Tiêu đề 5. DRUG DOSING IN THE ELDERLY AND PEDIATRICS AND OBESE PATIENTS.pdf ✅

PHARMD GURU Page 1 DRUG DOSING IN THE ELDERLY:  Defining “elderly” is difficult. The geriatric population is often arbitrarily defined as patients who are older than 65 years, and many of these people live active and healthy lives.  In addition, there is an increasing number of people who are living beyond 85 years old, who are often considered the “older elderly” population.  The aging process is more often associated with physiologic changes during aging rather than purely chronological age.  Chronologically, the elderly have been classified as the young old (ages 65–75 years), the old (ages 75–85 years), and the old old (ages >85 years).  Performance capacity and the loss of homeostatic reserve decrease with advanced age but occur to a different degree in each organ and in each patient.  Physiologic and cognitive functions tend to change with the aging process and can affect compliance, therapeutic safety, and efficacy of a prescribed drug.  The elderly also tend to be on multiple drug therapy due to concomitant illness (es).  Decreased cognitive function in some geriatric patients, complicated drug dosage schedules, and/or the high cost of drug therapy may result in poor drug compliance, resulting in lack of drug efficacy, possible drug interactions, and/or drug intoxication.  Several objectively measured vital physiologic functions related to age show that renal plasma flow, glomerular filtration, cardiac output, and breathing capacity can drop from 10% to 30% in elderly subjects compared to those at age 30 years.  The physiologic changes due to aging may necessitate special considerations in administering drugs in the elderly.  For some drugs, an age-dependent increase in adverse drug reactions or toxicity may be observed.  This apparent increased drug sensitivity in the elderly may be due to pharmacodynamic and/or pharmacokinetic changes.  The pharmacodynamic hypothesis assumes that age causes alterations in the quantity and quality of target drug receptors, leading to altered drug response. DRUG DOSING IN THE ELDERLY AND PEDIATRICS AND OBESE PATIENTS
PHARMD GURU Page 2  Quantitatively, the number of drug receptors may decline with age, whereas qualitatively, a change in the affinity for the drug may occur.  Alternatively, the pharmacokinetic hypothesis assumes that age-dependent increases in adverse drug reactions are due to physiologic changes in drug absorption, distribution, and elimination, including renal excretion and hepatic clearance.  In the elderly, age-dependent alterations in drug absorption may include a decline in the splanchnic blood flow, altered gastrointestinal motility, increase in gastric pH, and alteration in the gastrointestinal absorptive surface.  The incidence of achlorhydria in the elderly may have an effect on the dissolution of certain drugs such as weak bases and certain dosage forms that require an acid environment for disintegration and release.  From a distribution consideration, drug–protein binding in the plasma may decrease as a result of decrease in the albumin concentration, and the apparent volume of distribution may change due to a decrease in muscle mass and an increase in body fat.  Renal drug excretion generally declines with age as a result of decrease in the glomerular filtration rate (GFR) and/or active tubular secretion.  Moreover, the activity of the enzymes responsible for drug biotransformation may decrease with age, leading to a decline in hepatic drug clearance.  Elderly patients may have several different pathophysiologic conditions that require multiple drug therapy that increases the likelihood for a drug interaction.  Moreover, increased adverse drug reactions and toxicity may result from poor patient compliance. Both penicillin and kanamycin show prolonged t 1/2 in the aged patient, as a consequence of an age-related gradual reduction in the kidney size and function.  The Gault–Cockroft rule for calculating creatinine clearance clearly quantitates a reduction in clearance with increased age. Age-related changes in plasma albumin and α1-acid glycoprotein may also be a factor in the binding of drugs in the body. DRUG DOSING IN THE PEDIATRIC:  Infants and children have different dosing requirements than adults.  Information for pediatric dosing was generally lacking in the past. In December 1994, the FDA required drug manufacturers to determine whether existing data

PHARMD GURU Page 4  However, body composition is different in infants compared to adults. In general, complete hepatic function is not attained until the third week of life.  Oxidative processes are fairly well developed in infants, but there is a deficiency of conjugative enzymes, in particular, glucuronidation.  For example, kernicterus is a form of jaundice in the newborn characterized by very high levels of unconjugated bilirubin in the blood.  Since the tissues protecting the brain (the blood–brain barrier) are not well formed in newborns, unconjugated bilirubin may enter the brain and cause brain damage.  In addition to reduced liver function in infants, altered drug distribution may occur due to reduction in drug binding to plasma albumin and to different body composition, especially water and fat content.  Newborns show only 30%–50% of the renal function of adults on the basis of activity per unit of body weight.  Drugs that are heavily dependent on renal excretion will have a sharply decreased elimination half-life.  For example, the penicillins are excreted for the most part through the kidneys. The elimination half-lives of such drugs are much increased in infants.  When dosage guidelines are not available for a drug, empirical dose adjustment methods are often used.  These empirical dose adjustment methods are based on body surface area or body weight.  Dosage based on the child’s age and body weight, and normalized to drug dosages in adults, was used in the past. However, pharmacokinetic parameters may vary as a function of age.  Dosage based on body surface area has the advantage of avoiding some bias due to obesity or unusual body weight, because the height and the weight of the patient are both considered.  The body surface area method gives only a rough estimation of the proper dose, because the pharmacokinetic differences between patients of the same body surface area are not considered.  Dosage regimens for the newborn, infant, and child must consider the changing physiologic development of the patient and the pharmacokinetics of the specific drug for that age group.