WARFARIN PHARMACOLOGY - BY ABDUL RAUF

 WARFARIN PHARMACOLOGY

Warfarin Pharmacology - This blog will provide an overview of Warfarin, a medication used to treat and prevent blood clots.

Warfarin is an anticoagulant, or blood thinner. It works by blocking the formation of clotting factors in the blood. Warfarin is used to treat and prevent blood clots, such as those that occur in the legs (deep vein thrombosis), lungs (pulmonary embolism), and heart (heart attack). It is also used to prevent strokes in people with atrial fibrillation, a type of heart rhythm disorder.

 Warfarin is available in generic form. It is not available over-the-counter (OTC). Warfarin must be prescribed by a healthcare provider.

Warfarin's mechanism of action is that it inhibits the synthesis of vitamin K dependent clotting factors by inhibiting carboxylase enzymes (CYP2C9) which are necessary for activation of vitamin K dependent clotting factors II, VII, IX and X.   Warfarin is a vitamin K antagonist that works by inhibiting the synthesis of clotting factors II (prothrombin), VII, IX, and X. Warfarin inhibits the production of vitamin K-dependent clotting factors II (prothrombin), VII, IX and X. Warfarin inhibits vitamin K dependent clotting factor II (prothrombin), VII, IX and X synthesis.

PHARMACOKINETICS OF WARFARIN

Warfarin pharmacokinetics is the study of how warfarin behaves in the body after it is taken. It is important to know how warfarin is metabolized and excreted in order to ensure that it is being taken as prescribed and to avoid potential drug interactions. Warfarin has a slow onset and long duration of action. Long-term use causes homeostatic changes in the body, and these changes may not be fully reversible even after discontinuation.

Warfarin comprises of a racemic combination of two dynamic enantiomers — R-and S-structures — every one of which is cleared by various pathways. S-warfarin is 2-5 times more strong than the R-isomer in delivering an anticoagulant reaction. Warfarin is basically totally consumed, arriving at a most extreme plasma focus somewhere in the range of 2 and 6 hours. It circulates into a little volume of conveyance (10 L/70kg) and is disposed of by hepatic digestion with a tiny freedom (0.2 L/h/70kg). The disposal half-life is around 35 hours. A pharmacodynamic model for the impact of warfarin on the combination of thickening variables (prothrombin complex). Prothrombin complex amalgamation is repressed half at a warfarin centralization of around 1.5 mg/L. Warfarin focuses related with remedial anticoagulation are of comparative extent. A physiological model for the union and debasement of the prothrombin complex. The blend rate is around 5%/h/70kg and the end half-life assessed from changes in prothrombin time is roughly 17 hours. On normal it will require 3 days for the anticoagulant impact of warfarin to arrive at a steady worth when warfarin fixations are consistent. Warfarin is more slow acting than the normal anticoagulant heparin, however it has various benefits. Heparin should be given by infusion, while warfarin is accessible orally. Warfarin has a long half-life and need just be allowed one time each day. Heparin can likewise cause a prothrombotic condition, heparin-initiated thrombocytopenia (a neutralizer interceded decline in platelet levels), which builds the gamble for apoplexy. It requires a few days for warfarin to arrive at the helpful impact since the flowing coagulation factors are not impacted by the medication (thrombin has a half-life season of days). Warfarin's long half-life implies that it stays viable for a few days after it is halted. Moreover, whenever given at first without extra anticoagulant cover, it can increment apoplexy risk.

The anticoagulant action of warfarin is expected, by implication, to restraint of a vitamin K-subordinate advance in the hepatic blend of thickening elements II (prothrombin), VII, IX, and X. Top warfarin-instigated anticoagulant movement is postponed because of the moderately lengthy half-existences of a portion of the coagulating factors. Thickening Factor II half life is 60 hours, Factor-VII half life is 4 to 6 hours, factor-IX half life is 24 hours, and component X half life is 48 to 72 hours. The half-existences of proteins C and S are roughly 8 hours and 30 hours, individually. The portion of warfarin ought to be titrated to get wanted reaction for an individual (target INR) and that might require a few days. It requires 8 days to arrive at steady remedial levels. The span of activity is 2-5 days.

Patient who already have thrombosis issue warfarin should be started concomitantly with Low Molecular Weight Heparin or UFH. This is bridging step where INR result should be achieved at least 2. Usually kept between 2 to 3. Patient is counselled to take Warfarin along with LMWH for 2 days then on 3rd day go for INR test. If test result is 2 or more than 2 then LMWH is stopped and patient is kept on only warfarin. If result is less then 2 INR then bridging continues (Warfarin + LMWH) till the result of INR is achieved. Patients who are without any active thrombosis condition, but requiring warfarin for prophylactic indications e.g., atrial fibrillation can be initiated on warfarin alone.

INITIATION AND MAINTENANCE OF WARFARIN THERAPY

Patient received warfarin for the first time should begin with 5 mg dosing. Lower warfarin doses less then 5 mg should be considered for patients with any of the following factors: 

Age greater than 65 years.

Multiple co-morbid conditions.

Low albumin levels and poor nutritional status.

Impaired liver function, cardiac function and thyroid function. 

Higher end dose is acceptable in young patient with low bleeding risk and no interacting medications i.e., less than 50 years old, higher body weight and vitamin K intake. 

INR Monitoring – In the initial start baseline INR value should be done to determine any underlying coagulopathy. Monitoring can be done in inpatient and outpatient setting. 

During the first week INR should be monitored every 2-3 days and warfarin dose adjusted according to the INR value. Once the INR is seen maintained at desired level with stable dose of warfarin then INR test can be increase to weekly and then on 4-8 weeks.

INDICATIONS AND DURATION OF THERAPY OF WARFARIN

Indication of warfarin therapy are for preventing and treating venous and arterial thrombosis and embolism in patients with venous thromboembolic (VTE) disease, prosthetic heart valves, tissue heart valves, incidence of myocardial infarction, and atrial fibrillation.

VTE Disease – The therapy should be continued for 6 weeks for patients with provoked symptomatic calf vein thrombosis.  3- 6 months therapy is required for patients with proximal vein thrombosis with a precipitating cause such as surgery or immobilization. Patients with idiopathic proximal venous thrombosis or pulmonary embolism should receive therapy for at least 6 months.  Indefinite anticoagulation therapy is needed for patients having recurrent episodes of idiopathic proximal venous thrombosis. 

Prosthetic Heart Valves – Indefinite anticoagulation therapy is required for prevention of thromboembolic stroke or event. 

Atrial Fibrillation – Indefinite anticoagulation therapy is required for prevention of thromboembolic stroke or event. 

Tissue Heart Valves – Patients with newly replaced tissue heart valves requires anticoagulation therapy of 3 months. Patients with bio-prosthesis, atrial fibrillation, or severe left ventricular dysfunction should receive anticoagulation therapy for indefinite period. 

Left Ventricular Thrombosis – For such condition patient should receive therapy for at least 3 months.

Post myocardial infarction – Life long anticoagulation therapy is required. 

Post CABG – Patient should receive warfarin for at least 3 months. 

Catheter related thrombosis – Anti-coagulate patients for 3 months after removal of catheter.

MAINTAINING WARFARIN TREATMENT

Once the patient is stabilized, daily INR measurements can be reduced(according to concordance and control) to once weekly and then every 1-2 months.  More frequent monitoring is required in case of any changes to medication, diet or disease state. 

Before adjusting the dose of warfarin things should be reviewed are :  Previous dose of warfarin, earlier INR results, any changes to the patient’s clinical condition, any changes to medication or lifestyle,  and alcohol consumption.  

FACTORS INFLUENCING RESPONSE TO WARFARIN

Drug interactions (including herbal remedies)

Disease states

Pregnancy 

Diet

Alcohol

Warfarin in Pregnancy 

Warfarin showed to be teratogenic and is teratogenic.  

Warfarin crosses the placenta and may cause placental or fetal hemorrhage (1st& 3rd trimester)

 Alternative treatment in pregnancy is LMWH or unfractionated heparin. 

Women can breast-feed while on warfarin.

Warfarin contraindications 

Absolute:

Pregnancy (1st and 3rd trimester)

 Active peptic ulcer 

Severe hypertension (BP 200/120 mm/Hg) 

Caution required: 

Renal impairment Severe

liver disease Recent surgery

FEW DRUG DRUG INTERACTIONS OF WARFARIN 

DRUGS THAT CAN INCREASES INR

AZOLE ANTIFUNGALS   FOR EXAMPLE FLUCONAZOLE (The effects are usually mild; consequences may be bothersome or unnoticeable but should not significantly affect the therapeutic outcome).

CEPHALOSPORINS ( Decrease synthesis of clotting factors). The effects may cause badly influence patient's clinical status. Additional treatment, in hospitalization, or an extended hospital stay may be necessary. Usually avoid combination. 

FLOROQUNOLONES (Inhibition of warfarin metabolism).  Monitoring of INR is necessary if no alternate is available. 

MACROLIDES ( Inhibition of warfarin metabolism). Monitoring of INR is necessary with clarithromycin and erythromycin.  Azithromycin with very little chance of INR increase.

FENOFIBRATES ( Increase INR due to unexplained mechanisms).  Minimal risk; but monitoring of INR is necessary.

CORTICOSTEROIDS ( Both increase and decrease effects of warfarin has been noticed so far).  Monitoring of INR is necessary.  

SULPHA ANTIBIOTICS  Increases the INR, by inhibiting metabolism of warfarin.  Monitoring of INR is necessary. 

VITAMIN E  Increases the INR, by inhibiting metabolism of warfarin, causes decreased synthesis of clotting factors.  

DRUGS THAT CAN DECREASES INR

 ALCOHOL (CHRONIC USE) Induction of warfarin metabolism. 

 ASCORBIC ACID :  Decrease the INR with unexplained mechanism.

 BARBITURATES :  Induction of  warfarin metabolism. 

 ORAL CONTRACEPTIVES :  Results in increased clotting factor synthesis.

 PHENYTOIN:  Decreases INR by induction of warfarin metabolism.

 RIFAMYCINS:  Decreases INR by induction of warfarin metabolism. 

 SPIRONOLACTONE:  Decrease INR and increases the blood clotting factors.

VITAMIN K:  Decreases INR and increases the blood clotting factors.  Limit the use of vitamin K is recommended. 

HERBS AND SUPPLEMENTS THAT INTERACT WITH WARFARIN

Garlic -Can decrease platelets aggregation and lead to prolong bleeding

Ginkgo biloba -Having blood thinning property; can lead to serious bleeding

Ginseng – Decreases INR when given with Warfarin.

Green tea - Decreases INR when given with Warfarin.

St. John's wort - Decreases INR when given with Warfarin.

(WARFARIN PHARMACOLOGY - BY ABDUL RAUF)