Efecto clínico de la inyección intramuscular de alfaxalona sola o en combinación con dexmedetomidina y estudio farmacocinético-farmacodinámico en la especie felina

Abstract

Summary: Clinical effect of intramuscular administration of alfaxalone alone or in combination with dexmedetomidine and pharmacokinetic-pharmacodynamic study in feline The objectives are: o To study the sedative and/or anaesthetic effect of intramuscular administration of alfaxalone administered alone or in combination with dexmedetomidine in feline. o To determine the cardiorespiratory effects observed in cats after intramuscular use of these combinations. o To conduct a comparative pharmacokinetic and pharmacodynamic study following intramuscular and inytravenous administration of alfaxalone in feline. First Experience A blinded, randomized crossover study with a washout period of 15 days. Seven adult cats (body weight 3.5 ± 0.7 kg; age 3.8 ± 0.9 years) were assigned randomly to each of three treatments: A5 (alfaxalone 5 mg kg-1), D20A5 (dexmedetomidine 20 ?g kg-1 and alfaxalone 5 mg kg-1) and D40A5 (dexmedetomidine 40 ?g kg-1 and alfaxalone 5 mg kg-1). Drugs were administered intramuscularly into the epaxial muscles. Sedation or anaesthesia scores were evaluated by a modified numerical rating scale. Times to extubation, head-lift, sternal recumbency and standing were recorded. Heart and respiratory rates, systolic arterial pressure, arterial oxygen saturation of haemoglobin, end-tidal carbon dioxide tension and rectal temperature were measured at 5, 10, 15, 20, 30, 45, 60, 90, 120 and 150 minutes after drug administration. Adverse events were recorded. Data were analysed by one-way ANOVA with Tukey&apos;s post-hoc test for parametric values and, for non-normally distributed parameters, aKruskal-Wallis test and Mann-Whitney U-test for two independent samples (p < 0.05). Sedation scores were significantly different among the treatments. Cats in A5 were moderately to deeply sedated, whereas cats receiving dexmedetomidine reached a state compatible with general anaesthesia. The onset of action and the duration of anaesthesia were related to the dose of dexmedetomidine. Cardiorespiratory parameters remained stable in the A5 group. Lower heart rates, higher systolic blood pressures and occasional low pulse oximetry readings were observed in the dexmedetomidine groups. A limited number of adverse events (hyperkinesia, emesis) occurred during recovery. Alfaxalone administered intramuscularly at 5 mg kg-1 induced moderate to deep sedation in cats. The addition of dexmedetomidine at 20 and 40 ?g kg-1 to alfaxalone induced general anaesthesia. Second experience In a crossover experimental study, alfaxalone (5 mg kg-1) was administered intravenously and intramuscularlyin 5 European shorthair cats (body weight 4.2 ± 0.5 kg; age 3.8 ± 0.9 years). The intramuscular injections were administered in the epaxial muscles. Blood samples were collected from the jugular vein at predetermined times and plasma concentrations measured by a high performance liquid chromatography method with fluorescence detection. The plasma concentration-time curves were analysed by non-compartmental methods using WinNonlin v.5.1.1. The achieved sedation/anaesthesia was evaluated by a modified numerical scale previously described. Data are expressed as mean ± SD. Pharmacokinetics parameters were analyzed by a t-student for parametric and a Wilcoxon Rank Sum test for non-parametric data, and clinical effects by Kruskal-Wallis and Mann Whitney U tests (p < 0.05). Absorption after intramuscular administration was moderately rapid (tmax 0.35 ± 0.14 hours) reaching a Cmax of 1,009.86 ± 157.36 µg L-1. Bioavailability was 91.32 ± 9.73%. Mean half-life (1.33 ± 0.15 h) and mean residence time (2.11 ± 0.32 h) were significantly longer after intramuscular compared to intravenous administration (0.73 ± 0.20 and 0.84 ± 0.21 h, respectively) (p = 0.0012; 0.0024). Mean absorption time showed that the disposition of alfaxalone after intramuscular administration follows a flip-flop model, in which absorption is a limitant factor for drug elimination. For that reason, mean half-life is significantly prolonged after intramuscular compared to intravenous administration. Clearance after intravenous administration was 1.53 ± 0.31 L kg-1 h-1. Alfaxalone bioavailability following intramuscular administration at a dose of 5 mg kg-1 in cats was very high (91.32%). A rapid and profound anaesthetic effect lasting 15 minutes was observed after intravenous administration. Intramuscular alfaxalone showed a slower effect compatible with deep sedation from 15 to 45 minutes. Pharmacokinetic profile of alfaxalone after intramuscular administration was correlated with the onset of action and duration of the sedative effects observed in this study.