Alpha2-adrenergic agonists

Central stimulation of the cardiovascular system is carried out through the sympathetic nervous system through adrenergic alpha2 and imidazoline receptors. Adrenergic alpha2 receptors are localized in many parts of the brain, but the largest number is 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.

The main stimulating effect on a2-adrenergic receptors is methyldopa and guanfacin. Moxonidine and rilmenidine stimulate mainly imidazoline receptors. Among the antihypertensive drugs of this group, only clonidine has a form for papaenteral administration and is used in anesthesia practice both in the pre- and post-operation period. Highly selective stimulants of alpha2-adrenergic receptors include foreign α2-adrenoreceptor agonists-dexmedetomidine, which has an antihypertensive effect, but is used mainly as a sedative during anesthetic maintenance (for a long time - only in veterinary medicine, but not so long ago introduced into clinical practice in humans) .

Alpha-2-adrenoreceptor agonists: place in therapy

Clonidine can be successfully used to stop hypertensive reactions during and after surgery, to prevent the hyperdynamic response of the organism in response to stressful effects (intubation, awakening and extubation of the patient).

For premedication, clonidine is given orally. With intravenous administration of clonidine, a short-term rise in blood pressure initially occurs, which is followed by a prolonged hypotension. To introduce agonists of alpha2-adrenoreceptors in / in, preferably by titration.

Clonidine can be used in the perioperative period as an analgesic and sedative component of general anesthesia. This reduces the hemodynamic response to intubation of the trachea. As a component of general anesthesia, it allows stabilizing hemodynamics, reducing 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, low manageability, the possibility of developing severe hypotension during induction and maintaining anesthesia, clonidine has not been widely used. However, in a number of clinical situations, it is readily used for the purposes of premedication, as well as the potentiation of the effects of certain anesthetic agents in order to reduce their dosages during the maintenance phase, and also to relieve difficult-to-treat episodes of intraoperative hypertension. It is also used in the postoperative period with the aim of arresting postoperative hypertension.

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

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

[1], [2], [3], [4], [5], [6], [7], [8], [9]

Mechanism of action and pharmacological effects

As a result of stimulation of central a2-adrenergic receptors caused by drugs of this group and clonidine in particular, the vasomotor center is suppressed, the sympathetic impulse from the central nervous system decreases and the activity of adrenergic systems is suppressed at the periphery. The net effect is a reduction in OPS and, to a lesser extent, CB, which is manifested by a decrease in blood pressure. The agonists of alpha2-adrenergic receptors reduce the heart rate and reduce the severity of the baroreceptor reflex aimed at compensating for lowering 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 admission. Despite the decrease in blood pressure, the level of renal blood flow does not change. With prolonged use, clonidine causes a delay in the body of sodium and water and an increase in the total number of cerebral palsy, which is one of the reasons for the decrease in its effectiveness.

In large doses, alpha2-adrenergic receptor agonists activate peripheral presynaptic a2-adrenergic receptors at the ends of adrenergic neurons, through which the regulation of norepinephrine release is based on negative feedback and thus causes a brief increase in blood pressure due to vasoconstriction. In therapeutic doses pressornoe action clonidine is not detected, but with overdose can develop severe hypertension.

Unlike GHB and phentolamine, clonidine reduces BP, without causing a pronounced postural reaction. Clonidine also causes a decrease in intraocular pressure due to a decrease in secretion and an improvement in the outflow of aqueous humor.

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

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

Although the clonidine's own analgesic activity is not sufficient to achieve perioperative analgesia, the drug can potentiate the action of general anesthetics and narcotic substances, especially when intrathecal administration is made. This positive effect can significantly reduce the dose of anesthetics and narcotic drugs used during general anesthesia. An important feature of clonidine is its ability to reduce somatovegetative manifestations of opiate and alcohol withdrawal, which is also probably due to a decrease in central adrenergic activity.

Clonidine increases the duration of regional anesthesia, and also has a direct effect on postsynaptic alpha 2 receptors of the horn of the spinal cord.

Pharmacokinetics

Clonidine is well absorbed from the digestive tract. Bioavailability of clonidine for oral administration is on the average 75-95%. Its maximum concentration in the plasma is achieved in 3-5 hours. The drug binds to plasma proteins by 20%. Being a lipophilic substance, it easily penetrates the BBB and has a large volume of distribution. T1 / 2 clonidine is 8-12 hours and may be prolonged with renal insufficiency, tk. Approximately half of the drugs are excreted from the body by the kidneys in unchanged form.

Contraindications and cautions

Clonidine should not be used in patients with hypotension, cardiogenic shock, intracardiac blockade, weakness syndrome of the sinus node. When parenteral drug use it is necessary to carry out a careful monitoring of the level of blood pressure, which will allow timely diagnosis of severe hypotension and timely correct the development of the complication.

[10], [11], [12]

Tolerance and side effects

Clonidine is generally well tolerated by patients. When it is used, as with any hypotensive drug, it is possible to develop excessive hypotension. Some patients develop a pronounced bradycardia, which can be eliminated by M-holinoblokatorami. When appointing clonidine for the purpose of premedication, patients may experience dry mouth.

Agonists of alpha2-adrenergic receptors have a pronounced sedative effect, and inhibition, which is considered to be a side effect in the therapy of arterial hypertension, during premedication is the purpose of prescribing drugs. The disadvantage of clonidine is its poor controllability, the possibility of developing severe hypotension after its use during both 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 withdrawal. This is important to take into account in the preoperative preparation of patients systematically receiving clonidine. After a single use of clonidine, withdrawal syndrome is rare.

An overdose of clonidine can be life threatening. The state of acute poisoning includes transient hypertension, which is replaced by hypotension, bradycardia, QRS complex broadening, impaired consciousness, respiratory depression.

Interaction

Clonidine should not be used in combination with tricyclic antidepressants, which can weaken the hypotensive effect of clonidine due to the alpha-adrenergic blocking properties of tricyclic compounds. The weakening of the hypotensive effect of clonidine is also observed under the influence of nifedipine (antagonism in the influence of calcium ions on the intracellular current).

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