Pharmacokinetics and Pharmacodynamics of Warfarin - Essay Example

Pharmacokinetics and Pharmacodynamics of Warfarin Stereoselective metabolism of warfarin Warfarin is a racemic mixture consisting of equal amountsof R- and S- warfarin, and its metabolism is stereoselective. Humans metabolise S-warfarin almost entirely to form S-7-hydroxywarfarin and a lesser amount of S-6-hydroxywarfarin. R-warfarin is converted mainly to R-6-hydroxywarfarin and some 7-hydroxywarfarin. In vitro studies performed on human liver microsomes demonstrate that CYP2C9 catalyses both 6- and 7-hydroxylation of S-warfarin, whereas 6- and 7-hydroxylation of R-warfarin is mediated mainly by CYP1A2 and CYP2C19. (Lin JH and Lu AYH, 1997.) The S-enantiomer, which is approximately four-fold as active as the R-enantiomer, is responsible for most of warfarin’s anticoagulative action. The major deactivating pathway of warfarin is mediated predominantly by CYP2C9. However, CYP2C9 activity exhibits more than a twenty-fold variation. This variability reflects the genetic polymorphism of the gene encoding CYP2C9. “In addition to the wild-type allele (CYP2C9*1), two frequent allelic variants, CYP2C9*2 and CYP2C9*3, have been identified. Each of these variants contains a single base substitution that results in an amino acid change i.e., Arg144—>Cys144 and Ile359—>Leu359, respectively.” (Bloch A, Ben-Chetrit E, Muszkat M, Caraco Y, 2002). Various studies have evaluated the importance of CYP2C9 genetic polymorphism to warfarin metabolism and its anticoagulation effect. The findings of some of the studies can be summarized as follows: (Bloch A, Ben-Chetrit E, Muszkat M, Caraco Y, 2002.) 1. CYP2C9*1/CYP2C9*2 heterozygotes require significantly lower warfarin maintenance dosages when compared to patients who are homozygous for CYP2C9*1. 2. CYP2C9*1/CYP2C9*3 heterozygotes require a 33% reduction of the normal warfarin dosage when compared to patients who are homozygous for CYP2C9*1 (2 mg/day vs. 3 mg/day, respectively). 3. CYP2C9*3 homozygous patients exhibit extreme sensitivity to usual dosages of warfarin. 4. Even when warfarin dosages are decreased, carriers of CYP2C9-defective alleles experience major bleeding at a higher rate than in patients without a defective allele. “Approximately 20% of Caucasian patients carry a single CYP2C9 allelic variant (CYP2C9*2 or CYP2C9*3), and approximately 1% carry two mutated alleles.” (Bloch A, Ben-Chetrit E, Muszkat M, Caraco Y, 2002). Hence, these patients metabolise S-warfarin more slowly, and may exhibit excessive anticoagulation and enhanced bleeding diathesis if treated with the usual warfarin dosage. To enhance the safety of long-term warfarin therapy, the dosage may have to be reduced in such individuals. Since warfarin is metabolised by hepatic cytochrome P-450 (CYP) isoenzymes predominately to inactive hydroxylated metabolites (excreted in the bile), warfarin metabolism may be altered in the presence of hepatic dysfunction or advanced age. It also is metabolised by reductases to reduced metabolites (warfarin alcohols), which are excreted by the kidneys. However, warfarin metabolism is not affected by renal impairment. (Stein JC, Olson KR, et al., 2005). This is because only small amounts of warfarin are excreted unchanged in urine. (Dewsbury C, 2003.) Plasma protein binding and distribution After rapid intravenous or oral administration of an aqueous solution, warfarin has a distribution phase lasting 6 to 12 hours. The estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Approximately 99% of the drug is bound to plasma proteins. The volume of distribution (VD), also known as apparent volume of distribution, is defined as “the volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration”(Wikipedia). Warfarin has a VD of 8L, which reflects a high degree of plasma protein binding (Wikipedia). Drugs like warfarin, which have an extensive plasma protein binding, tend to stay more in the central blood compartment, and have lower volumes of distribution. “Albumin possesses a single strong binding site for warfarin. Binding to plasma albumin probably affects the duration and intensity of a drugs action and protects the body against the full pharmacologic effect of the drug by temporarily inactivating it in a circulating reservoir that is in equilibrium with the unbound, active form of the drug.” (OReilly RA, 1967.) The warfarin-albumin interaction confines the drug molecules within the vascular space in an inactive form. This prevents access to the sites of drug action, excretion, and metabolism. Therefore, warfarin sodium does not enter red blood cells, CSF, is not present in the urine, and has a small volume of distribution that is identical to the albumin space. This strong albumin-warfarin interaction also explains the long half-life of warfarin in plasma and the long biologic effects. The drug response of warfarin will be dependent on the free drug concentration. Any alteration of free concentration by drug interactions or disease state can alter the intensity of action of these drugs. (OReilly RA, 1967.) Antithrombotic Effect The antithrombotic effect of warfarin is not apparent till approximately the fifth day of therapy, and is dependent on the clearance of functional factor II or prothrombin, (which may take up to five days, and has a half-life of approximately 50 hours in patients with normal hepatic function.) Because of this reason, loading doses of warfarin (i.e., 10 mg or more per day) is of limited value, and may increase the patients risk of bleeding episodes early in therapy by eliminating or severely reducing the production of functional factor VII. One potential paradoxical consequence of loading doses is the development of a hypercoagulable state. This happens because of a steep reduction in the concentration of protein C and S during the first 36 hours of warfarin therapy, leading to clot formation and/or expansion. This necessitates the concurrent use of heparin. Therefore, the practice of using loading doses should be discontinued because it has no effect on the inhibition of thrombosis. (Horton JD, Bushwick BM.) Drug interactions Drugs can influence the pharmacodynamics of warfarin by inhibiting synthesis, increasing clearance of vitamin K– dependent coagulation factors or by interfering with other pathways of haemostasis. Drugs that inhibit warfarin metabolism and potentiates anticoagulant effect are, ciprofloxacin, chloramphenicol, erythromycin, fluconazole, ketoconazole, metrodinazole, miconazole, sulphonamides etc. (Laurence DR, Bennet PN, 1987). Salicylates (>1.5 g /day) and acetaminophen also augment the anticoagulant effect of warfarin, possibly due to a warfarin-like activity. Heparin potentiates the anticoagulant effect of warfarin. Drugs such as aspirin, NSAID drugs, penicillin (in high doses), and moxolactam, increase the risk of warfarin-associated bleeding by inhibiting platelet function. (Hirsh et al., 2003). Rifampicin increases warfarin metabolism and causes undercoagulation (Laurence DR, Bennet PN, 1987.) Genotyping Aithal GP, Day CP, et al., 1999, studied the effect of CYP2C9 polymorphism on the in-vivo warfarin dose requirement. They concluded that “CYP2C9 genotyping may identify a subgroup of patients who have difficulty at induction of warfarin therapy and are potentially at a higher risk of bleeding complications.” Carriers of mutant alleles should receive smaller initial doses of warfarin than the standard recommendation. Especially in case of therapy in high-risk elderly patients, a physician with the knowledge of the CYP2C9 genotype can decide against the use of warfarin and choose other coumarin derivatives, which are not influenced by CYP2C9. This also can predict the likelihood of successful drug therapy and the ability to individualize the drug dose (Genome Identification Diagnostics GMBH.)  *************************************************************************** References Aithal GP, Day CP, et al., 1999. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. Feb 27; 353(9154): 717-9 Bloch A, Ben-Chetrit E, Muszkat M, Caraco Y, 2002. Major Bleeding Caused by Warfarin in a Genetically Susceptible Patient. Pharmacotherapy 22(1):97-101. Dewsbury C, 2003. Warfarin: Drug Interactions. [Online]. [Accessed 20th November, 2005] Genome Identification Diagnostics GMBH . [Online]. [Accessed 20th November, 2005] Horton JD, Bushwick BM. Warfarin Therapy: Evolving Strategies in Anticoagulation. American Family Physician. [Online]. [Accessed 20th November, 2005] Hirsh et al., JACC 2003;41:1633-52. Laurence DR, Bennet PN, 1987, Clinical pharmacology. Drugs and haemostasis. 7th edition, pp. 479. ELBS.) Lin JH and Lu AYH, 1997. Role of Pharmacokinetics and Metabolism in Drug Discovery and Development. Vol. 49, Issue 4, 403-449. OReilly RA, 1967. Studies on the Coumarin Anticoagulant Drugs: Interaction of Human Plasma Albumin and Warfarin Sodium. Journal of Clinical Investigation Vol. 46. [Online]. [Accessed 20th November, 2005] Stein JC, Olson KR, et al., 2005. Toxicity, Warfarin and Superwarfarins. [Online]. [Accessed 20th November, 2005] Read More