Warfarin pharmacodynamics

Vigilance for drug-drug interactions is required because of the greater number of medications prescribed to elderly patients and enhanced sensitivity to adverse effects. Pharmacokinetic interactions include metabolic enzyme induction or inhibition and protein binding displacement interactions (e.g., divalproex and warfarin). Pharmacodynamic interactions include additive sedation and cognitive toxicity, which increases risk of falls and other impairments. 

Chan K, Lo AC, Yeung JH, Woo KS. The effects of Danshen Salvia miltiorrhiza) on warfarin pharmacodynamics and pharmacokinetics of warfarin enantiomers in rats. J Pharm Pharmacol 1995 47(5) 402-6. 

Meyer BH, Muller FO, B enhorst PN, Luus HG, De La Rey N. Multiple doses of trandolapril do not affect warfarin pharmacodynamics. SAfrMedJ (1995) 85, 768-70. 

Placebo-controlled, crossover 12 healthy subjects 5 mg daily for 14 days 40 mg daily for 7 days NR No change in steady-state warfarin pharmacodynamics 8... 

Simonson SG, Martin PD, Mitchell PD, Lasseter K, Gibson G, Schneck DW. Effect of rosuvastatin on warfarin pharmacodynamics and pharmacokinetics. J Clin Pharmacol 2005 45,927-34. 

Influences warfarin pharmacodynamic response and is also associated with specific warfarin maintenance dose... 

Pharmacogenetics the responses to dmgs may be significantiy different according to heritable factors that can modulate pharmacodynamic or pharmacogenetic factors (118). Atypical cholinesterase occurs in about 1 in 2000 Caucasians and is associated with a markedly reduced sensitivity to hydrolysis of the muscle-relaxant cholinesterase. Similarly, the reduced sensitivity to the anticoagulant warfarin is associated with a reduced receptor affinity. 

Toon S, Hopkins KJ, Garstang FM, et al. Comparative effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of warfarin. Eur ] Clin Pharmacol 1987 32 165-72. 

Bishydroxycoumarin (dicoumarol) is a natural occurring anticoagulant found in sweet clover. A number of coumarin derivatives have been synthesized as anticoagulants, warfarin, phenprocoumon and acenocoumarol being most frequently used. The nonpolar carbon substituent at the 3 position required for activity is asymmetrical. The enantiomers differ in both pharmacokinetic and pharmacodynamic properties. The coumarins are marketed as racemic mixtures. 

Most literature reports of pharmacodynamic botanical-drug interaction involve the anticoagulant warfarin, likely because it has therapeutic end points such as the INR and PT, which are routinely closely monitored. In addition, most botanicals possess anticoagulant and/or antiplatelet activities, and their combined use with warfarin provides a good example of pharmacodynamic interaction with additive pharmacological effect. 

Jiang X, Williams KM, Liauw WS, et al. Effect of St John s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2004 57(5) 592-599. 

Zhou M, Chan KW, Ng LS, Chang S, Li RC. Possible influences of ginseng on pharmacokinetics and pharmacodynamics of warfarin in rats. J Pharm Pharmacol 1999 51 175-180. 

Lo ACT, Chan K, Yeung JHK, Woo KS. Dang gui (Angelica sinensis) affects the pharmacodynamics but not the pharmacokinetics of warfarin in rabbits. Eur J Drug Metab Pharmacokinet 1995 20 53-60. 

Editor s Note Tile following references have been selected to provide the interested reader wiLli more detail on the pharmacologic complexities of anticoagulants Tile article by Edwin W. Salzman, M.D. is a short, but excellent summary of the status of antithrombotic drugs as of early 1992. The article on heparin by Jack Hirsh, MD. and the article on warfarin by the same author proride important fundamental background information on the pharmacokinetics and pharmacodynamics of the most widely used anticoagulant drugs, Brandjes. D.P.M., et al. Acenocoumarol and Heparin Compared with Acenocoumarol. Alone in the Initial Treatment of Proximal-Vein Thrombosis," N. Eng. J. Med., 1485 (November 19, 1992). 

To assess the potential for an interaction between raloxifene and warfarin, 15 healthy postmenopausal women each received single doses of warfarin 20 mg before and during 2 weeks of dosing with raloxifene 120 mg/day (37). Raloxifene reduced the oral clearance of R- and A -war-farin respectively by 7.1 and 14% and the oral volume of distribution by 7.4 and 9.8%. Raloxifene reduced the maximum prothrombin time by 10% and the area under the prothrombin versus time curve from 0-120 hours by an average of 8%. The authors concluded that raloxifene may produce a small increase in systemic warfarin exposure but a reduced pharmacodynamic effect. Since the effects are slight this interaction is unlikely to have clinical consequences. 

Miller 1W, Skerjanec A, Knadler MP, Ghosh A, Allerheiligen SR. Divergent effects of raloxifene HCI on the pharmacokinetics and pharmacodynamics of warfarin. Pharm Res 2001 18(7) 1024-8. 

Schall R, Muller FO, Hundt HK, Duursema L, Groenewoud G, Middle MV. Study of the effect of miglitol on the pharmacokinetics and pharmacodynamics of warfarin in healthy males. Arzneimittelforschung 1996 46(l) 41-6. 

In 21 healthy men, cerivastatin 300 micrograms did not alter the pharmacokinetics of R- and A -warfarin, or the pharmacodynamics of a single oral dose of warfarin 25 mg (93). 

Shikata E, leiri I, Ishiguru S, et al. Association of pharmacokinetics (CYP2C9) and pharmacodynamics (factors II, VII, IX, and X protein S and C and gamma-glutamyl carboxylase) gene variants with warfarin sensitivity. Blood 2004 103 2630-2635. 

Chan E, McLachlan AJ, O Reilly R, et al. Stereochemical aspects of warfarin drug interactions use of a combined pharmacokinetic-pharmacodynamic model. Clin Pharmacol Ther 1994 56 286-294. 

Pharmacokinetic and pharmacodynamic profiles of olanzapine have been extensively reviewed (266). Olanzapine does not inhibit CYP isozymes, and no clinically significant metabolic interactions were found of olanzapine with aminophylline, biperiden, diazepam, ethanol, fluoxetine, imipramine, lithium, or R/S-warfarin. 

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