Pharmacokinetics and Pharmacodynamics of Alpha2-Adrenergic Agonists

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Alpha2-adrenergic receptor agonists have been used for decades in veterinary medicine for their beneficial properties of sedation and analgesia. The α2-adrenergic receptor is a G-protein coupled receptor which is found in numerous tissues throughout the body; thus, drugs which bind to the receptor elicit a wide variety of pharmacologic effects. Agonists bound to receptors within the central nervous system result in sedation and analgesia, while those bound to receptors in the peripheral vasculature result in vasoconstriction. A combination of both central and peripheral receptor binding ultimately results in the undesirable effects of biphasic blood pressure alterations and significant bradycardia. Though an abundant amount of information has been obtained looking at the clinical effects of these drugs, published literature characterizing the pk analysis and pharmacodynamic analysis relationships is sparse.

The objectives of the present studies are to 1) determine individual horses' PK profiles for detomidine, medetomidine and dexmedetomidine in the horse and evaluate the associated physiological changes, 2) determine the PK profiles for each drug using a population analysis, and 3) develop a mechanism-based PK/PD model to describe the changes in head height and heart rate for all three drugs and changes in blood glucose concentrations for medetomidine and dexmedetomidine.

To evaluate the three drugs, three separate studies were conducted on eight horses from different populations. Individual PK analysis was conducted with WinNonlin and population PK/PD analysis was conducted with MONOLIX software. Population analysis used a nonlinear mixed effect model and incorporation of a minimal-physiological PK model was used for estimation of PK parameters. Pharmacodynamic analysis utilized an indirect response model to account for the transduction process associated with the receptor being G-protein coupled. Estimation of PK parameters revealed these drugs have relatively short half lives and large volumes of distribution. Comparison of PD estimates for the inhibitory concentrations related to sedation and bradycardia are multiple times larger for detomidine than medetomidine and dexmedetomidine, while the concentrations for dexmedetomidine are half that of medetomidine. Detomidine has a greater inhibitory effect on heart rate and medetomidine has a greater influence on changes in glucose. The proposed models presented in the current studies allow for quantification of PK/PD relationship and provide a framework which can be extended to models that incorporate complexities such as other mechanistic processes.