PDF herunterladen
Thromb Haemost 1988; 60(01): 035-038
DOI: 10.1055/s-0038-1647630
Original Article
Schattauer GmbH Stuttgart

4-Hydroxycoumarin Oral Anticoagulants : Pharmacokinetics-Response Relationship

H H W Thijssen
1   The Dept. of Pharmacology Medical Faculty, University of Limburg, Maastricht, The Netherlands
,
K Hamulyák
2   The Dept. of Haematology Medical Faculty, University of Limburg, Maastricht, The Netherlands
,
H Willigers
2   The Dept. of Haematology Medical Faculty, University of Limburg, Maastricht, The Netherlands
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 26. Oktober 1987

Accepted after revision 28. März 1988

Publikationsdatum:
30. Juni 2018 (online)

Auch verfügbar auf
  als PDF herunterladen  Lizenzen und Reprints

Summary

The blood coagulating factors II and VII and prothrombin times (Thrombotest) were followed during a dosage interval (= 24 h) in patients on acenocoumarol (n = 6) and on phenprocoumon (n = 6) therapy. The patients were on stable anti-coagulation (%TT: 7-13%) for at least 6 months. The study was performed to investigate the concentration-response relationship of the 4-hydroxycoumarin-type oral anticoagulants. The three parameters were stable during the 24-h interval for patients on phenprocoumon therapy. Patients on acenoumarol showed fluctuations in their factor VII levels; peak activities were observed at about 2 h, trough activities at about 16 h after acenocoumarol intake. Factor II and Thrombotest activities were stable. Plasma levels of phenprocoumon were stable during daytime whereas acenocoumarol levels declined exponentially (t½ about 12 h). The results indicate the oral anticoagulants to exhibit a concentration-response relationship common to drug-receptor interactions. The results also suggest that for stable and long-lasting anticoagulant therapy oral anticoagulants with half-lives beyond the dosage interval (t½>24 h) should be preferred.

Key words

Oral anticoagulants - Acenocoumarol - Factor VII - Factor II - INR - Thrombotest - Phenprocoumon
 

  • References

  • 1 Wessler S, Gitel SN. Warfarin from bedside to bench. N Engl J Med 1984; 311: 645-652
    CrossrefPubMedGoogle Scholar
  • 2 Gallop PM, Lian JB, Hauschka PV. Carboxylated calcium-binding proteins and vitamin K. N Engl J Med 1980; 302: 1460-1466
    CrossrefPubMedGoogle Scholar
  • 3 Jähnchen E, Meinertz T, Gilfrich H, Ulrich G, Martin M. The enantiomers of phenprocoumon: pharmacodynamic and pharmacokinetic studies. Clin Pharmacol Ther 1976; 20: 342-349
    CrossrefPubMedGoogle Scholar
  • 4 Kelly JG, O’Malley KO. Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet 1979; 4: 1-15
    CrossrefPubMedGoogle Scholar
  • 5 Thijssen HH W, Baars LG. Active metabolites of acenocoumarol. Do they contribute to the therapeutic effect Br J Clin Pharmacol 1983; 16: 491-496
    CrossrefPubMedGoogle Scholar
  • 6 Levine WG. Anticoagulant, antithrombotic and thrombotic drugs. In: The Pharmacological Basis of Therapeutics. Goodman LS, Gilman A. (eds) MacMillan Inc; New York: 1975. pp 1350-1368
    Google Scholar
  • 7 Holford NH G. Clinical pharmacokinetics and pharmacodynamics of warfarin. Understanding the dose-effect relationship Clin Pharmacokinet 1986; 11: 483-504
    CrossrefPubMedGoogle Scholar
  • 8 Murray B, Coleman R, McWaters D, Ludden T, Mungall D. Pharmacodynamics of warfarin at steady state. Ther Drug Monit 1987; 9: 1-5
    CrossrefPubMedGoogle Scholar
  • 9 Theofanous TG, Barile RG. Multiple-dose kinetics of oral anticoagulants. Methods of analysis and optimized dosing J Pharm Sci 1973; 62: 261-266
    CrossrefPubMedGoogle Scholar
  • 10 Nagashima R, O’Reilly RA, Levy G. Kinetics of pharmacologic effects in man. The anticoagulant action of warfarin Clin Pharmacol Ther 1969; 10: 22-35
    CrossrefPubMedGoogle Scholar
  • 11 Husted S. Andreasen E Individual variation in the response to phenprocoumon. Eur J Clin Pharmacol 1977; 11: 351-358
    CrossrefPubMedGoogle Scholar
  • 12 Loeliger EA, Van der Esch B, Mattem MJ, Den Brabander AS A. Behaviour of factors II, VII, IX, and X during longterm treatment with coumarin. Thromb Haemostas 1963; 9: 74-89
    PubMedGoogle Scholar
  • 13 Kazmier FJ, Spitteil JA, Thompson JJ, Owen CA, Minn R. Effect of oral anticoagulants on factors VII, IX, X, and II. Arch Intern Med 1965; 115: 667-673
    CrossrefPubMedGoogle Scholar
  • 14 Williams WJ. Life span of plasma coagulation factors. In: Hematology. Williams WJ, Beutler E, Erslev AJ, Lichtman MA. (eds) McGraw Hill; New York: 1983. pp 1230-1235
    Google Scholar
  • 15 Loeliger EA, Van den Besselaar AM H P, Lewis SM. Reliability and clinical impact of the normalization of the prothrombin times in oral anticoagulant control. Thromb Haemostas 1985; 53: 148-154
    PubMedGoogle Scholar
  • 16 Hemker HC, Swart AC W, Alink AJ M. Artificial reagents for one stage determinations in the extrinsic system. Thromb Diath Haemorrh 1972; 27: 205-211
    PubMedGoogle Scholar
  • 17 Brandt JT, Triplett DA, Fair DS. Characterization and comparison of immune-depleted and hereditary factor VII deficient plasmas as substrate plasmas for factor VII assays. Am J Clin Pathol 1986; 85: 583-589
    CrossrefPubMedGoogle Scholar
  • 18 Beverley P, Oxley A, Brigham K, Cox T, Hamilton PJ. Factor II, VII, IX and X concentrations in patients receiving long-term warfarin. J Clin Pathol 1987; 40: 94-98
    CrossrefPubMedGoogle Scholar
  • 19 O’Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs. Initiation of warfarin therapy without a loading dose. Circulation 1968; 38: 169-177
    CrossrefPubMedGoogle Scholar
  • 20 Østerud B, Flaegstad T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb Haemostas 1983; 49: 5-7
    PubMedGoogle Scholar
  • 21 Miller CL, Graziano C, Lim RC, Chin M. Generation of tissue factor by patient monocytes. Correlation to thromboembolic complications Thromb Haemostas 1981; 46: 489-495
    PubMedGoogle Scholar
  • 22 Fekkes N, De Jonge H, Veltkamp JJ, Bieger R, Loeliger EA. Comparative study of the clinical effect of acenocoumarol (Sintrom®) and phenprocoumon (Marcoumar®) in myocardial infarction and angina pectoris. Acta Med Scand 1971; 190: 535-540
    PubMedGoogle Scholar
  • 23 Loeliger EA, Roos J, Tijssen JG P, De Vries WA. Anticoagulants after myocardial infarction. Lancet 1981; 1: 1321
    PubMedGoogle Scholar
  • 24 Trenk D, Althen H, Jähnchen E, Meinertz T, Øie S. Factors responsible for interindividual differences in the dose requirement of phenprocoumon. Eur J Clin Pharmacol 1987; 33: 49-54
    CrossrefPubMedGoogle Scholar
  • 25 Fasco MJ, Principe LM. R-and S-warfarin inhibition of vitamin K and vitamin K 2,3-epoxide reductase activities in the rat. J Biol Chem 1982; 257: 4894-4901
    PubMedGoogle Scholar
  • 26 Thijssen HH W, Janssen CA T, Drittij-Reijnders JM. The effect of S-warfarin administration on vitamin K 2,3-epoxide reductase activity in liver, kidney and testis of the rat. Biochem Pharmacol 1986; 35: 3277-3282
    CrossrefPubMedGoogle Scholar