Reduction and reversal of the undesirable effects of medetomidine with two α2-adrenoceptor antagonists, vatinoxan and atipamezole, in sedated and ketamine-anaesthetized dogs

α₂-Adrenoceptor agonists, such as medetomidine and dexmedetomidine are considered to produce reliable sedation, muscle relaxation, and antinociception when used as sedatives or preanaesthetics. One important advantage is that their effects can be reversed with an α₂-adrenoceptor antagonist, atipamezole. However, notable cardiovascular depression associated with α₂-adrenoceptor agonists limit their use to healthy animals. A peripheral α₂-adrenoceptor antagonist vatinoxan (also known as MK-467 and L 659´066) has been shown to reduce these cardiovascular disturbances, without markedly affecting sedation after concomitant use with dexmedetomidine or medetomidine. Vatinoxan is therefore proposed to improve the clinical utility of α₂-adrenoceptor agonists in dogs. The main aim of this series of experiments was to investigate the reduction of medetomidine-induced cardiovascular changes with vatinoxan, atipamezole and ketamine, not only in laboratory dogs, but also in healthy client-owned dogs of various breeds in a clinical environment. The secondary aim was to assess the quality of sedation, hypnosis and recovery when these drugs interacted together. Two of the studies were performed under laboratory conditions with eight purpose-bred beagle dogs that were instrumented prior to each experiment. Heart rate, mean arterial pressure, central venous pressure, cardiac output and arterial blood gas partial pressures were measured and sedation was assessed. Blood samples were collected for plasma drug concentration analyses. Study Ⅰ aimed to investigate the ability of atipamezole to reverse the cardiovascular and sedative effects of medetomidine in the presence or absence of vatinoxan. Study Ⅱ aimed to explore the influence of vatinoxan on the cardiovascular function and quality of anaesthesia and recovery, when the dogs were premedicated with medetomidine and butorphanol, followed by ketamine, and subsequent reversal with atipamezole. In study Ⅲ the clinical utility of vatinoxan was then evaluated in client-owned dogs, sedated with medetomidine and butorphanol combination for non-invasive diagnostic imaging. The need for atipamezole reversal was also monitored. Plasma concentrations of the studied drugs were determined in each study to detect the influence of vatinoxan. In study Ⅰ, atipamezole failed to permanently increase heart rate or cardiac index without the presence of vatinoxan when administered intramuscularly 30 minutes after medetomidine. Momentary decrease in mean arterial pressure was observed shortly after atipamezole administration with and without vatinoxan. However, no clinically relevant hypotension was detected. Atipamezole reversed the sedative effect of medetomidine more efficiently with than without vatinoxan, probably due to increased plasma clearance of medetomidine. Relapse into sedation after intial arousal was observed during recovery when vatinoxan was not included in the treatment. The medetomidine-induced increase in systemic vascular resistance index was attenuated by vatinoxan, with significantly lower values observed throughout the studies Ⅰ and Ⅱ in its presence. Medetomidine-evoked bradycardia and decrease in cardiac index were similarly mitigated by vatinoxan in all of the present studies. In study Ⅱ, heart rate and cardiac index increased temporarily after ketamine administration and the effect was potentiated by vatinoxan. Ketamine decreased mean arterial pressure and mild hypotension was detected in two out of eight laboratory dogs that were given vatinoxan premedication. Hypotension was abolished by atipamezole administration at 60 minutes following ketamine. Vatinoxan reduced the exposure to ketamine. Therefore, the duration of anaesthesia was shorter in the presence of vatinoxan. The quality of recovery after atipamezole was impaired by nausea and increased need to defaecate with and without vatinoxan. In study Ⅲ, intramuscular medetomidine-butorphanol combination with and without vatinoxan provided reliable sedation for diagnostic imaging procedure. Vatinoxan hastened and increased the peak plasma concentrations of intramuscularly co-administered medetomidine and butorphanol. The clinically observed benefit was a faster onset of deeper sedation. Mean heart rate in the treatment group with vatinoxan during the study was approximately 50% higher than in the group without vatinoxan. Atipamezole was required less frequently to reverse medetomidine-evoked sedation when vatinoxan was included in the treatment because of shorter duration of sedation. To conclude, the two α₂-adrenoceptor antagonists, vatinoxan and atipamezole, interacted favourably in medetomidine-sedated dogs. Together they provided more complete reversal of medetomidine’s effects. While medetomidine-induced cardiovascular changes were transiently attenuated by ketamine and atipamezole, more complete improvement in haemodynamics was observed only in the presence of vatinoxan. Although vatinoxan premedicated dogs were more prone to hypotension during ketamine anaesthesia, heart rate and cardiac index were well maintained. The clinical utility of vatinoxan with medetomidine and butorphanol was demonstrated in a clinical trial. Vatinoxan alleviated the medetomidine-induced bradycardia and the drug combination including vatinoxan provided adequate sedation to complete short, non-invasive procedures. Faster decline in the plasma concentrations of co-administered drugs in the presence of vatinoxan was clinically manifested as shorter duration of sedation and anaesthesia when compared to treatment without vatinoxan.

Koirien rauhoituksessa ja anestesian esilääkityksessä yleisesti käytetyllä medetomidiini lääkeaineella on hyödyllisen, rauhoittavan ja lihaksia rentouttavan sekä kivun tuntemusta lievittävän ominaisuuden lisäksi haitallinen sydämen ja verenkiertoelimistön toimintaa heikentävä vaikutus. Tutkimusten tarkoituksena oli selvittää, miten medetomidiinin aiheuttamia haittavaikutuksia voitaisiin vähentää vastavaikuttavilla lääkeaineilla, vatinoksaanilla ja atipametsolilla, sekä sydän- ja verenkiertoelimistön toimintaa stimuloivalla anestesialääkkeellä, ketamiinilla. Vatinoksaani lievittää medetomidiinin ääreiskudoksissa aikaansaamaa verisuonten supistumista, verenpaineen nousua ja sydämen sykkeen sekä minuuttitilavuuden laskua. Vatinoksaani ei läpäise merkittävissä määrin veriaivoestettä, joten se ei kumoa medetomidiinin keskushermostovaikutuksia. Atipametsoli puolestaan kumoaa samanaikaisesti sekä medetomidiinin sydän- ja verenkiertoelimistöön kohdistuvat haitat, että keskushermoston kautta välittyvän rauhoitusvaikutuksen. Vatinoksaanin ja atipametsolin yhteisvaikutuksia tutkivassa kokeessa havaittiin, että atipametsoli ei pystynyt kumoamaan medetomidiinin sydän- ja verenkiertovaikutuksia. Yhdessä vatinoksaanin kanssa medetomidiinin epätoivotut vaikutukset sen sijaan kumoutuivat merkittävästi paremmin ja atipametsolin rauhoittumisen kumoava vaikutus oli täydellisempi. Sydän- ja verenkiertoelimistön toiminta tehostui merkittävästi, kun ketamiinia annosteltiin suonensisäisesti anestesian aikaansaamiseksi lihakseen annetun medetomidiini-butorfanoli esirauhoituksen jälkeen. Vatinoksaani voimisti ketamiinin hyödyllisiä, sydämen sykettä ja minuuttitilavuutta kohottavia vaikutuksia, vaikkakin kahdella kahdeksasta koirasta havaittiin matala verenpaine. Ketamiinin aikaansaaman anestesian kesto jäi lyhyemmäksi vatinoksaania esirauhoituksen yhteydessä saaneilla koirilla. Tämä oli todennäköisesti seurausta sydän- ja verenkiertoelimistön parantuneesta toiminnasta ja sen seurauksena ketamiinin kiihtyneestä poistumisesta. Kliinisessä kenttäkokeessa potilaskoirilla havaittiin, että vatinoksaani tehosti sen kanssa yhdessä lihakseen annetun medetomidiini-butorfanoli esilääkitykseen imeytymistä ja nopeutti täten rauhoitusvaikutuksen alkua. Rauhoituksen kokonaiskesto oli vatinoksaanin vuoksi lyhyempi ja rauhoitus täytyi harvemmin kumota atipametsolilla. Vatinoksaani nosti koirien keskimääräistä syketasoa merkittävästi, noin 50 prosentilla, rauhoituksen aikana. Vatinoksaani vaikuttaisi lisäävän medetomidiinin kliinistä käyttökelpoisuutta koirilla sen sydän- ja verenkiertoelimistön toimintaa parantavan vaikutuksen vuoksi.