We’ve already discussed the pharmacology of injectable anticoagulants, so now we’re going to turn our attention to their oral equivalents. Anticoagulant drugs are used in the treatment of venous thromboembolism and as prophylactics against deep vein thrombosis, among other conditions. They work by preventing the clotting – or coagulation – of blood. The oral anticoagulants we’ll look at in this section include vitamin K antagonists, direct factor Xa inhibitors, and specific direct thrombin inhibitors. There is some degree of overlap between this section and the injectable version, so it might be worthwhile to revise both of these sections. We’ll now explore the pharmacology of anticoagulant drugs (oral) – detailing the various classes, how they work, their pharmacokinetics and a brief look at their unwanted effects.
Pharmacology of Anticoagulant Drugs (Oral)
Here, we’re going to study the following classes of oral anticoagulants:
- Vitamin K antagonists
- Direct factor Xa inhibitors
- Direct thrombin inhibitors
Warfarin is the prime example of a vitamin K antagonist, a drug that inhibits vitamin K epoxide reductase. It is the most widely deployed oral anticoagulant, a drug saddled with a narrow therapeutic index. The direct factor Xa inhibitors we’ll study include rivaroxaban, apixaban, and edoxaban - drugs which have – unlike warfarin – a predictable anticoagulant effect. Finally, we’ll study dabigatran – a direct thrombin inhibitor – a prodrug which inhibits two types of thrombin: free circulating thrombin and thombus-bound thrombin (factor IIa). These last two classes – direct factor Xa inhibitors and direct thrombin inhibitors – are sometimes referred to as novel oral anticoagulants (NOACs).
Vitamin K Antagonists
Warfarin, a compound introduced in the 1940s as a pesticide, was approved for treating thromboembolic events in the 1950s. Since then, it has become the most widely used oral anticoagulant drug in North America. Despite being classed as a vitamin K antagonist, warfarin does not directly antagonise vitamin K1, instead it depletes its recycling by inhibiting the enzyme, vitamin K epoxide reductase.
This impairs the synthesis of clotting factors II (prothrombin), VII, IX, and X. Warfarin does not act immediately, as previous synthesised clotting factors need to be used up. It may take between 24-48 hours before any clinical effect of warfarin is realised. If immediate anticoagulant therapy is required, warfarin needs to be administered with heparin, for example.
Similarly, the anticoagulant effect of warfarin – on stopping treatment – depends on the rate it takes the body to develop new clotting factors. Given its narrow therapeutic index, patients taking warfarin need to be monitored – using what’s known as the international normalised ratio (INR). Target INR values depend on the patient and their condition, though typical values are:
- Prophylaxis of deep vein thrombosis: 2.0-2.5
- Prevention of thromboembolism in patients with atrial fibrillation: 2.0-3.0
- Thromboprophylaxis for hip/femur surgery: 2.0-3.0
- Prophylaxis of recurrent DVT: 3.0-4.5
- Prophylaxis of thrombosis on mechanical prosthetic heart valves: 3.0-4.5
The higher the value, the greater the likelihood of haemorrhage. If the values duck too low, the therapeutic effect of warfarin is compromised. Should haemorrhage occur, the patient can be administered the antidote, phytomenadione. Patients may experience no bleeding – even if their INR goes beyond 8 – and so may require a smaller dose of phytomenadione than patients with an active haemorrhage.
Another unwanted effect is warfarin necrosis. This tends to occur in patients with a deficiency in protein C – a natural anticoagulation factor. Warfarin initially decreases protein C levels, meaning coagulation risk increases during the initial treatment phase. In other words, warfarin increases the coagulation risk in the short term. This is why, on commencing treatment, warfarin is administered with heparin.
Other unwanted effects with warfarin include alopecia, hypersensitivity reactions, and osteoporosis. Warfarin is teratogenic – and it crosses the placenta. Warfarin also has quite a long half-life, around 1-2 days – though its activity is variable as a result of individual polymorphisms in the hepatic enzyme CYP2C19. Warfarin is also associated with a high number of clinically significant drug and food interactions. Among them include:
- Broad spectrum antibiotics reduce gut flora, flora which produce significant amounts of vitamin K1 – thus potentiating the effects of warfarin.
- Metronidazole and macrolides reduce metabolism of warfarin, increasing its effects.
- The effect of warfarin is reduced by foods with high vitamin K content – such as green leafy vegetables.
- Patients with hyperthyroidism boost the effects of warfarin, whereas patients with hypothyroidism are less responsive to warfarin treatment.
- Phenytoin induces CYP2C9, reducing the effect of warfarin.
- Ginger and garlic, and other spices, increase bleeding and bruising risk.
- St. John’s Wort increases warfarin metabolism, reducing its effect.
- Amiodarone and H2 receptor antagonists inhibit CYP2C9 – increasing the effects of warfarin.
Most of the pharmacology of anticoagulant drugs (oral) focuses on warfarin, not least because warfarin is the most widely used oral anticoagulant in North America. With this now covered, we can now move onto the final two oral anticoagulant drug classes: direct factor Xa inhibitors and direct thrombin inhibitors.
Direct Factor Xa Inhibitors
Examples of direct factor Xa inhibitors include rivaroxaban, apixaban, and edoxaban.
Rivaroxaban, unlike warfarin above, has a somewhat predictable anticoagulant effect. It is used in the prophylaxis of venous thromboembolism, though it has been used for other purposes. Rivaroxaban is well absorbed from the gut, and has a half-life of around 9-12 hours. It is partly metabolised in the liver and is partly eliminated via the kidneys. Unwanted effects include haemorrhage, nausea, and gastrointestinal upset.
Direct Thrombin Inhibitors
Dabigatran, unlike its cousin argatroban, is an orally active anticoagulant drug – which works by inhibiting two types of thrombin: free circulating thrombin and thombus-bound thrombin. This is in contrast to heparin, which only affects free circulating thrombin (through action at antithrombin III). Dabigatran is a prodrug with low oral bioavailability (5-7%) – its active ingredient having a half-life of around 40 minutes.
Fatty foods impair the absorption of dabigatran (though this doesn’t affect bioavailability). Unwanted effects with dabigatran include bleeding and gastrointestinal upset, particularly dyspepsia. One final note: direct thrombin inhibitors and direct factor Xa inhibitors, though effective, have no antidote unlike warfarin. This means if haemorrhage occurs, there is no antidote – like phytomenadione – to attenuate the bleeding.
That’s about it for the pharmacology of anticoagulant drugs (oral). While this section is not intended to be exhaustive, it serves as a solid foundation onto which you can build further. If you’d like to test your knowledge of anticoagulant drugs, check this this quiz for more information.