DRUG DISPOSITION IN PEDIATRIC PATIENTS
In spite of recent advances in this area, knowledge of the disposition and actions of drugs in children is lim-ited. This lack of information has made drug therapy for them difficult and dangerous. There are two major ob-stacles to clinical drug studies in children. One is an eth-ical issue, the inability to obtain true informed consent. The second obstacle is inherent to children; they grow and change rapidly. Drug studies must be performed on children at each stage of their development to deter-mine appropriate usage for all patients.
To study drug disposition in children it is most in-formative to divide them into five age groups: preterm infants, term infants from birth through the first month of life, children 1 month to 2 years of age, children 2 to12 years of age, and children 12 to 18 years of age. Tanner staging of sexual maturation may more appro-priately break down this latter group. Children that are Tanner stages I, II, and III are appropriately considered children; those who are Tanner stages IV and V are con-sidered adults.
Preterm infants, especially those near the limits of viability (24 weeks’ gestation), have glomerular filtration rates approximately one-tenth that of a term newborn. Because of limitations on tubular reabsorption, they have increased urinary loss of filtered substances. Glucuronidation pathways appear after 20 weeks of ges-tation and so are limited in extremely premature infants.
Recent advances have made it possible for drug therapy to begin prior to birth. Many mothers and therefore their infants are receiving corticosteroids to induce maturation of the lungs. Some fetal cardiac ar-rhythmias, such as supraventricular tachycardia, are suc-cessfully managed by treating the mother during preg-nancy. Since most drugs cross the placenta, the infant has the potential to be affected by drugs that the mother takes. Metabolism and excretion are not the re-sponsibility of the fetus, as the placenta and the mater-nal liver and kidneys contribute significantly to drug elimination.
At birth, term infants can metabolize and eliminate drugs. For most patients these systems did not function during fetal life and therefore even at birth are not very efficient. Table 6.1 outlines the time required for matu-ration of some of the systems used in drug absorption and elimination. Table 6.2 lists other factors that alter drug disposition in newborns. The ability to absorb and eliminate drugs increases slowly over the first month of life.
Maternally administered drugs also may affect in-fants who are breast-fed. Most drugs are present in breast milk in small quantities. However, several drugs can reach concentrations sufficient to adversely affect the newborn. Drugs that are contraindicated during breast-feeding include cocaine, ergotamine, and cimeti-dine. Unfortunately, for many drugs the information re-garding risks to the infant from drug in breast milk is not available.
The period from 1 month to 2 years of age is a time of rapid growth and maturation. By the end of this pe-riod, most systems function at adult levels. Paradoxically, between 2 and 12 years of age drug clearance greatly in-creases and often exceeds adult levels. Half-lives are shorter and dosing requirements are frequently greater than for adults (Table 6.3).
From 12 to 18 years of age sex differences start to appear. These differences are often associated with a decreased drug absorption and elimination in the fe-male as opposed to the male. Females have less gastric acidity and an increased gastric emptying time. Estro-gens decrease hepatic cytochrome P450 content and therefore may decrease metabolism of some drugs via phase I pathways. Cyclic changes in glomerular filtra-tion are noted during the menstrual cycle.
Oral absorption of drugs is influenced by gastric acidity and emptying time. Gastric acid is rarely found in the stomach of infants at less than 32 weeks’ gestation. Acid initially is secreted within the first few hours after birth, reaching peak levels within the first 10 days of life. It de-creases during the next 20 days of extrauterine life. Gastric acid secretion approaches the lower limits of adult values by 3 months of age. The initiation of acid secretion is often delayed in infants with delayed initia-tion of oral feedings, such as extreme preemies and those with anomalies of the gastrointestinal tract.
Gastric emptying time in infants is related to their age and to the type of formula they receive. Formulas containing long-chain fatty acids will delay gastric emp-tying. Both gastric emptying time and small-intestine peristalsis tend to be slow until the later part of the first year of life. In children aged 2 to 12 years gastric emp-tying time dramatically increases, as does splanchnic blood flow. These physiological changes result in faster drug absorption and increased peak blood concentra-tions of drug. The decreased small intestine transit time during this period may result in decreased absorption of some drugs. Because of low blood flow through muscles in the neonatal period, drugs administered intramuscu-larly are absorbed erratically.
Percutaneous drug absorption can present special problems in newborns, especially in preterm infants. While the skin of a newborn term infant may have the same protective capacity as the skin of an adult, a preterm infant will not have this protective barrier until after 2 to 3 weeks of life. Excessive percutaneous ab-sorption has caused significant toxicity to preterm ba-bies. Absorption of hexachlorophene soap used to bathe newborns has resulted in brain damage and death. Aniline dyes on hospital linen have caused cyanosis secondary to methemoglobinemia, and EMLA (lidocaine/prilocaine) cream may cause methemoglo-binemia when administered to infants less than 3 months of age.
The total body water of prematures, newborns, and in-fants is significantly greater than it is for older children and adults. This increased total body water increases the volume of drug distribution for water-soluble com-pounds. As a consequence, there is a need to administer loading doses of some drugs. Differences in total body water are basically insignificant after the first year of life. Newborns have decreased body fat and therefore less storage ability for fat-soluble drugs.
Newborns, especially prematures, have decreased plasma albumin and total plasma protein concentrations. In addition, albumin from these patients shows a de-creased drug-binding affinity. This may result in increased plasma levels of free drug and the potential for toxicity. In the past, concerns were raised that certain drugs, such as sulfonamides, could displace endogenous substances, like bilirubin, from albumin-binding sites. Theoretically, such an interaction would increase the risk for kernicterus. Although this belief has been challenged recently, reluc-tance to treat newborns with sulfonamides persists.
As with adults, the primary organ responsible for drug metabolism in children is the liver. Although the cy-tochrome P450 system is fully developed at birth, it functions more slowly than in adults. Phase I oxidation reactions and demethylation enzyme systems are signif-icantly reduced at birth. However, the reductive enzyme systems approach adult levels and the methylation pathways are enhanced at birth. This often contributes to the production of different metabolites in newborns from those in adults. For example, newborns metabolize approximately 30% of theophylline to caffeine rather than to uric acid derivatives, as occurs in adults. While most phase I enzymes have reached adult levels by 6 months of age, alcohol dehydrogenase activity appears around 2 months of age and approaches adult levels only by age 5 years.
Phase II synthetic enzyme reactions are responsible for the elimination of endogenous compounds, such as bilirubin, and many exogenous substances. The immatu-rity of the glucuronidation pathway was responsible for the development of gray baby syndrome (Preterm and newborn infants dying of this syndrome developed anemia and cardiovascular collapse because of high blood concentrations of unconjugated chlorampheni-col. The plasma half-life was found to be 26 hours in these patients compared with 4 hours in older children.
Infants and children have a greater capacity to carry out sulfate conjugation than do adults. For example, acetaminophen is excreted predominantly as a sulfate conjugate in children as opposed to a glucuronide con-jugate in adults. This enhanced sulfation of acetamino-phen, along with decreased metabolism via cytochrome P450 pathways and increased glutathione turnover, are thought to explain the decreased hepatotoxicity caused by this analgesic in children under 6 years of age. Phase II enzyme systems reach adult levels between 3 and 6 months of age.
Renal blood flow, glomerular filtration rate, and tubular function are reduced in both preterm and term neonates. Therefore, newborns, especially those less than 34 weeks’ gestation, require less frequent dosing inter-vals for many drugs. Aminoglycosides are administered every 8 hours in older children, every 12 hours in new-borns, and every 24 hours in extremely premature in-fants. The glomerular filtration rate of the term newborn is approximately 50% less than the adult level but reaches adult values by 1 year of age. Renal blood flow approaches adult values between ages 5 and 12 months. Tubular secretory functions mature at a slower rate than does glomerular filtration. Renal excretion of organic anions, such as penicillin, furosemide, and indomethacin, is very low in the newborn. Tubular secretion and reab-sorption reach adult levels by 7 months of age. Renal elimination of drugs appears to play a greater role than does metabolism in newborns. Over the first year of life the infant develops a more adult-type excretory pattern.
Most drugs are administered to infants and children for the same therapeutic indications as for adults. However, a few drugs have found unique uses in children. Among these are theophylline and caffeine, which are used to treat apnea of prematurity; indomethacin, which closes a patent ductus arteriosus; and prostaglandin E1, which maintains the patency of the ductus arteriosus. Para-doxically, drugs such as phenobarbital, which have a sedating action on adults, may produce hyperactivity in children, and some adult stimulant drugs, such as methyl-phenidate, are used to treat children with hyperactivity.
Children may display adverse reactions different from those noted in adult patients. Table 6.4 lists a number of drugs that demonstrate unique actions in children.
Several problems unique to pediatric drug therapy de-serve special mention. For example, most medications are commercially available only in adult dose forms. Preparing pediatric doses from adult tablets or capsules can be very difficult and may require special skill on the part of the pharmacist. For some drugs it is simpler to administer the intravenous (IV) preparation orally than to develop a preparation from the oral medication.
IV drug administration is most effective in children when given via a pump infusion system close to the site of IV insertion. Because of the small size of many pedi-atric doses and the fact that some drugs adhere to IV tubing, a significant percentage of the drug can be lost if it is given using techniques usually reserved for adults.
For many prematures and newborns, the volume of ad-ministration is also critical and therefore much more easily managed by IV infusion pumps.
Most adult drugs must be diluted to achieve appro-priate pediatric dosages. Some drugs must be diluted several times. This introduces the potential for signifi-cant error in dilution. Some drugs such as NPH (Neutral Protamine Hagedorn) insulin may lose their effective-ness if diluted.
Children with chronic illnesses require special con-sideration. For example, patients with cystic fibrosis have increased hepatic metabolism and therefore in-creased drug clearance. This may necessitate the admin-istration of increased drug dosages.
Calculation of pediatric dosages is usually done on the basis of weight (e.g., milligrams per kilogram) for in-fants and toddlers and on the basis of weight or body surface area (milligrams per square meter) for older children. Repeated increases in drug dosage are re-quired to accommodate for growth in children receiving chronic drug therapy.
In summary, children, especially those in the first year of life, present significant pharmacological chal-lenges. Drug administration must be tailored to meet the unique needs of children at their varied stages of de-velopment. Special attention must be given to unex-pected drug actions and adverse reactions in these pa-tients, who are maturing at variable rates. When planning drug therapy for children, it is important to remember:
· Children are not small adults.
· Infants are not small children
· Newborns are not small infants.
· Preemies are not small newborns.