Basic and Clinical Pharmacology, 13th Ed.

Special Aspects of Perinatal & Pediatric Pharmacology

Gideon Koren, MD*

The effects of drugs on the fetus and newborn infant are based on the general principles set forth in Chapters 14 of this book. However, the physiologic contexts in which these pharmacologic laws operate are different in pregnant women and in rapidly maturing infants. At present, the special pharmacokinetic factors operative in these patients are beginning to be understood, whereas information regarding pharmacodynamic differences (eg, receptor characteristics and responses) is still incomplete.

DRUG THERAPY IN PREGNANCY

Pharmacokinetics

Most drugs taken by pregnant women can cross the placenta and expose the developing embryo and fetus to their pharmacologic and teratogenic effects. Critical factors affecting placental drug transfer and drug effects on the fetus include the following: (1) the physicochemical properties of the drug; (2) the rate at which the drug crosses the placenta and the amount of drug reaching the fetus; (3) the duration of exposure to the drug; (4) distribution characteristics in different fetal tissues; (5) the stage of placental and fetal development at the time of exposure to the drug; and (6) the effects of drugs used in combination.

A. Lipid Solubility

As is true also of other biologic membranes, drug passage across the placenta is dependent on lipid solubility and the degree of drug ionization. Lipophilic drugs tend to diffuse readily across the placenta and enter the fetal circulation. For example, thiopental, a drug commonly used for cesarean sections, crosses the placenta almost immediately and can produce sedation or apnea in the newborn infant. Highly ionized drugs such as succinylcholine and tubocurarine, also used for cesarean sections, cross the placenta slowly and achieve very low concentrations in the fetus. Impermeability of the placenta to polar compounds is relative rather than absolute. If high enough maternal-fetal concentration gradients are achieved, polar compounds cross the placenta in measurable amounts. Salicylate, which is almost completely ionized at physiologic pH, crosses the placenta rapidly. This occurs because the small amount of salicylate that is not ionized is highly lipid-soluble.

B. Molecular Size and pH

The molecular weight of the drug also influences the rate of transfer and the amount of drug transferred across the placenta. Drugs with molecular weights of 250–500 can cross the placenta easily, depending upon their lipid solubility and degree of ionization; those with molecular weights of 500–1000 cross the placenta with more difficulty; and those with molecular weights greater than 1000 cross very poorly. An important clinical application of this property is the choice of heparin as an anticoagulant in pregnant women. Because it is a very large (and polar) molecule, heparin is unable to cross the placenta. Unlike warfarin, which is teratogenic and should be avoided during the first trimester and even beyond (as the brain continues to develop), heparin may be safely given to pregnant women who need anticoagulation. Yet the placenta contains drug transporters, which can carry larger molecules to the fetus. For example, a variety of maternal antibodies cross the placenta and may cause fetal morbidity, as in Rh incompatibility.

Because maternal blood has a pH of 7.4 whereas the fetal blood is 7.3, basic drugs with a pKa above 7.4 will be more ionized in the fetal compartment, leading to ion trapping and, hence, to higher fetal levels (see Chapter 1, Ionization of Weak Acids and Weak Bases).

C. Placental Transporters

During the last decade, many drug transporters have been identified in the placenta, with increasing recognition of their effects on drug transfer to the fetus. For example, the P-glycoprotein transporter encoded by the MDR1 gene pumps back into the maternal circulation a variety of drugs, including cancer drugs (eg, vinblastine, doxorubicin) and other agents. Similarly, viral protease inhibitors, which are substrates to P-glycoprotein, achieve only low fetal concentrations—an effect that may increase the risk of vertical HIV infection from the mother to the fetus. The hypoglycemic drug glyburide has much lower plasma levels in the fetus as compared with the mother. Recent work has documented that this agent is effluxed from the fetal circulation by the BCRP transporter as well as by the MRP3 transporter located in the placental brush border membrane. In addition, very high maternal protein binding of glyburide (> 98.8%) also contributes to lower fetal levels as compared with maternal concentrations.

D. Protein Binding

The degree to which a drug is bound to plasma proteins (particularly albumin) may also affect the rate of transfer and the amount transferred. However, if a compound is very lipid-soluble (eg, some anesthetic gases), it will not be affected greatly by protein binding. Transfer of these more lipid-soluble drugs and their overall rates of equilibration are more dependent on (and proportionate to) placental blood flow. This is because very lipid-soluble drugs diffuse across placental membranes so rapidly that their overall rates of equilibration do not depend on the free drug concentrations becoming equal on both sides. If a drug is poorly lipid-soluble and is ionized, its transfer is slow and will probably be impeded by its binding to maternal plasma proteins. Differential protein binding is also important since some drugs exhibit greater protein binding in maternal plasma than in fetal plasma because of a lower binding affinity of fetal proteins. This has been shown for sulfonamides, barbiturates, phenytoin, and local anesthetic agents.

E. Placental and Fetal Drug Metabolism

Two mechanisms help protect the fetus from drugs in the maternal circulation: (1) The placenta itself plays a role both as a semipermeable barrier and as a site of metabolism of some drugs passing through it. Several different types of aromatic oxidation reactions (eg, hydroxylation, N-dealkylation, demethylation) have been shown to occur in placental tissue. Pentobarbital is oxidized in this way. Conversely, it is possible that the metabolic capacity of the placenta may lead to creation of toxic metabolites, and the placenta may therefore augment toxicity (eg, ethanol, benzpyrenes). (2) Drugs that have crossed the placenta enter the fetal circulation via the umbilical vein. About 40–60% of umbilical venous blood flow enters the fetal liver; the remainder bypasses the liver and enters the general fetal circulation. A drug that enters the liver may be partially metabolized there before it enters the fetal circulation. In addition, a large proportion of drug present in the umbilical artery (returning to the placenta) may be shunted through the placenta back to the umbilical vein and into the liver again. It should be noted that metabolites of some drugs may be more active than the parent compound and may affect the fetus adversely.

Pharmacodynamics

A. Maternal Drug Actions

The effects of drugs on the reproductive tissues (breast, uterus, etc) of the pregnant woman are sometimes altered by the endocrine environment appropriate for the stage of pregnancy. Drug effects on other maternal tissues (heart, lungs, kidneys, central nervous system, etc) are not changed significantly by pregnancy, although the physiologic context (cardiac output, renal blood flow, etc) may be altered, requiring the use of drugs that are not needed by the same woman when she is not pregnant. For example, cardiac glycosides and diuretics may be needed for heart failure precipitated by the increased cardiac workload of pregnancy, or insulin may be required for control of blood glucose in pregnancy-induced diabetes.

B. Therapeutic Drug Actions in the Fetus

Fetal therapeutics is an emerging area in perinatal pharmacology. This involves drug administration to the pregnant woman with the fetus as the target of the drug. At present, corticosteroids are used to stimulate fetal lung maturation when preterm birth is expected. Phenobarbital, when given to pregnant women near term, can induce fetal hepatic enzymes responsible for the glucuronidation of bilirubin, and the incidence of jaundice is lower in newborns when mothers are given phenobarbital than when phenobarbital is not used. Before phototherapy became the preferred mode of therapy for neonatal indirect hyperbilirubinemia, phenobarbital was used for this indication. Administration of phenobarbital to the mother was suggested recently as a means of decreasing the risk of intracranial bleeding in preterm infants. However, large randomized studies failed to confirm this effect. Antiarrhythmic drugs have also been given to mothers for treatment of fetal cardiac arrhythmias. Although their efficacy has not yet been established by controlled studies, digoxin, flecainide, procainamide, verapamil, and other antiarrhythmic agents have been shown to be effective in case series. During the last two decades it has been shown that maternal use of zidovudine decreases by two thirds transmission of HIV from the mother to the fetus, and use of combinations of three antiretroviral agents can eliminate fetal infection almost entirely (see Chapter 49).

C. Predictable Toxic Drug Actions in the Fetus

Chronic use of opioids by the mother may produce dependence in the fetus and newborn. This dependence may be manifested after delivery as a neonatal withdrawal syndrome. A less well understood fetal drug toxicity is caused by the use of angiotensin-converting enzyme inhibitors during pregnancy. These drugs can result in significant and irreversible renal damage in the fetus and are therefore contraindicated in pregnant women. Adverse effects may also be delayed, as in the case of female fetuses exposed to diethylstilbestrol, who may be at increased risk for adenocarcinoma of the vagina after puberty.

D. Teratogenic Drug Actions

A single intrauterine exposure to a drug can affect the fetal structures undergoing rapid development at the time of exposure. Thalidomide is an example of a drug that may profoundly affect the development of the limbs after only brief exposure. This exposure, however, must be at a critical time in the development of the limbs. The thalidomide phocomelia risk occurs during the fourth through the seventh weeks of gestation because it is during this time that the arms and legs develop (Figure 59–1).

image

FIGURE 59–1 Schematic diagram of critical periods of human development. (Reproduced, with permission, from Moore KL: The Developing Human: Clinically Oriented Embryology, 4th ed. Saunders, 1988. © Elsevier.)

1. Teratogenic mechanismsThe mechanisms by which different drugs produce teratogenic effects are poorly understood and are probably multifactorial. For example, drugs may have a direct effect on maternal tissues with secondary or indirect effects on fetal tissues. Drugs may interfere with the passage of oxygen or nutrients through the placenta and therefore have effects on the most rapidly metabolizing tissues of the fetus. Finally, drugs may have important direct actions on the processes of differentiation in developing tissues. For example, vitamin A (retinol) has been shown to have important differentiation-directing actions in normal tissues. Several vitamin A analogs (isotretinoin, etretinate) are powerful teratogens, suggesting that they alter the normal processes of differentiation. Finally, deficiency of a critical substance appears to play a role in some types of abnormalities. For example, folic acid supplementation during pregnancy appears to reduce the incidence of neural tube defects (eg, spina bifida).

Continued exposure to a teratogen may produce cumulative effects or may affect several organs going through varying stages of development. Chronic consumption of high doses of ethanol during pregnancy, particularly during the first and second trimesters, may result in the fetal alcohol syndrome (see Chapter 23). In this syndrome, the central nervous system, growth, and facial development may be affected.

2. Defining a teratogenTo be considered teratogenic, a candidate substance or process should (1) result in a characteristic set of malformations, indicating selectivity for certain target organs; (2) exert its effects at a particular stage of fetal development, eg, during the limited time period of organogenesis of the target organs (Figure 59–1); and (3) show a dose-dependent incidence. Some drugs with known teratogenic or other adverse effects in pregnancy are listed in Table 59–1. Teratogenic effects are not limited only to major malformations, but also include intrauterine growth restriction (eg, cigarette smoking), miscarriage (eg, alcohol), stillbirth (eg, cigarette smoke), and neurocognitive delay (eg, alcohol, valproic acid).

TABLE 59–1 Drugs with significant teratogenic or other adverse effects on the fetus.

image

The widely cited FDA system for teratogenic potential (Table 59–2) is an attempt to quantify teratogenic risk from A (safe) to X (definite human teratogenic risk). This system has been criticized as inaccurate and impractical. For example, several drugs have been labeled “X” despite extensive opposite human safety data (eg, oral contraceptives). Diazepam and other benzodiazepines are labeled as “D” despite lack of positive evidence of human fetal risk. Presently the FDA is changing its system from the A, B, C grading system to narrative statements that will summarize evidence-based knowledge about each drug in terms of fetal risk and safety.

TABLE 59–2 FDA teratogenic risk categories.

image

3. Counseling women about teratogenic risk—Since the thalidomide disaster, medicine has been practiced as if every drug were a potential human teratogen when, in fact, fewer than 30 such drugs have been identified, with hundreds of agents proved safe for the unborn. Owing to high levels of anxiety among pregnant women—and because half of the pregnancies in North America are unplanned—every year many thousands of women need counseling about fetal exposure to drugs, chemicals, and radiation. In the Motherisk program in Toronto, thousands of women are counseled every month, and the ability of appropriate counseling to prevent unnecessary abortions has been documented. Clinicians who wish to provide such counsel to pregnant women must ensure that their information is up-to-date and evidence-based and that the woman understands that the baseline teratogenic risk in pregnancy (ie, the risk of a neonatal abnormality in the absence of any known teratogenic exposure) is about 3%. It is also critical to address the maternal-fetal risks of the untreated condition if a medication is avoided. Recent studies show serious morbidity in women who discontinued selective serotonin reuptake inhibitor therapy for depression in pregnancy.

DRUG THERAPY IN INFANTS & CHILDREN

Physiologic processes that influence pharmacokinetic variables in the infant change significantly in the first year of life, particularly during the first few months. Therefore, special attention must be paid to pharmacokinetics in this age group. Pharmacodynamic differences between pediatric and other patients have not been explored in great detail and are probably small except for those specific target tissues that mature at birth or immediately thereafter (eg, the ductus arteriosus).

Drug Absorption

Drug absorption in infants and children follows the same general principles as in adults. Unique factors that influence drug absorption include blood flow at the site of administration, as determined by the physiologic status of the infant or child; and, for orally administered drugs, gastrointestinal function, which changes rapidly during the first few days after birth. Age after birth also influences the regulation of drug absorption.

A. Blood Flow at the Site of Administration

Absorption after intramuscular or subcutaneous injection depends mainly, in neonates as in adults, on the rate of blood flow to the muscle or subcutaneous area injected. Physiologic conditions that might reduce blood flow to these areas are cardiovascular shock, vasoconstriction due to sympathomimetic agents, and heart failure. However, sick preterm infants requiring intramuscular injections may have very little muscle mass. This is further complicated by diminished peripheral perfusion to these areas. In such cases, absorption becomes irregular and difficult to predict, because the drug may remain in the muscle and be absorbed more slowly than expected. If perfusion suddenly improves, there can be a sudden and unpredictable increase in the amount of drug entering the circulation, resulting in high and potentially toxic concentrations of drug. Examples of drugs especially hazardous in such situations are cardiac glycosides, aminoglycoside antibiotics, and anticonvulsants.

B. Gastrointestinal Function

Significant biochemical and physiologic changes occur in the neonatal gastrointestinal tract shortly after birth. In full-term infants, gastric acid secretion begins soon after birth and increases gradually over several hours. In preterm infants, the secretion of gastric acid occurs more slowly, with the highest concentrations appearing on the fourth day of life. Therefore, drugs that are partially or totally inactivated by the low pH of gastric contents should not be administered orally.

Gastric emptying time is prolonged (up to 6 or 8 hours) in the first day or so after delivery. Therefore, drugs that are absorbed primarily in the stomach may be absorbed more completely than anticipated. In the case of drugs absorbed in the small intestine, therapeutic effect may be delayed. Peristalsis in the neonate is irregular and may be slow. The amount of drug absorbed in the small intestine may therefore be unpredictable; more than the usual amount of drug may be absorbed if peristalsis is slowed, and this could result in potential toxicity from an otherwise standard dose. Table 59–3 summarizes data on oral bioavailability of various drugs in neonates compared with older children and adults. An increase in peristalsis, as in diarrheal conditions, tends to decrease the extent of absorption, because contact time with the large absorptive surface of the intestine is decreased.

TABLE 59–3 Oral drug absorption (bioavailability) of various drugs in the neonate compared with older children and adults.

image

Gastrointestinal enzyme activities tend to be lower in the newborn than in the adult. Activities of α-amylase and other pancreatic enzymes in the duodenum are low in infants up to 4 months of age. Neonates also have low concentrations of bile acids and lipase, which may decrease the absorption of lipid-soluble drugs.

Drug Distribution

As body composition changes with development, the distribution volumes of drugs are also changed. The neonate has a higher percentage of its body weight in the form of water (70–75%) than does the adult (50–60%). Differences can also be observed between the full-term neonate (70% of body weight as water) and the small preterm neonate (85% of body weight as water). Similarly, extracellular water is 40% of body weight in the neonate, compared with 20% in the adult. Most neonates will experience diuresis in the first 24–48 hours of life. Since many drugs are distributed throughout the extracellular water space, the size (volume) of the extracellular water compartment may be important in determining the concentration of drug at receptor sites. This is especially important for water-soluble drugs (such as aminoglycosides) and less crucial for lipid-soluble agents.

Preterm infants have much less fat than full-term infants. Total body fat in preterm infants is about 1% of total body weight, compared with 15% in full-term neonates. Therefore, organs that generally accumulate high concentrations of lipid-soluble drugs in adults and older children may accumulate smaller amounts of these agents in less mature infants.

Another major factor determining drug distribution is drug binding to plasma proteins. Albumin is the plasma protein with the greatest binding capacity. In general, protein binding of drugs is reduced in the neonate. This has been seen with local anesthetic drugs, diazepam, phenytoin, ampicillin, and phenobarbital. Therefore, the concentration of free (unbound) drug in plasma is increased initially. Because the free drug exerts the pharmacologic effect, this can result in greater drug effect or toxicity despite a normal or even low plasma concentration of total drug (bound plus unbound). Consider a therapeutic dose of a drug (eg, diazepam) given to a patient. The concentration of total drug in the plasma is 300 mcg/L. If the drug is 98% protein-bound in an older child or adult, then 6 mcg/L is the concentration of free drug. Assume that this concentration of free drug produces the desired effect in the patient without producing toxicity. However, if this drug is given to a preterm infant in a dosage adjusted for body weight and it produces a total drug concentration of 300 mcg/L—and protein binding is only 90%—then the free drug concentration will be 30 mcg/L, or five times higher. Although the higher free concentration may result in faster elimination (see Chapter 3), this concentration may be quite toxic initially.

Some drugs compete with serum bilirubin for binding to albumin. Drugs given to a neonate with jaundice can displace bilirubin from albumin. Because of the greater permeability of the neonatal blood-brain barrier, substantial amounts of bilirubin may enter the brain and cause kernicterus. This was in fact observed when sulfonamide antibiotics were given to preterm neonates as prophylaxis against sepsis. Conversely, as the serum bilirubin rises for physiologic reasons or because of a blood group incompatibility, bilirubin can displace a drug from albumin and substantially raise the free drug concentration. This may occur without altering the total drug concentration and would result in greater therapeutic effect or toxicity at normal concentrations. This has been shown to happen with phenytoin.

Drug Metabolism

The metabolism of most drugs occurs in the liver (see Chapter 4). The drug-metabolizing activities of the cytochrome P450-dependent mixed-function oxidases and the conjugating enzymes are substantially lower (50–70% of adult values) in early neonatal life than later. The point in development at which enzymatic activity is maximal depends upon the specific enzyme system in question. Glucuronide formation reaches adult values (per kilogram body weight) between the third and fourth years of life. Because of the neonate’s decreased ability to metabolize drugs, many drugs have slow clearance rates and prolonged elimination half-lives. If drug doses and dosing schedules are not altered appropriately, this immaturity predisposes the neonate to adverse effects from drugs that are metabolized by the liver. Table 59–4demonstrates how neonatal and adult drug elimination half-lives can differ and how the half-lives of phenobarbital and phenytoin decrease as the neonate grows older. The process of maturation must be considered when administering drugs to this age group, especially in the case of drugs administered over long periods.

TABLE 59–4 Comparison of elimination half-lives of various drugs in neonates and adults.

image

Another consideration for the neonate is whether or not the mother was receiving drugs (eg, phenobarbital) that can induce early maturation of fetal hepatic enzymes. In this case, the ability of the neonate to metabolize certain drugs will be greater than expected, and one may see less therapeutic effect and lower plasma drug concentrations when the usual neonatal dose is given. During toddlerhood (12–36 months), the metabolic rate of many drugs exceeds adult values, often necessitating larger doses per kilogram than later in life.

Drug Excretion

The glomerular filtration rate is much lower in newborns than in older infants, children, or adults, and this limitation persists during the first few days of life. Calculated on the basis of body surface area, glomerular filtration in the neonate is only 30–40% of the adult value. The glomerular filtration rate is even lower in neonates born before 34 weeks of gestation. Function improves substantially during the first week of life. At the end of the first week, the glomerular filtration rate and renal plasma flow have increased 50% from the first day. By the end of the third week, glomerular filtration is 50–60% of the adult value; by 6–12 months, it reaches adult values (per unit surface area). Subsequently, during toddlerhood, it exceeds adult values, often necessitating larger doses per kilogram than in adults, as described previously for drug-metabolic rate. Therefore, drugs that depend on renal function for elimination are cleared from the body very slowly in the first weeks of life.

Penicillins, for example, are cleared by preterm infants at 17% of the adult rate based on comparable surface area and 34% of the adult rate when adjusted for body weight. The dosage of ampicillin for a neonate less than 7 days old is 50–100 mg/kg/d in two doses at 12-hour intervals. The dosage for a neonate over 7 days old is 100–200 mg/kg/d in three doses at 8-hour intervals. A decreased rate of renal elimination in the neonate has also been observed with aminoglycoside antibiotics (kanamycin, gentamicin, neomycin, and streptomycin). The dosage of gentamicin for a neonate less than 7 days old is 5 mg/kg/d in two doses at 12-hour intervals. The dosage for a neonate over 7 days old is 7.5 mg/kg/d in three doses at 8-hour intervals. Total body clearance of digoxin is directly dependent upon adequate renal function, and accumulation of digoxin can occur when glomerular filtration is decreased. Since renal function in a sick infant may not improve at the predicted rate during the first weeks and months of life, appropriate adjustments in dosage and dosing schedules may be very difficult. In this situation, adjustments are best made on the basis of plasma drug concentrations determined at intervals throughout the course of therapy.

Although great focus is naturally concentrated on the neonate, it is important to remember that toddlers may have shorter elimination half-lives of drugs than older children and adults, due probably to increased renal elimination and metabolism. For example, the dose per kilogram of digoxin is much higher in toddlers than in adults. The mechanisms for these developmental changes are still poorly understood.

Special Pharmacodynamic Features in the Neonate

The appropriate use of drugs has made possible the survival of neonates with severe abnormalities who would otherwise die within days or weeks after birth. For example, administration of indomethacin (see Chapter 36) causes the rapid closure of a patent ductus arteriosus, which would otherwise require surgical closure in an infant with a normal heart. Infusion of prostaglandin E1, on the other hand, causes the ductus to remain open, which can be lifesaving in an infant with transposition of the great vessels or tetralogy of Fallot (see Chapter 18). An unexpected effect of such infusion has been described when the drug caused antral hyperplasia with gastric outlet obstruction as a clinical manifestation in 6 of 74 infants who received it. This phenomenon appears to be dose-dependent. Neonates are also more sensitive to the central depressant effects of opioids than are older children and adults, necessitating extra caution when they are exposed to some narcotics (eg, codeine) through breast milk.

At birth, the function of drug transporters may be very low; for example, P-glycoprotein, which pumps morphine from the blood-brain barrier back to the systemic circulation. Low-level function of P-glycoprotein at birth may explain why neonates are substantially more sensitive than older children to the central nervous system depressant effects of morphine.

PEDIATRIC DOSAGE FORMS & COMPLIANCE

The form in which a drug is manufactured and the way in which the parent dispenses the drug to the child determine the actual dose administered. Many drugs prepared for children are in the form of elixirs or suspensions. Elixirs are alcoholic solutions in which the drug molecules are dissolved and evenly distributed. No shaking is required, and unless some of the vehicle has evaporated, the first dose from the bottle and the last dose should contain equivalent amounts of drug. Suspensions contain undissolved particles of drug that must be distributed throughout the vehicle by shaking. If shaking is not thorough each time a dose is given, the first doses from the bottle may contain less drug than the last doses, with the result that less than the expected plasma concentration or effect of the drug may be achieved early in the course of therapy. Conversely, toxicity may occur late in the course of therapy, when it is not expected. This uneven distribution is a potential cause of inefficacy or toxicity in children taking phenytoin suspensions. It is thus essential that the prescriber know the form in which the drug will be dispensed and provide proper instructions to the pharmacist and patient or parent.

Compliance may be more difficult to achieve in pediatric practice than otherwise, since it involves not only the parent’s conscientious effort to follow directions but also such practical matters as measuring errors, spilling, and spitting out. For example, the measured volume of “teaspoons” ranges from 2.5 to 7.8 mL. The parents should obtain a calibrated medicine spoon or syringe from the pharmacy. These devices improve the accuracy of dose measurements and simplify administration of drugs to children.

When evaluating compliance, it is often helpful to ask if an attempt has been made to give a further dose after the child has spilled half of what was offered. The parents may not always be able to say with confidence how much of a dose the child actually received. The parents must be told whether or not to wake the infant for its every-6-hour dose day or night. These matters should be discussed and made clear, and no assumptions should be made about what the parents may or may not do. Noncompliance frequently occurs when antibiotics are prescribed to treat otitis media or urinary tract infections and the child feels well after 4 or 5 days of therapy. The parents may not feel there is any reason to continue giving the medicine even though it was prescribed for 10 or 14 days. This common situation should be anticipated so the parents can be told why it is important to continue giving the medicine for the prescribed period even if the child seems to be “cured.”

Practical and convenient dosage forms and dosing schedules should be chosen to the extent possible. The easier it is to administer and take the medicine and the easier the dosing schedule is to follow, the more likely it is that compliance will be achieved.

Consistent with their ability to comprehend and cooperate, children should also be given some responsibility for their own health care and for taking medications. This should be discussed in appropriate terms both with the child and with the parents. Possible adverse effects and drug interactions with over-the-counter medicines or foods should also be discussed. Whenever a drug does not achieve its therapeutic effect, the possibility of noncompliance should be considered. There is ample evidence that in such cases parents’ or children’s reports may be grossly inaccurate. Random pill counts and measurement of serum concentrations may help disclose noncompliance. The use of computerized pill containers, which record each lid opening, has been shown to be very effective in measuring compliance.

Because many pediatric doses are calculated—eg, using body weight—rather than simply read from a list, major dosing errors may result from incorrect calculations. Typically, tenfold errors due to incorrect placement of the decimal point have been described. In the case of digoxin, for example, an intended dose of 0.1 mL containing 5 mcg of drug, when replaced by 1.0 mL—which is still a small volume—can result in fatal overdosage. A good rule for avoiding such “decimal point” errors is to use a leading “0” plus decimal point when dealing with doses less than “1” and to avoid using a zero after a decimal point (see Chapter 65).

DRUG USE DURING LACTATION

Despite the fact that most drugs are excreted into breast milk in amounts too small to adversely affect neonatal health, thousands of women taking medications do not breast-feed because of misperception of risk. Unfortunately, physicians contribute heavily to this bias. It is important to remember that formula feeding is associated with higher morbidity and mortality in all socioeconomic groups.

Most drugs administered to lactating women are detectable in breast milk. Fortunately, the concentration of drugs achieved in breast milk is usually low (Table 59–5). Therefore, the total amount the infant would receive in a day is substantially less than what would be considered a “therapeutic dose.” If the nursing mother must take medications and the drug is a relatively safe one, she should optimally take it 30–60 minutes after nursing and 3–4 hours before the next feeding. In some cases this may allow time for drugs to be partially cleared from the mother’s blood, and the concentrations in breast milk will be relatively low. Most antibiotics taken by nursing mothers can be detected in breast milk. Tetracycline concentrations in breast milk are approximately 70% of maternal serum concentrations and present a risk of permanent tooth staining in the infant. Isoniazid rapidly reaches equilibrium between breast milk and maternal blood. The concentrations achieved in breast milk are high enough so that signs of pyridoxine deficiency may occur in the infant if the mother is not given pyridoxine supplements.

TABLE 59–5 Drugs often used during lactation and possible effects on the nursing infant.

image

Most sedatives and hypnotics achieve concentrations in breast milk sufficient to produce a pharmacologic effect in some infants. Barbiturates taken in hypnotic doses by the mother can produce lethargy, sedation, and poor suck reflexes in the infant. Chloral hydrate can produce sedation if the infant is fed at peak milk concentrations. Diazepam can have a sedative effect on the nursing infant, but, most importantly, its long half-life can result in significant drug accumulation.

Opioids such as heroin, methadone, and morphine enter breast milk in quantities potentially sufficient to prolong the state of neonatal narcotic dependence if the drug was taken chronically by the mother during pregnancy. If conditions are well controlled and there is a good relationship between the mother and the physician, an infant could be breast-fed while the mother is taking methadone. She should not, however, stop taking the drug abruptly; the infant can be tapered off the methadone as the mother’s dose is tapered. The infant should be watched for signs of narcotic withdrawal. Although codeine has been believed to be safe, a recent case of neonatal death from opioid toxicity revealed that the mother was an ultra rapid metabolizer of cytochrome 2D6 substrates, producing substantially higher amounts of morphine. Hence, polymorphism in maternal drug metabolism may affect neonatal exposure and safety. A subsequent case control study has shown that this situation is not rare. The FDA has published a warning to lactating mothers to exert extra caution while using painkillers containing codeine.

Minimal use of alcohol by the mother has not been reported to harm nursing infants. Excessive amounts of alcohol, however, can produce alcohol effects in the infant. Nicotine concentrations in the breast milk of smoking mothers are low and do not produce effects in the infant. Very small amounts of caffeine are excreted in the breast milk of coffee-drinking mothers.

Lithium enters breast milk in concentrations equal to those in maternal serum. Clearance of this drug is almost completely dependent upon renal elimination, and women who are receiving lithium may expose the infant to relatively large amounts of the drug.

Radioactive substances such as iodinated 125I albumin and radioiodine can cause thyroid suppression in infants and may increase the risk of subsequent thyroid cancer as much as tenfold. Breast-feeding is contraindicated after large doses and should be withheld for days to weeks after small doses. Similarly, breast-feeding should be avoided in mothers receiving cancer chemotherapy or being treated with cytotoxic or immunomodulating agents for collagen diseases such as lupus erythematosus or after organ transplantation.

PEDIATRIC DRUG DOSAGE

Because of differences in pharmacokinetics in infants and children, simple proportionate reduction in the adult dose may not be adequate to determine a safe and effective pediatric dose. The most reliable pediatric dose information is usually that provided by the manufacturer in the package insert. However, such information is not available for the majority of products, even when studies have been published in the medical literature, reflecting the reluctance of manufacturers to label their products for children. Recently, the FDA has moved toward more explicit expectations that manufacturers test their new products in infants and children. Still, most drugs in the common formularies, eg, Physicians’ Desk Reference, are not specifically approved for children, in part because manufacturers often lack the economic incentive to evaluate drugs for use in the pediatric market.

Most drugs approved for use in children have recommended pediatric doses, generally stated as milligrams per kilogram or per pound. In the absence of explicit pediatric dose recommendations, an approximation can be made by any of several methods based on age, weight, or surface area. These rules are not precise and should not be used if the manufacturer provides a pediatric dose. When pediatric doses are calculated (either from one of the methods set forth below or from a manufacturer’s dose), the pediatric dose should never exceed the adult dose.

The current epidemic proportions of childhood obesity calls for a fresh and careful look at pediatric drug dosages. Studies in adults indicate that dosing based on per-kilogram body weight may constitute overdosing, because in obese subjects, drugs are distributed based on lean body weight.

Surface Area, Age, & Weight

Calculations of dosage based on age or weight (see below) are conservative and tend to underestimate the required dose. Doses based on surface area (Table 59–6) are more likely to be adequate.

TABLE 59–6 Determination of drug dosage from surface area.1

image

image

In spite of these approximations, only by conducting studies in children can safe and effective doses for a given age group and condition be determined.

REFERENCES

American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) of pediatric and neonatal patients: Pediatric basic life support. Circulation. 2005;112(24 Suppl):IV1.

Briggs GG, Freeman RK, Yaffe SJ: Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th ed. Williams & Wilkins, 2011.

de Wildt SN et al: Ontogeny of midazolam glucuronidation in preterm infants. Eur J Clin Pharmacol 2010;66:165.

Gavin PJ, Yogev R: The role of protease inhibitor therapy in children with HIV infection. Paediatr Drugs 2002;4:581.

Hansten PD, Horn JR: Drug Interactions, Analysis and Management. Facts & Comparisons. [Quarterly.]

Iqbal MM, Sohhan T, Mahmud SZ: The effects of lithium, valproic acid, and carbamazepine during pregnancy and lactation. J Toxicol Clin Toxicol 2001;39:381.

Ito S: Drug therapy for breast feeding women. N Engl J Med 2000;343:118.

Kearns GL et al: Developmental pharmacology—drug disposition, action and therapy in infants and children. N Engl J Med 2003;349:1157.

Koren G: Medication Safety during Pregnancy and Breastfeeding; A Clinician’s Guide, 4th ed. McGraw-Hill, 2006.

Koren G, Klinger G, Ohlsson A: Fetal pharmacotherapy. Drugs 2002;62:757.

Koren G, Nordeng H: Antidepressant use during pregnancy: The benefit-risk ratio. Am J Obstet Gynecol 2012;207:157.

Koren G, Pastuszak A: Prevention of unnecessary pregnancy terminations by counseling women on drug, chemical, and radiation exposure during the first trimester. Teratology 1990;41:657.

Koren G, Pastuszak A, Ito E: Drugs in pregnancy. N Engl J Med 1998;338:1128.

Koren G et al: Sex differences in the pharmacokinetics and bioequivalence of the delayed-release combination of doxylamine succinate-pyridoxine hydrochloride; Implications for pharmacotherapy in pregnancy. J Clin Pharmacol 2013;53:1268.

Loebstein R, Koren G: Clinical pharmacology and therapeutic drug monitoring in neonates and children. Pediatr Rev 1998;19:423.

Madadi P et al: Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: A case control study. Clin Pharmacol Ther 2009;85:31.

Namouz-Haddad S, Koren G: Fetal pharmacotherapy 2: Fetal arrhythmia. J Obstet Gynaecol Can 2013;35:1023.

Neubert D: Reproductive toxicology: The science today. Teratog Carcinog Mutagen 2002;22:159.

Peled N et al: Gastric-outlet obstruction induced by prostaglandin therapy in neonates. N Engl J Med 1992;327:505.

SickKids Drug Handbook and Formulary 2013/2014. The Hospital for Sick Children, Toronto.

Tetelbaum M et al:. Back to basics: Understanding drugs in children: Pharmacokinetic maturation. Pediatr Rev 2005;26:321.

Van Lingen RA et al: The effects of analgesia in the vulnerable infant during the perinatal period. Clin Perinatol 2002;29:511.

_______________

*Supported by grants from the Canadian Institutes for Health Research, The Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation, and Shoppers Drug Mart, Canada.