Pharmacokinetics of drugs during lactation. Features of the clinical pharmacology of drugs in pregnant women, lactating women Features of the use of drugs in lactating women

The need to prescribe drug therapy to lactating women is by no means a rare situation in our time. And if with an acute illness of mild severity or chronic pathology in a state of partial remission, you can try to cope without drugs, then in cases that threaten the life or health of the mother, such a possibility is not even discussed. No doctor will leave a patient with purulent mastitis and the threat of sepsis without antibiotic therapy or a woman with progressive macroprolactinoma without bromocriptine. In such situations, Ukrainian doctors usually recommend not breastfeeding. Is such a recommendation always justified? It turns out that it doesn't. In developed countries, where artificial feeding is not considered a worthy alternative to natural feeding, such a formal approach has long been abandoned. In most cases, European experts not only allow, but also strongly recommend drug treatment of a nursing mother to maintain lactation. To do this, you need to know the basic principles of prescribing drugs during lactation, as well as be able to choose the best drug.

Lyudmila Shtakkelberg (Berlin Pharmacovigilance Center

and embryonic toxicity).

The main sources of information for the doctor in assessing the safety of drugs prescribed during lactation are the instructions for use of the drug, pharmacological reference books, manuals on clinical pharmacology and therapy. In most cases, this information is not enough for the doctor to be able to give a full and comprehensive consultation to the patient during breastfeeding. Therefore, a call center was established at the Berlin Center for Pharmacovigilance and Embryonic Toxicity a few years ago, the task of which is to provide advice to doctors, as well as to pregnant and lactating women themselves, on drug therapy. What are the most frequently asked questions by our patients?

After analyzing the calls received by the center in 2006 (a total of 11,286 calls), we found that about 63% of the questions related to taking medication during pregnancy, 35% - during lactation, 2% - taking medication by the father of the child. The most frequently asked questions were about the safety of psychotropic, antihistamine, anti-inflammatory, hormonal, antibacterial drugs and analgesics.

How to evaluate the safety of a particular drug and the possibility of its use during lactation? Of course, this is determined by the pharmacokinetic characteristics of the drug. Moreover, in this case, pharmacokinetics is studied from the point of view of a three-component model: mother - mammary gland - child.

First of all, the ways in which the drug enters the mother's body, its distribution, metabolism and excretion are taken into account. An equally important factor is the characteristics of metabolism in the mammary gland, the degree and mechanism of transition into milk (passively, with the help of a carrier, actively). The transfer of drugs into breast milk is facilitated by the following properties: low molecular weight, low degree of dissociation, alkaline environment, good fat solubility, low protein binding. It should be remembered that in the first two or three days after childbirth, the structure of the mammary glands is such that substances with a large molecular weight (immunoglobulins, lipids, etc.) can also penetrate into the milk, although this is not dangerous due to the small amount of colostrum formed.

Be sure to take into account the pharmacokinetics of the drug in the child's body: oral bioavailability, metabolism, distribution in the child's body, the possibility of penetration through hematological barriers, excretion routes.

Oral bioavailability refers to the property of a drug to reach the systemic circulation after oral administration. Drugs with negligible oral absorption are either hardly resorbed from the gastrointestinal tract or are neutralized in the liver before reaching the systemic circulation. Drugs with virtually zero oral absorption include insulin, infliximab, gentamicin, omeprazole, ceftriaxone, heparin, and enoxaparin.

Thus, it is possible to highlight the main properties of drugs with low risk during breastfeeding:

- short half-life;

- inactive or rapidly excreted metabolites;

- low relative dose;

- low toxic potential;

- low oral bioavailability.

The two most widely used indicators, the relative infant dose and the ratio of drug concentration in mother's milk and plasma of the child, help to assess the risk to the child during maternal drug therapy. The relative infant dose is understood to be the part of the maternal daily dose of the drug in%, calculated per kilogram of mother's body weight, which the child will receive with full breastfeeding during the day, based on the child's body weight.

The ratio of the drug concentration in mother's milk and the plasma of the child is used to assess the accumulation or dilution of the drug in milk compared to maternal plasma.

There are a number of ways to minimize the risk of drug therapy in breastfeeding mothers. In some cases, it is possible to postpone treatment for a longer time or even refuse to take medication. When it is not possible to refuse the prescription of drugs, the doctor, of course, should choose drugs with a minimum transition into mother's milk. For some diseases, the optimal solution may be to change the form or method of administration of the drug, for example, inhalation instead of tablet forms, etc.

One of the most important principles of drug therapy during lactation is a pause between feedings during the peak concentration of the active substance in the mother's blood plasma and milk. If the treatment regimen allows, the drug should be taken before the child's longest sleep period, in most cases in the evening. When it is impossible to refuse treatment for the mother, and the medical risk to the child exceeds the benefits of breastfeeding, either a temporary pause or refusal to feed the child with mother's milk is resorted to.

The greatest care in drug therapy of a nursing mother should be observed in such cases: the neonatal period, premature babies, sick children, the use of high dosages or long-term treatment.

I would like to draw attention to situations in which, despite the prevailing opinion about the need to refuse breastfeeding, such a cardinal step is not mandatory. Our experience shows that lactation can be maintained with local anesthesia, the use of hormonal contraceptives, bromocriptine, cabergoline, tetracyclines, sulfonamides, co-trimoxazole, glucocorticosteroids, heparin and low molecular weight heparins, oral anticoagulants (prophylactic administration of vitamin K to a newborn is necessary in the first 4 weeks of life 1 mg 3 times a week).

An analysis of literature data and statistical indicators allows us to conclude that doctors tend to overestimate the side effects of mother's drug therapy on the child's body. So, Ito et al. (1993), having studied the effect on children of drugs used by a nursing mother (the number of child-mother pairs - 838), found that only in 11% of cases there were mild symptoms in a child (against the background of antibiotic therapy - "soft stools", the use of psychotropic drugs - sedative effect, antihistamine - excitability, etc.). None of the children experienced any severe side effects of the mother's drug therapy.

After analyzing one hundred references in the literature to date about the occurrence of side effects in breastfed children in the treatment of mothers, Anderson et al. found that the probable connection of symptoms with the drug took place in 47 cases, and in 53 - possible. In 3 cases, deaths were observed, and in all cases, psychotropic drugs were used, and children had additional significant risk factors. I would like to draw attention to the fact that 78 children out of a hundred were younger than 2 months (63 were newborns), and only four were older than 6 months.

One of the fatal outcomes of a child after drug therapy of the mother is described by Koren et al. (Lancet, 2006). After analgesic therapy in connection with the episiotomy (paracetamol 1000 mg 2 times a day + codeine 60 mg 2 times a day), the mother experienced a state of somnolence. From the 2nd day, the dose of drugs was halved, but the child began to notice a weakening of the sucking reflex, and from the 7th day - lethargy. On the 12th day, grayness of the skin was observed, and on the 13th, the death of the child was ascertained. Post mortem, the concentration in the blood and milk of the morphine-active metabolite of codeine was determined, which was 70 and 87 ng/ml, respectively. A familial polymorphism of the CYP2D6 enzyme was established in the child and mother, followed by the development of an intensive ultra-rapid metabolism of codeine to morphine.

The most problematic group of medications used for lactation are psychotropic drugs. Nevertheless, under strict medical supervision, lactation can be maintained in many neuropsychiatric diseases. Based on our experience, the safest antiepileptic drugs for a child are gabapentin, valproates, levetiracetam, vigabatrin.

We believe that if necessary, a nursing mother can take antidepressants. Many tricyclic antidepressants and selective serotonin reuptake inhibitors have a low relative dose (the exceptions are doxepin and fluoxetine, which should not be taken during lactation).

Our accumulated data allow us to conclude that phenothiazines, clozapine, risperidone, quetiapine, and olanzapine can be used as monotherapy among antipsychotics. Breastfeeding while taking lithium should only be permitted to the mother if the parents insist, as lithium has a long half-life (17-24 hours, up to 96 hours in newborns), low molecular weight, zero plasma protein binding, and 100% oral bioavailability. In this case, constant medical monitoring and regular determination of the concentration of lithium in the child's plasma is necessary.

When prescribing benzodiazepines, drugs with a short half-life should be chosen, used at low doses for a short time. The most favorable properties are drugs such as oxazepam (low fat solubility, relative dose less than 1%) and lormetazepam (relative dose 0.04%, degree of binding to plasma proteins 88%, inactive metabolite).

When prescribing antiepileptics and antipsychotics during lactation, a few basic rules should be remembered. Usually, monotherapy with these drugs is well tolerated by children. In the case of combination therapy, a strictly individual approach should be observed with constant monitoring of the child's condition. It is necessary to warn the mother that if the slightest symptoms appear, it is necessary to consult a doctor and, if possible, determine the concentration of the active substance in the child's blood serum.

In addition to combined therapy with psychotropic drugs, it is rather problematic to prescribe drugs such as cytostatics, radionuclides and iodine-containing contrast agents during lactation, as well as the use of iodine-containing antiseptics on a large surface of the body. In each case, the decision is made individually, in many cases it may be necessary to temporarily or permanently stop breastfeeding.

It is important for a practitioner to know which drugs of the most commonly prescribed groups of drugs should be chosen when treating a nursing mother. From non-steroidal anti-inflammatory drugs, ibuprofen, flurbiprofen, diclofenac, mefenamic acid can be used. They pass into milk in small quantities, have a short half-life and form inactive metabolites. The use of salicylates, ketoprofen, fenbufen (active metabolites), naproxen, piroxicam (long half-life), indomethacin (variable half-life due to enterohepatic circulation) is undesirable.

With pain syndrome, paracetamol (combinations with codeine, caffeine), ibuprofen, acetylsalicylic acid (isolated cases) can be the means of choice during lactation, with migraine - sumatriptan. For the purpose of antibiotic therapy, penicillins, cephalosporins, erythromycin, roxithromycin can be prescribed.

A group of researchers studied the safety of metronidazole in nursing mothers. The ratio of the concentration of the active substance in the mother's milk and the plasma of the child is 0.9. When taking a single dose of 2 g per os or long-term therapy of 1.2 mg / day, the concentration of the active substance in milk measured after 2-4 hours averaged 21 μg / ml, the maximum was 46 μg / ml (Erickson, 1981; Heisterberg, 1983 ; Passmore, 1988). The relative dose did not exceed 20% (average 12%) and corresponded to the children's dosage of metronidazole. Among the 60 mother-child pairs observed, not a single case of specific toxicity was noted. Thus, the studies conducted allow us to recommend continuing breastfeeding, using metronidazole in the evening after the last feeding.

For the treatment of bronchial asthma in a nursing mother, inhaled glucocorticoids, beta-2-adrenergic agonists, cromones, theophylline can be used, for allergic diseases - loratadine, cetirizine.

When prescribing drug therapy to a nursing woman, the effect of drugs on lactation should also be taken into account. A number of drugs are dopamine antagonists, stimulate the secretion of prolactin and lactation. These include antipsychotics (phenothiazines, haloperidol, risperidone, levosulpiride), α-methyldopa, domperidone, metoclopramide, reserpine. Ergotamine derivatives (bromocriptine, cabergoline, lisuride, methylergometrine), amphetamines, diuretics, estrogens have the opposite effect.

Summarizing all of the above, it is possible to determine the basic principles of drug therapy during lactation. First, it should be remembered that the lack of information about the tolerability of a particular drug during lactation does not mean the absence of danger. In addition, the results of new studies on the safety of such therapy appear regularly, and recommendations for the use of drugs in lactating women may change over time.

However, don't overdramatize the situation. Toxic reactions in children during drug treatment of the mother appear quite rarely and in most cases are mild. Currently, experts emphasize that the need for a pause during lactation occurs rarely, and the refusal of breastfeeding - in isolated cases. For most therapeutic indications, there are drugs of choice that are practically safe for a breastfed baby. If possible, monotherapy should be carried out, with a long course of treatment, the drug should be taken in the evening, after the last feeding.

For more information on the work of the Berlin Center for Pharmacovigilance and Embryonic Toxicity, please visit: www.embryotox.de.

L. Shtakkelberg
Prepared by Natalia Mishchenko

Of fundamental importance for the implementation of effective and safe pharmacotherapy in the postpartum period are the pharmacokinetic features of the drugs prescribed during these periods. According to P. J. Lewis (1982), 2/3 of all drugs used in the clinic in pregnant women are used in the postpartum period. The maximum amount of drugs entering the mother's milk does not exceed 1-2% of the dose administered to a nursing woman, and therefore, probably has no effect on the child's body.

The entry of drugs and their metabolites into breast milk is influenced by the same factors as their passage through other lipid membranes. The drug, which is in the body of a nursing woman, enters the milk through the epithelial cells of the mammary glands. The epithelial lipid membrane is a barrier between slightly alkaline serum and breast milk, which is slightly acidic.

The transfer of drugs from the blood into breast milk depends on the molecular weight of the drugs, their chemical properties, dissociation constant, lipid solubility, degree of ionization (pKa), degree of binding to the proteins of the woman's blood serum and breast milk, and the pH value of breast milk. The pH level of breast milk varies from 6.35 to 7.65. These fluctuations can significantly affect the level of excretion of drugs into breast milk.

Low molecular weight drugs pass into breast milk by passive diffusion; a higher degree of transition is typical for non-ionized lipid-soluble drugs. The passage through the membrane of partially ionized drugs depends on the pH of the medium and the M/P ratio (M is the concentration of the drug in breast milk; P is the concentration in plasma). It has been established that the M / P coefficient is lower for drugs that have an acidic reaction than an alkaline one [Soradi I., 1980].

Non-ionized fat-soluble substances with minimal ability to bind to plasma proteins diffuse better into breast milk. In order for the drug to get from the blood to the alveolar cells of the mammary gland, it must pass through the capillary endothelium, interstitial fluid, and cell membranes. Since non-ionized drug molecules are fat-soluble, and fat is the main component of cell membranes, drugs with low molecular weight (less than 200 Da), non-ionized drugs with high lipid solubility (for example, antipyrine) can quickly pass from the blood into breast milk.

So, according to Ph. O. Andersen (1979), along with breast milk, such drugs as indomethacin, antibiotics of the levomycetin group, benzylpenicillin, tetracyclines, sulfonamides, nalidixic acid, neodicumarin, reserpine, chlorpromazine and other phenothiazine derivatives, psychotropic, anticonvulsant drugs enter the child's body.

Factors such as the level of blood flow in the mammary gland, the daily production of breast milk, its fat and protein composition, as well as the coincidence of the time of feeding the child and taking the drug by the mother are also important.

The leading, but not always decisive factor is the ratio of drug concentrations in breast milk and mother's blood serum. The adverse effect of the effect of the drug on the infant is usually observed in cases where this coefficient is ≥1. This, however, does not mean that side effects must necessarily occur at this ratio. The amount of the drug that enters the child with breast milk depends on the degree of absorption of the drug in the mother's digestive tract. For example, digoxin, which has a relatively high M/P ratio, is not detected in the blood of a child in toxic concentrations. At the same time, some medicinal substances for which this coefficient is low can cause adverse reactions in children.

LP taken by the mother during pregnancy may have an undesirable effect on the fetus and newborn. No medicine, including for topical use, can be considered absolutely safe. According to statistics, at least 5% of all congenital anomalies are associated with medication. The penetration of drugs through the placenta depends on their physicochemical properties, the state of the placenta and placental blood flow. If it is necessary to use drugs, it should be taken into account that most of them penetrate the placental barrier, and the rate of their inactivation and excretion in the embryo and fetus is not high enough, which increases the risk of their adverse effect on the fetus.

In the intrauterine development of the fetus, three critical periods are distinguished, which differ in sensitivity to damaging exogenous and endogenous factors:

- 1st week of pregnancy- stage of pre-implantation development. At this time, the toxic effect of medicinal factors is manifested, most often, by the death of the embryo.

- Stage of organogenesis, which lasts about 8 weeks. Especially high risk of fetal damage in the first 3-6 weeks after conception. The drug used at this time in the treatment of a pregnant woman can:

Do not have a visible effect on the fetus;

Cause spontaneous miscarriage;

Cause a gross sublethal anomaly in the development of the organ that developed most intensively at the time the mother took the medicine (true teratogenic effect);

Become the cause of a not so significant, but irreversible metabolic or functional disorder (latent embryopathy), which may manifest itself later in life.

- 18-22 weeks pregnant when the bioelectrical activity of the brain changes rapidly in the fetus, the hematopoietic, endocrine systems are actively formed

Medicines prescribed to a pregnant woman immediately before childbirth can affect their course and cause various disorders in infants, especially premature ones, in the first hours and days of life. Among the actions of drugs in a pregnant woman, embryotoxic, embryolethal, teratogenic and fetotoxic are distinguished.

Depending on the possible risk of developing an adverse effect, drugs are divided into groups of high, significant and moderate risk (Table 5.1).

Table 5.1. The division of drugs depending on the degree of risk of developing adverse effects on the fetus.

High risk drugs	Medium risk drugs	Moderate risk drugs
Cytostatics Antifungal antibiotics Antitumor antibiotics Immunosuppressants Sex hormones (androgens, diethylstilbestrol)	Antibiotics Antiprotozoal drugs (aminoquinoline derivatives) Anticonvulsants (phenytoin, carbamazepine) Anti-Parkinsonian drugs Lithium salts Glucocorticosteroids (systemic action) NSAIDs Hypoglycemic oral drugs Neuroleptics Ethyl alcohol Indirect anticoagulants Antithyroid drugs (mercasolil, iodides) Bupivacaine Mepivacaine	Sulfonamides Metronidazole Tranquilizers Sex hormones (estrogens) Articaine Lidocaine Propranolol Diuretics

Many countries use the division of drugs into categories depending on the possible risk of adverse effects on the fetus, approved by the US Food and Drug Administration - FDA (Food and Drug Administration).

Category of drugs	Effect on the fetus
A	as a result of adequate and well-controlled studies, there is no risk of adverse effects on the fetus in the first trimester of pregnancy and there are no data on such a risk in subsequent trimesters
V	Animal reproduction studies have shown no risk of adverse effects on the fetus, and there are no adequate and well-controlled studies in pregnant women
WITH	Animal reproduction studies have shown adverse effects on the fetus, and there are no adequate and well-controlled studies in pregnant women, but the potential benefit associated with the use of the drug in pregnant women may justify its use, despite the possible risk.
D	there is evidence of the risk of adverse effects of drugs on the human fetus, obtained from research or practice, however, the potential benefits associated with the use of drugs in pregnant women may justify its use, despite the possible risk.
X	Animal tests or clinical trials have revealed fetal developmental disorders and / or there is evidence of the risk of adverse drug effects on the human fetus, obtained during research or in practice; The risk associated with the use of drugs in pregnant women outweighs the potential benefits.

Mechanisms of adverse effects on the fetus of drugs received from the mother during pregnancy:

Direct effect on the embryo, causing lethal, toxic or teratogenic effects;

Changes in the functional activity of the placenta (vasoconstriction) with impaired gas exchange and nutrient exchange between the mother and fetus;

Violation of the dynamics of biochemical processes in the maternal body, indirectly affecting the physiological state of the fetus;

Violation of hormonal, vitamin, carbohydrate and mineral balance in the body of a pregnant woman, which negatively affects the fetus.

When prescribing drugs during pregnancy, the following points should be considered:

The effect of drugs on the course of pregnancy;

The effect of pregnancy on the effect of the drug.

Most of the drugs are able to cross the placenta. The amount of a substance that enters the fetus is proportional to its concentration in the mother's blood and depends on the state of the placenta. The permeability of the placenta increases by the end of 32-35 weeks. Lipophilic, low molecular weight drugs penetrate the placenta better and are rapidly distributed to fetal tissues. The teratogenic effect can be due not only to the direct influence of the drug that has entered the embryo's body, but also to those metabolic and blood supply disorders of the uterus that it caused in the mother's body.

Some drugs are metabolized when passing through the placenta, and toxic degradation products may be formed. Once in the umbilical vein, they enter the fetal liver, where they are also metabolized. Since the activity of oxidative enzymes in the fetus is reduced, the metabolism of drugs is slow.

With toxicosis of pregnant women, due to fluid retention in the extracellular space, the distribution of LP changes. Glomerular filtration decreases, hepatic metabolism is disturbed, their half-life is prolonged, which leads to an increase in plasma concentration and the possible development of toxic effects (Table 5.3).

Table 5.3. Changes in the pharmacokinetics of drugs during pregnancy.

Pharmacokinetic parameter	Direction of change	Note
Absorption	Decrease in late pregnancy due to slower rate of evacuation from the stomach to the intestines
Communication with proteins	affects the rate and amount of the drug delivered through the placenta (the closer the relationship with the mother's proteins, the smaller the amount goes to the fetus)	Not significant for highly lipophilic drugs
Volume of distribution	Increase in the apparent volume of distribution of drugs due to an increase in BCC and total body weight	Has no clinical significance, tk. at the same time, clearance increases and the bound fraction of the drug decreases
Metabolism	decreased conjugation and oxidation increased sulfation No change in clearance of drugs with a high hepatic extraction ratio
Selection	increases glomerular filtration and elimination of drugs that are excreted mainly by the kidneys. In late pregnancy, slowing of renal blood flow and a decrease in the excretion of drugs are possible.	In late pregnancy, the excretion of drugs is affected by the position of the body of the pregnant woman.

Factors predisposing to the risk of developing adverse effects in the mother, fetus, newborn during dental treatment of a pregnant or lactating patient:

I trimester of pregnancy;

Repeated pregnancy, especially in a multiparous woman;

Age of the pregnant woman (over 25 years old);

Burdened obstetric and gynecological history;

Anamnesis, aggravated by somatic pathology, especially diseases of the elimination organs (liver, kidneys, intestines);

Pregnancy proceeding with toxicosis;

The use of drugs that cross the placenta and into breast milk;

A significant dose of the drug;

Features of the patient's neuropsychic status and the patient's negative attitude towards pregnancy and upcoming childbirth.

The secretion of milk under physiological conditions is controlled by the hormone of the anterior pituitary gland - prolactin. The rate of its production is regulated by the neurosecretory structures of the hypothalamus, which synthesize special substances that stimulate (prolactoliberin) or inhibit (prolactostatin) the release of prolactin.

The blood supply to the mammary glands, which is regulated to a certain extent by hormones such as somatotropin, adrenocorticotropin, insulin, etc., has a significant effect on milk formation. norepinephrine) in blood plasma. An increase in their content leads to a decrease in the volumetric rate of blood flow in the mammary gland and, consequently, to inhibition of milk secretion. The separation of the latter occurs with the help of myoepithelial cells located along the milk ducts, the activity of which is regulated by the hormone of the posterior pituitary gland oxytocin.

Naturally, drugs that affect the function of the endocrine glands, trophism and blood supply to the mammary gland can stimulate or inhibit its milk-forming function.

Hypolactia (reduced milk production) can be primary (caused by insufficient production of hormones that regulate the secretory function of the mammary glands) and secondary (develops against the background of any disease).

Synthetic hormones that stimulate the secretory function of the mammary gland (lactin ♠, demoxytocin, etc.) or drugs that stimulate the secretion of prolactin (metoclopramide, amisulpride, etc.) are usually used to treat primary hypolactia.

Treatment of secondary hypolactation is usually complex and is aimed at the underlying disease and restoration of lactation.

It should be noted that, in addition to taking drugs, in the treatment of hypolactia, a nursing mother must necessarily observe a sleep and rest regimen, eat rationally and fully, be sure to consume at least 1 liter of milk or fermented milk products daily, combining their intake with vitamin therapy (vitamins C, PP, E, B 1, B 2, B 6), etc.

In cases where lactation suppression is necessary, drugs such as bromocriptine, lisuride p, oral hormonal contraceptives, etc. are used.

An equally important medical problem is the question of the use of drugs by nursing mothers for the treatment of somatic or mental diseases. Currently, the number of women suffering from chronic diseases and requiring constant intake of one or more drugs during pregnancy and the entire period of breastfeeding is constantly growing. The complexity of this problem is due to the fact that most of the drugs used by nursing mothers are excreted in milk and can have a damaging effect on the child's body (including a significant impact on his mental status).

In addition, some drugs can affect the blood supply to the mammary glands, the secretion of prolactin, oxytocin and other hormones, which can reduce or completely suppress lactation. These drugs include drugs containing estrogens and progesterone, epinephrine and norepinephrine, the sympathomimetic ephedrine, the loop diuretic furosemide, the drug for the treatment of parkinsonism levodopa, etc.

Drugs pass into milk only when they are not bound to plasma proteins, i.e. present in it in a free active state. As a rule, their relative molecular weight does not exceed 200. In most cases, the excretion of drugs into milk is carried out through passive diffusion. Only non-ionized low-polarity lipophilic drug molecules are capable of it. Due to the fact that the pH of milk (6.8) is less than the pH of blood plasma (7.4), drugs whose molecules are weak bases are more likely to accumulate in milk than drugs whose molecules are weak acids. A small amount of drugs can be excreted into milk through active transport and pinocytosis. Due to the fact that milk is a fat emulsion, some drugs can accumulate in its lipid fraction at a higher concentration than in blood plasma.

As a rule, a child with milk receives 1-2% of the dose of the drug taken by the mother, but this amount of drugs is enough to have a damaging effect on his body. In addition to the concentration of the drug in mother's milk, the functional state of the gastrointestinal tract of the child is essential. Drugs present in breast milk in high concentrations (for example, aminoglycosides), in the normal state of the intestinal mucosa of the child, are practically not absorbed. With its inflammatory changes, such drugs are actively absorbed in the intestine and have a damaging effect on the child's body.

It must be clearly understood that there are many individual characteristics of the functioning of the body of the mother and child and too many unknown or unpredictable factors that can affect the excretion of drugs into milk and their absorption of the gastrointestinal tract of the child. That is why, when prescribing drugs to nursing mothers, a medical worker should adhere to the following rule: if possible, try to replace a drug that penetrates well into milk with a drug of a similar effect that poorly or does not penetrate into it at all and does not have a damaging effect on the child's body. If such a drug does not exist, PT should be carried out only in situations where the deterioration of the mother's health may cause more harm to the child than the drug prescribed to her.

In cases where the appointment of drugs is necessary, in order to minimize the damaging effect on the child, the intake should be made during feeding or immediately after it, since this minimizes the concentration of drugs in mother's milk. If taken once a day, it is rational to take the drug in the evening, and replace nightly breastfeeding with milk expressed before taking the drug.

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Introduction

The issues of pharmacotherapy during pregnancy and lactation are very relevant. A significant number of complications of pregnancy, as well as extragenital diseases. encountered during it, require drug therapy, often multicomponent. The same applies to lactation.

At the same time, many general practitioners and doctors of narrow specialties are completely unaware of the dangers of certain drugs for a pregnant woman, her fetus and a child who is breastfed. Pharmacists also often dispense drugs without considering the above. The consequences of such rash actions can be negative. It should become an indispensable rule for a doctor of any specialty and pharmacists (pharmacists) before prescribing (selling) any medicine to a woman of reproductive age, it is imperative to clarify the presence or absence of pregnancy or lactation. Pregnancy is a specific condition of a woman, which requires increased caution when prescribing medications. The ratio of risk to potential benefit from prescribing a drug is the main problem of pharmacotherapy during pregnancy.

1. The use of drugs during pregnancy

Features are due to the fact that drugs (hereinafter referred to as drugs) act: on the fetus, placenta, woman. The placenta has limited permeability. Depending on this, medicinal substances can be divided into three groups:

1) not penetrating the placenta, therefore not causing direct harm to the fetus;

2) penetrating the placenta, but not having a harmful effect on the fetus;

3) penetrating the placenta and accumulating in the tissues of the fetus, and therefore there is a risk of damage to the latter.

Most drugs cross the placenta by diffusion and/or active transport.

The rate of diffusion depends on a number of factors:

1) Molecular weight: less than 500 D easily pass, more than 1000 D do not penetrate the placental barrier.

2) The rate of placental blood flow: the greater the rate of blood flow, the faster the drug enters the fetus.

3) Communication with proteins: the greater the percentage of communication with the protein, the less it crosses the placenta.

4) Women's health status: The permeability of the placenta is higher with hypoxia, toxicosis of pregnancy, endocrine disorders, stressful situations.

5) Permeability increases when smoking, drinking alcohol. Muscle relaxants for which it is permeable can penetrate.

2. Principles of pharmacotherapy in pregnant women

The widespread use of drugs for the treatment of pregnant women has become an objective reality, determined both by the deterioration in the health of women of childbearing age and the increase in the age of "primiparas". There are the following are common principles of pharmacotherapy of pregnant women:

2) Avoid prescribing drugs in the first 6-8 weeks of pregnancy.

3) The first 3-4 months of drug treatment should be avoided or carried out with extreme caution.

4) For drug treatment, drugs should be used:

a) less penetrating through the placenta

b) less cumulative

c) not possessing embryo-, terato-, fetotoxic action.

5) The potential benefit must exceed the possible harm that the drug can cause to a woman or fetus

The risk of pathological changes depends on:

1. Nature, properties, dosage of drugs

2. The age of the woman

3. Timing of pregnancy

There are several critical periods in which the greatest sensitivity of the embryo to drugs is noted.

Implantation period (7-14 days) - the introduction of the embryo into the uterine wall

Placentation period (3-4 weeks) - the placenta is formed

The period of the main organogenesis (5-6 weeks) is the laying of organs and systems.

3. The concept of embryotoxic, teratogenic and fetotoxic effects

1. Embryotoxic action drugs - the negative effect of the substance on the zygote and blastocyst located in the lumen of the fallopian tubes or in the uterine cavity. Most often, the result is the formation of gross malformations, which leads to termination of pregnancy, fetal hypoxia often occurs, sometimes death, and in the mother - toxicosis of pregnant women (gestosis), spontaneous abortion.

Embryotoxic effects are characterized as intrauterine death in the early stages of embryonic development (the first weeks). On the principle of "all or nothing".

Embryotoxic effect

hormones (e.g. estrogen)

Cytostatics (antimetabolites - inhibit certain biochemical processes that are critical for the reproduction of malignant tumor cells, that is, for the process of division, mitosis, DNA replication, which also affects the dividing cells of the embryo),

barbiturates,

sulfa drugs,

Antibiotics (inhibit protein synthesis)

nicotine.

Hormonal contraceptives are very dangerous. They should be discontinued at least 6 months before the planned pregnancy.

2. Teratogenic effect - the ability of drugs to cause fetal malformations. Occurs approximately from 2 to 16 weeks (during the period of the most intensive tissue differentiation).

Teratogenic effect depends on a number of circumstances:

1. Pregnancy period. The most severe defects incompatible with life arise from damaging effects in the early stages of embryogenesis (the first 56 days). They consist in gross violations of the development of the brain, cardiovascular system, gastrointestinal tract. At the end of this period, a teratogenic substance can cause less severe malformations, often compatible with life (malformations of the heart, limbs, genital area), but it makes a person disabled. After 8 gestational weeks, when the differentiation of organs and tissues is basically completed, but the development of the central nervous system, reproductive tract continues, non-infection of the upper lip and palate, the intake of a teratogenic substance by a woman causes minor morphological defects, such as non-occlusion of the upper palate or lips, and defects of the fingers and reproductive tract.

2. The size of the dose and the duration of the use of the teratogen are of great importance.

3. Teratogenesis is promoted by dysfunction of the eliminating organs (liver and kidneys).

There is a group of drugs whose teratogenicity has been proven and the use of which in pregnant women is unacceptable.

These include:

high doses of vitamin A-cleavage of the palate,

diphenin - anticonvulsant, antiarrhythmic agent and muscle relaxant (stabilization of neuronal membranes of the body of the nerve cell, axons and in the synapse area) - mental retardation, microcephaly, shortened phalanges of the fingers,

androgens,

Anorexia drugs

antitumor,

antiepileptic,

Antiestrogen (clomiphene citrate, tamoxifen) - Down syndrome, malformations of the nervous system

antimalarial,

indirect anticoagulants,

progestogens,

Tetracycline - teratogenic effect possible deformities.

folic acid antagonists - trimethoprim, pyremethamine, their combined preparations (biseptol, bactrim) - hydrocephalus

cytostatics,

Alcohol - 2% of all teratogenic effects (contributes to the occurrence of alcohol syndrome, growth deficiency, impaired coordination of movements, fetal hypotrophy.)

suspected: sulfonamides, glucocorticoids. diazepam

3. Fetotoxic action- violation of any function of the fetus as a result of the action of drugs on the fetus. From 4 months to the end of pregnancy.

Render:

anaprilin-fetal bradycardia

morphine - depression of the respiratory center

· Aminoglycosides (streptomycin, gentamicin, amikacin - bound to the 30S subunit of bacterial ribosomes and disrupt the biosynthesis of proteins in ribosomes, causing a break in the flow of genetic information in the cell). Aminoglycosides pass through the placenta and can have nephrotoxic effects on the fetus, ototoxicity. There are reports of the development of irreversible bilateral congenital deafness.

thyreostatics (thiamazole, iodine preparations) - congenital goiter, hypothyroidism

Levomycetin - a decrease in the number of leukocytes, anemia.

4. Classification of drugs according to the degree of risk of a teratogenic effect

pregnancy teratogenic drug pharmacotherapy

Based on data obtained in humans and, to a greater extent, in animals, drugs are classified according to the degree of risk to the fetus. There are a large number of classifications, I will give the main ones.

Category B: experimental studies did not reveal a teratogenic effect or complications observed in animals were not found in children whose mothers took drugs included in this group (insulin, metronidazole);

Category C: teratogenic or embryotoxic effects of the drug have been identified in animals, controlled trials have not been conducted or the effect of the drug has not been studied (isoniazid, fluoroquinolones, gentamicin, antiparkinsonian drugs, antidepressants);

Category X: the teratogenic effect of drugs in this group has been proven, their use is contraindicated before and during pregnancy (isotretinoin, carbamazepine, streptomycin). It has been proven that drugs of category X do not provide a sufficient therapeutic effect, and the risk of their use outweighs the benefits.

Also, drugs are classified as follows:

1. High risk (100%).

2. Significant risk (up to 10 weeks) - cause abortion and / or malformations

3. Moderate risk - rarely, only in predisposing situations.

Risk conditions:

1. Reception in the 1st trimester of pregnancy

2. Age<17 или >35 years

3. Appointment of high doses.

6. The main clinical forms of toxicosis of pregnant women. The choice of drugs for pharmacotherapy.

Diseases that occur during pregnancy and stop at its end.

The final reasons why toxicosis develops during pregnancy have not been established. Several etiopathogenetic theories have been put forward, which include:

Neurogenic (it is associated with increased psycho-emotional stress, unsettled personal life, etc.)

humoral (according to it, early toxicosis is considered as a reflection of various hormonal imbalances);

reflex (with the pathology of one organ, irritation of its nerve pathways occurs, which leads to pathological impulses, accompanied by various clinical manifestations).

Classification:

1. early toxicosis - the first 20 weeks

2. late toxicosis - after 30 weeks

Toxicosis in early pregnancy It is customary to divide into two large groups - these are often found and rarely found.

The former include vomiting of pregnant women, salivation, and the latter - dermatitis, jaundice, bronchial asthma and other manifestations.

Vomiting of pregnant women is one of the most frequent clinical forms of early toxicosis. It has an episodic character, does not cause a sharp disturbance of well-being, does not require treatment.

In 10%, symptoms increase: vomiting daily or several times a day. The main hypothesis: a violation of the nervous and endocrine regulation.

Herbal sedatives - valerian, etc.,

Tranquilizers: diazepam - normalizes the state of the central nervous system, improves sleep and helps to eliminate symptoms.

In severe cases, antiemetics are added: etaperazine, droperidol. Metoclopramide is contraindicated.

Use when necessary! Do not drink courses!

Splenin normalizes the detoxification function of the liver.

B vitamins, ascorbic acid.

Correction of water-salt metabolism: Ringer-Locke solutions, sodium chloride. 5% solution of glucose. With severe toxicosis up to 2.5-3 liters.

Parenteral nutrition: protein preparations, fat emulsions. Until the vomiting stops.

Late toxicosis or hestasis

characterized by the appearance of edema, protein in the urine, weight gain of more than 300 grams per week and blood pressure higher than 130/100. The stronger the symptoms, the more difficult the condition of the pregnant woman. Treatment of preeclampsia is carried out based on the specific situation and its severity.

Clinical manifestations:

1. Dropsy of pregnancy (edema) - accumulation of fluid due to a violation of water and electrolyte metabolism. Sign: rapid increase in body weight >300 g per week.

2. Nephropathy:

b) proteinuria.

c) hypertension.

Causes: generalized vascular angiospasm, which leads to impaired uterine circulation and fetal hypoxia; decrease in cerebral circulation, scratching blood flow.

3. Preeclampsia - a condition caused by impaired cerebral circulation (brain edema, increased intracranial pressure)

Symptoms: headache, blurred vision.

4. Eclampsia - the development of seizures. Complications: Death of the fetus. stroke, liver or kidney failure.

Treatment:

1. Limitation of the volume of water consumed - no more than 1l / day.

2. Salt restriction<5 г.

3. Hypertonic glucose solution, vit. C, cocarboxylase.

4. Drugs strengthening the vascular wall - ascorutin, calcium gluconate.

5. With nephropathy, diuretics: thiazides-hypothiazide, furosemide 25 mg / day for 3-4 days, break + KCl.

Treatment of nephropathy is clearly carried out in a hospital:

1. Herbal sedative drugs.

2. Tranquilizers.

3. Magnesia therapy according to Brovkin: magnesia 25% solution 20 ml + novocaine = every 4-6 hours (no more than 24 g / day).

4. Vasodilating IV: dibazol, eufillin, no-shpa.

5. In case of inefficiency: nifedipine, hydrolasin injection.

6. For long-term therapy: dopegit, pindolol (visket), prazosin, nifedipine DO NOT ACE inhibitors, BRAT-2

7. In severe cases - diuretics: lasix, mannitol.

8. Drugs that strengthen the vascular wall.

Treatment for preeclampsia:

1. Hospitalization in intensive care.

2. Tranquilizers-diazepam.

3. Antipsychotics-droperidol.

4. Glucose 40%.

5. see treatment of nephropathy from point 3.

Treatment for eclampsia:

1. see points 1-3 above.

2. IV oxybutyrate to relieve seizures.

3. short-term inhalation of photorotane + nitric oxide 1 + oxygen.

4. hypotensive: eufillin, dibazol, azomethonium.

5. severe hypertension -> controlled hypotension with arfonade, hygronia.

6. correction of metabolic solutions: glucose-novocaine mixture, vitamins.

7. improvement of microcirculation - rheopolyglucin.

8. diuretics-lasix, mannitol, IV albumins.

9. hemodez.

7. Main disorders of the contractile function of the uterus: types and clinical significance. Pharmacotherapeutic characteristics of drugs used to correct the contractile function of the myometrium.

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