From the beginning to the end of life, the human body changes in many ways. These changes have a dramatic effect on the four phases of pharmacokinetics—drug absorption, distribution, metabolism, and excretion. Newborn, pediatric, and elderly patients each have special needs. Drug therapy at the two ends of the spectrum of life is more likely to result in adverse effects and toxicity. This is especially true if certain basic principles are not understood and followed. Fortunately, response to drug therapy changes in a predictable manner in younger and older patients. Knowing the effect that age has on the pharmacokinetic characteristics of drugs helps predict these changes.

Most experience with drugs and pharmacology has been gained from the adult population. The majority of drug studies have focused on the population between 13 and 65 years of age. It has been estimated that 75% of currently approved drugs lack U.S. Food and Drug Administration (FDA) approval for pediatric use and therefore lack specific dosage guidelines for neonates and children. Fortunately, many excellent pediatric drug dosage books are available. Most drugs are effective in younger and older patients, but drugs often behave very differently in patients at the opposite ends of the age spectrum. It is vitally important from the standpoint of safe and effective drug administration to understand what these differences are and how to adjust for them.

Drug Therapy During Pregnancy

A fetus is exposed to many of the same substances as the mother, including any drugs that she takes—prescription, nonprescription, or street drugs. The first trimester of pregnancy is generally the period of greatest danger of drug-induced developmental defects.

Transfer of both drugs and nutrients to the fetus occurs primarily by diffusion across the placenta, although not all drugs cross the placenta. Recall from chemistry that diffusion is a passive process based on differences in concentration between different tissues. Active transport requires the expenditure of energy and often involves some sort of cell-surface protein pump. The factors that contribute to the safety or potential harm of drug therapy during pregnancy can be broadly broken down into three areas: drug properties, fetal gestational age, and maternal factors.

Drug properties that impact drug transfer to the fetus include the drug’s chemistry, dosage, and concurrently administered drugs. Examples of relevant chemical properties include molecular weight, protein binding, lipid solubility, and chemical structure. Important drug dosage variables include dose and duration of therapy.

Fetal gestational age is an important factor in determining the potential for harmful drug effects to the fetus. The fetus is at greatest risk for drug-induced developmental defects during the first trimester of pregnancy. During this period, the fetus undergoes rapid cell proliferation. Skeleton, muscles, limbs, and visceral organs are developing at their most rapid rate. Self-treatment of minor illness is strongly discouraged anytime during pregnancy, but especially during the first trimester. Gestational age is also important in determining when a drug can most easily cross the placenta to the fetus. During the last trimester, the greatest percentage of maternally absorbed drug gets to the fetus.

Maternal factors also play a role in determining drug effects on the fetus. Any change in the mother’s physiology can affect the amount of drug to which the fetus may be exposed. Maternal kidney and liver function affect drug metabolism and excretion. Impairment in either kidney or liver function may result in higher drug levels and/or prolonged drug exposure, and thus increased fetal transfer. Maternal genotype may also affect how certain drugs are metabolized (pharmacogenetics). The lack of certain enzyme systems may result in adverse drug effects to the fetus when the mother is exposed to a drug that is normally metabolized by the given enzyme.

Although exposure of the fetus to drugs is most detrimental during the first trimester, drug transfer to the fetus is more likely during the last trimester. This is the result of enhanced blood flow to the fetus, increased fetal surface area, and increased amount of free drug in the mother’s circulation.

It is important to use drugs judiciously during pregnancy; however, there are certain situations that require their use. Without drug therapy, maternal conditions such as hypertension, epilepsy, diabetes, and infection could seriously endanger both the mother and the fetus, and the potential for harm far outweighs the risks of appropriate drug therapy.

The FDA classifies drugs according to their safety for use during pregnancy. This system of drug classification is based primarily on animal studies and limited human studies. This is due in part to ethical dilemmas surrounding the study of potential adverse effects on fetuses. We have learned from several unfortunate mistakes, such as the maternal use of thalidomide, which causes birth defects, and diethylstilbestrol (DES), which causes a high incidence of gynecologic malignancy in female offspring. The most widely used index of potential fetal risk of drugs is the FDA’s pregnancy safety category system. The five safety categories are described in Table 3-1. The FDA is in the process of changing the pregnancy categories; however, the information is not yet published at the time of this writing. The information will be posted on http://evolve.elsevier.com/Lilley once it becomes available.

TABLE 3-1

PREGNANCY SAFETY CATEGORIES

CATEGORY	DESCRIPTION
Category A	Studies indicate no risk to the human fetus.
Category B	Studies indicate no risk to the animal fetus; information for humans is not available.
Category C	Adverse effects reported in the animal fetus; information for humans is not available.
Category D	Possible fetal risk in humans has been reported; however, in selected cases consideration of the potential benefit versus risk may warrant use of these drugs in pregnant women.
Category X	Fetal abnormalities have been reported, and positive evidence of fetal risk in humans is available from animal and/or human studies. These drugs are not be used in pregnant women.

Drug Therapy During Breastfeeding

Breastfed infants are at risk for exposure to drugs consumed by the mother. A wide variety of drugs easily cross from the mother’s circulation into the breast milk and subsequently to the breastfeeding infant. Drug properties similar to those discussed in the previous section influence the exposure of infants to drugs via breastfeeding. The primary drug characteristics that increase the likelihood of drug transfer via breastfeeding include fat solubility, low molecular weight, nonionization, and high concentration.

Fortunately, breast milk is not the primary route for maternal drug excretion. Drug levels in breast milk are usually lower than those in the maternal circulation. The actual amount of exposure depends largely on the volume of milk consumed. The ultimate decision as to whether a breastfeeding mother takes a particular drug depends on the risk/benefit ratio. The risks of drug transfer to the infant in relation to the benefits of continuing breastfeeding and the therapeutic benefits to the mother must be considered on a case-by-case basis.

Considerations for Neonatal and Pediatric Patients

Pediatric patients are defined based on age. A neonate is defined as between birth and 1 month of age. An infant is between 1 and 12 months of age, and a child is between 1 and 12 years of age. The age ranges that correspond to the various terms applied to pediatric patients are shown in Table 3-2.

TABLE 3-2

CLASSIFICATION OF YOUNG PATIENTS

AGE RANGE	CLASSIFICATION
Younger than 38 weeks’ gestation	Premature or preterm infant
Younger than 1 month	Neonate or newborn infant
1 month up to 1 year	Infant
1 year up to 12 years	Child

NOTE: The meaning of the term pediatric may vary with the individual drug and clinical situation. Often the maximum age for a pediatric patient may be identified as 16 years of age. Consult manufacturer’s guidelines for specific dosing information.

Physiology and Pharmacokinetics

Pediatric patients handle drugs much differently than adult patients, based primarily on the immaturity of vital organs. In both neonates and older pediatric patients, anatomic structures and physiologic systems and functions are still in the process of developing. The Patient-Centered Care: Lifespan Considerations for the Pediatric Patient box on this page lists those physiologic factors that alter the pharmacokinetic properties of drugs in young patients.

Pharmacodynamics

Drug actions (or pharmacodynamics) are altered in young patients, and the maturity of various organs determines how drugs act in the body. Certain drugs may be more toxic, whereas others may be less toxic. The sensitivity of receptor sites may also vary with age; thus, higher or lower dosages may be required depending on the drug. In addition, rapidly developing tissues

PATIENT-CENTERED CARE: LIFESPAN CONSIDERATIONS FOR THE PEDIATRIC PATIENT

Pharmacokinetic Changes in the Neonate and Pediatric Patient

Absorption

• Gastric pH is less acidic because acid-producing cells in the stomach are immature until approximately 1 to 2 years of age.

• Gastric emptying is slowed because of slow or irregular peristalsis.

• First-pass elimination by the liver is reduced because of the immaturity of the liver and reduced levels of microsomal enzymes.

• Intramuscular absorption is faster and irregular.

Distribution

• Total body water is 70% to 80% in full-term infants, 85% in premature newborns, and 64% in children 1 to 12 years of age.

• Fat content is lower in young patients because of greater total body water.

• Protein binding is decreased because of decreased production of protein by the immature liver.

• More drugs enter the brain because of an immature blood-brain barrier.

Metabolism

• Levels of microsomal enzymes are decreased because the immature liver has not yet started producing enough.

• Older children may have increased metabolism and require higher dosages once hepatic enzymes are produced.

• Many variables affect metabolism in premature infants, infants, and children, including the status of liver enzyme production, genetic differences, and substances to which the mother was exposed during pregnancy.

Excretion

• Glomerular filtration rate and tubular secretion and resorption are all decreased in young patients because of kidney immaturity.

• Perfusion to the kidneys may be decreased, which results in reduced renal function, concentrating ability, and excretion of drugs.

may be more sensitive to certain drugs, and therefore smaller dosages may be required. Certain drugs are contraindicated during the growth years. For instance, tetracycline may permanently discolor a young person’s teeth; corticosteroids may suppress growth when given systemically (but not when delivered via asthma inhalers, for example); and quinolone antibiotics may damage cartilage.

Dosage Calculations for Pediatric Patients

Most drugs have not been sufficiently investigated to ensure their safety and effectiveness in children. In spite of this, there are numerous excellent pediatric dosage references. Because pediatric patients (especially premature infants and neonates) have small bodies and immature organs, they are very susceptible to drug interactions, toxicity, and unusual drug responses. Pediatric patients require different dosage calculations than do adults. Characteristics of pediatric patients that have a significant effect on dosage include the following:

• Skin is thinner and more permeable.

• Stomach lacks acid to kill bacteria.

• Lungs have weaker mucous barriers.

• Body temperature is less well regulated, and dehydration occurs easily.

• Liver and kidneys are immature, and, therefore, drug metabolism and excretion are impaired.

Many formulas for pediatric dosage calculation have been used throughout the years. Formulas involving age, weight, and body surface area (BSA) are most commonly employed as the basis for calculations. BSA-based formulas are the most accurate of these dosage formulas.

To use the BSA method, the nurse needs the following information:

• Drug order with drug name, dose, route, time, and frequency

• Information regarding available dosage forms

• Pediatric patient’s height in centimeters (cm) and weight in kilograms (kg)

• BSA nomogram for children (e.g., West nomogram, shown in Figure 3-1)

• Recommended adult drug dosage

The West nomogram (see Figure 3-1) uses a child’s height and weight to determine the child’s BSA. This information is then inserted into the BSA formula to obtain a drug dosage for a specific pediatric patient. Consider the following examples:

BSA of adultBSA of child×adult dose=estimated child’s dose

BSAofchild(m2)×manufacturer’srecommendeddosem2=estimated child’sdose

Calculating the dosage according to the body weight is the most commonly used method today. Most drug references recommend dosages based on milligrams per kilogram of body weight. The following information is needed to calculate the pediatric dosage:

• Drug order (as discussed previously)

• Pediatric patient’s weight in kilograms (1 kilogram = 2.2 pounds) (For example, a 10-lb baby weighs 4.5 kg; divide the number of pounds by 2.2 to determine kilograms.)

• Pediatric dosage as per manufacturer or drug formulary guidelines

• Information regarding available dosage forms

When using either of the previous methods, you must do the following to ensure the correct pediatric dose:

• Determine the pediatric patient’s weight in kilograms.

• Use a current drug reference to determine the usual dosage range per 24 hours in milligrams (mg) per kilogram (kg). It must be noted that some drugs are stated as mg/kg/dose.

• Determine the dose parameters by multiplying the weight by the minimum and maximum daily doses of the drug (the safe range).

• Determine the total amount of the drug to administer per dose and per day.

• Compare the drug dosage prescribed with the calculated safe range.

• If the drug dosage raises any concerns or varies from the safe range, contact the health care provider or prescriber immediately and do not give the drug!

A common source of medication error and potential toxicity is confusing pounds with kilograms. Unless otherwise noted, the child’s weight is to be given in kilograms, not pounds. Take great care to ensure that the correct weight is reported to the prescriber. In calculating pediatric dosages, the factor of organ maturity must always be considered along with BSA, age, and weight. When all of these physical developmental factors are

PATIENT-CENTERED CARE: LIFESPAN CONSIDERATIONS FOR THE PEDIATRIC PATIENT

Age-Related Considerations for Medication Administration from Infancy to Adolescence