The article will describe the characteristics of imidazoline receptor agonists.
Medicines that weaken the central parts of the sympathetic control of the heart and vascular systems occupy a significant place among modern antihypertensive drugs.
Currently, the issue of improving antihypertensive drugs of central action, based on the concept of imidazoline-type receptors, is relevant. Four selective imidazoline receptor agonists have already been produced. Drugs are available under various trade names. The main funds of this group are moxonidine (Cint, Physiotens) and rilmenidine (Tenaxum, Albarel). These are the most popular medications that are on the list of imidazoline receptor agonists.
Functional specificity and receptor localization
Imidazoline receptors are usually divided into two main groups, called I1 and I2.
Classification, their significance and functional features form the basis of many scientific studies.
I1 receptors are located in the neural membranes of the brain stem, kidneys, adrenal gland brain cells, platelets, and pancreas. It is precisely with the predominant receptor stimulation 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 the alleged object of pharmacological influence has so far been less studied.
Consider the mechanism of action of imidazoline receptor agonists.
Mechanism of action
The main target for antihypertensive drugs is the type I imidazoline central receptors, which are located on 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 the sympathetic nerves, which causes a weakening of the release of norepinephrine from adrenergic neurons. An addition to this mechanism is a decrease in adrenaline production of adrenaline, which also has imidazoline I1 receptors. The result of this effect is a decrease in the tone of resistive vessels, increased electrical stability of the myocardium and bradycardia.
Among other things, imidazoline receptors are located on the mitochondrial membranes of the tubular epithelium and in the kidneys.
Their stimulation (most researchers believe that these receptors are of type I1), which leads to suppression of sodium ion reabsorption and diuretic effect, is also involved in the activation of the hypotensive effect. Contributes to this and 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, the pancreatic I1 gland glands cause increased insulin secretion, which responds to carbohydrate loading and causes hypoglycemic effects.
Consider the most effective imidazoline receptor agonists.
Moxonidine (Cint, Physiotens)
The drug has almost no effect on α-adrenergic receptors and selectively excites the I1 imidazoline medulla receptors. The tone of sympathetic innervation decreases as a result, due to which the total peripheral vascular resistance decreases and, to a lesser extent, the strength and frequency of heart contractions. The volume of cardiac output is practically unchanged. Myocardial oxygen demand is reduced. Experimentally proven such action of moxonidine, as cardioprotective. It smoothly and effectively reduces diastolic and systolic blood 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 development and reduction of myocardial hypertrophy that already exists in the patient.
Among other things, 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 hypolipidemic effect of moxinidine was also established.
The latter is perfectly absorbed in the tract of the stomach and intestines (approximately 90%). It is excreted through the kidneys mainly in an unchanged form (through the liver to a lesser extent), but there is no significant cumulation even with moderate and mild renal failure. The hypotensive effect of this imidazoline receptor agonist lasts about a day. Moxonidine addiction and withdrawal syndrome are not recorded.
Indications of this tool
Symptomatic arterial hypertension and hypertension, especially when combined with the second type of diabetes and obesity (“metabolic syndrome”), as well as the 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 (inside after or during meals). With insufficient effectiveness, after two weeks, the dosage increases 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 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 fully and quickly absorbed when taken under the tongue; moxonidine is successfully used for hypertensive crises sublingually (once 0.4 mg in powdered form), in combination with calcium channel blockers or independently, especially with isradipine.
Data 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, facial flushing. Systolic pressure gradually decreases by about 19-20%, diastolic by 14-15, heart rate by 8-10.
When using moxonidine, you need to constantly monitor the pressure.
Side symptoms
This imidazoline receptor agonist rarely causes dizziness, orthostatic hypotension. Dryness in the oral cavity is insignificant; it occurs only in 7-12% of patients. In rare cases, a slight sedative effect is noted.
Contraindications
Atrioventricular blockade of the second or third degree, sinus node weakness syndrome, bradycardia (below 50 beats per minute), fourth degree of circulatory failure, severe renal failure, unstable angina, Raynaud's disease, age category up to 16 years (there is currently no experience with use 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. With the simultaneous administration of β-blockers and moxonidine, it is advisable to cancel the first blocker. Less commonly, clonidine enhances the effects of alcohol, sleeping pills and sedatives, but it is better to avoid such combinations. It goes well with diuretics. May increase the effect of hypoglycemic drugs.
Another imidazoline I1 receptor agonist is described below.
Rilmenidine (Tenaxum, Albarel)
An agent representing an oxazosine derivative has increased selectivity for reciprocal action with imidazoline I1 receptors both in the brain and in the periphery. The hemodynamic structure of the hypotensive effect is mainly associated with a decrease in peripheral vascular resistance in general. Monotherapy with rilmenidine makes it possible to effectively control pressure in 70% of patients with hypertension. Usually the antihypertensive effect is achieved quickly and smoothly, it is maintained stably during the day due to the duration reaching up to 24 hours.
The anti-hypertensive effect of an imidazoline receptor agonist is no worse than thiazide diuretics, angiotensin-converting enzyme inhibitors, β-adrenergic blocking agents, while being distinguished by excellent tolerance and few side effects. Recommended use with insufficient effectiveness of the above funds. I must say about the metabolic neutrality of rilmenidine - a beneficial effect on the functional renal condition, a decrease in microalbuminaria, and the absence of negative changes in lipid and carbohydrate metabolism.
Fully and quickly absorbed when ingested, there is no effect of the first passage of the drug through the liver. Rilmenidine is poorly metabolized, mainly excreted in the urine, its concentration in patients who use the drug for more than a year is almost stable.
In what cases is shown?
Arterial hypertension, including elderly patients, with renal failure, diabetes mellitus, creatinine clearance of at least 15 ml per minute.
The drug is often prescribed one tablet (1 mg) once a day before meals. If the hypotensive effect is insufficient during the 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. In this case, the cancellation should be gradual.
Rarely, due to rilmenidine, mood decreases, sleep and palpitations are disturbed, epigastrium and asthenia discomfort appear. In isolated situations, diarrhea or constipation, itching, rash on the skin, cooling of the legs and arms are recorded. Dry mouth is almost not observed.
Contraindications to the use of rilmenidine
Pregnancy, severe kidney failure, lactation, severe depression. Special care should be taken when prescribing the drug to patients who have recently suffered myocardial infarction or impaired blood circulation in the brain.
Interaction with other substances
It is impossible to combine rilmenidine with antidepressants that have different mechanisms of influence - tricyclic and MAO inhibitors (in the first case, the hypotensive effect is weakened). The combination of the drug with alcohol should be avoided.
In conclusion, it must be said that there are significant differences between the different selective agonists of imidazoline receptors I1, despite the similarity of pharmacodynamics. Considering the experience of using these drugs, their wider implementation in practice is a significant reserve for enhancing the safety and effectiveness of the treatment of arterial hypertension, especially when accompanied by diabetes mellitus.
We examined how imidazoline receptor agonists work.