**4. Medications used in the preterm labor**

The use of medications should take place primarily in compliance with the principles of patient safety and the minimum risk of side effects. The problem of therapy in pregnancy is related to the limited possibility of testing the effects of the medication on the pregnant woman and the fetus, and often the lack of consent to perform such tests. Therefore, medications used in pregnancy often have limited indications and are administered taking into account the individual risks and benefits of therapy. The pharmacological action of the medication in the fetus must take into account the kinetics of its transformations in the mother's organism as well as in the placenta. The distribution of the medication and its metabolism in the mother's body determine its availability to the fetus. Since pregnancy involves profound physiological and biochemical changes, the metabolism of many medications is also significantly altered. Data from animal studies suggest that the rate of metabolism of medications in the liver decreases during pregnancy and their availability to the fetus may be greater than expected. The transfer of the medication from the mother's body to the fetus takes place from arterial blood through the intervillous spaces to the fetal capillaries in the villi and further through the umbilical vein.

Despite the fact that the placenta is treated as a specific protective barrier for the fetus, it has little ability to metabolize medications. Many medications can reach the fetus in the form of metabolites, often more toxic [10]. The safety of the use of tocolytics is still a significant perinatological problem. The duration of tocolysis should be short enough to allow the full effect of steroid therapy on the fetus, with the least negative impact on the health of the mother and child [11].

The most commonly used medications that inhibit uterine contractions are discussed below, with particular emphasis on their effects on the circulatory system of the mother and the fetus.

#### **4.1 Calcium channel blockers – nifedipine**

Nifedipine contains the formula of a short- and long-acting 1,4-dihydropyridine calcium channel blocker. It prevents contraction of calcium-dependent myocytes and their vessels by blocking the influx of calcium into smooth muscle cells. The second possible vasodilatory mechanism is the inhibition of pH-dependent calcium influx by inhibiting smooth muscle carbonic anhydrase. Nifedipine is used to treat high blood pressure and chronic stable angina. At therapeutic sub-toxic concentrations, it has little effect on myocardium and conducting cells. Inhibition of calcium influx lowers smooth muscle contraction, which causes dilation of the coronary and systemic arteries, increased oxygen delivery to the muscle tissue, reduced total peripheral resistance, blood pressure and afterload.

The most common side effect of nifedipine reported by mothers is headache associated with a transient reduction in blood pressure after initiating therapy. The second common effect is tachycardia. In addition, dizziness, drowsiness, nausea, a sharp drop in blood pressure, slurred speech and weakness may occur. One in ten patients may experience palpitations and hot flushes. Severe side effects, such as myocardial infarction, maternal dyspnea, patient hypoxia, severe maternal hypotension with intrauterine fetal death, atrial fibrillation were also observed during nifedipine therapy. Pulmonary edema has been reported in a group of pregnant patients after taking nifedipine.

It is not recommended for use in patients with twin pregnancies due to the more frequent occurrence of dyspnea. It is absolutely contraindicated in the group of patients with heart disease, maternal hypertension and intrauterine infection. Dyspnea occurring in twin pregnancy is explained by a reduced blood flow and the degree of lung ventilation due to the higher elevated diaphragm dome [11–15]. Nifedipine has no effect on motor activity, heart rate and blood flow in the fetus. The occurrence of side effects is not related to the level of this medication in the patient's blood serum, so there is no need to adjust its dose based on body weight, body mass index (BMI) or gestational age [14].

In a study carried out on laboratory animals, the effect of nifedipine on the normal development of pregnancy was assessed. After administration of three and thirty times higher doses of nifedipine than recommended for humans, dilatation of blood vessels, increased vascularization of the uterus and placenta, and trophoblast hyperplasia were observed in both groups. Higher placental weights were seen in the higher dose group, but this had no effect on fetal survival or an increased risk of birth defects. Fetal weight did not differ from the control group at the lower dose, but statistically significantly lower weight was reported for the group with the higher dose of the drug. As expected, there were changes in the uterine muscle and collagen structure of the cervix during tocolysis. The authors concluded that the use of nifedipine in pregnancy in acceptable doses should not have a negative impact on the condition of fetuses and newborns, and that this therapy often improves the prognosis [16].

The optimal dose of nifedipine is still being determined. The starting dose in most studies was 10 mg either orally or sublingually. If uterine contractions were maintained, the dose was repeated every 15–20 minutes, until a dose of 40 mg was obtained in the first hour. Then, maintenance therapy is 20 mg every 6–8 hours for two to three days [14].

In a comparative study of nifedipine and another tocolytic combined with steriodotherapy, no significant risk to the fetuses was observed [17].

#### **4.2 Beta-adrenergic receptor agonists**

Ritodrine stimulates the beta-2-adrenergic receptor, increasing the level of cAMP and decreasing the concentration of intracellular calcium, which in turn leads to the relaxation of uterine smooth muscles and a reduction in the frequency of uterine contractions.

Terbutaline is a relatively selective bronchodilator with little or no effect on alpha-adrenergic receptors. It appears to have a greater effect on stimulating the beta receptors of the bronchi, vessels and smooth muscle, including the uterus (beta-2 receptors), than at the heart receptors (beta-1). This drug relaxes smooth muscles and inhibits uterine contractions, but it can also have a stimulating effect on the heart and central nervous system.

The mechanism of action is based on the stimulation of beta-adrenergic receptors in intracellular adenylate cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic adenosine 3 ', 5'-monophosphate (c-AMP). Elevated levels of c-AMP are associated with relaxation of bronchial smooth muscles and inhibition of the release of immune system mediators, especially from mast cells.

Fenoterol stimulates beta-2 receptors in the lungs and causes bronchial smooth muscle relaxation, bronchodilation and increased air flow. Symptoms of overdose are chest pain, dizziness, dry mouth, fatigue, flu-like symptoms, headaches, heart abnormalities, high or low blood pressure, high blood glycemia, insomnia, muscle spasms, nausea, nervousness, rapid heartbeat, seizures and tremors.

#### **4.3 Prostaglandin synthesis inhibitors – indomethacin**

As an analgesic and antipyretic drug, indomethacin inhibits the secretion of prostaglandins involved in the pain reaction, fever and inflammation. Symptoms of overdose: nausea, vomiting, severe headache, dizziness, confusion or lethargy. There have been reports of paraesthesia, numbness and convulsions.

#### **4.4 Magnesium sulfate**

Magnesium sulfate reduces striated muscle contraction and blocks neuromuscular transmission, reducing the release of acetylcholine. In addition, magnesium inhibits the inflow of calcium, enhancing the relaxing effect of vascular smooth muscles [12]. It is currently treated as a mild tocolytic. Used in fetal neuroprotection in preterm labor below 32 weeks of pregnancy.

#### **4.5 Oxytocin receptor antagonist – atosiban**

It is a competitive antagonist of human oxytocin at the receptor level. In rats and guinea pigs, atosiban has been observed to bind to oxytocin receptors, reducing the frequency of contractions and the tension of the uterine muscles, thereby reducing uterine contractions. Atosiban has also been observed to bind to vasopressin receptors, reducing its effect. In animals, atosiban had no effect on the cardiovascular system. In women at risk of preterm labor, atosiban, at the recommended doses, prevents uterine contractions and induces a resting state of the uterus. Uterine relaxation following atosiban administration is rapid, uterine contractions are significantly reduced within ten minutes, and uterine quiescence of less than four contractions per hour is achieved and stable for twelve hours.

In women at risk of preterm labor receiving atosiban by intravenous infusion (300 micrograms per minute for six to twelve hours), steady-state plasma concentrations were reached within one hour of starting the infusion.

The use of atosiban below 24 and above 33 weeks of pregnancy is contraindicated. There was no evidence of fetal toxicity. Small amounts of the drug are excreted into breast milk, no effect of the drug on breastfeeding has been acknowledged.

The most common side effects of treatment with this preparation include nausea, headache and dizziness, hot flushes and an increase in heart rate [18].

#### **4.6 Medications that relax the uterine muscles**

Scopolamine (hyoscine) is an alkaloid. Along with its derivatives, it resembles atropine and has a similar effect, but with a greater influence on the nervous system. Hyoscine belongs to a group of medications called parasympatholytics. The action of cholinolytic medications is to block the stimulation of cholinergic receptors (activated by acetylcholine). Hyoscine acts on muscarinic receptors and relaxes smooth muscles of the gastrointestinal, biliary and urogenital tract.

Side effects may include dry mouth, atonic constipation, increased urination disorders, urinary retention, decreased sweat secretion, increased heart rate (tachycardia), hypotension, and visual disturbances [12, 18].

Drotaverine inhibits the activity of the phosphodiesterase IV enzyme, which leads to an increase in the concentration of cAMP and a further cascade of intracellular reactions that result in the relaxation of the muscle cell. It may also have calcium channel blocking abilities.

The relaxant effect affects the smooth muscles of the gastrointestinal tract, urogenital system, cardiovascular system and bile ducts and is stronger than that of papaverine. It is used in the case of contraction of smooth muscles of both nervous and muscular origin. Side effects are rare and similar to scopolamine [12, 18].
