Principles of Drug Therapy

The clinical pharmacology of a given drug reflects a multifaceted set of properties that pertain to not only the disposition and action of drugs, but also the response (e.g., adverse effects, therapeutic effects, therapeutic outcomes) to their administration or use. The 3 most important facets of clinical pharmacology are pharmacokinetics, pharmacodynamics, and pharmacogenomics. Pharmacokinetics describes the movement of a drug throughout the body and the concentrations (or amounts) of a drug that reach a given body space or tissue and its residence time there. Pharmacokinetics of a drug are conceptualized by considering the characteristics that collectively are the determinants of the dose-concentration-effect relationship: absorption, distribution, metabolism, and excretion. Pharmacodynamics describes the relationship between drug dose or drug concentration and response. The response may be desirable (effectiveness) or untoward (toxicity). Although in clinical practice the response to drugs in different patient populations is often described by a standard dosing or concentration range, response is best conceptualized along a continuum where the relationship between dose and response(s) is not linear. Pharmacogenomics is the study of how variant forms of human genes contribute to interindividual variability in drug response. The finding that drug responses can be influenced by the patient's genetic profile has offered great hope for realizing individualized pharmacotherapy, in which the relationship between genotype and phenotype (either disease and/or drug response) is predictive of drug response (see Chapter 72 ). In the developing child, ontogeny has the potential to modulate drug response through altering both pharmacokinetics and pharmacodynamics.

General Pharmacokinetic and Pharmacodynamic Principles

A drug effect is produced only when an exposure (both amount and duration) occurs that is sufficient to produce a drug-receptor interaction capable of modulating the cellular milieu and inducing a physiologic response. Thus, exposure-response relationships for a given drug represent an interface between pharmacokinetics and pharmacodynamics, which can be simply conceptualized by consideration of 2 profiles: plasma concentration vs effect ( Fig. 73.1 ) and plasma concentration vs time ( Fig. 73.2 ).

Fig. 73.1, Plasma concentration vs effect curve.

Fig. 73.2, Semilogarithmic plot of the plasma concentration vs time curve for a hypothetical drug following extravascular administration.

The relationship between drug concentration and effect for most drugs is not linear ( Fig. 73.1 ). At a drug concentration of zero, the effect from the drug is generally zero or not perceptible (E ₀ ). After drug administration and with dose escalation, the concentration increases, as does the effect, first in an apparent linear fashion (at low drug concentrations), followed by a nonlinear increase in effect to an asymptotic point in the relationship where a maximal effect (E _max ) is attained that does not perceptibly change with further increases in drug concentration. The point in the concentration-effect relationship where the observed effect represents 50% of the E _max is defined as EC ₅₀ , a common pharmacodynamic term used to compare concentration-effect relationships between patients (or research participants) and between drugs that may be in a given drug class.

Because it is rarely possible to measure drug concentrations at or near the receptor, it is necessary to utilize a surrogate measurement to assess exposure-response relationships . In most cases this surrogate is represented by the plasma drug concentration vs time curve. For drugs whose pharmacokinetic properties are best described by first-order (vs zero- or mixed-order) processes, a semilogarithmic plot of plasma drug concentration vs time data for an agent given by an extravascular route of administration (e.g., intramuscular, subcutaneous, intracisternal, peroral, transmucosal, transdermal, rectal) produces a pattern depicted by Fig. 73.2 . The ascending portion of this curve represents a time during which the liberation of a drug from its formulation, dissolution of the drug in a biologic fluid (e.g., gastric or intestinal fluid, interstitial fluid; a prerequisite for absorption), and absorption of the drug are rate limiting relative to its elimination. After the time (T _max ) where maximal plasma concentrations (C _max ) are observed, the plasma concentration decreases as metabolism and elimination become rate limiting; the terminal portion of this segment of the plasma concentration vs time curve is representative of drug elimination from the body. Finally, the area under the plasma concentration vs time curve ( AUC ), a concentration- and time dependent parameter reflective of the degree of systemic exposure from a given drug dose, can be determined by integrating the plasma concentration data over time.

Being able to characterize the pharmacokinetics of a specific drug allows the clinician to use the data to adjust “normal” dosing regimens and individualize them to produce the degree of systemic exposure associated with desired pharmacologic effects. For drugs where a therapeutic plasma concentration range or “target” systemic exposure (i.e., AUC) is known, a priori knowledge of pharmacokinetic parameters for a given population or patient within a population can facilitate the selection of a drug dosing regimen. Along with information on the pharmacodynamic behavior of a drug and the status of the patient (e.g., age, organ function, disease state, concomitant medications), the application of pharmacokinetics allows the practitioner to exercise a real degree of adaptive control over therapeutic decision-making through the selection of a drug and dosing regimen with the greatest likelihood of producing both efficacy and safety.

Impact of Ontogeny on Drug Disposition

Development represents a continuum of biologic events that enable adaptation, somatic growth, neurobehavioral maturation, and eventually reproduction. The impact of development on the pharmacokinetics of a given drug is determined to a great degree by age-related changes in body composition and the acquisition of function in organs and organ systems important in determining drug metabolism and excretion. Although it is often convenient to classify pediatric patients on the basis of postnatal age in providing drug therapy, with neonates ≤1 mo of age, infants 1-24 mo, children 2-12 yr, and adolescents 12-18 yr, it is important to recognize that the changes in physiology are not linearly related to age and may not correspond to these age-defined breakpoints. In fact, the most dramatic changes in drug disposition occur during the 1st 18 mo of life, when the acquisition of organ function is most dynamic. It is important to note that the pharmacokinetics of a given drug may be altered in pediatric patients because of intrinsic (e.g., gender, genotype, ethnicity, inherited diseases) or extrinsic (e.g., acquired diseases, xenobiotic exposure, diet) factors that may occur during the 1st 2 decades of life.

Selection of an appropriate drug dose for a neonate, infant, child, or adolescent requires an understanding of the basic pharmacokinetic properties of a given compound and how the process of development impacts each facet of drug disposition. Accordingly, it is most useful to conceptualize pediatric pharmacokinetics by examining the impact of development on the physiologic variables that govern drug absorption, distribution, metabolism, and elimination (ADME) .

Pediatrics encompasses a broad range of ages at which certain stages of life profoundly influence drug response and disposition. Dramatic pharmacokinetic, pharmacodynamic, and psychosocial changes occur as preterm infants mature toward term, as infants mature through the 1st few years of life, and as children reach puberty and adolescence ( Fig. 73.3 ). To meet the needs of these different pediatric groups, different formulations are needed for drug delivery that can influence drug absorption and disposition, and different psychosocial issues influence compliance, timing of drug administration, and reactions to drug use. These additional factors must be considered in conjunction with known pharmacokinetic and pharmacodynamic influences of age when developing an optimal, patient-specific drug therapy strategy.

Fig. 73.3, Developmental changes in physiologic factors that influence drug disposition in infants, children, and adolescents.

Drug Absorption

Drug absorption mainly occurs through passive diffusion, but active transport or facilitated diffusion may also be necessary for drug entry into cells. Several physiologic factors affect this process, one or more of which may be altered in certain disease states (e.g., inflammatory bowel disease, diarrhea), and thus produce changes in drug bioavailability. The rate and extent of absorption can be significantly affected by a child's normal growth and development.

Peroral Absorption

The most important factors that influence drug absorption from the gastrointestinal (GI) tract are related to the physiology of the stomach, intestine, and biliary tract ( Fig. 73.3 C and Table 73.1 ). The rate and extent of peroral absorption of drugs depend primarily on the pH-dependent passive diffusion and motility of the stomach and intestinal tract, because both these factors will influence transit time of the drug. Gastric pH changes significantly throughout development, with the highest (alkaline) values occurring during the neonatal period. In the fully mature neonate the gastric pH ranges from 6-8 at birth and drops to 2-3 within a few hours of birth. However, after the 1st 24 hr of life, the gastric pH increases because of the immaturity of the parietal cells. As the parietal cells mature, the gastric acid secretory capacity increases (pH decreases) over the 1st few months of life, reaching adult levels by age 3-7 yr. As a result, the peroral bioavailability of acid-labile drugs (e.g., penicillin, ampicillin) is increased. In contrast, the absorption of weak organic acids (e.g., phenobarbital, phenytoin) is relatively decreased, a condition that may necessitate administration of larger doses in very young patients to achieve therapeutic plasma levels.

Table 73.1

Developmental Alterations in Intestinal Drug Absorption

Data from Morselli PL: Development of physiological variables important for drug kinetics. In Morselli PL, Pippenger CE, Penry JK, editors: Antiepileptic drug therapy in pediatrics, New York, 1983, Raven Press.

PHYSIOLOGIC ALTERATION	NEONATES	INFANTS	CHILDREN
Gastric pH	>5	4 to 2	Normal (2-3)
Gastric emptying time	Irregular	Increased	Slightly increased
Intestinal motility	Reduced	Increased	Slightly increased
Intestinal surface area	Reduced	Near adult	Adult pattern
Microbial colonization	Reduced	Near adult	Adult pattern
Biliary function	Immature	Near adult	Adult pattern

Direction of alteration given relative to expected normal adult pattern.

Gastric emptying time is prolonged throughout infancy and childhood as a result of reduced motility, which may impair drug passage into the intestine, where most absorption takes place. Gastric emptying rates reach or exceed adult values by 6-8 mo of life. As such, intestinal motility is important for the rate of drug absorption and, as with other factors, is dependent on the age of the child. Consequently, the rate of absorption of drugs with limited water solubility (e.g., phenytoin, carbamazepine) can be dramatically altered consequent to changes in GI motility. In older infants and young children, more rapid rates of intestinal drug transit can reduce the bioavailability for some drugs (e.g., phenytoin) and drug formulations (e.g., sustained-release) by reducing their residency time at the absorption surfaces in the small intestine.

Neonates, particularly premature neonates, have a reduced bile acid pool and biliary function, resulting in a decreased ability to solubilize and absorb lipophilic drugs. Biliary function develops in the 1st few months of life, but it may be difficult for the neonate and young infant to absorb fat-soluble vitamins because low concentrations of bile acids are necessary for their absorption.

Extravascular Drug Absorption

Intravenous (IV) drug administration is assumed to be the most dependable and accurate route for drug delivery, with a bioavailability of 100%. Absorption of drugs from tissues and organs (e.g., intramuscular, transdermal, rectal) can also be affected by development ( Table 73.2 ). Intramuscular (IM) blood flow changes with age, which can result in variable and unpredictable absorption. Reduced muscular blood flow in the 1st few days of life, the relative inefficiency of muscular contractions (useful in dispersing an IM drug dose), and an increased percentage of water per unit of muscle mass may delay the rate and extent of drugs given intramuscularly to the neonate. Muscular blood flow increases into infancy, and thus the bioavailability of drugs given by the IM route is comparable to that seen in children and adolescents.

Table 73.2

Influence of Ontogeny on Drug Absorption

PHYSIOLOGIC ALTERATION	NEONATES	INFANTS	CHILDREN
Oral absorption	Erratic	Increased	Near adult
Intramuscular absorption	Variable	Increased	Near adult
Percutaneous absorption	Increased	Increased	Near adult
Rectal absorption	Very efficient	Efficient	Near adult

Direction of alteration given relative to expected normal adult pattern.

In contrast, mucosal permeability (rectal and buccal) in the neonate is increased and thus may result in enhanced absorption by this route. Transdermal drug absorption in the neonate and very young infant is increased because of the thinner and more hydrated stratum corneum ( Fig. 73.3 E ). In addition, the ratio of body surface area to body weight is greater in infants and children than in adults. Collectively, these developmental differences may predispose the child to increased exposure and risk for toxicity for drugs or chemicals placed on the skin (e.g., silver sulfadiazine, topical corticosteroids, benzocaine, diphenhydramine), with higher likelihood of occurrence during the 1st 8-12 mo of life.

Normal developmental differences in drug absorption from most all extravascular routes of administration can influence the dose–plasma concentration relationship in a manner sufficient to alter pharmacodynamics. The presence of disease states that influence a physiologic barrier for drug absorption or the time that a drug spends at a given site of absorption can further influence drug bioavailability and effect.

Drug Distribution

Drug distribution is influenced by a variety of drug-specific physiochemical factors, including the role of drug transporters, blood-tissue protein binding, blood-tissue pH, and perfusion. However, age-related changes in drug distribution are primarily related to developmental changes in body composition and the quantity of plasma proteins capable of drug binding. Age-dependent changes in the relative sizes of body water — total body water (TBW) and extracellular water (ECW)—and fat compartments may alter the apparent volume of distribution (VD) for a given drug. The absolute amounts and distribution of body water and fat depend on a child's age and nutritional status. Also, certain disease states (e.g., ascites, dehydration, burn injuries, skin disruption involving large surface area) can influence body water compartment sizes and thereby, further impact the VD for certain drugs.

Newborns have a much higher proportion of body mass in the form of water (approximately 75% TBW) than older infants and children ( Fig. 73.3 B ). In addition, the percentage of ECW changes (decreases) from the newborn stage (approximately 45%) into adulthood (20–30%). In fact, the increase of TBW in the neonate is attributable to ECW. The reduction in TBW is rapid in the 1st year of life, with adult values (approximately 55%) achieved by approximately 12 yr of age. In contrast, the percentage of intracellular water (ICW) as a function of body mass remains stable from the 1st months of life through adulthood. The impact of developmental changes in body water spaces are exemplified by drugs such as the aminoglycoside antibiotics; compounds that distribute predominantly throughout the extracellular fluid space and have a higher VD (0.4-0.7 L/kg) in neonates and infants than in adults (0.2-0.3 L/kg).

Body fat percentage and composition increase during normal development. The body fat percentage in a neonate is approximately 16% (60% water and 35% lipid). Despite the relatively low body fat content in the neonate, it is important to note that the lipid content in the developing central nervous system (CNS) is high, which has implications for the distribution of lipophilic drugs (e.g., propranolol) and their CNS effects during this period. The body fat percentage tends to increase up to about age 10 yr, then changes composition with respect to puberty and sex to approach adult body fat composition (26% water and 71% lipid). In addition, a sex difference exists as the child transitions into adolescence. Whereas the total body fat in males is reduced to 50% between 10 and 20 yr of life, the reduction in females is not as dramatic and decreases 28–25% during this same developmental stage.

Albumin, total proteins, and total globulins (e.g., α ₁ -acid glycoprotein) are the most important circulating proteins responsible for drug binding in plasma. The absolute concentration of these proteins is influenced by age, nutrition, and disease ( Table 73.3 ). The concentrations of almost all circulating plasma proteins are reduced in the neonate and young infant (approximately 80% of adult) and reach adult values by 1 yr of age. A similar pattern of maturation is observed with α ₁ -acid glycoprotein (an acute-phase reactant capable of binding basic drugs), for which neonatal plasma concentrations are approximately 3 times lower than in maternal plasma and attain adult values by approximately 1 yr of age.

Table 73.3

Factors Influencing Drug Binding in Pediatric Patients

PHYSIOLOGIC ALTERATION	NEONATES	INFANTS	CHILDREN
Plasma albumin	Reduced	Near adult	Near adult
Fetal albumin	Present	Absent	Absent
Total proteins	Reduced	Decreased	Near adult
Total globulins	Reduced	Decreased	Near adult
Serum bilirubin	Increased	Normal	Adult pattern
Serum free fatty acids	Increased	Normal	Adult pattern

Direction of alteration given relative to expected normal adult pattern.

The extent of drug binding to proteins in the plasma may influence distribution characteristics. Only free, unbound drug can be distributed from the vascular space into other body fluids and, ultimately, to tissues where drug-receptor interaction occurs. Drug protein binding depends on a number of age-related variables, including the absolute amount of proteins and their available binding sites, the conformational structure of the binding protein (e.g., reduced binding of acidic drugs to glycated albumin in patients with poorly controlled diabetes mellitus), the affinity constant of the drug for the protein, the influence of pathophysiologic conditions that either reduce circulating protein concentrations (e.g., ascites, major burn injury, chronic malnutrition, hepatic failure) or alter their structure (e.g., diabetes, uremia), and the presence of endogenous or exogenous substances that may compete for protein binding (i.e., protein displacement interactions).

Developmentally associated changes in drug binding can occur because of altered protein concentrations and binding affinity. Circulating fetal albumin in the neonate has significantly reduced binding affinity for acid drugs such as phenytoin, which is extensively (94–98%) bound to albumin in adults, compared to 80–85% in the neonate. The resultant 6-8-fold difference in the free fraction can result in CNS adverse effects in the neonate when total plasma phenytoin concentrations are within the generally accepted “therapeutic range” (10-20 mg/L). The importance of reduced drug-binding capacity of albumin in the neonate is exemplified by interactions between endogenous ligands (e.g., bilirubin, free fatty acids) and drugs with greater binding affinity (e.g., ability of sulfonamides to produce kernicterus).

Drug transporters such as P-glycoprotein and multidrug-resistant proteins 1 and 2 can influence drug distribution. These drug transporters can greatly influence the extent that drugs cross membranes in the body and whether drugs can penetrate or are secreted from the target sites (inside cancer cells or microorganisms or crossing the blood-brain barrier). Thus, drug resistance to cancer chemotherapy, antibiotics, or epilepsy may be conferred by these drug transport proteins and their effect on drug distribution. Growing evidence on the ontogeny of drug transport proteins demonstrates their presence as early as 12 wk gestation and low levels in the neonatal period, which rapidly increase to adult values by 1 to 2 yr of age, depending on the transporter. In addition, genetic variation can affect drug transporter expression and function but may not be readily apparent until adult levels are obtained (see Chapter 72 ).

Drug Metabolism

Metabolism reflects the biotransformation of an endogenous or exogenous molecule by one or more enzymes to moieties that are more hydrophilic and thus can be more easily eliminated by excretion, secretion, or exhalation. Although metabolism of a drug generally reduces its ability to produce a pharmacologic action, metabolism also can result in metabolites that have significant potency and thereby contribute to the drug's overall pharmacodynamic profile (e.g., biotransformation of the tricyclic antidepressant amitriptyline to nortriptyline; codeine to morphine; cefotaxime to desacetyl cefotaxime; theophylline to caffeine). In the case of prodrugs (e.g., zidovudine, enalapril, fosphenytoin) or some drug salts or esters (e.g., cefuroxime axetil, clindamycin phosphate), biotransformation is required to produce a pharmacologically active moiety. Finally, for some drugs, cellular injury and associated adverse reactions are the result of drug metabolism (e.g., acetaminophen hepatotoxicity, Stevens-Johnson syndrome associated with sulfamethoxazole).

The primary organ responsible for drug metabolism is the liver, although the kidney, intestine, lung, adrenals, blood (phosphatases, esterases), and skin can also biotransform certain compounds. Drug metabolism occurs primarily in the endoplasmic reticula of cells through 2 general classes of enzymatic processes: phase I (nonsynthetic) and phase II (synthetic) reactions. Phase I reactions include oxidation, reduction, hydrolysis, and hydroxylation reactions. Phase II reactions primarily involve conjugation with an endogenous ligand (e.g., glycine, glucuronide, glutathione or sulfate). Many drug-metabolizing enzymes demonstrate an ontogenic profile with generally low activity at birth and maturation over months to years ( Table 73.4 and Fig. 73.3 A ).

Table 73.4

Impact of Development on Drug Metabolism

PHYSIOLOGIC ALTERATION	NEONATE	INFANTS	CHILDREN
Cytochrome P450 activity	Reduced	Increased	Slightly increased
Phase II enzyme activity	Reduced	Increased	Near adult
Blood esterase activity	Reduced	Normal (by 1 yr)	Adult pattern
Presystemic enzyme activity	Reduced	Increased	Near adult

Direction of alteration given relative to expected normal adult pattern.

Many enzymes are capable of catalyzing the biotransformation of drugs and xenobiotics, but quantitatively the most important are represented by cytochrome P450 ( CYP ), a supergene family with at least 16 primary enzymes. The specific CYP isoforms responsible for the majority of human drug metabolism are represented by CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. These enzymes represent the products of genes that in some cases are polymorphically expressed, with allelic variants producing enzymes generally resulting in either no or reduced catalytic activity (a notable exception being the *17 allele of CYP2C19, which may have increased activity) (see Chapter 72 ). At birth the concentration of drug-oxidizing enzymes in fetal liver (corrected for liver weight) appears similar to that in adult liver. However, the activity of these oxidizing enzyme systems is reduced, which results in slow clearance (and prolonged elimination) of many drugs that are substrates for them (e.g., phenytoin, caffeine, diazepam). Postnatally, the hepatic CYPs appear to mature at different rates. Within hours after birth, CYP2E1 activity increases rapidly, with CYP2D6 being detectable soon thereafter. CYP2C (CYP2C9 and CYP2C19) and CYP3A4 are present within the 1st mo of life, a few months before CYP1A2. CYP3A4 activity in young infants may exceed that observed in adults, as reflected by the clearance of drugs that are substrates for this enzyme (e.g., cyclosporine, tacrolimus).

Compared to phase I drug-metabolizing enzymes, the impact of development on the activity of phase II enzymes (acetylation, glucuronidation, sulfation) is not characterized as well. Phase II enzyme activity is decreased in the newborn and increases into childhood. Conjugation of compounds metabolized by isoforms of glucuronosyltransferase ( UGT ) (e.g., morphine, bilirubin, chloramphenicol) is reduced at birth but can exceed adult values by 3-4 yr of age. Also, the ontogeny of UGT expression is isoform specific. Newborns and infants primarily metabolize the common analgesic acetaminophen by sulfate conjugation, since the UGT isoforms responsible for its glucuronidation (UGT1A1 and UGT1A9) have greatly reduced activity. As children age, the glucuronide conjugate becomes predominant in the metabolism of therapeutic doses of acetaminophen. In contrast, the glucuronidation of morphine (a UGT2B7 substrate) can be detected as early as 24 wk gestation.

The activity of certain hydrolytic enzymes, including blood esterases, is also reduced during the neonatal period. Blood esterases are important for the metabolic clearance of cocaine, and the reduced activity of these plasma esterases in the newborn may account for the delayed metabolism (prolonged effect) of local anesthetics in the neonate. In addition, this may account for the prolonged effect that cocaine has on the fetus with prenatal exposures. Adult esterase activity is achieved by 10-12 mo of age.

The development of presystemic clearance or “first-pass” metabolism is unclear given the involvement of multiple enzymes and transporters in the small intestine, many of which have patterns of developmental expression that may be more or less concordant. However, given that the activity of almost all drug-metabolizing enzymes is markedly reduced in the neonate, the extent of bioavailability of drugs given by the peroral route that may be subjected to significant presystemic clearance in older children and adults would appear to be greatly increased during the 1st days to weeks of life. It is important for the clinician to recognize that estimates of bioavailability for a host of drugs available in reference texts and therapeutic compendia are most often derived from studies conducted in young adults. Thus, estimates of the rate and extent of absorption (including a propensity to be affected by presystemic clearance) from adults cannot be accurately used to extrapolate how a peroral drug dose may need to be age-adjusted for a neonate or infant.

With regard to the impact of development on drug metabolism, it must be recognized that most therapeutic drugs are polyfunctional substrates for a host of enzymes and transporters. It is the isoform-specific ontogenic profile ( Fig. 73.3 ) that must be considered in the context of deducing how development can affect the metabolic portion of drug clearance. True developmental dependence of drug clearance must also consider the role of pharmacogenetic constitution on the activity of enzymes and transporters (see Chapter 72 ) and the impact of ontogeny on the nonmetabolic routes (e.g., renal drug excretion, salivary/biliary drug excretion, pulmonary drug excretion), which contribute to the overall drug clearance (Total CL = CL _hepatic + CL _renal + CL _nonrenal ).

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