A rare but serious complication resulting from warfarin treatment is warfarin necrosis, which is more common shortly after starting treatment in patients deficient in protein C, a congenital anticoagulant that, like the procoagulant factors whose synthesis warfarin inhibits, requires vitamin K-dependent carboxylation for its activity. Since warfarin initially lowers C protein levels faster than clotting factors, it can paradoxically increase the tendency of the blood to clot at the beginning of treatment (many patients who start warfarin receive heparin in parallel to combat this), leading to massive thrombosis with skin necrosis and gangrene of the limbs. Its natural counterpart, purpura fulminans, occurs in children who are homozygous for certain mutations in protein C. [44] Administration of warfarin in the second and third trimesters is much less often associated with birth defects and, when they occur, differ significantly from those of FSWS. The most common birth defects associated with warfarin use in late pregnancy are central nervous system disorders, including spasticity and seizures, and eye abnormalities. [34] [35] Because of these subsequent birth defects, warfarin anticoagulation is a problem in pregnant women who require warfarin for vital indications, such as stroke prevention in patients with artificial heart valves. Oral anticoagulant therapy with warfarin has not been fully studied in clinical trials in patients with valvular heart disease associated with atrial fibrillation, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, for these patients, a moderate dosing regimen (INR 2.0-3.0) may be used. Warfarin also interacts with many herbs and spices,[64] some of which are used in foods (such as ginger and garlic) and others used exclusively for medicinal purposes (such as ginseng and ginkgo biloba). All may increase bleeding and bruising in people taking warfarin; Similar effects have been reported with borage oil (starflower oil).
[65] St. John`s wort, which is sometimes recommended to help relieve mild to moderate depression, reduces the effectiveness of a certain dose of warfarin; It induces enzymes that break down warfarin in the body, resulting in a reduced anticoagulant effect. [66] The terminal half-life of warfarin after a single dose is approximately 1 week; However, the effective half-life is between 20 and 60 hours, with an average of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, so the half-life of rwarfarin is longer than that of S-warfarin because the volumes of distribution are similar. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabelled drugs have shown that up to 92% of the orally administered dose is recovered in the urine. Very little warfarin is excreted unchanged in the urine. Excretion in the urine occurs in the form of metabolites. Has a dose-response relationship been demonstrated for the interacting drug? Changes in dose of the drug or food interacting with warfarin correlated with subsequent changes in coagulation variables, suggesting a dose-response relationship. However, the maximum anticoagulant effect can be delayed from 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days.The effects of warfarin sodium may become more pronounced when the effects of daily maintenance doses overlap. Some people may react differently to warfarin because of their heredity or genetic makeup. Your doctor may order a blood test to find the best dose of warfarin for you. Wear identification or wristband indicating that you are taking warfarin. Ask your pharmacist or doctor how to get this card or bracelet. Include your name, medical conditions, medications and dosages, and the doctor`s name and phone number on the card. The elimination of warfarin occurs almost exclusively by metabolism. Warfarin is metabolised stereoselectively by hepatic microsomal enzymes of cytochrome P-450 (CYP450) to inactive hydroxylated metabolites (predominant pathway) and by reductases to reduced metabolites (warfarin alcohols) with minimal anticoagulant activity. Identified metabolites of warfarin include dehydrowarfarin, two diastereomeric alcohols and 4`-, 6-, 7-, 8- and 10-hydroxywarfarin. CYP450 isoenzymes involved in warfarin metabolism include CYP2C9, 2C19, 2C8, 2C18, 1A2 and 3A4. CYP2C9, a polymorphic enzyme, is probably the main form of the human liver CYP450 that modulates the in vivo anticoagulant activity of warfarin. Patients with one or more CYP2C9 alleles have decreased S-warfarin clearance [see Pharmacogenomics].
Warfarin is best used for anticoagulation (inhibition of clot formation) in areas where blood flows slowly (e.g., through veins and blood accumulated behind artificial and natural valves) and in blood accumulated in dysfunctional atria. Therefore, frequent clinical indications for the use of warfarin are atrial fibrillation, the presence of artificial heart valves, deep vein thrombosis and pulmonary embolism (where embolized clots first form in the veins). Warfarin is also used in antiphospholipid syndrome. It has sometimes been used after heart attacks (myocardial infarction), but is much less effective in preventing further thrombosis in the coronary arteries. Prevention of clotting in the arteries is usually done with antiplatelet drugs, which act by a mechanism other than warfarin (which usually does not affect platelet function). [19] It can be used to treat people after ischemic stroke due to atrial fibrillation, although direct oral anticoagulants (DOACs) may offer greater benefits. [20] Broad-spectrum antibiotics may enhance the effects of warfarin by reducing the gut flora that produces vitamin K. Similarly, orlistat may reduce the absorption of vitamin K. Cholestyamine and sucralfate may decrease the absorption of warfarin. Warfarin is excreted in breast milk in small amounts.
However, at the therapeutic dose of warfarin, no effect on the breastfed child is expected. Warfarin can be used during breastfeeding. Herbal preparations containing St. John`s wort (Hypericum perforatum) should not be used while taking warfarin, as there is evidence that there is a risk of reduced plasma concentrations and reduced clinical effects of warfarin. This updated review shows that the number of reports of interactions between warfarin and drugs or food is increasing, confirming both the widespread use of the anticoagulant and its use with concomitant drugs. Although the true mechanisms of drug interactions are almost always unknown, there are several pharmacokinetic and pharmacodynamic factors that could influence the action of warfarin. Cholestyramine is thought to reduce gastrointestinal absorption of warfarin.97,234 The stronger isomer of warfarin-S is metabolized by cytochrome P-450 (CYP) 2C9. Many drugs identified as potentiating warfarin are known inhibitors of CYP 2C9, including amiodarone, fluconazole, fluvastatin, fluvoxamine, isoniazid, lovastatin, phenylbutazone, and sertraline.235 both rifampicin and secobarbital are known inducers of CYP 2C9.93,102 The R-isomer of warfarin is metabolized by CYP 1A2 and CYP 3A4, and quinolones16,139 inhibit CYP 1A2 and macrolides11,124,126 inhibit CYP 3A4. Azoles (several ratios with metronidazole, fluconazole, trimethoprim-sulfamethoxazole, miconazole and voriconazole25,28,79,81-83,236) are also considered to inhibit CYP 1A2 or CYP 3A4. The pharmacodynamics of warfarin may be influenced by medications that affect vitamin K or clotting factors.237 Sudden changes in dietary sources of vitamin K, such as leafy greens or a supplement regimen, followed by a change in the effects of warfarin, are relatively easy to understand.106,238-240 For many medications, including cephalosporins, levothyroxine and clofibrate, your suspected pharmacodynamic interactions with warfarin are very poorly understood.76,214,241 Keep all appointments with your doctor and laboratory. Your doctor will regularly order a blood test (PT [prothrombin test] reported as INR [International Normalized Ratio]) to check your body`s response to warfarin.
If surgery is required and warfarin cannot be stopped 3 days before, anticoagulation with low-dose vitamin K should be reversed. Lavrenty Beria and I. V. Khrustalyov allegedly conspired to use warfarin to poison Soviet leader Joseph Stalin. Warfarin is tasteless and colorless, causing symptoms similar to Stalin`s. [95] If your doctor tells you to stop taking warfarin, the effects of this medication may last 2 to 5 days after you stop taking warfarin. In a prospective, randomized, open-label, positive controlled study in 254 patients with mechanical heart valve replacements, it was found that the interval without thromboembolic was significantly larger in patients treated with warfarin alone than in patients treated with dipyridamole/aspirin (p<0.005) and patients treated with pentoxifylline/aspirin (p<0.05). The results of this study are presented in Table 5. X-ray crystallographic studies of warfarin show that it is present in tautomeric form, in the form of cyclic hemicetal, which is formed from 4-hydroxycoumarin and ketone in the 3-position substituent. [71] However, the existence of many 4-hydroxycoumadin anticoagulants (e.g., phenprocoumon), which do not have a ketone group in substituent 3 to form such a structure, suggests that hemidetal must tautomerize to the 4-hydroxy form for warfarin to be active.
[72] Warfarin has a narrow therapeutic spectrum and caution should be exercised in all adjunctive therapies.
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