Drug Metabolism and Disposition in Pediatric and Gerontological Stages of Life

The clinical responses to drug administration can be greatly influenced both by the chronological age of the patient and by the relative maturity of the particular organ system that is being targeted.Human development follows a continuum of time-related events. There are unique therapeutic differences and concerns associated with the treatment of the very young and the elderly patient. Age-dependent changes in body function are known to alter the pharmacokinetic parameters that determine each compound’s duration of action, extent of drug–receptor interaction, and the drug’s rates of absorption, distribution, metabolism, and excretion. This chapter discusses some of these principles and the cautions that must be considered when treating these particular patient populations.

DRUG DISPOSITION IN PEDIATRIC PATIENTS :-

                                                                                           In spite of recent advances in this area, knowledge of the disposition and actions of drugs in children is limited.This lack of information has made drug therapy for them difficult and dangerous.There are two major obstacles to clinical drug studies in children.One is an ethical issue,the inability to obtain true informed consent. The second obstacle is inherent to children; they grow and change rapidly.Drug studies must be performed on children at each stage of their development to determine appropriate usage for all patients. 

To study drug disposition in children it is most informative to divide them into five age groups: preterm infants, term infants from birth through the first month of life, children 1 month to 2 years of age, children 2 to

12 years of age, and children 12 to 18 years of age. Tanner staging of sexual maturation may more appropriately break down this latter group.Children that are Tanner stages I,II,and III are appropriately considered children;those who are Tanner stages IV and V are considered adults. 

Preterm infants, especially those near the limits of viability (24 weeks’ gestation),have glomerular filtration rates approximately one-tenth that of a term newborn. Because of limitations on tubular reabsorption, they have increased urinary loss of filtered substances. Glucuronidation pathways appear after 20 weeks of gestation and so are limited in extremely premature infants. 

At birth, term infants can metabolize and eliminate drugs. For most patients these systems did not function during fetal life and therefore even at birth are not very efficient. outlines the time required for maturation of some of the systems used in drug absorption and elimination.

The period from 1 month to 2 years of age is a time of rapid growth and maturation. By the end of this period,most systems function at adult levels.Paradoxically, between 2 and 12 years of age drug clearance greatly increases and often exceeds adult levels. Half-lives are shorter and dosing requirements are frequently greater than for adults.

From 12 to 18 years of age sex differences start to appear. These differences are often associated with a decreased drug absorption and elimination in the female as opposed to the male. Females have less gastric acidity and an increased gastric emptying time. Estrogens decrease hepatic cytochrome P450 content and therefore may decrease metabolism of some drugs via phase I pathways. Cyclic changes in glomerular filtration are noted during the menstrual cycle.

Absorption:-

                    Oral absorption of drugs is influenced by gastric acidity and emptying time. Gastric acid is rarely found in the

stomach of infants at less than 32 weeks’ gestation.Acid initially is secreted within the first few hours after birth, reaching peak levels within the first 10 days of life.It decreases during the next 20 days of extrauterine life. Gastric acid secretion approaches the lower limits of adult values by 3 months of age. The initiation of acid secretion is often delayed in infants with delayed initiation of oral feedings, such as extreme preemies and those with anomalies of the gastrointestinal tract.