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A new-ish canine sedative

Zenalpha® is a newly approved combination of medetomidine (0.5 mg/mL) and the peripheral alpha-2 antagonist vatinoxan (10 mg/mL), designed to provide sedation through activation of alpha-2 receptors in the CNS while preventing the peripherally mediated vasoconstriction and reflex bradycardia caused by vascular alpha-2 receptors.

In order to understand this drug and its putative advantages over solo alpha-2 agonists, let’s take a close look at the mechanisms of action. Alpha-2 receptors are distributed throughout the central and peripheral nervous system and mediate the release of norepinephrine, with presynaptic receptors forming an inhibitory feedback loop. Sedation, anxiolysis, and analgesia as provided by alpha-2 agonist drugs such as detomidine and dexmedetomidine are a result of a decrease in release of norepinephrine in the CNS.

This is a totally anatomically and physiologically accurate drawing of what happens at the cellular level rendered by yours truly. Alpha-2 agonists interact with the presynaptic alpha-2 receptor to decrease norepinephrine release. It is worth noting that this mechanism explains why extremely stressed patients (that is, patients who are sympathetically wound up and dumping norepi left and right) may not respond well or fight through the sedation provided by alpha-2 agonists.

The sometimes dramatic hemodynamic effects of alpha-2 agonist drugs however are due to postsynaptic activation of alpha-2 receptors on arteries and veins leading to a reflex bradycardia (which in turn is mediated by increased baroreceptor activity and subsequent modification of autonomic input to the heart). The increase in afterload increases myocardial work and halves cardiac output and oxygen delivery. These cardiovascular effects are only somewhat dose dependent and reach a ceiling effect at very low doses (Pypendop & Verstegen 1998). Eventually, the peripheral vasoconstriction wears off and there is a transition to a centrally-mediated sympatholysis. At this point, bradycardia continues but systemic vascular resistance decreases. This decrease in sympathetic tone is the basis for the idea of dexmedetomidine providing “cardiovascular stability” in human patients and also why oral alpha-2 agonists have been used as an anti-hypertensive agents for people. Note that dexmedetomidine is typically used in humans at comparatively low doses and as an infusion.

Vatinoxan will antagonize the peripheral hemodynamic effects of medetomidine but since it is excluded from the CNS, it does not interfere greatly with the sedation or analgesia provided by administration of alpha-2 agonists. This means that we can avoid the sometimes disturbing cardiovascular effects of alpha-2 agonists while still achieving profound sedation and analgesia. For example, Rolfe et al. (2012) determined that cardiac output (CO), heart rate (HR), and oxygen delivery (DO2) were higher and mean arterial pressure lower in dogs administered an intramuscular combination of medetomidine at 20 mcg/kg and vatinoxan (then known as MK-467) at 0.4 mg/kg. Generally, their findings were similar for IV administration of half those doses to the same dogs (i.e. medetomidine 10 mcg/kg and vatinoxan 0.2 mg/kg). It should be noted however that although vatinoxan attenuated the cardiovascular effects of medetomidine, it did not completely eliminate them, and when compared to baseline CO, HR, and DO2 were lower after the administration of the combination of drugs - just not as low as medetomidine alone. It also appears that the immediate cardiovascular effects of medetomidine may still occur but are lessened over time by the co-administration of vatinoxan (Restitutti et al. 2017).

No matter what drug combination you choose, the most important thing you can do to increase safety for sedated patients is to have a highly trained, dedicated technician monitoring them closely at all times. Being a veterinary technician is sometimes physically challenging, often messy, and rarely glamorous but essential to high quality patient care. Have you hugged your veterinary technician today?

Onset of sedation appears to be a little faster and of shorter duration than medetomidine alone. In addition, intensity and duration of analgesia may be somewhat reduced by the combination of vatinoxan with medetomidine. This is thought to be due to the fact cardiac output remains relatively higher, resulting in a larger volume of distribution, increased perfusion of clearance organs, and lower plasma concentration (Honkavaara et al. 2012; Bennet et al. 2016).

I haven’t used Zenalpha yet but am looking forward to the opportunity to see how it handles on the clinic floor. I suspect that I may not find it all that glorious compared to the way in which I tend to use dexmedetomidine in the perioperative time period, that is, at low doses (~2 – 5 mcg/kg) or as an infusion (~0.25 – 1 mcg/kg/hr). In fact, I could see the lack of vasoconstriction prior to administration of inhalant anesthetics being a bit of a bummer at times. But I do think that for short, minimally invasive procedures requiring sedation (e.g. imaging, laceration repair with local anesthesia etc.), Zenalpha® might make for a somewhat less tense monitoring experience for the anesthetist.

It seems like a good thing to attenuate the profound increase in afterload and resulting cardiovascular fallout caused by alpha-2 agonists and I am willing to bet that Zenalpha® will be sold as a “safer” alternative to dexmedetomidine, but it remains to be seen if this combination actually results in improved clinical safety or better outcomes. I generally believe that improved education and training of veterinary anesthetists will garner larger improvements in patient safety than small refinements of the cardiorespiratory toxins currently necessary to induce sedation and anesthesia.


Bennett, R. C., Salla, K. M., Raekallio, M. R., Hänninen, L., Rinne, V. M., Scheinin, M., & Vainio, O. M. (2016). Effects of MK-467 on the antinociceptive and sedative actions and pharmacokinetics of medetomidine in dogs. Journal of veterinary pharmacology and therapeutics, 39(4), 336–343.

Honkavaara, J., Restitutti, F., Raekallio, M., Salla, K., Kuusela, E., Ranta-Panula, V., Rinne, V., Vainio, O., & Scheinin, M. (2012). Influence of MK-467, a peripherally acting α2-adrenoceptor antagonist on the disposition of intravenous dexmedetomidine in dogs. Drug metabolism and disposition: the biological fate of chemicals, 40(3), 445–449.

Restitutti, F., Kaartinen, M. J., Raekallio, M. R., Wejberg, O., Mikkola, E., Del Castillo, J., Scheinin, M., & Vainio, O. M. (2017). Plasma concentration and cardiovascular effects of intramuscular medetomidine combined with three doses of the peripheral alpha2-antagonist MK-467 in dogs. Veterinary anaesthesia and analgesia, 44(3), 417–426.

Rolfe, N. G., Kerr, C. L., & McDonell, W. N. (2012). Cardiopulmonary and sedative effects of the peripheral α2-adrenoceptor antagonist MK 0467 administered intravenously or intramuscularly concurrently with medetomidine in dogs. American journal of veterinary research, 73(5), 587–594.

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