Newly Published
Perioperative Medicine  |   May 2017
High Concentrations of Tranexamic Acid Inhibit Ionotropic Glutamate Receptors
Author Notes
  • From the Departments of Physiology (I.L., D.-S.W., K.K., C.D.M., B.A.O.) and Anesthesia (C.D.M., B.A.O.), University of Toronto; Department of Anesthesia, Keenan Research Centre for Biomedical Science and the Li Ka Shing Knowledge Institute, St. Michael’s Hospital (C.D.M.); and Department of Anesthesia, Sunnybrook Health Sciences Centre (B.A.O.), Toronto, Ontario, Canada.
  • This is a Coagulation 2016 submission. I.L. and D.-S.W. contributed equally to this article.
    This is a Coagulation 2016 submission. I.L. and D.-S.W. contributed equally to this article.×
  • Submitted for publication July 29, 2016. Accepted for publication March 31, 2017.
    Submitted for publication July 29, 2016. Accepted for publication March 31, 2017.×
  • Acknowledgments: The authors thank Ella Czerwinska, M.Sc., and Junhui Wang, M.D., Ph.D., Department of Physiology, University of Toronto, Toronto, Ontario, Canada, for their assistance with the cell cultures.
    Acknowledgments: The authors thank Ella Czerwinska, M.Sc., and Junhui Wang, M.D., Ph.D., Department of Physiology, University of Toronto, Toronto, Ontario, Canada, for their assistance with the cell cultures.×
  • Research Support: This work was supported by operating grants from the Canadian Institutes of Health Research (CIHR), Ottawa, Ontario, Canada, to Dr. Orser (grant Nos.: 416838, 480143). Dr. Lecker was supported by the Frederick Banting and Charles Best Doctoral Scholarship from CIHR. K. Kaneshwaran was supported by the Kirk Weber Award in Anesthesia from the Department of Anesthesia, Sunnybrook Health Services Centre, Toronto, Ontario, Canada; and the Ontario Graduate Scholarship, Ontario, Canada.
    Research Support: This work was supported by operating grants from the Canadian Institutes of Health Research (CIHR), Ottawa, Ontario, Canada, to Dr. Orser (grant Nos.: 416838, 480143). Dr. Lecker was supported by the Frederick Banting and Charles Best Doctoral Scholarship from CIHR. K. Kaneshwaran was supported by the Kirk Weber Award in Anesthesia from the Department of Anesthesia, Sunnybrook Health Services Centre, Toronto, Ontario, Canada; and the Ontario Graduate Scholarship, Ontario, Canada.×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Orser: Department of Physiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. beverley.orser@utoronto.ca. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Central and Peripheral Nervous Systems / Coagulation and Transfusion
Perioperative Medicine   |   May 2017
High Concentrations of Tranexamic Acid Inhibit Ionotropic Glutamate Receptors
Anesthesiology Newly Published on May 11, 2017. doi:10.1097/ALN.0000000000001665
Anesthesiology Newly Published on May 11, 2017. doi:10.1097/ALN.0000000000001665
Abstract

Background: The antifibrinolytic drug tranexamic acid is structurally similar to the amino acid glycine and may cause seizures and myoclonus by acting as a competitive antagonist of glycine receptors. Glycine is an obligatory co-agonist of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors. Thus, it is plausible that tranexamic acid inhibits NMDA receptors by acting as a competitive antagonist at the glycine binding site. The aim of this study was to determine whether tranexamic acid inhibits NMDA receptors, as well as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate subtypes of ionotropic glutamate receptors.

Methods: Tranexamic acid modulation of NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate receptors was studied using whole cell voltage-clamp recordings of current from cultured mouse hippocampal neurons.

Results: Tranexamic acid rapidly and reversibly inhibited NMDA receptors (half maximal inhibitory concentration = 241 ± 45 mM, mean ± SD; 95% CI, 200 to 281; n = 5) and shifted the glycine concentration–response curve for NMDA-evoked current to the right. Tranexamic acid also inhibited α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (half maximal inhibitory concentration = 231 ± 91 mM; 95% CI, 148 to 314; n = 5 to 6) and kainate receptors (half maximal inhibitory concentration = 90 ± 24 mM; 95% CI, 68 to 112; n = 5).

Conclusions: Tranexamic acid inhibits NMDA receptors likely by reducing the binding of the co-agonist glycine and also inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors. Receptor blockade occurs at high millimolar concentrations of tranexamic acid, similar to the concentrations that occur after topical application to peripheral tissues. Glutamate receptors in tissues including bone, heart, and nerves play various physiologic roles, and tranexamic acid inhibition of these receptors may contribute to adverse drug effects.