Alpha2-adrenoreceptor agonists

Central stimulation of the cardiovascular system is mediated by the sympathetic nervous system via adrenergic alpha2- and imidazoline receptors. Adrenergic alpha2-receptors are localized in many parts of the brain, but the greatest number of them are in the nuclei of the solitary tract. Imidazoline receptors are localized mainly in the rostral ventrolateral part of the medulla oblongata, as well as in the chromaffin cells of the adrenal medulla.

Methyldopa and guanfacine have a predominant stimulating effect on a2-adrenoreceptors. Moxonidine and rilmenidine stimulate mainly imidazoline receptors. Among the antihypertensive drugs of this group, only clonidine has a form for papenteral administration and is used in anesthesiology practice in both the pre- and postoperative periods. Highly selective alpha2-adrenoreceptor stimulants include foreign alpha2-adrenoreceptor agonists - dexmedetomidine, which has an antihypertensive effect, but is used mainly as a sedative during anesthesia (for a long time - only in veterinary medicine, but not so long ago introduced into clinical practice in humans).

Alpha2-adrenergic receptor agonists: place in therapy

Clonidine can be successfully used to relieve hypertensive reactions during and after surgery, to prevent the body's hyperdynamic reaction in response to stress factors (intubation, awakening and extubation of the patient).

For premedication, clonidine is administered orally or intramuscularly. When clonidine is administered intravenously, there is initially a short-term increase in blood pressure, which is followed by a more prolonged hypotension. It is advisable to administer alpha2-adrenergic receptor agonists intravenously by titration.

Clonidine can be used in the perioperative period as an analgesic and sedative component of general anesthesia. In this case, the hemodynamic response to tracheal intubation is reduced. As a component of general anesthesia, it helps stabilize hemodynamics, reduce the need for inhalation anesthetics (by 25-50%), hypnotics (by about 30%), and opioids (by 40-45%). Postoperative administration of alpha2-agonists also reduces the need for opioids, preventing the development of tolerance to them.

Due to a number of side effects, poor controllability, and the possibility of developing severe hypotension during induction and maintenance of anesthesia, clonidine has not received widespread use. However, in a number of clinical situations, it is readily used for premedication purposes, as well as potentiating the effects of some anesthetic agents in order to reduce their dosages at the stage of its maintenance, as well as to relieve difficult-to-treat episodes of intraoperative hypertension. It is also used in the postoperative period to relieve postoperative hypertension.

Clonidine may be used to relieve chills in the postoperative period.

Respiratory depression is accompanied by miosis and resembles the action of opioids. Treatment of acute poisoning includes ventilation support, administration of atropine or sympathomimetics to control bradycardia, and volume support. If necessary, dopamine or dobutamine are prescribed. For alpha2-agonists, there is a specific antagonist - atipamezole, the administration of which quickly reverses their sedative and sympatholytic effects.

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Mechanism of action and pharmacological effects

As a result of stimulation of central a2-adrenoreceptors caused by drugs of this group and, in particular, clonidine, there is inhibition of the vasomotor center, a decrease in sympathetic impulses from the central nervous system and suppression of the activity of adrenergic systems in the periphery. The resulting effect is a decrease in TPR and, to a lesser extent, SV, which is manifested by a decrease in blood pressure. Alpha2-adrenoreceptor agonists slow down the heart rate and reduce the severity of the baroreceptor reflex aimed at compensating for the decrease in blood pressure, which is an additional mechanism for the development of bradycardia. Clonidine reduces the formation and content of renin in the blood plasma, which also contributes to the development of the hypotensive effect with long-term use. Despite the decrease in blood pressure, the level of renal blood flow does not change. With long-term use, clonidine causes sodium and water retention in the body and an increase in TCP, which is one of the reasons for the decrease in its effectiveness.

In high doses, alpha2-adrenoreceptor agonists activate peripheral presynaptic a2-adrenoreceptors in the terminals of adrenergic neurons, through which the release of norepinephrine is regulated by negative feedback and thus causes a short-term increase in blood pressure due to vasoconstriction. In therapeutic doses, the pressor effect of clonidine is not detected, but severe hypertension may develop in case of overdose.

Unlike GHB and phentolamine, clonidine reduces blood pressure without causing a pronounced postural reaction. Clonidine also causes a decrease in intraocular pressure by reducing secretion and improving the outflow of aqueous humor.

The pharmacological effects of alpha2-adrenergic agonists are not limited to the antihypertensive action. Clonidine and dexmedetomidine are also used due to their distinct sedative, anxiolytic, and analgesic properties. The sedative effect is associated with depression of the main adrenergic nucleus of the brain - locus ceruleus in the rhomboid fossa of the medulla oblongata. As a result of the suppression of adenylate cyclase and protein kinase mechanisms, neuronal impulses and the release of neurotransmitters are reduced.

Clonidine has a pronounced sedative effect and suppresses the body's hemodynamic response to stress (for example, the hyperdynamic response to intubation, the traumatic stage of surgery, awakening and extubation of the patient). While exhibiting a sedative effect and potentiating the action of anesthetics, clonidine does not significantly affect the EEG pattern (which is very important during operations on the brachiocephalic arteries).

Although the analgesic activity of clonidine is insufficient to achieve perioperative analgesia, the drug is capable of potentiating the action of general anesthetics and narcotics, especially when administered intrathecally. This positive effect allows for a significant reduction in the doses of anesthetics and narcotics used during general anesthesia. An important feature of clonidine is its ability to reduce the somatovegetative manifestations of opiate and alcohol withdrawal, which is probably also due to a decrease in central adrenergic activity.

Clonidine increases the duration of regional anesthesia and also has a direct effect on postsynaptic alpha2 receptors in the dorsal horn of the spinal cord.

Pharmacokinetics

Clonidine is well absorbed from the gastrointestinal tract. The bioavailability of clonidine when taken orally is on average 75-95%. Its maximum concentration in plasma is achieved after 3-5 hours. The drug is 20% bound to plasma proteins. Being a lipophilic substance, it easily penetrates the BBB and has a large distribution volume. T1/2 of clonidine is 8-12 hours and can be extended in renal failure, since approximately half of the drug is excreted from the body by the kidneys unchanged.

Contraindications and warnings

Clonidine should not be used in patients with hypotension, cardiogenic shock, intracardiac block, sick sinus syndrome. When using the drug parenterally, it is necessary to conduct careful monitoring of blood pressure levels, which will allow timely diagnosis of severe hypotension and timely correction of the developed complication.

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Tolerability and side effects

Clonidine is generally well tolerated by patients. When using it, as with any antihypertensive drugs, excessive hypotension may develop. Some patients develop severe bradycardia, which can be eliminated by M-anticholinergics. When prescribing clonidine for premedication, patients may experience dry mouth.

Alpha2-adrenoreceptor agonists have a pronounced sedative effect, and lethargy, which is considered a side effect in the treatment of arterial hypertension, is the purpose of prescribing the drug during premedication. The disadvantage of clonidine is its poor controllability, the possibility of developing severe hypotension after its use both during induction and during anesthesia, as well as the development of withdrawal syndrome, which is clinically manifested by the development of severe hypertension 8-12 hours after its cancellation. This is important to take into account in the preoperative preparation of patients systematically receiving clonidine. Withdrawal syndrome is rare after a single use of clonidine.

Overdose of clonidine can be life-threatening. Acute poisoning includes transient hypertension followed by hypotension, bradycardia, widening of the QRS complex, impaired consciousness, and respiratory depression.

Interaction

Clonidine should not be used in combination with tricyclic antidepressants, which may weaken the hypotensive effect of clonidine due to the alpha-adrenoblocking properties of tricyclic compounds. Weakening of the hypotensive effect of clonidine is also observed under the influence of nifedipine (antagonism in the effect on the intracellular flow of calcium ions).

Neuroleptics may enhance the sedative and hypotensive effects of alpha2-agonists.