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Basic and Clinical Pharmacology > Chapter
59. Special Aspects of Perinatal & Pediatric Pharmacology >
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Special Aspects of Perinatal & Pediatric
Pharmacology: Introduction
The effects of drugs on the
fetus and newborn infant are based on the general principles set forth in
Chapters 1, 2, 3, and 4 of this book. However, the physiologic contexts
in which these pharmacologic laws operate are different in pregnant women
and in rapidly maturing infants. At present, the special pharmacokinetic
factors operative in these patients are beginning to be understood,
whereas information regarding pharmacodynamic differences (eg, receptor
characteristics and responses) is still incomplete.
*Supported by a grant from the
Canadian Institutes for Health Research.
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Drug Therapy in Pregnancy
Pharmacokinetics
Most drugs taken by pregnant
women can cross the placenta and expose the developing embryo and fetus
to their pharmacologic and teratogenic effects. Critical factors affecting
placental drug transfer and drug effects on the fetus include the
following: (1) the physicochemical properties of the drug; (2) the rate
at which the drug crosses the placenta and the amount of drug reaching
the fetus; (3) the duration of exposure to the drug; (4) distribution
characteristics in different fetal tissues; (5) the stage of placental
and fetal development at the time of exposure to the drug; and (6) the
effects of drugs used in combination.
Lipid Solubility
As is true also of other
biologic membranes, drug passage across the placenta is dependent on
lipid solubility and the degree of drug ionization. Lipophilic drugs tend
to diffuse readily across the placenta and enter the fetal circulation.
For example, thiopental, a drug commonly used for cesarean sections,
crosses the placenta almost immediately and can produce sedation or apnea
in the newborn infant. Highly ionized drugs such as succinylcholine and
tubocurarine, also used for cesarean sections, cross the placenta slowly
and achieve very low concentrations in the fetus. Impermeability of the
placenta to polar compounds is relative rather than absolute. If high
enough maternal-fetal concentration gradients are achieved, polar
compounds cross the placenta in measurable amounts. Salicylate, which is
almost completely ionized at physiologic pH, crosses the placenta
rapidly. This occurs because the small amount of salicylate that is not
ionized is highly lipid-soluble.
Molecular Size
The molecular weight of the drug
also influences the rate of transfer and the amount of drug transferred
across the placenta. Drugs with molecular weights of 250–500 can cross
the placenta easily, depending upon their lipid solubility and degree of
ionization; those with molecular weights of 500–1000 cross the placenta
with more difficulty; and those with molecular weights greater than 1000
cross very poorly. An important clinical application of this property is
the choice of heparin as an anticoagulant in pregnant women. Because it
is a very large (and polar) molecule, heparin is unable to cross the
placenta. Unlike warfarin, which is teratogenic and should be avoided
during the first trimester and even beyond (as the brain continues to
develop), heparin may be safely given to pregnant women who need
anticoagulation. Yet the placenta contains drug transporters, which can
carry larger molecules to the fetus. For example, a variety of maternal
antibodies cross the placenta and may cause fetal morbidity, as in Rh
incompatibility.
Placental Transporters
During the last decade, many
drug transporters have been identified in the placenta, with increasing
recognition of their effects on drug transfer to the fetus. For example,
the P-glycoprotein transporter encoded by the MDR1 gene pumps
back into the maternal circulation a variety of drugs, including cancer
drugs (eg, vinblastine, doxorubicin) and other agents. Similarly, viral
protease inhibitors, which are substrates to P-glycoprotein, achieve only
low fetal concentrations—an effect that may increase the risk of vertical
HIV infection from the mother to the fetus. The hypoglycemic drug
glyburide cannot be measured in umbilical blood despite therapeutic
maternal concentrations. Recent work has documented that this agent is
effluxed from the fetal circulation by the BCRP transporter as well as by
the MRP3 transporter located in the placental brush border membrane.
Protein Binding
The degree to which a drug is
bound to plasma proteins (particularly albumin) may also affect the rate
of transfer and the amount transferred. However, if a compound is very
lipid-soluble (eg, some anesthetic gases), it will not be affected
greatly by protein binding. Transfer of these more lipid-soluble drugs
and their overall rates of equilibration are more dependent on (and
proportionate to) placental blood flow. This is because very
lipid-soluble drugs diffuse across placental membranes so rapidly that
their overall rates of equilibration do not depend on the free drug
concentrations becoming equal on both sides. If a drug is poorly
lipid-soluble and is ionized, its transfer is slow and will probably be
impeded by its binding to maternal plasma proteins. Differential protein
binding is also important since some drugs exhibit greater protein
binding in maternal plasma than in fetal plasma because of a lower
binding affinity of fetal proteins. This has been shown for sulfonamides,
barbiturates, phenytoin, and local anesthetic agents.
Placental and Fetal Drug
Metabolism
Two mechanisms help protect the
fetus from drugs in the maternal circulation: (1) The placenta itself
plays a role both as a semipermeable barrier and as a site of metabolism
of some drugs passing through it. Several different types of aromatic
oxidation reactions (eg, hydroxylation, N-dealkylation,
demethylation) have been shown to occur in placental tissue.
Pentobarbital is oxidized in this way. Conversely, it is possible that
the metabolic capacity of the placenta may lead to creation of toxic
metabolites, and the placenta may therefore augment toxicity (eg,
ethanol, benzpyrenes). (2) Drugs that have crossed the placenta enter the
fetal circulation via the umbilical vein. About 40–60% of umbilical
venous blood flow enters the fetal liver; the remainder bypasses the
liver and enters the general fetal circulation. A drug that enters the
liver may be partially metabolized there before it enters the fetal
circulation. In addition, a large proportion of drug present in the
umbilical artery (returning to the placenta) may be shunted through the
placenta back to the umbilical vein and into the liver again. It should
be noted that metabolites of some drugs may be more active than the
parent compound and may affect the fetus adversely.
Pharmacodynamics
Maternal Drug Actions
The effects of drugs on the
reproductive tissues (breast, uterus, etc) of the pregnant woman are
sometimes altered by the endocrine environment appropriate for the stage
of pregnancy. Drug effects on other maternal tissues (heart, lungs,
kidneys, central nervous system, etc) are not changed significantly by
pregnancy, although the physiologic context (cardiac output, renal blood
flow, etc) may be altered, requiring the use of drugs that are not needed
by the same woman when she is not pregnant. For example, cardiac
glycosides and diuretics may be needed for heart failure precipitated by
the increased cardiac workload of pregnancy, or insulin may be required
for control of blood glucose in pregnancy-induced diabetes.
Therapeutic Drug Actions in the
Fetus
Fetal therapeutics is an
emerging area in perinatal pharmacology. This involves drug
administration to the pregnant woman with the fetus as the target of the
drug. At present, corticosteroids are used to stimulate fetal lung
maturation when preterm birth is expected. Phenobarbital, when given to
pregnant women near term, can induce fetal hepatic enzymes responsible
for the glucuronidation of bilirubin, and the incidence of jaundice is
lower in newborns when mothers are given phenobarbital than when
phenobarbital is not used. Before phototherapy became the preferred mode
of therapy for neonatal indirect hyperbilirubinemia, phenobarbital was
used for this indication. Administration of phenobarbital to the mother
was suggested recently as a means of decreasing the risk of intracranial
bleeding in preterm infants. However, large randomized studies failed to
confirm this effect. Antiarrhythmic drugs have also been given to mothers
for treatment of fetal cardiac arrhythmias. Although their efficacy has
not yet been established by controlled studies, digoxin, flecainide, procainamide,
verapamil, and other antiarrhythmic agents have been shown to be
effective in case series. During the last two decades it has been shown
that maternal use of zidovudine decreases by two thirds transmission of
HIV from the mother to the fetus, and use of combinations of three
antiretroviral agents can eliminate fetal infection almost entirely (see
Chapter 49).
Predictable Toxic Drug Actions
in the Fetus
Chronic use of opioids by the
mother may produce dependence in the fetus and newborn. This dependence
may be manifested after delivery as a neonatalwithdrawal syndrome. A less
well understood fetal drug toxicity is caused by the use of
angiotensin-converting enzyme inhibitors during pregnancy. These drugs
can result in significant and irreversible renal damage in the fetus and
are therefore contraindicated in pregnant women. Adverse effects may also
be delayed, as in the case of female fetuses exposed to
diethylstilbestrol, who may be at increased risk for adenocarcinoma of
the vagina after puberty.
Teratogenic Drug Actions
A single intrauterine exposure
to a drug can affect the fetal structures undergoing rapid development at
the time of exposure. Thalidomide is an example of a drug that may
profoundly affect the development of the limbs after only brief exposure.
This exposure, however, must be at a critical time in the development of
the limbs. The thalidomide phocomelia risk occurs during the fourth
through the seventh weeks of gestation because it is during this time
that the arms and legs develop (Figure 59–1).
Teratogenic Mechanisms
The mechanisms by which
different drugs produce teratogenic effects are poorly understood and are
probably multifactorial. For example, drugs may have a direct effect on
maternal tissues with secondary or indirect effects on fetal tissues.
Drugs may interfere with the passage of oxygen or nutrients through the
placenta and therefore have effects on the most rapidly metabolizing
tissues of the fetus. Finally, drugs may have important direct actions on
the processes of differentiation in developing tissues. For example,
vitamin A (retinol) has been shown to have important
differentiation-directing actions in normal tissues. Several vitamin A
analogs (isotretinoin, etretinate) are powerful teratogens, suggesting
that they alter the normal processes of differentiation. Finally,
deficiency of a critical substance appears to play a role in some types
of abnormalities. For example, folic acid supplementation during
pregnancy appears to reduce the incidence of neural tube defects (eg,
spina bifida).
Continued exposure to a
teratogen may produce cumulative effects or may affect several organs
going through varying stages of development. Chronic consumption of high
doses of ethanol during pregnancy, particularly during the first and
second trimesters, may result in the fetal alcohol syndrome (see Chapter
23). In this syndrome, the central nervous system, growth, and facial
development may be affected.
Defining a Teratogen
To be considered teratogenic, a
candidate substance or process should (1) result in a characteristic set
of malformations, indicating selectivity for certain target organs; (2)
exert its effects at a particular stage of fetal development, eg, during
the limited time period of organogenesis of the target organs (Figure
59–1); and (3) show a dose-dependent incidence. Some drugs with known
teratogenic or other adverse effects in pregnancy are listed in Table
59–1. Teratogenic effects are not limited only to major malformations,
but also include intrauterine growth restriction (eg, cigarette smoking),
miscarriage (eg, alcohol), stillbirth (eg, cigarette smoke), and
neurocognitive delay (eg, alcohol).
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Table 59–1 Drugs with
Significant Teratogenic or Other Adverse Effects on the Fetus.
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Drug
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Trimester
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Effect
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ACE
inhibitors
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All,
especially second and third
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Renal
damage
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Aminopterin
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First
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Multiple
gross anomalies
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Amphetamines
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All
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Suspected
abnormal developmental patterns, decreased school performance
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Androgens
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Second and
third
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Masculinization
of female fetus
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Antidepressants,
tricyclic
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Third
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Neonatal
withdrawal symptoms have been reported in a few cases with
clomipramine, desipramine, and imipramine
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Barbiturates
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All
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Chronic use
can lead to neonatal dependence.
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Busulfan
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All
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Various
congenital malformations; low birth weight
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Carbamazepine
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First
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Neural tube
defects
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Chlorpropamide
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All
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Prolonged
symptomatic neonatal hypoglycemia
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Clomipramine
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Third
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Neonatal
lethargy, hypotonia, cyanosis, hypothermia
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Cocaine
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All
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Increased
risk of spontaneous abortion, abruptio placentae, and premature
labor; neonatal cerebral infarction, abnormal development, and
decreased school performance
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Cyclophosphamide
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First
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Various
congenital malformations
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Cytarabine
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First,
second
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Various
congenital malformations
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Diazepam
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All
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Chronic use
may lead to neonatal dependence
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Diethylstilbestrol
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All
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Vaginal
adenosis, clear cell vaginal adenocarcinoma
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Ethanol
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All
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Risk of
fetal alcohol syndrome and alcohol-related neurodevelopmental defects
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Etretinate
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All
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High risk
of multiple congenital malformations
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Heroin
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All
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Chronic use
leads to neonatal dependence
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Iodide
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All
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Congenital
goiter, hypothyroidism
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Isotretinoin
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All
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Extremely
high risk of CNS, face, ear, and other malformations
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Lithium
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First
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Ebstein's
anomaly
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Methadone
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All
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Chronic use
leads to neonatal dependence
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Methotrexate
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First
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Multiple
congenital malformations
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Methylthiouracil
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All
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Hypothyroidism
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Metronidazole
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First
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May be
mutagenic (from animal studies; there is no evidence for mutagenic or
teratogenic effects in humans)
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Misoprostol
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First
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Möbius
sequence
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Mycophenolate
mofetil
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First
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Major
malformations of the face, limbs, and other organs
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Organic
solvents
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First
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Multiple
malformations
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Penicillamine
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First
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Cutis laxa,
other congenital malformations
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Phencyclidine
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All
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Abnormal
neurologic examination, poor suck reflex and feeding
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Phenytoin
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All
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Fetal
hydantoin syndrome
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Propylthiouracil
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All
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Congenital
goiter
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Smoking
(constituents of tobacco smoke)
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All
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Intrauterine
growth retardation; prematurity; sudden infant death syndrome;
perinatal complications
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Streptomycin
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All
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Eighth
nerve toxicity
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Tamoxifen
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All
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Increased
risk of spontaneous abortion or fetal damage
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Tetracycline
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All
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Discoloration
and defects of teeth and altered bone growth
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Thalidomide
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First
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Phocomelia
(shortened or absent long bones of the limbs) and many internal
malformations
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Trimethadione
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All
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Multiple
congenital anomalies
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Valproic
acid
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All
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Neural tube
defects, cardiac and limb malformations
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Warfarin
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First
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Hypoplastic
nasal bridge, chondrodysplasia
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Second
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CNS
malformations
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Third
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Risk of
bleeding. Discontinue use 1 month before delivery.
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The widely cited FDA system for
teratogenic potential (Table 59–2) is an attempt to quantify teratogenic
risk from A (safe) to X (definite human teratogenic risk). This system
has been criticized as inaccurate and impractical. For example, several
drugs have been labeled "X" despite extensive opposite human
safety data (eg, oral contraceptives). Diazepam and other benzodiazepines
are labeled as "D" despite lack of positive evidence of human
fetal risk. Presently the FDA is changing its system from the A, B, C
grading system to narrative statements that will summarize evidence-based
knowledge about each drug in terms of fetal risk and safety.
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Table 59–2 FDA Teratogenic
Risk Categories.
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Category
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Description
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A
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Controlled
studies in women fail to demonstrate a risk to the fetus in the first
trimester (and there is no evidence of a risk in late trimesters),
and the possibility of fetal harm appears remote.
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B
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Either
animal-reproduction studies have not demonstrated a fetal risk, but
there are no controlled studies in pregnant women, or
animal-reproduction studies have shown an adverse effect (other than
a decrease in fertility) that was not confirmed in controlled studies
in women in the first trimester (and there is no evidence of a risk
in later trimesters).
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C
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Either
studies in animals have revealed adverse effects on the fetus (teratogenic
or embryocidal or other) and there are no controlled studies in women
or studies in women and animals are not available. Drugs should be
given only if the potential benefit justifies the potential risk to
the fetus.
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D
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There is
positive evidence of human fetal risk, but the benefits from use in
pregnant women may be acceptable despite the risk (eg, if the drug is
needed in a life-threatening situation or for a serious disease for
which safer drugs cannot be used or are ineffective).
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X
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Studies in
animals or human beings have demonstrated fetal abnormalities or
there is evidence of fetal risk based on human experience or both,
and the risk of the use of the drug in pregnant women clearly
outweighs any possible benefit. The drug is contraindicated in women
who are or may become pregnant.
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Counseling Women About
Teratogenic Risk
Since the thalidomide disaster,
medicine has been practiced as if every drug were a potential human teratogen
when, in fact, fewer than 30 such drugs have been identified, with
hundreds of agents proved safe for the unborn. Owing to high levels of
anxiety among pregnant women—and because half of the pregnancies in North
America are unplanned—every year many thousands of women need counseling
about fetal exposure to drugs, chemicals, and radiation. In the Motherisk
program in Toronto, thousands of women are counseled every month, and the
ability of appropriate counseling to prevent unnecessary abortions has
been documented. Clinicians who wish to provide such counsel to pregnant
women must ensure that their information is up-to-date and evidence-based
and that the woman understands that the baseline teratogenic risk in
pregnancy (ie, the risk of a neonatal abnormality in the absence of any
known teratogenic exposure) is about 3%. It is also critical to address
the maternal-fetal risks of the untreated condition if a medication is
avoided. Recent studies show serious morbidity in women who discontinued
selective serotonin reuptake inhibitor therapy for depression in
pregnancy.
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Drug Therapy in Infants & Children
Physiologic processes that
influence pharmacokinetic variables in the infant change significantly in
the first year of life, particularly during the first few months.
Therefore, special attention must be paid to pharmacokinetics in this age
group. Pharmacodynamic differences between pediatric and other patients
have not been explored in great detail and are probably small except for
those specific target tissues that mature at birth or immediately
thereafter (eg, the ductus arteriosus).
Drug Absorption
Drug absorption in infants and
children follows the same general principles as in adults. Unique factors
that influence drug absorption include blood flow at the site of
administration, as determined by the physiologic status of the infant or
child; and, for orally administered drugs, gastrointestinal function,
which changes rapidly during the first few days after birth. Age after
birth also influences the regulation of drug absorption.
Blood Flow at the Site of
Administration
Absorption after intramuscular
or subcutaneous injection depends mainly, in neonates as in adults, on
the rate of blood flow to the muscle or subcutaneous area injected.
Physiologic conditions that might reduce blood flow to these areas are
cardiovascular shock, vasoconstriction due to sympathomimetic agents, and
heart failure. However, sick preterm infants requiring intramuscular injections
may have very little muscle mass. This is further complicated by
diminished peripheral perfusion to these areas. In such cases, absorption
becomes irregular and difficult to predict, because the drug may remain
in the muscle and be absorbed more slowly than expected. If perfusion
suddenly improves, there can be a sudden and unpredictable increase in
the amount of drug entering the circulation, resulting in high and
potentially toxic concentrations of drug. Examples of drugs especially
hazardous in such situations are cardiac glycosides, aminoglycoside
antibiotics, and anticonvulsants.
Gastrointestinal Function
Significant biochemical and
physiologic changes occur in the neonatal gastrointestinal tract shortly
after birth. In full-term infants, gastric acid secretion begins soon
after birth and increases gradually over several hours. In preterm
infants, the secretion of gastric acid occurs more slowly, with the
highest concentrations appearing on the fourth day of life. Therefore,
drugs that are partially or totally inactivated by the low pH of gastric
contents should not be administered orally.
Gastric emptying time is
prolonged (up to 6 or 8 hours) in the first day or so after delivery.
Therefore, drugs that are absorbed primarily in the stomach may be
absorbed more completely than anticipated. In the case of drugs absorbed
in the small intestine, therapeutic effect may be delayed. Peristalsis in
the neonate is irregular and may be slow. The amount of drug absorbed in
the small intestine may therefore be unpredictable; more than the usual
amount of drug may be absorbed if peristalsis is slowed, and this could
result in potential toxicity from an otherwise standard dose. Table 59–3
summarizes data on oral bioavailability of various drugs in neonates compared
with older children and adults. An increase in peristalsis, as in
diarrheal conditions, tends to decrease the extent of absorption, because
contact time with the large absorptive surface of the intestine is
decreased.
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Table 59–3 Oral Drug Absorption
(Bioavailability) of Various Drugs in the Neonate Compared with Older
Children and Adults.
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Drug
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Oral
Absorption
|
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Acetaminophen
|
Decreased
|
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Ampicillin
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Increased
|
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Diazepam
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Normal
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Digoxin
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Normal
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Penicillin
G
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Increased
|
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Phenobarbital
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Decreased
|
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Phenytoin
|
Decreased
|
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Sulfonamides
|
Normal
|
|
|
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Gastrointestinal enzyme
activities tend to be lower in the newborn than in the adult. Activities
of  -amylase and other pancreatic enzymes
in the duodenum are low in infants up to 4 months of age. Neonates also
have low concentrations of bile acids and lipase, which may decrease the
absorption of lipid-soluble drugs.
Drug Distribution
As body composition changes with
development, the distribution volumes of drugs are also changed. The
neonate has a higher percentage of its body weight in the form of water
(70–75%) than does the adult (50–60%). Differences can also be observed
between the full-term neonate (70% of body weight as water) and the small
preterm neonate (85% of body weight as water). Similarly, extracellular
water is 40% of body weight in the neonate, compared with 20% in the
adult. Most neonates will experience diuresis in the first 24–48 hours of
life. Since many drugs are distributed throughout the extracellular water
space, the size (volume) of the extracellular water compartment may be important
in determining the concentration of drug at receptor sites. This is
especially important for water-soluble drugs (such as aminoglycosides)
and less crucial for lipid-soluble agents.
Preterm infants have much less
fat than full-term infants. Total body fat in preterm infants is about 1%
of total body weight, compared with 15% in full-term neonates. Therefore,
organs that generally accumulate high concentrations of lipid-soluble
drugs in adults and older children may accumulate smaller amounts of these
agents in less mature infants.
Another major factor determining
drug distribution is drug binding to plasma proteins. Albumin is the
plasma protein with the greatest binding capacity. In general, protein
binding of drugs is reduced in the neonate. This has been seen with local
anesthetic drugs, diazepam, phenytoin, ampicillin, and phenobarbital.
Therefore, the concentration of free (unbound) drug in plasma is
increased initially. Because the free drug exerts the pharmacologic
effect, this can result in greater drug effect or toxicity despite a
normal or even low plasma concentration of total drug (bound plus
unbound). Consider a therapeutic dose of a drug (eg, diazepam) given to a
patient. The concentration of total drug in the plasma is 300 mcg/L. If
the drug is 98% protein-bound in an older child or adult, then 6 mcg/L is
the concentration of free drug. Assume that this concentration of free
drug produces the desired effect in the patient without producing
toxicity. However, if this drug is given to a preterm infant in a dosage
adjusted for body weight and it produces a total drug concentration of
300 mcg/L—and protein binding is only 90%—then the free drug
concentration will be 30 mcg/L, or five times higher. Although the higher
free concentration may result in faster elimination (see Chapter 3), this
concentration may be quite toxic initially.
Some drugs compete with serum
bilirubin for binding to albumin. Drugs given to a neonate with jaundice
can displace bilirubin from albumin. Because of the greater permeability
of the neonatal blood-brain barrier, substantial amounts of bilirubin may
enter the brain and cause kernicterus. This was in fact observed when
sulfonamide antibiotics were given to preterm neonates as prophylaxis
against sepsis. Conversely, as the serum bilirubin rises for physiologic
reasons or because of a blood group incompatibility, bilirubin can
displace a drug from albumin and substantially raise the free drug
concentration. This may occur without altering the total drug
concentration and would result in greater therapeutic effect or toxicity
at normal concentrations. This has been shown to happen with phenytoin.
Drug Metabolism
The metabolism of most drugs
occurs in the liver (see Chapter 4). The drug-metabolizing activities of
the cytochrome P450-dependent mixed-function oxidases and the conjugating
enzymes are substantially lower (50–70% of adult values) in early
neonatal life than later. The point in development at which enzymatic
activity is maximal depends upon the specific enzyme system in question.
Glucuronide formation reaches adult values (per kilogram body weight)
between the third and fourth years of life. Because of the neonate's
decreased ability to metabolize drugs, many drugs have slow clearance
rates and prolonged elimination half-lives. If drug doses and dosing
schedules are not altered appropriately, this immaturity predisposes the
neonate to adverse effects from drugs that are metabolized by the liver.
Table 59–4 demonstrates how neonatal and adult drug elimination half-lives
can differ and how the half-lives of phenobarbital and phenytoin decrease
as the neonate grows older. The process of maturation must be considered
when administering drugs to this age group, especially in the case of
drugs administered over long periods.
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Table 59–4 Comparison of
Elimination Half-Lives of Various Drugs in Neonates and Adults.
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Drug
|
Neonatal Age
|
Neonates t1/2
(hours)
|
Adults t1/2
(hours)
|
|
Acetaminophen
|
|
2.2–5
|
0.9–2.2
|
|
Diazepam
|
|
25–100
|
40–50
|
|
Digoxin
|
|
60–70
|
30–60
|
|
Phenobarbital
|
0–5 days
|
200
|
64–140
|
|
|
5–15 days
|
100
|
|
|
|
1–30 months
|
50
|
|
|
Phenytoin
|
0–2 days
|
80
|
12–18
|
|
|
3–14 days
|
18
|
|
|
|
14–50 days
|
6
|
|
|
Salicylate
|
|
4.5–11
|
10–15
|
|
Theophylline
|
Neonate
|
13–26
|
5–10
|
|
|
Child
|
3–4
|
|
|
|
|
Another consideration for the
neonate is whether or not the mother was receiving drugs (eg,
phenobarbital) that can induce early maturation of fetal hepatic enzymes.
In this case, the ability of the neonate to metabolize certain drugs will
be greater than expected, and one may see less therapeutic effect and
lower plasma drug concentrations when the usual neonatal dose is given.
During toddlerhood (12–36 months), the metabolic rate of many drugs
exceeds adult values, often necessitating larger doses per kilogram than
later in life.
Drug Excretion
The glomerular filtration rate
is much lower in newborns than in older infants, children, or adults, and
this limitation persists during the first few days of life. Calculated on
the basis of body surface area, glomerular filtration in the neonate is
only 30–40% of the adult value. The glomerular filtration rate is even
lower in neonates born before 34 weeks of gestation. Function improves
substantially during the first week of life. At the end of the first
week, the glomerular filtration rate and renal plasma flow have increased
50% from the first day. By the end of the third week, glomerular
filtration is 50–60% of the adult value; by 6–12 months, it reaches adult
values (per unit surface area). Subsequently, during toddlerhood, it
exceeds adult values, often necessitating larger doses per kilogram than
in adults, as described previously for drug-metabolic rate. Therefore,
drugs that depend on renal function for elimination are cleared from the
body very slowly in the first weeks of life.
Penicillins, for example, are
cleared by preterm infants at 17% of the adult rate based on comparable
surface area and 34% of the adult rate when adjusted for body weight. The
dosage of ampicillin for a neonate less than 7 days old is 50–100 mg/kg/d
in two doses at 12-hour intervals. The dosage for a neonate over 7 days
old is 100–200 mg/kg/d in three doses at 8-hour intervals. A decreased
rate of renal elimination in the neonate has also been observed with
aminoglycoside antibiotics (kanamycin, gentamicin, neomycin, and
streptomycin). The dosage of gentamicin for a neonate less than 7 days
old is 5 mg/kg/d in two doses at 12-hour intervals. The dosage for a
neonate over 7 days old is 7.5 mg/kg/d in three doses at 8-hour
intervals. Total body clearance of digoxin is directly dependent upon
adequate renal function, and accumulation of digoxin can occur when
glomerular filtration is decreased. Since renal function in a sick infant
may not improve at the predicted rate during the first weeks and months
of life, appropriate adjustments in dosage and dosing schedules may be
very difficult. In this situation, adjustments are best made on the basis
of plasma drug concentrations determined at intervals throughout the
course of therapy.
Although great focus is
naturally concentrated on the neonate, it is important to remember that
toddlers may have shorter elimination half-lives of drugs than
older children and adults, due probably to increased renal
elimination and metabolism. For example, the dose per kilogram of digoxin
is much higher in toddlers than in adults. The mechanisms for these
developmental changes are still poorly understood.
Special Pharmacodynamic
Features in the Neonate
The appropriate use of drugs has
made possible the survival of neonates with severe abnormalities who
would otherwise die within days or weeks after birth. For example,
administration of indomethacin (see Chapter 35) causes the rapid closure
of a patent ductus arteriosus, which would otherwise require surgical
closure in an infant with a normal heart. Infusion of prostaglandin E1,
on the other hand, causes the ductus to remain open, which can be
lifesaving in an infant with transposition of the great vessels or
tetralogy of Fallot (see Chapter 18). An unexpected effect of such
infusion has been described. The drug caused antral hyperplasia with
gastric outlet obstruction as a clinical manifestation in 6 of 74 infants
who received it. This phenomenon appears to be dose-dependent. Neonates
are also more sensitive to the central depressant effects of opioids than
are older children and adults, necessitating extra caution when they are
exposed to some narcotics (eg, codeine) through breast milk.
|
|
Pediatric Dosage Forms & Compliance
The form in which a drug is
manufactured and the way in which the parent dispenses the drug to the
child determine the actual dose administered. Many drugs prepared for
children are in the form of elixirs or suspensions. Elixirs are
alcoholic solutions in which the drug molecules are dissolved and evenly
distributed. No shaking is required, and unless some of the vehicle has
evaporated, the first dose from the bottle and the last dose should
contain equivalent amounts of drug. Suspensions contain
undissolved particles of drug that must be distributed throughout the
vehicle by shaking. If shaking is not thorough each time a dose is given,
the first doses from the bottle may contain less drug than the last
doses, with the result that less than the expected plasma concentration
or effect of the drug may be achieved early in the course of therapy.
Conversely, toxicity may occur late in the course of therapy, when it is
not expected. This uneven distribution is a potential cause of inefficacy
or toxicity in children taking phenytoin suspensions. It is thus
essential that the prescriber know the form in which the drug will be
dispensed and provide proper instructions to the pharmacist and patient
or parent.
Compliance may be more difficult
to achieve in pediatric practice than otherwise, since it involves not
only the parent's conscientious effort to follow directions but also such
practical matters as measuring errors, spilling, and spitting out. For
example, the measured volume of "teaspoons" ranges from 2.5 to
7.8 mL. The parents should obtain a calibrated medicine spoon or syringe
from the pharmacy. These devices improve the accuracy of dose
measurements and simplify administration of drugs to children.
When evaluating compliance, it
is often helpful to ask if an attempt has been made to give a further
dose after the child has spilled half of what was offered. The parents
may not always be able to say with confidence how much of a dose the
child actually received. The parents must be told whether or not to wake
the infant for its every-6-hour dose day or night. These matters should
be discussed and made clear, and no assumptions should be made about what
the parents may or may not do. Noncompliance frequently occurs when
antibiotics are prescribed to treat otitis media or urinary tract
infections and the child feels well after 4 or 5 days of therapy. The
parents may not feel there is any reason to continue giving the medicine
even though it was prescribed for 10 or 14 days. This common situation
should be anticipated so the parents can be told why it is important to
continue giving the medicine for the prescribed period even if the child
seems to be "cured."
Practical and convenient dosage
forms and dosing schedules should be chosen to the extent possible. The
easier it is to administer and take the medicine and the easier the
dosing schedule is to follow, the more likely it is that compliance will
be achieved.
Consistent with their ability to
comprehend and cooperate, children should also be given some
responsibility for their own health care and for taking medications. This
should be discussed in appropriate terms both with the child and with the
parents. Possible adverse effects and drug interactions with
over-the-counter medicines or foods should also be discussed. Whenever a
drug does not achieve its therapeutic effect, the possibility of
noncompliance should be considered. There is ample evidence that in such
cases parents' or children's reports may be grossly inaccurate. Random
pill counts and measurement of serum concentrations may help disclose
noncompliance. The use of computerized pill containers, which record each
lid opening, has been shown to be very effective in measuring compliance.
Because many pediatric doses are
calculated—eg, using body weight—rather than simply read from a list,
major dosing errors may result from incorrect calculations. Typically,
tenfold errors due to incorrect placement of the decimal point have been
described. In the case of digoxin, for example, an intended dose of 0.1
mL containing 5 mcg of drug, when replaced by 1.0 mL—which is still a
small volume—can result in fatal overdosage. A good rule for avoiding
such "decimal point" errors is to use a leading "0"
plus decimal point when dealing with doses less than "1" and to
avoid using a zero after a decimal point (see Chapter 65).
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|
Drug Use during Lactation
Despite the fact that most drugs
are excreted into breast milk in amounts too small to adversely affect
neonatal health, thousands of women taking medications do not breast-feed
because of misperception of risk. Unfortunately, physicians contribute
heavily to this bias. It is important to remember that formula feeding is
associated with higher morbidity and mortality in all socioeconomic
groups.
Most drugs administered to
lactating women are detectable in breast milk. Fortunately, the
concentration of drugs achieved in breast milk is usually low (Table
59–5). Therefore, the total amount the infant would receive in a day is
substantially less than what would be considered a "therapeutic
dose." If the nursing mother must take medications and the drug is a
relatively safe one, she should optimally take it 30–60 minutes after
nursing and 3–4 hours before the next feeding. This allows time for many
drugs to be cleared from the mother's blood, and the concentrations in
breast milk will be relatively low. Drugs for which no data are available
on safety during lactation should be avoided or breast-feeding
discontinued while they are being given.
|
Table 59–5 Drugs Often Used
during Lactation and Possible Effects on the Nursing Infant.
|
|
|
Drug
|
Effect on
Infant
|
Comments
|
|
Ampicillin
|
Minimal
|
No
significant adverse effects; possible occurrence of diarrhea or
allergic sensitization.
|
|
Aspirin
|
Minimal
|
Occasional
doses probably safe; high doses may produce significant concentration
in breast milk.
|
|
Caffeine
|
Minimal
|
Caffeine
intake in moderation is safe; concentration in breast milk is low.
|
|
Chloral
hydrate
|
Significant
|
May cause
drowsiness if infant is fed at peak concentration in milk.
|
|
Chloramphenicol
|
Significant
|
Concentrations
too low to cause gray baby syndrome; possibility of bone marrow suppression
does exist; recommend not taking chloramphenicol while
breast-feeding.
|
|
Chlorothiazide
|
Minimal
|
No adverse
effects reported.
|
|
Chlorpromazine
|
Minimal
|
Appears
insignificant.
|
|
Codeine
|
Minimal
|
Safe in
most cases. Neonatal toxicity described when the mother is an ultra
rapid 2D6 metabolizer, producing substantially more morphine from
codeine.
|
|
Diazepam
|
Significant
|
Will cause
sedation in breast-fed infants; accumulation can occur in newborns.
|
|
Dicumarol
|
Minimal
|
No adverse side
effects reported; may wish to follow infant's prothrombin time.
|
|
Digoxin
|
Minimal
|
Insignificant
quantities enter breast milk.
|
|
Ethanol
|
Moderate
|
Moderate
ingestion by mother unlikely to produce effects in infant; large
amounts consumed by mother can produce alcohol effects in infant.
|
|
Heroin
|
Significant
|
Enters
breast milk and can prolong neonatal narcotic dependence.
|
|
Iodine
(radioactive)
|
Significant
|
Enters milk
in quantities sufficient to cause thyroid suppression in infant.
|
|
Isoniazid
(INH)
|
Minimal
|
Milk
concentrations equal maternal plasma concentrations. Possibility of
pyridoxine deficiency developing in the infant.
|
|
Kanamycin
|
Minimal
|
No adverse
effects reported.
|
|
Lithium
|
Significant
|
Mother
should avoid breast-feeding unless levels can be measured.
|
|
Methadone
|
Significant
|
(See
heroin.) Under close physician supervision, breast-feeding can be
continued. Signs of opioid withdrawal in the infant may occur if
mother stops taking methadone or stops breast-feeding abruptly.
|
|
Oral
contraceptives
|
Minimal
|
May
suppress lactation in high doses.
|
|
Penicillin
|
Minimal
|
Very low
concentrations in breast milk.
|
|
Phenobarbital
|
Moderate
|
Hypnotic
doses can cause sedation in the infant.
|
|
Phenytoin
|
Moderate
|
Amounts
entering breast milk are not sufficient to cause adverse effects in
infant.
|
|
Prednisone
|
Moderate
|
Low
maternal doses (5 mg/d) probably safe. Doses 2 or more times physiologic
amounts (> 15 mg/d) should probably be avoided.
|
|
Propranolol
|
Minimal
|
Very small
amounts enter breast milk.
|
|
Propylthiouracil
|
Significant
|
Can
suppress thyroid function in infant.
|
|
Spironolactone
|
Minimal
|
Very small
amounts enter breast milk.
|
|
Tetracycline
|
Moderate
|
Possibility
of permanent staining of developing teeth in the infant. Should be
avoided during lactation.
|
|
Theophylline
|
Moderate
|
Can enter
breast milk in moderate quantities but not likely to produce
significant effects.
|
|
Thyroxine
|
Minimal
|
No adverse
effects in therapeutic doses.
|
|
Tolbutamide
|
Minimal
|
Low
concentrations in breast milk.
|
|
Warfarin
|
Minimal
|
Very small
quantities found in breast milk.
|
|
|
|
Most antibiotics taken by
nursing mothers can be detected in breast milk. Tetracycline
concentrations in breast milk are approximately 70% of maternal serum
concentrations and present a risk of permanent tooth staining in the
infant. Isoniazid rapidly reaches equilibrium between breast milk and
maternal blood. The concentrations achieved in breast milk are high
enough so that signs of pyridoxine deficiency may occur in the infant if
the mother is not given pyridoxine supplements.
Most sedatives and hypnotics
achieve concentrations in breast milk sufficient to produce a
pharmacologic effect in some infants. Barbiturates taken in hypnotic
doses by the mother can produce lethargy, sedation, and poor suck
reflexes in the infant. Chloral hydrate can produce sedation if the
infant is fed at peak milk concentrations. Diazepam can have a sedative
effect on the nursing infant, but, most importantly, its long half-life
can result in significant drug accumulation.
Opioids such as heroin,
methadone, and morphine enter breast milk in quantities potentially
sufficient to prolong the state of neonatal narcotic dependence if the
drug was taken chronically by the mother during pregnancy. If conditions
are well controlled and there is a good relationship between the mother
and the physician, an infant could be breast-fed while the mother is
taking methadone. She should not, however, stop taking the drug abruptly;
the infant can be tapered off the methadone as the mother's dose is
tapered. The infant should be watched for signs of narcotic withdrawal.
Although codeine has been believed to be safe, a recent case of neonatal
death from opioid toxicity revealed that the mother was an ultra rapid
metabolizer of cytochrome 2D6 substrates, producing substantially higher
amounts of morphine. Hence, polymorphism in maternal drug metabolism may
affect neonatal exposure and safety. A subsequent case control study has
shown that this situation is not rare. The FDA has published a warning to
lactating mothers to exert extra caution while using painkillers
containing codeine.
Minimal use of alcohol by the
mother has not been reported to harm nursing infants. Excessive amounts
of alcohol, however, can produce alcohol effects in the infant. Nicotine
concentrations in the breast milk of smoking mothers are low and do not
produce effects in the infant. Very small amounts of caffeine are
excreted in the breast milk of coffee-drinking mothers.
Lithium enters breast milk in
concentrations equal to those in maternal serum. Clearance of this drug
is almost completely dependent upon renal elimination, and women who are
receiving lithium may expose the infant to relatively large amounts of
the drug.
Radioactive substances such as
iodinated 125I albumin and radioiodine can cause thyroid
suppression in infants and may increase the risk of subsequent thyroid
cancer as much as tenfold. Breast-feeding is contraindicated after large
doses and should be withheld for days to weeks after small doses. Similarly,
breast-feeding should be avoided in mothers receiving cancer chemotherapy
or being treated with cytotoxic or immunomodulating agents for collagen
diseases such as lupus erythematosus or after organ transplantation.
|
|
Pediatric Drug Dosage
Because of differences in
pharmacokinetics in infants and children, simple proportionate reduction
in the adult dose may not be adequate to determine a safe and effective
pediatric dose. The most reliable pediatric dose information is usually
that provided by the manufacturer in the package insert. However, such
information is not available for the majority of products, even when
studies have been published in the medical literature, reflecting the
reluctance of manufacturers to label their products for children.
Recently, the FDA has moved toward more explicit expectations that
manufacturers test their new products in infants and children. Still,
most drugs in the common formularies, eg, Physicians' Desk Reference,
are not specifically approved for children, in part because manufacturers
often lack the economic incentive to evaluate drugs for use in the
pediatric market.
Most drugs approved for use in
children have recommended pediatric doses, generally stated as milligrams
per kilogram or per pound. In the absence of explicit pediatric dose
recommendations, an approximation can be made by any of several methods
based on age, weight, or surface area. These rules are not precise and
should not be used if the manufacturer provides a pediatric dose. When
pediatric doses are calculated (either from one of the methods set forth
below or from a manufacturer's dose), the pediatric dose should never
exceed the adult dose.
Surface Area, Age, & Weight
Calculations of dosage based on
age or weight (see below) are conservative and tend to underestimate the
required dose. Doses based on surface area (Table 59–6) are more likely
to be adequate.
|
Table 59–6 Determination of
Drug Dosage from Surface Area.1
|
|
|
Weight
|
Approximate
Age
|
Surface Area
(m2)
|
Percent of
Adult Dose
|
|
(kg)
|
(lb)
|
|
3
|
6.6
|
Newborn
|
0.2
|
12
|
|
6
|
13.2
|
3 months
|
0.3
|
18
|
|
10
|
22
|
1 year
|
0.45
|
28
|
|
20
|
44
|
5.5 year
|
0.8
|
48
|
|
30
|
66
|
9 years
|
1
|
60
|
|
40
|
88
|
12 years
|
1.3
|
78
|
|
50
|
110
|
14 years
|
1.5
|
90
|
|
60
|
132
|
Adult
|
1.7
|
102
|
|
70
|
154
|
Adult
|
1.76
|
103
|
|
|
1For example, if adult dose is 1 mg/kg, dose for
3-month-old infant would be 0.18 mg/kg or 1.1 mg total.
Reproduced,
with permission, from Silver HK, Kempe CH, Bruyn HB: Handbook of
Pediatrics, 14th ed. Originally published by Lange Medical
Publications. Copyright © 1983 by the McGraw-Hill Companies, Inc.
|
Age (Young's rule):
Weight (somewhat more precise is Clark's rule):
or
In spite of these approximations, only by conducting
studies in children can safe and effective doses for a given age group
and condition be determined.
|
|
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Bennett PN: Drugs and Human
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