title: Tranexamic acid concentrations associated with human seizures inhibit glycine receptors.
abstract: Antifibrinolytic drugs are widely used to reduce blood loss during surgery. One serious adverse effect of these drugs is convulsive seizures; however, the mechanisms underlying such seizures remain poorly understood. The antifibrinolytic drugs tranexamic acid (TXA) and ε-aminocaproic acid (EACA) are structurally similar to the inhibitory neurotransmitter glycine. Since reduced function of glycine receptors causes seizures, we hypothesized that TXA and EACA inhibit the activity of glycine receptors. Here we demonstrate that TXA and EACA are competitive antagonists of glycine receptors in mice. We also showed that the general anesthetic isoflurane, and to a lesser extent propofol, reverses TXA inhibition of glycine receptor-mediated current, suggesting that these drugs could potentially be used to treat TXA-induced seizures. Finally, we measured the concentration of TXA in the cerebrospinal fluid (CSF) of patients undergoing major cardiovascular surgery. Surprisingly, peak TXA concentration in the CSF occurred after termination of drug infusion and in one patient coincided with the onset of seizures. Collectively, these results show that concentrations of TXA equivalent to those measured in the CSF of patients inhibited glycine receptors. Furthermore, isoflurane or propofol may prevent or reverse TXA-induced seizures.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Irene
authors.initials: I
authors.lastname: Lecker
authors.forename: Dian-Shi
authors.initials: DS
authors.lastname: Wang
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Romaschin
authors.forename: Mark
authors.initials: M
authors.lastname: Peterson
authors.forename: C David
authors.initials: CD
authors.lastname: Mazer
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015119:Aminocaproic Acid / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D007611:Aprotinin / Q000494:pharmacology; D001667:Binding, Competitive; D002478:Cells, Cultured; D058787:GABA-A Receptor Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D005998:Glycine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D007530:Isoflurane / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D015742:Propofol / Q000494:pharmacology; D011485:Protein Binding; D011963:Receptors, GABA-A / Q000378:metabolism; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced*; D013116:Spinal Cord / Q000473:pathology; D009435:Synaptic Transmission / Q000187:drug effects; D014148:Tranexamic Acid / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D005680:gamma-Aminobutyric Acid; D014148:Tranexamic Acid; D007611:Aprotinin; D007530:Isoflurane; D005998:Glycine; D015119:Aminocaproic Acid; D015742:Propofol