The Interplay between Pharmacokinetics

and Pharmacodynamics
Tracy L. Sandritter, PharmD, BCPPS,*† Matthew McLaughlin, MD, MS,† Michael Artman, MD,‡ Jennifer Lowry, MD†
*University of Missouri–Kansas City School of Pharmacy, Kansas City, MO
†
Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation and
‡
Department of Pediatrics, Children’s Mercy Hospital, Kansas City, MO

Practice Gap
Drug efficacy and safety depend on all aspects of pharmacokinetics and
pharmacodynamics for optimal treatment. Assessment of efficacy, drug-
drug interactions, and adverse drug reactions is essential for optimal
outcomes. Pediatricians should fully consider these aspects of drug
therapy every time a medication is prescribed.

Objectives
1. Recognize that drug efficacy depends on multiple factors, including
pharmacokinetics (absorption, distribution, metabolism, and elimination)
and pharmacodynamics (the effect of the drug at the end organ).
AUTHOR DISCLOSURE Drs Sandritter,
McLaughlin, Artman, and Lowry have 2. Identify situations where dose adjustments are necessary to maintain
disclosed no financial relationships relevant to the serum concentration within the normal therapeutic range and
this article. This commentary does not contain
prevent toxicities.
a discussion of an unapproved/investigative
use of a commercial product/device. 3. Understand important intrinsic and extrinsic factors affecting drug
ABBREVIATIONS
response.
ADHD attention-deficit/hyperactivity 4. Review synergistic and detrimental drug-drug interactions that lead to
disorder
ADME absorption, distribution,
altered pharmacodynamic responses due to the presence of another
metabolism, and elimination drug, a food, or herbal treatment.
ADR adverse drug reaction
5. Discuss predictable and idiosyncratic adverse drug reactions and
CYP cytochrome P450
ED50 pharmacologic effect in 50% of identify federal adverse drug reporting systems.
patients
FDA Food and Drug Administration
GFR glomerular filtration rate
HLA human leukocyte antigen INTRODUCTION
NSAID nonsteroidal anti-inflammatory
drug Pharmacokinetics and pharmacodynamics determine the clinical effects of drug
OTC over the counter therapy. Pharmacokinetics (what the body does to the drug) is defined as the
OTFC oral transmucosal fentanyl citrate quantitative study of drug absorption, distribution, metabolism, and elimination
P-gp P-glycoprotein
(ADME). Pharmacodynamics is clinically more elusive and difficult to precisely
SSRI selective serotonin reuptake
inhibitor
quantify. Pharmacodynamics is the study of the biochemical and physiological
TD50 toxic effect in 50% of patients effects of drugs in the body. Thus, pharmacodynamics can be thought of as “what
TI therapeutic index the drug does to the body.” Despite being 2 distinct entities, there is substantial

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 interplay between pharmacokinetics and the resultant phar-
macodynamics. Understanding this can be challenging.
The correlation between the dose administered and the re-
sulting drug concentration at the site of action ultimately
contributes to the pharmacodynamic response. Thus, phar-
macodynamics describes the relationship between drug
concentration and the desirable clinical effects of a medi-
cation as well as unwanted adverse effects. In addition, in
pediatric patients, growth and development affect pharma-
cokinetics and pharmacodynamics. This article reviews
the interplay between pharmacokinetics and pharmacody-
namics (ie, dose-exposure-response relationships).
PHARMACOKINETICS
Pharmacokinetics (ADME) determines the concentration
or amount of drug in the body that is available to have the
desired effect. For a drug to have a positive or negative effect
internally, the medication must first enter the body (eg,
ingestion, dermal, rectal, submucosal) and be absorbed into
the bloodstream. Once in the bloodstream, the drug can be
distributed, ultimately reaching the site in the body where it
may produce the desired effect at a receptor or drug target.
After the drug-receptor interaction, the medication returns
to the bloodstream and is taken to the liver, where it can be
metabolized to substances that are more easily eliminated
in the urine or feces.
Absorption
Absorption is the process by which a drug enters the
bloodstream or another body compartment from the site
of administration. Bioavailability is defined as the rate and
extent to which the active drug is absorbed and becomes
available at the site of drug action to produce a pharmaco-
logic response. Drugs administered via the intravenous
route are considered to be 100% bioavailable, meaning that
the entire drug dose has reached the circulation. Routes that
require absorption include oral, intramuscular, subcutane-
ous, and topical/transdermal and can result in adverse ef-
fects if given in sufficient quantities. Drug absorption plays
a pivotal role in determining pharmacodynamic responses.
For a drug to be absorbed into the circulation, the active
drug must first be liberated from the dosage form. Liberation
depends on physiochemical factors of the drug, the dosage
form, and the environment at the site of administration.
There are multiple mechanisms by which drugs are absorbed
into the circulation, including passive diffusion, convective
transport, active transport, facilitated transport, ion pair trans-
port, and pinocytosis. Except in the case of pinocytosis, a drug
must be released into solution to be absorbed.
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Passive diffusion is one of the most important mecha-
nisms of drug absorption; however, active transporters such
as P-glycoprotein (P-gp) can be particularly important owing
to drug-drug and drug-food interactions. P-glycoprotein is a
transporter located in the endothelium of multiple organs,
including the gastrointestinal tract lumen and the blood-
brain barrier. This efflux transporter is responsible for
pumping drugs back into the gut lumen and decreasing
bioavailability. Digoxin is an example of a drug that is
transported by P-gp. Inhibition of P-gp will increase the
bioavailability of a P-gp substrate such as digoxin, and,
conversely, induction of P-gp will reduce the bioavailability
of digoxin and other P-gp substrates. This type of interac-
tion has direct relevance to the clinical setting. For example,
erythromycin, clarithromycin, and quinidine are P-gp inhib-
itors and, thus, when coadministered with digoxin, can re-
sult in an increased serum digoxin concentration. Grapefruit
juice, guava, and mango also inhibit P-gp and can similarly
affect the bioavailability of P-gp substrates. In addition to
P-gp, other patient-specific factors, such as age, sex, body
weight, gastric emptying rate, intestinal motility, gastric pH,
blood flow, liver function, length of the intestines (short
gut syndrome), type of diet, and presence/absence of food,
can modify the efficiency and rate of absorption.
Absorption of a drug and the resulting serum concen-
tration can depend on food intake and the time to medica-
tion exposure (Table 1). Medications are weak acids or weak
bases that become ionized or un-ionized depending on the
pH in the environment in which absorption takes place.
Consuming a medication in the presence or absence of food
can change the ionization state of the medication and affect
absorption. Some medications are destroyed by stomach
acid and should be taken on an empty stomach because food
increases acid secretion. In addition, foods such as grape-
fruit juice can inhibit the intestinal enzyme cytochrome
P450 (CYP) 3A4, resulting in increased drug absorption
and higher serum concentrations. Insulin and oral an-
tidiabetic agents are generally recommended to be ad-
ministered with food to prevent hypoglycemia. Aspirin,
nonsteroidal anti-inflammatory drugs (NSAIDs), and cor-
ticosteroids should be administered with food to prevent
local gastric irritation and ulceration.
Depending on the indication for therapy, various routes
of administration can be exploited because the efficiency
and rate of absorption depend on the dosage form. Fentanyl,
an opioid agonist, is an example of a medication that is
available in different formulations. Intravenous fentanyl ad-
ministration is beneficial for acute pain relief because the
entire dose is delivered immediately to the bloodstream,
which shortens the time required to reach the site of action.
 plasma concentration and a higher peak plasma concentra-
TABLE 1. Common Medications Requiring tion provide more rapid analgesia or sedation, which can be
Dosing Considerations Related to important in an emergency department setting.
Food Intake Bioequivalent drug products are formulations contain-
ing the same active ingredient and having comparable phar-
MEDICATIONS MEDICATIONS COMMON
macokinetic and pharmacodynamic potential (adverse effects
TAKEN ON AN TAKEN INTERACTIONS
EMPTY STOMACH WITH FOOD WITH GRAPEFRUIT and efficacy). Differences in the formulation can alter the
bioequivalence as excipients and inactive substances can
Loratidine Carvedilol Statin class of
medications modify the ability of the active drug component to go into
Captopril NSAIDs/aspirin Midazolam
solution. All generic medications must undergo bioequiva-
lence studies compared with the original brand name prod-
Omeprazole Baclofen Diazepam
uct before being released to the market. These studies must
Tetracycline Corticosteroids Fentanyl show that the generic version releases its active drug ingredi-
Methotrexate Trazodone Estrogen/ ent into the bloodstream at essentially the same speed and
progesterone in the same amounts as the original drug. Because the active
Levothyroxine Doxycycline Methadone ingredient in the generic drug has already been proved in clin-
Quinolone antibiotics Lovastatin/ Digoxin ical trials to be safe and effective, manufacturers of generic
rosuvastatin products do not need to repeat safety and efficacy studies.
Iron supplements Griseofulvin
Itraconazole solution Itraconazole
Distribution
capsules Drug distribution is influenced by drug-related factors (eg,
Pancrealipase molecular size and weight, acid dissociation constant), the
presence and location of drug transporters, protein binding,
The available concentration of a medication after administration may systemic pH, and overall tissue perfusion. Age-dependent
be affected by the presence or absence of food. In the example of
quinolone antibiotics, the amount of absorption decreases significantly changes in drug volume of distribution are related to changes
if taken with cations, such as iron, zinc, or calcium. The NSAIDs are in body composition (water, fat) and nutritional status. Disease
advised to be taken with food to prevent gastric adverse effects. states such as ascites, dehydration, burn injuries, and cystic
Grapefruit juice is a known potent inhibitor of cytochrome P450 3A4,
fibrosis can also affect drug distribution. Drug distribution
which would result in increases in serum concentrations of several of the
medications listed, leading to adverse drug events. NSAID¼nonsteroidal affects the concentration of a drug at the site of action and plays
anti-inflammatory drug. a crucial role in the pharmacodynamics of the medication.
Volume of distribution is a theoretical value that represents
the degree to which a drug is distributed into tissues. Drug
Another method of administration of fentanyl is a trans- dosing, volume of distribution, and concentration are related.
dermal delayed-release system, which provides a constant The following equation represents a simple correlation:
rate of 25 to 100 mg/hour. In adult clinical trials, maximum Drug  Concentration ¼ Drug  Dose=
serum concentrations were not reached until 17 to 48 hours
Volume  of   Distribution:
after initial placement of a fentanyl patch, in stark contrast
to the peak serum concentration immediately observed after Depending on the chemical characteristics of a medica-
intravenous administration. Slower rise to peak concentra- tion, a medication may be more water soluble or more fat
tion and sustained release of medication achieving a steady- soluble. Medications with high lipid solubility or low plasma
state concentration make the transdermal delivery system binding capacities have higher volumes of distribution (eg,
most suitable for treating chronic pain. In pediatric pa- tricyclic antidepressants); however, medications that are
tients, dosing fentanyl by an oral transmucosal route fur- highly bound to plasma proteins or are more polar stay
ther highlights the differences observed between differing within the water compartments and have a low volume of
routes of administration. Oral transmucosal fentanyl citrate distribution (eg, aminoglycosides and penicillins).
(OTFC) is a formulation embedded in a sweetened matrix Protein binding and drug transporters can also affect the
that dissolves in the mouth. Comparing the absorption of an volume of distribution. Drug protein binding affects the free
oral solution of fentanyl (liquid) with the OTFC formula- fraction of a drug. The free fraction of a drug is that amount
tion (dissolving solid), peak plasma concentrations occur that is available to contribute to the pharmacologic effects
sooner and higher with the OTFC formulation. A faster peak (ie, efficacy and toxicity). Proteins that bind drugs may also

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 bind endogenous substances (eg, phenytoin versus bili-
rubin), resulting in competition for the binding site. This
may increase the free fraction of drug and affect the phar-
macologic effects produced (eg, toxicity). Drug transpor-
ters allow and inhibit medications from crossing biological
membranes and distributing into compartments other than
the central intravascular compartment. For example, the
blood-brain barrier is a physiologic barrier containing P-gp
that prevents rapid and widespread distribution of many
medications into this compartment.
Renal insufficiency, as well as hepatic failure, can contrib-
ute to changes in a drug’s volume of distribution. With edema
and ascites, the apparent volume of distribution for water-
soluble medications is increased, which may lead to inade-
quate plasma levels. The uremia that can result from renal
dysfunction can reduce the plasma protein binding of drugs
(eg, salicylate, phenytoin) so that their free fraction may rise to
toxic levels. Predicting the consequences of changes in pro-
tein binding can be difficult; thus, when available, monitoring
the free fraction of the drug is suggested.
Hepatic Drug Metabolism
Drug metabolism, which occurs primarily in the cellular
endoplasmic reticulum, is the biochemical modification of
medications via specialized enzymatic systems to convert
substances into more readily excreted hydrophilic prod-
ucts. The metabolic rate determines the duration and inten-
sity of a given drug’s pharmacologic effects. Drug metabolism
is divided into 2 phases: phase I (nonsynthetic) and phase
II (synthetic). Phase I enzymes introduce reactive or polar
groups into the chemical that are then further modified
by phase II compounds to more polar compounds. Phase
I reactions include oxidation, reduction, hydrolysis, and hy-
droxylation. Phase I enzymes include the CYP–dependent
mixed-function oxidases. Phase II reactions primarily in-
volve conjugation with an endogenous ligand (eg, glycine,
glucuronide, glutathione, or sulfate). Phase II reactions are
catalyzed by many different enzymes. For example, UDP-
glucuronosyltransferases are involved in the metabolism
of opiates and acetaminophen. The efficiency of drug-
metabolizing enzymes varies with age and corresponds
to the range of physiologic stages from infancy to ado-
lescence: generally, activity is lower at birth, maturing to
higher levels over months to years.
Although many enzymes are capable of catalyzing the
biotransformation of medications, the quantitatively most
important are the CYPs. The most important CYP isoforms
involved in human drug metabolism include CYP1A2,
CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. For
some of these enzymes, single-nucleotide polymorphisms
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produce allelic variants of the gene, resulting in changes to
the catalytic activity (reduced or increased). Single-nucleotide
polymorphisms associated with rapid metabolism of a drug
may result in lack of therapeutic response with normally
recommended drug dosing. Single-nucleotide polymor-
phisms that can lead to decreased drug metabolism lead
to higher drug concentrations in the blood, with resulting
increased adverse effects (Fig). Induction or inhibition of
these enzymes by other drugs may occasionally produce
clinically important drug interactions (see the Drug Inter-
actions section for more details).
One of the initial ways the hepatic system alters phar-
macodynamic effects is by first-pass metabolism, which
affects drug bioavailability by reducing the amount of drug
available to the systemic circulation after oral absorption.
This reduction in the systemic drug concentration occurs
due to efflux transporters (eg, P-gp), enzymes in the gut lu-
men (eg, CYP3A4), or entry of the drug into the portal sys-
tem for early metabolism by liver enzymes before reaching
the systemic circulation. As a result, the amount of drug
available to reach the receptors is decreased. The pain
medication morphine has a high first-pass metabolism,
with only 40% to 50% of an oral dose reaching the blood-
stream for distribution to sites of action in the central
nervous system. To overcome first-pass metabolism, doses
of the medications may need to be increased.
Codeine is another example of the impact of metabolism
on pharmacodynamic response. Codeine is metabolized to
several different products with varying levels of affinity for
the opioid receptors that modulate pain. The most potent
metabolite of codeine is morphine. The conversion from
codeine to morphine largely depends on the variation of
CYP2D6. Genetic variations of CYP2D6 have resulted in
Figure. Pharmacokinetic and pharmacodynamic correlation.
This graph is a generalization of the correlation between the
pharmacokinetics and pharmacodynamics of medications. The upward
slope represents drug absorption, and the downward slope represents
elimination. The blue arrows point to the time of dose administration.
These relationships do not hold true for prodrugs.
pharmacodynamic differences in populations. Specifi-
cally, 5% to 10% of the white population has no activity of
CYP2D6, which results in lack of analgesic effect due to
decreased morphine production. Alternatively, a small per-
centage of the population has duplications in the enzyme,
resulting in ultra-rapid metabolism. This has been shown to
be clinically important because a breastfed neonate whose
mother was prescribed codeine died as a result of morphine
overdose. In patients who are ultra-rapid metabolizers, such
as the mother in this case, much more morphine is pro-
duced, which exposed her infant to toxic levels of morphine
when breastfeeding. In addition, there are reports of serious
or fatal outcomes in children who are CYP2D6 ultra-rapid
metabolizers who were prescribed codeine postoperatively
after adenotonsillectomy for obstructive sleep apnea.
Although not as well characterized, the impact of devel-
opment on the activity of phase II enzymes generally fol-
lows the same pattern as that of phase I enzymes: decreased
activity in the newborn, subsequently increasing through
childhood. For example, newborns and infants primarily
metabolize acetaminophen by sulfate conjugation because
the UDP-glucuronosyltransferase isoforms responsible for
its glucuronidation have markedly reduced activity, result-
ing in a higher risk of toxicity. With age, glucuronidation
capability increases and becomes the predominant pathway
in acetaminophen metabolism.
Renal Elimination
The primary organ responsible for the excretion of drugs
and their metabolites is the kidney. The development of
renal function is not completely mature until early child-
hood. In both term and preterm neonates, the glomerular
filtration rate (GFR) averages 2 to 4 mL/min per 1.73 m2 at
birth. An increase in GFR occurs in the first few days after
birth due to a drop in renal vascular resistance with a resultant
net increase in renal blood flow and a redistribution of intra-
renal blood flow from a predominantly medullary distribution
to a cortical distribution. The GFR increases rapidly during
infancy and approaches adult values by 10 to 12 months of age.
The rapid change in GFR occurring during infancy leads to
frequent dosage adjustments for medications that are pre-
dominantly eliminated by glomerular filtration (eg, amino-
glycosides). In the neonatal period, aminoglycoside dosing is
based on weight, gestational age, and days after birth, which
reflects the estimation of GFR in the population. Given the
narrow therapeutic index (TI) for these medications, the
dosage should subsequently be individualized based on se-
rum concentration monitoring. The dosing interval for these
medications may need to be prolonged when coadminis-
tered with ibuprofen or indomethacin or in neonates with
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a history of birth hypoxia/asphyxia or cyanotic congenital
heart disease. In addition, for any patient with decreased
renal perfusion (eg, shock), dosage reductions should be
considered. Tubular secretion is not fully developed until
approximately 1 year of age, which would affect medications
such as penicillin antibiotics that rely on tubular secretion
in addition to glomerular filtration for clearance.
Many drug classes, including over-the-counter (OTC) and
prescription agents, have a risk of nephrotoxicity that may
contribute to the need for adjustment of medication regi-
mens in patients. The kidney is especially poised as a target
for toxicity because it receives a significant percentage of
cardiac output and is regularly exposed to drugs and drug
metabolites. In addition, as tubular fluid flows through the
loop of Henle, water is reabsorbed, which increases the
tubular concentration of drug to potentially cytotoxic levels.
Last, certain therapeutic and diagnostic agents may have
inherent toxic potential based on the pharmacology of the
medication itself. Specific medications to consider include
NSAIDs, angiotensin-converting enzyme inhibitors, angio-
tensin II receptor blockers, aminoglycosides, sulfameth-
oxazole/trimethoprim, vancomycin, ciprofloxacin, antivirals,
amphotericin B, many cancer chemotherapeutic agents,
calcineurin inhibitors, lithium, and radiocontrast agents.
Dosage adjustments for renally eliminated medications
may be required in patients with primary pathologic kidney
disease, chronic kidney disease, and acute kidney injury from
impaired drug clearance. Patients with lower muscle mass
(eg, neonates, females, malnourished patients) and decreased
total body water/dehydration (eg, with vomiting, diarrhea,
diuretic use) may develop increased serum drug concentra-
tions with routine dosing and potential attainment of toxic
levels. In addition, because creatinine is a breakdown product
of muscle, patients with lower muscle mass may have a lower
serum creatinine level, which may falsely be interpreted as a
higher GFR. This could lead to inappropriately high drug
dosing. Most resources that provide drug dosing informa-
tion will provide recommendations for altering the dose based
on an estimation of GFR. Pharmacist utilization in clinical
practice can be useful in these situations. Additional variables
to consider include polypharmacy with nephrotoxic agents
in patients with comorbid conditions because this may pre-
dispose them to acute kidney injury.
Published renal dosing adjustments for medications are
based on patients with chronic, stable renal disease. How-
ever, adoption of the dosing recommendations for patients
with acute renal failure is still frequently practiced. Depend-
ing on the medication, if available, early pharmacokinetic
monitoring to individualize dosing for a patient with acute
renal failure is essential.
Vol. 38 No. 5 MAY 2017 199
 The appropriate time to obtain serum drug concentra-
tions depends on the specific medication to be monitored
and the reason these levels are obtained. For most medica-
tions, trough concentrations are ideal. Trough concentra-
tions are obtained at the end of a dosing interval just before
the next dose is administered to verify that the drug’s con-
centration is still in the therapeutic range. However, for
aminoglycosides, monitoring peak serum concentrations is
required because the response to these agents is related to
the peak concentration. Thus, serum drug concentrations
should be obtained throughout the course of therapy to (1)
prevent toxicity (concentrations obtained with the first dose
of therapy) and (2) assess pharmacodynamic changes by ac-
hieving therapeutic effect while preventing adverse effects.
DRUG EFFECT (PHARMACODYNAMICS)
In general, medications exert clinical effects by either mim-
icking or inhibiting normal biochemical processes. Drug effi-
cacy is related to successful receptor, protein target (enzymes,
structural proteins, or carrier proteins), or ion channel inter-
actions. The receptors or proteins that serve as drug targets
may be localized or distributed throughout the body. For
example, morphine binds to receptors on neurons in the
central nervous system to alleviate pain, whereas serotonin
reuptake inhibitors bind at receptors in the central nervous
system and the gastrointestinal tract, making them useful for
a variety of diagnoses. Variability also occurs in the receptors
with which drugs interact. For example, the concentration
of drug in the body may be within the desired range for ef-
ficacy but genetic variability in the receptor may limit the
drug-receptor interaction. The desired response may not
occur even with what would typically be an adequate drug
concentration.
Intrinsic and extrinsic factors can affect pharmacodyna-
mics. Intrinsic factors include the density of receptors on
the cell surface, the process of signal transmission by second
messengers, and factors that control gene translation and
protein production. Drug response is also affected by the
duration of effect, which is determined by the time that a
drug is engaged not only on the receptor but also on intracel-
lular signaling and gene regulation. For some drugs, such as
opiates, tolerance can develop, leading to decreased effec-
tiveness with continued use unless the dosage is increased.
Tolerance is also commonly seen in patients taking stimu-
lant medications (eg, amphetamines, methylphenidates) for
attention-deficit/hyperactivity disorder (ADHD). Both phar-
macokinetics (ADME) and pharmacodynamics are impor-
tant in determining the effect that a drug regimen is likely
to produce.
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Extrinsic factors such as environmental exposures or
concomitant medications can affect the efficacy of a med-
ication. Smoking tobacco can induce CYP1A2, resulting in
increased enzymatic activity, higher clearance, lower plasma
levels, and efficacy for some drugs (eg, clozapine, imipra-
mine, amitriptyline, clomipramine, duloxetine, fluvoxamine,
and mirtazapine). As another example, corticosteroid resis-
tance may be more prevalent in children exposed to tobacco
smoke. In addition to such exposure, other extrinsic factors
(eg, age, perceived asthma phenotype, a variety of triggers)
may modulate the response to corticosteroids.
The interplay between pharmacokinetics and pharmaco-
dynamics is apparent when assessing therapeutic efficacy,
adverse effects, and toxicity. Medication administration
regimens combined with subsequent drug metabolism
contribute to the therapeutic efficacy as well as the potential
for adverse effects. The TI is the margin of safety between
the dose needed to obtain an effect that is measurable and
desirable and the concentration that causes dangerous
adverse effects. The dose that causes dangerous toxicity
in 50% of patients is abbreviated TD50. Along with the dose
that leads to the pharmacological effect in 50% of patients
(ED50), TD50 makes up the equation for the TI:
TD50
TI ¼
ED50
The intent in establishing the dose for any medication is
to attain a bloodstream concentration high enough to en-
sure clinical efficacy but below that associated with toxicity
(Fig 1). Drug metabolism lowers the serum concentration
over time, resulting in drug concentrations lower than
needed for clinical effect without repeated dosing. A med-
ication with a much wider TI (eg, amoxicillin) allows for less
precision with dosing. In medications with very narrow
therapeutic indices (eg, aminoglycosides), toxicity or under-
treatment can occur with less drastic changes to drug dos-
ages or pharmacokinetic factors.
The half-life of a medication represents the time re-
quired to reduce the amount of drug in the body by 50%.
Traditionally, medications take 4 to 5 half-lives to reach
steady state. As each new dose is entering the body, a certain
amount of each previous dose has been cleared. After the
first dose of a medication is administered, the body starts to
clear it. By the time the 4th or 5th dose is administered, little
of that initial dose is circulating in the body. Because the
rate of clearance is similar to the rate of administration,
a steady state of a medication is achieved. Ideally, this
steady state falls within the TI for successful treatment.
Medications with longer half-lives are not cleared as
rapidly, and, if dosed at too frequent intervals, a cumulative
increase in blood concentration and toxicity occurs. Ideal
dosing strategies maintain a medication concentration
below the level of toxicity while still falling within the
therapeutic range.
DRUG INTERACTIONS
Drug interactions, whether from the presence of another
drug, a food, an herb, or another environmental agent, can
alter the therapeutic response. Specifically, these events
lead to changes in the drug concentration, therapeutic drug
effect, or both. These interactions are especially important
for drugs that exhibit a narrow TI.
Drug-drug interactions occur when 2 or more prescribed,
recreational, or OTC medications are taken around the same
time. However, some drugs may result in interactions days
to weeks after discontinuation of the interacting substance
because of prolonged elimination half-lives (eg, fluoxetine)
or because there is a time delay or a long-term effect of
a drug on the activity of a drug metabolizing enzyme. An
example is the effect of carbamazepine on inducing the
activity of CYP3A4, an enzyme that is involved in the me-
tabolism of numerous drugs. Hence, carbamazepine may
increase the elimination and thereby reduce the bioavail-
ability (and therefore efficacy) of a variety of other drugs. To
better predict possible drug-drug interactions, pharmaco-
logic mechanisms by which these adverse reactions occur
must be understood.
Drug-drug interactions may result from perturbations in
pharmacokinetics or pharmacodynamics. Pharmacokinetic
effects are the result of altered blood or tissue concentra-
tions due to interactions that affect drug absorption, distri-
bution, metabolism, or excretion, and pharmacodynamic
interactions are the result of altered pharmacologic effect
because both drugs have the same or related biologically
active (receptor) sites of action. Absorption interactions
include inhibition of the efflux pump P-gp in the gastroin-
testinal tract (eg, amiodarone and digoxin) and complex
formation between the drug and antacids or cations (qui-
nolone or tetracycline antibiotics binding with Caþ2, Mgþ2,
Feþ3, Alþ3). Drug interactions with cations can also occur
after the medication has reached the bloodstream. Ceftriax-
one, when given with intravenous fluids containing cal-
cium, forms crystalline deposits in the lungs and kidneys
of neonates. Drugs that increase the gastric pH can alter
absorption of medications dependent on an acidic environ-
ment for absorption (eg, ketoconazole and itraconazole).
Ceftriaxone may displace bilirubin from albumin-binding
sites, potentiating the risk of kernicterus in neonates. Dis-
tribution interactions are particularly important when a
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drug that is highly protein bound is displaced by another
agent, resulting in an increase in the free fraction of a medi-
cation, thereby potentiating efficacy but increasing the
risk of adverse effects. Medications affecting tubular secre-
tion can result in increased serum levels when used con-
comitantly (eg, penicillin/probenecid and methotrexate/
aspirin).
Many drug-drug interactions result from either induc-
tion or inhibition drug-metabolizing enzyme systems,
most notably the CYP450 enzymes. Inhibitors impede drug
metabolism, resulting in higher serum drug concentrations
and increased risk of adverse effects, and inducers lead to
increased drug metabolism and lack of therapeutic benefit.
Rifampin is a well-known enzyme inducer, whereas eryth-
romycin, cimetidine, ciprofloxacin, ritonavir, itraconazole,
and quinidine are all inhibitors. When prescribing medi-
cations to patients, providers should have access to refer-
ences that can help them check for clinically relevant
medication and drug-drug interactions via the CYP system.
One such online reference, which does not require sub-
scription to a database, is maintained by the Division of
Clinical Pharmacology at the University of Indiana (http://
medicine.iupui.edu/clinpharm/ddis/main-table).
Pharmacodynamic interactions cause additive, synergistic,
or antagonistic effects between medications. Use of multi-
ple medications with similar adverse effect profiles can lead
to additive adverse effects, including increased sedation
(opiates plus benzodiazepines), increased QT prolongation
(class 1A antiarrhythmics with erythromycin or methadone),
and increased potential for nephrotoxicity (aminoglycosides
plus vancomycin, NSAIDs). Synergistic interactions occur
when 2 drugs with similar pharmacodynamic effects are
simultaneously administered, resulting in greater than sim-
ple additive effects. Improved bactericidal efficacy against
some gram-positive organisms is observed when penicillin
and aminoglycosides are used together for treatment. The
use of penicillin inhibits bacterial cell wall synthesis, which
for some gram-positive organisms can improve the intra-
cellular penetration of the aminoglycoside, which further
inhibits bacterial cell protein synthesis by binding to 30S
and 50S ribosomal subunits. Antagonism can be therapeu-
tically beneficial when trying to reverse the adverse effects of
a particular medication, such as reversal of opiate-induced
respiratory depression by naloxone.
Drug-drug interactions can also occur with OTC medica-
tions and herbal/complementary therapies. Although selec-
tive serotonin reuptake inhibitors (SSRIs) are prescribed in
pediatric patients to treat anxiety and depression, they
block the reuptake of serotonin not only in the central
nervous system but also on the surface of platelets. The risk
Vol. 38 No. 5 MAY 2017 201
 of gastrointestinal bleeding is increased by 50% to
60% owing to additional reduced platelet activity with
concomitant use of NSAIDs with SSRIs compared with
using an NSAID alone. This is an example of an additive
pharmacodynamic interaction. Pharmacokinetic interac-
tions should also be considered with these agents. The
SSRIs, in particular fluvoxamine, paroxetine, and sertraline,
are inhibitors of CYP2C9, which is responsible for the
metabolism of NSAIDs such as ibuprofen and naproxen.
Inhibition of NSAID metabolism has the potential to con-
tribute to its accumulation and toxicity. Although not an
absolute contraindication, families should be counseled on
the appropriate use of NSAIDs in patients taking SSRIs.
Thus, it is imperative that clinicians consider how each
agent is used when considering prescribed drugs and the
interactions that may occur with medications used as
needed for other common concerns.
With the growing use of herbal and complementary med-
ications, the risk of adverse reactions from drug-drug in-
teractions is becoming more apparent. For example, many
herbal supplements (eg, ginkgo, garlic, ginger, bilberry, dong
quia, willow, and coumarin-containing herbs such as cham-
omile, motherwort, horse chestnut, fenugreek, and red
clover) inhibit platelets. When these herbs are taken with
an NSAID, the risk of bleeding is increased. Some herbs, such
as echinacea and kava, are associated with hepatotoxicity,
which could be potentiated when combined with acetamin-
ophen. Willow and meadowsweet are herbs that contain
salicylate, for which there could theoretically be an
increased risk of additive adverse events when combined
with aspirin or other NSAIDs. Valerian, kava, and cham-
omile are used by patients with insomnia owing to their
sedative properties. Combining these herbal agents with
opiates may increase the opiate sedative effects. Drug-
drug interaction studies are not required in the regulation
of herbal and complementary therapies, yet there is
increased interest in all-natural therapies. There is a gen-
eral misconception that natural is safer. Drug information
centers associated with schools of pharmacy can help
prescribers find reliable information regarding drug-herb
interactions.
ADVERSE DRUG REACTIONS
Adverse drug reactions (ADRs) can be classified into 2
subtypes. Type A reactions are dose related and predictable
based on known pharmacologic properties of the medica-
tion. They occur by nonimmunologic mechanisms and
include pharmacokinetic and pharmacodynamic varia-
tions as well as drug interactions. Type B reactions are
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not dose related and cannot be anticipated based on the
drug’s pharmacology; thus, they are unpredictable or
unexpected. These reactions are idiosyncratic or allergic
and generally occur in genetically susceptible individuals.
Because they are not dose related, these events can occur at
doses significantly below, above, or within the therapeutic
range. Pseudoallergic reactions have clinical features con-
sistent with allergic reactions but are caused by non–
immunoglobulin E–mediated release of mediators from
mast cells and basophils.
Nonimmunologic, type A reactions account for up to
85% of ADRs. Pharmacologic adverse effects are the
undesirable or toxic effects that cannot be separated from
the desired pharmacologic actions of the drug. For exam-
ple, dry mouth can occur with antihistamine use, thrush
can occur while taking antibiotics, and opiates can cause
constipation and sedation. Parents and patients should be
educated to understand that a type A reaction does not
prevent the use of a drug in the future if its benefits
outweigh the adverse effects. Because many people refer
to any adverse effect as an “allergy,” the prescriber has to
determine whether the reaction was really immunologi-
cally mediated. For example, approximately 10% of people
report themselves to be allergic to penicillin, whereas
the true incidence of allergy is probably less than 1%. The
type and severity of the reaction must be assessed before
making prescribing decisions.
Other reactions in this category include pseudoallergic
reactions. Opiates can induce pseudoallergic reactions by
directly inducing mast cell degranulation, resulting in
generalized pruritus, flushing, itching, hives, urticaria, and
mild hypotension. Pseudoallergic reactions are more appro-
priately characterized as adverse effects. The opiates more
commonly associated with this reaction include codeine,
morphine, and meperidine. With the occurrence of such a
reaction, treatment options include reducing the dose, pre-
treatment with an antihistamine, or switching to another,
albeit more potent, opiate such as hydrocodone, oxycodone,
or fentanyl.
Type A adverse reactions can still pose a risk of serious
harm to patients. Opiates can cause respiratory depression,
and stimulants used to treat ADHD may cause dysrhyth-
mias. In response to a Food and Drug Administration (FDA)
warning about the risk of sudden cardiac death in children
with structural heart disease and amphetamine use, the
American Heart Association recommended that any child
treated with a stimulant first have a screening echocar-
diogram. However, the American Academy of Pediat-
rics concluded that the evidence does not show that
routine echocardiographic screening would be effective
in preventing sudden cardiac death and recommends care-
ful assessment for cardiac abnormalities by history and
physical examination, with further testing only when
indicated.
Type B reactions are less common, accounting for 15%
of ADRs, and are largely unpredictable. These are some-
times referred to as “allergic” (eg, anaphylaxis, Stevens-
Johnson syndrome, and toxic epidermal necrolysis). These
reactions are immunologically mediated and can be
classified by the Gell and Coombs classification system
(Table 2). These reactions can also be referred to as
idiosyncratic, which is a term that has been used in many
ways and has no clear definition. However, an idiosyn-
cratic reaction is specific to an individual patient. In
general, it is impossible to predict who will develop this
type of ADR. These reactions are rare and often life-
threatening. Examples of idiosyncratic reactions include
troglitazone-induced liver failure, clozapine-induced
agranulocytosis, and sulfonamide-induced toxic epider-
mal necrolysis.
Some drug hypersensitivity reactions are now known to
be related to human leukocyte antigen (HLA) alleles so the
general concept that all type B ADRs are unpredictable
or idiosyncratic may no longer hold true for some medica-
tions. For example, HLA allele B*1502 genotype is a marker
for carbamazepine-induced Stevens-Johnson syndrome
and toxic epidermal necrolysis in Han Chinese individuals,
and the FDA recommends genotyping all Asians for the al-
lele before prescribing carbamazepine.
The FDA has a mechanism whereby consumers, pre-
scribers, and other health care practitioners can voluntarily
report ADRs. If a manufacturer receives an adverse event
report, the manufacturer is legally required to send a
report to the FDA. The FDA Adverse Event Reporting
System database contains adverse event information
and medication error reports. This system is used to
support postmarketing safety surveillance of drugs and
therapeutic biologicals. When potential safety concerns
TABLE 2. Gell and Coombs Classification System
REACTION TYPE MECHANISM
Type I reactions Immunoglobulin E mediated
Type II reactions Cytotoxic
Type III reactions Immune complex (serum sickness or serum sickness–
like syndrome)
Type IV reactions Delayed, cell mediated
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are identified, further investigation is undertaken. When
sufficient evidence supports safety concerns, the FDA
may require that a drug company update the product’s
labeling information, restrict the use of the drug, or
communicate new safety information to the public. In
more rare situations, a drug may be removed from the
market.
Adverse reaction reporting can be completed by visiting
the MedWatch website (http://www.fda.gov/Safety/MedWatch/
HowToReport/default.htm). This site can be used to report a
serious adverse event, product quality problems or use
errors, and suspected therapeutic inequivalence. Given
that most medications prescribed to children have not
actually been tested in children and are, thus, prescribed
to children on an off-label basis, it is particularly impor-
tant to report safety concerns to the FDA. Children may
have drugs prescribed at unapproved doses or unapproved
indications, and data regarding safety and efficacy often
are not available. One-third to one-half of ADRs occur-
ring in a pediatric hospital involved off-label drug use.
Another study found that 17% of the ADRs were associ-
ated with off-label drug use, of which 60% were serious
events.
APPLICATION AND CLINICAL PRACTICE
Prescribers are tasked with providing safe and effective
drug therapy for their patients. This requires an under-
standing and appreciation of the interplay between phar-
macokinetics and pharmacodynamics, including the
mechanisms by which ADRs and drug-drug interactions
occur. In a hospital setting, multidisciplinary teams pro-
vide prescribers additional decision support at the bedside.
Clinical pharmacists can assist with reviewing a patient’s
medication profile for therapeutic duplications, ADRs, and
potential drug-drug interactions. For physicians in private
practice settings, developing a relationship with a phar-
macist in the retail setting or with a pharmacist at a local/
EXAMPLE
b-lactam antibiotics
Drug-induced hemolytic anemia
Equine-based antitoxins and antivenins
Cefaclor
Aromatic antiepileptics (eg, phenytoin)
Vol. 38 No. 5 MAY 2017 203
 regional children’s hospital can be valuable in caring for
patients.
DEFINITIONS
Excipients
An excipient is an inactive substance used in drug for-
mulation to provide long-term stabilization, to bulk up
(fillers or diluents) solid formulations, or to enhance the
active ingredient in the final dosage form by facilitating drug
absorption, reducing viscosity, or improving solubility.
Polar
Drugs or other molecular entities are grouped as polar or
nonpolar molecules. These terms refer to the arrangement
of the atoms in the molecule. For polar molecules (drugs),
one end of the molecule has a positive electrical charge and
the other side has a negative charge compared with non-
polar molecules, in which the electrical charge is more
evenly balanced across the molecule. Drug molecules that
are polar are water soluble, and nonpolar molecules are fat
soluble.
204 Pediatrics in Review
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Summary
• Based on an accumulation of strong research evidence, it is clear
that physicians must understand the disease being treated and
the medications that they prescribe to provide the best practice
for their patients. (1)
• Strong research evidence indicates that gene-gene, gene-
disease, and gene-environment interactions can have a profound
effect on the response to a medication. (1)(2)
• Based primarily on consensus opinion, it is the ultimate
responsibility of the prescriber to anticipate drug interactions and
adverse reactions and to educate patients and their families on
appropriate use of medications.
• Although not carefully studied, expert consensus suggests that
understanding the interplay between pharmacokinetics (what the body
does to the drug) and pharmacodynamics (what the drug does to the
body) can help the pediatrician prescribe the right drug at the right dose.
References for this article are at http://pedsinreview.aappubli-
cations.org/content/38/5/195.
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1. A 5-year-old boy is brought to the emergency department (ED) by his parents after REQUIREMENTS: Learners
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child’s laceration. He consults Child Life and orders a dose of fentanyl to help manage the
To successfully complete
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2017 Pediatrics in Review
Which of the following routes is the most appropriate to use at this time to administer the
articles for AMA PRA
fentanyl dose in this patient?
Category 1 CreditTM, learners
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C. Oral solution. higher on this assessment,
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D. Transdermal/patch.
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2. A 3-year-old girl with a known seizure disorder has been well-controlled on phenytoin activity. If you score less than
twice daily. She is followed regularly by Neurology. Her last seizure was more than 9 60% on the assessment, you
months ago. She presents today to the ED with pallor and breakthrough seizures will be given additional
associated with nystagmus, ataxia, and confusion. There is a history of vomiting and blood- opportunities to answer
tinged diarrhea, which occurred 10 days before presentation. Laboratory studies showed questions until an overall 60%
findings consistent with hemolytic uremic syndrome. No active bleeding is noted. or greater score is achieved.
Which of the following is the most likely cause of the acute change in her neurologic
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A. Decreased phenytoin absorption due to diarrhea. Dec. 31, 2019, however, credit
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D. Decrease in her seizure threshold due to intercurrent illness.
E. Severe dehydration.
3. In addition to intravenous fluid hydration, which of the following is the most appropriate
next step in the management of the described patient?
A. Intravenous antibiotics.
2017 Pediatrics in Review now
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C. Intravenous phenytoin bolus. Maintenance of Certification
D. Platelet transfusion. (MOC) Part 2 credits by the
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4. You are called to the newborn nursery to assess a 9-hour-old female with poor feeding, Portfolio Program. Complete
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You perform a sepsis evaluation and start the neonate on ampicillin and gentamycin. claiming MOC credits as early
Which of the following is the most appropriate measure to take to prevent nephrotoxicity from as October 2017.
gentamycin in this patient?
A. Follow each gentamycin dose with a fluid bolus.
B. Monitor urine specific gravity.
C. Obtain baseline and follow-up serum creatinine levels.

Vol. 38 No. 5 MAY 2017 205

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 D. Obtain peak and trough serum concentrations after the first dose.
E. Start with half of the recommended dose for the neonate’s weight.
5. A 17-year-old girl was seen in the ED and was diagnosed as having a urinary tract infection,
for which she was started on rifampin. The patient is taking combination oral contraceptive
pills (OCPs) and is sexually active. She reports using condoms inconsistently. She presents
today to the clinic with nausea, morning emesis, and delayed menses. Her last menstrual
period was 2 months ago. She is worried as her periods have been regular. Results of a
urine pregnancy test are positive. She is surprised as she has been very compliant with her
OCPs.
Which of the following mechanisms contributed to failure of her contraceptive regimen?
A. Competition between OCPs and rifampin for the same receptor.
B. Decreased levels of OCPs due to rifampin induction of cytochrome P450.
C. Impaired absorption of OCPs due to altered gastric flora by rifampin.
D. Impaired volume of distribution of OCPs due to rifampin intake.
E. Increased renal excretion of OCPs secondary to rifampin use.

206 Pediatrics in Review

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 The Interplay between Pharmacokinetics and Pharmacodynamics
Tracy L. Sandritter, Matthew McLaughlin, Michael Artman and Jennifer Lowry
Pediatrics in Review 2017;38;195
DOI: 10.1542/pir.2016-0101

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 The Interplay between Pharmacokinetics and Pharmacodynamics
Tracy L. Sandritter, Matthew McLaughlin, Michael Artman and Jennifer Lowry
Pediatrics in Review 2017;38;195
DOI: 10.1542/pir.2016-0101

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/38/5/195

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
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