Warfarin (Dosage)

Warfarin is one of the most widely used anticoagulant drugs at present, although its narrow therapeutic margin implies a high risk of hemorrhagic complications. The genetic study of variants in the genes involved in its metabolism makes it possible to guide the dose requirement necessary to maintain an effective and safe anticoagulant effect.

Warfarin is an anti-vitamin K oral anticoagulant. This drug inhibits the formation in the liver of coagulation active factors II, VII, IX and X by inhibiting gamma carboxylation of precursor proteins mediated by vitamin K.

CONTRAINDICATIONS

Warfarin is contraindicated in the following cases:

Hypersensitivity

Pregnancy.

Lack of cooperation of the patient.

Hemorrhagic diathesis and / or hematic dyscrasia. Organic lesions susceptible to bleeding. Recent or planned surgical interventions in the CNS, ophthalmological operations or surgeries exposing large areas of tissue.

Gastroduodenal ulcer or hemorrhages in the gastrointestinal, urogenital or respiratory tracts, cerebrovascular hemorrhages, pericarditis, pericardial effusions, slow endocarditis.

Severe arterial hypertension, severe lesions of the hepatic and renal parenchyma. Increased fibrinolytic activity.

High doses of NSAIDs (non-steroidal anti-inflammatory), miconazole (general route and oral gel), phenylbutazone (general route), high doses of ASA and other salicylates.

CAUTIONS:

Precautions should be taken in the prescription of warfarin in the following cases:

If there is a risk of bleeding, necrosis (if it exists, replace with heparin), release of emboli or atheromatous plaques.

Moderate-severe renal insufficiency, moderate-severe hepatic insufficiency, moderate-severe arterial hypertension, infectious diseases or alterations of the intestinal flora, catheters, deficiency in the anticoagulant response mediated by protein C or its cofactor, protein S (risk of tissue necrosis) ; monitor INR (International Normalized Ratio of Warfarin).

There are no data to support its use in children, stop treatment if calcifilaxis appears (exists increased risk in advanced kidney disease on dialysis).

SIDE EFFECTS

Bleeding in any organ.

PHARMACOLOGIC INTERACTIONS

The effect of warfarin is inhibited by: enzyme inducers (aminoglutethimide, carbamazepine, phenazone, griseofulvin, phenobarbital, secobarbital, rifampicin, H. perforatum), drugs that reduce its absorption (sucralfate, ascorbic acid), vitamin K, ginseng and food rich in vitamin K (cereals, broccoli, cabbage, carrots, fowl giblets).

The effect of warfarin is enhanced by:

  • Enzyme inhibitors (allopurinol, dextropropoxyphene, tramadol, amiodarone, ciprofloxacin, clarithromycin, erythromycin, norfloxacin, ofloxacin, pefloxacin, chloramphenicol, cimetidine, omeprazole, ranitidine, cisapride, disulfiram, fluvastatin, lovastati
  • Drugs that displace it from its binding to plasma proteins (ethacrynic acid, nalidixic acid, diclofenac, phenylbutazone, feprazone, ibuprofen, ketoprofen, mefenamic acid, sulindac, benziodarone, bicalutamide, carnitine, gemfibrozil, chloral hydrate, mic
  • Decrease in availability of vitamin K (levothyroxine, neomycin, cefamandole, clofibrate, stanozolol).
  • Drugs that decrease the synthesis of coagulation factors (danazol, paracetamol, quinidine, quinine, vitamin E, ethanol).
  • AAS, diflunisal.
  • Doxycycline, tetracycline (hypoprothrombinemia).
  • Clindamycin: can increase the anticoagulant activity with increase in the values of the coagulation tests (TP-prothrombin time / INR) and / or bleeding.
  • Others: benzbromarone, propranolol, piracetam.

Warfarin increases the prothrombin time in concomitant prescription with: sulfamethoxazole, flutamide.

Warfarin decreases the prothrombin time with: chlorthalidone, spironolactone.

The anticoagulant effect of warfarin can be variable by the intake of: oral contraceptives, phenytoin, disopyramide, cholestyramine.

BRAND NAMES

  • Coumadin ®
  • Aldocumar ®
  • Jantoven ®

Genes analyzed

CYP2C9 CYP4F2 p13 VKORC1

Bibliography

Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing. Clin Pharmacol Ther, 2011; 90(4):625–9.

Kawai VK, Cunningham A, Vear SI, Van Driest SL, Oginni A, Xu H, et al. Genotype and risk of major bleeding during warfarin treatment. Pharmacogenomics, 2014; 15(16):1973–83.

Shaw K, Amstutz U, Kim RB, Lesko LJ, Turgeon J, Michaud V, et al. Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy. Ther Drug Monit, 2015; 37(4):428–36.

Nunnelee JD. Review of an Article: The international Warfarin Pharmacogenetics Consortium (2009). Estimation of the warfarin dose with clinical and pharmacogenetic data. NEJM 360 (8): 753-64. J Vasc Nurs, 2009; 27(4):109.

Schelleman H, Chen J, Chen Z, Christie J, Newcomb CW, Brensinger CM, et al. Dosing algorithms to predict warfarin maintenance dose in Caucasians and African Americans. Clin Pharmacol Ther, 2008; 84(3):332–9.

Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Frye-Anderson A, et al. Genetic Determinants of Response to Warfarin during Initial Anticoagulation. N Engl J Med, 2008; 358(10):999–1008.

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