Coumarin anticoagulants prothrombin

Warfarin, a coumarin anticoagulant, is incorporated into commeal for use as a rat poison. Repeated exposure results in sufficient inhibition of prothrombin synthesis to cause fatal internal hemorrhage. 

The fibrates potentiate the actions of the coumarin anticoagulants, such as warfarin, so care should be taken to reduce the dose of simultaneously administered anticoagulants, and plasma prothrombin should be frequently measured until the level stabilizes. As mentioned earlier, great care should be given to combining a statin with a fibrate, since this combination may increase the risk of myositis and perhaps rhabdomyolysis. Table 23.4 summarizes major interactions of drugs that lower cholesterol. 

Potentates coumarin anticoagulants. Therefore, reduce dose of anticoagulant and monitor plasma prothrombin. 

Suttie, J.W. (1986). Vitamin K-dependent carboxylase and coumarin anticoagulant action. In Prothrombin and Other Vitamin K Proteins, Vol. 2 (W.H. Seegers, D.A. Walz, eds), pp. 17-47. CRC Press, FL. 

Griseofulvin is a potent inducer of cytochrome P450 and has a significant effect on P450 expression in hepatocytes (SEDA-12, 236). It therefore increases the rate of metabolism of coumarin anticoagulants (50). However, both increases and decreases in prothrombin time have been reported (SED-12, 676) (18). 

In an early, double-blind, placebo-controlled study of the interaction between coumarin anticoagulants and paracetamol, there was a statistically significant lengthening of the prothrombin time (124). The effect, although statistically significant, was very small and was considered to be clinically unimportant. 

In this equation, kd is the apparent first-order degradation rate constant (also called out). This constant can be obtained experimentally from the slope of a ln(P) versus time plot, after administration of a synthesis-blocking dose of coumarin anticoagulant (Nagashima et al., 1969 Pitsui et al., 1993). P0 is the baseline value of the prothrombin time, Cw(S) is the concentration of ( -warfarin and IC50s is the concentration of warfarin at 50% of maximal blocking effect. It was also possible to estimate the half-life of the apparent first-order degradation. 

The coumarin anticoagulants include dicumarol, warfarin sodium (coumadin sodium), warfarin potassium (Athrombin-K), acenocoumarol, and phenprocouman. Phenprocouman, acenocoumarol, and ethyl biscoumacetate are not generally available in the United States but are prescribed in Europe and elsewhere. Phenprocouman (Marcumar) has a longer plasma half-life (5 days) than warfarin, as well as a somewhat slower onset of action and a longer duration of action (7 to 14 days). It is administered in daily maintenance doses of 0.75 to 6.0 mg. By contrast, acenocoumarol (Nicoumar-lone Sinthrome) has a shorter half-life (10 to 24 hours), a more rapid effect on the prothrombin time, and a shorter duration of action (2 days). The maintenance dose is 1 to 8 mg daily. Ethyl biscoumacetate (Tromexane) has a very short half-life of 2 to 3 hours and is seldom used. 

The combination of dipyridamole and coumarin anticoagulants does not alter the prothrombin time, but might cause an increased risk of serious bleeding when compared with anticoagulants alone. There is some evidence that the risk of bleeding may be lower, without a reduction in efficacy, if the INR is maintained within a lower range. 

Voriconazole is a known inhibitor of the cytochrome P450 isoenzymes CYP2C9 and CYP3A4, by which the coumarins (phenprocoumon, acenocoumarol and warfarin) are metabolised. The manufacturers advise close monitoring of the prothrombin time in any patient on a coumarin anticoagulant who is given voriconazole. Dose adjustments of the coumarin should be made accordingly. ... 

Weiner M, Moses D. The effect of glucagon and insulin on tiie prothrombin response to coumarin anticoagulants. Proc SocExp BiolMed( 96 ) 127, 761-3. 

Heparin may prolong the one-stage prothrombin time. The US manufae-turer notes that, if a valid prothrombin time is to be obtained in a patient starting warfarin or other coumarins, a period of a least 5 hours after the last intravenous heparin dose or 24 hours after the last subeutaneous dose should be left before measuring the prothrombin time. Note that it is usual clinical practice to start heparin and a coumarin anticoagulant at the same time. Further, it is clear that the concurrent use of warfarin and heparin will have an at least additive anticoagulant effect. 

Some of the normal tests of anticoagulation (prothrombin time, thrombotest) are unreliable for a few hours after giving intravenous danaparoid to patients taking coumarins. 

Because of the data with tamoxifen, the manufacturers of toremifene (indicated for hormone-dependent metastatic breast cancer in postmenopausal women) contraindicate the concurrent use of coumarin anticoagulants in the UK, but just recommend careful monitoring of prothrombin time in the US. However, there appear to be no published reports of any interaction between toremifene and warfarin. 

The coumarin anticoagulants are employed in therapy to depress blood coagulation and to prevent thrombosis in diseases of the coronary artery and in other conditions [419]. These compounds act only in vivo by blocking the synthesis of four proteins in the prothrombin complex (factors II = prothrombin, VII = proconvertin, IX = plasma thromboplastin component, and X = Stuart-Prower factor) necessary for the normal blood coagulation process. These proteins are... 

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. 

Twenty to 24 million prescriptions of Coumadin were dispensed in the United States during 2003-2005. Coumadin is an anticoagulant that acts by preventing the synthesis of active vitamin K, a necessary cofactor for synthesizing active clotting factors. Thus, preventing the synthesis of active vitamin K indirectly inhibits the formation of active clotting factors, notably factor II (prothrombin), VII, IX, and X in the liver. Ironically, coumarins, of which Coumadin is a member, are also used as rodenticides. 

Coumarins are competitive inhibitors of vitamin K, which is required for the formation in the liver of the amino acid, gamma-carboxyglutamic acid. This is necessary for the synthesis of prothrombin and factors VII, IX and X (Figure 17.1). After starting treatment the anticoagulant effect is delayed until the concentration of normal coagulation factors falls (36-72 h). The effects can be reversed by vitamin K (slow maximum effect only after 3-6 h) or by whole blood or plasma (fast). Gut bacteria synthesise vitamin K and thus are an important source of this vitamin. Consequently, antibiotics can cause excessive prolongation of the prothrombin time in patients otherwise adequately controlled on warfarin. 

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