Pharmacokinetics and pharmacodynamics of intravenous continuous rate infusion and repeated intramuscular administration of dexmedetomidine in standing horses

Abstract

An ideal dexmedetomidine protocol has yet to be determined for standing sedation in horses. It was hypothesized that an IV bolus followed by CRI dexmedetomidine would have a quicker increase in plasma concentrations compared with repeated IM injections. In a crossover design, eight adult, female horses were randomly placed into two groups: the CRI group (IV bolus dexmedetomidine at 0.005 mg/kg followed by a CRI at 0.01 mg/kg/h for 15 min then 0.005 mg/kg/h for 60 min) and the IM group (dexmedetomidine at 0.01 mg/kg, followed by 0.005 mg/kg in 30‐min intervals for 60 min). Clearance and elimination half‐life were 134 ± 67.4 ml/kg/min and 44.3 ± 26.3 min, respectively, in the CRI group, and apparent clearance and half‐life were 412 ± 306 ml/kg/min (Cl/F) and 38.9 ± 18.6 min, respectively, in the IM group. Analgesia was evaluated using mechanical pressure threshold. Intravenous dexmedetomidine produced faster onset of sedation and increased pressure threshold compared with IM administration. Individual horses had a large variability in dexmedetomidine plasma concentrations between CRI and IM administration. The odds of a decreased GI motility following IV administration was 12.34 times greater compared with IM administration.

Pharmacokinetics of dexmedetomidine in anaesthetized horses following repeated subcutaneous administration and intravenous constant rate infusion

“…As reported by other authors, DEX pharmacokinetics is affected by many factors and it is not simple and properly useful to compare results deriving from different clinical settings and designed for different clinical purposes [ 10 , 12 , 13 ]. Indeed, when considering animals undergoing general anaesthesia, the main factors able to influence DEX pharmacokinetics are represented by the co-administration of drugs within the balanced protocol and the hemodynamic effects on the cardiovascular system induced by anaesthesia itself [ 6 ].…”

“…In the analyses of repeated administration, it has been assumed that DEX followed linear dosing, as the majority of drugs and as previously stated for repeated extravascular administrations of the same drug in horses [ 12 ]. The mean residence time (MRT 0-last ) was determined after SC administration, by using the following equation: MRT 0-last =AUMC 0-last /AUC 0-last whereas for CRI administration it was adjusted by infusion time as follows MRT 0-last = (AUMC 0-last /AUC 0-last ) – (T inf /2), where T inf is the length of infusion.…”

“…Dexmedetomidine (DEX) is the most selective and potent alpha-2-adrenergic receptor agonist that has been investigated in horses as an ideal adjuvant agent for sedation and balanced anaesthesia due to its beneficial pharmacological profile [ 6 , 12 – 14 ].…”

“…In equine practice, the most common DEX administration route employed for either sedation or general anaesthesia is the intravenous one, delivered as a bolus or as a CRI, with several studies that investigated the pharmacokinetics and the pharmacodynamics of this drug for clinical purposes [ 10 , 12 , 13 , 15 – 18 ]. Conversely, information regarding other types of DEX administration routes in horses is limited.…”

“…Conversely, information regarding other types of DEX administration routes in horses is limited. Only two studies explored alternative delivery routes in this species, in the study by Shane et al, (2021) [ 12 ], DEX pharmacokinetic profile and pharmacodynamic properties were determined following CRI and repeated intramuscular injections administered for standing sedation. The other work, recently published by the authors of the present investigation, evaluated DEX clinical effects within the intranaesthetic period and the recovery phase when administered as CRI or following repeated subcutaneous (SC) injections [ 19 ].…”