The Stress Related Neuroendocrine and Metabolic Effects of Alpha-2 Adrenergic Agents and Their Combinations with Injectable Analgesics in Dogs

Abstract

The α2-adrenoceptor agonists, medetomidine and xylazine, are widely used in veterinary practice as sedative, muscle relaxant and analgesic agents for different species. Although α2-agonists are multipotent drugs, they should be used carefully, because unexplained and sometimes fatal accidents may be associated with their use in the healthy small animal patient, even without painful intervention. These are usually associated with the cardiovascular side effects of these drugs. However, whether the neuroendocrine and metabolic effects of α2-agonists are involved in the causes of these accidents are not fully understood. Medetomidine can reduce stress response to surgery as assessed by the attenuation of plasma catecholamine, adrenocorticotrophic hormone and cortisol levels. Stress is a generalised response of the body to various factors, called stressors. Pain, blood loss, excitement, and underlying pathological conditions may all act as stressors in the surgical patient. The endocrine and metabolic stress response is characterised by the increase of catecholamine, cortisol, glucose, and NEFA blood levels, and the decrease of insulin levels. Adrenoceptors play an important role in the co-ordination of these events therefore α2-adrenergic agents may interfere to the pathophysiology of stress response before, during and after anaesthesia. That is why there is an increasing interest in using medetomidine as a pre-anaesthetic adjuvant or as a part of balanced anaesthesia in combination with several analgesics. On the other hand, analgesics also have endocrine and metabolic effects. Because analgesics act on similar receptor systems than the physiological stress-response there are certain analogy between the endocrine effects of analgesics and stress-response. Consequently, the examination of the effects of different analgesics on stress-response is also important. The aim of this study was to examine the stress-related neurohormonal and metabolic effects of α2-adrenergic agents and their combinations with opioid drugs (butorphanol and fentanyl) and ketamine in healthy adult beagle dogs without surgical intervention. In chapter 2, the effects of medetomidine (10, 20, 40 and 80 αg/kg, IM) and xylazine (1, 2, 4 and 8 mg/kg, IM) were compared. Both drugs similarly, dose-dependently inhibited norepinephrine release and lipolysis. Medetomidine suppressed epinephrine release dose-dependently with greater potency than xylazine. Xylazine also tended to decrease epinephrine levels dose-dependently. The cortisol and glucagon levels did not change significantly in any treatment group. Both drugs suppressed insulin secretion and increased glucose levels. The hyperglycaemic effect of medetomidine, in contrast with xylazine, was not dose-dependent at the tested dosages. The results suggested that the effect of medetomidine on glucose metabolism might not be due only to α2-adrenoceptor mediated actions. In chapter 3, the antagonistic effects of atipamezole (40, 120, and 320 αg/kg, IM) and yohimbine (110 αg/kg, IM) were compared 30 minutes following medetomidine (20 αg/kg, IM). The effects of medetomidine were similar then described in the chapter 2. Both atipamezole and yohimbine antagonised these effects. The reversal effects of atipamezole were dose-dependent, except on epinephrine. Yohimbine caused prolonged increases in plasma norepinephrine and insulin levels comparing to atipamezole, possibly because of its longer elimination half-life. Only yohimbine increased the cortisol levels. Neither glucagon nor lactate levels changed significantly. Based on these findings, when medetomidine-induced sedation is antagonised in dogs, we recommend using atipamezole IM, from 2 to 6 folds the dose of medetomidine, unless otherwise indicated. In chapter 4, effects of three injectable analgesics butorphanol (0.1 mg/kg, IM) fentanyl (10 αg/kg, IM) and ketamine (10 mg/kg, IM) were compared. Plasma levels of epinephrine and cortisol significantly increased after every treatment. Norepinephrine levels only increased after ketamine treatment and glucose levels increased after fentanyl and ketamine treatments. Changes in cortisol levels were not in correlation with those of the epinephrine levels in any treatment group, but changes in glucose levels significantly correlated to the epinephrine levels after butorphanol and fentanyl but not after ketamine treatments. The NEFA levels also significantly correlated to the epinephrine levels in the butorphanol group and had tendency for correlation in the fentanyl group but not in the ketamine group. Based on these findings, single injections of butorphanol and fentanyl induced hormonal and metabolic changes similar to the physiological stress response but the effects of ketamine were somewhat different. Epinephrine seems to be the key mediator of these changes after butorphanol and fentanyl but not after ketamine treatments. The effects of ketamine can not be explained with its antagonistic effect on N-methyl-D-aspartate (NMDA) receptors. The involvement of other receptor systems in these effects of ketamine is highly probable. The hormonal and metabolic changes observed in this study are undesirable for the stress free management of the patients, therefore butorphanol, fentanyl and ketamine are recommended to use as part of a balanced anaesthesia and not as single treatments. In chapter 5, the effects of balanced anaesthesia with medetomidine (20 αg/kg, IM) in combination with butorphanol (0.1 mg/kg, IM), fentanyl (10 αg/kg, IM) or ketamine (10 mg/kg, IM) were examined. Norepinephrine, epinephrine, insulin, and NEFA levels significantly decreased in every treatment groups. However, the norepinephrine levels were significantly higher in the medetomidine-ketamine than in the medetomidine-saline groups. Cortisol levels did not change significantly. Plasma glucose levels significantly increased in every group except for the medetomidine-butorphanol group where only increasing tendency was observed. Interestingly, the glucose levels in the medetomidine-saline group were significantly higher than in the other groups. The neurohormonal and metabolic effects of medetomidine were predominant in the balance anaesthesia protocols examined in this study. The norepinephrine levels were less depressed in the medetomidine-ketamine group probably because of the potency of ketamine to increase sympathoneural activity. On the other hand, balanced anaesthesia with butorphanol, fentanyl and ketamine provided lower plasma glucose levels than medetomidine alone. In conclusion, α2-adrenergic agents suppress sympathoneural, sympathoadrenal and adrenocortical activities and lipolysis therefore able to attenuate stress-response from this point of view. On the other hand, they suppress insulin secretion and causes hyperglycaemia, similarly to stress-response itself. Therefore, medetomidine can not be considered as an ideal agent for reducing stress-response to various stimuli. The main different between medetomidine and xylazine was in their hyperglycaemic effect. Xylazine caused significantly dose-dependent hyperglycaemia, whereas medetomidine did not. The α2-adrenoceptor antagonist yohimbine is not a well-fitted antagonist for medetomidine because it causes prolonged increase in sympathoadrenal activity and insulin secretion. Based on these findings, when medetomidine-induced sedation is antagonised in dogs, we recommend using atipamezole IM, from 2 to 6 folds the dose of medetomidine, unless otherwise indicated. Combining medetomidine to opiates or ketamine may offer advantages in reducing sympathoneural, sympathoadrenal and adrenocortical activities as well as hyperglycaemia.