6 Drug Metabolism and

Disposition in Pediatric and

Gerontological Stages of Life
Jeane McCarthy

The clinical responses to drug administration can be 12 years of age, and children 12 to 18 years of age.
greatly influenced both by the chronological age of the Tanner staging of sexual maturation may more appro-
patient and by the relative maturity of the particular or- priately break down this latter group. Children that are
gan system that is being targeted. Human development Tanner stages I, II, and III are appropriately considered
follows a continuum of time-related events. There are children; those who are Tanner stages IV and V are con-
unique therapeutic differences and concerns associated sidered adults.
with the treatment of the very young and the elderly pa- Preterm infants, especially those near the limits of
tient. Age-dependent changes in body function are viability (24 weeks’ gestation), have glomerular filtration
known to alter the pharmacokinetic parameters that de- rates approximately one-tenth that of a term newborn.
termine each compound’s duration of action, extent of Because of limitations on tubular reabsorption, they
drug–receptor interaction, and the drug’s rates of ab- have increased urinary loss of filtered substances.
sorption, distribution, metabolism, and excretion. This Glucuronidation pathways appear after 20 weeks of ges-
chapter discusses some of these principles and the cau- tation and so are limited in extremely premature infants.
tions that must be considered when treating these par- Recent advances have made it possible for drug
ticular patient populations. therapy to begin prior to birth. Many mothers and
therefore their infants are receiving corticosteroids to
induce maturation of the lungs. Some fetal cardiac ar-
rhythmias, such as supraventricular tachycardia, are suc-
DRUG DISPOSITION IN PEDIATRIC cessfully managed by treating the mother during preg-
PATIENTS nancy. Since most drugs cross the placenta, the infant
In spite of recent advances in this area, knowledge of has the potential to be affected by drugs that the
the disposition and actions of drugs in children is lim- mother takes. Metabolism and excretion are not the re-
ited. This lack of information has made drug therapy for sponsibility of the fetus, as the placenta and the mater-
them difficult and dangerous. There are two major ob- nal liver and kidneys contribute significantly to drug
stacles to clinical drug studies in children. One is an eth- elimination.
ical issue, the inability to obtain true informed consent. At birth, term infants can metabolize and eliminate
The second obstacle is inherent to children; they grow drugs. For most patients these systems did not function
and change rapidly. Drug studies must be performed on during fetal life and therefore even at birth are not very
children at each stage of their development to deter- efficient. Table 6.1 outlines the time required for matu-
mine appropriate usage for all patients. ration of some of the systems used in drug absorption
To study drug disposition in children it is most in- and elimination. Table 6.2 lists other factors that alter
formative to divide them into five age groups: preterm drug disposition in newborns. The ability to absorb and
infants, term infants from birth through the first month eliminate drugs increases slowly over the first month of
of life, children 1 month to 2 years of age, children 2 to life.

56
 6 Drug Metabolism and Disposition in Pediatric and Gerontological Stages of Life 57

TA B L E 6.1 Age-related Maturation TA B L E 6.3 Age-dependent t1/2

of Selected Systems of Trimethoprim

System Age Adult Level Attained Age t1/2 (hr)

Gastric acid production 3 mo Newborn 10.8

Gastric emptying 6–8 mo 1–3 yr 3.7
Hepatic metabolism 8–10 yr 5.4
Phase I enzyme reactions 5 mo–5 yr Young adult 11.2
Phase II enzyme reactions 3–6 mo
Excretion
Glomerular filtration 3–5 mo
Tubular secretion 6–9 mo stomach of infants at less than 32 weeks’ gestation. Acid
Renal blood flow 5–12 mo initially is secreted within the first few hours after birth,
reaching peak levels within the first 10 days of life. It de-
creases during the next 20 days of extrauterine life.
Maternally administered drugs also may affect in- Gastric acid secretion approaches the lower limits of
fants who are breast-fed. Most drugs are present in adult values by 3 months of age. The initiation of acid
breast milk in small quantities. However, several drugs secretion is often delayed in infants with delayed initia-
can reach concentrations sufficient to adversely affect tion of oral feedings, such as extreme preemies and
the newborn. Drugs that are contraindicated during those with anomalies of the gastrointestinal tract.
breast-feeding include cocaine, ergotamine, and cimeti- Gastric emptying time in infants is related to their
dine. Unfortunately, for many drugs the information re- age and to the type of formula they receive. Formulas
garding risks to the infant from drug in breast milk is containing long-chain fatty acids will delay gastric emp-
not available. tying. Both gastric emptying time and small-intestine
The period from 1 month to 2 years of age is a time peristalsis tend to be slow until the later part of the first
of rapid growth and maturation. By the end of this pe- year of life. In children aged 2 to 12 years gastric emp-
riod, most systems function at adult levels. Paradoxically, tying time dramatically increases, as does splanchnic
between 2 and 12 years of age drug clearance greatly in- blood flow. These physiological changes result in faster
creases and often exceeds adult levels. Half-lives are drug absorption and increased peak blood concentra-
shorter and dosing requirements are frequently greater tions of drug. The decreased small intestine transit time
than for adults (Table 6.3). during this period may result in decreased absorption of
From 12 to 18 years of age sex differences start to some drugs. Because of low blood flow through muscles
appear. These differences are often associated with a in the neonatal period, drugs administered intramuscu-
decreased drug absorption and elimination in the fe- larly are absorbed erratically.
male as opposed to the male. Females have less gastric Percutaneous drug absorption can present special
acidity and an increased gastric emptying time. Estro- problems in newborns, especially in preterm infants.
gens decrease hepatic cytochrome P450 content and While the skin of a newborn term infant may have the
therefore may decrease metabolism of some drugs via same protective capacity as the skin of an adult, a
phase I pathways. Cyclic changes in glomerular filtra- preterm infant will not have this protective barrier until
tion are noted during the menstrual cycle. after 2 to 3 weeks of life. Excessive percutaneous ab-
sorption has caused significant toxicity to preterm ba-
Absorption bies. Absorption of hexachlorophene soap used to
bathe newborns has resulted in brain damage and
Oral absorption of drugs is influenced by gastric acidity death. Aniline dyes on hospital linen have caused
and emptying time. Gastric acid is rarely found in the cyanosis secondary to methemoglobinemia, and EMLA
(lidocaine/prilocaine) cream may cause methemoglo-
binemia when administered to infants less than 3
months of age.
TA B L E 6.2 Other Factors Affecting
Newborn Drug Disposition Distribution
Increased body water The total body water of prematures, newborns, and in-
Decreased body fat fants is significantly greater than it is for older children
Decreased exocrine pancreatic function and adults. This increased total body water increases the
Decreased albumin concentration and binding
volume of drug distribution for water-soluble com-
Decreased total plasma protein
pounds. As a consequence, there is a need to administer
58 I GENERAL PRINCIPLES OF PHARMACOLOGY

loading doses of some drugs. Differences in total body Excretion

water are basically insignificant after the first year of
life. Newborns have decreased body fat and therefore Renal blood flow, glomerular filtration rate, and tubular
less storage ability for fat-soluble drugs. function are reduced in both preterm and term
Newborns, especially prematures, have decreased neonates. Therefore, newborns, especially those less than
plasma albumin and total plasma protein concentrations. 34 weeks’ gestation, require less frequent dosing inter-
In addition, albumin from these patients shows a de- vals for many drugs. Aminoglycosides are administered
creased drug-binding affinity. This may result in increased every 8 hours in older children, every 12 hours in new-
plasma levels of free drug and the potential for toxicity. In borns, and every 24 hours in extremely premature in-
the past, concerns were raised that certain drugs, such as fants. The glomerular filtration rate of the term newborn
sulfonamides, could displace endogenous substances, like is approximately 50% less than the adult level but
bilirubin, from albumin-binding sites. Theoretically, such reaches adult values by 1 year of age. Renal blood flow
an interaction would increase the risk for kernicterus. approaches adult values between ages 5 and 12 months.
Although this belief has been challenged recently, reluc- Tubular secretory functions mature at a slower rate than
tance to treat newborns with sulfonamides persists. does glomerular filtration. Renal excretion of organic
anions, such as penicillin, furosemide, and indomethacin,
is very low in the newborn. Tubular secretion and reab-
Metabolism sorption reach adult levels by 7 months of age. Renal
As with adults, the primary organ responsible for drug elimination of drugs appears to play a greater role than
metabolism in children is the liver. Although the cy- does metabolism in newborns. Over the first year of life
tochrome P450 system is fully developed at birth, it the infant develops a more adult-type excretory pattern.
functions more slowly than in adults. Phase I oxidation
reactions and demethylation enzyme systems are signif- Drug Action
icantly reduced at birth. However, the reductive enzyme Most drugs are administered to infants and children for
systems approach adult levels and the methylation the same therapeutic indications as for adults. However, a
pathways are enhanced at birth. This often contributes few drugs have found unique uses in children. Among
to the production of different metabolites in newborns these are theophylline and caffeine, which are used to
from those in adults. For example, newborns metabolize treat apnea of prematurity; indomethacin, which closes a
approximately 30% of theophylline to caffeine rather patent ductus arteriosus; and prostaglandin E1, which
than to uric acid derivatives, as occurs in adults. While maintains the patency of the ductus arteriosus. Para-
most phase I enzymes have reached adult levels by 6 doxically, drugs such as phenobarbital, which have a
months of age, alcohol dehydrogenase activity appears sedating action on adults, may produce hyperactivity in
around 2 months of age and approaches adult levels children, and some adult stimulant drugs, such as methyl-
only by age 5 years. phenidate, are used to treat children with hyperactivity.
Phase II synthetic enzyme reactions are responsible
for the elimination of endogenous compounds, such as
bilirubin, and many exogenous substances. The immatu- Adverse Reactions
rity of the glucuronidation pathway was responsible for Children may display adverse reactions different from
the development of gray baby syndrome (see Chapter those noted in adult patients. Table 6.4 lists a number of
47) in newborns receiving chloramphenicol. Preterm drugs that demonstrate unique actions in children.
and newborn infants dying of this syndrome developed
anemia and cardiovascular collapse because of high
blood concentrations of unconjugated chlorampheni-
Special Considerations
col. The plasma half-life was found to be 26 hours in Several problems unique to pediatric drug therapy de-
these patients compared with 4 hours in older children. serve special mention. For example, most medications
Infants and children have a greater capacity to carry are commercially available only in adult dose forms.
out sulfate conjugation than do adults. For example, Preparing pediatric doses from adult tablets or capsules
acetaminophen is excreted predominantly as a sulfate can be very difficult and may require special skill on the
conjugate in children as opposed to a glucuronide con- part of the pharmacist. For some drugs it is simpler to
jugate in adults. This enhanced sulfation of acetamino- administer the intravenous (IV) preparation orally than
phen, along with decreased metabolism via cytochrome to develop a preparation from the oral medication.
P450 pathways and increased glutathione turnover, are IV drug administration is most effective in children
thought to explain the decreased hepatotoxicity caused when given via a pump infusion system close to the site
by this analgesic in children under 6 years of age. Phase of IV insertion. Because of the small size of many pedi-
II enzyme systems reach adult levels between 3 and 6 atric doses and the fact that some drugs adhere to IV
months of age. tubing, a significant percentage of the drug can be lost if
 6 Drug Metabolism and Disposition in Pediatric and Gerontological Stages of Life 59

• Newborns are not small infants.

TA B L E 6.4 Pediatric Specific Adverse • Preemies are not small newborns.
Drug Reactions

Drug Reaction DRUG DISPOSITION IN GERIATRIC

Furosemide (Lasix) Nephrocalcinosis
PATIENTS
Indomethacin (Indocin) Renal Failure, bowel perforation The elderly (individuals over 65 years of age) constitute
Adrenocorticoids Delayed development, growth
more than 13% of the population. This figure is increas-
suppression
Tetracyclines Discolored teeth ing steadily and is expected to reach 50 million by the
Phenobarbital Hyperactivity, impaired intellec- year 2020. This segment of our society is the most highly
tual development drug-treated and accounts for about 25% of prescrip-
Phenytoin (Dilantin) Thickened skull, coarse features tion drugs dispensed. The average Medicare patient in
Chloramphenicol Gray baby syndrome
an acute-care hospital receives approximately 10 differ-
Phenothiazines Extrapyramidal reaction
Valproic acid (Depakene) Hepatotoxicity (2 yr) ent drugs daily, and this translates into a higher inci-
Aspirin Reye’s syndrome in patients with dence of adverse drug reactions in geriatric patients
chickenpox or influenza than in the general population.
Chronological aging may not necessarily be an accu-
Compiled from Outslander JG. Drug therapy in the Elderly. Ann
Intern Med 1981;95:711; and Richey DP and Bender AD. rate index of biological aging, which is the result of
Pharmacokinetic consequences of aging. Annu Rev Pharmacol many genetic and environmental factors. While most 20-
Toxicol 1977;17:49; and references therein.
year-olds have a similar response to a given drug, it is
difficult to predict the response among 80-year-olds. A
clear relationship between the appearance of untoward
it is given using techniques usually reserved for adults.
effects to drugs and aging has been demonstrated only
For many prematures and newborns, the volume of ad-
for about 10 drugs. For some 90 other drugs in common
ministration is also critical and therefore much more
clinical use, age alone was not a major determinant of
easily managed by IV infusion pumps.
clinical toxicity. It is apparent that an increase in life
Most adult drugs must be diluted to achieve appro-
span is accompanied by an increase in chronic illnesses
priate pediatric dosages. Some drugs must be diluted
such as hypertension, congestive heart failure, arthritis,
several times. This introduces the potential for signifi-
and diabetes. The pharmacological management of
cant error in dilution. Some drugs such as NPH (Neutral
these conditions, especially when the same person has
Protamine Hagedorn) insulin may lose their effective-
several diseases, becomes increasingly complex.
ness if diluted.
Age-related alterations in pharmacokinetics (ab-
Children with chronic illnesses require special con-
sorption, distribution, metabolism, and excretion) have
sideration. For example, patients with cystic fibrosis
received considerable attention. Thus, physiological
have increased hepatic metabolism and therefore in-
changes in elderly patients, when taken together, may
creased drug clearance. This may necessitate the admin-
contribute to impairments in drug clearance in this seg-
istration of increased drug dosages.
ment of the population (Table 6.5).
Calculation of pediatric dosages is usually done on
the basis of weight (e.g., milligrams per kilogram) for in-
fants and toddlers and on the basis of weight or body Absorption
surface area (milligrams per square meter) for older Elderly patients may absorb drugs less completely or
children. Repeated increases in drug dosage are re- more slowly because of decreased splanchnic blood flow
quired to accommodate for growth in children receiving or delayed gastric emptying. Reduced gastric acidity may
chronic drug therapy. decrease the absorption of drugs that require high acidity.
In summary, children, especially those in the first
year of life, present significant pharmacological chal-
lenges. Drug administration must be tailored to meet
Distribution
the unique needs of children at their varied stages of de- Drug distribution in elderly patients may be altered by
velopment. Special attention must be given to unex- hypoalbuminemia, qualitative changes in drug-binding
pected drug actions and adverse reactions in these pa- sites, reductions in relative muscle mass, increases in the
tients, who are maturing at variable rates. When proportion of body fat, and decreases in total body
planning drug therapy for children, it is important to water. The plasma level of free, active drug is often a di-
remember: rect function of the extent of drug binding to plasma
proteins. There is a well-documented age-dependent
• Children are not small adults. decline (about 20%) in plasma albumin concentration
• Infants are not small children. in humans due to a reduced rate of hepatic albumin
60 I GENERAL PRINCIPLES OF PHARMACOLOGY

ume, and blood flow (Fig. 6.1). Phase I oxidative path-

TA B L E 6.5 Plasma Half-lives of Several ways are decreased with age, while phase II conjugation
Drugs in Young Adult and pathways are unchanged.
Elderly Patients In a carefully controlled clinical study, the plasma
half-life of diazepam (Valium), a widely used antianx-
Plasma or serum t1/2 iety agent, exhibited a striking age dependency. In pa-
tients aged 20 years, the t1/2was about 20 hours, and this
Young Elderly
increased linearly with age to about 90 hours at 80
Drug (20–30 yr) (65–80 yr)
years. Half-lives of other drugs in young and old pa-
Penicillin G 20.7 min 39.1 min tients are presented in Table 6.5. These data demon-
Dihydrostreptomycin 5.2 hr 8.4 hr strate changes in drug half-life with increasing age,
Tetracycline 3.5 hr 4.5 hr
suggesting that at least for some drugs, elderly patients
Kanamycin 107.0 min 282.0 min
Digoxin 52.0 hr 73.0 hr have reduced metabolism, drug clearance, or both.
Aminopyrine 3.0 hr 10.0 hr
Phenobarbital 71.0 hr 107.0 hr Excretion
Diazepam 20.0 hr 80.0 hr
Lidocaine 80.6 min 139.6 min Renal elimination of foreign compounds may change
Chlordiazepoxide 8.9 hr 16.7 hr dramatically with increasing age by factors such as re-
Antipyrine 12.0 hr 17.4 hr
Phenylbutazone 81.2 hr 104.6 hr
duced renal blood flow, reduced glomerular filtration
Isoniazid 1.4 hr 1.5 hr rate, reduced tubular secretory activity, and a reduction
Warfarin 37.0 hr 44.0 hr in the number of functional nephrons. It has been esti-
mated that in humans, beginning at age 20 years, renal
Source: Compiled from J.G. Ouslander, Drug therapy in the function declines by about 10% for each decade of life.
elderly. Ann. Intern. Med. 95:711, 1981; and D.P. Richey and
A.D. Bender, Pharmacokinetic consequences of aging. Annu.
This decline in renal excretion is particularly important
Rev. Pharmacol. Toxicol. 17:49, 1977, and references therein. for drugs such as penicillin and digoxin, which are elim-
inated primarily by the kidney.

[Link] changes in serum albumin may affect the Adverse Drug Effects
free drug concentration for a number of highly bound
drugs, such as phenytoin, warfarin, and meperidine. The incidence of iatrogenic complications is three to
five times greater in the elderly than in the general pop-
ulation. Adverse drug reactions account for 20 to 40%
Metabolism of these complications. Inappropriate drug use has been
In addition to changes in metabolism that occur as a re- noted in almost half of hospitalized elderly patients.
sult of reduced hepatic enzyme activity, metabolism One-fourth of these patients were receiving contraindi-
may be impaired by a reduction in hepatic mass, vol- cated drugs, and three-fourths were receiving unneces-
Hepatic Drug Metabolism

Birth Puberty Adulthood Elderly (65 yr)

FIGURE 6.1
The ontogeny of hepatic drug metabolic activity.
 6 Drug Metabolism and Disposition in Pediatric and Gerontological Stages of Life 61

sary drugs. Half of adverse drug reactions occur in pa- Reevaluate the continued use of all medications the
tients receiving inappropriate drugs. patient is receiving, including over-the-counter medica-
Delirium and cognitive impairment are common ad- tions, on a regular basis.
verse reactions in the elderly. While almost every class Noncompliance is a significant problem, with almost
of drugs has the potential to produce delirium in the 50% of elderly patients failing to take their medications
elderly, it is most frequent with psychoactive drugs. The as prescribed. Some of the reasons for noncompliance are
risk increases with the number of drugs the patient is re- inability to pay for the drug, side effects, mental impair-
ceiving, reaching a 14-fold increase in risk for patients ment, and inability to understand complex instructions.
taking more than 6 drugs.
SUMMARY
Physicians should exercise caution when prescribing
Special Considerations drugs for pediatric and geriatric patients. This is virtually
The following should be considered when prescribing axiomatic in premature infants, whose severely restricted
drugs for elderly patients. ability to metabolize drugs is well documented. Caution
Drugs should be prescribed only if nonpharmaco- also must be exerted in prescribing for the elderly popu-
logical techniques are ineffective, such as for problems lation, since these individuals may be taking 10 to 15 dif-
like sleeplessness and anxiety. When drugs are pre- ferent drugs daily. Problems associated with drug interac-
scribed for these conditions, they should be given for a tion and declining physiological function are very real. It
limited time and the patient closely monitored for ad- is simply inadequate to administer drugs to very young
verse effects. Dosage should start at or below the lowest and very old patients strictly on a body mass basis. Dose
recommended levels. adjustments often must be made empirically, depending
Keep it simple. Prescribe drugs only if you have upon the changing pharmacokinetic characteristics of the
available extensive experience and prescribing informa- drug in question, the nature of the disease, and the physi-
tion for that drug in elderly patients. Use the least num- ological status of the major organs and tissues involved in
ber of drugs and doses per day. drug absorption, distribution, metabolism, and excretion.

Study Questions

1. It is well established that most drugs taken by preg- (C) Increase in the levels of plasma proteins
nant women are capable of crossing the placenta (D) General increase in hepatic drug metabolizing
and reaching the developing fetus. The placenta it- capacity
self can aid in the protection of the fetus from exces- (E) Decrease in renal clearance of many drugs
sive exposure to drugs in the maternal circulation by 4. A neonate is given drug A, a compound with a high
(A) Impairing diffusion of lipid soluble drugs affinity for plasma proteins, in a dose that does not
(B) Preventing the passage of drugs having a mo- exceed the binding capacity of albumin. Later, a
lecular weight under 250 second drug, B, that also binds strongly to albumin,
(C) Playing a role as a site of drug metabolism is given in amounts that greatly exceed albumin’s
(D) Secreting drugs from the fetal circulation to binding capacity. Which of the following statements
the maternal circulation is most likely to be true?
2. Neonates having a patent ductus arteriosus can be (A) The free plasma concentration of drug A is de-
treated with which agent to induce a relatively rapid creased.
closure and thus often avoid surgical intervention? (B) The relative free drug concentration of both
(A) Phenobarbital compounds is unchanged.
(B) Indomethacin (C) The concentration of drug A in tissues is likely
(C) Hydrochlorothiazide to be increased.
(D) Prostaglandin E1 (D) The concentration of drug A in tissues is likely
(E) Epinephrine to be decreased.
3. Which of the following is an accurate description of (E) The free plasma concentration of drug B
changes taking place in elderly individuals com- would likely be markedly increased if drug A were
pared to younger adults? given second rather than first.
(A) Increased lean body mass 5. Mr. Johnson, a 70-year-old, has come into a physi-
(B) Diminished body fat as a relative percentage cian’s office complaining of not being able to sleep
of total body mass well at night because of residual pain associated
62 I GENERAL PRINCIPLES OF PHARMACOLOGY

with a recent hip replacement. He is taking a thi- its albumin binding site and lead to an increase in
azide diuretic (A) for mild hypertension, digitalis free drug. The latter is then available to be distrib-
(B) for congestive heart failure, and an oral hypo- uted outside the blood compartment and reach tis-
glycemic agent (C) for mild type 2 diabetes. An opi- sues where its concentrations will increase.
oid analgesic (D) that gave him considerable pain 5. D. The elderly are frequently sensitive to the pul-
relief when he broke his arm 30 years ago is pre- monary depressing actions of opioid analgesics.
scribed. About a week later Mr. Johnson is seen in These agents should be used with caution in the
the emergency department complaining of short- elderly until an adequate dosage has been deter-
ness of breath and a feeling of suffocation. Which of mined for a particular patient. This does not mean
the drugs he is receiving is a likely possible cause of that the older patient should not be given opioid
this particular symptom? analgesics for pain, however, since appropriate pain
management should always be part of any total
ANSWERS clinical treatment plan.
1. C. The placenta can serve as a site of metabolism
for some drugs passing through it. The placenta can SUPPLEMENTAL READING
carry out a number of drug metabolizing reactions, Avorn J and Gurwitz JH. Drug use in the nursing
including dealkylation and hydroxylation. Lipophilic home. Ann Intern Med 1995;123:195–204.
drugs readily diffuse across the placenta and enter Briggs GG, Freeman RK, and Yaffe SJ. Drugs in
the fetal circulation; drugs with a molecular weight Pregnancy and Lactation (5th ed.). Baltimore:
of under 500 generally can easily cross the placenta; Williams & Wilkins, 1998.
and no known active transport systems play any im- Hazzard WR et al. Principles of Geriatric Medicine and
portant role in drug secretion in the placenta. Gerontology (4th ed.). New York: McGraw-Hill,
2. B. Indomethacin’s action as a potent nonselective 1999.
COX inhibitor appears to be important in speeding Medical Letter. Some drugs that cause psychiatric
up ductus closure. The other drugs do not have such symptoms. 1998;40:21–24.
an action, and prostaglandin E1 given by infusion Nahata MC. Variability in clinical pharmacology of
would cause the ductus to remain open. drugs in children. J Clin Pharmacol Ther 1992;
3. E. The kidney, the most important organ involved 17:365–368.
in drug clearance, especially of highly water-soluble Rochon P and Gurwitz JH. Drug therapy. Lancet
drugs, shows an age-related decline in function. 1995;346:32–36.
Lean body mass decreases, percentage of body fat Rylace GW. Pharmacology. In Rennie JM and
increases, production of plasma proteins decrease, Roberton NRC (eds.). Textbook of Neonatology.
and drug metabolism decreases for most drugs as Edinburgh: Churchill Livingstone, 1999.
patients reach their seventh and eighth decade. Sastry BVR (ed). Placental Toxicology. Boca Baton,
4. C. The large amounts of drug B that are given can FL: CRC, 1995.
displace the almost completely bound drug A from

Case Study A Choice of Sedative

M rs. Jones celebrated her 71st birthday by

taking her grandchildren to the park. She fell
while pushing the merry-go-round and broke her
with active metabolites, such as diazepam, would
normally be expected to have a prolonged half-life.
The half-life would be even more prolonged in Mrs.
wrist. She has no pain now but is too uncomfortable Jones because of the increase in body fat and
with the cast to sleep well. She has tried soothing decreased renal excretion that are typical for
music, reading, and relaxing techniques but is still persons of her age. After several weeks of
unable to sleep. She has requested a sleeping pill. administration, daytime confusion may occur in this
Based on knowledge of psychotropic drugs in patient and may put her at risk for a fall and
elderly patients, what medication would be an another serious injury. A short-acting
appropriate choice? benzodiazepine with inactive metabolites, such as
oxazepam, could provide the desired effect with
ANSWER: Benzodiazepines are effective for short-
minimal adverse effects.
term use as sedative–hypnotics. Long-acting types