The article will present the characterization of imidazoline receptor agonists.
Drugs that weaken the central parts of the sympathetic control of the heart and vascular system occupy a significant place among modern antihypertensive drugs.
Currently, the issue of improving centrally acting antihypertensive drugs based on the concept of imidazoline-type receptors is topical. Four selective imidazoline receptor agonists have already been produced. The drugs are produced under different trade names. The main agents of this group are moxonidine (Cint, Physiotens) and rilmenidine (Tenaxum, Albarel). These are the most popular drugs that are on the list of imidazoline receptor agonists.
Functional specificity and localization of receptors
Receptorsimidazoline is usually divided into two main groups, called I1 and I2.
Classification, their meaning and functional features form the basis of many scientific studies.
I1-receptors are located in the neuronal membranes of the brainstem, kidneys, cells of the substance of the adrenal medulla, platelets and pancreas. It is precisely with the predominant receptor excitation of this type that the influence of modern antihypertensive drugs is associated. Type I2 receptors are localized in the neurons of the cerebral cortex, platelets, liver and kidney cells. Their significance as an alleged object of pharmacological influence has so far been studied to a lesser extent.
Let's consider the mechanism of action of imidazoline receptor agonists.
Mechanism of action
The main target for antihypertensive drugs is type I1 imidazoline central receptors, which are located in the ventrolateral rostral region of the medulla oblongata. Their activation leads to a decrease in the tone of the motor center of the vessels, a decrease in the activity of sympathetic nerves, due to which there is a weakening of the release of norepinephrine from adrenergic neurons. In addition to this mechanism, there is a decrease in the production of adrenaline by the adrenal glands, which also have imidazoline I1 receptors. The result of such an impact is a decrease in the tone of resistive vessels, an increase in the electrical stability of the myocardium and bradycardia.
Among other things, imidazoline receptors are located on membranesmitochondria of the epithelium of the tubules and in the kidneys.
Stimulation of them (most researchers believe that these receptors are type I1), which leads to the suppression of sodium ion reabsorption and diuretic effect, is also involved in the activation of the hypotensive effect. This is also facilitated by a decrease in renin production, which is due in part to a decrease in sympathetic influences.
When excited in the cells of the β-islets of Langerhans of the pancreas, I1 receptors cause increased secretion of insulin, which responds to a carbohydrate load and causes a hypoglycemic effect.
Let's consider the most effective imidazoline receptor agonists.
Moxonidine (Cint, Physiotens)
The drug has almost no effect on α-adrenergic receptors and selectively excites I1 imidazoline receptors in the medulla oblongata. As a result, the sympathetic innervation tone decreases, due to which the total peripheral vascular resistance decreases and, to a lesser extent, the strength and frequency of heart contractions. The volume of ejection of the heart is practically unchanged. Decreased myocardial oxygen demand. Experimentally proven such action of moxonidine as cardioprotective. It smoothly and effectively reduces diastolic and systolic pressure, reduces the degree of angiotensin-II, norepinephrine and aldosterone in the blood, and renin activity. An important feature of moxonidine is the prevention of the development and reduction of myocardial hypertrophy already existing in the patient.
BesidesIn addition, the drug has a concomitant hypoglycemic effect, due to the excitation of imidazoline pancreatic receptors. It consists in increasing the delivery of glucose to cells, a stronger synthesis of glycogen. The lipid-lowering effect of moxinidin has also been established.
The latter is perfectly absorbed in the tract of the stomach and intestines (about 90%). It is excreted through the kidneys mainly in unchanged form (through the liver to a lesser extent), however, there is no significant cumulation even with moderate and mild kidney failure. The hypotensive effect of this imidazoline receptor agonist lasts about a day. Habituation to moxonidine and withdrawal syndrome are not recorded.
Indications of this tool
Symptomatic arterial hypertension and hypertension, especially when combined with type 2 diabetes mellitus and obesity (“metabolic syndrome”), as well as suppression of hypertensive crises.
What are the indications for an imidazoline receptor agonist? If the treatment is planned, the initial amount of moxonidine is 0.2 mg in the morning once a day (orally after or during a meal). With insufficient effectiveness after two weeks, the dosage is increased to 0.4 mg in the morning or 0.2 mg in the evening and in the morning. The maximum single amount is 0.4 mg, per day - 0.6 mg. If the renal excretory function is impaired, a single dosage is 0.2 mg, per day (if divided into two doses) - a maximum of 0.4 mg. The medicine is especially completely and quickly absorbed also when taken under the tongue, successfullymoxonidine is used in hypertensive crises sublingually (once 0.4 mg in crushed form), in combination with calcium channel blockers or alone, especially with isradipine.
Data from Nikitina A. N. indicate that in this case, after 20 minutes, there is a decrease, and after an hour - the disappearance of noise in the head and headache, flushing of the face. Systolic pressure gradually decreases by about 19-20%, by 14-15 - diastolic, by 8-10 - heart rate.
During treatment with moxonidine, pressure must be constantly monitored.
Side symptoms
This imidazoline receptor agonist rarely causes dizziness, orthostatic hypotension. Dryness in the oral cavity is insignificant, occurs only in 7-12% of patients. In rare cases, there is a slight sedative effect.
Contraindications
Atrioventricular blockade of the second or third degree, sick sinus syndrome, bradycardia (below 50 beats per minute), fourth degree circulatory failure, severe kidney failure, unstable angina, Raynaud's disease, age category up to 16 years (in currently there is no experience with the use of the drug for the treatment of adolescents and children), obliterating endarteritis, lactation, parkinsonism, pregnancy, epilepsy, glaucoma and mental depression.
How does this selective central imidazoline receptor agonist interact with other agents?
Interaction with other substances
Increases the effect of other antihypertensive drugs and can be combined with them. When taking β-blockers and moxonidine at the same time, it is desirable to cancel the first blocker. Less commonly, clonidine enhances the effect of alcoholic beverages, sleeping pills and sedatives, but it is better to avoid such combinations. Works great with diuretics. May increase the effect of hypoglycemic drugs.
Another imidazoline I1 receptor agonist is described below.
Rilmenidine (Tenaxum, Albarel)
The agent, which is a derivative of oxazosin, has an increased selectivity of mutual action with imidazoline I1 receptors both in the brain and on the periphery. The hemodynamic structure of the hypotensive effect is mainly associated with a decrease in peripheral vascular resistance in general. Monotherapy with rilmenidine allows effective pressure control in 70% of hypertensive patients. Usually, the hypotensive effect is achieved quickly and smoothly, maintained stably throughout the day due to the duration, reaching the day.
Agonist of imidazoline receptors in antihypertensive effect is not worse than thiazide diuretics, angiotensin-converting enzyme inhibitors, β-blockers, while differing in excellent tolerability and a small number of side effects. Use is recommended in case of insufficient effectiveness of the above funds. It should be said about the metabolic neutrality of rilmenidine - a beneficial effect onfunctional renal condition, decrease in microalbuminaria, no negative changes in lipid and carbohydrate metabolism.
Completely and quickly absorbed when taken orally, there is no effect of the first passage of the drug through the liver. Rilmenidine is poorly metabolized, predominantly excreted in the urine, its concentration in patients using the drug for more than a year is almost stable.
When shown?
Hypertension arterial, including elderly patients, with renal failure, diabetes mellitus, creatinine clearance of at least 15 ml per minute.
The drug is often given one tablet (1 mg) once a day before meals. If the hypotensive effect is insufficient within a month of treatment, it is advisable to increase the dosage to two tablets per day (morning and evening). Therapy can be long, up to several months. At the same time, the cancellation should be gradual.
Rarely, due to rilmenidine, mood decreases, sleep and heartbeat are disturbed, epigastric discomfort and asthenia appear. In isolated situations, diarrhea or constipation, itching, skin rash, cold feet and hands are recorded. Dry mouth is almost non-existent.
Contraindications for the use of rilmenidine
Pregnancy, severe kidney failure, lactation, severe depression. Particular care should be taken when prescribing the drug to patients who have recently had a myocardial infarction or cerebrovascular accident.
Interaction with otherssubstances
It is impossible to combine rilmenidine with antidepressants with different mechanisms of action - tricyclic and MAO inhibitors (in the first case, the hypotensive effect is weakened). Avoid combining the drug with alcohol.
In conclusion, it must be said that there are significant differences between different selective agonists of imidazoline I1 receptors, despite the similarity of pharmacodynamics. Considering the experience of using these drugs, their wider introduction into practice is a significant reserve for enhancing the safety and efficacy of arterial hypertension therapy, especially when accompanied by diabetes mellitus.
We looked at how imidazoline receptor agonist drugs work.
