WarfarinQuestions & Answersby Moh el Gamal 19/4/2011

????????what is Pharmacokinetic and pharmacodynamics of warfarin? what is mechanism of action of warfarin indication ,CI ,SE ? what is blood test for monitoring,? what is warfarin resistance --- warfarin failure? Can I use warfarin with asprin ? Can I start ttt by warfarin monotherapy? What are new drugs follow warfarin?

WarfarinWarfarin, a coumarin derivative first synthesized in 1948, is still the only oral anticoagulant available for longterm use in the United States.

Indicationsthe treatment and, the prevention of arterial and venous thromboembolism. long-term anticoagulation in patients with atrial arrhythmias (atrial fibrillation and atrial flutter) mechanical heart valves

Onset of action:

: 24-72 hours

Peak effect: Full therapeutic effect: 5-7 days; INR may increase in 36-72 hours (clearance of circulating prothrombin )Absorption: Oral: Rapid, complete Time to peak, plasma: Oral: ~4 hours

Protein binding: 99%Metabolism: Hepatic, primarily via CYP2C9; minor pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4

Half-life elimination: 20-60 hours; Mean: 40 hours; highly variable among individuals

Excretion: Urine (92%, primarily as metabolites

Dosing:Oral: Start 2-5 mg daily for 2 days or 5-10 mg daily for 1-2 days) Oral: Administer with or without food. Take at the same time each dayDosing: Renal Impairment . No adjustment required,Dosing: Hepatic Impairment Monitor effect at usual doses. The response to oral anticoagulants may be markedly enhanced in (obstructive jaundice, hepatitis, and .cirrhosis. INR should be closely monitored

MECHANISM OF ACTION1-Warfarin, a coumarin derivative, inhibits clotting by limiting hepatic production of the biologically active vitamin K-dependent clottingfactors (activated factors II, VII, IX, and X).Normally, the precursors of these factors undergo a carboxylation reaction to be con-verted to their activated forms. .

2-warfarin also interferes with production of the bodys natural anticoagulants, protein C and protein S, and can therefore sometimes exert a procoagulant response.

Genteic of warfarin

Clotting cascade

Test for Intrinsic pathway1- clotting time 2-APTT n: 4-6m n :30s

Test for Extrinsic pathway1-PT n :15s 2-prothrombin concetraion n:100 % 3- INR

WHAT IS

Thrombin time ??? Bleeding time???

Warfarin monotherapyIs contraindicated in the initial treatment of warfarin initially inhibits the synthesis of protein C, potentially accelerating the underlying active .thrombotic process

Combination warfarin and aspirin ???(1)at

least 3 months after AMI in high-risk patients (2) AF + CAD (3) prosthetic heart valves (4) patients with clinically relevant residual risk for thromboembolic events despite a therapeutic INR

Risk factors for bleeding with warfarinPatients walk a tightrope between bleeding and clottingand a hundred things can tip the balance) (INR >4) age (65 years) history of GI bleeding, hypertension, malignancy cerebrovascular disease, serious heart disease, vasculitis anemia, severe diabetes,, trauma, hepatic ,renal insufficiency, polycythemia vera,, open wound, PUD, drug-drug interactions, long duration of therapy (

WARFARIN Side Effectcardiovascular: Angina, chest pain, edema, hemorrhagic shock, hypotension, pallor, syncope, vasculitis Central nervous system: Coma, dizziness, fatigue, fever, headache, lethargy, malaise, pain, stroke

Dermatologic: Alopecia, bullous eruptions, dermatitis, rash, pruritus, urticariaGastrointestinal: Abdominal cramps, abdominal pain, anorexia, diarrhea, flatulence, gastrointestinal bleeding, mouth ulcers, nausea, taste disturbance, vomiting Genitourinary: Hematuria, priapism

Hematologic: Agranulocytosis, anemia, leukopenia, retroperitoneal hematoma, unrecognized bleeding sites (eg, colon cancer) may be uncovered by anticoagulationHepatic: Cholestatic jaundice, hepatic injury, hepatitis, transaminases increased Neuromuscular & skeletal: Joint pain, muscle pain, osteoporosis (potential association with long-term use), paralysis, paresthesia, weakness Respiratory: Dyspnea, tracheobronchial calcification Miscellaneous: Anaphylactic reaction, cold intolerance, hypersensitivity/allergic reactions, skin necrosis, gangrene, purple toes syndrome

Warfarin contrindication and precautionHypersensitivity to warfarin Condition with risk of hemorrhage Hemorrhagic tendency Inadequate laboratory techniques Protein C & S deficiency Vitamin K deficiency Intramuscular injections

recommends the INR be checked at least four times during the first week of therapy and then less frequently, depending on the stability of the INR. checking the INR daily or every other day until the INR is in the therapeutic range for 2 consecutive days, checked every 3 to 5 days. INR and warfarin dose remain stable for 1 week, the INR shouldbe checked weekly . INR and warfarin dose remain stable 2 to 3 weeks, the testing interval can be extended to every 4 weeks.

The College of American Pathologists

Def.Warfarin ResistancePatients who need more than 105 mg per week (15 mg/day) To reach target therputic INR should be considered warfarin-resistant.

Warfarin failurewhich is defined as a new thrombotic event despite a therapeutic prothrombin time and INR. This situation is commonly seen in patients with malignant diseases

Potentiate warfarinGingko Levofloxacin (Levaquin) Levothyroxine (Synthroid) Nonsteroidal anti-inflammatory drugs Omeprazole (Prilosec) Paclitaxel (Taxol) Propafenone (Rythmol) Ritonavir (Norvir) Tramadol (Ultram) Trimethoprim-sulfamethoxazole (Bactrim) Vitamin E

Warfarin drug drug interaction

Potentiate warfarinAcetaminophen (Tylenol) Alcohol Allopurinol (Zyloprim) Amiodarone (Cordarone) Amoxicillin-clavulanate (Augmentin) Aspirin Celecoxib (Celebrex) Ciprofloxacin (Cipro) Erythromycin Fenofibrate (Tricor) Fluconazole (Diflucan) Fluvastatin (Lescol)

Inhibit warfarinAzathioprine (Imuran) Barbiturates Bosentan (Tracleer) Carbamazepine (Tegretol) Cholestyramine Cortisone Dicloxacillin Etodolac (Lodine) Ginseng Multivitamins Haloperidol (Haldol) Mercaptopurine (Purinethol)

Inhibit warfarinNafcillin (Unipen) Oral contraceptives Parenteral and enteral nutritional supplements Ribavirin (Rebetol) Rifampin (Rifadin) Ritonavir (Norvir) Spironolactone (Aldactone) Trazodone (Desyrel) Vitamin C Vitamin K

In general, the onset of effect for inhibitors is quicker than for inducers and may occur after only several doses of the inhibitor. Similarly, the offset tends to be quicker for inhibitors but again depends on the half-life of the medication. For example, amiodarone, with its extremely long half-life, may have an offset lasting several months.

WHAT CAUSES WARFARIN RESISTANCE?Acquired resistance to warfarin may result from: Poor patient compliance (the most common cause) High consumption of vitamin K Decreased absorption of warfarin Increased clearance (see warfarin is metabolized by P450 enzymes on this page511) Drug interactions (TABLE 1).1

Hereditary resistance to warfarinHereditary resistance genetic factors that result either in faster metabolism of the drug (a form of pharmacokinetic resistance) or in lower activity of the drug (pharmacodynamic resistance). Polymorphisms may play a role, as some VKORC1 and CYP2C9 variant alleles

Foods High in Vitamin KFoods High in Vitamin K Green leafy vegetables ,Broccoli, brussels sprouts, cabbage, collard greens ,endive, green scallion, kale, spinach, turnip greens watercress Salad Oils canola, salad, and soybean oils mayonnaise ,Liver, green tea : ,

Pharmacokynatic resistanceMalabsorption .emesis, diarrhea Gentic clearanceDisease Hypoalbuminemia may increase the free fraction of warfarin, leading to enhanced rates of clearance and a shorter plasma half-life . Hyperalbuminemia may paradoxically also contribute to warfarin resistance via drug binding.Hyperlipidemia. Several observers have found that lowering serum lipids, primarily triglycerides, increases the sensitivity to warfarin

Congestive heart failure: can cause hepatic congestion of blood flow and inhibit warfarin metabolism. Hypothyroidism :decreases the catabolism of the vitamin K clotting factors., hypothyroidism decreased INR values with a need for increased warfarin doses.

Hyperthyroidism, increases the catabolism of the vitamin K clotting factors and could be suspected if there is a general trend toward increased INR values with a need for decreased warfarin doses. Hepatic failure may significantly elevate the INR due to decreased production of clotting s.

This most likely results in a decreased pool of vitamin K, some of which is bound to triglycerides. Conversely, patients receiving intravenous lipids with total parenteral nutrition warfarin resistance, ahave shown an association

Diuretics

: may decrease the response to warfarin by reducing the plasma volume, with a subsequent increase in clotting factor activity.24

Pharmacodynamic resistanceIncreased affinity of vitamin K1, 2,3-epoxide reductase complex (VKOR) for Vitamin K Prolongation of normal clotting factor activity Production of clotting factors that is not dependent on vitamin K Decreased VKOR sensitivity to warfarin

Home messageThe most common cause of warfarin resistance is noncompliance.poor absorption, high vitamin K intake,

Patient education is necessary to improve compliance ,avoid side effects . Future, genetic testing will be recomeended for determine dosageIn true hereditary warfarin resistance, two approaches to treatment: increase the warfarin dosage(perhaps to as high as 100 mg/day or more), switch toanother anticoagulant.

We can use combined warfarin and aspirin in special situations Starting warfarin montherapy increase thrombotic events Clotting time can substitute APTT but not PT OR INRWarfarin take once daily at the same time

Thank You