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Ketamine and midazolam decrease cerebral blood flow and consequently their own rate of transport to the brain: An application of mass balance pharmacokinetics with a changing regional blood flow

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Abstract

Mass balance pharmacokinetics, with simultaneous blood sampling from an artery and the internal jugular vein, was used to characterize the cerebral uptake of ketamine, norketamine, and midazolam in normoventilated pigs. Intravenous injections of ketamine or midazolam decreased the cerebral blood flow (CBF)by one third, as measured by intermittent 133Xewashout. By means of pharmacodynamic models, the effects on the CBFcould be predicted from the arterial drug concentrations. The high-resolution CBFvs. time curves thus generated allowed the calculation of cerebral drug levels from arteriovenous concentration gradients in spite of a continuously changing regional blood flow. By their effects on the CBF,ketamine and midazolam decreasetheir own rateof transport to the brain, the immediate 30-35% drops in CBFgiving similar reductions in initial net influx of drug. Physiological pharmacokinetic models assuming a constant regional blood flow are therefore not appropriate. Under clinical conditions, the CBFis determined mainly by the effects of the anesthetics and by the arterial CO 2 tension. CBFchanges in either direction influence the transport of drugs to the brain and may consequently result in impaired or exaggerated drug effects.

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Author information

Correspondence to Sven Björkman.

Additional information

The study was supported by grants from the Swedish Medical Research Council (B91-14X-00084-27A), the Medical Faculty at Lund University, Malmö General Hospital, The Tore Nilsson Foundation for Medical Research, Warner-Lambert Scandinavia AB, Roche-Produkter AB, and the Laerdal Foundation for Acute Medicine.

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Björkman, S., åkeson, J., Nilsson, F. et al. Ketamine and midazolam decrease cerebral blood flow and consequently their own rate of transport to the brain: An application of mass balance pharmacokinetics with a changing regional blood flow. Journal of Pharmacokinetics and Biopharmaceutics 20, 637–652 (1992). https://doi.org/10.1007/BF01064423

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Key words

  • ketamine
  • midazolam
  • mass balance
  • brain
  • cerebral blood flow