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CHAPTER 10 Pharmacology in Neonatal Care
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micafungin clearance compared with older patients
and required a threefold-higher dose than adults
to achieve similar drug exposures.
34,77
Decreased
protein-bound micafungin in neonates could
explain why neonates have higher clearance
rates compared with adults. Neonates demonstrate
a lower fraction of protein-bound micafungin compared with adults (96.7% vs. 99.6%). Because there
is a greater amount of unbound micafungin in neonates, more of the drug is available to the elimination
mechanisms, resulting in much faster elimination in
the younger population. Due to these differences in
neonatal physiology, the micafungin doses needed
for treating neonates (10 to 12 mg/kg IV daily in
extremely low-birth-weight infants) differ greatly
from the doses used to treat adults (100 to 150 mg
IV daily, which would be 1.5 to 2 mg/kg/dose based
on a 70-kg average adult patient).
DOSE–CONCENTRATION–TIME
CONSIDERATIONS RELATED TO AGE
In the NICU, doses and intervals must be
adjusted based on changes in the dose–concentration and the concentration–response relationships. Measurements of total drug concentrations
using therapeutic drug monitoring (TDM) enable
a more accurate and precise response to changes in
dose–concentration effects. Unfortunately, not all
drugs have TDM assays readily available for clinicians. As with the micafungin case, clinicians must
observe for clinical effects and assess the influences
of other factors that can affect free drug concentrations to estimate drug efficacy and the responsiveness of receptors and cellular processes to the drug.
As noted earlier, pharmacokinetics describes the
delivery and removal of a drug to and from the body.
Four major processes can affect a drug’s disposition: drug entry (absorption), distribution, biotransformation (metabolism), and elimination. Doses and
dose intervals are expressed mathematically by pharmacokinetic parameters related to absorption, distribution,
biotransformation, and elimination, such as the time to
reach maximum drug concentrations, volume of distribution, clearance, and half-life. There are many factors
unique to newborns that can alter the dose–concentration relationships seen in this population.
Absorption
The process of absorption defines the rate and
amount of a drug that enters the bloodstream.
In the NICU, various routes are used for drug
administration. Drugs are frequently given directly
into the bloodstream by IV injection. When a drug
is given through IV injection, it is said to have
100% bioavailability, meaning that all of the
drug given reach the circulatory system. Drugs
are also frequently given by other means that do
not introduce drugs directly into the bloodstream,
including intramuscularly, via inhalation, intranasally,
intrarectally, topically, and subcutaneously. When
extravascular administration methods are used, the
drug must overcome physical, chemical, mechanical, and biologic variables to enter the circulation.
Oftentimes, these obstacles can result in a bioavailability that is less than 100%, meaning that not all of
the drug administered will reach the bloodstream.
When considering extravascular administration,
clinicians must keep in mind the clinical and
developmental stage of the patient. For example,
in extremely premature infants, transdermal absorption is much greater than in term infants due to a
thinner stratum corneum and less adipose tissue, but
intestinal absorption in the extremely premature
infant may be less due to slower transit time and
delayed gastric emptying.
40,77
Bioavailability is represented by the parameter
F, indicating the percentage of administered drug
that becomes available in the systemic circulation,
with F = 1 indicating the drug is 100% available.
Systematic studies of absorption in critically ill newborns are lacking, and differences in absorptive processes are expected but generally remain unmeasured.
Some differences in newborns that potentially affect
bioavailability include developmental changes in the
surface area and permeability of gastrointestinal (GI)
mucosa, age-dependent changes in acid secretion in
the stomach (neonates have higher gastric pH than in
older children and adults in the first postnatal days),
changes in gastric emptying time and total GI transit
time, and the composition of intestinal microflora.
Drugs such as ranitidine and metoclopramide also
affect the absorption of other medications by altering
gastric and intestinal pH and gastric emptying time
and intestinal motility (faster transit time results in
less absorption).
77
First-pass elimination occurs when a drug
is eliminated after administration but prior to
reaching the systemic circulation. Common sites
of first-pass metabolism for orally administered
drugs include the liver and the gastrointestinal tract.
Other sites of first-pass elimination include the
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vascular endothelium and lungs.64 Different drugs
are absorbed at different rates, and different
formulations of the same drug may be protected from first-pass metabolism.37 The first-pass
phenomenon is why many drugs (e.g., furosemide,
propranolol, morphine) require larger doses when
given orally compared with intravenously.
Distribution
Medications rely on many factors for distribution to their sites of action, including blood
flow, organ size, presence of drug transporters,
and drug permeability. The volume of distribution
(Vd) for a drug is a parameter that relates the
total amount of drug distributed throughout the
body to the serum or plasma concentration.14
It is an attempt to quantify the space in which
the drug can go. Strictly defined, the volume of
distribution is the hypothetical volume of body
fluid necessary to dissolve the total amount of drug
as found in the serum. The volume of distribution
must be used to estimate the amount of a loading dose or a change in plasma concentration
with any bolus dose.
The volume of distribution usually is expressed as a
function of body weight, with units of volume per
kilogram. Major factors that affect the volume
of distribution include plasma protein binding
and body composition.8 Changes in body com-
position happen throughout fetal and newborn
life. Total body water as a percentage of body
weight decreases with increasing age: 85% in
extremely preterm infants; 70% in term infants;
and 55% in most adults. Total body water may
increase with conditions such as the syndrome
of inappropriate antidiuretic hormone (SIADH)
excretion. About half of the total body water
is found in the extracellular space in a healthy
term neonate, where large, water-soluble drugs
will tend to accumulate. Intravascular water
makes up only about 10% of the body weight;
protein-bound medications are trapped in this
smaller compartment. Preterm infants have more
total body water as a percentage of body weight
compared with term infants, and water-soluble
drugs such as penicillins, aminoglycosides, and
cephalosporins have greater volumes of distribution in preterm infants than in older infants.
Preterm infants also have greater volumes of distribution for these water-soluble drugs and require
a higher dose per kilogram than term infants to
achieve the same exposure.
51,77
Plasma protein amounts and binding capaci-
ties also differ with gestational and chronologic
age. Protein binding is decreased in newborns due
to lower total amounts of albumin. Additionally,
fetal albumin has less capacity to bind certain drugs.
Acidic drugs such as ampicillin, phenytoin, and phenobarbital bind less to fetal albumin, thus increasing
the unbound fraction of the drug, thereby increasing the amount of free drug available to exert the
drug’s effect. Changes in pH also can affect a
drug’s affinity for albumin.
Fat content varies with gestational age
and degree of illness. For fat-soluble drugs,
increased adipose tissue increases the volume of
distribution for lipophilic drugs such as propofol
and fentanyl.
40,77
As described previously, the interaction of circulating unconjugated bilirubin and protein-bound
drugs is particularly concerning in neonates. Several
anionic drugs, like ceftriaxone, bind to albumin
and can displace bilirubin, increasing free bilirubin and increasing its potential for neurotoxicity. For other drugs, bilirubin can have a higher
affinity for albumin than the drug; it may displace
these drugs from albumin, increasing the concentration of unbound drug and, therefore, the potential
to reach toxic levels.
3,5
Biotransformation
Biotransformation, or drug metabolism, occurs
most commonly in the liver. Drug metabolism
results in the modification of the structure of
drugs in the body, leading to their eventual
elimination from the body. Phase I metabolism
describes the nonsynthetic metabolism of medications and includes oxidation, reduction, and hydrolysis reactions. Phase I metabolism does not always
inactivate the drug; in some cases, the metabolite
formed can retain active properties sometimes more
potent than the parent drug. Phase II, also known
as conjugation, is synthetic metabolism, in which
small molecular moieties are added to the drug in
the body to aid in its elimination; examples of phase
II metabolism include glucuronidation, sulfation,
and acetylation. The enzymes responsible for
these reactions change with age, disease states,
and interactions with certain drugs. For exam-
ple, many enzymes responsible for the oxidation
CHAPTER 10 Pharmacology in Neonatal Care
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231
and glucuronidation of drugs are decreased in
newborns.
Drugs that rely on these reactions for elimination, such as acetaminophen, phenobarbital, and
phenytoin, will be eliminated more slowly and
result in higher exposures in the neonate compared
with the adult. The possibility of prolonged peak
concentrations of available drug or active metabolites for many pharmaceuticals mandates careful
monitoring of drug levels and clinical conditions to
titrate doses. Additionally, a decrease in plasma protein binding (or any other change in the volume of
distribution) may increase the hepatic metabolism
and subsequent clearance of a drug, as seen with the
micafungin example.
Clearance (Elimination)
Drug clearance or elimination occurs by excretion
of the active drug or biotransformation to an
inactive metabolite. Most drug-elimination path-
ways can become saturated if the dose is too high
or if the dose intervals are too frequent. Most drugs
used in the NICU have therapeutic doses less than
those necessary to saturate the elimination system.
When clearance mechanisms are not saturated, the
Css in plasma is proportional to the dose. Clearance
equals the rate of drug elimination divided by
the drug concentration.37 Just as the volume of
distribution relates to the loading dose and initial
concentration, clearance relates to a maintenance
dose that keeps a drug’s concentration at steady
state. The appropriate dose rate can be calculated
if the clinician can specify the desired steady-state
plasma concentration and knows the clearance and
bioavailability of a drug (from peak and trough levels in a particular patient).
RENAL EXCRETION
The kidney is the primary route of excretion
for many drugs commonly used in the NICU.
The kidney clears drugs through glomerular
filtration and tubular secretion. Examples of
medications eliminated through the kidney are
aminoglycosides, digoxin, diuretics, and penicillins.
Doses and dose intervals of drugs that have renal
excretion must be adjusted for age and disease
state. The glomerular filtration rate (GFR; the
amount of blood filtered by the kidney in a unit
of time) is low at birth and gradually increases
over the first few weeks. In preterm infants,
the GFR starts even lower than in term infants,
with a significant increase occurring around
34 weeks’ PMA. Nephrogenesis begins at 5 to 6
weeks of gestational age, with over 60% of nephrons
being formed during the last trimester.68 Preterm
infants born before 36 weeks’ gestational age are at
risk of having a decreased nephrogenic potential.1
Tubular secretion also matures with increasing
gestational age and depends on tubular function.
In adults, aminoglycosides may be dosed based on
creatinine clearance, but in neonates less than 1
week old, serum creatinine may reflect maternal
levels, as well as renal impairment. Acidosis and a
history of hypoxia or ischemia also may modify
an infant’s renal function, slowing excretion and
altering pharmacokinetics. Again, measuring levels
through TDM in cases of suspected renal impairment, whether from suspicious history or laboratory
values, is important in determining an appropriate
dosage strategy.
Half-Life
A drug’s half-life (t½) is the time necessary for
the drug concentration to decrease by 50%. The
half-life is used to predict and interpret the time
course of changes in plasma drug concentrations
and is related to both the volume of distribution
(Vd) and clearance (CL). For example, the time to
reach Css with repeated dosing is 4 to 5 half-lives.
The half-life is useful in selecting dosing intervals
and determining whether a loading dose is necessary. This concept is illustrated in Fig. 10.3.
Loading doses help expedite the attainment
of the desired therapeutic concentrations, especially for drugs with long half-lives, in which
a desired effect is needed immediately. For
example, caffeine is a drug used to treat apnea of
prematurity in premature infants. In this patient
population, the half-life of caffeine can be as long
as 3 to 4 days. Given that the time to reach Css is 4
to 5 half-lives, administering just the maintenance
dose will require 12 to 20 days to reach the target
concentration and presumably achieve a therapeutic
response. For this reason, a loading dose is given
to reach the target concentration immediately to
achieve a rapid therapeutic response. For drugs
with one-compartment distribution that stay in the
circulation and are not stored in cells or tissue, the
loading dose may be given as a single dose. Drugs
that are fat soluble or stored intracellularly are more
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LD (Vd C)/ F 0.8 L/kg × 20mg/L
16mg of caffeine/kg
=
=
=
×
Time (hours)
Serum drug concentration
ls
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Maximum
safe
concentration
Minimum
effective
concentration
Accumulation to toxic leve
Optimal therapeutic levels
Subtherapeutic levels
03 6912
FIGURE 10.3 Effect on serum drug concentration of multiple dosages along with different time intervals between doses. (From Roberts
RJ. Drug Therapy in Infants. Philadelphia: WB Saunders; 1984.)
15 18 21 24
difficult to assess, and the volume of distribution of
those drugs must be included in the loading-dose
assessment.
preterm infants is 0.8 L/kg, 20 mg/L is the desired
concentration, and F for an IV dose is assumed to be
1, a loading dose can be calculated as follows:
depressed newborn undergoing therapeutic hypo-
thermia, the prolonged half-life of medications
is due to significantly reduced metabolism and
clearance. For example, studies have shown that
phenobarbital has a prolonged half-life of 8 to 22
days in these patients.
clearance and longer half-life of gentamicin in cooling infants mandates spacing out the dosing intervals
to every 36 hours versus the standard dosing of
every 24 hours to prevent accumulation.
Pharmacogenetics and
Pharmacogenomics
In the 30,000-plus known genes, there are over 4
million “common” variants (occurring in more than
1% of the population), many of which directly affect
the function of the coded proteins. In certain cases,
these genetic differences can result in changes in
If the volume of distribution for caffeine in
In certain clinical conditions, such as a birth-
23,74
Similarly, the decreased
26
the expression and function of proteins involved
in the absorption, distribution, metabolism, and
elimination of certain drugs. These changes can lead
to significant clinical consequences. Pharmacogenetics
is the study of the role of inheritance in the individual variation in drug response. Pharmacogenomics
is the study of the influence of multiple genes,
and their interaction with each other and the
environment, on drug effects.
15,68,77
Genetic variations affecting the ability of patients
to metabolize drugs have been well described. Over
40 years ago, one of the first reports of a genetically
caused variation in drug metabolism focused on
butyrylcholinesterase, the enzyme responsible for the
hydrolysis of succinylcholine. One in 3500 people
is homozygous for the gene encoding an atypical
form of butyrylcholinesterase. Patients with the
atypical form of the enzyme are poor metabolizers
of succinylcholine and thus eliminate succinylcholine much more slowly than people with the normal
enzyme variant. Because metabolism is significantly
hindered in patients with the atypical enzyme form,
succinylcholine levels in patients with the atypical
variant are more likely to accumulate to levels that
can lead to prolonged muscle paralysis.
The cytochrome P-450 (CYP) enzymes are a
group of enzymes responsible for the metabolism
and subsequent elimination of many of the drugs
used to treat patients. CYP2D6 is an example of a
CYP enzyme with genetic variations resulting in
clinically significant consequences. Codeine is an
opioid used in the treatment of pain. For codeine
CHAPTER 10 Pharmacology in Neonatal Care
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233
to achieve its clinical effect of pain relief, it must
first be converted by CYP2D6 to its active form,
which is morphine. Certain patients have genetic
variants of this enzyme that result in decreased
function of CYP2D6, thus making these patients
poor codeine metabolizers and, therefore, poor
responders to codeine. There are also patients
who have genetic variants that result in increased
function of CYP2D6, thus making these patients
ultra-rapid metabolizers of codeine. These patients
can metabolize codeine into morphine much
faster than the normal patient, resulting in faster
formation and accumulation of morphine and
increased risk for toxicity. This can have especially
important consequences in breastfeeding women.
A breastfeeding woman who is an ultra-rapid
metabolizer of codeine can develop morphine
levels high enough to transfer to her infant
through the breast milk and lead to signs of
opioid toxicity in the infant, such as sleepiness,
poor feeding, and even respiratory depression. In
the worst cases, this has resulted in infant death
due to morphine toxicity.47 In 2007, the U.S.
Food and Drug Administration (FDA) issued a
public health advisory on life-threatening side
effects in nursing babies of some women who
were prescribed and taking codeine. Since then,
the FDA (and the European Medicines Agency)21
issued a strengthened warning in 2017 for codeine
and a new warning for tramadol in breastfeeding
mothers due to the same concern with ultra-rapid
metabolizers.
A genetic variant in mitochondrial DNA, the
A1555G mutation, has been linked to a risk of
hearing loss associated with aminoglycoside toxicity. The frequency of this mutation in the general
population is estimated to be between 1% and 3%,
but among deaf subjects tested, the concurrence of
deafness with the aminoglycoside treatment associated
with this mutation is more common. This suggests that
in the future, testing for the mutation before the use
of aminoglycosides might be warranted. However, it is
currently unknown whether tighter control of aminoglycoside levels in these patients would reduce the risk
of hearing loss. No recommendations can be made
until more extensive, population-based studies are
done. Such studies must include controlling for drug
levels and duration and genotypes in the assessment of
the risk of hearing loss.
In addition to drug metabolism, genetic variants
can also affect the expression and function of drug
83
56
targets. These include adrenergic and dopamine
receptors and enzymes, such as acetylcholinesterase,
and are likely to have effects on the response to drugs
targeting these proteins, such as bronchodilators, vasopressors, and inotropes, and angiotensin-converting
enzyme (ACE) inhibitors such as enalapril and
captopril.
There have been few studies focused on pharmacogenomics in neonates, particularly those
who are premature. However, genetic differences
with clinically important consequences have been
described in premature infants.4 For example,
polymorphisms in the enzyme UGT2B7, which
is responsible for the metabolism of morphine,
have resulted in pharmacokinetic differences in
infants treated with morphine.48 Also, polymorphisms affecting the expression of the opioid
receptors upon which morphine exerts its effects
have resulted in differences in the need for rescue
doses of morphine among premature infants on
mechanical ventilators.49 Still, very little is known
about the clinical effects of many genetic polymorphisms among infants; pharmacogenetics and
pharmacogenomics are areas deserving more study
in infants.
DATA COLLECTION
Monitoring Safety and Efficacy of
Pharmacotherapies in the Clinical
Setting
Clinicians must be aware of a medication’s
desired therapeutic effects, side effects, and toxicities; know when these are expected to occur;
and continuously monitor for these effects.
Whether or not a dose effect occurs requires documentation. The exact time when therapeutic drug
monitoring is conducted should be recorded in
order to accurately evaluate the dose–plasma
concentration. If the drug’s serum concentration
relates to clinical response, the plasma concentration
should be monitored in addition to clinical signs.
To optimally assess drug serum levels, the expected
plasma concentration is calculated from the dosage
history, and patient variables that may affect pharmacokinetics and the timing of blood samples are
considered. A comparison of expected values with
measured values allows rational adjustment of future
dosages.15 Potential explanations for differences
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½
Total body weight : 1 kg
t
Time to stead
Css F Dose / (Dose interval C1)
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BOX
10.1
POTENTIAL EXPLANATIONS FOR
DISCREPANCIES BETWEEN MEASURED
AND EXPECTED DRUG CONCENTRATIONS
• Inadequatecompliance
• Inadequatemedicationdelivery
• Inappropriatetimingofsamples
• Laboratoryerror
• RevisionininitialestimatesofnecessarypKrequired
pK, Pharmacokinetics.
between measured and expected concentrations are
listed in Box 10.1.
Even if predictable pharmacokinetic and pharmacodynamic changes are considered, other factors may influence a drug’s effect. Clinical end
points must be followed and recorded, with
dosage regimens adjusted accordingly. One example is the monitoring of renal function with
indomethacin dosage; an indication for using IV
indomethacin is for treatment of hemodynamically significant patent ductus arteriosus (PDA).
Some of these infants may exhibit compromised
perfusion to their kidneys because of the PDA
steal phenomenon. However, if clinical signs
of renal dysfunction (a potential side effect
of indomethacin) are noted, the drug is not
administered. A pharmacist on the caregiving team can clarify the dose and disposition
parameters for individual neonates with a
variety of conditions.
If a suboptimal clinical response is noted in
conjunction with a subtherapeutic plasma concentration, revised estimates of clearance require
adjustments with one or two available plasma
concentrations. If a single level is drawn after
drug absorption and distribution are complete
or concentrations are near steady state, then the
maintenance-dose formula can be rearranged to
calculate the revised clearance. The commonsense
approach suggests that if a patient has half the
expected concentration of a drug, then perhaps the
clearance is twice the initial estimate. If the patient
has twice the expected concentration, the clearance likely is half the initial estimate. However,
this technique is misleading if a steady state has
not been reached. If a drug’s level is higher than
expected and higher than what is considered
safe, or if toxicity is noted, the drug should be
discontinued until the concentration decreases
to the appropriate target range.
Examples
The following examples illustrate the need to pay
close attention to issues of dose and clinical effects.
The following examples are for caffeine citrate in
neonates. The half-life of caffeine citrate in premature neonates is 3 to 4 days, the Vd is 0.8 to 0.9 L/
kg, and clearance is 0.008 L/kg/h.
EXAMPLE 1: A 15-day-old, 1-kg preterm
infant receives oral caffeine for apnea of prematurity. After the loading dose of 20 mg/kg, the infant
has received 5 mg every 24 hours of caffeine for 5
days. At 8 am on the fifth day, 4 hours after the last
dose, the baby’s heart rate is more than 180 beats/
min, but apnea has not been a problem. Clinical
and laboratory evaluation of tachycardia includes
consideration of caffeine toxicity. A blood sample
for caffeine is sent to the laboratory. To estimate
the concentration of caffeine, use the following
formula:
Necessary data (assume F = 1):
Vd 0.8 L / kg 0.8 L in this patient
C1 0.00
t 0.7 Vd / C1 0.7 0.8 L / (0.008 L/hr)
Therefore:
The Css was estimated using average Vd and Cl
values reported in similar infants, adjusted for this
infant’s weight. If this infant has diminished clearance relative to the “average” infant, toxicity may
result from the standard dose. Toxicity may not have
been noted until day 5 because of the estimated
time to steady state (Tss) of 115 hours.
EXAMPLE 2: When the next dose of caffeine is
due at 4 am, 24 hours after the last dose, a caffeine
concentration of 27 mg/L is reported. This is within
the therapeutic range for caffeine in neonates, but this
infant is exhibiting tachycardia, a side effect of the
8 L/ kg/ hr 0.008L / hr in this patien
½
70h
y state (Tss) 4t280 h
1 5 mg/(24 hr 0.008 L/hr )
CHAPTER 10 Pharmacology in Neonatal Care
Clearance revised F Dose / (Interval Css)
0.008L/h
Revised t 0.7 Vd/ C1
0.7 0.7L/0.008 L/h 70 h
Dose (Interval C 1 Css)/ F
1
3.8 mg caffeine PO q 24 h
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235
drug, at this level. His heart rate is now consistently
>190 beats/min. The patient is stable on room air,
with no occurrence of apnea. Because of the slightly
higher-than-expected level, it is most likely the result
of decreased clearance. Using this concentration, estimate the time when the concentration will decline
to 20 mg/L, and determine a 24-hour dosage schedule to maintain that concentration. The 4 am dose is
held, and the tachycardia resolves 24 hours later.
1 5 m g/(24h 27 mg/L )
desiver½
Therefore, the concentration 70 hours later should
be one half of the measured 27 mg/L, or about 13.5
mg/L. To maintain a concentration of 20 mg/L:
revised
(24 hours 0.008L/h 20 mg / L)/
EXAMPLE 3: Before the new oral regimen is
initiated, another blood specimen is drawn 70 hours
after the first and is found to be 14 mg/L. Because
tachycardia has resolved, an oral regimen based on
the last two levels is resumed to maintain a caffeine
concentration of 20 mg/L. Estimate the necessary
maintenance dose: The concentration fell 50%, from
27 to 13.5 mg/L in 70 hours, which confirmed our
original estimate of half-life. Although caffeine has
a wide therapeutic index, clinicians can use TDM
and pharmacokinetic calculations to help individualize dosing regimens to provide optimal clinical
responses while minimizing side effects.
PHARMACOLOGY AND
BREASTFEEDING CATEGORIES
Breastfeeding mothers may require treatment with
medications for acute or chronic conditions, resulting in concerns for safety with exposures to drugs
excreted in breast milk. In all cases, the benefits of
breastfeeding must be weighed against the risk of
drug exposures to the infant. When possible, certain
considerations may be taken to lessen the risk of unintended drug exposures to the infant through breast
milk, including the following: avoidance of long-acting
medication formulations, timing medications with
breastfeeding to achieve minimum concentrations at
the time of feedings, choosing medications that will
accumulate the least in breast milk, providing a therapeutic interchange with another medication that has
a safer profile in neonates, and monitoring the infant
closely for abnormal signs and symptoms related to the
medications being taken by the mother.
66,67,71
Although most medications are safe for mothers and the nursing infant, some drugs are known
to potentially cause harm to the nursing infant
and are contraindicated during breastfeeding, such
as anticancer drugs and drugs with radioactivity.87 Lactation risk categories can be assigned to
drugs based on available information.32 Categories
range from safest, designated as L1, to hazardous,
designated as L5. Only drugs categorized as L5
are contraindicated during breastfeeding. Other
categories require balancing of risk versus benefit
to the mother and the infant in the decision on
whether to allow breastfeeding in conjunction with
the medication being questioned. Table 18.7 pro-
vides information about specific maternal drugs
excreted in breast milk.
DRUG CATEGORIES
Antimicrobial Agents
Antimicrobial agents inhibit microbial growth
or kill microorganisms; they include antibacterial, antiviral, and antifungal agents. Bacteriostatic
agents limit microbial growth, allowing host defenses
to control spread; this will not reliably eliminate a
pathogen but can prevent its proliferation. Bactericidal
agents kill the pathogen. Bactericidal agents at low
concentrations may be bacteriostatic. The minimum
inhibitory concentration (MIC) is the lowest concentration of an antimicrobial that stops the spread
of an organism in laboratory culture media. This
cannot be directly measured in an infected neonate and depends on tissue concentration and the
number of bacteria present. The minimum bactericidal
concentration (MBC) is the lowest concentration of
antimicrobial that reduces the microbial number in
laboratory media by 99.9%. Pathogens can develop
resistance to antimicrobials by changing their cellular
structures or producing enzymes that reduce antimicrobial activity.
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For effective antimicrobial action, the drug
must reach an adequate concentration in the
infected tissue. The ideal concentration elicits a
maximum effect on the pathogen with minimum
effects on the patient. Selection criteria for antimi-
crobials include the microorganism’s sensitivity, the
availability of the drug to the target tissue (e.g., when
treating central nervous system (CNS) infections, it
is important to note that some antibiotics do not
cross the blood–brain barrier), the bioactivity of the
antimicrobial in the target tissue, the known MIC
and MBC relative to side-effect and toxic-effect
levels for the medication, and the infant’s biologic
state—that is, whether the systems of absorbance
(e.g., intestinal integrity) and elimination (e.g., kidney and liver function) are working adequately for
effective and safe drug delivery and removal. When
the use of antimicrobial agents is planned in an
infant, as with other drugs, consideration must
be given to clinical status and PMA and PNA
in order to appropriately select the right drug
at the right dose for the right indication for the
right duration.
In particular, the pharmacokinetics of antifungal
drugs in neonates have been studied, and these data
have guided optimal dosing in the neonatal population for an infection associated with high morbidity
and mortality rates.
6,20,44
For example, one cited
study on the use of fluconazole, a synthetic triazole,
suggested that a loading dose (25 mg/kg) prior to
starting maintenance dosing achieved the therapeutic
target more rapidly than without a loading dose in
infants.63 When treating Candida infections in neonates, immediate attainment of the target level of fluconazole (area under the concentration curve/MIC)
is paramount. As more pharmacokinetic studies of
commonly used antimicrobials in critically ill neonates are completed, such as with clindamycin, metronidazole, piperacillin-tazobactam, and meropenem,
dosing regimens based on PMA and PNA continue
to be updated and improved in the NICU.
17,18,29,52,76
Diuretics
Diuretics are used in the NICU to remove excessive extracellular fluid. Diuretics commonly cause
a loss of electrolytes along with water. Response
to any diuretic depends on renal function and
the drug’s ability to reach its target in adequate amounts. Most diuretics work within the
tubule, but any drug that increases GFR can
increase water loss. Drugs that increase cardiac
output without decreasing renal perfusion, and
others that specifically increase renal blood flow, can
also cause diuresis.
In infants, renal tubular function improves
with increasing chronologic and gestational age.
Poor absorption and response to aldosterone (especially in extremely preterm infants) and electrolyte
losses can be clinically significant with the addition
of a loop diuretic such as furosemide or bumetanide.
The ongoing losses may lead to hypochloremic
metabolic alkalosis and less response to the diuretic.
Delivery of diuretics to the kidney loop
increases with increasing chronologic and gestational age. Most diuretics rely on secretion from
the proximal tubule and filtration through the
glomerulus to reach their site of action. Both these
functions improve with age. Enteral absorption of
some diuretics is limited, so clinical effectiveness and
electrolyte stability must be monitored closely to
help determine safe and effective dosage regimens.
The kidney also is responsible for diuretic excretion,
again through tubular secretion and glomerular
filtration. These functions are age dependent; the
clinician must ensure that the clearance time is adequate to avoid toxic levels.
Cardiovascular Drugs
Medicines used to improve cardiovascular function
include digitalis and the sympathomimetic amines,
which include drugs such as dopamine, dobutamine, and epinephrine. Antiarrhythmics, including
digoxin, act to control the electrical conduction
within the myocardium.
The sympathomimetic amines bind to β and G
receptors; the number and availability of receptors
determine response. A β1 receptor response leads to
constriction of vascular smooth muscle. β2 receptors
cause a decrease in GI motility. Stimulation of the
G1 receptor stimulates cardiac contractility, and the
G2 response includes vascular and bronchial smooth
muscle relaxation. The response in any individual, and in any individual’s specific organ system,
depends on the relative amount of these receptors.
Receptor numbers and their linked response elements within cells vary with gestation and clinical
condition, and the response must be monitored to
aid in dosage decisions. Prolonged administration of
sympathomimetic amines can lead to a decreased
response—an example of tachyphylaxis.
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Antihypertensive agents occasionally are used
in neonates for essential hypertension and occasionally to decrease afterload in infants with
heart failure. These include volume reducers such
as diuretics, inhibitors of physiologic regulators of
blood pressure like enalapril, and drugs that decrease
vascular resistance through β and G receptors. ACE
inhibitors, such as enalapril, should be avoided in
preterm infants because they are at significant risk
of acute renal failure after exposure to this class of
41,43,45
drugs.
The pathophysiology of neonatal disease should
direct the choice of cardiovascular agent. Extremely
close monitoring of physiologic effects helps determine the safety and efficacy of therapy. Monitoring
must include very frequent, if not continuous,
monitoring of blood pressure, heart rate, perfusion,
and oxygen saturation (preductal and postductal in
some cases). Other drugs are often given con-
comitantly while a neonate is receiving cardiovascular medicines; thus, thorough knowledge
of possible drug interactions is mandatory. The
absorption of cardiovascular drugs is unpredictable.
The sympathomimetic amines, such as epinephrine, must be given by the IV route unless used
in an emergency situation in which endotracheal
(ET) administration is indicated. Once dosed,
the drug must be delivered to the target organ system. Infants in shock may not have the circulatory
wherewithal to deliver the medication to elicit the
desired therapeutic response. Due to the variability
in β- and G-receptor development and distribution,
undesired side effects in various organ systems may
accompany desired responses. Rapid metabolism
of the sympathomimetic amines demands continuous IV infusion, and infiltration of IV fluids
may lead to significant tissue damage. Along
with the physiologic effects, these IV lines must be
carefully monitored to prevent adverse effects as
well as to ensure the infant receives the drug.
46,72
Also related to the cardiovascular system are
drugs used to treat patent ductus arteriosus (PDA)
in neonates. The ductus arteriosus is a vascular
connection between the aorta and the pulmonary
artery. In utero, the ductus arteriosus serves the
important function of bypassing blood flow away
from the nonfunctioning fetal lungs and back into
the systemic circulation through the aorta, where
the blood can then travel to the placenta. The
ductus arteriosus typically closes spontaneously
after birth. If the ductus arteriosus fails to close
after birth, the resulting PDA can result in shunting of blood away from the body and back to the
lungs and cause significant problems to the infant,
including pulmonary overcirculation and decreased
perfusion to vital organs such as the kidneys. The
presence of prostaglandins is known to keep the
ductus arteriosus patent, which can be produced
endogenously by the infant at the ductus arteriosus
or be administered as a drug for certain congenital
heart defects.
Pharmacotherapies are used to treat a PDA
when more conservative treatments, including
volume restriction and diuretics, have failed.
These pharmacotherapies are directed at inhibiting
the formation of prostaglandins at the ductus arteriosus. Indomethacin, a nonsteroidal anti- inflammatory
drug (NSAID), is often used to treat a PDA in
these cases. Indomethacin works by inhibiting the
enzyme cyclooxygenase, which prevents the formation of prostaglandins, allowing the PDA to close.50
When indomethacin is used, close monitoring
is necessary for several important side effects,
including decreased kidney function and thrombocytopenia. Contraindications against the use of
indomethacin include extremely elevated serum
creatinine levels, severe oliguria or anuria, and
severe thrombocytopenia. Studies have also
demonstrated an increased risk in the development of spontaneous intestinal perforations
among premature infants treated with indomethacin and hydrocortisone concomitantly; the use
of indomethacin with hydrocortisone, and likely
other corticosteroids, in this population should
be avoided if possible.
86
More recently, there has been increased use of
acetaminophen/paracetamol for the treatment of
PDA in infants. Acetaminophen may cause PDA
closure through the inhibition of prostaglandins,
although the exact mechanism of how acetaminophen results in PDA closure is still unknown. A
recent Cochrane review evaluating eight studies
that included a total of 916 preterm infants demonstrated that acetaminophen performed similarly
to ibuprofen or indomethacin and better
than placebo for successfully treating PDAs.59
Furthermore, acetaminophen may be safer than
ibuprofen or indomethacin, without the adverse
effects related to NSAIDs, including decreased
renal and mesenteric blood flow. However, the
authors of the review concluded that further
studies, including long-term neurodevelopment
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outcome studies, must be conducted before acetaminophen can be recommended as a standard
treatment for PDAs.
59
Central and Peripheral Nervous
System Drugs
Nervous system drugs include analgesics, which
decrease pain sensations; anesthetics, which control pain peripherally or in the CNS; sedatives/
hypnotics, including barbiturates (phenobarbital)
and nonbarbiturates (lorazepam), which do not
control pain and can control some seizures; and
antiepileptic agents, which are designed to control seizures (phenytoin, fosphenytoin). These
drugs are associated with problems of addiction,
tolerance, dependence, and withdrawal.
Neonates are incapable of developing addic-
tion but are able to develop tolerance, dependence, and withdrawal to these medications.
Addiction is a complex lifestyle change that involves
drug-seeking behavior, which is not applicable to
neonates. Tolerance occurs with many drug types.
Tolerance exists when increasing doses and serum
concentrations of a medicine are necessary to
achieve a desired effect. A patient is dependent on
a medication when regular drug administration
is necessary for physical well-being. Withdrawal is
a collection of physiologic and behavioral signs
attributed to the absence of a medication in
a dependent individual. There are two distinct
types of withdrawal in neonatal patients. Neonatal
abstinence syndrome is secondary to in utero
exposure to illicit substances, such as heroin,
or prescribed medications, such as methadone or
buprenorphine, taken by mothers during pregnancy.
Iatrogenic withdrawal is induced by prolonged
exposure to opioids, benzodiazepines, and other
sedatives used in sick infants who often require
prolonged mechanical ventilation. Withdrawal
has been identified for many medications, but it has
been classified and described, along with weaning
protocols, for opioid analgesics and benzodiazepines22 (see Chapter 11).
The mechanism of most CNS medications
is not clearly known. Again, careful monitoring
of therapeutic effects relative to dose, duration,
and serum concentrations is extremely important.
Significant respiratory depression can occur with
most CNS medications, so appropriate resuscitation equipment must be available. Variations in
hepatic metabolism and the volume of distribution
are important in the ongoing assessment of dose
response. Some medications are highly fat bound
and are slowly released into the circulatory system,
causing prolonged effects, both therapeutic and
undesired (e.g., respiratory depression, poor gastric
motility, and abnormal neurologic function such as
feeding difficulties).
If therapeutic hypothermia is used for infants
with hypoxic-ischemic encephalopathy (HIE),
evidence suggests that opioids accumulate in
the circulation in excess of the accumulation in
similar infants with HIE who are not cooled.
Therefore, when using opioids in cooled infants
with HIE, opioid levels are likely to be higher
than expected for a given dose, and the expectations for the neurologic examination must be
modified given the accumulation of high levels
and delayed neurologic findings.
68
Pharmacokinetics During
Hypothermia
In recent years, therapeutic hypothermia has
become the standard approach in NICUs for
term newborns with neonatal HIE.72 (see
Chapter 26) Therapeutic hypothermia entails
lowering the core body temperature below
34°C for the first 72 postnatal hours, followed
by gradual rewarming.73 Neonatal HIE is often
accompanied by metabolic acidemia in the first
postnatal hours to days, along with kidney and liver
injury. This complex combination of end-organ
injury and cooling below the usual physiologic core
body temperature influences the pharmacokinetics
of commonly used medications in the NICU.
Antiepileptics, opioids, and antibiotics are
among the more commonly used medications
for infants with HIE. In adults, the systemic clear-
ance of drugs metabolized by cytochrome P-450 is
decreased between approximately 7% and 22% per
degree Celsius below 37°C during cooling. Several
studies have assessed specific medications often used
for term neonates with HIE.
Hypoxic newborns are at high risk of seizures. Clinicians who are treating these infants
with HIE should understand the antiepileptic agents
and their dosing and pharmacokinetic profiles.
Phenobarbital (PB) administered to newborns
under whole-body hypothermia results in higher
plasma concentrations and longer half-lives
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