Cátedra de Farmacología, Terapéutica y Farmacia, Facultad de Veterinaria. Universidad Complutense de Madrid
For four decades, the α2- adrenergic agonists they have been used in the veterinary medicine to obtain sedation, analgesia and muscle relaxation, in a great variety of domestic and exotic species, although the relation of these actions with the stimulation of α2- adrenoreceptors were not established until 1981 by Hsu. The first drug of this group used in the veterinary medicine it was the xylazine and from this they have been synthesized different molecules like detomidine, medetomidine and romifidine that have been improving fundamentally the pharmacodynamic characteristics of the xylazine and they use profusely in the present veterinary medicine.
PHARMACOLOGICAL EFFECTS OF α2-ADRENERGIC AGONISTS
Before to develop specifically the pharmacological effects of these drugs, we must consider that the presence of α2- adrenoreceptors in multiple organic locations it does that the physiological responses derived of the activation of these receptors can be very varied and employees of different organs and tissues. On the other hand, it does not complete selectivity of these drugs on α2- adrenoreceptors, it causes that they can activate in greater or minor measured and depending on each molecule in particular, α1-adrenergic receptors fundamentally, and even other types like imidazoline receptors. Finally, the possibility of differences exists between species in sensitivity, as much to the therapeutic effects, like a collateral effects derived from its use.
Due to these factors, their administration it gives rise to a plenty variety of pharmacological actions, some of as justify its clinical use, as they are sedation, analgesia, muscular relaxation and anxiolysis. But also they produce another series of actions that we considered true collateral effects associate to its use and both groups of actions can appear with different intensity depending on the sensitivity of each species in particular.
The sedative effects of the α2- adrenergic agonists is mainly attributed to its capacity to reduce the activity of noradrenergic neurons of Locus coeruleus (LC) on the pons and lower brainstem and thus to diminish activity of the noradrenergic activator projections ascending towards superior cerebral structures. It can also contribute to its sedative actions, the presence of postsynaptic α2- adrenergic receptors in the frontal cortex, to mediate its activation the inhibition of the cortical activity. Additionally, when acting on presynaptic α2- adrenergic receptors located on noradrenergic neurons like on other non-noradrenergic neurons, these drugs can modulate the release and the recaptation of norepinephrine and others neurotransmitters that also take place in the regulation of the arousal and vigilance.
These drugs produce a powerful analgesic effect by stimulating α2- adrenergic receptors located at various sites in the pain pathway within the brain, include the LC, and spinal cord. According to the necessities, they are possible to be administered by different routes to obtain analgesia.
Analgesia after systemic administration
The activation of α2- adrenoreceptors presents in the LC, through the descendent projections that leave from this structure towards the spinal cord, produces analgesia by means of mechanism of activation of the opioid interneurons of the spinal cord that it gives rise to the release of enkephalins. Additionally, the activation of presynaptic α2- adrenergic receptors located on neurons of the dorsal horn of spinal cord, where nociceptive fibers synapse, also produces the inhibition of the nociceptive responses to inhibit the release of exciter nociceptive neurotransmitters.
Analgesia after epidural and intrathecal administration (subarachnoid)
These antinociceptive effects are related to the stimulation of α2- adrenergic receptors located in the nociceptive neurons of the dorsal horn of spinal cord.
Analgesia after the local administration
These drugs have the capacity of produce an anaesthetic effect when they are locally administered. These effects have not been related to the activation of specific receptors and are had to a blockade of the potential of action and the conduction of impulses on the primary afferent nervous fibers.
This action is of central origin. Activation of presynaptic α2- adrenoreceptors at the interneuron level of the spinal cord, reduce the release of amino acidic exciting neurotransmitters in the spinal cord and produce inhibition of the spinal polysynaptic reflect routes and to motoneurons.
The results derived from animal models of anxiety, seem to indicate that the spectre of activity of these drugs include the anxiolysis when they are administered to low doses. Ansiolytic activity of the α2- adrenergic agonists seems to be similar to the drugs that operate through serotonergic mechanisms and that act like 5-HT1A receptor partial agonists.
COLLATERAL EFFECTS ASSOCIATED TO THE USE OF THE α2-ADRENERGIC AGONISTS
Stimulation of presynaptic α2- adrenoreceptors located on the bulbar vasomotor centres by these drugs, determines a reduction of the pre and postganglionary discharges in the sympathetic system and an increase of the vagal tone that gives rise to vasodilatation and hypotension, bradycardia and associated bradyarrhythmias, a dramatic reduction of cardiac output and an increase in the systemic vascular resistance. It has been described that these drugs they increase the ability of catecholamines to produce dysrhythmias. α2- adrenergic agonists can produce effects on coronary circulation that include local vasoconstriction and reduction in the oxygen input to the myocardium.
Stimulation of α2- adrenoreceptors of CNS respiratory centres produce respiratory depression and a reduction in respiratory rate although degree of depression produced by α2-adrenergic agonists alone is less than that others sedatives. In a 33% of the sedated animals cyanosis takes placebut this one, in general, does not accompany itself by significant changes of the oxygen arterial tension and oxygen saturation is normally superior to 95%. Nevertheless, oxygen venous tension diminishes and an increase of arterial carbon dioxide tension can be observed. Probably cyanosis is likely due to low blood flow through peripheral capillary beds and an actual venous desaturation.
Because the adrenergic regulation of gastrointestinal motility and secretions seems to be mainly dependent of the activation or inhibition of α2- adrenoreceptors located both presinaptically, in peripheral cholinergic terminals, and postsinaptically, these drugs produce modifications in the intestinal motility and in gastric and salivary secretions. In general, α2-adrenergic agonists decrease acid gastric and salivary secretions and prolong intestinal transit time, in particular decrease dramatically the motility of the colon in dogs.
The vomiting effect induced by these drugs have been related to the activation of α2- adrenoreceptors located in the chemoreceptor trigger zone, which is close to the Locus coeruleus in the brain.
They inhibit the release of ACTH by activation of hypothalamic α2- adrenoreceptors; in addition, they inhibit the insulin release by direct action on α2- adrenoreceptors presents in the pancreatic β cells.
Renal and urinary effects
The α2- adrenergic agonists typically induce diuresis; this effect has been associated with the actions of these drugs on antidiuretic hormone (ADH) and the renin-angiotensin system by activation of α2- adrenoreceptors located in the hypothalamus and the juxtaglomerular apparatus.
It is true that activation of α- adrenoreceptors presents in myometrium increase the contractility of the pregnant and non pregnant uterus, producing an increase in the tone of myometrium and the intrauterine pressure. For these reasons classically drug companies does not recommended α2- adrenergic agonists for use in pregnant animals due anecdotal reports of premature labour and abortions after xylazine administration in cows and also his administration has been related to a diminution of the foetal diaphragmatic activity. However, the effects of α-adrenergic agonists depend to a high degree on the level of steroid hormones: estrogens increase the sensitivity of α-adrenoreceptors while high levels of progesterone during pregnancy stimulate the sensitivity of β-adrenoreceptors and actually decrease the contractility of the uterus. The use of medetomidine does not appear to promote abortions in pregnant dogs and no literature was found that related the effects of α2- adrenergic agonists on the feline uterus.
The use of these drugs includes his use single or combined with other drugs according to the different actions that we want to obtain. Its use as unique drugs allows us to obtain dose-dependent sedation and analgesia and also certain degree of muscular relaxation in domestic, exotic and wild species. Additionally, these drugs are combined with opioid analgesic and with other different anaesthetics during premedication.
CONTRAINDICATIONS AND PRECAUTIONS
Actually we will have to observe the following contraindications: cardiopathies, hypotension and shock, respiratory diseases, hepatic insufficiency, renal dysfunctions and urinary tract obstructions, endocrine alterations (diabetes mellitus...), ill and debilitated animals, and perhaps last third of the gestation and accomplishment of obstetrical manoeuvres.
The α2- adrenergic agonists act synergically with opioid analgesics. When they are administered in anaesthetic premedication, the required doses of the inductive agent or intravenous and inhalant anesthetics they are reduced until in 50% in majority of the cases. Its combination with phenothiazines causes severe hypotension even after the use of low doses. Its combination with thiopental, ketamine or halothane, can increase the dysrhythmogenic effects of both.
The possibility of revert its actions by means of the administration of specific antagonists, increases security and versatility of use of these drugs. They have developed antagonists with every time greater degree of selectivity and affinity on α2- adrenergic receptor. Atipamezole is actually the antagonist more used in veterinary medicine. The use of α2- adrenergic antagonists it makes possible, to revert the effects of the agonists and to shorten the periods of recovery, to reduce the frequency of presentation of associate complications to the prolonged sedation and the treatment of accidental overdoses. However, it use may also have adverse effects and IV administration is only recommended in emergency cases. A transient hypotension may still occur even with IM administration of atipamezole in medetomidine-sedated dogs but this may not be clinically significant in healthy stable animals.
The debate on the importance of cardiovascular, renal and respiratory actions that accompany the sedative and analgesic effects of α2 adrenergic agonists probably will continue. Identification of different subtypes of α2 adrenergic receptors, it can provide new develop opportunities of agonists and antagonists more selective and specific on a certain subtype of α2 adrenergic receptors, that make possible to obtain one much greater selectivity of therapeutic effects. On the other hand, at the present time the possibility of co-administration of low doses of α2 adrenergic agonists, opioid analgesics and benzodiazepines monopolize one great attention in the veterinary community, when introducing the concept of which activation of different receptor populations from the SNC can give rise synergic anaesthetic responses associated upon presentment of minimums adverse effects. This approach along with the fact that the actions of each one of these drug groups can be reverted with the use of specific antagonists (atipamezole, naloxone and flumazenil) it enters to us in a new era in which the obtaining of the anaesthesia will be able to be made by means of selective activation of different receptor populations from the SNC and that these actions could be modified or also completely reverted with the selective use of one or several antagonists. Thus, still they are not had developed all the possibilities of clinical use of these compounds.
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