Factor Xa Inhibitors For Antithrombotic Use Biology Essay

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Haemostasis is part of the natural human response to bleeding involving the formation of blood clots close the ruptured blood vessels. This stops the bleeding in order to prevent major blood loss. However, the formation of static blood clots attached to blood vessel can also be very dangerous depending on its size and site. Antithrombotic drugs are used in order to reduce the risk of clot formation. For the past 60 years, Warfarin has been used to reduce the risk of their formation. However, it has come with a lot of negative factors affecting the patient's lifestyle. The action of both drugs will be compared to determine whether Rivaroxaban could possibly replace Warfarin.

In order to initiate my research textbooks from the library were used to gain an overview of the topic, the physiology of the human body and to inform me of drug mechanisms. Google, BMJ, PubMed and Metalib were then be used to find research surrounding Warfarin and Rivaroxaban.

The BNF informed me on the procedure of prescribing and monitoring the drugs in a clinical setting. Finally, a Cochrane systematic review of the drugs and comparison between both was found using "Direct thrombin inhibitors versus vitamin K antagonists" as the search phrase.

For my search terms, synonyms were used to get more results, but also AND and OR operators along with other keywords were used to cut down on the results and get more specific ones. My sources were critically appraised to ensure they were valid, in-date and corroborate with each other.

Warfarin

Mechanism of action

The action of Warfarin revolves around the natural pathway vitamin K would take within the body, yet it has an opposite effect on the blood since it competes with it for the same site of action since both are similar in chemical structures (Figure 1). Vitamin K is a fat soluble vitamin, obtained mainly through leafy plants such as lettuce, but can also be obtained from other sources such as meats, dairy products and eggs.

In the liver, vitamin K is part of a synthetic pathway used to make clotting factors: II, VII, IX and X which are all glycoproteins containing traces of γ-carboxyglutamic acid. Naturally, vitamin K would be reduced while acting as a coenzyme in the synthesis pathway which inactivates it. Epoxide reductase would then oxidise the inactive form of vitamin K back to an active form allowing for it to be reused.

Within the liver, Warfarin inhibits the action of epoxide reductase during the vitamin K dependant reactions. This inhibition leads to depletion of active form of vitamin K and a built up of the inactive form. In turn this results in a reduction in the amount of γ-carboxyglutamic acid within the endothelium of blood vessels. This results in a reduction of the blood's ability to coagulate since γ-carboxyglutamic acid is essential for the coagulation of the blood.1 2

Pharmacokinetics and pharmacodynamics

Warfarin is racemic mixture of approximately equal amounts of the R and S enantiomers with the S form being the more active half.

Once a tablet is taken orally, it's absorbed quickly and completely through the gastrointestinal tract.1 It reaches maximum concentration in the blood within 60-90 minutes after administration.1 However it takes 48 hours for the action of Warfarin to produce full effect. A single dose affects the body for 4 to 5 days.1 This is because for the blood to start thinning, the body's reserves of vitamin K and coagulation factors need to be reduced dramatically.2 The quickest elimination half-life of a clotting factor is VII which is 6 hours, the longest is Factor II with an elimination half-life of 60 hours.1 This results in the elimination half-life of Warfarin within the body averaging out to be 36-42 hours. Genetic and environmental factors are major influencing factors for specifying the patients' individual dose.

Warfarin's anticoagulant response is influenced by pharmacokinetic factors such as concurrent medication and food interactions. These can affect the absorption in the gastrointestinal tract, distribution in the blood, metabolism in the liver and its execration. Pharmacodynamic factors can also impact the extent of the haemostatic response to the administered dose. Patients whom are prescribed Warfarin for a long period of time are very sensitive to varying levels of vitamin K through their diet. Certain drugs may also interfere by either inhibiting or stimulating the vitamin K synthesis pathways of some coagulation factors.

Dosage

The dose required for each patient is unique to them, influenced by several factors including the cause of the prescription. There is no established algorithm for determining the prescription dose.

INR is a measure of prothrombin time (PT) which is the time needed for the blood to coagulate. It's standardised by taking the logarithm of a ratio of the patients' PT compared to the average PT of the population. It is measured via a blood test. Table 2 shows the target INR range for each disease:

Patients are usually started off on a high loading dose of 2-5mg daily for 4-5 days before reassessing their INR levels to decide on their maintenance dose. During this timeframe it allows for Warfarin's course of action to take place. A significant change in INR can be achieved by small changes of 15% or less to the administered dose. Elderly and immobile patients are usually prescribed a lower dose due to reduced serum albumin; this reduces the risk of haemorrhaging. It's crucial that the patient takes their prescribed dose at the same time and maintains a constant level of vitamin K and is careful of drug interactions with any other medication they are on.7

After 20 hours of the first dose of 4.5mg of Warfarin, the INR is usually 1.3 in an average patient. A higher INR would suggest the patient is sensitive to Warfarin and would require a lower dose. If the INR is greater than 1.8 the second dose needs to be lot smaller, such 1mg. If the INR is between 1.0 and 1.1 the second dose should be around 10mg, however anything between INR ranges of 1.2 to 1.8 would require the second dose being altered between 1.0 to 9.0mg to accommodate for the INR value.

Pharmacogenomics

Genetics plays a pivotal role in determining the patient's dose of Warfarin. There is evidence which suggests that resistance to Warfarin is hereditary. Patients suffering with this type of resistance usually require doses 5 to 20 times stronger than average in order to achieve the same INR.6 Polymorphism in the genes coding for and VKORC1 have been linked with patients' resistance to Warfarin.

The gene VKORC1 produces a key enzyme in the vitamin K cycle. This enzyme is inhibited by Warfarin. Mutations in this gene are responsible for 30% of the dosage variations. For people of African origin this mutation manifests itself in increased resistance to Warfarin which is a contrast to people of Asian origin whom a mutation results in increased sensitivity to Warfarin.

The gene CYP2C9 produces an enzyme which metabolises the S form of Warfarin. A mutation in this gene is most common in people of Caucasian origin and is responsible for 10% of dose variation. These mutations usually leads to a shortening of the time needed for the INR to exceed 4. 6

Rivaroxaban

Mechanism of action

Factor X is an endopeptidase which plays a part in the coagulation cascade. It is synthesised in the liver in presence of vitamin K. Factor X is present in both the intrinsic and extrinsic coagulation pathways. It is needed for the formation of the prothrombin complex at which point it becomes activated. Once factor X becomes activated, it is referred to as factor Xa.

Rivaroxaban is administered orally and is a highly selective factor Xa inhibitor. Selective inhibition of factor Xa leads to disruption of both the intrinsic and extrinsic pathway of blood coagulation. It also inhibits the formation of thrombin, which is an enzyme that acts on fibrinogen to cause blood clots yet does not inhibit its action. Finally, it will inhibit the development of static blood clots formed within a blood vessel.

Pharmacokinetics

Rivaroxaban has a high bioavailability (80-100%) with blood concentration reaching its peak between 2-4 hours after oral administration of a dose of 10mg dose. Food intake has no effect on its bioavailability and can be taken with or without food. It's distributed via the blood with 92-95% binding to the plasma with albumin being the main carrier.

Out of the administered dose, two thirds is metabolised by the liver while the remaining third is directly excreted unchanged via urine. Out of the metabolised proportion, half is execrated via urine while the other half is excreted via the faecal route.

Rivaroxaban is mainly metabolised by CYP3A4, CYP2J2 which are cytochrome P450 enzymes in the liver but also other hepatic mechanisms which are independent of cytochrome P450. The half-life of a 10mg dose of Rivaroxaban in the body is between 7-11 hours.

Dosage

The drug manufacturer recommends that a 10mg of Rivaroxaban should be taken once daily. The treatment course should start 6 to 10 hours after surgery provided the bleeding has been stopped.13

The length of the treatment course is unique to the patient depending on the operation they had and their risk of blood clots forming in their veins. For patients undergoing hip surgery, treatment duration of 5 weeks is recommended, where as for patients undergoing knee surgery it's only 2 weeks.13

If the patient misses their dose, it is advised they should take it as soon as they realise and continue the following day as before.13

Comparison

In table 3 I have compared both Warfarin and Rivaroxaban. The dosage required each patient prescribed Warfarin is variable. It requires regular monitoring via blood testing whereas with Rivaroxaban it is Rivaroxaban it is a single dose of 10mg orally. The bioavailability of both is very high although with Rivaroxaban a certain amount will pass through the system without being facilitated for its intended purpose. Warfarin interacts with a lot more food and drugs compared to Rivaroxaban making it harder to specify the right dose per patient. The patient needs to maintain a constant diet and take their dose at the same time daily.

Conclusion

Warfarin is an old drug which has been prescribed for a long time. It has a lot of side effects, difficulties in determining the exact dose and a lot of interactions with the patients' diet and other drugs. Regular INR checks and constant dose adjustments means that it becomes part of the patients' lifestyle and uses up a lot of time and money. Rivaroxaban offers an insight into what the future of antithrombotic drugs can potentially become, however we are not ready to offer it as a mainstream replacement to the conventional Warfarin. Its main advantages are that it does not interact with many drugs or food products and single defined daily dose is suitable for the majority of the population without any INR checks. However, it costs £132.44 for a single month's course compared to £1.49 for Warfarin for the same duration. We should not be hastened to get rid of a treatment which is tried and tested for a new treatment without further research.

Appendix

Figure 11

Disease

INR Range

Prophylaxis DVT / PE

2.0-3.0

Atrial Fibrillation

2.0-3.0

Myocardial Infarction

2.0-3.0

Mechanical Heart Valves

2.5-3.5

Figure 27

Warfarin

Rivaroxaban

Dosage

Variable depending on patient

10mg tablet daily

Bioavailability

100%

80-100%

Mechanism of action

Vitamin K antagonist

Direct Factor Xa inhibitor

Cmax

1-1.5 hours

2-4 hours

Time to take effect

2-4 days

12 - 24 hours

Food interactions

Very sensitive towards vitamin K.

Interacts with: Alcohol, Cranberry juice.

Can be taken before or after food.

No food interactions known

Drug Interactions

Anabolic steroids, certain analgesics and NSAIDs, Anti-arrhythmics, antibacterials, antidepressants, corticosteroids, cytotoxics and many more.

Strong inhibitors of both CYP3A4 and P-gp such as azole-antimycotics and HIV protease inhibitors.

Monitoring

Regular INR checkups

None

Figure 3 1 3 4 13

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