hours
• Esophageal varices being large

9.2. Relative contraindications

There is need of relative contraindications with respect to the careful balancing of the warfarin’s risks against the thromboembolism’s risks before deciding the drug’s administration. They include:

• Hypertension that is not treated or controlled poorly
• Alcoholism, particularly binge drinking
• Likelihood of the poor compliance of the patient due to cognitive impairment or dementia with no availability of the caretaker
• The recent history episodes of falling with patient at greater risk of bleeding
• Peptic ulceration’s history within past three months that should be waited until the completion of peptic ulcer treatment and the continual of the treatment with warfarin
• Major extracranial bleeding’s recent history without a cause known

10. Conclusion

The information available pertaining to potential drug food interactions and their information is on the basis of case reports or vitro data. Without clinical trials that are well designed, it is not easy in proving definitive cause and effect relationship between these warfarin and foods.

The interactions of the drug and food with warfarin have the potential of leading to thromboembolism or hemorrhage. Thus, the healthcare professionals should have the awareness of potential implications that relates the interaction of drug-food with warfarin. There should be awareness of the changes in the habits related to diet that can affect the efficacy of the warfarin.

There can be occurrence of drug interactions that is clinically significant when interacting food and drug is added to the therapy of warfarin, discontinuity in the treatment of warfarin or intermittently used during the treatment of warfarin. This situation is representative of considerable risks for the development of interactions that require careful attention in avoiding any adverse outcome.

The contraindications related to the warfarin are of two types: absolute contraindications and relative contraindications. With these two types of contraindications, the physicians offset the risks related to thromboembolism and bleeding complications.

The omega-3 fatty acids with therapeutic use help in managing the factors of cardiovascular risk to be increasing. However, the needed doses to achieve reliably and clinically with meaningful effects are usually higher compared to the dietary supplementation levels recommended.

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