Pharmacodynamic effects and pharmacokinetic profile of a long‐term continuous rate infusion of racemic ketamine in healthy conscious horses

Abstract

effects and pharmacokinetic profile of a long-term continuous rate infusion of racemic ketamine in healthy conscious horses. J. vet. Pharmacol. Therap. 29,[477][478][479][480][481][482][483][484][485][486][487][488] Ketamine (KET) possesses analgesic and anti-inflammatory activity at subanesthetic doses, suggesting a benefit of long-term KET treatment in horses suffering from pain, inflammatory tissue injury and/or endotoxemia. However, data describing the pharmacodynamic effects and safety of constant rate infusion (CRI) of KET and its pharmacokinetic profile in nonpremedicated horses are missing. Therefore, we administered to six healthy horses a CRI of 1.5 mg/kg/h KET over 320 min following initial drug loading. Cardiopulmonary parameters, arterial blood gases, glucose, lactate, cortisol, insulin, nonesterified fatty acids, and muscle enzyme levels were measured, as were plasma concentrations of KET and its metabolites using liquid chromatographytandem mass spectrometry (LC-MS/MS). Levels of sedation and muscle tension were scored. Respiration and heart rate significantly increased during the early infusion phase. Glucose and cortisol significantly varied both during and after infusion. During CRI all horses scored 0 on sedation. All but one horse scored 0 on muscle tension, with one mare scoring 1. All other parameters remained within or close to physiological limits without significant changes from pre-CRI values. The mean plasma concentration of KET during the 1.5 mg/kg/h KET CRI was 235 ng/mL. The decline of its plasma concentration-time curve of both KET and norketamine (NKET) following the CRI was described by a twocompartmental model. The metabolic cascade of KET was NKET, hydroxynorketamine (HNK), and 5,6-dehydronorketamine (DHNK). The KET median elimination half-lives (t 1/2a and t 1/2b ) were 2.3 and 67.4 min, respectively. The area under the KET plasma concentration-time curve (AUC), elimination was 76.0 lgAEmin/mL. Volumes of C 1 and C 2 were 0.24 and 0.79 L/kg, respectively. It was concluded that a KET CRI of 1.5 mg/kg/h can safely be administered to healthy conscious horses for at least 6 h, although a slight modification of the initial infusion rate regimen may be indicated. Furthermore, in the horse KET undergoes very rapid biotransformation to NKET and HNK and DHNK were the major terminal metabolites.(Paper

CE provides evidence of the stereoselective hydroxylation of norketamine in equines

“…They found 4-hydroxyketamine and new metabolites, including 3,4-dehydronorketamine, deaminonorketamine, 5,6-deaminodehydronorketamine and two methoxyketamine isomers, but no hydroxylated norketamine metabolites. Ketamine, norketamine, hydroxynorketamine and 5,6-dehydronorketamine levels were determined by LC-MS in liquid/ liquid extracts of equine plasma after single intravenous administration as well as during and following continuous rate infusion of racemic ketamine [24].…”

Neuropathic Pain Management in Chronic Laminitis

“…A CRI of 400-1500 µg•kg -1 •hr -1 has been used safely in conscious horses. 140 However, with both infusion regimens the measured plasma ketamine concentrations were about 10 times below concentrations (2-4 µg/mL) associated with measurable acute antinociceptive effects. 141 Matthews et al 142 administered ketamine via infusion (400 and 800 µg•kg -1 •hr -1 ) for up to 5 days in eight horses with osteomyelitis, septic joint disease, burns, or colic in a search for possible analgesic effects.…”

The effect of romifidine, ketamine and lidocaine on the thermal nociceptive threshold in horses

“…Ketamin wird in der Pferdemedizin vor allem als dissoziatives Anästhetikum genutzt. Es hat jedoch auch einen analgetischen Effekt, wenn es bei Pferden in subanästhetischen Dosierungen eingesetzt wird (Fielding et al 2006, Lankveld et al 2006, Peterbauer et al 2008, wobei keine sedierende Wirkung bei entsprechenden Dosierungen und Plasmakonzentrationen nachgewiesen werden konnte (Lankveld et al 2006). …”

“…Das Gerät erzeugt einen thermischen Stimulus mittels eines Heizelements, welches direkt auf der Haut des Tieres aufgebracht wird (Dixon et al 2002). Die Überprüfung der Effekte von Analgetika mit Hilfe des thermischen nozizeptiven Schwellenwertes erwies sich in mehreren Studien am Tier als geeignet (Dixon et al 2002, Love et al 2011, Poller 2013a (Zielmann et al 1997, Lankveld et al 2006. Dieser Effekt erklärt den Anstieg der Herzfrequenz in der Ket-Gruppe zum Zeitpunkt T30.…”