Use of clofelin in late toxicosis of pregnancy

Clonidine is an antihypertensive agent whose action is associated with a characteristic effect on neurogenic regulation of vascular tone. Like naphthyzine, clonidine stimulates peripheral alpha1-adrenoreceptors and has a short-term pressor effect. However, penetrating the blood-brain barrier, it stimulates alpha2-adrenoreceptors of the vasomotor centers, reduces the flow of sympathetic impulses from the central nervous system and reduces the release of norepinephrine from nerve endings, thus exerting a sympatholytic effect to a certain extent.

In this regard, the main manifestation of the action of clonidine is the hypotensive effect. A persistent hypotensive effect may be preceded by a short-term hypertensive effect - due to the excitation of peripheral alpha-adrenoreceptors. The hypertensive phase (lasting several minutes) is usually observed only with rapid intravenous administration and is absent with other routes of administration or slow intravenous administration. The hypotensive effect usually develops 1-2 hours after oral administration of the drug and continues after a single dose for 6-8 hours.

The discovery of the analgesic effect of clonidine marked a new stage in the development of the problem of non-reimbursable drug analgesia. The analgesic effect of clonidine with various, including systemic, routes of administration was revealed in experiments on animals and humans. It was established that alpha-adrenomimetic compounds significantly increase pain thresholds in various tests and inhibit the responses of neurons in the posterior horn of the spinal cord to nociceptive stimuli.

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

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

For high blood pressure, clonidine is administered intramuscularly, subcutaneously or intravenously. For intravenous administration, 0.5-1.5 ml of a 0.01% solution of clonidine is diluted in 10-20 ml of isotonic sodium chloride solution and administered slowly - over 3-5 minutes. The hypotensive effect when administered intravenously appears after 3-5 minutes, reaching a maximum after 15-20 minutes, and lasts for 4-8 hours.

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

Clinical studies show that clonidine causes a moderate hypotensive effect, the addition of diuretics enhances it. The drug reduces cardiac output due to a decrease in stroke volume and bradycardia. In addition, clonidine significantly reduces total peripheral resistance in a standing position. Blood flow in the muscles changes little, with a hypotensive reaction, 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 a physiological course of pregnancy, kidney function deteriorates. With long-term treatment, tolerance to the hypotensive effect of clonidine develops.

Absorption, distribution and excretion. The drug is a fat-soluble substance, 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 sufficient to prescribe the drug twice a day. Almost half of it is excreted in the urine unchanged.

Clinical and experimental rationale for the use of clonidine in premature birth

The experiment showed that the use of reduced doses of partusisten (1.25 mcg/kg) and clonidine (5 mcg/kg) showed their pronounced tocolytic effect. Suppression of uterine contractile activity lasted for at least 90 minutes.

Clonidine in doses of 0.05-0.5 mg/kg has a depressing effect on the contractile activity of the uterus of intact rats and has a pronounced and prolonged tocolytic effect at different stages of pregnancy, manifested in a 70-80% decrease in the frequency and amplitude of myometrial contractions. The adrenergic nature of the tocolytic effect of clonidine has been demonstrated. In the range of tocolytic doses, clonidine has a pronounced analgesic effect, inhibits shifts in arterial pressure during pain, and does not have a negative effect on breathing.

Method of using clonidine in premature birth:

A) in case of high and moderate threat of miscarriage, it is advisable to administer clonidine intravenously by drip using microperfusion method 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 contractions have stopped, the drug is administered at a dose of 0.05-0.075 mg 3 times a day. In case of low threat of miscarriage, clonidine is administered immediately at a dose of 0.05-0.075 mg 3 times a day for 10-14 days with a gradual reduction of the dose.

Clonidine is the drug of choice for the treatment of threatened miscarriage in women with the hypertensive form of late toxicosis;

• in case of a high degree of threat of termination of pregnancy, an effective method of preventing premature birth is the combined use of clonidine and a beta-adrenergic agonist, partusisten. The maximum clinical effect is achieved with intravenous administration of half the therapeutic dose of clonidine using a microperfusor with the simultaneous administration of partusisten. This combination of substances is most effective at earlier stages of the threat of termination of pregnancy (34-36 weeks);
• In case of moderate threat of miscarriage and poor tolerance of partusisten or contraindications to its use, a combination of clonidine in the above dosages with a calcium antagonist - nifedipine at a dose of 30 mg orally is recommended (the drug is administered 10 mg orally at intervals 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 at 32-35 weeks of pregnancy and less pronounced (60%) at 36-37 weeks of pregnancy.

No negative effects of the above combinations of substances on the mother's body, the condition of the fetus, or the subsequent course of labor have been identified. This combination of substances is advisable to use for the purpose of prolonging pregnancy in the case of prenatal rupture of membranes.

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Pain relief during labor with clonidine in women in labor with hypertensive forms of late toxicosis of pregnancy

The concept of adrenergic regulation of pain sensitivity and blood circulation during pain was formulated, which defined new directions of non-reimbursable drug therapy of pain syndromes:

• as a means of anesthetic assistance;
• to enhance the analgesic effect of narcotic anapgesics and ensure a stable state of the cardiovascular system under conditions of opiate analgesia (clonidine, levodopa).

1. Enteral administration technique. Clonidine is recommended to be administered in a single dose of 0.00015 g. In this case, its hypotensive effect begins to manifest itself after 30-60 minutes, reaching its maximum expression after 2-3 hours and lasting for at least 6-8 hours. Against the background of the maximum effect, the average blood pressure decreases by approximately 15 mm Hg, reliable bradycardia (a decrease in pulse rate by 8-15 beats / min) and a tendency to a slight decrease in stroke volume of the heart are observed. It is necessary to remember that the woman in labor should actively participate in the second period of labor (the expulsion period), therefore, increasing the dose of clonidine above 0.00015 is inappropriate both because of the possible significant decrease in blood pressure in some cases, and in order to avoid too pronounced psychodepressant and general sedative effects of the drug.

Along with the hypotensive effect, the use of clonidine in the indicated dose leads to the development of distinct analgesia. When assessing the various components of the pain syndrome using special individualized scales, it turned out that already 30 minutes after taking clonidine, the severity of the pain syndrome subjectively assessed by women in labor decreases (the assessment is made in points: 0 - no pain, 1 - weak, 2 - moderate, 3 - strong, 4 - very strong, 5 - unbearable; by nature: 1 - a feeling of heaviness, 2 - pressing, 3 - squeezing, 4 - stabbing, 5 - burning).

The analgesic effect progresses over time and reaches its maximum by the 90th minute after taking clonidine. Against this background, a reliable 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 were used - matrices of states and conditional transitions.

It is important to emphasize that the analgesic effect of clonidine and its certain psychotropic effect practically do not change the nature of labor, and according to hysterography, a decrease in the basal (main) tone of the uterus was even noted. The ability of clonidine to inhibit not only the emotional and motor manifestations of pain syndrome is also noteworthy. Against the background of the drug's action, a stable state of central hemodynamics indicators is noted, without the "hypertensive suppositories" characteristic of periods of increased uterine activity. Obviously, clonidine has not only an anti-pain and emotionally normalizing effect, but also a vegetative-stabilizing effect.

The latter fundamentally distinguishes clonidine from narcotic analgesics such as promedol and fentanyl, which form the basis of anesthetic care during labor. This allows us to consider clonidine not only as a means of treating hypertensive conditions during labor, but also as a kind of means for "premedication" of labor, which has an independent set of positive effects. Moreover, it seems very promising to combine clonidine with narcotic analgesics. In this case, it is possible to achieve a pronounced analgesic effect with an almost halved dosage of analgesics, which reduces their consumption and the severity of adverse reactions (vomiting, respiratory depression of the mother and the condition of the fetus, etc.), and also ensures stabilization of central hemodynamic parameters, which is rarely observed with the independent use of morphine-like compounds.

2. Intravenous microperfusion technique. This technique is recommended in labor to relieve high blood pressure and provide anesthetic assistance at the same time. Two variants are offered, differing in the severity of the hypotensive effect.

• to reduce blood pressure by 15-20 mm Hg. The rate of clonidine administration is on average 0.0005-0.001 mg/(kg - h), which, with a microperfusion duration of 90-120 min, ensures the introduction of clonidine into the body of the woman in labor in doses not exceeding therapeutic ones. A decrease in blood pressure occurs on average by the 15-17th minute from the start of microperfusion. The effect persists throughout microperfusion, as well as in the next 180-240 minutes with complete fading by the 280-320th minute from the start of clonidine administration, after which there is a need for repeated administration of clonidine (by the time the effect of the first microperfusion ends) or a transition to other methods of antihypertensive therapy. Against the background of maximum arterial hypotension, no significant changes in the main volumetric indices of central hemodynamics are observed. Statistically, only systemic arterial tone decreases significantly according to KIT data by an average of 1.5 units. No negative effect of the drug on the fetus was detected according to cardiotocography and direct fetal electrocardiography data.
• to reduce blood pressure to normal (i.e. values close to the blood pressure of a given woman in labor before pregnancy). The perfusion rate is from 0.003 to 0.005 mg / (kg - h), which, with a similar duration of administration described above, leads to some 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, a decrease in volumetric hemodynamic parameters is noted - the stroke and cardiac indices by the end of clonidine perfusion decrease by 50-55 and 35-40%, respectively. A decrease in the minute volume of blood circulation occurs mainly due to a decrease in the stroke capacity of the heart and is not compensated for by a sharp increase in heart rate (on average by 67% of the initial level). The change in stroke capacity of the heart is obviously associated with a significant decrease in systemic arterial vascular tone (according to KIT data - by more than 6 units).

In parallel with the increase in arterial hypodynamics, there is a change in the vital signs of the fetus. With an unchanged average fetal heart rate, the myocardial reflex and the severity of oscillation on the integrated direct fetal ECG decrease. 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 points according to the N. N. Rastrigin scale 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 means 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 vital indications on the part of the woman in labor, and with mandatory cardiotocographic monitoring of the contractile activity of the uterus and the condition of the intrauterine fetus.

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Clonidine in the practice of the postpartum department

When clonidine was used in women in labor with nephropathy, arterial pressure (systolic) decreased by an average of 25 mm Hg on the 3rd day from the start of treatment and by 15 mm Hg - diastolic. Treatment continued for 7-14 days. With gradual withdrawal of clonidine, blood pressure remained normal all subsequent days after childbirth. The number of postpartum complications in the study group was significantly less than in the control group. Lactation in all women in labor who received clonidine was sufficient, despite the fact that nephropathy is a factor that disrupts lactation. The average bed-day after childbirth in women in labor who received clonidine treatment is significantly lower than in the control group. The content of catecholamines in the blood after clonidine treatment returns to normal after 5-8 days, but the release of norepinephrine remains reduced. Conducted clinical and laboratory studies on the use of clonidine for the treatment of late toxicosis revealed a favorable effect on the course of this disease, which allows us to recommend wider use of the drug in pregnant women and women in labor with hypertensive forms of toxicosis.

Epidural microinjections of clonidine for anesthetic purposes

In recent years, the prospect of clinical anesthesia by direct delivery of drugs to the spinal cord substance (intrathecally) or to the cerebrospinal fluid bathing the spinal cord (peridurally) has been increasingly discussed. The epidural method of drug administration is technically simpler than the intrathecal method and, therefore, more accessible for clinical practice. Observations of the effects of morphine, which is mainly used for microinjections, have made it possible to establish the positive and negative aspects of epidural anesthesia. Rapid and long-term pain relief, a significant reduction in drug consumption are noted. At the same time, some side effects characteristic of analgesics cannot be avoided, primarily respiratory depression. The latter is explained by insufficient lipoidotropism of morphine, as a result of which the drug slowly diffuses into the spinal cord substance, 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 effectiveness and safety of using clonidine (clonidine) for spinal anesthesia.

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

• greater analgesic activity;
• higher lipoidotropism;
• absence of a depressing effect on breathing;
• the presence of a vegetative-normalizing effect on pain;
• the absence of the state of “sympathetic deficit” characteristic of morphine and manifested by urinary retention and other symptoms.

The available experience allows us to recommend microinjections of clonidine for the purpose of relieving pain of various origins in pregnant women and women in labor.

A single epidural injection of clonidine in the dose range of 100-50 ml is accompanied by the development of a rapid analgesic effect (after 5-10 minutes), which remains at the achieved level for at least 4-8 hours. During this period, stabilization of systemic hemodynamic parameters is observed at the level of average values recorded before microinjection, without any adverse reactions from either the pregnant woman or the fetus. For microinjections, it is advisable to use a standard ampoule solution (0.01%), which is administered in an amount of no more than 0.05 ml (50 mcg) to achieve the above dosage. The current insignificant experience of repeated microinjections shows that at least two-time administration of clonidine in a single dose of 50 mcg is possible, which ensures prolongation of the therapeutic effect and satisfactory relief of pain within 24 hours.

Thus, the use of clonidine during pregnancy significantly expands the arsenal of drugs in the treatment of hypertensive conditions in obstetric practice, as well as in the provision of anesthetic assistance during childbirth and in the postoperative period.

Treatment regimens for clonidine during pregnancy

1. In pregnant women at high risk for developing late toxicosis, it is recommended to begin prophylactic use of calcium antagonists (finoptin 40 mg x 2 times a day) from 24 weeks of pregnancy.
2. The combination of clonidine at a dose of 0.075 mg 1-2 times a day with finoptin at a dose of 40 mg x 2 times a day is optimal for the treatment of hypertensive conditions during pregnancy, starting from the 20th week of pregnancy in pregnant women with vegetative-vascular dystonia of the hypertensive type and hypertension. The doses of the drugs should be individually selected for each patient. Treatment should be carried out without interruption 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 by small doses of calcium antagonists - nifedipine with sequential intravenous administration of these drugs to animals. It is believed that inhibition of the intracellular Ca ²⁺ current under the influence of substances blocking slow calcium channels is the reason for the elimination of the hypotensive effect of clonidine. The authors used the drugs according to the following scheme: on the 1st day, clonidine once at a dose of 0.075 mg orally, followed 60 minutes later by nifedipine at a dose of 20 mg; on the 2nd day - nifedipine at the same dose, then 60 minutes later - clonidine.

The hypotensive effect of nifedipine at a dose of 20 mg orally is maximal after 50-60 minutes and gradually decreases by the 4th hour of observation. The hypotensive effect of clonidine when taken orally at a dose of 0.075 mg is fully manifested after 60 minutes and gradually decreases after a 2-3-hour period of stable hypotensive effect. It was found that 60 minutes after taking clonidine, BPs decreased by an average of 27 mm Hg, BPd - by an average of 15 mm Hg.

Nifedipine does not exert a hypotensive effect when used against the background of the hypotensive effect of clonidine. 60 minutes after a single dose of nifedipine, BP decreased by an average of 35 mm Hg. Subsequent administration of clonidine leveled the hypotensive effect of nifedipine in such a way that the decrease in BP when using the two drugs in the same sequence at the 120th minute of observation was 10 mm Hg less than the hypotensive effect of nifedipine alone.

3. To normalize the main hemodynamic parameters in pregnant women with hypertensive syndrome of late toxicosis, intravenous microperfusion of clonidine at a dose of 1 ml of a 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) is indicated.
4. The use of clonidine is indicated in pregnant women with hypertensive syndrome in high-risk groups for miscarriage for prophylactic purposes at a dose of 0.05 mg 3 times a day with a gradual reduction in the dose. The effect of clonidine on the contractile activity of the myometrium allows to reduce the number of premature termination of pregnancy in this category of patients.
5. It is advisable to carry out antihypertensive therapy with clonidine under the control of central hemodynamic parameters, preventing a sharp decrease in blood pressure in patients.

In addition to clinical signs, it is recommended to use criteria such as the level of norepinephrine, cortisol, and beta-endorphin to assess the effectiveness of treatment and prevention of late toxicosis.

Adverse reactions of clonidine during pregnancy

The drug causes drowsiness (central sedative effect) and dry mouth due to inhibition of salivation, as well as through central mechanisms. In addition, dizziness, constipation, parotid gland tenderness, gastrointestinal dysfunction and allergic reactions, sometimes hallucinations are noted. Orthostatic phenomena are often noted. Clonidine 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. If the drug is suddenly discontinued, irritability and a dangerous, often fatal, increase in blood pressure occur. Withdrawal syndrome is treated with clonidine alone or in combination with alpha- and beta-blockers. If it is necessary to discontinue clonidine treatment, this should be done gradually. If surgery is planned, it is recommended to switch to other drugs. Clonidine causes persistent sodium retention in the body and therefore tolerance to it as an antihypertensive drug quickly develops if it is used without the use of diuretics.

It has been established that the use of clonidine for the treatment of late toxicosis of pregnancy (LTP) 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 grades 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 pregnancy.

In pregnant women with severe nephropathy that developed against the background of hypertension, a predominantly 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 stroke index, and an increase in the integral tonicity coefficient.

Combined therapy of hypertensive syndrome aimed at normalizing the central and vegetative systems with the alpha-adrenergic drug clonidine and the calcium antagonist finoptin, which relaxes the smooth muscles of arterioles, improves microcirculation, reduces total peripheral vascular resistance, the integral tonicity coefficient, and mean arterial pressure. Prevention of late toxicosis of pregnancy by combined use of clonidine and finoptin in women of high-risk groups reduces the incidence of this pregnancy complication.

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

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