The haemodynamic and pharmacologic interaction of medetomidine and peripheral antagonist MK-467 and their dose-dependency in dogs

The alpha-2 agonist, medetomidine (MED), and its pure active enantiomer dexmedetomidine (DMED), are used clinically in small animal practice as potent sedatives, analgesic agents, muscle relaxants, and as adjunct agents for balanced anaesthesia. However, their cardiovascular effects limit their use. The use of constant rate infusion (CRI) for administration of MED was studied in order to provide the sedation and analgesia while decreasing the adverse cardiovascular effects. The second avenue of investigation performed was addition of the peripheral alpha-2 antagonist, MK-467, to limit the haemodynamic effects of MED. The cardiovascular effects of MED CRI were investigated in a dose-finding study. Six dose levels were administered during general anaesthesia from very-low dose to a high, positive-control dose, in order to quantify dose-dependency. In order to elucidate an appropriate agonist-antagonist dose ratio, a step-down infusion protocol of MED and addition of step-up infusion protocol of MK-467 was performed in anaesthetised dogs. The effects and interaction of both drugs during the absorption and distribution phase were studied during an intramuscular study protocol using a co-administration of both drugs, where three doses of MK-467 were investigated. Plasma concentration measurements provided pharmacokinetic parameter estimates. MED-CRI administration showed promising results in demonstrating the dosedependency of the cardiovascular effects. With the low doses of MED CRI, the adverse effects may be minimised, although not completely avoided. A complex pharmacokinetic and pharmacodynamic interaction between the two molecules was revealed; after intramuscular (IM) co-administration of both drugs the absorption of MED was accelerated by the addition of MK-467 to the treatment. The step infusions revealed that MK-467 also increased the elimination of MED. The optimal dose ratio finding is complicated as the context in which the drugs are given (IM, IV, CRI, under general anaesthesia etc.) affects the disposition of MED. The combined pharmacokinetic and dynamic results provide good initial pharmacokinetic estimates for future PK-PD modelling to predict the interaction of these two drugs, MED and MK-467, in dogs. List of Original publications This thesis is based on the following original articles referred to in the text by their Roman numerals: