Background

The pediatric population is generally classified into five age groups:

• premature infants - those who are born before 38 weeks of pregnancy
• newborns - those who are less than one month old
• infants - those who are one month to one year of age
• children - those who are one to twelve years of age
• adolescents - those who are thirteen to seventeen years of age

From birth through adolescence, the pediatric patient is continually changing. Drug therapy in pediatric patients, therefore, presents a challenge. Furthermore, information on drug therapy in children is limited. Only 25% of all Food and Drug Administration- (FDA) approved drugs have approval for pediatric use. Most drugs are studied and labeled for use in adults. As a result, many indications and drug dosages are based on experience instead of large, well-done studies. An understanding of how children differ from adults can help prevent medication errors in young patients.

The fallacy in using drugs in pediatrics is assuming that they are "just small adults". However, differences in age, body size, disease states, and physiology lead to differences in the way the body handles the drug (phrmacokinetics), the effects of the drug (pharmacodynamics), and side effects in this population. The age-related changes in absorption, distribution, metabolism, and elimination of drugs further affect where and how much of each drug is deposited in the body and ultimately lead to pediatric drug dosing.

Absorption

The route of administration influences absorption of a drug. The types of administration include the following: via the skin, gastrointestinal (GI) tract including the rectum; intramuscularly (IM); and intravenously (IV).

First, absorption through the skin is related to the thickness of the skin. Since the newborn infant begins life with skin that is much thinner than the adult skin, drugs may be absorbed more quickly than in adults, which may lead to toxicity. For example, side effects from skin applications of iodine (an antibacterial cleanser), hexachlorophene (an antibacterial cleanser), salicylic acid ointments (for removal of warts), and hydrocortisone creams have occurred in neonates and infants.

Differences between pediatric patients and adults must also be considered when using the GI tract as a route of administration for drugs. For example, for the first 10-15 days after birth, a newborn has a relative lack of stomach acid. A child does not have adult values of stomach acidity (pH) until two years of age. This factor may lead to increased absorption of certain drugs like penicillin and ampicillin. Furthermore, stomach emptying in the newborn is irregular, unpredictable, and prolonged, reaching adult values at about six- to eight months of age. The slower emptying time leads to increased absorption of various medications because of increased contact time with the GI tract.

Thirdly, muscle (IM) absorption is erratic in newborns because of relative lack of muscle and fat tissue. Also, IM administration of drugs is avoided because it may damage immature tissues. Similarly, rectal absorption is not reliable except for rectal Valium for seizures.

Distribution

Drug distribution to various parts of the body differs between adults and newborns. Distribution of drugs is influenced by total body water, protein-binding of drugs, and changes in the makeup and size of organs.

An adult’s total body water accounts for approximately 60% of body weight. The preterm infant may be composed of as much as 90% water and a normal newborn about 75% water. In contrast to body water, however, fat stores represent a very small percentage of body weight in preterm infants, generally in the range of 1-5%. Fat stores comprise about 15% of body weight in the term infant, which is similar to the adult. Depending on how water- or fat-soluble a medication is, it will be distributed differently in the pediatric patient than in an adult. In addition, because of their lower protein concentrations, newborns have low binding of drugs to blood proteins as compared to adults. This means that more of the drug is available in the unbound and active form, a phenomenon that could lead to toxicity of certain drugs. Furthermore, the blood-brain barrier is immature in the infant. (Blood vessels of the brain are very selective in allowing material to pass from blood into the brain, hence the term blood-brain barrier.) This barrier allows for greater distribution of drugs into the central nervous system in the infant. All of these factors influence how a drug is distributed in the body.

Metabolism

Metabolism refers to the changes in the structure of the drug that help the body eliminate that drug. (drugs are foreign substances, and the body will try to do what it can to eliminate them) The main organ responsible for metabolism of drugs is the liver. Metabolism of drugs by the liver changes significantly with age. Newborns metabolize drugs at a rate several times lower than that observed in adults; this is due to the relative lack of maturation of metabolic (enzyme) machinery at different ages for different metabolic pathways. Although most drugs are metabolized to less active forms, some may be transformed to active metabolites. An example is the conversion of theopylline (an asthma and emphysema medicine) to caffeine. This is due to one of the metabolic pathways called methylation reactions, which is generally low in adults, but high in term infants.

Elimination

Elimination of drugs generally depends on kidney function, which also changes widely in early childhood. There is a decreased clearance of drugs in newborns relative to adults. Overall kidney function increases with age. Therefore, as the kidney function matures, there may be a shift from potential drug overdose to potential underdose for some drugs, such as theophylline.

Drug administration

The administration of drugs to children requires special knowledge and expertise. For administration of oral medications, caution must be taken not to choke the child. Liquid medications should be placed on the middle of the tongue or in the cheek area by using a dropper. Usually the taste of medicine is disguised by using juice, applesauce or ice cream. Children should always be praised for cooperating in taking their medications. To administer ear drops in children up to three years of age, the external ear is held down and out, which helps deliver the drug to the middle ear. In older patients, the ear is held up and back to straighten the ear canal. To administer nose drops, the child is placed on his/her back across a bed with shoulders over the edge so that the head is lower than the body. The child is kept in this position for 2-5 minutes after the medication is administered. To administer eye drops, caution should be taken to prevent injury to the eye. The lower lid must be gently pulled down by the thumb, and the hand holding the dropper should be balanced on the head of the child so that the hand moves with the head in case the child turns or jumps.

Drug toxicity unique to children

Sulfonamides (sulfa drugs) displace bilirubin (a byproduct of red blood cells that causes jaundice in newborns and adults) from its binding sites. This leads to high levels of bilirubin in the blood, which may cause a condition called kernicterus in infants, which is a non-reversible brain damage due to high bilirubin levels in brain. The antibiotic chloramphenicol, given to newborns, causes gray baby syndrome, characterized by vomiting, ashen color, cardiovascular collapse, and death. This is caused by the inability of the newborns to metabolize the drug leading to accumulation of the drug.

Quinolones (a class of antibiotics including Cipro) have shown to cause cartilage defects in beagle dogs and are generally avoided in pediatrics, who have growing cartilage. Because they cause permanent discoloration of the teeth and enamel and affect skeletal development and bone growth, tetracyclines are avoided in children less than 9 years of age. Aspirin causes Reye's Syndrome, a condition characterized by liver injury, low-blood sugar, and vomiting in children with chicken pox or flu symptoms of high fever, headache, and muscle pain. Therefore, one must never give aspirin to a child who has flu symptoms. Also, due to the immature livers of newborns, the preservative benzyl alcohol in solutions used to flush the umbilical lines has caused death.