Introduction to Warfarin Pharmacology

Warfarin is one of the most widely prescribed drugs; an important medicine in the treatment of deep vein thrombosis and in 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 a rat poison, where it induced internal bleeding and death. This anticoagulant effect was then harnessed for medicinal purposes – with warfarin now the go-to treatment option 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, referring to coumarin, the chemical class to which warfarin belongs.

Warfarin is used in the treatment of the following conditions:

  • 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.

Because events – such as myocardial infarction – are caused by platelet aggregation, warfarin cannot be used to prevent MI. For this reason, antiplatelet drugs – such as aspirin and clopidogrel – must be used for this clinical purpose.

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, which is then oxidised. An enzyme – known as vitamin K epoxide reductase – then reactivates the oxidised vitamin K.

This is the point at which warfarin comes in.

Warfarin inhibits vitamin K epoxide reductase, thereby preventing the reactivation of vitamin K and the synthesis of pro-clotting coagulation factors.

Side Effects

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 those who have experienced some form of physical trauma. Rarely, warfarin can cause severe bleeding abnormalities including 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

Clinical Considerations

When we talk about warfarin pharmacology, the following points should be considered:

  • Warfarin is monitored using the INR – international normalized ratio. Clinicians will determine what the optimum value. Normal INR values on patients not on warfarin therapy is 0.8 – 1.2. Often, patients with DVT will need to achieve an INR of between 2-3. Warfarin doses will be 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 because it has an immediate anticoagulant effect. Once the effects of warfarin come in, heparin can be withdrawn. Usually, full treatment plans with warfarin can last between 3 and 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 in control of the patient. For example – foods rich in vitamin K, such as green leafy vegetables, interfere with the mechanism of warfarin. Similarly, alcohol also interacts with warfarin and can skew any potential clinical outcome. Patients must be counselled to ensure they control factors such as this.
  • Warfarin should be avoided in patients who are at an immediate risk of bleeding – including patients who have experienced physical trauma and those who require surgical intervention. 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 causes a collection of effects known as fetal warfarin syndrome (FWS), which leads to nasal hypoplasia and narrowed nasal bridge and other limb and cardiac abnormalities. Warfarin use in the second and third trimester is most associated with CNS abnormalities, such as ocular defects and seizures. Low birth weight and developmental disabilities may also arise.
  • 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 synthesize vitamin K, many antibacterial drugs can increase anticoagulation in patients taking warfarin.
  • The effects of warfarin 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; the must-know pharmacology and clinical considerations that healthcare students need to know.

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