The use of clonidine in late toxicosis of pregnant women

Clopheline is an antihypertensive drug whose action is associated with a characteristic effect on the neurogenic regulation of vascular tone. Like naphthyzine, clonidine stimulates peripheral alpha 1-adrenergic receptors and has a short pressor effect. But, penetrating through the blood-brain barrier, it stimulates alpha-2-adrenoreceptors of the vasomotor centers, reduces the flow of sympathetic impulses from the CNS, and reduces the release of norepinephrine from the nerve endings, thus providing a certain sympatholytic effect.

In connection with this, the main manifestation of the action of clonidine is the hypotensive effect. Persistent hypotensive action may be preceded by a short-term hypertensive effect - due to the excitation of peripheral alpha-adrenergic receptors. The hypertensive phase (lasting several minutes) is usually observed only with rapid intravenous and is absent in other ways of administration or slow introduction into a vein. The hypotensive effect usually develops 1-2 hours after ingestion and continues after a single dose of 6-8 hours.

The discovery of an analgesic effect in clonidine marked a new stage in the development of the problem of unpaid drug analgesia. An analgesic effect of clonidine at various, including systemic methods of administration, was found in animal and human experiments. It has been established that alpha-adrenomimetic compounds significantly increase the pain thresholds in different tests and inhibit the responses of neurons of the horn of the spinal cord to nociceptive stimuli.

The drug is effective in very small doses. Doses should be selected strictly individually. When administered orally as an anti-hypertensive agent is prescribed, usually starting with 0.075 mg (0.000075 g) 2-4 times a day. If the hypotensive effect is insufficient, increase the single dose every 1-2 days by 0.0375 mg (Ug tablets containing 0.075 mg) to 0.15-0.3 mg per reception up to 3-4 times a day.

Daily doses are usually 0.3-0.45 mg, sometimes 1.2-1.5 mg.

At high pressure, clonidine is administered intramuscularly, subcutaneously or intravenously. For intravenous administration, dilute 0.5-1.5 ml of 0.01% clonidine solution in 10-20 ml of isotonic sodium chloride solution and inject slowly - within 3-5 minutes. The hypotensive effect when injected into a vein manifests itself in 3-5 minutes, reaching a maximum after 15-20 minutes, and persists for 4-8 hours.

Long-term treatment with clonidine (clonidine) at doses of 0.3-1.5 mg / day is accompanied by a decrease in blood pressure in patients who are in both horizontal and vertical position.

Clinical studies suggest that clonidine causes a mild hypotensive effect, the addition of diuretics enhances it. The drug reduces cardiac output due to a decrease in the shock volume of blood and bradycardia. In addition, clonidine significantly reduces the overall peripheral resistance in the patient's standing position. Blood flow in the muscles varies little, with an antihypertensive reaction, the blood flow in the kidneys is maintained at a sufficient level, which is an advantage of the drug over others. This is important for obstetric practice, because according to modern data, even with the physiological course of pregnancy, the kidney function worsens. With long-term treatment, tolerance to the hypotensive effect of clonidine develops.

Absorption, distribution and excretion. The drug is a fat-soluble substance, it is well absorbed from the intestine and has a high volume of distribution. The half-life in blood plasma is about 12 hours, so it is enough to prescribe the drug twice a day. Almost half of it is excreted in the urine unchanged.

Clinical and experimental substantiation of the use of clonidine in preterm labor

In the experiment it was shown that the use of reduced doses of partusisten (1.25 μg / kg) and clonidine (5 μg / kg) showed their pronounced tocolytic effect. Oppression of contractile activity of the uterus continued for at least 90 minutes.

Clopheline in doses of 0.05-0.5 mg / kg exerts a depressant effect on the contractile activity of the uterus of intact rats and has a pronounced and prolonged tocolytic effect at different gestation times, manifested by a 70-80% decrease in the frequency and amplitude of contractions of the myometrium. The adrenergic nature of the tocolytic effect of clonidine is shown. In the tocolytic dose range, clonidine has a pronounced analgesic effect, inhibits blood pressure shifts in pain, and does not adversely affect breathing.

The technique of using clonidine in preterm labor:

A) at a high and moderate degree of threat of termination of pregnancy, clonidine should be administered intravenously drip by microperfusion at a dose of 0.01% solution of 1 ml in 50 ml of isotonic sodium chloride solution at an average rate of 17-24 ml / h. After the cessation of fights, the drug is prescribed in a dose of 0.05-0.075 mg 3 times a day. With a low degree of threat of termination of pregnancy, clonidine is administered immediately at a dose of 0.05-0.075 mg 3 times a day for 10-14 days with a gradual decrease in dose.

Clopheline is the drug of choice for treating the threat of termination of pregnancy in women with hypertensive form of late toxicosis;

• with a high degree of threat of interruption of pregnancy an effective method of preventing premature birth is the combined use of clonidine and beta-adrenomimetic - partusisten. The maximum clinical effect is achieved by intravenous administration of a half the therapeutic dose of clonidine with a microperfusion with the simultaneous appointment of partusisten. This combination of substances is most effective at earlier terms of the threat of abortion (34-36 weeks);
• with a moderate threat of interruption of pregnancy and poor tolerance of partuscysten or contraindications to its use, recommend the combination of clofheline in the above dosages with a calcium antagonist-nifedipine at a dose of 30 mg orally (the drug is administered 10 mg orally at an interval of 15-30 minutes 3 times under the control of blood pressure and heart rate in the mother). A pronounced tocolytic effect was noted in 65% of pregnant women with a gestational age of 32-35 weeks and less pronounced (60%) with gestational age of 36-37 weeks.

Negative effects of these combinations of substances on the mother's body, the condition of the fetus and the subsequent course of the birth act is not revealed. This combination of substances is appropriate to use with the purpose of prolonging pregnancy with prenatal discharge of amniotic fluid.

[1], [2], [3], [4]

Anesthesia of labor with clonidine in women in labor with hypertensive forms of late toxicosis of pregnant women

The concept of adrenergic regulation of pain sensitivity and circulation in pain is formulated, which has defined new directions for the unpaid medicamental therapy of pain syndromes:

• as a means of anesthesia;
• to enhance the analgesic effect of narcotic anapgetics and ensure a stable state of the cardiovascular system in conditions of opiate analgesia (clonidine, levodopa).

1. The method of enteral administration. Clo-phenol is recommended to be administered at a dose of 0.00015 g once. At the same time, after 30-60 minutes, its hypotensive effect begins to manifest, reaching its maximum expression after 2-3 hours and lasting not less than 6-8 hours. Against the background of maximum effect, the average basal arterial pressure decreases by approximately 15 mm Hg. A significant bradycardia is observed (a decrease in pulse rate by 8-15 beats / min) and a tendency to an insignificant decrease in the shock volume of the heart. It must be remembered that the mother in childbirth should actively participate in the second stage of labor (the period of expulsion), so increasing the dose of clonidine over 0.00015 is not advisable, either because of the possible significant reduction in blood pressure in some cases, and to avoid too pronounced psychoaggregating and generalized effects of the drug.

Simultaneously with the hypotensive effect, the use of clonidine in this dose leads to the development of a clear analgesia. In assessing the various components of the pain syndrome according to special individualized scales, it was found that 30 minutes after the reception of clonidine, the severity of the pain syndromes subjectively estimated by the women in labor decreases (the score is made in points: 0 - no pain, 1 - weak, 2 - moderate, 3 - 4 - very strong, 5 - unbearable, in nature: 1 - a feeling of heaviness, 2 - pressing, 3 - compressive, 4 - stitching, 5 - burning).

The analgesic effect progresses in time and reaches a maximum by the 90th minute after taking clonidine. Against this background, a significant weakening of the prevalence of pain and its motor manifestations is added. To assess the reliability and significance of the analgesic effect of clonidine, special mathematical methods of data processing - the matrix of states and conditional transitions - were used.

It is important to emphasize that the analgesic effect of clonidine and its some psychotropic effect practically do not change the nature of labor activity, and according to hysterography, even a decrease in the basal tone of the uterus is noted. The ability of clonidine to inhibit not only the emotional and motor manifestations of the pain syndrome is noteworthy. Against the backdrop of the drug is stable, without characteristic for periods of increased activity of the uterus, "hypertensive suppositories", the state of indicators of central hemodynamics. Obviously, clonidine has not only an anti-pain and emotion-normalizing, but also vegetostabilizing influence.

The latter in principle distinguishes clonidine from narcotic analgesics such as promedola, fentanyl, which form the basis of anesthesia in labor. This allows us to regard clonidine not only as a means of treating hypertensive conditions in childbirth, but also as a peculiar means for "premedication" of labor, which has an independent complex of positive effects. Moreover, combining clonidine with analgesics of the narcotic series seems very promising. It is possible to achieve a pronounced analgesic effect with an almost halved dosage of analgesics, which reduces their consumption and the severity of unwanted reactions (vomiting, respiratory depression of the parturient and fetal conditions, etc.), and also stabilizes the indices of central hemodynamics, which is rarely observed when used alone morphine-like compounds.

2. The technique of intravenous microcirculation. This technique is recommended in childbirth to stop high blood pressure figures and provide an anesthetic benefit at the same time. Offer its two options, differing in the severity of the hypotensive effect.

• to reduce blood pressure by 15-20 mm Hg. Art. The rate of clonidine administration is on the average 0.0005-0.001 mg / kg-hr, which, with a micro-perfusion time of 90-120 min, allows the introduction of clonidine in the body at doses not exceeding therapeutic. Reduction of blood pressure occurs on the average to 15-17th minute from the beginning of microperfusion. The effect persists through microperfusion, and also in the subsequent 180-240 min with complete extinction to the 280-320th minute from the beginning of clonidine administration, after which it becomes necessary to conduct repeated appointments of clonidine (by the time of the end of the first micro perfusion) or transition to another methods of antihypertensive therapy. Against the background of maximum arterial hypotension, there are no significant changes in the main volume indices of central hemodynamics. Only the systemic arterial tone is statistically reliably reduced according to the CIT data by an average of 1.5 units. There was no adverse effect of the drug on the fetal status according to cardiotocography and direct electrocardiography of the fetus.
• to reduce blood pressure to normal (i.e., values close to the arterial pressure in this woman in labor before pregnancy). The perfusion rate is from 0.003 to 0.005 mg / kg-hr, which, in the same manner as described above, results in a slight excess of single therapeutic doses of clonidine. The dynamics of the hypotensive effect of clonidine is the same as with microperfusion of the drug in smaller doses. At the same time, the volume indices of hemodynamics decrease - the shock and heart indexes by the end of the perfusion of clonidine decrease by 50-55 and 35-40%, respectively. Reduction of the minute volume of blood circulation is mainly due to a decrease in cardiac output and is not compensated by a sharp increase in the heart rate (an average of 67% of the initial level). The change in cardiac output is evidently associated with a significant decrease in systemic arterial vascular tone (according to KIT data, more than 6 units).

In parallel with the increase in arterial hypodynamics, there is a change in the indices of the life of the fetus. With the unchanged mean fetal heart rate, the myocardial reflex and the severity of the oscillations on the integrated direct ECG of the fetus decrease. The perfusion of clonidine does not significantly affect the frequency and amplitude of contractions and leads to a decrease in the basal tone of the uterus. Evaluation of the analgesic effect of clonidine in scores on the scale of N. N. Rastrigina did not reveal significant differences in the manifestations of the analgesic effect of clonidine in different doses. Therefore, clonidine when used in the form of intravenous perfusion at a rate of 0.0005-0.001 mg / (kg * h) is a tool that provides a complex of positive effects for the woman in labor - hypotensive and analgesic. At the same time, the use of microperfusion at a higher rate can be recommended only in exceptional cases, according to the vital indications from the parturient woman, and with the obligatory cardiotocographic control of the contractile activity of the uterus and the state of the fetus.

[10], [11], [12], [13]

Clopheline in postpartum practice

With the use of clonidine in puerperas with nephropathy, blood pressure (systolic) decreased on average by 25 mm Hg. Art. On the third day from the start of treatment and at 15 mm Hg. Art. - diastolic. Treatment lasted for 7-14 days. With the gradual abolition of clonidine, blood pressure remained normal the next days after birth. The number of postpartum complications in the study group was significantly less than in the control group. Lactation in all women who received clonidine was sufficient, despite the fact that nephropathy is a factor that violates lactation. The average bed-day after birth in puerperas treated with clonidine is significantly lower than in the control group. The content of catecholamines in the blood after treatment with clonidine after 5-8 days comes to normal, however, the release of noradrenaline remains low. Clinico-laboratory studies on the use of clonidine for the treatment of late toxicosis have revealed a favorable effect on the course of this disease, which allows us to recommend a wider use of the drug in pregnant women and puerperas with hypertensive forms of toxicosis.

Peridural microinjection of clonidine with the aim of anesthesia

In recent years, the prospect of clinical anesthesia is increasingly being discussed by direct delivery of drugs to the spinal cord material (intrathecally) or to the cerebrospinal fluid washing (epidural). The peridural route of administration of substances is technically more simple than intrathecal, and therefore more accessible to clinical practice. Observations of the effects of morphine, which is mainly used for microinjection, allowed to establish the positive and negative sides of epidural anesthesia. They note a rapid and prolonged anesthesia, a significant decrease in the consumption of drugs. At the same time, some of the side effects characteristic of analgesics and, first of all, of respiratory depression can not be avoided. The latter is explained by the lack of lipidotropicity of morphine, as a result of which the drug slowly diffuses into the substance of the spinal cord, which means that conditions are created for its spread with the aqueous phase of the cerebrospinal fluid in the rostral direction to the structures of the respiratory "center".

Clinical anesthesiology has only a few observations showing the efficacy and safety of using clonidine (clonidine) for spinal anesthesia.

In this regard, promising for epidural analgesia is clonidine, which differs from morphine-like compounds in a number of positive qualities:

• greater analgesic activity;
• higher lipidotropicity;
• absence of depressing effect on respiration;
• presence of vegetative normalizing effect in pain;
• absence of the state of "sympathetic deficiency", characteristic of morphine and manifested by the retention of urine and other symptoms.

The existing experience makes it possible to recommend microinjection of clonidine in order to arrest pain syndrome of various nature in pregnant and parturient women.

The peridural administration of clonidine in the dose range of 100-50 ml is accompanied once and for a time by the development of a rapid analgesic effect (after 5-10 min), remaining at the achieved level for at least 4-8 hours. During this period, the system hemodynamics indicators stabilize at the level of average values registered before microinjection, without any unwanted reactions from both the pregnant and intrauterine fetuses. For microinjection, it is advisable to use a standard ampoule solution (0.01%), which, in order to achieve the above dosage, is administered in an amount of not more than 0.05 ml (50 μg). A slight current experience of repeated microinjections shows that a minimum of twice the administration of clonidine in a single dose of 50 μg is possible, which ensures the prolongation of the therapeutic effect and satisfactory relief of the pain syndrome during the day.

Thus, the use of clonidine in pregnancy significantly expands the arsenal of medicines in the treatment of hypertensive conditions in obstetric practice, as well as in the provision of anesthesia in labor and in the postoperative period.

Schemes of treatment with clonidine in pregnancy

1. In pregnant high-risk groups for the development of late toxicosis, it is recommended to begin prophylactic application of calcium antagonists (finaptin 40 mg x 2 times a day) from 24 weeks gestation.
2. The combination of clonidine in a dose of 0.075 mg 1-2 times a day with phinoptin at a dose of 40 mg x 2 times a day is optimal for the treatment of hypertensive conditions in pregnancy, starting at 20 weeks of gestation in pregnant women with vegetative-vascular dystonia in hypertensive type and hypertensive disease. Doses of drugs should be individually selected for each patient. Treatment should be conducted without interruptions until delivery.

In this regard, it is important to take into account the pharmacodynamic interaction of clonidine and calcium antagonists, in particular nifedipine. It has been established that the hypotensive effect of clonidine (clonidine) is significantly reduced under the influence of small doses of calcium antagonists - nifedipine with sequential intravenous administration of these drugs to animals. It is believed that inhibition of the intracellular current of Ca ²⁺ under the influence of substances blocking slow calcium channels is the reason for eliminating the hypotensive effect of clonidine. The authors used the drugs according to the scheme: on the first day, clonidine once in a dose of 0.075 mg orally, followed by 60 minutes with nifedipine at a dose of 20 mg; on the second day - nifedipine in the same dose, then after 60 minutes - clonidine.

The hypotensive effect of nifedipine in a dose of 20 mg orally is maximum expressed after 50-60 minutes and gradually decreases by the 4 th hour of observation. The hypotensive effect of clonidine on oral administration at a dose of 0.075 mg completely manifests itself after 60 minutes and gradually decreases after a 2-3-hour period of stable hypotensive effect. It was found that after 60 minutes after taking clonidine ADP decreased by an average of 27 mm Hg. St., ADD - an average of 15 mm Hg. Art.

Nifedipine does not have an antihypertensive effect when used against the background of the hypotensive effect of clonidine. After 60 min after a single admission of nifedipine, the ADP decreased by an average of 35 mm Hg. Art. Subsequent administration of clonidine neutralized the hypotensive effect of nifedipine in such a way that the decrease in blood pressure when using two drugs in the same sequence at the 120th minute of observation was 10 mm Hg. Art. Less than the hypotensive effect of a single nifedipine.

3. To normalize the basic parameters of hemodynamics in pregnant women with hypertensive syndrome of late toxicosis, intravenous microfusion of clonidine in a dose of 1 ml of 0.01% solution (1 ml per 50 ml of isotonic sodium chloride solution) or intravenous infusion (1 ml per 200 ml of isotonic sodium chloride solution) .
4. The use of clonidine is indicated in pregnant women with hypertensive syndrome in high-risk groups for miscarriage with a prophylactic goal at a dose of 0.05 mg 3 times a day with a gradual dose reduction. The effect of clonidine on the contractile activity of the myometrium can reduce the number of premature termination of pregnancy in this category of patients.
5. Hypotensive therapy with clonidine is advisable to conduct under the control of central hemodynamics, not allowing a sharp drop in blood pressure in patients.

In addition to clinical signs, criteria such as the level of norepinephrine, cortisol, beta-endorphin are recommended as an evaluation of the effectiveness of treatment and the prevention of late toxicosis.

Adverse reactions of clonidine during pregnancy

The drug causes drowsiness (central sedation) and dry mouth, due to inhibition of salivation, and also through central mechanisms. There are, in addition, dizziness, constipation, soreness of the parotid glands, violations of the function of the gastrointestinal tract and allergic reactions, sometimes hallucinations. Orthostatic phenomena are often noted. Clopheline potentiates insulin-induced hypoglycemia in humans. In toxic doses, it causes pronounced bradycardia, miosis and hypotension.

In combination with beta-blockers, clonidine causes severe drowsiness. With a sharp withdrawal of the drug, irritability and a dangerous, often fatal outcome, increase in blood pressure. Treatment of withdrawal syndrome is performed with one clonidine or in combination with alpha and beta-blockers. If it is necessary to cancel the treatment with clonidine, it should be done gradually. If operative intervention is supposed, it is recommended to switch to other drugs. Clopheline causes a persistent sodium retention in the body and therefore, as a hypotensive agent, tolerance develops rapidly if it is treated without the use of diuretics.

It has been established that the use of clonidine for the treatment of late toxicosis of pregnant women (PTB) leads to a decrease in the level of norepinephrine, an increase in the content of cortisol and a decrease in the level of beta-endorphin in the blood plasma of pregnant women with nephropathy of grade II-III. There is a positive correlation between the content of catecholamines and beta-endorphin in pregnant women with hypertensive forms of late toxicosis of pregnant women.

In pregnant women with severe nephropathy, which develops against the background of hypertension, a hypokinetic type of blood circulation is formed, characterized by a significant increase in mean arterial pressure, total peripheral vascular resistance, a decrease in cardiac and shock index, and an increase in the coefficient of integral tonicity.

Combined therapy of hypertensive syndrome aimed at normalization of the central and vegetative system by alpha-adrenergic drug clonidine and calcium antagonist by phinoptin, relaxing the smooth muscles of arterioles, leads to improved microcirculation, reduction of total peripheral vascular resistance, integral tonicity, mean arterial pressure. Prevention of late toxicosis of pregnant women combined use of clonidine and phinoptin in women at high risk reduces the incidence of this complication of pregnancy.

Changes in the level of catecholamines, cortisol and beta-endorphin in women with pregnancy complicated by late toxicosis are interdependent and reflect the process of maladaptation of the organism in this disease. Positive changes in the level of hormones, mediators and neuropeptides during the treatment testify to the importance of these mechanisms of adaptation regulation, the potential resources of the body's biological systems that determine the restoration of physiological parameters in the rational therapy of late toxicosis.

[5], [6], [7], [8], [9]