快樂小藥師 Im pharmacist nichts glücklich

Marcel J. Casavant
Chief, Pharmacology-Toxicology, Nationwide Children's Hospital; Medical Director, Central Ohio Poison Center; Clinical Professor, The Ohio State University Colleges of Medicine and Pharmacy
Jill RK Griffith
Clinical Pharmacist, Mount Carmel West Hospital; Clinical Assistant Professor, The Ohio State University College of Pharmacy

Introduction

Although pharmacotherapy for children is guided by the same principles and rules as pharmacotherapy for adults, the many differences between the immature human and the adults of our species add great complexity and risk to the administration of drugs to children. For far too long, ethical and practical problems minimized the use of children in drug studies; therefore, much of pediatric pharmacotherapy even today is based more on error than trial.

This Update has three parts. Part 1 and, presented here, part 2 review the history of pediatric drug therapy including pediatric pharmacology disasters and issues related to drug testing in children. Parts 1 and 2 also describe the differences between pediatric and adult pharmacokinetics and highlight why kids are not simply small adults.

Part 3, to be published in the near future, will discuss important requirements in pediatric drug therapy: The need for off-label prescribing, the need for special formulations for children, and the need to assess adherence and solve drug administration problems. Part 3 will also provide specific suggestions for the safe and rational prescribing and administration of medicines to children.

Pediatric Pharmacokinetics: Kids Are Not Just Little Adults

Pediatric pharmacokinetics was not well studied at the time of the chloramphenicol "gray baby" syndrome and sulfisoxazole-bilirubin displacement-induced kernicterus tragedies. Due to increased knowledge of pediatric pharmacokinetics and advances in therapeutic drug monitoring, adult dosing should no longer be “scaled down” and “extrapolated” to pediatric patients.

Absorption: Factors Contributing to GI Absorption of Drugs in Children

The rate and extent of absorption from the pediatric gastrointestinal (GI) tract is determined primarily by five factors: gastric acidity, GI mobility, enzymatic activity, biliary function, diet and bacterial flora. All factors are reduced in the neonate except gut enzymatic activity. The complicated interaction of these components coupled with maturational changes make predicting medication bioavailability nearly impossible.

Gastric acidity changes most rapidly during the first month of life. At birth, the gastric pH is neutral (pH 6-8) due to ingested amniotic fluid in the stomach.¹ Within 48 hours, gastric pH falls to between 1 and 3 due to gastric acid secretion. Gastric acidity is poorly maintained in the neonate and gastric pH returns to neutral.^2,3 Adult levels of acidity are not reached until 3 to 7 years of age. In addition, consumption of alkaline milk likely contributes to decreased gastric acidity in the child. As a consequence, acid-labile drugs such as penicillin, ampicillin, and nafcillin have greater bioavailability in the more alkaline pediatric GI tract.

Although some drugs require transport proteins for absorption across the GI tract, most drugs are absorbed by pH-dependent passive diffusion. When a drug is ionized, its diffusion through a lipid membrane is impeded, and when it is non-ionized, it has a higher lipid solubility and greater diffusion through cell membranes. Therefore, drugs that are weak acids (e.g., phenobarbital, phenytoin) are ionized in the more alkaline pediatric GI tract and will be slowly absorbed. In contrast, drugs that are weak bases (e.g., penicillin, ampicillin, erythromycin) will be non-ionized in the GI tract of the neonate and will be more quickly absorbed as compared with adults.

Another factor impacting drug absorption is gastric emptying. Gastric emptying in the neonate and infant is prolonged. Adult rates of gastric emptying (10 to 20 minutes) are not approached until 6 to 8 months of age. Peristalsis is irregular and GI transit may also be prolonged in neonates and infants.⁴ Theoretically, drugs which are poorly absorbed in adults should be well absorbed in the neonate or infant because of prolonged transit and contact with the GI tract. However, the limited data currently available show reduced and delayed drug absorption after birth with gradual improvement by three months.^5,6,7,8

Biliary function develops over the first month of life in neonates and infants.⁹ Because bile acid salts and pancreatic enzymes are diminished, this may impact the absorption of some lipophilic medications (e.g., diazepam). Enzymatic activity within the neonatal gut is also different from that of adults. Beta-glucuronidase and UDP-glucuronyl transferase have increased capacity and this may also reduce drug absorption.¹⁰ Finally, the development of intestinal flora, which can also contribute to metabolism of drugs, depends largely on diet, more so than age.

Dermal and intramuscular absorption are different in the pediatric patient than the adult. Dermal absorption is inversely related to the thickness of the stratum corneum and directly related to hydration.¹¹ The neonatal and infant stratum corneum is underdeveloped and skin hydration is increased. For this reason, pediatric skin is more permeable to topically applied drug than adult skin. Dermal application of rubbing alcohol or salicylate-containing muscle rubs can be toxic to children.¹² Intramuscular absorption in neonates, infants, and children is variable and unpredictable due to decreased muscle tone and contraction, and variable blood flow and oxygenation. Intramuscular injections are generally avoided in children.

Distribution

Volume of distribution (Vd) is exceedingly important in developmental pharmacology because age-related changes in body water and fat affect drug distribution. Premature infants have a greater percentage of body weight that is water (85 percent total body water) as compared with term infants (75 percent total body water). Adult total body water content (55 percent) is reached by 12 years of age.^13,14 Extracellular fluid may account for up to 50 percent of premature infant body weight, up to 35 percent in a 4 to 6 month old, up to 25 percent in a 1 year old child, and up to 19 percent in an adult. The Vd of drugs that parallel total body water and extracellular fluid are thus higher for infants than adults. For example, gentamicin distribution is 0.48 L/kg in a neonate and 0.20 L/kg in an adult.

Body fat, on the other hand, increases with age. A premature infant does not have body fat while a term infant has 16 percent total body fat.¹⁵ Body fat continues to increase with normal development. As a consequence, drugs that are fat soluble such as diazepam have lower Vds in infants and children than in adults. Diazepam distribution in neonates and infants is 1.4 to 1.8 L/kg and 2.2 to 2.6 L/kg in adults.¹⁶

Premature infants have increased membrane permeability allowing easier drug diffusion into compartments such as the brain. Infants also have increased central nervous system (CNS) permeability, as we saw with the kernicterus episode, as well as increased receptor sensitivity to many drugs.¹⁷ This combination makes infants more susceptible to the effects of centrally acting medications such as analgesics and anticonvulsants.

Protein binding is another important component in determining Vd. Alpha1-acid glycoprotein and albumin are important drug binding proteins in serum. Albumin binds more acidic agents (e.g., phenytoin) whereas alpha1-acid glycoprotein binds more basic agents (e.g., propranolol). Both proteins are decreased in the neonate. Albumin is the principle drug binding protein in serum and does not reach adult concentrations until 1 year of age. Neonatal serum contains only 80 percent of the albumin that an adult would have.¹⁸ The albumin that is present in neonates has a decreased affinity for drugs such as phenytoin, phenobarbital, and theophylline. Competitive binding by bilirubin and free fatty acids that are present in higher concentrations in neonates, also contributes to the decreased albumin affinity noted for some drugs. Hyperbilirubinemia is known to reduce the protein binding of penicillin, ampicillin, phenobarbital, and phenytoin. The resulting effect is a larger free fraction of drug in serum and therefore increased drug effect. Recall that competitive binding by drugs can displace bilirubin; kernicterus resulted after a sulfonamide (sulfisoxazole) displaced bilirubin, resulting in hyperbilirubinemia, bilirubin deposition in the brain, and encephalopathy (See Part 1 of this Update).

Metabolism

Drug metabolism generally transforms a lipophilic parent compound to a hydrophilic metabolite for excretion into the urine or bile. Other metabolic effects can include the generation of an active metabolite, such as the conversion of morphine to its 6-glucuronide metabolite, which is 20 times more active than morphine.¹⁹ Another metabolic effect is prodrug activation. Prodrug transformations include theophylline to caffeine, and codeine to morphine.

Drug metabolism is best categorized by two major reactions, termed Phase I and Phase II. Phase I reactions (catalyzed by CYPs, cytochrome P450s) add a functional group to the parent molecule via oxidation, reduction, methylation, or hydroxylation. Phase II reactions (conjugation) entail attachment of a hydrophilic molecule to the drug via glucuronidation, sulfation, or acetylation.

Phase I reactions are intact but not at full capacity until 6 months to 1 year of age. As a result, oxidation of diazepam, theophylline, phenobarbital, and phenytoin are impaired in the neonate. Relative to one another, phenobarbital and phenytoin are metabolized at faster rates than theophylline, with phenytoin metabolism exceeding adult rates by 2 weeks of age.²⁰ Insufficiency of one CYP enzyme may be compensated for by another. The development of oxidative de-methylation lags behind in neonates and may take several months to fully develop. Premature infants metabolize theophylline to the active metabolite caffeine via methylation, and significant amounts of caffeine may be present following administration of theophylline to premies. This pathway becomes insignificant in older children and adults.²¹

Neonatal phase II activity is 50 to 70 percent of the adult rate and increases with age. Glucuronidation is not well developed in the neonate; acetaminophen glucuronidation is greatly reduced compared with adults. The sulfation pathway is well developed in neonates and partly compensates for the low rates of glucuronidation. Thus, acetaminophen is excreted primarily as sulfate conjugates in neonates whereas adults excrete acetaminophen primarily as the glucuronide conjugate.^22,23 The glucuronidation pathway may take up to 3 or 4 years to fully develop, which can slow the metabolism of endogenous substrates and drugs such as bilirubin, morphine, and chloramphenicol. Thus, higher serum concentrations of morphine are required for infants because infants cannot metabolize morphine to the active 6-glucuronide metabolite.¹⁹ Infants also cannot metabolize chloramphenicol to the inactive chloramphenicol glucuronate. Serum monitoring could have prevented the gray baby syndrome caused by chloramphenicol accumulation and which resulted in hypotension, cyanosis, and often death.

Excretion: Glomerular Filtration Rate (GFR) and Age