I1-imidazoline receptor agonists

The generation of imidazoline receptors is represented by two subtypes: Ione-imidazoline and I2-imidazoline receptors. Central Ione-imidazoline receptors are located in the rostral ventrolateral part of the medulla oblongata, which is responsible for tonic and reflex control over the sympathetic nervous system. Peripheral Ione– and I2-imidazoline receptors are found on the membranes of epithelial cells of the renal tubules and chromaffin cells of the adrenal glands, in the endings of sympathetic nerves, pancreas, adipose tissue, and placenta. There is reason to believe that imidazoline receptors belong to the family of neurocytokine receptors. The endogenous ligand of imidazoline receptors is decarboxylated arginine – agmantine. To agonists Ione-imidazoline receptors include moxonidine and rilmenidine.
Arousal Ione-imidazoline receptors in the ventrolateral part of the medulla oblongata leads to suppression of the activity of sympathetic preganglionic neurons of the intermediate zone of the spinal cord, which is accompanied by inhibition of the activity of the sympathetic nervous system with a decrease in the release of catecholamines from the endings of sympathetic neurons, a decrease in sympathetic impulses to the vessels and heart. This is manifested by a decrease in the tone of resistive vessels, a decrease in blood pressure and OPSS, a moderate decrease in heart rate, a decrease in the release of adrenaline from the adrenal medulla, an improvement in the electrical stability of the myocardium, and a decrease in platelet aggregation. In part, the antihypertensive effect of moxonidine and rilmenidine is also associated with the stimulation of α2-adrenergic receptors on the membranes of neurons in the nuclei of the solitary tract. With prolonged use, the end systolic and diastolic volumes of the left ventricle, pulmonary vascular resistance, and left ventricular hypertrophy decrease. They do not violate the physiological reaction, which is manifested by a change in heart rate in response to physical activity. At therapeutic doses, they practically do not affect myocardial contractility, cardiac output, cardiac electrophysiological indices, renal blood flow, glomerular filtration characteristics and filtration fraction volume.
Peripheral I activationone-imidazoline receptors leads in adrenomedullary cells of the adrenal glands to a decrease in the release of adrenaline from the medulla, in the kidneys – to a decrease in renin release, a decrease in the concentration of aldosterone and angiotensin II, to a decrease in sodium and water reabsorption, in the endings of sympathetic nerves – to inhibition of the release of norepinephrine.
Through central Ione-imidazoline and through peripheral Ione– and I2-imidazoline receptors are also mediated by the following effects: an increase in glucose-dependent release of insulin and the transfer of glucose into cells, and, as a consequence, a decrease in hyperglycemia, an improvement in tissue energy supply due to an increase in aerobic oxidation of glucose and an increase in glycogen synthesis, a decrease in lactate production, an increase in glucose sensitivity of brain tissues , increased lipolysis, increased sensitivity to lowering blood pressure and hypoxia / hypercapnia of the carotid glomeruli. In the kidneys, the development of glomerulosclerosis, tubular atrophy, cortical interstitial fibrosis and cellular infiltration in the renal cortex slows down. Agonists Ione-imidazoline receptors practically do not affect bronchial resistance in patients with hypertension and concomitant bronchial asthma. Agmantin also has a vasodilating effect, exerting an indirect triggering effect on the enzyme that catalyzes the formation of an endothelial relaxing factor.
In young patients with arterial hypertension, absolute blood pressure is normalized, and with stable hypertensive syndrome, the daily variability of blood pressure significantly decreases and the degree of its nighttime decrease increases. With arterial hypertension of I – II degrees in elderly patients, an optimal decrease in blood pressure is ensured during the day and at night, the reverse development of left ventricular hypertrophy is observed, the pathogenic effect of hypertension on the functioning of the prefrontal structures of the brain decreases, which is manifested in the improvement of memory and thinking parameters. In patients with diabetes mellitus, an improvement in microcirculation is observed: an increase in the blood flow rate, a decrease in the number of intravascular aggregates, a decrease in tissue insulin resistance and the level of glycemia.
Moxonidine and rilmenidine are rapidly and almost completely absorbed in the gastrointestinal tract. They bind to plasma proteins by about 8%, are metabolized to an insignificant extent with the formation of metabolites with low specific activity. The main route of excretion is through the kidneys unchanged. Against the background of impaired renal function, excretion slows down and correlates with the value of creatinine clearance (in renal failure, a correction of the dosage regimen is required). In case of insufficiency of liver function, T is lengthened1/2.
The antihypertensive effect does not diminish with prolonged use, and sudden withdrawal is not accompanied by the development of “rebound” hypertension.
Mutually enhance the effect of other antihypertensive drugs (vasodilators, diuretics) and depressants (alcohol, tranquilizers, barbiturates, antipsychotics), tricyclic antidepressants weaken the hypotensive effect. Concomitant use with MAO inhibitors is not recommended.
Agonist therapy Ione-imidazoline receptors are accompanied by the development of a number of side effects: drowsiness or insomnia, asthenia, headache, dizziness, weakness during exercise, fear, depression, convulsions, palpitations, cold extremities, orthostatic hypotension, hot flashes, dry mouth, epigastric pain, diarrhea , nausea, constipation, peripheral edema, sexual dysfunction, skin rashes, itching.
The most common dry mouth, which is mild and moderate, dose-dependent, appears 2-3 hours after taking the drug, decreases or disappears during treatment. Headache, dizziness, sleep disturbance are usually mild and disappear within 2-3 weeks of therapy, without requiring dose adjustment or discontinuation of the drug.
The main contraindications for the appointment of agonists Ione-imidazoline receptors are: hypersensitivity, sick sinus syndrome, impaired sinoatrial and AV conduction of II-III degree, bradycardia less than 50 beats per minute, severe cardiac arrhythmias, heart failure (NYHA functional class IV), unstable angina pectoris, severe liver dysfunction and kidneys, peripheral circulatory disorders (obliterating atherosclerosis of the vessels of the lower extremities with intermittent claudication syndrome, Raynaud’s disease), Parkinson’s disease, depression, epilepsy, glaucoma, pregnancy, breastfeeding (during treatment, you should stop taking drugs, because they penetrate into breast milk), adolescence and childhood (lack of sufficient clinical experience).
During treatment, alcohol consumption is excluded. It is not recommended (especially at the beginning of treatment) to work with mechanisms that require increased attention and quick physical and mental reactions.
Imidazoline receptor agonists are a new effective class of antihypertensive substances, the use of which is not accompanied by the development of tolerance and withdrawal syndrome. Positive influence on metabolic processes, cardio- and nephroprotective effects, lack of influence on bronchial conduction allow us to recommend them as “first-line” drugs in patients with arterial hypertension of I – II stages, incl. in elderly people and with concomitant pathology, primarily in patients with impaired glucose tolerance and diabetes mellitus. The ability of these drugs to inhibit the tone of the sympathetic nervous system determines the appropriateness of their use for prolonged sympathetic hyperactivity, including metabolic syndrome and arterial hypertension in menopause.
Below is a list of agonists Ione-imidazoline receptors:

  • Rilmenidine
  • Moxonidine