Veterinary Neuropharmacology

α2 - adrenergic receptor agonists

α₂ - ADRENERGIC RECEPTOR AGONIST

Clonidine

• Is a partial α₂ - adrenergic receptor agonist. Rapid IV injection causes a transient increase in BP due to activation of post junctional α₂ receptors in peripheral vascular smooth muscles. However, this effect is followed by a more sustained hypotensive responsive mediated through activation of presynaptic α₂ adrenoceptors in the lower brain stem (vasomotor centre in medulla oblongata), that causes decrease in central sympathetic outflow.
• In CNS α₂ receptors regulate the neuronal release of noradrenaline and several other transmitters and involved in the modulation of sympathetic outflow and cardiovascular and endocrine functions. In addition to central effects clonidine activates the prejunctional α₂ receptors that suppress release of noradrenaline from peripheral nerve endings. Clonidine also stimulates parasympathetic outflow, which produces the bradycardia.
• In addition to the CVS effect, clonidine produces other effects like: central sedative and analgesic effect, contraction of pregnant uterus leading to premature labour, inhibition of insulin and rennin secretion, stimulation of growth hormone, elevation of blood glucose level and activation of salt absorption from gut mucosa.

Clinical use

• Widely used in humans for treatment of hypertension. Also used for treating persons addicted to narcotics, alcohol and tobacco.

Xylazine

• It is structurally related to clonidine and is a α₂- receptor agonist.
• It is primarily used as a central sedative- analgesic with muscle relaxant properties.

Mechanism of action

• α₂-receptor activation produces analgesia and sedation similar to the of opioid receptor stimulation in the CNS. Both the receptors are found in similar region of the brain and on some of the same neurons.
• Even though the receptors are different, both α₂ and opioid receptors are connected to the same signal transducer and both types use the same effector mechanism. Hence when xylazine binds to α₂ receptors, it causes activation of membrane associated G- proteins. This inturn opens potassium channels in the neuronal membrane , making the cell membrane hyperpolarized. Thus the neuronal cells become insensitive to exciting input and, the transmission pathway blocked. This finally results in sedation and analgesia .
• Xylazine like clonidine also stimulates the prejunctional α₂ receptors in peripheral synopsis and decrease the release of nor adrenaline.

Pharmacological effect

• CNS: it produces sedation, analgesia, muscle relaxation and anxiolysis. in cats it causes emesis. Xylazine depresses thermoregulatory mechanisms and may produce either hypothermia or hyperthermia depending on the ambient temperature.
• CVS: It produces transient hypertension, followed by longer lasting hypotension and decreased COP.
• Clinical uses: Sedative, preanesthetic sedative prior to general anesthesia, inhalation or injectable) local anesthesia, as a general anesthetic in combination with ketamine, as emetic in cats.

Other selective α₂-receptor agonists

• Detomidine, Medetomidine, Romifidine. (These are mostly in veterinary practice as anaesthetics, analgesics like xylazine.)