Raimo Virtanen

Medetomidine — a novel α2-adrenoceptor agonist: A review of its pharmacodynamic effects

Abstract 1. 1. The pharmacodynamic effects of medetomidine, a novel α2-adrenoceptor agonist, are reviewed. 2. 2. In receptor binding experiments, and in isolated organ preparations medetomidine shows high specificity and selectivity to α2-adrenoceptors. Its α 2 α 2 selectivity ratio is 1620 compared to 220 of clonidine. It is a highly potent full agonist at α2-adrenoceptors, a fact that also distinguishes it from clonidine. 3. 3. Medetomidine induces a dose-dependent decrease in the central release and turnover of norepinephrine (NE) measured as changes in metabolite concentrations or using pharmacological intervention techniques. 4. 4. The selectivity, specificity and potency of medetomidine is further supported by various in vivo experiments showing dose-dependent hypotensive, bradycardic, sedative, anxiolytic mydriatic, hypothermic and analgesic effects. 5. 5. The pharmacological, neurochemical and behavioral effects of medetomidine can be inhibited by prior, simultaneous or subsequent administration of selective and specific α2-antagonists. 6. 6. In humans medetomidine is well-tolerated and pharmacodynamic effects including e.g. dose-dependent decrease of vigilance, blood pressure, heart rate, salivary secretion and plasma NE are compatible with an agonistic action at α2-adrenoceptors.

Comparison of the effects of detomidine and xylazine on some α2-adrenoceptor-mediated responses in the central and peripheral nervous systems

The effects of detomidine, a novel veterinary sedative analgesic, on some alpha 2-adrenoceptor-mediated responses in the central and peripheral nervous systems were studied. In pithed rats, detomidine was a very potent agonist at both pre- and postsynaptic alpha 2-adrenoceptors. Doses of 1.9 micrograms/kg and 6.5 micrograms/kg inhibited electrically induced tachycardia by 50% and increased mean blood pressure by 50 mmHg, respectively. In comparison, xylazine, though similar in specificity, was 40 times less potent than detomidine in this preparation. In unanaesthetized rats, detomidine both caused sedation and induced complex changes in body temperature. Low doses caused decreases in rectal temperature but these were reversed as the dose was increased. The decrease in rectal temperature could be blocked by yohimbine. Prazosin somewhat inhibited but did not eliminate the hyperthermia seen with the very high doses of detomidine. Xylazine caused much more severe falls in rectal temperature which could not be completely antagonized by alpha 2-adrenoceptor blockade. Both detomidine and xylazine caused dose-dependent mydriasis in anaesthetized rats, detomidine being about 10 times more potent than xylazine. The mydriatic effects of detomidine could be prevented by alpha 2- but not by alpha 1-adrenoceptor blockade. It is concluded that detomidine is a potent and rather specific alpha 2-adrenoceptor agonist in the central and peripheral nervous systems. In comparison with xylazine, detomidine has higher potency and greater specificity, especially at central alpha 2-adrenoceptors.

Evaluation of the α1- and α2-adrenoceptor effects of detomidine, a novel veterinary sedative analgesic

Abstract The in vitro receptor interactions of detomidine, a novel veterinary sedative analgesic, were studied. Detomidine caused a concentration-dependent inhibition of the twitch response in electrically stimulated mouse vas deferens with a pD 2 value of 8.8. Clonidine and xylazine had the same effect with pD 2 values of 8.7 and 7.5 respectively. The effect of detomidine was competitively antagonized by the α 2 -blocking agents yohimbine, rauwolscine and idazoxan but not by the α 1 -antagonists prazosin and corynanthine. The effect of detomidine was not antagonized by the opioidergic antagonist naloxone, the dopaminergic antagonist sulpiride, the serotonergi antagonist methysergide, the histamine H 2 -antagonist cimetidine, the histamine H 1 -antagonist diphenhydramine and the cholinergic muscarine antagonist atropine. Detomidine, as well as clonidine and xylazine, produced concentration-dependent contractions of rat anococygeal muscle and rabbit aortic strips with pD 2 values between 2.5 and 6.4. Intrinsic activities (compared to phenylephrine) varied between 0.5 and 0.7. The effects of detomidine in these two muscles could be antagonized by low concentrations of prazosin. In receptor binding experiments detomidine showed strong affinity to α 2 -receptors. There was some binding affinity towards α 1 -receptors also butonly negligible or no affinity towards dopamine, opiate and adenosine receptors. In conclusion, the present results suggest that detomidine is a potent α 2 -adrenoceptor agonist and that at high concentrations it can also stimulate α 1 -adrenoceptors.

Effects of acute GR38032F (odansetron), a 5-HT3 receptor antagonist, on dopamine and serotonin metabolism in mesolimbic and nigrostriatal dopaminergic neurons

The acute administration of GR38032F, a selective 5-HT3 receptor antagonist, did not change the concentrations of dopamine (DA) or 5-hydroxytryptamine (5-HT) or their deaminated metabolites in nucleus caudatus, nucleus accumbens or substantia nigra. Pretreatment with GR38032F failed to modify the haloperidol-induced activation of DA turnover. It is concluded that the blockade of central 5-HT3 receptors by GR38032F under these experimental conditions does not result in alternations in metabolism of DA or 5-HT in major ascending dopaminergic areas.

Effects of yohimbine and idazoxan on monoamine metabolites in rat cerebrospinal fluid.

Effects of two alpha 2-adrenoceptor antagonists, idazoxan and yohimbine, on the concentrations of monoamine metabolites in cisternal cerebrospinal fluid (CSF) of freely moving rats were investigated. Both drugs caused a dose-dependent, up to 250% increase in the concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG) in CSF indicating enhanced release, metabolism and turnover of noradrenaline in the central nervous system (CNS). In addition, a similar increase in homovanillic acid (HVA) in CSF was observed, while the level of 5-hydroxyindoleacetic acid was unchanged. The present results demonstrate the usefulness of monitoring drug-induced alterations in noradrenergic activity in the CNS by measurement of free MHPG in repeatedly collected cisternal CSF samples from awake rats. The possibility that the observed increase in the concentration of HVA after the highly specific alpha 2-antagonist idazoxan reflects increased noradrenergic rather than dopaminergic neuronal activity is discussed.

α2-adrenoceptor agonists decrease free 3-methoxy-4-hydroxyphenylglycol in rat cerebrospinal fluid

The effects of alpha 2-adrenoceptor agonists on the concentrations of monoamine metabolites in cisternal cerebrospinal fluid (CSF) of freely moving rats were determined. Clonidine and two new imidazole derivatives, detomidine and medetomidine, and diazepam (as a control substance) were administered in sedative doses and the concentrations of unconjugated 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in CSF were monitored for 48 h. The alpha 2-agonists caused a dose-dependent, statistically significant decrease in the concentration of MHPG in CSF compared to the concentration in animals treated with saline or diazepam. Detomidine caused a statistically significant increase in the concentration of 5-HIAA compared to control treatments. The present results demonstrate the usefulness of monitoring drug-induced alterations in central nervous system (CNS) noradrenergic activity by measuring free MHPG in repeatedly collected cisternal CSF samples from freely moving rats. The alpha 2-agonists reduced the concentration of MHPG in CSF, indicating a decreased release, metabolism and turnover of noradrenaline in the CNS.

Radioimmunoassay for tricyclic antidepressants

A sensitive radioimmunoassay for the determination of tricyclic antidepressants is described. The antibodies were produced in rabbits immunized with a conjugate of N-succinyl-nortriptyline and human serum albumin and they were shown to be specific for the tricyclic antidepressant group of drugs. The assay was tested for the determination of amitriptyline and nortriptyline concentrations in plasma or serum. Specificity was achieved by coupling a simple extraction procedure (based on selective extraction of amitriptyline and nortriptyline at different pH-values) to the assay. Using [3H]imipramine as the tracer the sensitivity of the assay is 3.8-18.0 nmol/l depending on whether the extraction procedure is used or not and it can be carried out with 50-200 microliter sample volumes. Because of its advantages (sensitivity, specificity, simplicity, small sample volumes, low cost) this procedure is suitable for drug monitoring both during controlled tricyclic therapy and pharmacokinetic studies.

Chronic dexmedetomidine, a selective α2-agonist, decreases serotonin but not noradrenaline turnover in rat brainstem nuclei

The effects of a chronic treatment with dexmedetomidine, the active d-isomer of a selective alpha 2-agonist, medetomidine, on the metabolism and turnover of catecholamines and indoleamines in discrete rat brain stem and mesencephalic nuclei were investigated. Chronic dexmedetomidine (3 or 10 micrograms/kg per h for 14 days, delivered by osmotic minipumps) did not change the basal concentrations of noradrenaline, dopamine or 3,4-dihydroxyphenylacetic acid, or the rates of accumulation of 3,4-dihydroxyphenylalanine after inhibition of decarboxylase by NSD 1015. In contrast, the concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and/or 5-HIAA/5-HT were significantly reduced in the nucleus tractus solitarii, raphe dorsalis, locus coeruleus, A1-C1 area, A9 and A10 areas after 10 micrograms/kg per h of dexmedetomidine. The accumulation of 5-hydroxytryptophan was significantly reduced in the locus coeruleus and nucleus tractus solitarii. It is concluded that chronic dexmedetomidine treatment significantly decreases the turnover of 5-hydroxytryptamine in discrete brainstem and mesencephalic nuclei, while the rate of synthesis of noradrenaline in the same areas is not changed.