A drug interaction is either the result of pharmacokinetic changes of a
drug or its metabolites due 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. Whereas 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.
Some patient populations are more vulnerable to drug interactions
because 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).
Administration/Absorption: Drug interactions resulting from alterations in
absorption are caused by (1) changes in gastric pH, (2) formation of
complexes in the gastrointestinal (GI) tract, (3) changes in GI motility,
and (4) modulation of P-glycoprotein (P-gp) intestinal absorption of
Distribution: Drug interactions resulting from displacement of drug bound
to protein sites (e.g., 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.
Metabolism: A common cause of clinically significant drug interactions
during multiple drug therapy involves drug metabolism in which
cytochrome P450 isoenzymes (CYPs) play a significant role. Many
drug interactions occur as a result of inhibition or induction of CYP
Excretion/Elimination: Drugs are eliminated mainly through renal tubular
excretion and biliary excretion. Drug 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.
Pharmacodynamic interactions occur when the presence of one drug
changes the effect of another drug without pharmacokinetic alterations.
It may be due to competition at the drug receptor level by indirect
systems, involving interference with physiologic mechanisms, resulting in
additive or synergistic interactions or antagonistic interactions.
RESOURCES AND EVIDENCE FOR CLINICAL DECISION SUPPORT
Patient safety initiatives have expanded in efforts to improve the
on devising optimal approaches to managing drug interactions. A key
challenge is that computerized drug interaction screening systems detect
a large number of drug–drug interactions of questionable clinical
significance. Expert groups have provided recommendations to improve
the usability of clinical decision support alerts for managing drug
Because healthcare 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 will introduce 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
Drug interactions can be broadly categorized as either pharmacokinetic or
1,2 Pharmacokinetic drug interactions involve absorption,
distribution, metabolism, and excretion, whereas pharmacodynamic interactions can
be characterized into three subgroups: (1) direct effect at receptor function; (2)
interference with a biologic or physiologic control process; and (3) additive or
attenuated pharmacologic effect.
3 Another key area of consideration is the biologic
variance in a given individual: genetics, age, disease, as well as the internal
environmental factors (i.e., the patient’s medications, dietary intake, and social habits
such as smoking and alcohol consumption).
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).”
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. Whereas 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.”
In 2015, consensus recommendations for evaluating drug–drug interactions were
published by an expert group that included definitions of relevant terminology for
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 healthcare professionals.
RISK FACTORS FOR DRUG INTERACTIONS
Some patient populations are more vulnerable to drug interactions because of age,
gender, race, 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
9–11 Elderly patients are at an increased risk of drug interactions given
the rates of polypharmacy (estimated at 20% to 50%) in the older population, along
12-14 Adverse drug reactions have been observed 2 to 3
times more frequently in older persons and account for 5% to 17% of all hospital
15Age 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.
population, the frail elderly represents a subgroup in which comorbidities primarily
account for the observed changes in pharmacokinetic and pharmacodynamic
12 When considering the impact of aging, it is important to differentiate the
subgroup of fit elderly from that of the frail elderly, as those who are frail are at
increased risk of death, institutionalization, and worsening disability.
of studies have shown that females are at greater risk for drug interactions.
Further research is needed in this area to better understand gender differences with
20-23 The distribution of many drugs may be significantly altered due
to marked increases in total body weight (TBW).
24 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.
15,25 Critically ill patients, those with poor
nutritional status, and immunocompromised patients are at greater 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
cytochrome P450; enzymes induced by tobacco smoking may also increase the risk of
cancer by enhancing metabolic activation of carcinogens.
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 a 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.
Drug–drug interaction (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, and therefore, a
DDI could occur in the exposed patient
Clinically relevant DDI Drug–drug interaction associated with either toxicity or loss of
efficacy that warrants the attention of healthcare professionals.
for clinical decision support. Drug Saf. 2015;38:197–206.
An individual’s genetic makeup determines his/her complement of metabolizing
enzymes, and based on their genotype, patients may be classified as having a
phenotype for ultrarapid metabolizer, extensive metabolizers, intermediate
metabolizers, or poor metabolizers (Refer to Chapter 4, Pharmacogenomics and
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 decision-making 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 adverse drug
reactions and drug interactions. Whereas 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.
Risk Factors for Drug Interactions
Category Risk Factor Potential Effect
Age (< 5 years and ≥ 65 years) Alterations in drug distribution; ↓ clearance
which may result in drug accumulation
Female gender ↓ ability to metabolize compared to males
Social factors Nutrition Affects cytochrome p450 activity (e.g.,
grapefruit juice inhibits CYP 3A4 activity)
Smoking Affects cytochrome p450 activity (i.e.,
Alcohol Affects cytochrome p450 activity
Organ dysfunction ↓ renal function ↓ clearance, which may result in ↑ serum
concentrations of drug and accumulation
↓ hepatic function ↓ metabolism, which may result in ↑ serum
concentrations and accumulation of the
Heart Failure (HF) ↑ risk due to number of medications
↑ risk due to number of medications
Metabolic and endocrine Obesity ↑ distribution of lipophilic drugs
Fatty liver Altered metabolism
Hypoproteinemia ↑ serum drug concentration
Acute medical conditions Dehydration ↑ serum drug concentrations
Small volume of distribution Drug confined to the plasma
Cytochrome p450 substrate ↓↑ serum drug concentration with
coadministration inducer or inhibitor
P-glycoprotein substrate ↓↑ serum drug concentration with
coadministration inducer or inhibitor
Other factors Polypharmacy Risk of adverse drug interactions ↑ with
increase in number of medicines
Number of prescribers Number of prescribed drugs ↑ with multiple
Number of pharmacies utilized Number of prescribed drugs ↑ with multiple
Pharmacist may not have knowledge of all
Self-prescribing OTC medicines interacting with prescribed
Duration of hospitalstay Susceptible to hospital-acquired conditions
aRefer to Chapter 4 Pharmacogenomics and Personalized Medicine for further information.
QUESTION 1: N.M. is a 68-year-old obese, Hispanic female who underwent a total knee replacement at a
weeks. The first dose will be administered in the evening on the day of surgery.
recall the names of the products. Her renal and hepatic functions are within normal range.
Describe N.M.’s risk factors for drug interactions with the addition of warfarin postsurgery.
N.M. has multiple factors including patient-specific and drug-specific ones that
increase her risk for drug interactions. Her patient risk factors include obesity, age,
Metabolic: obesity—increased distribution of lipophilic drugs (phenytoin);
comorbidities: hypertension; and hypercholesterolemia
Age: 66 years old—altered pharmacokinetics and pharmacodynamics
Smoking history—induces the cytochrome (CYP) P450 system
With regard to drug-specific factors, N.M. has been taking phenytoin, a drug with a
NTI, for the past 10 years. She will be receiving warfarin, another agent with NTI.
Both medications are metabolized via cytochrome P450 system. In addition, N.M. is
at increased risk of additional drug interactions due to polypharmacy because she has
chronic disease comorbidities (i.e., seizure disorder, hypertension, and
Warfarin—NTI, highly protein bound to albumin, small volume of distribution,
metabolized by cytochrome P450 system
Phenytoin—NTI, highly protein bound to albumin, metabolized by CYP2C9 and
CYP2C19 isoforms, and susceptible to drugs that inhibit hepatic microsomal
Pravastatin—whereas pravastatin does not appear to interact with warfarin, other
agents in this class (i.e., atorvastatin, fluvastatin, rosuvastatin and simvastatin)
have been suspected or are known to alter the INR in patients who receive
Lisinopril—a concern when administered concomitantly with diuretics or potassium
Polypharmacy—prior to admission, she is already on 3 prescription drugs and also
takes OTC products. She is a poor historian.
Mechanisms of Drug Interactions
Following oral administration, most drug absorption occurs in the proximal small
37 However, drug interactions that alter absorption may occur throughout the
gastrointestinal (GI) tract by a variety of different mechanisms, including
complexation (adsorption or chelation), changes in pH, changes in GI motility,
altered drug transport, and enzymatic metabolism. The net effect of one or more of
these mechanisms is a change in the rate of absorption, the extent of absorption, or a
combination of both. While interactions that result in a reduced rate of absorption are
generally not clinically significant for drugs given over the long term in multiple
doses, for acutely administered drugs, such as analgesics or hypnotics, this can lead
to an unaccepted delay or therapeutic failure.
With regard to changes in gastric pH, the majority of drugs orally administered
must be dissolved and absorbed in a gastric pH between 2.5 and 3. Drugs, such as
antacids, proton pump inhibitors (PPIs), or H2-antagonists, can alter the kinetics of
3 Antifungal agents, such as ketoconazole or itraconazole,
require an acidic environment to be properly dissolved. Coadministration with drugs
that increase gastric pH may cause a reduction in the dissolution and absorption of
antifungal drugs. It is recommended that these antifungal agents be administered at
least 2 hours after the administration of antacids.
Coadministration of medications around the same time can result in drug
interactions that may be clinically significant. Some antibiotics, such as tetracyclines,
will combine with metal ions (e.g., calcium, magnesium, aluminum, iron) to form
complexes that are poorly absorbed. Antacids also reduce the absorption of
fluoroquinolones (e.g., ciprofloxacin) and tetracyclines because the metal ions form
complexes with the drug. Therefore, the antacids and fluoroquinolones should be
administered at least 2 hours apart. These types of interactions can decrease clinical
effectiveness of the antibiotic and can lead to the emergence of resistant organisms.
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