Central and peripheral cholinolytics (antispasmodics)

Excitation of muscarinic cholinergic receptors of the myometrium causes increased hydrolysis of phosphoinositides, activation of phospholipase A ₂, activation of protein kinase C, and contraction. Increased hydrolysis of phosphoinositides is selectively blocked by 4-DAMP, but not by pirenzepine or AF-DX116. The ability of muscarinic antagonists to reduce myometrial contractions caused by an agonist and the data on the interaction of M-antagonists with myometrial M-cholinergic receptors obtained in functional studies and in binding experiments coincide. It is believed that it is difficult to consider that there are different subtypes of muscarinic cholinergic receptors in the myometrium. It is assumed that muscarinic cholinergic receptors of the guinea pig myometrium belong to the M1 subtype. Muscarinic responses are more diverse in ionic mechanisms than nicotinic ones. The muscarinic cholinergic receptor is apparently in all cases connected with ion channels not directly, but through a system of biochemical reactions. There are two main pathways - increased phosphoinositide metabolism and inhibition of adenylate cyclase activity. Both of these reaction cascades can lead to an increase in the intracellular concentration of Ca ²⁺, which is necessary for many muscarinic responses. It is carried out by increasing the permeability of the membrane, which allows calcium ions to enter the cell from the external environment, or by releasing Ca ²⁺ from intracellular reserves.

The use of anticholinergics, i.e. substances that block cholinergic reactive biochemical structures by predominantly central or peripheral action, during labor seems promising. By using certain anticholinergics, the physician has the ability to selectively influence the transmission of cholinergic impulses in various parts of the brain or on the periphery - in the ganglia. If we take into account that during labor the cholinergic mechanisms involved in the regulation of the birth act are especially strongly toned, then the danger of overexcitation of this highly sensitive system becomes obvious. In-depth study of the issues under consideration by pharmacologists has shown that the central effect of some anticholinergics leads to a restriction of the flow of central impulses and, consequently, promotes the normalization of relations between the higher centers of the nervous system and the internal organs. This provides the latter with the necessary physiological rest and restoration of impaired functions.

Spasmolitin (cyfacil, trazentin) belongs to the group of central anticholinergic substances, as it has a pronounced effect on central cholinergic synapses. Central anticholinergics enhance the effect of neurotropic and analgesic agents, and, unlike M-anticholinergics, have a facilitating effect on higher nervous activity in the form of enhancing excitatory and inhibitory processes, regulating higher nervous activity.

Spasmolytin has a relatively small atropin-like activity (j4) of atropine). In therapeutic doses, it does not affect the pupil size, salivary secretion, or heart rate. For obstetric practice, it is important that the myotropic effect of the drug, expressed no worse than that of papaverine, plays a major role in its spasmolytic effects. In this regard, spasmolytin is used in the clinic as a universal spasmolytic agent. Spasmolytin has a blocking effect on the autonomic ganglia, adrenal medulla, and pituitary-adrenal system.

It is believed that spasmolitin and aprofen are the most promising for clinical use. Unlike M-anticholinergics, N-anticholinergics have fewer side effects (dilated pupils, dry mucous membranes, intoxication, drowsiness, etc.).

Spasmolitin at a dose of 100 mg orally causes an improvement in conditioned reflex activity in humans, affecting the H-cholinergic structures of the subcortical formations, and also affects increased motor activity, which is important in women in labor with pronounced psychomotor agitation. Thus, pronounced motor agitation during labor is observed in 54.5% of cases.

Central anticholinergics, by blocking the cholinergic reactive systems of the brain, primarily the reticular formation, as well as the cerebral cortex, prevent overexcitation and exhaustion of the central nervous system and thereby prevent shock states.

Doses of spazmolitin during pregnancy and labor: single dose - 100 mg orally; total dose of spazmolitin during labor - 400 mg. No side effects or contraindications for the use of spazmolitin in pregnant women and women in labor have been noted.

Aprofen. The drug has peripheral and central M- and N-cholinolytic action. It is more active in peripheral cholinolytic effect than spasmolitin. It also has spasmolytic action. It causes increased tone and increased contractions of the uterus.

In obstetrics and gynecology, it is used to stimulate labor: along with increased uterine contractions, aprofen reduces spasm of the pharynx and promotes faster opening of the cervix in the first stage of labor.

Prescribed orally after meals in a dose of 0.025 g 2-4 times a day; 0.5-1 ml of a 1% solution is administered subcutaneously or intramuscularly.

Metacin. The drug is a very active M-cholinolytic agent. It is a selectively acting peripheral cholinolytic. Metacin acts on peripheral cholinergic receptors more strongly than atropine and spasmolytin. Metacin is used as a cholinolytic and spasmolytic agent for diseases accompanied by spasms of smooth muscles. Metacin can be used to relieve increased excitability of the uterus in the event of a threat of premature birth and late miscarriages, for premedication during cesarean section. The use of the drug reduces the amplitude, duration and frequency of uterine contractions.

Metacin is prescribed orally before meals at 0.002-0.005 (2-5 mg) 2-3 times a day. 0.5-2 ml of a 1% solution is injected subcutaneously, into muscles and into a vein.

Halidor (benzcyclane) is a drug that is many times more effective than papaverine in peripheral, spasmolytic and vasodilatory action. In addition, the drug has a tranquilizing and local anesthetic effect. Halidor is a low-toxic compound and causes only minor side effects.

It has been proven that halidore is less toxic than papaverine by all routes of administration. The teratogenic effect was studied on a large number of animals - mice, rabbits, rats (100-300). According to research data, when halidore was administered at 10-50-100 mg/kg to rats and mice and at 5-10 mg/kg to rabbits from the very beginning of pregnancy, despite the extremely high doses, no teratogenic effect was detected.

Halidor has a pronounced direct myotropic effect: in a concentration 2-6 times lower than papaverine, it relieves spastic contractions of the myometrium caused by oxytocin. The drug also has a clear local anesthetic effect.

When studying the effect of halidorin on blood circulation in an experiment on anesthetized cats and dogs, intravenous administration at a dose of 1-10 mg/kg of body weight caused a temporary decrease in arterial pressure, but to a lesser extent and less long-lasting than papaverine. The drug increases coronary blood circulation and reduces the resistance of the coronary arteries, and intracarotid administration of the drug causes a significant, but short-term increase in blood supply to the brain (in an experiment on cats).

In terms of the strength and duration of its effect on cerebral circulation, halidor is superior to no-shpa and papaverine, without creating a disproportion between the blood supply to the brain and the oxygen consumption of brain tissue.

In clinical conditions, significant peripheral vasodilatory effect of halidorin has been revealed. The drug is also used to relieve peripheral spasms under anesthesia and surgery. Halidorin is widely used in the treatment of coronary circulation disorders, as it sharply increases the utilization of oxygen by the myocardium and shifts the ratio of the concentration of oxidized and reduced forms towards accumulation of the latter in the myocardium.

Recently, new data on the effect of halidorin on the heart have been obtained. Its "classic" effect, which dilates coronary vessels, is beneficial for various forms of angina pain, since the drug is not a very strong vasodilator - it has an antiserotonin effect. A vagolytic effect on the heart has been revealed, as well as a specific inhibition of certain metabolic processes that affects the metabolism of the heart.

The visceral spasmolytic effect of halidorin is most characteristic for obstetric practice. Cessation of dysmenorrhea pains is noted. Due to its tranquilizing effect, the drug reduces mental stress in the premenstrual period. In an experiment, some authors have developed an in vivo method for assessing the spasmolytic activity of drugs in rats by measuring smooth muscle contractions in response to local application of acetylcholine. The proposed experimental design allows for rapid assessment of the potential selectivity of the action of spasmolytics on individual internal organs - the relative activity of spasmolytics in relation to the suppression of contractions of a hollow organ (uterus, bladder, colon and rectum) caused by local application of acetylcholine is determined.

Halidor is successfully prescribed during the period of cervical dilation and expulsion of the fetus. In cases of spastic state of the uterine os, under the influence of the drug, the duration of the first and second stages of labor decreases. Studies have studied the spasmolytic effect of halidor in coordinated labor, dystocia of the cervix. Shortening of the period of dilation and smoother movement of the head along the birth canal were noted.

Compared with no-shpa and papaverine, halidor has a more pronounced antispasmodic effect without changing the pulse rate and blood pressure. The drug is well tolerated by women in labor at a dose of 50-100 mg orally, intramuscularly and intravenously in a mixture with 20 ml of 40% glucose solution.

There are no absolute contraindications to the use of halidorin. Side effects are extremely rare and safe. There are reports of nausea, dizziness, headache, dry mouth, throat, drowsiness, and allergic skin rashes.

When the drug is administered parenterally, local reactions occur in extremely rare cases.

Release forms: tablets (dragees) of 0.1 g (100 mg); 2.5% solution in ampoules of 2 ml (0.05 g or 50 mg of the drug).

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