Drugs used in obstetrics

PHARMACOTHERAPY IN OBSTETRICS. MEDICAL ETHICS AND DEONTOLOGY. PHARMACOKINETICS AND PHARMACODINAMICS  OF DRUGS.

                                                                       Prepared by Korda I.

One of the most neglected areas in clinical pharmacology and pharmaceutical research involves the study of drugs given to pregnant women. As a consequence, only a handful of drugs have been approved by the Food and Drug Administration (FDA) for use in pregnancy, or contain obstetric information in the product or package insert except for possible fetal effects.

Pregnancy poses a unique situation because although drugs are mostly given to treat the mother, the fetus is almost always a recipient. Concern over the fetal consequences of maternal drug therapy has totally overshadowed the need to study the biodisposition of drugs in the mother. Conceptually, the mother has been viewed as a woman that “carries” the fetus and not as a woman whose pregnancy may significantly alter the biodisposition of drugs.

The pharmacologic and toxic effects of drugs on the mother and the fetus are governed by a complex but integrated set of variables consisting of mother, uterus, placenta, amniotic fluid, and fetus. Because all components of this unit are constantly and dynamically changing throughout pregnancy, the system truly presents a formidable pharmacologic challenge. For ethical reasons, the human fetus is largely beyond reach for pharmacologic investigation (except for observational studies). Thus, experimental animals have been widely used to seek pharmacologic and toxicologic data. It is now obvious from the compiled literature that animal data often have little relevance to the human fetus. This imposes a serious dilemma for the practitioner who must translate pharmacologic data into clinical practice.

This chapter summarizes the clinical implications of obstetric and fetal pharmacology and concentrates on relating the pharmacodynamics and pharmacokinetics of drugs to the physiologic changes and pathophysiologic disturbances that occur during pregnancy. Concepts are emphasized to enable the obstetrician and perinatologist to provide optimal therapeutics without adverse effects based on evidenced-based pharmacology.

GENERAL PRINCIPLES

Drugs undergo a series of interactions in the body before combining with specific tissue receptors and producing the desired pharmacologic effect. The intensity and duration of the pharmacologic effect can be modified by a number of variables: rate and extent of absorption, volume of distribution, rate and nature of metabolism and excretion, and interaction with other compounds.

Factors that determine the rate and the percentage of the compound that is absorbed (bioavailability) are the physiochemical characteristics of the drug, its rate of dissolution, the gastric and intestinal pH, gastric emptying time, composition of intestinal contents, intestinal motility, and mesenteric blood flow. Determinant factors of absorption by other routes (i.e., intramuscular, subcutaneous, epidural) are degree of ionization, physiochemical composition, water or lipid solubility, and blood flow at the site of injection. After absorption, drugs enter the intravascular system and either circulate in free form or are bound to plasma proteins to differing degrees depending on their binding characteristics and other competing ligands.

Distribution of unbound drugs throughout the body is frequently a rapid process that allows a diffusion equilibrium to be quickly established between blood and other body compartments. In some situations, however, the access of a drug to the sites of its pharmacologic action may require considerable time. Under these circumstances, measurements of drug concentrations in blood may not correlate with pharmacologic effects (at least not until “steady state” has been reached).

Among other factors, drug distribution is influenced by lipid solubility, degree of ionization, blood flow, and binding affinities to proteins in plasma and specific tissues. From the pharmacologic standpoint, a drug is eliminated either by excretion or by metabolic biodegradation into pharmacologically inactive metabolites. Although renal excretion of the unchanged drugs is by far the most important excretory route, there are several other excretory pathways (such as biliary excretion or alveolar elimination) used by certain compounds. These excretory pathways may assume greater importance in certain pathologic conditions that preclude the use of the primary excretory route.

Deontological moral systems are characterized by a focus upon adherence to independent moral rules or duties. To make the correct moral choices, we have to understand what our moral duties are and what correct rules exist to regulate those duties. When we follow our duty, we are behaving morally. When we fail to follow our duty, we are behaving immorally. Typically in any deontological system, our duties, rules, and obligations are determined by God. Being moral is thus a matter of obeying God.

 

Deontological moral systems typically stress the reasons why certain actions are performed. Simply following the correct moral rules is often not sufficient; instead, we have to have the correct motivations. This might allow a person to not be considered immoral even though they have broken a moral rule, but only so long as they were motivated to adhere to some correct moral duty.

Nevertheless, a correct motivation alone is never a justification for an action in a deontological moral system and cannot be used as a basis for describing an action as morally correct. It is also not enough to simply believe that something is the correct duty to follow. Duties and obligations must be determined objectively and absolutely, not subjectively. There is no room in deontological systems of subjective feelings; on the contrary, most adherents condemn subjectivism and relativism in all their forms.

Perhaps the most significant thing to understand about deontological moral systems is that their moral principles are completely separated from any consequences which following those principles might have. Thus, if you have a moral duty not to lie, then lying is always wrong — even if that results in harm to others. For example, you would be acting immorally if you lied to Nazis about where Jews were hiding.

The word deontology comes from the Greek roots deon, which means duty, and logos, which means science. Thus, deontology is the "science of duty." Key questions which deontological ethical systems ask include:

 What is my moral duty?

 What are my moral obligations?

 How do I weigh one moral duty against another?

Types of Deontological Ethics

Some examples of deontological ethical theories:

Divine Command: the most common forms of deontological moral theories are those which derive their set of moral obligations from a god. According to many Christians, for example, an action is morally correct whenever it is in agreement with the rules and duties established by God.

Duty Theories: an action is morally right if it is in accord with some list of duties and obligations.

Rights Theories: an action is morally right if it adequately respects the rights of all humans (or at least all members of society). This is also sometimes referred to as Libertarianism, the political philosophy that people should be legally free to do whatever they wish so long as their actions do not impinge upon the rights of others.

 

Contractarianism: an action is morally right if it is in accordance with the rules that rational moral agents would agree to observe upon entering into a social relationship (contract) for mutual benefit. This is also sometimes referred to as Contractualism.

Monistic Deontology: an action is morally right if it agrees with some single deontological principle which guides all other subsidiary principles.

Problems With Deontological Ethics

A common criticism of deontological moral systems is that they provide no clear way to resolve conflicts between moral duties. a deontological moral system should include both a moral duty not to lie and one to keep others from harm, for example, but in the above situation how is a person to choose between those two moral duties? A popular response to this is to simply choose the "lesser of two evils," but that means relying on which of the two has the least evil consequences and, therefore, the moral choice is being made on a consequentialist rather than a deontological basis.

Some critics argue that deontological moral systems are, in fact, consequentialist moral systems in disguise. According to this argument, duties and obligations which set forth in deontological systems are actually those actions which have been demonstrated over long periods of time to have the best consequences. Eventually, they become enshrined in custom and law and people stop giving them or their consequences much thought — they are simply assumed to be correct. Deontological ethics are thus ethics where the reasons for particular duties have been forgotten, even if things have completely changed.

A second criticism is that deontological moral systems do not readily allow for grey areas where the morality of an action is questionable. They are, rather, systems which are based upon absolutes — absolute principles and absolute conclusions. In real life, however, moral questions more often involve grey areas than absolute black & white choices. We typically have conflicting duties, interests, and issues that make things difficult.

Another common criticism of deontological ethical theories is the question of just which duties qualify as those which we should all follow, regardless of the consequences. Duties which might have been valid in the 18th century are not necessarily valid now, but who is to say which ones should be abandoned and which are still valid? And if any are to be abandoned, how can we say that they really were moral duties back in the 18th century?

If these were duties created by God, how can they possibly stop being duties today? Many attempts to develop deontological systems focus on explaining how and why certain duties are valid at any time or at all times and how we can know that. Religious believers are often in the difficult position of trying to explain what believers of the past treated certain duties as objective, absolute ethical requirements created by God but today they aren't — today we have different absolute, objective ethical requirements created by God. These are all reasons why irreligious atheists rarely subscribe to deontological ethical systems, though it can't be denied that they can at times have ethical insights to offer.

PHARMACOLOGY OF PREGNANCY

Normal human pregnancy is accompanied by such remarkable physiologic changes that drug disposition and effect may be entirely different from those in nonpregnant patients. These differences are important not only for maternal therapy but also for understanding the effects of fetal drug exposure.

Role of Gender

The effects of the pregnant state on the disposition and action of drugs are superimposed on the changes associated with the female sex. Gender differences on drug disposition in experimental animals has been known for more than 60 years, but it was not until 1993 that the FDA encouraged the inclusion of women in clinical trials.1 There are striking differences in body processes between men and women. Physiologic differences between the sexes may explain variations in the absorption of drugs. Compared to men, women have slower gastric emptying time and prolonged colonic transit time. These differences may be heightened during pregnancy. There are also differences in drug biotransformation.

Factors that determine the rate and the percentage of the compound that is absorbed (bioavailability) are the physiochemical characteristics of the drug, its rate of dissolution, the gastric and intestinal pH, gastric emptying time, composition of intestinal contents, intestinal motility, and mesenteric blood flow. Determinant factors of absorption by other routes (i.e., intramuscular, subcutaneous, epidural) are degree of ionization, physiochemical composition, water or lipid solubility, and blood flow at the site of injection. After absorption, drugs enter the intravascular system and either circulate in free form or are bound to plasma proteins to differing degrees depending on their binding characteristics and other competing ligands.

Distribution of unbound drugs throughout the body is frequently a rapid process that allows a diffusion equilibrium to be quickly established between blood and other body compartments. In some situations, however, the access of a drug to the sites of its pharmacologic action may require considerable time. Under these circumstances, measurements of drug concentrations in blood may not correlate with pharmacologic effects (at least not until “steady state” has been reached).

Among other factors, drug distribution is influenced by lipid solubility, degree of ionization, blood flow, and binding affinities to proteins in plasma and specific tissues. From the pharmacologic standpoint, a drug is eliminated either by excretion or by metabolic biodegradation into pharmacologically inactive metabolites. Although renal excretion of the unchanged drugs is by far the most important excretory route, there are several other excretory pathways (such as biliary excretion or alveolar elimination) used by certain compounds. These excretory pathways may assume greater importance in certain pathologic conditions that preclude the use of the primary excretory route.

A multienzyme system is responsible for the degradation of hydrophobic molecules. In a sequential manner, hydrophobic molecules are biotransformed by phase I enzymes and then conjugated by phase II enzymes. The cytochrome P450 superfamily (or CYP) is the major phase I group of isoenzymes. These enzymes are expressed mostly in the liver but also to a lesser extent in other tissues (e.g., intestine). The expression pattern of different CYP isoforms differs in the sexes. For example, the cytochrome P450 CYP3A4 is more active in women than in men.2 Theophylline and acetaminophen, which are metabolized by CYP3A4, are eliminated faster by women. Other drugs, such as diazepam, caffeine, and some anticonvulsants, metabolized by CYP2C19 or CYP1A2 appear to be metabolized faster in men than in women.3 Gender differences in drug biodisposition has been linked to variations in sex hormones.

There are also sex differences in the sensitivity to drugs .4 Opioids such as pentazocine show a greater drug response in women, whereas ibuprofen produces a better response in men.5,6 In addition, there are gender differences in the incidence of adverse drug reactions. For example, drug-induced torsades des pointes and the cough induced by angiotensin-converting enzyme inhibitors occur more commonly in women.7,8

Mother-Fetus: A Two-Compartment System

A fundamental aspect of fetal pharmacology is that of fetal dose. The amount and rate of transfer of drugs to the fetus determine the presence or absence of pharmacologic or toxic effects.

With the rare exception of drugs injected directly into the fetal compartment, the path a drug must take from its administration to the mother is across the maternal organism to its site of action in the fetus.

This multicompartment system is especially complicated because it does not represent a constant relationship but one that is continuously changing throughout pregnancy

ROLE OF THE PLACENTA

For years the placenta has been regarded as the somewhat passive and inert barrier to the transfer of drugs between the fetal and maternal compartments. However, recent work has uncovered a bewildering number of complex functions affecting both maternal and fetal physiology. Two aspects of placental pharmacology assume equal importance: the transfer and disposition of xenobiotics reaching the organ from the maternal and fetal side, and the biodegradation properties affecting xenobiotics or being affected by them. The three major factors affecting drug transfer across the placenta are physiochemical characteristics of the compound, pharmacologic properties of the placental tissue, and maternal and fetal placental blood flow.

Physiochemical characteristics include molecular weight, lipid solubility, degree of ionization, molecular configuration, and tissue binding protein properties. Generally, lipophilic substances and compounds with low molecular weight tend to diffuse rapidly into the fetal circulation. Poorly ionized drugs at physiologic pH, such as thiopental, reach the fetal circulation quite rapidly. Certain compounds, such as the sympathomimetic agents, salbutamol, ritodrine, and norepinephrine, appear to have a low transfer rate despite their small molecular weights (170 to 290). Still, sufficient amounts of both salbutamol and ritodrine are transferred to produce fetal tachycardia. The limited transfer rate of norepinephrine may be attributed in part to biodegradation by placental tissue. The purported placental impermeability to polar compounds is relative rather than absolute. The high lipid solubility of certain compounds, such as salicylates, allows for rapid transfer despite being almost 100% ionized at physiologic pH. Xenobiotics cross the placenta by different transfer mechanisms: simple diffusion, facilitated diffusion, active transport, and pinocytosis. The metabolic conversion by the placenta of one compound into another compound that in turn may be transferred cannot be discounted. Most drugs cross the placenta by simple diffusion at a rate that is directly related to the difference between the maternal and fetal blood concentrations. Recent studies have shown that the syncytiotrophoblast expresses membrane proteins that act as drug transporters.28 P-glycoprotein, an ATP-dependent drug efflux pump, is present in the brush border of the syncytiotrophoblast.29 Drug transport by P-glycoprotein is unidirectional from the fetal to the maternal side and thus protects the fetus from toxic compounds. A wide variety of drugs are substrates for this transporter (e.g., digoxin, verapamil, chemotherapeutic agents). Transporters in the opposite direction have not been sufficiently characterized.

The placenta undergoes continuous structural changes during its life span that are likely to significantly affect rates of drug diffusion. Studies in the pregnant rodent seem to indicate that drug transfer is lowest in midgestation and peaks at the beginning and end of pregnancy.30 There is little information on the effect of placental aging on drug transfer in normal human pregnancy, let alone those changes that occur during abnormal conditions, when drugs are most often prescribed. The relative maternal and fetal blood flow through the placenta is of paramount importance in determining the rate of drug transfer from mother to fetus and vice versa.

Adequate measurements of uterine blood flow are flawed by technical difficulties. Despite this, several studies have shown an increase in uterine flow per kilogram of uterine weight toward term. When data are analyzed in terms of uterine blood flow per kilogram of fetus, however, a decrease is demonstrated at term. The time course of uterine and fetal plasma concentrations usually follows the following pattern:

Establishment of a maternal—fetal concentration gradient

Equilibration phase, in which the highest fetal drug concentration will depend on the placental factors discussed above

Fetal drug elimination phase. During this period, the combined effects of maternal drug biodegradation and elimination lower maternal drug concentrations, creating a fetal—maternal gradient and reversing the direction of drug transfer across the placenta.

Delivery can occur at any point during this sequential pattern, and its timing will determine the amount of drug present and the ability of the newborn to handle xenobiotics. Many factors can influence maternal and fetal hemodynamics, thereby disturbing maternal and fetal drug distribution. Those affecting maternal hemodynamics are briefly reviewed here. A decrease in uteroplacental blood flow may be secondary to vasoconstriction of myometrial arterioles or obstruction of uterine venous outflow. The amount of drug transfer to the fetus, especially after a single intravenous pulse injection, will vary depending on the type of blood flow obstruction and the temporal relationship between drug administration and the onset of uterine hypoperfusion. For drugs given before the onset of uterine blood flow obstruction, myometrial arteriole vasoconstriction will tend to protect the fetus, whereas venous obstruction, by allowing a longer period of placental residency time, will result in increased fetal drug extraction. Alterations in uterine blood flow of particular interest are those related to abnormal labor, excessive uterine activity (spontaneous or oxytocin-induced), vasoactive drugs, or vena cava compression and supine hypotension, as may occur at the time of removal of amniotic fluid.

Pathophysiologic conditions such as preeclampsia, hypertension, and diabetes, which may be associated with impaired uteroplacental blood flow, can be expected to decrease drug transfer across the placenta. On the other hand, these pathophysiologic conditions often are associated with profound fetal hemodynamic changes that favor drug distribution to the fetal brain.

The demonstration that the human placenta is capable of metabolizing xenobiotics spurred a burst of investigative activity. Placental CYP1A1 is inducible by maternal smoking. CYP4B1 and CYP19 may contribute to the metabolism of some drugs.31 The picture emerging from the available research, however, indicates that although the placenta is a major metabolic organ for the biotransformation of endogenous substances, especially steroidal hormones, its contribution to the overall degradation of drugs during pregnancy is quantitatively meager.32 The demonstration that foreign organic substances could undergo oxygenation in human placental tissues raises the possibility that xenobiotics and endogenous steroids might share common biotransformation reactions. The balance of present evidence, however, refutes this contention and supports the existence of separate P450 species of isoenzymes for the catalysis of xenobiotic and steroidal hydroxylation reactions. The discovery that the placental mono-oxygenase activities are inducible by maternal cigarette smoking and not by other inducers is of considerable interest in this regard.33 The placental tissue of smokers contains bioactivating enzymes that catalyze the formation of metabolites that covalently bind to DNA34 or produce mutations in Salmonella typhimurium.35 It remains a challenge for researchers in the next decade to determine whether the demonstrated bioactivating capacity of the placenta allows the formation of reactive metabolites of chemical carcinogens and mutagens that could damage the embryo or the fetus.

Drugs may be used to modify uterine contractions. These include oxytocic drugs used to stimulate uterine contractions both in induction of labour and to control postpartum haemorrhage and beta2 -adrenoceptor agonists used to relax the uterus and prevent premature labour.

POSTPARTUM HAEMORRHAGE

Ergometrine and oxytocin differ in their actions on the uterus. In moderate doses oxytocin produces slow generalized contractions with full relaxation in between; ergometrine produces faster contractions superimposed on a tonic contraction. High doses of both substances produce sustained tonic contractions. Oxytocin is now recommended for routine use in postpartum and  post-abortion haemorrhage since it is more stable than ergometrine. However, ergometrine may be used if oxytocin is not available or in emergency situations.

PREMATURE LABOUR

Salbutamol is a beta2 -adrenoceptor agonist which relaxes the uterus and can be used to prevent premature labour in uncomplicated cases between 24 and 33 weeks of gestation. Its main purpose is to permit a delay in delivery of at least 48 hours. The greatest benefit is obtained by using this delay to administer corticosteroid therapy or to implement other measures known to improve perinatal health. Prolonged therapy should be avoided since the risks to the mother increase after 48 hours and the response of the myometrium is reduced.

ECLAMPSIA AND PRE-ECLAMPSIA

Magnesium sulfate has a major role in eclampsia for the prevention of recurrent seizures. Monitoring of blood pressure, respiratory rate and urinary output is carried out, as is monitoring for clinical signs of overdosage (loss of patellar reflexes, weakness, nausea, sensation of warmth, flushing, double vision and slurred speech—calcium gluconate injection is used for the management of magnesium toxicity.

  Magnesium sulfate is also used in women with pre-eclampsia who are at risk of developing eclampsia; careful monitoring of the patient (as described above) is necessary.

Ergometrine maleate

Ergometrine is a representative oxytocic drug. Various drugs can serve as alternatives

Tablets, ergometrine maleate 200 micrograms

Injection (Solution for injection), ergometrine maleate 200 micrograms/ml, 1-ml ampoule

NOTE.

Injection requires transport by ‘cold chain’ and refrigerated storage

Uses: prevention and treatment of postpartum and post-abortion haemorrhage in emergency situations and where oxytocin not available

Contraindications:

induction of labour, first and second stages of labour; vascular disease, severe cardiac disease especially angina pectoris; severe hypertension; severe renal and hepatic impairment; sepsis; eclampsia

Precautions:

cardiac disease, hypertension, hepatic impairment and renal failure, multiple pregnancy, porphyria; interactions:

Dosage:

Prevention and treatment of postpartum haemorrhage, when oxytocin is not available, by intramuscular injection, ADULT and adolescent 200 micrograms when the anterior shoulder is delivered or immediately after birth

Excessive uterine bleeding, by slow intravenous injection, ADULT and adolescent 250–500 micrograms when the anterior shoulder is delivered or immediately after birth

Secondary postpartum haemorrhage, by mouth , ADULT and adolescent 400 micrograms 3 times daily for 3 days

Adverse effects:

nausea, vomiting, headache, dizziness, tinnitus, abdominal pain, chest pain, palpitations, dyspnoea, bradycardia, transient hypertension, vasoconstriction; stroke, myocardial infarction and pulmonary oedema also reported

Magnesium sulfate

Injection (Solution for injection), magnesium sulfate 500 mg/ml, 2-ml ampoule, 10-ml ampoule

Uses: prevention of recurrent seizures in eclampsia; prevention of seizures in pre-eclampsia

Precautions:

hepatic impairment, renal failure ; in severe hypomagnesaemia administer initially via a controlled infusion device; interactions: Appendix 1

Dosage:

Prevention of recurrent seizures in eclampsia, by intravenous injection , ADULT and adolescent initially 4 g over 5–15 minutes followed either by intravenous infusion , 1 g/hour for at least 24 hours after the last seizure or by deep intramuscular injection 5 g into each buttock then 5 g every 4 hours into alternate buttocks for at least 24 hours after the last seizure; recurrence of seizures may require additional intravenous injection of 2 g

Prevention of seizures in pre-eclampsia, by intravenous infusion , adult and adolescent initally 4 g over 5–15 minutes followed either by intravenous infusion , 1 g/hour for 24 hours or by deep intramuscular injection 5 g into each buttock then 5 g every 4 hours into alternate buttocks for 24 hours; if seizure occurs, additional dose by intravenous injection of 2 g

DILUTION AND ADMINISTRATION.

According to manufacturer’s directions

For intravenous injection concentration of magnesium sulfate should not exceed 20% (dilute 1 part of magnesium sulfate injection 50% with at least 1.5 parts of water for injection); for intramuscular injection , mix magnesium sulfate injection 50% with 1 ml lidocaine injection 2%

Adverse effects:

generally associated with hypermagnesaemia (see also notes above), nausea, vomiting, thirst, flushing of skin, hypotension, arrhythmias, coma, respiratory depression, drowsiness, confusion, loss of tendon reflexes, muscle weakness; see also Appendix 2

Oxytocin

Injection (Solution for injection), oxytocin 10 units/ml, 1-ml ampoule

Uses: routine prevention and treatment of postpartum and post-abortion haemorrhage; induction of labour

Contraindications:

hypertonic uterine contractions, mechanical obstruction to delivery, fetal distress; any condition where spontaneous labour or vaginal delivery inadvisable; avoid prolonged administration in oxytocin-resistant uterine inertia, in severe pre-eclamptic toxaemia or in severe cardiovascular disease

Precautions:

induction or enhancement of labour in presence of borderline cephalopelvic disproportion (avoid if significant); mild to moderate pregnancy-associated hypertension or cardiac disease; age over 35 years; history of low-uterine segment caesarean section; avoid tumultuous labour if fetal death or meconium-stained amniotic fluid (risk of amniotic fluid embolism); water intoxication and hyponatraemia (avoid large volume infusions and restrict fluid intake); caudal block anaesthesia (risk of severe hypertension due to enhanced vasopressor effect of sympathomimetics);

Induction of labour, by intravenous infusion, ADULT and adolescent , initially 0.001–0.002 units/minute increased in 0.001–0.002 units/minute increments at intervals of 30 minutes until a maximum of 3–4 contractions occur every 10 minutes; maximum recommended rate 0.02 units/minute; no more than 5 units should be administered in 24 hours

NOTE..

The dose shown above is suitable for use in hospital where equipment to control the infusion rate is available; alternative recommendations may be suitable for other settings (consult Managing Complications in Pregnancy and Childbirth : A guide for midwives and doctors 2003 . Geneva: WHO)

 

IMPORTANT.

Careful monitoring of fetal heart rate and uterine motility essential for dose titration (never give intravenous bolus injection during labour); discontinue immediately in uterine hyperactivity or fetal distress

Prevention of postpartum haemorrhage, by slow intravenous injection , ADULT and adolescent 5 units when the anterior shoulder is delivered or immediately after birth

Prevention of postpartum haemorrhage, by intramuscular injection , adult and adolescent 10 units when the anterior shoulder is delivered or immediately after birth

Treatment of postpartum haemorrhage, by slow intravenous injection , adult and adolescent 5–10 units or by intramuscular injection , 10 units, followed in severe cases by intravenous infusion , a total of 40 units should be infused at a rate of 0.02–0.04 units/minute; this should be started after the placenta is delivered

DILUTION AND ADMINISTRATION.

According to manufacturer’s directions. Prolonged intravenous administration at high doses with large volume of fluid (for example in inevitable or missed abortion or postpartum haemorrhage) may cause water intoxication with hyponatraemia. To avoid: use electrolyte-containing diluent (not glucose), increase oxytocin concentration to reduce fluid, restrict fluid intake by mouth; monitor fluid and electrolytes

Adverse effects:

uterine spasm, uterine hyperstimulation (usually with excessive doses—may cause fetal distress, asphyxia and death, or may lead to hypertonicity, tetanic contractions, soft-tissue damage or uterine rupture); water intoxication and hyponatraemia associated with high doses and large-volume infusions; nausea, vomiting, arrhythmias, rashes and anaphylactoid reactions also reported

Salbutamol

Salbutamol is a representative myometrial relaxant. Various drugs can serve as alternatives

Tablets , salbutamol (as sulfate) 4 mg

Injection (Solution for injection), salbutamol (as sulfate) 50 micrograms/ml, 5-ml ampoule

Uses: uncomplicated premature labour between 24–33 weeks gestation; asthma

Contraindications:

1.     first and second trimester of pregnancy;

2.     cardiac disease,

3.     eclampsia and pre-eclampsia,

4.     intra-uterine infection,

5.     intra-uterine fetal death,

6.     antepartum haemorrhage,

7.     placenta praevia,

8.     cord compression,

9.     ruptured membranes

Precautions:

monitor pulse and blood pressure and avoid over-hydration; suspected cardiac disease, hypertension, hyperthyroidism, hypokalaemia, diabetes mellitus; if pulmonary oedema suspected, discontinue immediately and institute diuretic therapy; interactions : Appendix 1

Dosage:

Premature labour, by intravenous infusion ,

 ADULT initially 10 micrograms/minute, rate gradually increased according to response at 10-minute intervals until contractions diminish then increase rate (maximum of 45 micrograms/minute) until contractions have ceased, maintain rate for 1 hour then gradually reduce; or by intravenous or intramuscular injection , ADULT 100–250 micrograms repeated according to response, then by mouth , 4 mg every 6–8 hours (use for more than 48 hours not recommended)

Adverse effects:

nausea, vomiting, lushing, sweating,tremor;hypokalaemia, tachycardia,palpitations, ypotension,increased tendency to uterine bleeding; pulmonary oedema; chest pain or tightness and arrhythmias; hypersensitivity reactions including bronchospas murticaria and angioedema reported