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Drug Interactions
Michelle Ceresia, Caroline S. Zeind, John Fanikos, and Michael G.
Carvalho
CORE PRINCIPLES
CHAPTER CASES
A drug interaction is either the result of
pharmacokinetic changes of a drug or
its metabolites owing to alteration in
absorption, distribution, metabolism, or
excretion or is the result of
pharmacodynamic changes, impacting
the effect or mechanism of action. There
are several types of drug interactions.
Although the classic interaction involves
two drugs (drug–drug interaction or
DDI), a drug interaction can involve the
interaction of a drug with a nutrient,
chemical, food, herbal, disease, or
laboratory test.
Case 3-1 (Questions
2–6)
Case 3-2 (Questions
2, 3)
Case 3-3 (Question 1),
Tables 3-1, 3-3, and 34
Some patient populations are more
vulnerable to drug interactions because
Case 3-1 (Question 1)
Case 3-2 (Question 1)
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1
2
3
4
of age, gender, race, and comorbidities,
such as renal and hepatic insufficiency.
Drugs that have a higher potential for an
interaction are those with a narrow
therapeutic index (NTI).
Case 3-3 (Question 1),
Table 3-2
PHARMACOKINETIC CHANGES
Administration/absorption: Drug
interactions resulting from alterations in
absorption are caused by (a) changes in
gastric pH, (b) formation of complexes in
the gastrointestinal (GI) tract, (c)
changes in GI motility, and (d)
modulation of P-glycoprotein (P-gp)
intestinal absorption of drugs.
Case 3-1 (Question 1)
Case 3-2 (Question 3),
Table 3-3
Distribution: Drug interactions resulting
from displacement of drug bound to
protein sites (eg, albumin), particularly
with drugs with a high degree of plasma
protein binding that are more likely to be
displaced by a drug with greater affinity
for the same binding site.
Case 3-1 (Question 2),
Figure 3-1, Table 3-3
Metabolism: A common cause of
clinically significant drug interactions
during multiple drug therapy involves
drug metabolism in which cytochrome
P450 (CYP) isoenzymes play a
significant role. Many drug interactions
occur as a result of inhibition or
induction of CYP enzymes.
Case 3-1 (Questions
3, 5, 6)
Case 3-2 (Question 2)
Case 3-3 (Question 1),
Figure 3-2, Table 3-3
Excretion/elimination: Drugs are
eliminated mainly through renal tubular
excretion and biliary excretion. Drug
Case 3-2 (Question 2),
Table 3-3
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1
interactions may occur during the
elimination of drugs and their
metabolites by the kidney as a result of
competition at the level of active tubular
secretion, interference with tubular
transport, or during tubular reabsorption.
PHARMACODYNAMICS CHANGES
Pharmacodynamic interactions occur
when the presence of one drug changes
the effect of another drug without
pharmacokinetic alterations. It may be
owing to competition at the drug
receptor level by indirect systems,
involving interference with physiologic
mechanisms, resulting in additive or
synergistic interactions or antagonistic
interactions.
Case 3-1 (Question 4)
Case 3-2 (Questions
2, 3), Table 3-4
RESOURCES AND EVIDENCE FOR CLINICAL DECISION
SUPPORT
Patient safety initiatives have expanded
in efforts to improve the health care
delivery system with medication error
prevention as a high-priority area.
Health care providers have become
increasingly challenged on devising
optimal approaches to managing drug
interactions. A key challenge is that
computerized drug interaction screening
systems detect a large number of DDIs
of questionable clinical significance.
Expert groups have provided
recommendations to improve the
Case 3-1 (Question 6)
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usability of clinical decision support
(CDS) alerts for managing drug
interactions.
INTRODUCTION
Because health care professionals are committed to ensuring patient
safety and preventing drug-related harm, it is important to
understand drug interaction principles and how to apply drug
interaction decision support tools to provide evidence-based clinical
decisions. This chapter introduces the reader to general principles
and concepts of drug interactions. Case studies are incorporated to
illustrate the application of key concepts and to highlight the
importance of understanding the mechanisms by which drugs
interact and how it impacts the clinical assessment and management
of drug therapy. Disease-specific chapters within this textbook will
also apply drug interaction concepts and incorporate case studies
relevant to disease management.
DEFINITION
Drug interactions can be broadly categorized as either
pharmacokinetic or pharmacodynamic in nature.
1,2
Pharmacokinetic
drug interactions involve absorption, distribution, metabolism, and
excretion, whereas pharmacodynamic interactions can be
characterized into three subgroups: (a) direct effect at receptor
function, (b) interference with a biologic or physiologic control
process, and (c) additive or attenuated pharmacologic effect.
3
Another key area of consideration is the biologic variance in a given
individual: genetics, age, disease, and the internal environmental
factors (ie, the patient’s medications, dietary intake, and social habits
such as smoking and alcohol consumption).
4
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A drug–drug interaction (DDI) is defined “as a clinically meaningful
alteration in the exposure and/or response to a drug (object drug)
that has occurred as a result of the coadministration of another drug
(precipitant drug).”
1–2,5,6
Drug interactions may have beneficial effects
because some drug interactions are used to enhance therapeutic
outcomes, whereas other interactions may have deleterious effects
that result in serious toxicity or may inhibit the effects of a drug,
leading to suboptimal therapeutic outcomes. Although the classic
interaction involves two drugs (DDI), a drug interaction can involve
the interaction of a drug with a nutrient, chemical, food, herbal,
disease, or laboratory test.
7,8
A potential drug interaction is defined
“as the occurrence in which two drugs that are known to interact are
concurrently prescribed, regardless of whether adverse events
occurred.”
8
In 2015, consensus recommendations for evaluating DDIs were
published by an expert group that included definitions of relevant
terminology for evaluation of DDI evidence.5 Table 3-1 highlights
their recommendations for key terms of relevant terminology for
evaluation of DDI evidence. (The reader is referred to the complete
list of definitions agreed upon by this expert group that are provided
in their supplementary publication.)5 They emphasize the importance
of consistent use of relevant terminology for evaluation of DDI
evidence. For example, a clinically relevant DDI is defined as one
that is associated with either toxicity or loss of efficacy that warrants
the attention of health care professionals.
2
Table 3-1
Terminology Related to DDI
Terminology
DDI Clinically meaningful alteration in the exposure and/or response to
a drug (object drug) that has occurred as a result of the
coadministration of another drug (precipitant drug)
Potential DDI Coprescription of two drugs known to interact; therefore, a DDI
could occur in the exposed patient.
Clinically
relevant
Drug–drug interaction associated with either toxicity or loss of
efficacy that warrants the attention of health care professionals
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DDI
NTI drugs Drugs for which even a small change in drug exposure may lead to
toxicity or loss of efficacy
DDI, drug–drug interaction; NTI, narrow therapeutic index.
Source: Adapted by permission from Springer. Scheife RT, Hines LE, Boyce RD, et
al. Consensus recommendations for systematic evaluation of drug-drug interaction
evidence for clinical decision support. Drug Saf. 2015;38(2):197–206.
The Food and Drug Administration (FDA) has now provided
guidance to evaluate DDIs as part of a company’s assessment of the
drug’s benefits and risks during the drug development process.
9
Clinically relevant DDIs should be recognized at the time of drug
approval, monitored after approval, and communicated in the
package labeling. Studies will be completed to determine whether
cytochrome P450 (CYP) enzyme- and transporter-mediated DDIs
alter the pharmacokinetics of new drug or the pharmacokinetics of
other drugs. Studies will also determine the clinical significance of
the observed or expected DDIs and any appropriate management or
prevention strategies. Because known agents will be used to
determine whether a new medication is a victim or perpetrator of
DDIs, clinicians can expect to see a list of common offending
medications reported in the package labeling.
RISK FACTORS FOR DRUG INTERACTIONS
Some patient populations are more vulnerable to drug interactions
because of age, gender, and comorbidities, such as renal and
hepatic insufficiency. Polypharmacy, defined as the concomitant use
of multiple drugs or the administration of more medications that are
indicated clinically, is a leading cause of DDIs, resulting in higher
rates of adverse events, higher drug costs, and medication
nonadherence.
10–12
Elderly patients are at an increased risk of drug
interactions given the rates of polypharmacy (estimated at 20%–
50%) in the older population, along with multiple comorbidities.
13–15
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Adverse drug reactions (ADRs) have been observed two to three
times more frequently in older persons and account for 5% to 17% of
all hospital admissions.16 Age alone is a key risk factor in the elderly
population as altered pharmacokinetics and pharmacodynamics may
result in a slower intestinal transit time, diminished absorption
capacity, decreased liver metabolism and renal excretion, and
alterations in volemia and body fat distribution.
17,18
Within the older
population, the frail elderly represents a subgroup in which
comorbidities primarily account for the observed changes in
pharmacokinetic and pharmacodynamic properties.13 When
considering the impact of aging, it is important to differentiate the
subgroup of fit elderly from that of the frail elderly, because those
who are frail are at increased risk of death, institutionalization, and
worsening disability.
13,19,20
A number of studies have shown that
females are at higher risk for drug interactions.
21–24
Further research
is needed in this area to better understand gender differences with
drug interactions.
21–24
The distribution of many drugs may be
significantly altered because of marked increases in total body
weight (TBW).25 Drugs that are lipophilic will have an increased
volume of distribution. Patients who are obese and those who are
malnourished will have altered levels of metabolizing enzymes,
increasing their susceptibility to drug interactions.
16,26
Critically ill
patients, those with poor nutritional status, and patients who are
immunocompromised are at higher risk of drug interactions.
Cigarette smoking can affect drug therapy by both pharmacokinetic
and pharmacodynamic mechanisms. It can affect drug therapy by
enzyme induction of CYP; enzymes induced by tobacco smoking
may also increase the risk of cancer by enhancing metabolic
activation of carcinogens.27 Drugs that have a higher potential for an
interaction are ones with a narrow therapeutic index (NTI) because
there are small differences between therapeutic and toxic doses. For
example, lithium, a monovalent cation, is a drug with an NTI that is
influenced by changes of serum sodium. Patients taking lithium and
who are also receiving chronic treatment with thiazides are at risk of
lithium toxicity because thiazides can cause a high excretion of
sodium that may increase lithium reabsorption.
3
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An individual’s genetic makeup determines their complement of
metabolizing enzymes, and based on their genotype, patients may
be classified as having a phenotype for ultrarapid metabolizer,
extensive metabolizer, intermediate metabolizer, or poor metabolizer
(refer to Chapter 4, Pharmacogenomics and Personalized
Medicine).28 Individuals who use multiple providers and/or multiple
pharmacies are more likely to have incomplete information available
for both the providers and themselves; this impacts clinical decisionmaking and increases the likelihood that a drug interaction may go
undetected. Individuals who self-prescribe and take over-the-counter
(OTC) products (including dietary supplements, vitamins, minerals,
and herbal agents) may not understand the potential risk for drug
interactions. In addition, if they do not maintain a complete listing of
OTC products for themselves and their providers, there is a greater
likelihood for ADRs and drug interactions. Although disease-specific
chapters in this textbook will provide a wide array of risk factors for
drug interactions, Table 3-2 outlines examples of risk factors for drug
interactions.
Table 3-2
Risk Factors for Drug Interactions
1,13–34
Category Risk Factor Potential Effect
Patient
characteristics
Demographics
Age (<5 years and ≥65
years)
Alterations in drug distribution; ↓
clearance that may result in drug
accumulation
Female gender ↓ Ability to metabolize compared to
males
Social factors Nutrition Affects cytochrome p450 (CYP)
activity (eg, grapefruit juice
inhibits CYP3A4 activity)
Smoking Affects CYP activity (ie, induces
CYP1A2)
Alcohol Affects CYP activity, specifically
CYP2E1
Organ
dysfunction
↓ Renal function ↓ Clearance, which may result in ↑
serum concentrations of drug
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and accumulation
↓ Hepatic function ↓ Metabolism, which may result in ↑
serum concentrations and
accumulation of the parent drug
and/or metabolite
Heart failure (HF) ↑ Risk owing to the number of
medications prescribed with
comorbidities
Chronic obstructive
pulmonary disease
(COPD)
↑ Risk owing to the number of
medications prescribed with
comorbidities
Metabolic and
endocrine
Obesity ↑ Distribution of lipophilic drugs
Fatty liver Altered metabolism
Hypoproteinemia ↑ Serum drug concentration
Genetic
a
Genetic polymorphisms
(ultrarapid, extensive,
intermediate, or poor
metabolizers)
Altered metabolism
Acute medical
conditions
Dehydration ↑ Serum drug concentrations
Hypotension ↓ Clearance
Hypothermia ↓ Clearance
Infection ↑ Catabolism
Drug
characteristics
Narrow therapeutic index
(NTI)
↑ Risk of dose-related adverse
drug events
Highly protein bound ↑ Free fraction (active drug) from
protein displacement
Small volume of
distribution
Drug confined to the plasma
CYP substrate ↓↑ Serum drug concentration with
coadministration of inducer or
inhibitor precipitant drug
P-glycoprotein substrate ↓↑ Serum drug concentration with
coadministration of inducer or
inhibitor precipitant drug
Other factors Polypharmacy Risk of adverse drug interactions ↑
with increase in number of
medicines
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Number of prescribers Number of prescribed drugs ↑ with
multiple prescribers
Number of pharmacies
utilized
Number of prescribed drugs ↑ with
multiple pharmacies
Pharmacist may not have
knowledge of all drugs
prescribed to patient.
Self-prescribing OTC medicines interacting with
prescribed medicines
Duration of hospital stay Susceptible to hospital-acquired
conditions and subsequent drug
therapy
OTC, over-the-counter.
a
Refer to Chapter 4, Pharmacogenomics and Personalized Medicine for further
information.
CASE 3-1
QUESTION 1: F.D. is a 79-year-old female patient who underwent a total hip
replacement at a large teaching hospital. The medical team plans to start F.D.
on warfarin therapy for venous thromboembolism prophylaxis with an
international normalized ratio (INR) target range of 1.8 to 2.3 for a total duration
of 3 weeks. The first dose will be administered in the evening on the day of
surgery.
Her medical history includes newly diagnosed osteoporosis, recently started
on alendronate; epilepsy that developed several years ago, controlled with
phenytoin; and hypercholesterolemia for the past 9 years, for which she takes
fluvastatin. She does not drink alcohol and has never smoked. She takes an
OTC medicine, but does not recall the name of the product. She has some renal
dysfunction (creatinine clearance 70 mL/minute). Her hepatic function is within
normal range. F.D. requests that the medical team electronically transmit her
new prescriptions postdischarge to a pharmacy located in close proximity to her
friend’s home because she will be recuperating there.
What are F.D.’s risk factors for drug interactions with the addition of warfarin
postsurgery?
F.D. has multiple factors including patient- and drug-specific ones
that increase her risk for drug interactions. Her patient risk factors
include age, gender, and renal dysfunction.
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