Which Enzymes Are Inhibited By Warfarin?

Warfarin, a medication used in many clinical settings, is primarily affected by moderate to strong inhibitors/inducers of cytochrome P450 (CYP) 2C9, which is responsible for the elimination of the more potent S-isomer of warfarin. A large fraction of these effects are due to inhibition of enzymes involved in drug metabolism and transport, particularly cytochrome P450 (P450) enzymes.

Warfarin and other vitamin K antagonists (VKAs), also known as coumarins, are used in many settings. Enzyme inducers decrease the amount of active warfarin in the body and thus decrease its efficacy (decrease INR). These include St John’s wort, phenytoin, and carbamazepine. Enzyme inhibitors increase the amount of warfarin.

Warfarin competitively inhibits the vitamin K epoxide reductase complex subunit 1 (VKORC1), an enzyme essential for activating available vitamin K. Through this mechanism, warfarin can deplete functional vitamin K reserves, thereby reducing the synthesis of active clotting factors.

S-warfarin is 3-5 times more potent an inhibitor of the vitamin K epoxide reductase complex than R-warfarin. Several cytochrome P450 (CYP450) enzymes, including CYP2C9, CYP3A4, CYP1A2, and CYP2C19, contribute to the elimination of warfarin.

Warfarin decreases blood clotting by blocking vitamin K epoxide reductase, an enzyme that reactivates vitamin K. Without sufficient active vitamin K, the anticoagulant effect of warfarin is reduced. Warfarin is a coumarin derivative that acts by inhibiting the gamma-carboxylation of glutamic acid residues in the clotting proteins II (prothrombin), VII, IX, and warfarin.

What inhibits warfarin?

Fibriic acid derivatives, such as phenytoin and rifampin, can potentiate the effects of warfarin. Phenytoin increases the intravascular resistance (INR) due to its displacement from protein binding sites, while rifampin induces CYP enzymes, leading to increased INR. Patients on warfarin should avoid alcohol consumption, as it can inhibit warfarin metabolism and result in lower INR.

Herbal products like American ginseng and green tea have been linked to decreased INR in individuals taking warfarin. However, it is difficult to demonstrate clinically significant drug-herbal interactions with warfarin due to limited standardization. Drug-drug and drug-herbal interactions are common, but clinicians should always consult a drug information source when determining potential interactions.

Warfarin has both absolute and relative contraindications, with most absolute contraindications related to conditions and procedures with active bleeding or bleeding tendency. It is also contraindicated during pregnancy due to fetal warfarin syndrome, spontaneous abortions, and stillbirth. Patients with malignant hypertension should not use warfarin due to the risk of hemorrhagic stroke with extremely high blood pressure.

Potential drug-drug interactions require evaluation based on clinical risk and benefit of the medications.

What is inhibited by warfarin?

Warfarin inhibits the enzyme VKORC1, aka vitamin K oxido-reductase. This enzyme is responsible for taking oxidized (aka used, electron-depleted) vitamin K and reducing it (aka adding electrons). Only the reduced form can be used as a cofactor in the carboxylation process for activating clotting factors.

Steph and Brandon’s Note: Imagine it’s your first week of an APPE rotation at an anticoagulation clinic. You’re excited and a little nervous. You’ve been brushing up on your Lovenox. You’ve read all you can about Eliquis and Xarelto and Pradaxa (oh my!). You’re ready to impress.

Then there’s the elephant in the room that is warfarin. Sure, you know lots of random drug trivia about it. But how do you actually DOSE warfarin?

Because it’s so different from patient to patient and because the NAPLEX may not drill into the specifics of it, the dosing of warfarin is often pushed off for you to learn somewhere during your practice experience.

Is warfarin a CYP450 inhibitor?

Warfarin, a medication, is metabolized by hepatic microsomal cytochrome P-450 (CYP) enzymes. However, there is limited research on warfarin interactions with drugs that induce CYP enzymes, which can enhance warfarin metabolism and reduce its anticoagulant effect. Anticonvulsants like carbamazepine, oxcarbazepine, phenobarbital, and phenytoin, and certain antibiotics like rifampin and dicloxacillin, are medications with known potential to induce CYP enzymes. Evidence of warfarin interactions with CYP inducers is limited to case reports and cohort studies. A recent nationwide cohort study found carbamazepine to increase the mean warfarin dose. However, the impact of CYP induction on the INR can be masked by warfarin dose adjustments in response to an out-of-range INR. To overcome this, the warfarin dose/INR ratio can be used to measure the impact of interacting drugs on warfarin anticoagulant response. This study aimed to assess the impact of newly initiated therapy with CYP-inducing anticonvulsants on the anticoagulant response using the ratio of warfarin dose/INR in patients receiving chronic warfarin therapy. The study was conducted at Kaiser Permanente Colorado (KPCO), an integrated health-care delivery system providing comprehensive medical care to 600, 000 members in the Denver/Boulder metropolitan area.

What type of inhibitor is warfarin?

Warfarin is an inhibitor of VKORC1, the vitamin K epoxide reductase a key component in the vitamin K cycle. It is a competitive inhibitor when VKORC1 is in the partially oxidized state, but when in the oxidized state warfarin binding is essentially irreversible (Article:35748323).

What enzyme does warfarin inhibit?

Mechanism of Action. Warfarin competitively inhibits the vitamin K epoxide reductase complex subunit 1 (VKORC1), an enzyme essential for activating available vitamin K. Through this mechanism, warfarin can deplete functional vitamin K reserves, thereby reducing the synthesis of active clotting factors. The hepatic synthesis of coagulation factors II, VII, IX, and X, as well as coagulation regulator proteins C and S, requires vitamin K. Vitamin K is an essential cofactor for synthesizing these vitamin K-dependent clotting factors.

Drug Composition: Warfarin is a racemic mixture composed of ( R )- and ( S )- enantiomers. Each enantiomer is metabolized through unique pathways, and the ( S )-enantiomer is 3 to 5 times more potent than the ( R )- enantiomer.

Absorption: Warfarin is rapidly and completely absorbed. The onset of action is typically 24 to 72 hours, and the duration of action is 2 to 5 days. Peak plasma concentrations are achieved in approximately 4 hours. A peak therapeutic effect is generally seen 5 to 7 days after initiation. However, the patient’s international normalized ratio (INR) may increase within 36 to 72 hours after initiating treatment.

What proteins does warfarin inhibit?

Since vitamin K is required for the synthesis of the clotting factors II, VII, IX, X, protein C and protein S, warfarin inhibits their production producing the anticoagulant effect.