WARFARINBAD DRUG OR WEAPON

MISUSED?

Prepared by:Dr. Basheer Abd El Rahman Pharm.D Degree, BCPSICU Clinical PharmacistKSMC

Supervised by:Dr. Sulafa Al ShanawaniMSc.Pharm,BCPS. ICU Clinical PharmacistHead of ICU Pharmacy ServicesKSMC

Outlines Introduction. Indications. Mechanism of Action. Pharmacodynamics/Pharmacokinetics. Drug Interactions. Bridging. Dosing. Over dose treatment. References.

WARFARIN

Is a synthetic anticoagulant normally used in the prevention of thrombosis and thromboembolism, and the formation of blood clots in the blood vessels and their migration elsewhere in the body respectively.

It was initially introduced in 1948 as a pesticide against rats and mice and still used for this purpose.

WARFARIN

Is used to treat blood clots and/or to prevent new clots from forming in the body. And this will helps to reduce the risk of a stroke or heart attack.

Warfarin is commonly called a "blood thinner," but it is more correct term is anticoagulant. It helps to keep blood flowing smoothly by decreasing the amount of certain substances (clotting proteins) in the blood.

Indications

 Prophylaxis and treatment of thromboembolic disorders (eg, venous, pulmonary).

Embolic complications arising from atrial fibrillation or cardiac valve replacement.

Adjunct to reduce risk of systemic embolism (eg, recurrent MI, stroke) after myocardial infarction.

Use - Unlabeled Prevention of recurrent transient ischemic attacks.

WARFARIN Mechanism of Action

Hepatic synthesis of coagulation factors II, VII, IX, and X, as well as proteins C and S, requires the presence of vitamin K. These clotting factors are biologically activated by the addition of carboxyl groups to key glutamic acid residues within the proteins’ structure. In the process, “active” vitamin K is oxidatively converted to an “inactive” form, which is then subsequently reactivated by vitamin K epoxide reductase complex 1 (VKORC1). Warfarin competitively inhibits the subunit 1 of the multi-unit VKOR complex, thus depleting functional vitamin K reserves and hence reduces synthesis of active clotting factors.

When this occurs, the coagulation factors are no longer carboxylated at certain glutamic acid residues, and are incapable of binding to the endothelial surface of blood vessels, and are thus biologically inactive.

1972 CS

Warfarin

Synthesis of Non

Functional Coagulation Factors

Antagonismof

Vitamin K

Mechanism of Action

Vitamin K

VII

IX

X

II

Mechanism of ActionClotting Cascade

Warfarin full antithrombotic effect is not achieved UNTIL adequate reductions in prothrombin (factor II) occur and possibly factor X.  Early reductions in factors VII and IX do NOT represent the full therapeutic effect of warfarin. Anticoagulant effects occur in a minimum of 4-6 days  for an initial antithrombotic effect.

Protein C half life 4-6 hours.Protein S half life 40-60 hours.

Pharmacodynamics

Onset of action: Anticoagulation: Oral: 24-72 hours.

Peak effect: Full therapeutic effect: 5-7 days; INR may increase in 36-72 hours.

Duration: 2-5 days.

Pharmacokinetics Absorption: Oral: Rapid, complete.

Protein binding: 99%.

Distribution: 0.14 L/kg, Vd: 8-10 L.

Metabolism: Hepatic, primarily via CYP2C9.

Half-life elimination: 20-60 hours; Mean: 40 hours.

Excretion: Urine (92%).

Drug Interactions

Decreased warfarin effect (Lower INR)Carbamazepin

eRibavirin Mesalamine

Phenobarbital Rifampin Nafcillin 

Phenytoin Cholestyramine Vitamin K

Drug InteractionsIncreased warfarin effect  Allopurinol Amiodaro

neArgatroban  Azithromyci

nFluconazole

Citalopram Diltiazem Aspirin Clarithromycin

Isoniazid

Gemfibrozil Simvastatin Sulfamethoxazole

Ciprofloxacin Levofloxacin

Influenza vaccine

Cimetidine Tamoxifen Erythromycin Metronidazole

Drug Interactions

Category X Interactions:

Apixaban.

Rivaroxaban.

Dabigatran Etexilate.

Tamoxifen.

Streptokinase.

Drug Interactions

Category D Interactions:

Allopurinol. Amiodarone . Antithyroid Agents. Barbiturates. Carbamazepine. Clopidogrel. Fluconazole. Metronidazole. Phenytoin.

Drug Potential effect Recommendation

Warfarin plus ciproprofloxacin , clarithromycin , erythromycin, metronidazole, fluconazole, metronidazole or trimethoprim-sulfamethoxazole

Increased effect of warfarin. Select alternative -antibiotic.OR decrease 30%

Warfarin  plus Acetaminophen

Increased bleeding, increased INR. Use lowest possible acetaminophen dosage and monitor INR.

Warfarin plus acetylsalicylic acid (aspirin)

Increased bleeding, increased INR. Limit aspirin dosage to 100 mg per dayand monitor INR.

Warfarin plus NSAID Increased bleeding, increased INR. Avoid concomitant use if possible; if coadministration is necessary, use a cyclooxygenase-2 inhibitor and monitor INR.

Warfarin plus Amiodarone Increased bleeding Consider empiric reduction of 30% to 50% in warfarin dose.

Warfarin plus Rifampin Decrease Warfarin Increase dose 50-0%

Warfarin plus Carbamazipine Decrease Warfarin Increase dose 30%

Bridging

What Is Bridging Anticoagulation?

Bridging anticoagulation refers to giving a short-acting blood thinner, usually low-molecular-weight heparin given by subcutaneous injection for 10 to 12 days around the time of the surgery/procedure, when warfarin is interrupted and its anticoagulant effect is outside a therapeutic range. Bridging anticoagulation aims to reduce patients risk for developing blood clots, such as stroke, but may also increase patients’ risk for developing potentially serious bleeding complications after surgery.

Bridging

Patients on long-term warfarin therapy who undergo minor invasive procedures and are taken off their oral anticoagulation for up to 5 days have a less than 1% risk of experiencing a thromboembolic event.

Bridging

In patients with a mechanical heart valve or atrial fibrillation or venous thromboembolism (VTE):At high risk for thromboembolism, bridging anticoagulation is recommended with therapeutic-dose subcutaneous (SC) low-molecular-weight heparin (LMWH) or intravenous unfractionated heparin (UFH) rather than no bridging during temporary interruption of vitamin K antagonist (VKA) therapy.

Bridging

At moderate risk for thromboembolism, it's proposed to use bridging anticoagulation with therapeutic-dose SC LMWH, therapeutic-dose IV UFH, or low-dose SC LMWH over no bridging during temporary interruption of VKA therapy.

Bridging

At low risk for thromboembolism, low-dose SC LMWH (Prophylaxis) or no bridging over bridging with therapeutic-dose SC LMWH or IV UFH is recommended.

In patients with a bare metal coronary stent who require surgery within 6 weeks of stent placement, the ACCP recommends to continue aspirin and clopidogrel in the perioperative period.

BRIDGE STUDY

Dosing

Initiation of Warfarin:

When warfarin is newly started, it may promote clot formation temporarily. This is because the level of protein C and protein S are also dependent on vitamin K activity. Warfarin causes decline in protein C levels in first 36 hours. In addition, reduced levels of protein S lead to a reduction in activity of protein C , therefore reduced degradation of factor Va and factor VIIIa.

Dosing

Initiation of Warfarin:

Although loading doses of warfarin over 5 mg also produce a rapid decline in factor VII, resulting in an initial prolongation of the INR, full antithrombotic effect does not take place until significant reduction in factor II occurs days later. The haemostasis system becomes temporarily biased towards thrombus formation, leading to a prothrombotic state. Thus, when warfarin is loaded rapidly at greater than 5 mg per day, it is beneficial to co-administer heparin, an anticoagulant that acts upon antithrombin and helps reduce the risk of thrombosis, with warfarin therapy for four to five days, in order to have the benefit of anticoagulation from heparin until the full effect of warfarin has been achieved.

Dosing

Initiation of Warfarin:1) Consider Contraindications

2) Establish baseline INR 3) Initial Dose: Initial dose of warfarin is

typically 5 mg/day in most patients. A starting dose of less than 5 mg may be considered for patients greater than 70 years of age, elevated baseline INR greater than 1.1, hypoalbuminemic patients (e.g., malnourished, liver disorders, post-operative), impaired nutrition (weight < 45 kg), heart failure, known to take medications that increase sensitivity of warfarin, or previously documented increased sensitivity to warfarin.

4) INR Target and Frequency of Monitoring Two therapeutic ranges are recommended, depending on the indication for anticoagulation.

5) Dosage Adjustment & Maintenance TherapyDosage adjustment is not required for minor fluctuations of INR as long as the results remain within the patient’s target range.

The recent trend is to change the total weekly warfarin dose (TWD). For example, if the patient is taking 5mg/ day, the weekly dose is 35mg. If the dose must be decreased by 10%, then the weekly dose should be (35 mg - 3.5 mg=31.5 mg) and the daily dose becomes 31.5 mg/7=4.5 mg.

3 3 3333 3

Mon Tue Wed Thu Fri Sat Sun

TotalWeeklyDose

21 mg

2 3 3323 3 19 mg

2 2 3333 2 18 mg

Warfarin Dosing Schedule

10%

15%

3 3 3333 3

Mon Tue Wed Thu Fri Sat Sun

TotalWeeklyDose

21 mg

4 3 3343 3 23 mg

4 4 3333 4 24 mg

Warfarin Dosing Schedule

10%

15%

Overdose

Although excessively elevated INR values are clearly associated with an increased risk of bleeding, in particular for INR values of > 5.0, data from a large registry of warfarin-treated patients suggest that the short-term risk for major bleeding is low for someone with a single INR value between 5.0 and 9.0 (0.96% at 1 month).

Overdose

Reversal Strategies:1. Interruption of Warfarin treatment.2. Administration of vitamin K.3. Fresh frozen plasma4. Prothrombin complex concentrates 5. Recombinant activated factor VII.

Overdose

Interruption of Warfarin may be sufficient in patients who need an elective invasive procedure or in asymptomatic patients with an elevated INR value and a low risk for bleeding. In this latter case, it must be noted that it takes approximately 2.5 days for an INR between 6.0 and 10.0 to decline to , 4.0.

Overdose

How to use Vitamin K as antidote for warfarin?

Vitamin K is usually needed for a patient with an INR over 9 or has serious bleeding. It's usually NOT needed for INRs under 5. However it is controversial when INR is between 5 and 9 and when there is no bleeding. because vitamin K can bring the INR down faster than just holding warfarin, but it doesn't seem to decrease bleeding risk.

Overdose

For most of these patients, the suggestion is holding warfarin for a dose or two and then adjusting it to get the INR in the appropriate range.  But for patients with an INR between 5 and 9 on top of a high risk of bleeding, the suggestion is giving 1 to 2.5 mg vitamin K. About 1 mg is often enough to lower the INR into the therapeutic range in these patients.

Overdose

Overdose

References

1. UWHC Guidelines for Inpatient Warfarin Management in Adults.2. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, and Comerota AJ. American

College of Chest Physicians. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008; 133: 454-545.

3. The BRIDGE Study Investigators a Surgery or Procedure? Bridging Anticoagulation: Is it Needed When Warfarin Is Interrupted Around the Time of Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2012 American Heart Association, Inc. All rights reserved.

4. American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy.

5. Anticoagulants and the perioperative period Craig Oranmore-Brown MBBCh FRCA Richard Griffiths MD FRCA.

6. Evidence-Based Clinical Practice Guidelines ed: American College of Chest Physicians Therapy and Prevention of Thrombosis, 9th Oral Anticoagulant Therapy : Antithrombotic.

7. Bridging Anticoagulation: Is it Needed When Warfarin Is Interrupted Around the Time of a Surgery or Procedure?

8. GUIDELINES & PROTOCOLS ADVISORY COMMITTEE Warfarin Therapy Management Effective Date: October 1, 2010.

9. American College of Chest Physicians, 9th ed: Diagnosis of DVT : Antithrombotic Therapy.