Plasma warfarin concentrations

TMP-SMX is a known inhibitor of CYP450 and can substantially increase warfarin plasma concentrations and hypopro-thrombinemic response. 

There are small changes in serum albumin concentration with age, with concomitant small effects on protein binding of some highly bound drugs such as naproxen, salicylate, and warfarin. For such drugs the free concentration rather than the total plasma concentration is a better predictor of drug dose requirements, particularly for drugs with low therapeutic index (difference between the therapeutic... 

Dyspepsia is the most common side effect of zileuton. Liver transaminase levels are elevated in a small percentage of patients taking zileuton. Serum Uver transaminase levels should be monitored and treatment halted if significant elevations occur. Zileuton inhibits the metabolism of theophylline. Thus, when these agents are used concomitantly, the dose of theophylline should be reduced by approximately one-half, and plasma concentrations of theophylline should be monitored closely. Caution should also be exercised when using zileuton concomitantly with warfarin, terfenadine, or propranolol, as zileuton inhibits the metabolism of these agents. Zileuton is contraindicated in patients with acute liver disease and should be used with caution in patients who consume substantial quantities of alcohol or have a history of liver disease. 

Zafirlukast and montelukast are well tolerated. Zafirlukast increases plasma concentrations of warfarin and decreases the concentrations of theophylline and erythromycin. In rare cases, treatment of patients with CysLT receptor antagonists is associated with the development of Churg-Strauss syndrome, a condition marked by acute vasculitis, eosinophilia, and a worsening of pulmonary symptoms. Because these symptoms often appear when patients are given the leukotriene receptor antagonists when they are being weaned from oral corticosteroid therapy, it is not clear whether they are related to the action of the antagonists or are due to a sudden reduction in corticosteroid therapy. 

The SSRIs bind tightly to plasma proteins and may interfere with other protein-bound drugs (e.g., warfarin, digitoxin), causing a shift in plasma concentrations that can potentially result in adverse effects (Schrefer, 2001). As mentioned above, the SSRI medications can... 

Carbamazepine + phenytoin, tricyclic antidepressants, typical neuroleptics, valproate, clonazepam, warfarin, nefazodone and propoxyphene —> reduced plasma concentration of carbamazepine due to increased metabolism. 

BICALUTAMIDE ANTICOAGULANTS-WARFARIN t plasma concentrations of warfarin Bicalutamide displaces warfarin from protein-binding sites Monitor INR at least weekly until stable at initiation and discontinuation of concurrent therapy... 

ANTICOAGULANTS-ORAL CNS STIMULANTS -MODAFINIL May cause moderate T plasma concentrations of warfarin Modafinil is a reversible inhibitor of CYP2C9 and CYP2C19 when used in therapeutic doses Be aware... 

Toxicity as an extension of therapeutic action is usually associated with a small therapeutic index, which is simply the ratio of the toxic plasma concentration over the therapeutic plasma concentration. It should be apparent that drugs with a small therapeutic index require the most attention and alertness with respect to variations in metabolism and elimination. Such variations may easily cause the concentration within the body to either exceed the toxicity threshold, or drop below the minimum amount required for the therapeutic effect. Accordingly, in our example, patients receiving warfarin treatment need to have their blood clotting function measured at regular, frequent intervals. 

The NADPH-dependent reduction of vitamin K quinone to the hydroquinone is not inhibited by warfarin. In the presence of adequate amounts of vitamin K, the carboxylation of glutamate residues can proceed normally, despite the presence of warfarin, with the stoichiometric formation of vitamin K epoxide that cannot be reutilized. Small amounts of vitamin K epoxide, and hydroxides formed by its reduction by other enzymes, are normally found in plasma. In warfarin-treated animals and patients, there is a significant increase in the plasma concentration of both. There is also an increase in the urinary excretion of the products of side-chain oxidation of the epoxide and hydroxides. 

Therapeutic Concentration. In plasma, usually in the range 1 to 3 pg/ml but there are considerable intersubject variations in sensitivity to warfarin and measurement of the plasma concentration is generally of little value since the pharmacological effect can be easily measured. 

Welling, P.G., Lee, K.P., Khanna, U., Wagner, J.G. (1970). Comparison of plasma concentrations of warfarin measured hy both simple extraction and thin-layer liquid chromatographic methods. J. Pharm. Sci. 59 1621-5. 

Nagashima et al. (33) developed a model in which the forcing function was modeled as proportional to the logarithm of the warfarin concentration in plasma. However, Pitsiu et al. (34) subsequently found that a sigmoid E ax model (Equation 19.11) is more suitable for modeling the relationship between plasma concentrations of S-warfarin, the active isomer of warfarin, and inhibition of coagulation factor formation. 

Pharmacokinetic interaction the drugs interact remotely from the target site to alter plasma (and other tissue) concentrations so that the amount of the drug at the target site of clinical effect is altered, e.g. enzyme induction by rifampicin will reduce the plasma concentration of warfarin enzyme inhibition by ciprofloxacin will elevate the concentration of theophylline. 

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