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Characterization of inhibition of platelet function by paracetamol and its interaction with diclofenac in vitro
Author(s) -
Munsterhjelm E.,
Niemi T. T.,
Ylikorkala O.,
Silvanto M.,
Rosenberg P. H.
Publication year - 2005
Publication title -
acta anaesthesiologica scandinavica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.738
H-Index - 107
eISSN - 1399-6576
pISSN - 0001-5172
DOI - 10.1111/j.1399-6576.2005.00707.x
Subject(s) - medicine , pharmacology , antipyretic , diclofenac , platelet , analgesic , thromboxane , cyclooxygenase , metabolite , aspirin , acetaminophen , thromboxane b2 , whole blood , thromboxane a2 , bleeding time , chemistry , platelet aggregation , biochemistry , enzyme
Background: Paracetamol (acetaminophen) is an effective analgesic and a weak inhibitor of cyclo‐oxygenase (COX). Clinically paracetamol is often used together with traditional NSAIDs, which are strong inhibitors of COX. We studied binding of paracetamol to COX and its action on platelet function together with diclofenac. Methods: Blood was collected from healthy donors and platelet function was assessed by photometric aggregometry, a platelet function analyser (PFA‐100™, Dade Behring, Deerfield, IL) and by measuring the release of thromboxane B 2 (TxB 2 ), the stable metabolite of thromboxane A 2 , after addition of paracetamol (10–80 µg ml −1 ). A concentration‐inhibition relationship was established and the inhibition coefficient ( K i ) demonstrating 50% binding to COX was determined using a Schild‐plot. Interaction of paracetamol (5–20 µg ml −1 ) and diclofenac (0.1–0.8 µg ml −1 ) was determined and an isobolographic analysis was performed. Results: Paracetamol added to platelet‐rich plasma (PRP) caused a concentration‐dependent inhibition of platelet function. Photometric aggregometry and TxB 2 release was significantly inhibited by paracetamol from 10 µg ml −1 onwards. The PFA‐100™ closure time was significantly prolonged by paracetamol at a high concentration only. K i was 15.2 µg ml −1 with a 95% confidence interval of 11.8–18.6 µg ml −1 . Inhibition of aggregation by diclofenac was augmented by paracetamol. Isobolographic analysis showed synergism. Conclusions: The 95% confidence interval of K i equals the antipyretic plasma concentration of paracetamol, i.e. 10–20 µg ml −1 . High doses of paracetamol and a combination of diclofenac and paracetamol cause platelet inhibition and thus may increase risk of surgical bleeding.