DONE: Factors That Affect Drug Disposition In Children Flashcards
Higher Metabolic ________.
Rate
CYP2C9 and, to a lesser extent, CYP2C19 are primarily responsible for the biotransformation of phenytoin. The apparent half-life of phenytoin is prolonged (to approximately 75 hours) in preterm infants, but it decreases to approximately 20 hours in term infants during the first week of life and to approximately 8 hours after the second week of life. Concentration-dependent metabolism (i.e., that accounted for by Michaelis–Menten kinetics) does not appear until approximately 10 days of age, demonstrating the developmental acquisition of CYP2C9 activity. The maximal velocity of phenytoin (which reflects the extent of CYP2C9 activity) declines from an average value of 14 mg per kilogram per day in infants to 8 mg per kilogram per day in adolescents, producing a profound corresponding age- related difference in the daily therapeutic dose requirement.
Rapidly growing ______.
tissue
Although it is generally accepted that development can alter the action of and response to a drug, little information exists about the effect of human ontogeny on interactions between drugs and receptors and the consequence of these interactions (i.e., the pharmacodynamics). For example, the apparent developmental differences in the pharmacodynamics of famotidine in neonates are directly associated with the reduced plasma clearance of the drug owing to the developmentally dependent reductions in the glomerular filtration rate. However, data on certain other drugs appear to support the existence of true age-dependent differences either in the interaction between a drug and its specific receptor (e.g., warfarin and cyclosporine) or in the relation be- tween the plasma level and the pharmacologic effect of a given drug (e.g., sedation associated with midazolam).
Increased percentage of ________.
Extracellular Fluid and Total Body Water
Age-dependent changes in body composition alter the physiologic spaces into which a drug may be distributed. The relatively larger extracellular and total-body water spaces in neonates and young infants as compared with adults, coupled with adipose stores that have a higher ratio of water to lipid, result in lower plasma levels of drugs in these compartments when the drugs are administered in a weight-based fashion. The influence of age on the apparent volume of distribution is not as readily apparent for lipophilic drugs that are primarily distributed in tissue.
Lower body _______.
Fat
Age dependent changes in body composition alter the physiologic spaces into which a drug may be distributed. The relatively larger extracellular and total body water spaces in neonates and young infants as compared with adults, coupled with adipose stores that have a higher ratio of water to lipid, result in lower plasma levels of drugs in these compartments when the drugs are administered in a weight based fashion. The influence of age on the apparent volume of distribution is not as readily apparent for lipophilic drugs that are primarily distributed in tissue.
________ Hepatic Metabolism.
Immature
Delayed maturation of drug-metabolizing enzyme activity may account for the marked toxicity of drugs in the very young, as exemplified by the cardiovascular collapse associated with the gray syndrome in newborns treated with chloramphenicol. Important developmental changes in the biotransformation of drugs prompt the need for age-appropriate dose regimens for many drugs commonly used in neonates and young infants, such as the methylxanthines, nafcillin, third-generation cephalosporins, captopril, and morphine.
Altered absorption patterns in ______ system.
Gastrointestinal system
Most drugs are administered orally to children. Changes in the intraluminal pH in different segments of the gastrointestinal tract can directly affect both the stability and the degree of ionization of a drug, thus influencing the relative amount of drug available for absorption. During the neonatal period, intragastric pH is relatively elevated (greater than 4) consequent to reductions in both basal acid output and the total volume of gastric secretions. Thus,oral administration of acid labile compounds such as penicillin produces greater bioavailability in neonates than in older infants and children. In contrast, drugs that are weak acids, such as phenobarbital, may require larger oral doses in the very young in order to achieve therapeutic plasma levels.
Increased permeability of the _____ and _____.
skin and conjunctiva
Developmental changes also can alter the absorption of drugs by other extravascular routes. Enhanced percutaneous absorption during infancy may be accounted for, in part, by the presence of a thinner stratum corneum in the preterm neonate and by the greater extent of cutaneous perfusion and hydration of the epidermis (relative to adults) throughout childhood.
Decrease in protein ________.
Binding
Changes in the composition and amount of circulating plasma proteins such as albumin and a1-acid glycoprotein can also influence the distribution of highly bound drugs. A reduction in the quantity of total plasma proteins (including albumin) in the neonate and young infant increases the free fraction of drug, thereby influencing the availability of the active moiety. The presence of fetal albumin (which has reduced binding affinity for weak acids) and an increase in endogenous sub- stances (e.g., bilirubin and free fatty acids) capable of displacing a drug from albumin binding sites during the neonatal period may also contribute to the higher free fractions of highly protein-bound drugs in neonates. Other factors associated with development or disease, such as variability in regional blood flow, organ perfusion, permeability of cell membranes, changes in acid–base balance, and cardiac output, can also influence drug binding and distribution.
__________ Cardiovascular System.
Immature
The presence of fetal albumin (which has reduced binding affinity for weak acids) and an increase in endogenous substances (e.g., bilirubin and free fatty acids) capable of displacing a drug from albumin binding sites during the neonatal period may also contribute to the higher free fractions of highly protein-bound drugs in neonates. Other factors associated with development or disease, such as variability in regional blood flow, organ perfusion, permeability of cell membranes, changes in acid–base balance, and cardiac output, can also influence drug binding and distribution.
Delayed gastric ________.
emptying
Gastric emptying and intestinal motility are the primary determinants of the rate at which drugs are presented to and dispersed along the mucosal surface of the small intestine. At birth, the coordination of antral contractions improves, resulting in a marked increase in gastric emptying during the first week of life. Similarly, intestinal motor activity matures throughout early infancy, with consequent increases in the frequency, amplitude, and duration of propagating contractions. Unfortunately, few studies have systematically evaluated the effect of these developmental changes on drug absorption in infants and children.
______ Renal Function.
Immature
Maturation of renal function is a dynamic process that begins during fetal organogenesis and is complete by early childhood. The developmental increase in the glomerular filtration rate relies on the existence of normal nephrogenesis, a process that begins at 9 weeks of gestation and is complete by 36 weeks of gestation, followed by postnatal changes in renal and intrarenal blood flow. The glomerular filtration rate is approximately 2 to 4 ml per minute per 1.73 m2 in term neonates, but it may be as low as 0.6 to 0.8 ml per minute per 1.73 m2 in pre-term neonates. The glomerular filtration rate increases rapidly during the first two weeks of life and then rises steadily until adult values are reached at 8 to 12 months of age. Similarly, tubular secretion is immature at birth and reaches adult capacity during the first year of life. Collectively, developmental changes in renal function can dramatically alter the plasma clearance of compounds with extensive renal elimination and thus constitute a major determinant of the age-appropriate selection of a dose regimen.
______ Blood Brain Barrier.
Immature
Allows medications to easily affect the Central Nervous System. Although much of the distribution of a drug is the result of simple passive diffusion along concentration gradients and associated binding of the drug to tissue components, the expression by tissue of transporters capable of producing a biologic barrier also contributes. P-glycoprotein, a member of the ATP-binding cassette family of transporters that functions as an efflux transporter capable of extruding selected toxins and xenobiotics from cells, is one such example.
