Warfarin (in sodium form) is an oral coumarin analogue anticoagulant that competitively antagonises the effects vitamin K. Normally the drug takes 2-3 days for the drug to completely work. Heparin which is given intravenously is used if immediate and short acting anticoagulant is required. Primary use of drug is for deep vein thrombosis (DVT) but not used for cerebral artery thrombosis in first line therapy. Other uses include pulmonary embolism, atrial fibrillation which could lead to embolisation. The main types used are the non-proprietary warfarin, acenocoumarol and phenindione.
Heparin is more suited for prophylaxis for venous thromboembolism whereas warfarin is used if someone is using drug long term and has chance of venous thromboembolism.
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. 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 (Australian press) (increased risk when INR<4.0) and INR is taking into consideration to reduce haemorrhaging due to its toxicity.
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Aspirin (Acetylsalicylic acid) is given as daily dose of 75mg and acts as an antiplatelet drug and used as a less effective treatment of thrombotic cardiovascular disease. The drug is more suited to reduce risk in transient ischaemic attack. The drug lowers the aggregation of platelets and in fast flowing vessels, inhibits thrombus formation in arterial circulation. Haemorrhage (especially gastro intestinal) is also a common side effect in aspirin.
1. Joint Formulary Committee. British National Formulary. 59th ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2010. pg 141-6
Vitamin K is found in leafy green vegetables and is fat soluble but demand for it in human diet is small as bacteria in intestine produce the vitamin too.
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. Thrombosis occurs when blood vessels are obstructed because of too much fibrin production. Three steps that govern coagulation cell mechanism in vivo: Initiation, amplification and propagation as shown by figure . (harhun) Initiation is from transmembrane protein which is chiefly outside the blood vessels called tissue factor (TF) binding to VIIa (a means activated) 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.
Coagulation takes place in activated cell surfaces, controlled by Ca2+ linking anionic phospholipid and Î³-carboxyglutamin acid residues of clotting factors. Protein C and S (endogenous anticoagulants) prevents clotting by inactivating Va and VIIIa.
Figure shows warfarin (oral anticoagulant) inhibits II, VII, IX, X factors and Protein C to activated forms.
Warfarin is a common drug and is 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 but four times more potent.
Warfarin block Î³-carboxylation in many residues of glutamate in the four factors (as explained before) 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 . 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.
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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.
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) Drugs with no marked effect on thrombin time are benzodiazepines, opioids and most antibiotics.
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 ) 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 required.
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 moment.
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.
Harhun M. Anti-coagulants. [Lecture] PY2050 Systems Pharmacology Handbook One. St Georgeâ€™s University. 10th February 2011
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 shows the process of conversion of Arachidonic acid to TXA2 (thromboxane A2 and PGI2 (Prostaglandin I2) by Cyclooxygenase. (COX) (Aspirin prevents (via irreversible acetylation) the action of COX-1 and COX-2 (COX-1 inactivated in preference in low doses) 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. In low oral doses of aspirin, inhibition of 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 recommended along with control of blood cholesterol and blood pressure and secondary in vascular events. (i.e. thrombosis)
(PGE is Alprostadil; relaxes smooth muscle and PGF is Misoprostol; prevent peptic ulcer.)
Katzung BG.(10th edition) Basic and Clinical Pharmacology. New York:McGraw-Hill. 2007. p 549-558
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 and efficacy compared to warfarin is lowered
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
Borosak M, Choo S, Street A. Warfarin: balancing the benefits and harms. Aust Prescr. 2004;27:88-92
Warfarin and aspirin can be given simulanteously.This is either aspirin added to warfarin (mechanical heart valve) 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 multiplied by 2.75 and major bleeding was multiplied by 2.06 so risk overshadows benefits. (i.e. reduced risk of thromboembolic event, mortality, myocardial infarction, ischaemic stroke)
Keeling D. Weighing up the risks and benefits of warfarin plus aspirin. Prescriber. 2009; 20(4):3-6