|WHAT IS NEW?
|Year : 2014 | Volume
| Issue : 1 | Page : 86-87
Newer oral anticoagulants
Ravichandra Volabailu, Padmaja Udaykumar
Department of Pharmacology, Father Muller Medical College, Kankanady, Mangalore, Karnataka, India
|Date of Web Publication||15-Mar-2014|
Department of Pharmacology, Father Muller Medical College, Kankanady, Mangalore, Karnataka
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Volabailu R, Udaykumar P. Newer oral anticoagulants. Muller J Med Sci Res 2014;5:86-7
Warfarin a hydroxycoumarin has been in use in medical practice after an attempted suicide of an army recruit was foiled with a blood transfusion and vitamin K. Phenprocoumon and acenocoumarol are other vitamin K antagonists used in Europe. The oral anticoagulant warfarin has been the standard of care for a wide variety of indications for nearly 50 years.
| Disadvantages|| |
- Though warfarin is administered once daily, the dosage varies depending on genetic polymorphism and diet of the individual.
- It takes 8-12 h for its onset of action.
- Anticoagulant effect requires close monitoring through prothrombin time.
- Food interaction food rich in vitamin K - such as spinach, mustard green, collards and beets alter therapeutic levels of warfarin.
- Warfarin is subjected to many drug interactions due to enzyme inhibition, enzyme induction or decreased plasma protein binding. Antibiotics such as metronidazole, cephalosporins, fluconazole are associated with such interaction.
- Warfarin is teratogenic, causing abnormal fetal bone formation and hemorrhagic disorders.
- Side-effects range from skin necrosis to inflammation of breast, intestine and extremities. Efforts have been made to develop substitutes of warfarin with a more favorable pharmacokinetic profile.
| Factor Xa and Factor IIa Inhibitors|| |
Newer anticoagulants inhibit a single factor (factor Xa and factor IIa) within the coagulation cascade, providing a more predictable and consistent pharmacokinetic and pharmacodynamic response. 
Several oral formulations of factor Xa and thrombin inhibitors are being developed. These drugs have more predictable anticoagulant response and do not require monitoring for effective anti-coagulation. They have a faster onset of action and it is hypothesized that there is no need for an antidote. There is no rebound thrombin generation, which could lead to thrombus formation.
Several inhibitors of factors Xa and factor IIa are at different stages of clinical trials. Three drugs namely dabigatran, rivaroxaban and apixaban have been approved whereas ximelagatran has recently been withdrawn from the market.
| Direct Thrombin Inhibitors|| |
Dabigatran etexilate a reversible competitive, direct thrombin inhibitor has been approved for stroke prevention in atrial fibrillation (150 mg orally BD).  It is strongly basic and has a low bioavailability of 6%. Cytochromes P450 (CYP) enzymes are not involved in its activation. Its half-life is 12-14 h and is excreted mainly through urine. Dabigatran is a substrate of efflux protein P-glycoprotein. Therefore the dose of dabigatran is reduced when used with drugs such as rifampicin, which uses this transporter. Co-administration with blood thinners such as clopidogrel, ticlopidine and non-steroidal anti-inflammatory drugs increases the risk of bleeding.
The most common side-effects are bleeding and gastrointestinal (GI) effects such as nausea, dyspepsia and diarrhea. The overall risk of GI bleeding was similar to that of warfarin. There are currently no available antidotes for its overdose complications. 
AZD 0837 is a selective and reversible direct thrombin inhibitor, being evaluated in phase II clinical trials.
| Factor Xa Inhibitors|| |
Rivaroxaban is a direct, competitive inhibitor of factor Xa, approved in the USA, Canada and Europe for thromboprophylaxis after orthopedic surgery. The dosage is 10 mg, 6-10 h after establishment of surgical hemostasis. It is contraindicated in severe renal failure (Cr Cl <15 ml/mm), liver failure with coagulopathy and in patients below 18 years of age.
Rivaroxaban has high bioavailability (80%), is extensively bound to plasma proteins with half-life of 7-11 h. Its modes of excretion include renal elimination (66%) and fecal elimination. Rivaroxaban was not monitored with any clotting assays in clinical trials. It is metabolized by CYP3A4, CYP2J2 and other mechanisms leading to a variety of drug interactions. It is also a substrate for P-glycoprotein transporters. Therefore it is contraindicated with anti-human immunodeficiency virus protease inhibitors and azoles. It has to be used cautiously along with rifampicin. Bleeding and anemia are expected side effects. Nausea, elevated liver enzymes, tachycardia, syncope pruritus and hypotension are also reported. 
Apixaban is a direct, selective inhibitor of factor Xa with > 30,000 fold selectivity over other coagulation proteases. Apixaban is in various stages of clinical trials for different indications such as stroke prevention in atrial fibrillation and thromboprophylaxis in hip and knee replacement patients.  It is well absorbed when given orally, with half-life 8-15 h, depending on whether it is given once or twice daily. It is metabolized mainly by O-demethylation. Apixaban has drug interactions with other drugs that induce or inhibit CYP3A4. Potent inhibitors such as ketoconazole are to be stopped at 14 days prior to the use of apixaban.
Bleeding is the main concern with the use of apixaban similar to other antithrombotics.  Concomitant use of antiplatelet agents leads to an increase in the incidence of bleeding. As antidotes are not available, blood products may be required in acute hemorrhage cases.
Other factor Xa inhibitors in development include edoxaban, TAK 442, betrixaban and YM150. These are under various stages of investigation and have differences in their pharmacokinetic and pharmacodynamic profiles. They may be useful in special populations such as patients with renal or liver dysfunction. 
| Summary|| |
Newer oral anticoagulants add to the pharmacologic agents currently available. The newer ones though do not require monitoring, lack reversal agents and supportive treatment with blood products is the only option currently available. Use of the newer oral anticoagulants is expected to rise after their safety and toxicity profiles are well explored by investigators.
| References|| |
|1.||Weitz JI. Blood coagulation and anticoagulant, fibrinolytic and antiplatelet drugs. In: Brunton LL, editor. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 12 th ed. New York: The Mc Graw-Hill Companies, Inc.; 2012. p. 860-6. |
|2.||Boehringer Ingelheim Pharm, 2011. PRADAXAR_ (dabigatran etexilate): Reducing risk of stroke from atrial fibrillation (AFib). Available from: http://www.pradaxa.com/. (Last accessed 2014 Feb 25). |
|3.||Bayer Schering Pharma AG, 2011. Xarelto R: Summary of product characteristics. Available from: http://www.xarelto. (Last accessed 2014 Feb 25). |
|4.||Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17. |
|5.||APPRAISE Steering Committee and Investigators, Alexander JH, Becker RC, Bhatt DL, Cools F, Crea F, et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: Results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009;119:2877-85. |
|6.||Weitz JI, Gross PL. New era in antithrombotic therapy. New oral anticoagulants: Which one should my patient use? American Society of Hematology Education Program. 2012. p. 536-40. |