Warfarin half-life

In contrast, several cases of markedly reduced warfarin effects (warfarin resistance) have been seen with intravenous nafcillin, with a 75% reduction in warfarin half-life documented in one case. Similarly, other studies and cases suggest that dicloxacillin may cause a modest reduction in warfarin effects in many patients, and that some may experience greater reductions, with thrombosis being reported in one case. 

The two most widely used coumarins are warfarin (US, Canada, and UK) and phenprocoumon (continental Europe). The long half-life (60 h) of prothrombin means that coumarin cannot achieve therapeutic anticoagulation for at least 5 days following initiation. Thus, for patients with acute thrombosis, oral anticoagulants are usually started only when the patient is receiving a rapidly active agent, usually UFH or LMWH. 

Phenprocoumon has a long plasma half-life of 5 days and thus a duration of action that can last 7-10 days. On the other hand acenocoumarol has a half-life of 10-24 hours and therefore a shorter duration of action. The half-life of warfarin ranges from 25-60 hours and its the duration of action is 2-5 days. Both warfarin and phenprocoumon are highly protein bound and interactions may occur with other drugs that bind to albumin. 

Answer The half-life of amiodarone is 35 days. Approximately five half-Uves are required for functionally complete drug elimination. Thus, it will take approximately 6 months (5 half-lives) before the amiodarone is eliminated from the body. Since amiodarone strongly inhibits metabolism of S-warfarin (active enantiomer), it will continue to affect warfarin metabolism for 6 months following discontinuation of amiodarone. Thus, the dose of warfarin will have to be monitored approximately every month and adjusted if necessary. This monthly monitoring should be continued for at least 6 months, until the metabolism of warfarin stabilizes and a constant dose of warfarin can again be maintained. 

Argatroban is a small molecule thrombin inhibitor that is FDA-approved for use in patients with HIT with or without thrombosis and coronary angioplasty in patients with HIT. It, too, has a short half-life, is given by continuous intravenous infusion, and is monitored by aPTT. Its clearance is not affected by renal disease but is dependent on liver function dose reduction is required in patients with liver disease. Patients on argatroban will demonstrate elevated INRs, rendering the transition to warfarin difficult (ie, the INR will reflect contributions from both warfarin and argatroban). (INR is discussed in detail in the discussion of warfarin administration.) A nomogram is supplied by the manufacturer to assist in this transition. 

Warfarin is generally administered as the sodium salt and has 100% bioavailability. Over 99% of racemic warfarin is bound to plasma albumin, which may contribute to its small volume of distribution (the albumin space), its long half-life in plasma (36 hours), and the lack of urinary excretion of unchanged drug. Warfarin used clinically is a racemic mixture composed of equal amounts of two enantiomorphs. The levorotatory S-warfarin is four times more potent than the dextrorotatory R-warfarin. This observation is useful in understanding the stereoselective nature of several drug interactions involving warfarin. 

Organochlorine insecticides are also well-known inducers. Treatment of rats with either DDT or chlordane, for example, will decrease hexobarbital sleeping time and offer protection from the toxic effect of warfarin. Persons exposed to DDT and lindane metabolized antipyrine twice as fast as a group not exposed, whereas those exposed to DDT alone had a reduced half-life for phenylbutazone and increased excretion of 6-hydroxy cortisol. 

Figure 2 The half-life of the oral anticoagulant warfarin is shortened and its clearance increased when given as a single dose (1.5 mg/kg) before (o) and while ( ) subjects have taken the enzyme inducer rifampin 600 mg daily for 3 days prior to and 10 days following warfarin administration. The peak and duration in elevation of the prothrombin time, a measure of the anticoagulant response, are both decreased when rifampin is coadministered. Source From Ref. 6.

Sitaxsentan is a potent and selective agent which inhibits ET-1 binding to ETA receptors (IC50 = 1.4 nM), while being essentially inactive at ETB receptors (IC50 = 9.8 pM).23 In the clinic, it was found to have excellent oral bioavailability (70-100%) and a terminal elimination half-life of 10 h, and is administered as a once daily 100 mg dose. It is highly protein bound in plasma (> 99%) and extensively metabolized in the liver to inactive metabolites, predominantly by CYPs 2C9 and 3A4. Excretion is 50 60% renal, with the balance in the feces.25 Sitaxsentan inhibits CYP 2C9, and was observed to increase exposure to warfarin by over twofold. The use of cyclosporine A is also contraindicated, but no interactions were observed with sildenafil.15 Sitaxsentan was well tolerated in trials, with only minor side effects reported. Reversible liver enzyme abnormalities were also observed, but less frequently than with bosentan.15 25... 

Drug Interactions Prolonged prothrombin times in patients receiving warfarin have been reported. Plasma half-life of pheny-toin (see p. 147) may be increased due to an inhibition of its metabolism. Methotrexate (see p. 378) levels may rise due to displacement from albumin binding sites by the sulfamethoxazole. 

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