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: Irene Lecker, Dian-Shi Wang, Alexander D Romaschin, Mark Peterson, C David Mazer, Beverley A Orser
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 122 Issue 12 Pg. 4654-66 (Dec 2012) ISSN: 1558-8238 [Electronic] United States
• PMID: 23187124 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• GABA-A Receptor Antagonists
• Receptors, GABA-A
• Receptors, Glycine
• gamma-Aminobutyric Acid
• Tranexamic Acid
• Aprotinin
• Isoflurane
• Glycine
• Aminocaproic Acid
• Propofol

Topics

• Adult
• Aged
• Aged, 80 and over
• Aminocaproic Acid (adverse effects, pharmacology)
• Animals
• Anticonvulsants (pharmacology)
• Aprotinin (pharmacology)
• Binding, Competitive
• Cells, Cultured
• GABA-A Receptor Antagonists (adverse effects, pharmacokinetics, pharmacology)
• Glycine (pharmacology)
• Humans
• In Vitro Techniques
• Inhibitory Concentration 50
• Inhibitory Postsynaptic Potentials (drug effects)
• Isoflurane (pharmacology)
• Membrane Potentials (drug effects)
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Middle Aged
• Neurons (drug effects, metabolism, physiology)
• Patch-Clamp Techniques
• Propofol (pharmacology)
• Protein Binding
• Receptors, GABA-A (metabolism)
• Receptors, Glycine (antagonists & inhibitors)
• Seizures (chemically induced)
• Spinal Cord (pathology)
• Synaptic Transmission (drug effects)
• Tranexamic Acid (adverse effects, pharmacokinetics, pharmacology)
• Young Adult
• gamma-Aminobutyric Acid (pharmacology)