Abstract
The pharmacodynamic (PD) interaction between the benzodiazepine agonist midazolam and the α2-adrenergic agonist dexmedetomidine was characterized for defined measures of anesthetic action and cardiovascular and ventilatory side effects in 33 rats. For various combinations of constant plasma concentrations of midazolam (0.1–20 μg/ml) and dexmedetomidine (0.3–19 ng/ml) obtained by target-controlled infusion, the whisker reflex (WR), righting reflex (RR), startle reflex to noise (SR), tail clamp response (TC), and corneal reflex (CR) were assessed. EEG (power in 0.5–3.5-Hz frequency band), mean arterial pressure, and heart rate were recorded continuously. Blood gas values and arterial drug concentrations were determined regularly. The nature and extent of PD interaction was quantified by the model parameter synergy (SYN < 0, antagonism; SYN = 0, additivity; andSYN > 0, synergy). With increasing drug concentrations WR was lost first, followed by RR, SR, TC, and CR. These effects were accompanied by an increase of the EEG measure. The drug interaction was synergistic for all stimulus-response measures and the degree of synergy increased with deeper levels of central nervous system depression (SYN was 7.3, 145, 560, 374, and 1490 for WR, RR, SR, TC, and CR, respectively). The cardiovascular side effects of dexmedetomidine, evaluated at similar PD endpoints, were reduced in the presence of midazolam. Ventilatory side effects were minor for all drug combinations. The nature and extent of the PD interactions were not reflected in the EEG measure.
Footnotes
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Send reprint requests to: Cornelis J.J.G. Bol, Ph.D., Department of Clinical Pharmacokinetics, Janssen Pharmaceutica, B-2340 Beerse, Belgium. E-mail: kbol{at}janbe.jnj.com
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↵1 This study was supported in part by a National Institutes of Health Shannon Award GM-51309. This research was conducted at the Department of Anesthesia, Stanford University School of Medicine, Stanford, CA.
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↵2 Current address: Department of Clinical Pharmacokinetics, Janssen Pharmaceutica, Beerse, Belgium.
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↵3 Current address: Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.
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↵4 Current address: Department of Nonclinical Drug Safety, Hoffman-La Roche, Nutley, NJ.
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↵5 Current address: Pharsight Corporation, Mountain View, CA.
- Abbreviations:
- CNS
- central nervous system
- PK
- pharmacokinetic
- PD
- pharmacodynamic
- bpm
- beats per minute
- RR
- righting reflex
- MAP
- mean arterial pressure
- TCI
- target-controlled infusion
- WR
- whisker reflex
- SR
- startle reflex to noise
- TC
- tail clamp response
- CR
- corneal reflex
- SYN
- synergy
- N
- steepness of the curves
- GABA
- γ-aminobutyric acid
- Received November 4, 1999.
- Accepted March 15, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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