γ-Aminobutyric acid type A (GABAA) receptor agonists are known to cause involuntary muscle movements. The mechanism of these movements is not known, and its relationship to depth of anesthesia monitoring is unclear. We have explored the effect of involuntary muscle movement on the pharmacokinetic-pharmacodynamic model for the GABAA receptor agonist ABP-700 and its effects on the Bispectral Index (BIS) as well as the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scores.
Observations from 350 individuals (220 men, 130 women) were analyzed, comprising 6,312 ABP-700 concentrations, 5,658 ABP-700 metabolite (CPM-acid) concentrations, 25,745 filtered BIS values, and 6,249 MOAA/S scores, and a recirculatory model developed. Various subject covariates and pretreatment with an opioid or a benzodiazepine were explored as covariates. Relationships between BIS and MOAA/S models and involuntary muscle movements were examined.
The final model shows that the pharmacokinetics of ABP-700 are characterized by small compartmental volumes and rapid clearance. The BIS model incorporates an effect-site for BIS suppression and a secondary excitatory/disinhibitory effect-site associated with a risk of involuntary muscle movements. The secondary effect-site has a threshold that decreases with age. The MOAA/S model did not show excitatory effects.
The GABAA receptor agonist ABP-700 shows the expected suppressive effects for BIS and MOAA/S, but also disinhibitory effects for BIS associated with involuntary muscle movements and reduced by pretreatment. Our model provides information about involuntary muscle movements that may be useful to improve depth of anesthesia monitoring for GABAA receptor agonists.
- The γ-aminobutyric acid type A receptor agonist cyclopropyl-methoxycarbonyl metomidate (ABP-700), a second-generation analog of etomidate, produces a rapid onset of sedation and deep general anesthesia
- Side effects of ABP-700 include excitatory phenomena such as involuntary muscle movements
- The effects of involuntary muscle movement on pharmacokinetic-pharmacodynamic models of the effects of ABP-700 on the Bispectral Index (BIS) and the Modified Observer’s Assessment of Alertness/Sedation scores were studied using data from 266 individuals
- In the ABP-700 pharmacokinetic-pharmacodynamic model, a secondary disinhibitory effect-site for BIS that functions in opposition to drug effects underlying suppression of the BIS signal was associated with involuntary muscle movements
- The ABP-700 pharmacokinetic-pharmacodynamic model of its effects on Modified Observer’s Assessment of Alertness/Sedation scores did not indicate a relationship between involuntary muscle movement and clinical hypnosis