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3 Predisposing Factors forAdverse Drug Reactions
69
ensures avoidance or minimizing ADRs in relation
to the predisposing factors, wherever possible.
Special attention must be paid to potential
drug–drug interactions (including interaction
with OTC drugs and herbal medicines) and food–
drug interactions. Pharmacists should inform the
prescriber of anypotential safety issues with the
drugs prescribed.
6.2.3 Administration oftheDrug
Predisposing factors need to be carefully considered when the drug is administered by the clinician or nurse. Necessary precautions should be
taken to avoid ADRs and immediate management
to be instituted if it occurs. An appropriate review
of the patient, disease, and drug details before
administration will help minimize or prevent the
occurrence of ADRs.
6.2.4 Use by Patients
Patient education and understanding will increase
the chance of safer medication use with careful
consideration of predisposing factors. Support
for the patient should be provided during the
entire drug use process.
6.2.5 Monitoring/Follow-Ups
There might be specic monitoring parameters
for individual drugs to check the presence or
development of predisposing factors. These monitoring steps should be informed to the patient at
the time of prescribing and their involvement in
adhering to these steps. Appropriate action should
be taken wherever required based on the results
of these monitoring parameters.
7 Summary andConclusions
The existence of predisposing factors for ADRs
explains why not all patients who use a drug
develop a specic ADR and those who develop
do not experience it with the same seriousness,
severity, at the same time, or with the same drug
posology. Predisposing factors for ADRs can be
considered as components of a sufcient cause
that, along with the drug, can lead to an adverse
event. The identication of predisposing factors
is important to reduce the burden of ADRs and is
of importance in pharmacovigilance as they are
the target of risk minimization measures such as
the restriction of indications or the addition of
contraindications or warnings on the drug label.
The knowledge of predisposing factors is also
imperative to the individual care of patients, as
physicians could individualize the pharmacological treatment in an effective way, and patients
could be better informed, thereby preventing and
managing ADRs in a more useful manner.
Predisposing factors can be grouped into four
categories, including those related to patient
characteristics, those related to the underlying
diseases, those related to environmental factors,
and those that are drug-related. Among the various tools available for identication and evaluation of predisposing factors, analytical
epidemiological studies are the main one.
Predisposing factors should be managed at public health, regulatory, and clinical practice levels.
At the public health and regulatory levels, management involves updating of the drug label,
active implementation of additional risk minimization measures by marketing authorization
holders, and/or adoption of restrictive regulatory
measures. Predisposing factors for ADRs require
careful consideration at various steps of drug use
in clinical practice, which highlights the unique
role of various stakeholders and the need for a
multidisciplinary approach.
8 Case Studies
8.1 Case Study 1: A
Pharmacovigilance Signal
Suggesting a Predisposing
Factor
The pharmacovigilance center, at which you are
working, has received 40 spontaneous reports of
acute liver injury associated with the use of drug
A after 6 months of its marketing. Most cases
were serious enough to require hospitalization,
but no fatalities were reported. Remarkably, in 32
out of the 40 reports (80%), the patients were
females.
70
J. Jose and F. J. de Abajo
1. With this information, might you consider that
the female sex is a predisposing factor for
acute liver injury?
Not necessarily. Such distribution of cases
may reect the actual use of drug A (it may
occur thataround 80% of users are women).
2. Which additional data will you look for, and
what assessment will you make depending on
the results?
At least, drug consumption by sex in the
same geographical area or country from where
the ADR reports are obtained must be looked
for. If the distribution of use by sex is similar
to that found in the ADR reporting series, then
it will rule out that female sex was actually a
predisposing factor for this ADR. However, if
the distribution by sex is extremely different in
the series of the ADR reports compared to that
of the population, then the next step would be
to assess how likely selective reporting is in
females. For instance, it would be important to
look at the indication for which the drug was
administered, the dose, the duration, and the
concomitant medications. It may happen that
the ADR would occur more often when the
drug is used for a certain disease, at a certain
dose, or duration, or when used with certain
medications (potential pharmacological interaction) that may be specic or more frequent
in females. Moreover, it could happen that
women treated with the drug are older than
men, and, then, age may be the real predisposing factor behind the greater frequency of the
ADR among women; in this case, we would
say that age is a “confounding factor” that
leads us to observe a spurious association
between the ADR and female sex.
3. If a study is judged necessary, which kind of
study would you propose to carry out and how
would you determine whether the female sex
is a predisposing factor?
The type of study to be carried out would
be an analytical study, for instance, a cohort
study, or a case–control study, in which it
would be possible to properly assess the
potential epidemiological interaction between
drug exposure and sex to induce liver injury
while controlling for the confounding factors.
If female sex is a predisposing factor for liver
injury induced by drug A, then the measure of
association between drug and liver injury will
be much greater among females than among
males. Such a difference can be assessed
through an interaction test (like the Altman
and Bland test). Alternatively, relative excess
risk due to interaction (RERI) can be estimatedand, if greater than 0, it would suggest
that the female sex is a predisposing factor for
liver injury associated with drug A.
If the ADR was detected in premarketing
clinical trials, it would be interesting to
request the marketing authorization holder to
explore the clinical database and make a subgroup analysis by sex.
4. If the whole available evidence conrms that
female sex is a predisposing factor, then how
would you manage the issue at the regulatory
level? How will you manage the issue at the
clinical practice level?
At the regulatory level, it would be necessary to perform an overall benet–risk assessment in females. Depending on this and the
seriousness of the ADR, the risk minimization
measures would range from including a warning on the drug label up to including a contraindication to avoid the use of drug A in women.
The possibility of applying additional risk minimization measures should also be considered,
such as educational material for physicians and
patients, or the possibility of implementing
clinical or analytical monitoring (e.g., liver
enzymes) to prevent or, at least, to detect the
safety issue as soon as possible. It will also be
necessary to communicate the safety issue to
the health-care professionals and patients, recommending specic actions to prevent or minimize the risk (such as analytical monitoring).
At the clinical practice level, physicians
should apply regulatory decisions. If drug A is
contraindicated in women, then the physician
should abstain from prescribing this drug to
them. If not contraindicated, then the physi-
3 Predisposing Factors forAdverse Drug Reactions
71
cians should inform the female patients and
discuss with them the benets and risks of this
drug and also the possible alternatives. If the
drug is nally prescribed, then the clinical
team (including nurses and pharmacists) will
ensure that the risk minimization measures
are correctly implemented.
8.2 Case Study 2: The Hazard of
Ignoring an Important
Predisposing Factor
An 81-year-old patient is admitted to a hospital
for pancytopenia. He had myasthenia gravis (an
autoimmune disease) treated with azathioprine
since 3years at a dose of 75mg/day and pyridostigmine (a cholinesterase inhibitor) at a
dose of 60 mg four times daily, with good
response. The thiopurine methyltransferase
(TPMT) activity performed before prescribing
azathioprine was 21.4U/mL, which indicates a
normal function. Among the antecedents, the
patient reports that the primary care physician
found hyperuricemia in an analytical test
(8.4 mg/dL) and decided to initiate treatment
with allopurinol (300 mg/day) to reduce this
level.
1. Pancytopenia is a well-known ADR of azathi-
oprine. What type of ADR is it? Can you identify any predisposing factor in this case?
Bone marrow toxicity is an ADR resulting
from the augmentation of the pharmacological action of azathioprine (a type A ADR).
Old age and, presumably, an impaired renal
function can be considered as predisposing
factors. However, in this particular case, the
most important risk factor seems to be a drug–
drug interaction with allopurinol (a triggering
factor, actually). Allopurinol is a xanthine oxidase inhibitor and, by this mechanism, inhibits the formation of uric acid, but this enzyme
also contributes partly to metabolize azathioprine. So, its inhibition by allopurinol
increases the pharmacological action of azathioprine and predisposes patients to bone
marrow toxicity. It is a well-known pharma-
cokinetic interaction described in the drug
labels of both drugs.
2. Could this health problem have been pre-
vented? How should it have been managed in
clinical practice?
As the bone marrow toxicity of azathioprine is a dose-dependent ADR, it can be minimized with an appropriate dose. Physicians
should take into account factors that can
increase the pharmacological action of azathioprine, such as renal function and the concomitant use of xanthine oxidase inhibitors.
In the latter case, the recommended daily dose
should be reduced to 25% of the usual one.
On the other hand, it seems that allopurinol
has been prescribed to treat an asymptomatic
hyperuricemia, and this is an inappropriate
use. Allopurinol is indicated to prevent acute
gout ares (by maintaining the uricemia level
below 6mg/dL). Thus, as the patient had no
antecedents of gout attacks, allopurinol should
not have been prescribed. It can be considered
as a medication error.
3. What is TMPT activity, and why is it impor-
tant to know its value before prescribing
azathioprine?
Azathioprine is metabolized by the enzyme
thiopurine methyltransferase (TPMT), which
is polymorphic. When its activity is below
5U/mL, patients are at high risk of presenting
bone marrow toxicity, so it is better to avoid
its use for nonmalignant indications.
Alternatively, if TPMT can be genotyped,
azathioprine should be avoided for nonmalignant indications in patients who are poor
metabolizers (carriers of two nonfunctional
alleles) or the starting dose should be reduced
(30–80% of normal dose) in case of intermediate metabolizers [95].
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Drug Interactions andTheir
Management
SuzanneMcCarthy andAoifeFleming
4
Abstract
With the increasing prevalence of polypharmacy, it is more important than ever to consider the possibility of drug–drug interactions.
A drug–drug interaction occurs when the way
in which a drug works is altered by the presence of another drug. Interactions can also
occur between drugs and other substances contained in herbs, supplements, food, and smoking. Further drug interactions can include
drug–disease and drug–laboratory test interactions. Drug–drug interactions can be classied
into two main categories: pharmacokinetic and
pharmacodynamic. Pharmacokinetic drug
interactions occur when one drug alters the
rate or extent of absorption, distribution,
metabolism, or excretion of another drug.
Many drug interactions that occur in practice
are pharmacokinetic in nature, for example,
those interactions affecting the metabolism of
a drug through the involvement of cytochrome
S. McCarthy (*)
School of Pharmacy, University College Cork,
Cork, Ireland
e-mail: s.mccarthy@ucc.ie
A. Fleming
School of Pharmacy, University College Cork,
Cork, Ireland
Pharmacy Department, Mercy University Hospital,
Cork, Ireland
P450 enzymes in the liver. Pharmacodynamic
drug interactions occur when the action of a
drug in the body is altered by a coadministered
drug. In this chapter, we will consider the
mechanisms by which drug interactions occur,
examine some clinically relevant drug interactions, outline how drug interactions can be
managed and prevented in practice by healthcare professionals, and consider the future
research needs relating to drug interactions.
Keywords
Drug interactions · Pharmacokinetic ·
Pharmacodynamic · Cytochrome P450
enzymes
Learning Objectives
By the end of this chapter, readers should be able
to:
• Discuss the prevalence of drug interactions
and the factors that increase the risk of their
occurrence.
• Categorize drug interactions according to
their mechanisms of action.
• Describe the different mechanisms by which
pharmacokinetic drug interactions occur and
their effects.
• Describe the different types of pharmacody-
namic drug interactions and their effects.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
J. Jose et al. (eds.), Principles and Practice of Pharmacovigilance and Drug Safety,
https://doi.org/10.1007/978-3-031-51089-2_4
77
78
S. McCarthy and A. Fleming
• Appreciate various clinically relevant drug
interactions.
• Discuss drug–herb, drug–food, drug–disease,
and drug–laboratory test interactions.
• Describe ways in which pharmacists and
health-care professionals can prevent and
manage drug interactions in practice.
Key Points
• Drug interactions can occur between two
or more medications or between a medication and another substance, including
foods, supplements and herbs, diseases,
and laboratory tests.
• Drug interactions can lead to reduced
efcacy of the medication, increased
side effects, or unexpected adverse
reactions.
• Types of drug interactions based on
mechanism include pharmacokinetic
interactions that affect the absorption,
distribution, metabolism, and excretion
of drugs and pharmacodynamic interactions that occur when the pharmacological effect of one drug is altered by that
of the other.
• Health-care professionals must consider
a patient’s medical history, current medications, and individual characteristics
to predict and manage potential
interactions.
• Patients also play a pivotal role in pre-
venting interactions by informing their
health-care providers about all medications and supplements they are taking.
• Some interactions are well- documented
and studied, whereas others may be less
understood, emphasizing the importance of continuous research and vigilance in the eld. Overall, awareness of
drug interactions is essential for ensuring safe and effective patient care.
1 Introduction
Globally, people are living longer, with the average life expectancy at 73.4years in 2019 up from
66.8years in the year 2000 [1]. This demographic
change results in an increase in older people living with chronic medical conditions requiring
medical and medication interventions. The use of
multiple medications is frequently observed in
practice where single conditions may require several medications such as in the case of type 2 diabetes mellitus or hypertension and, in addition,
where patients present with multiple conditions,
thus requiring many more medications. We often
consider the term “polypharmacy,” commonly
dened as the use of ve or more medicines [2],
as synonymous with inappropriate prescribing,
and, while this is not the case, it is important to
consider that the more medications a patient is
prescribed, the higher the risk of adverse drug
reactions and harm [3]. One of the mechanisms
by which this can occur is through drug interactions. In this chapter, we will examine in detail
the different types of drug interactions that exist,
the mechanism by which they occur, and how to
prevent and manage them.
2 An Overview ofDrug
Interactions
2.1 What Are Drug Interactions?
A drug interaction occurs when the effects of
one drug are altered by the coadministration of
another drug, food, or substance [4]. We often
think of drug interactions occurring when the
way in which a drug works is altered by the
presence of another drug (drug–drug interaction
(DDI)), which may be a prescribed medication
or a medication purchased over the counter
(OTC) at a pharmacy. However, drug interactions can also occur when a drug is altered by
the presence of excipients in medications, by the
4 Drug Interactions andTheir Management
79
presence of food, herbs, or dietary supplements,
or other environmental chemical agents [4].
Drug interactions can be classied in several
ways. They can be classied according to their
mechanisms of action, e.g., pharmacokinetic or
pharmacodynamic (Sect. 3), classied as actual or
potential interactions, and classied according to
the risk of harm for the patient. “Potential drug–
drug interaction” is the term that is used to refer to
the possibility that a drug can alter the effects of
another drug when they are administered simultaneously [5]. Actual drug–drug interactions are
when we consider that the interactions have
occurred in the patient. The drug interaction
resource Lexicomp® provides denitions of drug
interactions based on the risk to the patient as follows: Major-Severity Major, which are potentially
severe or life-threatening interactions, the signicance of which is supported by the primary literature; Moderate-Severity Moderate, which are
interactions that may cause deterioration in the
patient’s clinical status, the signicance of which
is supported by the primary literature; ModerateSeverity Major, which are interactions that
although may cause major effects, the literature to
support their signicance is highly limited; MinorSuspected, which are interactions that are unlikely
to be clinically relevant, the signicance of which
is supported by the limited primary literature;
Doubtful/Unknown, which are interactions that
are unlikely to be clinically signicant and in addition are only supported by limited or conicted
data [6].
2.2 Prevalence ofDrug–Drug
Interactions
Determining how prevalentDDIs are can be difcult. First, many DDIs may not be recognized
by health-care professionals and adverse drug
reactions that may occur as a result may be attributed to a new medical condition. Second, even
when DDIs are identied, they may be underreported by health-care professionals. A systematic
review examining factors associated with under-
reporting of adverse drug reactions reported that
ignorance of the need to report, difdence, lethargy, indifference to the benet of reporting,
insecurity in determining causation, and complacency that all drugs that are available on the market are safe were attributed to health-care
professional reporting [7]. Finally, studies that
investigate the epidemiology of DDIs lack standardization in terms of classifying DDIs and the
methods used (for example, considering actual
DDI occurrence or the potential for DDI based on
medications prescribed), all leading to heterogeneity among studies and huge variability in the
reported gures [8]. A systematic review and
meta-analysis in hospitalized patients reported
the prevalence of potential DDIs among 33% of
general patients and 67% of intensive care
patients [9]. A systematic review of the prevalence of drug interactions in hospitalized elderly
patients reported the prevalence of DDIs to be
between 8.34% and 100% [8]. Studies in the
community-dwelling population also report high
levels of DDIs among older people; a study by
Hughes et al. in Ireland reported that approximately one-quarter of people aged 70years and
older were potentially exposed to at least one
severe DDI affecting the cardiovascular or central nervous system [10]. Although there is certainly variability across the studies, it is evident
that even at the lowest end of this range, DDIs are
a signicant patient safety issue.
2.3 Risk Factors Associated
withDrug–Drug Interactions
The risk factors associated with DDIs are numerous; increasing age, multimorbidity, and polypharmacy are frequently reported in studies [10,
11]. The involvement of multiple prescribers has
also been reported as a risk factor for DDIs [12,
13]. This is important to consider in light of a
study conducted by Dumbreck etal. who examined the potential for DDIswithin UK National
Clinical Guidelines for type 2 diabetes mellitus,
heart failure, and depression [14]. This study
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