Drug Therapy in the Newborn
Robert M. Ward
Ralph A. Lugo
Jacob V. Aranda
Drugs are vital in neonatal practice and are widely used in the sick newborn infant (1). More than 400 drugs are used in newborns (1), most of which have not been approved by regulatory agencies (Food and Drug Administration and the European Medicines Agency). The developmental uniqueness of the neonate has tremendous impact on drug therapy. This uniqueness and the potential for dramatic and rapid developmental changes beginning shortly after birth defy accurate generalizations, and mandate the need for age-specific studies in the increasingly premature patients surviving today. These developmental changes affect all aspects of drug action, from absorption, distribution, and protein binding to receptor interaction, metabolism, and elimination. Collectively, these changes can have a substantial impact on drug dosages and regimens in the newborn. The newborn population is an extremely heterogenous group with unique pharmacokinetic profiles and drug dosages arising from interactions of fetal maturity (gestational age) and postnatal age. Thus, a term newborn infant at birth differs substantially from an extremely low-birth-weight infant at one month of age. This chapter deals with the principles of pharmacology as applied to the newborn infant.
▪ PRINCIPLES OF PHARMACOLOGY APPLIED TO NEONATES
Free-Drug Theory and Protein Binding
Most clinical drug assays measure both bound and unbound drug; however, it is only the non-protein-bound or free-drug molecules that are active, that is, cross membranes, bind to receptors to exert pharmacologic action, and undergo metabolism and excretion (1). Serum protein binding usually is a rapidly reversible process, so that additional drug is released to replace the unbound drug removed by distribution into tissue or by elimination. The rate of release from serum protein binding usually is much faster than the rate of transfer across membranes. Seldom is the rate of release from serum proteins so slow that it limits the availability of drug molecules for transfer across membranes to exert pharmacologic effects (2).
For most drugs in premature infants, the percentage of unbound drug in the circulation is greater than in adults, because both the amount and the binding affinity of circulating proteins are decreased. For example, the albumin of term newborns, compared to that of adults, binds less theophylline, warfarin, and sulfonamides but similar amounts of diazepam (3,4). Because the effects of a drug are related to the amount of unbound drug reaching the site of action, some drug effects in newborns may be explained only by measuring circulating concentrations of free drug. Furthermore, circulating total drug concentrations that are in the therapeutic range for adults or older children may represent free-drug concentrations that are in a toxic range in the premature neonate (3).
Absorption
In drug treatment, absorption refers to the transfer of drug from the site of administration into the circulation. The rates of drug absorption are related to several factors, beginning with the route of administration and including the same characteristics that influence transfer of any substance across lipid bilayers: degree of ionization, molecular weight, lipid solubility, concentration gradient, and active transport.
Enteral
Enteral drug treatment of neonates may not produce reliable and reproducible circulating drug concentrations for a variety of reasons. Although most studies of enteral drug therapy have been conducted in adults, many of the problems of enteral drug administration identified from these studies are likely to occur in neonates.
Intestinal villi and microvilli increase the surface area of the gastrointestinal tract, so that rates of drug absorption are usually much greater from the intestine than from the stomach. Delayed gastric emptying slows passage of drug into the intestine, which prolongs the absorption phase of many drugs. Elimination begins during this absorption phase, so that delayed gastric emptying reduces the area under the curve (AUC) for circulating drug concentration versus time. This reduces the desired therapeutic effect for many drugs whose effects are directly proportional to the AUC. Gastroesophageal reflux is common in neonates and may be associated with delayed gastric emptying that reduces the therapeutic effects of drugs administered orally. Few studies have addressed this aspect of drug treatment of newborns (5).
Additional problems, unique to the immature patient, may affect enteral drug treatment of newborns. Neonates, especially premature neonates, malabsorb fat, which may alter enteral drug absorption. Elevated right atrial pressure, leading to passive congestion of hepatic and mesenteric circulations, often reduces enteral drug absorption in adults. Prolonged enteral drug administration often is necessary for treatment of infants with chronic disorders. These include bronchopulmonary dysplasia (BPD) and congestive heart failure, which may increase right atrial pressure and cause intestinal venous congestion that decreases enteral drug absorption and bioavailability. Therefore, larger doses may be required to achieve the desired therapeutic response. This phenomenon has been reported with furosemide in an infant with BPD, who required a sixfold higher enteral dose to reach plasma concentrations comparable to a 1 mg/kg dose administered intravenously (IV) (5).
Intramuscular
Intramuscular drug absorption is directly proportional to blood flow and the surface area of the drug deposited in the muscle (6). Although intramuscular drug administration is often considered more reliable than is enteral, the sick or hypothermic neonate with limited muscle mass and poor perfusion of muscle may not absorb intramuscular doses rapidly or completely. As a result of limited amounts of muscle, injections intended for the muscle may enter subcutaneous tissue, from which absorption is slow and unpredictable. Caustic drugs (e.g., phenytoin, pH = 12) damage surrounding tissues and isolate the dose of drug from blood flow, or precipitate to a chemical form that is absorbed very slowly in what has been described as a depot effect (6). Intramuscular injection sites
in neonates may leave sterile abscesses that later require surgical repair. In general, prolonged intramuscular administration of drugs in neonates should be avoided.
in neonates may leave sterile abscesses that later require surgical repair. In general, prolonged intramuscular administration of drugs in neonates should be avoided.
Intravenous
Intravenous drug administration is most likely to ensure effective drug therapy in neonates. Although this route of drug treatment is the most reliable, certain problems must be recognized that are unique to neonates. The infusion rate for IV fluids in extremely small neonates is so slow that drug doses injected distant from where the IV enters the vessel or up the IV tubing away from the patient may not reach the circulation for several hours (7).
The most reliable method for administering medications intravenously to neonates is to use a small-volume syringe pump and microbore tubing connected as close to the patient as possible. If the syringe is prepared to contain the exact dose, the tubing must be flushed following drug administration to ensure complete drug delivery. Alternatively, it may be preferable to include overfill in the syringe so that the tubing may be primed prior to drug administration. Thus, once the drug is infused, the tubing will contain extra drug that may be discarded without the necessity of flushing.
Distribution
Distribution is the partitioning of drug from the circulation into various body fluids, organs, and tissues (8). At equilibrium, this distribution is related to organ blood flow; pH and composition of body fluids and tissues; physical and chemical properties of the drug including lipid solubility, polarity, and size; and the extent of binding to plasma and tissue proteins.
Dramatic developmental changes in body composition of newborns influence the distribution of polar and nonpolar drugs within the body. At 24 weeks of gestation, water constitutes about 89% of body weight, with 0.1% to 0.5% as fat (9,10). Thus, water-soluble drugs that distribute primarily into extracellular fluid will have larger distribution volumes in premature neonates. By 40 weeks of gestation, the body is approximately 75% water and 15% fat, compared to adults in whom the body is about 65% water and the fat content is variable. The low fat content of the brain of the extremely premature newborn may affect the distribution and effects of centrally active drugs, such as barbiturates and gaseous anesthetics (11).
TABLE 52.1 Developmental Patterns for Important Cytochrome P450 Enzymes in the Neonate | ||||||||||||||||||||
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Metabolism
Many drugs require biotransformation to more polar forms before they can be eliminated from the body. Biotransformation reactions are designated phase I reactions that make the drug more polar through oxidation, reduction, or hydrolysis or phase II, conjugation reactions, such as glucuronidation, sulfation, and acetylation (8). The liver is the primary site for biotransformation; however, other organs are also involved. As early as 9 to 22 weeks of gestation, metabolic enzyme activities of the fetal liver vary from 2% to 36% of adult activity (12). This variation precludes broad generalizations regarding hepatic drug metabolism in premature newborns. Over the past decade, intense research into the biochemistry of drug metabolism has revealed multiple forms of cytochrome P450 with different substrate specificities and different activities during development from the fetus to the adult (1,13,14,15,16,17). Clinicians should have an understanding of P450 nomenclature in addition to understanding which isoforms are responsible for metabolism of commonly used drugs. Both induction and inhibition of specific isoforms may require more frequent therapeutic drug monitoring and dosage adjustments.
Cytochromes P450
Quantitatively, the most important of the phase I enzymes are the cytochromes P450, a superfamily of heme-containing proteins that catalyze the metabolism of many lipophilic substances. The cytochrome P450 isozymes are designated as CYPs, which are grouped by the degree of identity in their amino acid sequences. The designation CYP is followed in order by (a) an Arabic number representing the gene family for enzymes with greater than 40% identity; (b) a letter that indicates the subfamily for enzymes with greater than 55% identity; and (c) sequential numbering of the P450 enzymes for different isoforms within each subfamily (8,16). Isozymes, which are important in human drug metabolism, are found mostly in the CYP1, CYP2, and CYP3 gene families. Table 52.1 outlines some of the P450 isozymes important in newborns and their substrates.
Research in the early 1970s revealed that newborn infants have significantly reduced total quantities of cytochrome P450 in liver microsomes (18). This hemoprotein increases with gestational age but reaches only 50% of adult values at term (18). Reduced cytochrome P450 in neonates explains the low clearance and significantly prolonged half-lives of theophylline, caffeine, phenytoin, phenobarbital, and other substances that are metabolized
via cytochrome P450 (3,19,20,21). Although newborns are poor metabolizers of many xenobiotics, specific P450 cytochromes exhibit unique developmental patterns during gestation and postnatal life that invalidate broad generalizations about drug metabolism. Table 52.1 outlines important developmental patterns for many of these enzymes.
via cytochrome P450 (3,19,20,21). Although newborns are poor metabolizers of many xenobiotics, specific P450 cytochromes exhibit unique developmental patterns during gestation and postnatal life that invalidate broad generalizations about drug metabolism. Table 52.1 outlines important developmental patterns for many of these enzymes.
Ontogeny of Important P450 Cytochromes
Cytochrome P4501A2 is extensively involved in the metabolism of caffeine (1,3,7-trimethylxanthine) (22,23) and theophylline (1,3-dimethylxanthine) (24,25), drugs that are commonly used to treat neonatal apnea and bradycardia. CYP1A2 is not significantly expressed in human fetal liver, and expression is very low in neonates, reaching only 50% of adult activity by 1 year of age (24,26). Metabolically, this limits N-3- and N-7-demethylation of caffeine in the newborn period (22). Caffeine elimination in both preterm and term infants is significantly prolonged (27). Maturation of this pathway to adult levels occurs between 4 and 6 months postnatally (28,29). A similar pharmacokinetic trend is noted with theophylline in which 3-demethylation and 8-hydroxylation are catalyzed by CYP1A2 (24,25). Clinically, theophylline clearance and urine metabolite patterns reach adult values by 55 weeks of postconceptional age or approximately 4 to 5 months postnatally (30).
Other P450 enzymes that appear to be reduced or absent in the fetus include CYP2D6 and CYP2C9 (14,15,31). The former is responsible for the metabolism of numerous important therapeutic compounds including β-blockers, antiarrhythmics, antidepressants, antipsychotics, and codeine. Although CYP2D6 is absent in the fetal liver and appears to be expressed postnatally (14), activity remains low for an extended period (see Table 52.1) (32). In contrast to the slow development of CYP1A2 and CYP2D6, other enzymes such as CYP2C9 (responsible for the metabolism of nonsteroidal anti-inflammatory drugs, warfarin, and phenytoin) develop more rapidly after birth. For example, although CYP2C9 is not significantly present during fetal life (31), it matures rapidly after birth, decreasing ibuprofen half-life from 42 hours at 2 days of age to around 10 hours by 8 days (33). This is relevant to treatment of the PDA, because the ductus arteriosus once closed by inhibition of cyclooxygenase reopens when NSAID levels decrease to a level at which prostaglandin synthesis resumes (34).
For drug metabolism, the most important of the cytochromes P450 is CYP3A, because of the large number of therapeutic substrates for this subfamily of enzymes (see Table 52.1). Additionally, CYP3A accounts for the majority of P450 cytochromes present in the adult human liver (8). Unlike most of the other important cytochromes, CYP3A is functionally present during embryogenesis, primarily as CYP3A7 (35,36). CYP3A activity is detectable in large amounts as early as 17 weeks of gestation and reaches 10% of adult activity at 30 weeks’ gestation (14,36). In vivo, CYP3A activity matures to around 50% of adult activity by 6 to 12 months after birth (36). Postnatally, CYP3A changes in a nonlinear pattern from the fetal form, CYP3A7, to the predominant adult isoform CYP3A4 by one year of age (36).
Phase II Reactions
The phase II reactions are known as synthetic or conjugation reactions and function to increase the hydrophilicity of drug molecules, which facilitates renal and biliary elimination (8). The phase II enzymes include glucuronosyltransferase, sulfotransferase, N-acetyltransferase, glutathione S-transferase, and methyl transferase. Although the ontogeny of phase II reactions as a group is not well studied, developmental changes during infancy influence drug clearance (see Table 52.2).
Most conjugation reactions show low activity during fetal development, although sulfation is relatively active in the fetus (16,37,38). One of the most common synthetic reactions involves conjugation with uridine diphosphoglucuronosyltransferases (UDP-GT). This enzyme system, which is comprised of numerous isoforms, is also responsible for glucuronidation of endogenous compounds such as bilirubin (39). Although UDP-GT activity for bilirubin develops relatively rapidly after birth (37), the ability of the infant to glucuronidate xenobiotics is significantly limited during the newborn period.
TABLE 52.2 Developmental Patterns for Important Conjugation Reactions in the Neonate | |||||||||||||||
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Thus, without dosage adjustments, drugs may accumulate to toxic concentrations during the newborn period. A tragic example occurred in the early 1960s when newborns received standard pediatric doses of chloramphenicol and developed fatal circulatory collapse, a condition known as the gray baby syndrome (40,41,42). The clearance of chloramphenicol is low during the neonatal period, and dosage adjustments are necessary in preterm and full-term infants to avoid chloramphenicol toxicity (43).
Other drugs used in the newborn period that undergo glucuronidation include morphine, acetaminophen, and lorazepam. The major metabolic pathway of morphine in children and adults is glucuronidation in the 3- and 6-position (44,45). However, neonates have limited ability to glucuronidate morphine and thus require dosage adjustment (46,47,48). Morphine clearance (46,49), in particular 3- and 6-glucuronide formation, is low at birth and increases with birth weight (48), gestational age (50), and postnatal age (44,47,51). Morphine’s clearance and half-life begin to approach adult values after the age of 1 month (47,52), although other reports indicate that adult values are not reached until at least 5 to 6 months (46,53). Overall, the maturation of glucuronosyltransferase enzymes is isoform specific; however, adult activity is usually achieved by 6 to 18 months of age (16).
In contrast to glucuronosyltransferase, the sulfotransferase enzyme system is well developed in the newborn and may compensate for limited glucuronidation, as is the case with the metabolism of acetaminophen. Although acetaminophen is primarily glucuronidated in adults, the half-life of acetaminophen is only moderately prolonged in term newborns as compared to older infants and adults (54
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