Warfarin is one of the most widely prescribed drugs; an important medicine in the treatment of deep vein thrombosis and for the prevention of embolic complications. Here, we review the facts about warfarin pharmacology that you need to know.
Warfarin (sold under Coumadin and others) was originally used as rat poison, where it caused internal bleeding and death. This anticoagulant effect was then harnessed for medicinal purposes. Warfarin is now one of the go-to medicines for patients with thrombosis.
Warfarin was first approved for medical use in the United States in 1954. Warfarin takes its name from the acronym WARF – the Wisconsin Alumni Research Foundation – which helped develop the medicine and -arin, after coumarin, the chemical class to which warfarin belongs.
Warfarin is used for the following indications:
- To prevent clot extension and recurrence in patients with DVT, deep vein thrombosis, and pulmonary embolism. Together, these conditions are referred to as venous thromboembolism (VTE).
- Prophylaxis of embolic complications in patients with atrial fibrillation, for example – reducing the risk of stroke.
- Prophylaxis of embolic complications in patients after heart valve replacement.
Warfarin is not used to prevent myocardial infarction because this is caused by platelet aggregation. Instead, antiplatelet drugs such as aspirin and clopidogrel are used to prevent MI. B
Mechanism of Action
Warfarin works by inhibiting the hepatic production of vitamin K-dependent clotting factors and cofactors.
To synthesize these clotting factors, vitamin K must be in its reduced form. During the synthetic process, warfarin is oxidized. An enzyme – vitamin K epoxide reductase – then reactivates that oxidized vitamin K.
Warfarin inhibits vitamin K epoxide reductase, preventing reactivation of vitamin K and the synthesis of pro-clotting coagulation factors.
The primary side effect of warfarin is bleeding.
Warfarin is a narrow therapeutic index drug – meaning that the difference between therapeutic and toxic doses is narrow. In other words, a small dose change can cause an enormous difference – including an increased risk of bleeding.
Furthermore, warfarin increases bleeding risk in patients with underlying conditions – for example, in patients with established peptic ulcer disease, or in patients who have experienced some form of physical trauma. Rarely, warfarin can cause severe bleeding abnormalities such as retroperitoneal hemorrhage.
Other adverse effects of warfarin include:
- Purple toe syndrome – due to cholesterol deposits breaking loose and causing embolisms in the lower extremities.
- Warfarin necrosis – most associated with patients who have a deficiency of protein C.
- Osteoporosis-related bone fractures
When we talk about warfarin pharmacology, we must consider the following factors:
- Warfarin is monitored using the INR – international normalized ratio. Clinicians will determine the optimum value range for each patient. Normal INR values for patients not on warfarin therapy is between 0.8 – 1.2. Often, patients with DVT are assigned a target INR score of between 2-3. Warfarin doses are increased or decreased depending on how the patient reacts to the medicine.
- Warfarin is taken orally, once daily – usually at 6pm – which improves patient adherence whilst also allowing for the effects of warfarin to be monitored the following morning. Typically, the first dose is 5-10mg on Day 1, with a lower dose administered to patients who are older, or lighter, or who are at an increased bleeding risk (for example – who are taking medicines that increase the risk of bleeding with warfarin). Warfarin effects are not immediately seen. Instead, it takes several days for its clinical effects to manifest. For this reason, heparin is often co-administered at the beginning of warfarin treatment if an immediate anticoagulant effect is required. Once the effects of warfarin kick in, heparin therapy can be withdrawn. Typically treatment regimens with warfarin last between 3-6 months.
- Warfarin treatment is always a delicate balance between benefits and risks. Often, the risk of new bleeding outweighs any clinical benefit. How patients respond to warfarin depends on several lifestyle factors. For example – foods rich in vitamin K, such as green leafy vegetables, interfere with the mechanism of warfarin. Similarly, alcohol interacts with warfarin. Patients are counseled to limit their consumption of vitamin K-rich foods and alcohol.
- Warfarin should be avoided in patients who are at immediate risk of bleeding – including patients who have experienced physical trauma or patients undergoing surgery. Patients with established liver disease are at an elevated risk of bleeding.
- Coumarins – such as warfarin – are teratogenic and so should be avoided in pregnancy. Often during the first trimester, a low-molecular-weight heparin – such as enoxaparin – may be used. Heparins do not cross the placental barrier and so do not cause birth defects. When taken during the first trimester, warfarin can cause fetal warfarin syndrome (FWS), leading to nasal hypoplasia and a narrowed nasal bridge, and other limb and cardiac abnormalities. Warfarin use in the second or third trimester can cause CNS abnormalities, such as ocular defects and seizures. Low birth weight and developmental disabilities can also occur.
- Many drugs increase the risk of bleeding. These include NSAIDs, other antiplatelet or anticoagulant drugs, and CYP 450 inhibitors – such as macrolides, fluconazole, and protease inhibitors. CYP 450 inducers – such as phenytoin and carbamazepine and rifampin – increase warfarin metabolism and so increase the risk of blood clot formation. By killing gut flora which ordinarily synthesizes vitamin K, many antibacterial drugs increase the risk of bleeding with warfarin.
- Warfarin effects can be reversed by using the antidote phytomenadione, or by using fresh frozen plasma or prothrombin complex concentrate.
That completes our review of warfarin pharmacology. Check back to our pharmacy blog soon for more exclusive content to help you master the science of drugs and medicines!