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This essay will investigate how warfarin and aspirin are medicinally utilised to treat venous and arterial thrombosis. This will be achieved by examining the aetiology of thrombosis and comparing the pharmacodynamics, pharmokinetics and pharmacotherapeutics of the two drugs.
Haemostasis is the maintenance of fluidity of blood and its aim is to repair the body in vascular injury and limit blood loss by producing sufficient amounts of fibrin (coagulation) at site of injury. Three steps that govern coagulation cell mechanism in vivo: Initiation, amplification and propagation as shown by Figure 1. Initiation is from transmembrane protein which is chiefly outside the blood vessels called tissue factor (TF) binding to VIIa (a signifies activated form of factor) by TFPI. (Tissue factor pathway inhibitor) Factors IX and X are activated as a result. Prothrombinase is produced by Xa and Va that catalyses Factor II (Prothrombin) to thrombin, activating clotting factors (i.e. V,VIII and XI) and is amplifies thrombin production.1 Coagulation takes place in activated cell surfaces, controlled by Ca2+ linking anionic phospholipid and γ-carboxyglutamin acid residues of clotting factors. Protein C and S (endogenous anticoagulants) prevents clotting by inactivating Va and VIIIa.2
Thrombosis occurs when blood vessels are obstructed because of too much fibrin production and blood clot is still present in blood vessel. Virchow's triad model suggests that there are three main changes of events that are the aetiology of thrombosis. 1,3 These are changes in normal blood flow, constituents of blood and vessel wall of blood. Blood flow can be altered by stasis, which is when leg movement is restricted for long periods of time (including air travel, illness) causing irregular circulation in deep vein of legs. Vessel diameter or length could also change forming in more clots resulting in varicose veins. Constituents of blood can be altered in dehydration (from intake of diuretics like alcohol and caffeine) which raises concentration of blood, taking oestrogen or high concentration of lipid in blood. Blood vessel wall is comprised of endothelial cells and this can be weakened by smoking or low oxygen concentrations (i.e. in aeroplane) The blood clot could spread to other areas of body and lead to pulmonary embolism, (if in pulmonary artery) ischemic stroke (if in brain) or myocardial infarction (if in coronary arteries) 1
Ideally, initiation process of TF-VIIa should be maintained and secondary propagation of clot development should be reduced but this is still not possible with any drug on market at the moment. Warfarin and aspirin are examples of two drugs that help to prevent/ maintain thrombosis. Other treatments in thrombosis include Clopidogrel, (ADP receptor antagonist) Abciximab (GPIIb/IIIa receptor antagonist), Streptokinase and Reteplase. (Thrombolytic drugs) Drugs that inhibit TF-VIIa, IXa, Xa, IIa and currently in research/clinical process.1
Warfarin (in sodium form) is a common drug but not used as often it should considering its proven clinical benefits. This includes 100% bioavailability, plasma half-life of 36 hours (long), absence of urinary excretion of unchanged drug as well as more than 99% racemic mixture bound to plasma albumin. Stereoselectivity of drug interactions take into account that the S enantiomer is in equal amounts of R (racemic) but four times more potent.2
Mechanism of Action:
Figure 1 shows warfarin (oral coumarin analogue anticoagulant) prevents II, VII, IX, X factors and Protein C to convert to the activated forms. Warfarin competitively antagonises the effects vitamin K. and blocks γ-carboxylation in many residues of glutamate in the four factors and protein C and S. This would produce incomplete coagulation factors that are biologically inactive. (KO) Prothrombin carboxylation by carboxylase (enzyme) is combined with vitamin K oxidation as shown in Figure 2. The drug stops the reactivation of vitamin by blocking reduction to hydroquinone structure. (KH2)
Inhibition of coagulation are controlled by half-life degradation in circulation. Commencement of the effects of drug are increased up to 0.75mg/kg but then above that amount, pharmokinetics are unchanged of dose size and only serve to lengthen the plasma concentration of plasma to inhibit the coagulation.
Use: Primary use of warfarin is for deep vein thrombosis (DVT) but not used for cerebral artery thrombosis in first line therapy. Other uses include pulmonary embolism and atrial fibrillation which could lead to embolisation. 4 The other types of oral anti-coagulants used are acenocoumarol and phenindione. Heparin is a natural anticoagulant which is normally given intravenously and used if immediate and short acting anticoagulant is required. Heparin is more suited for prophylaxis for venous thromboembolism where warfarin is used if someone is using drug long term and exhibits a possibility of venous thromboembolism.
Normally warfarin takes 2-3 days for the drug to completely work. Initially, first day dose for rapid coagulation of 5-10mg is prescribed and then increased depending on prothrombin time. (in severe liver disease this time could be prolonged alternatives to warfarin should be prescribed) A non rapid loading dose is lower throughout 3-4 weeks with regular dose of 3-9mg. 4 (Doses are different in Acenocoumarol and Phenindione) Big changes in diet (i.e. salads and vegetables) and alcohol can affect the dose given.
INR (international normalised ratio) was created by WHO (World Health Organisation) and determines extrinsic pathway of coagulation (factors II, VII, IX and X) and therefore clotting time. INR of 2.5 is used in DVT treatment whereas 3.5 are used in repeated DVT and needs to be closely monitored. Haemorrhage is a common adverse effect especially in first three months of treatment5 (increased risk when INR<4.0) and INR is taking into consideration to reduce haemorrhaging due to its toxicity.
Pharmokinetics: The pharmokinetics of warfarin can be altered by other drugs through enzyme induction, enzyme inhibition and reduced plasma protein binding. Cimetidine and Fluconazole can increase prothrombin time whereas Barbiturates and Rifampin significantly decrease prothrombin time. The pharmacodynamics of warfarin are changed by other drugs through synergism, competitive antagonism and different physiological control loop for vitamin K. Prothrombin time can be increased (i.e. by high doses of aspirin, heparin and hepatic disease) or decreased. (i.e. by diuretics, vitamin K and hereditary resistance) Resistance to warfarin can be developed by mutational change of enzyme (vitamin K epoxide reductase) or in gastrointestinal cancer. This can be evident in repeated thrombotic event, resulting in increase in INR followed by higher risk of bleeding or daily injections of low molecular weight heparin.
Drugs with no marked effect on thrombin time are benzodiazepines, opioids and most antibiotics. Warfarin is not recommended during pregnancy (especially in first trimester) as it can travel through placenta and affect early development and increase risk of haemorrhage at any time so heparin is given by subcutaneous injection.
Extreme warfarin effects like bleeding can be reversed by halting administration of drug and taking oral or parental vitamin K1,(due to similar structures of warfarin and vitamin K1 as seen in Figure 3) fresh frozen plasma and prothrombin complex compounds. The long half-life of warfarin would need to be taken into account so more than one dose could be 2
Mechanism of action: Role of platelet is maintained by three types of constituents; produced on within (i.e. ADP), outside (i.e. thrombin) of platelet that react with membrane receptors and inside platelet (i.e. thromboxane A2) targeting within platelet. Figure 4 shows the process of conversion of Arachidonic acid to TXA2 (thromboxane A2 and PGI2 (Prostaglandin I2) by Cyclooxygenase. (COX) Aspirin (Acetylsalicylic acid) prevents (via irreversible acetylation) the action of COX-1 and COX-2 (COX-1 inactivated in preference in low doses of 75 and 300mg) and therefore lower TXA2, PGI2 and PGD2.TXA2 stimulates platelet aggregation in platelet so delay bleeding time while PGI2 and PGD2 inhibits platelet aggregation. Aspirin is the only NSAID (Non Steroid Anti-inflammatory Drug) that irreversibly blocks action of COX-1 and COX-2.
Haemorrhage (especially gastro intestinal) and resistance (especially to prevent a repeat ischemic stroke) is evident (like in warfarin) in aspirin.
(PGE is Alprostadil; relaxes smooth muscle and PGFα is Misoprostol; prevent peptic ulcer)
Use: In low oral doses of aspirin, inhibition of platelet (anti platelet) COX production is greater than inhibition of endothelial COX production, (i.e. PGI2) which is opposite in case of high oral dose. Therefore, low dose of aspirin is used in first line of myocardial infarction, where smoking is not strongly recommended and blood cholesterol and blood pressure is maintained and with other drugs, could also be used for angina pectoris. Aspirin is second line treatment in vascular events, in particular arterial rather than venous thrombosis as there is more platelets in arterial vein than venous.
Pharmokinetics: After administration of the low dose aspirin (apart from modified release form) is absorbed mainly in stomach and small intestine very fast (20 minutes), peaking in concentration after 1-2 hours after intake and will possibly last for 7-10 days.2
If target INR (2-3) for warfarin exhibits high risk of bleeding, alternatives such as low molecular weight heparin, aspirin or reduced dose of warfarin could be considered. If warfarin is contraindicated with atrial fibrillation, aspirin can be given as stroke risk is lowered by 42% compared to placebo but bleeding is still an issue. Warfarin treatment can only be stopped when clinical benefit out prevail over risk of bleeding and should be reviewed. Bleeding can vastly increase morbidity or mortality.5
Warfarin and Aspirin combined therapy
Warfarin and aspirin can be given simultaneously. This is either aspirin added to warfarin (mechanical heart valve disease) or aspirin added to warfarin (secondary coronary artery disease) or both for different conditions. However, a recent study has shown the combined therapy showed haemorrhage multiply by 2.75 and major bleeding was multiply by 2.06 so risk overshadows benefits. (i.e. reduced risk of thromboembolic event, mortality, myocardial infarction, ischaemic stroke) 6
Warfarin (venous) and aspirin (arterial and intracardial) are therapeutically used orally to treat thrombosis and have different mechanisms of action. Heparin (and its derivatives) are sometimes replace warfarin in certain situations (i.e. pregnancy) and is administered by injection. Warfarin is an anti-coagulant which antagonises vitamin K while aspirin (in low doses) is an anti-platelet inhibiting COX action. (more COX-1 than 2) Warfarin is the primary treatment of thrombosis and more widely used while aspirin is used in secondary treatment for thrombosis but both display risk of gastro intestinal bleeding and even fatal bleeding in the brain in the case of warfarin. Therefore closely monitoring (especially INR values in warfarin usage) to ensure the best effective treatment for the individual patient, considering lifestyle and genetic factors.