Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5631_Библиотеки_им_академика_М_И_Перельмана
.pdf
3 Predisposing Factors forAdverse Drug Reactions
Table 3.1 Categories of predisposing factors based on timing of causal components with respect to drug
administration
Pure predisposing
factors Co-inducers Cooperators Triggering factors
Timing
with respect
to the drug
use
Capability
of inducing
the adverse
event (in
the absence
of the drug)
Examples – Old age is a pure
Usually before At the same time At the same time After
Usually but not
necessarily
predisposing factor
for upper
gastrointestinal
bleeding induced by
aspirin
– HLA-B*15:02 is a
pure predisposing
factor for the
Stevens–Johnson
syndrome/toxic
epidermal necrolysis
induced by
carbamazepine in
South Asian
populations
– Renal failure is a
pure predisposing
factor for type A
ADRs induced by
drugs eliminated
unaltered by urine
when it exists before
the drug intake (for
chronic treatments,
an impairment of
renal function may
increase the risk of
type A ADRs, but, in
this case, it would
behave as a
triggering factor)
Always Never Usually but not
necessarily
– Nonsteroidalanti-
inammatory drugs
(NSAIDs) and
anticoagulants are
co-inducers of
upper
gastrointestinal
bleeding if
administered
simultaneously (if
the NSAID is
administered in a
patient already
anticoagulated, then
the anticoagulant
may be considered a
pure predisposing
factor for the upper
gastrointestinal
bleeding induced by
the NSAID, and
vice versa)
– Most drug–drug
pharmacodynamic
interactions usually
fall under this
category
– Potent inhibitors of
CYP450 3A4, like
macrolides, are
cooperators of the
toxicity provoked by
colchicine overdose, but
they are not an
independent cause of
such toxicity (in the
absence of colchicine). If
the patient is already
treated with a macrolide
before using colchicine,
then the former can also
be viewed as a pure
predisposing factor for
colchicine toxicity
– Most drug–drug or
food–drug
pharmacokinetic
interactions fall under
this category
– Estrogen explosion
in puberty was
presumed to be the
triggering factor of
vaginal cancer
observed in young
women whose
mothers used
diethylstilbestrol
during pregnancy
(after around
15years)
– Dental intervention
is a triggering
factor for
osteonecrosis of the
jaw induced by
bisphosphonates
49
3 The Importance
ofPredisposing Factors
inPharmacovigilance
andClinical Practice
The identication of predisposing factors is of
utmost importance in pharmacovigilance as they
are the target of minimization measures such as
the restriction of indications or the addition of
contraindications or warnings on the drug label.
Often, these measures are concerned with predisposing factors like age, sex, the presence of a disease that impairs the elimination of the drug (e.g.,
renal failure) or increases its effect (e.g., previous
peptic ulcer that increases the risk of experiencing an upper gastrointestinal complication in
50
J. Jose and F. J. de Abajo
patients using nonsteroidal anti-inammatory
drugs (NSAIDs)), ethnic origin, carrier of a
genetic biomarker, etc. The evaluation of causal
relationships at the individual level may be benecial when the ADR report contains information
on potential predisposing factors. Some causality
algorithms include the existence of predisposing
factors as an item to assess such as the one by the
Spanish Pharmacovigilance System [3] and others [4].
Knowledge of predisposing factors is also
important for the individual care of patients, as a
physician could individualize the pharmacological treatment in a better way. For instance, the
prescription of a drug, which is eliminated unaltered by urine from a patient with moderate or
severe renal insufciency without dose adjustment, could lead to drug accumulation and dosedependent ADRs (e.g., metformin and lactic
acidosis, or dabigatran and bleeding). Actually,
these cases can be categorized as medication
errors, with legal consequences to both the practitioner and the health system. In this line, drug
utilization studies often use the presence of wellknown predisposing factors to assess the quality
of the prescription. Finally, patients should be
informed by their health-care professionals
(physicians, pharmacists, and nurses) on the
well- known predisposing factors (e.g., anticoagulated patients should be advised to not use
NSAIDs, including those dispensed over the
counter (OTC), without informing their doctors
rst). Health education programs focused on
therapy should include the information on the
predisposing factors for ADRs as an essential
part.
Table 3.2 provides a summary of how the
knowledge of predisposing factors may contribute positively to pharmacovigilance and clinical
practice.
The burden of disease due to ADRs is considerable, as many studies have pointed out [5, 6],
and the identication of certain predisposing factors can help reduce such a burden when effective
measures are implemented at the population
level. An extraordinary example is the 87.1%
reduction of the risk of Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN)
Table 3.2 Examples on how the knowledge of predisposing factors may help improve pharmacovigilance and
clinical practice
Pharmacovigilance practice
Individual causality assessment of ADRs (some
algorithms include predisposing factors as an item). To
this end, ADR reporting should include information on
potential predisposing factors
Changes in the drug label (e.g., inclusion of
contraindications, warnings, interactions)
Proposing risk minimization measures in risk
management plans
Assessing the quality of prescription through drug
utilization studies
Assessing medication errors (the presence of a
well-known predisposing factor may be the basis for
considering an ADR as a medication error)
Clinical practice
Selecting an alternative drug for the patient with a
predisposing factor
Selecting the most appropriate dose schedule for the
patient with a predisposing factor
Closer monitoring of patients with predisposing factors
(e.g., request of serum levels of the drug)
Intervening on modiable predisposing factors (e.g.,
alcohol intake, drug–drug interactions, and food–drug
interactions)
Patient education to avoid or minimize the inuence of
modiable predisposing factors
Collectively, adequate consideration of predisposing
factors contributes to the preventabilityof ADRs
induced by carbamazepine in Taiwan after the
implementation of a national program of screening for HLA-B*15:02in patients who are candidates to receive the drug and selection of an
alternative drug in carriers of that trait [7]. Similar
trends have also been observed in other Asian
countries [8], so that genotyping to prevent these
ADRs is now considered the standard of care.
Another example is the reduction of hospitalizations (from 54.6 to 25.8 per 100,000 personyears) due to peptic ulcer bleeding (many of
which were caused by drugs such as NSAIDs,
low-dose aspirin, and anticoagulants) detected in
Spain [9], due to the increasing eradication of
Helicobacter pylori from the population and the
wide use of proton pump inhibitors in patients at
a high risk of experiencing such complications
(e.g., the elderly, antecedents of peptic ulcer, concomitant use of NSAIDs with low-dose aspirin,
anticoagulants, or other interacting drugs).
3 Predisposing Factors forAdverse Drug Reactions
51
4 Types ofPredisposing
Factors
There is much information available on the general predisposing factors for ADRs as well as
specic information on the predisposingfactors
for ADRs to specic drugs and specic types of
reactions. Pharmacokinetic and pharmacodynamic factors may lead to toxic or exaggerated
responses to normal drug doses, thereby leading
to adverse events. It could be due to altered
pharmacokinetics, resulting in excessively high
concentrations of the unbound drug or metabolite at the site of action. Alternatively, a response
to a given concentration of drug or metabolite at
the site of the action may be exaggerated or
unusual because of pharmacodynamic factors,
including changes in the number and/or binding
afnity of the target receptors as well as alternations in the signal transduction pathways [10].
The pharmacokinetic and pharmacodynamic
behaviors of drugs may be inuenced by various
factors related to patient demographics, disease
state, physiological status, drug interactions,
and lifestyle. There are essentially four types of
predisposing factors: those related to patient
characteristics, those related to the underlying
diseases, those related to environmental and
lifestyle factors, and those related to the use of
other drugs.
4.1 Factors Related toPatient
Characteristics
4.1.1 Age
Age is a well-identied, signicant predisposing
factor for the development of adverse drug effects
to which geriatric and pediatric populations are
more prone.
The Elderly
The International Conference on Harmonization
considers older people a “special population,” as
they differ from younger adults in terms of
comorbidity, polypharmacy, and pharmacokinetics and thereby have a higher predisposition to
ADRs [11]. The increase in the number of dis-
eases in older people leads to polypharmacy,
which naturally increases the risk of drug interactions and adverse events [12]. Aging is associated with physiological changes that affect an
individual’s medicine-handling capacity, including alterations to body composition, causing
changes in volumes of drug distribution and
alterations in organ mass, and to blood circulation, causing changes in metabolism and clearance [13, 14].
The majority of ADRs in older people are
type A reactions; i.e., they are attributable to a
predictable known pharmacological effect of a
drug but an exaggerated response resulting in an
adverse effect [13]. Age-related decline in renal
function and hepatic metabolism may lead to
toxicity through excess drug accumulation.
Reduced hepatic size and blood ow also contribute to reduced rst-pass metabolism, which
is especially relevant for drugs with high hepatic
extraction that undergo signicant rst-pass
metabolism, e.g., propranolol. In the elderly, the
glomerular ltration rate (GFR) is signicantly
affected due to age-related reductions in renal
function and disease states that are common.
This can affect the clearance of drugs predominantly eliminated by the kidneys, e.g., penicillin, diuretics, and digoxin. The relative decrease
in total body water seen in the elderly may result
in a smaller volume of distribution and therefore
in higher serum concentrations for water-soluble drugs (e.g., alcohol, gentamicin). On the
other hand, the higher proportion of body fat
seen in aging can prolong the half-lives of fatsoluble drugs like diazepam and amitriptyline
[13, 15]. Elderly patients may have altered phar-
macodynamic responses, e.g., the risk of orthostatic hypotension is greater in older people who
are prescribed vasodilators because of attenuated baroreceptor responses [13]. Of the many
transporters expressed at the blood–brain barrier (BBB) endothelium, several have been
implicated in inux and/or efux of drugs into
the central nervous system (CNS). Decreased
expression and/or defective function of
thesetransporters leads to increased BBBpermeability and thereby toxic effects of drugs
[16].
52
J. Jose and F. J. de Abajo
The main risk factors or predictors of ADRrelated admissions among older people are
advanced age, polypharmacy, comorbidity, longer duration of treatment, and potentially inappropriate medications [17–19]. In the systematic
review conducted by Alhawassi et al. [20] for
assessing the prevalence and risk factors for
ADRs in the elderly in an acute care setting, it
was noticed that at least 1in 10 elderly patients
experienced an ADR, leading to or during their
hospital stay.
Children
There are multiple factors that inuence the different responses of children to drugs compared
with adults. The prevalence and nature of ADRs
may differ depending on the age of children. For
example, neonates are more likely to be sensitive
to the adverse effects of morphine, whereas
drugs like sodium valproate are associated with
an increased risk of problems in children of any
age [21]. The risk of specic ADRs may be
increased by neonatal differences in body composition, metabolism, and other physiological
parameters. With regard to body composition,
higher body water content can increase the volume of distribution for water-soluble drugs, and
reduced albumin and total protein may result in a
higher concentration of highly protein-bound
drugs. The immature BBB in neonates can
increase sensitivity to drugs acting on the CNS,
such as morphine [21, 22]. Chloramphenicol,
digoxin, and ototoxic antibiotics such as streptomycin are examples of drugs that have a higher
risk of toxicity in the rst weeks of life [22].
Although case reports of chloramphenicol toxicity have also been reported in children and adolescents, premature infants and neonates are at
highest risk of the gray baby syndrome from
chloramphenicol exposure due to their decreased
hepatic and renal function [23].
Compared to the available information on the
benets/risks in individual adults, the currently
existing information to enable informed decisions to identify and quantify ADRs in neonates
and infants is much more limited. Infants com-
monly receive drugs used off-label, at dosages
extrapolated from those in older children or
adults. Besides the lack of labeling, inappropriate formulations, polypharmacy, immature organ
function, and multiple illnesses further raise the
risk of ADRs in neonates and infants [24]. Drugs
administered to the mother in the perinatal
period also constitute a major route of exposure
to ADRs [25].
It is not only neonates, infants, and young
children who exhibit increased susceptibility to
ADRs but older children and young adults may
also do so. A classic example is the increased risk
of extrapyramidal effects associated with metoclopramide in children and young adults (15–
19years of age) [26]. The heightened probability
of dosing errors due to dose calculations using
body weight can also contribute to potential
harms [22]. When drugs are newly introduced to
the market, they usually do not possess adequate
safety information related to children, as this
group is under-represented in clinical trials.
Moreover, children may present specic ADRs
related to maturity, growth, and development that
are nonexistent in adults. An example is the
growth retardation observed with systemic corticosteroids [27].
In a focused analysis on adverse drug events
as reported in the MedWatch adverse event
reports system, Moore et al. identied 7111
reports (1.5% of the total dataset) in infants and
children under 2 years of age over a period of
3 years, with a high mortality rate in the rst
month of life [25]. All reports of suspected ADRs
with a fatal outcome in children received by the
UK Committee on Safety of Medicines through
its Yellow Card Scheme from 1964 until
December 2000 were reviewed. It was identied
that there were 331 deaths with 390 suspected
medicines reported for children aged 16years or
less. The medicines most frequently mentioned
were anticonvulsants, cytotoxics, anesthetic
agents, and antibiotics, and the individual drug
most frequently mentioned was sodium valproate. Hepatic failure was the most frequently
occurring serious ADR [28].
3 Predisposing Factors forAdverse Drug Reactions
53
4.1.2 Sex
In general, women may be more susceptible to
ADRs and the female sex is considered as a risk
factor for the development of ADRs in a variety
of drug groups [10, 22, 29]. It is postulated that
women are more at risk of developing ADRs due
to differences in pharmacokinetics, pharmacodynamics, toxicokinetics, toxicodynamics, and
drug use compared to men [10, 22, 29, 30].
Women generally have a lower lean body mass,
reduced hepatic clearance, differences in the
activity of cytochrome P450 (CYP) enzymes,
and metabolize drugs at different rates compared
to men [10]. Furthermore, hormonal status, body
composition (the relative proportions of muscular and adipose tissues), amount of drug-binding
proteins, renal blood ow, and sex-specic differences in the immune system could inuence
drug responses [30, 31]. Sex-dependent activity
of clinically relevant CYP families is present,
with evidence suggesting that CYP2E1 and
CYP1A2 activities are higher in males than in
females, whereas CYP3A, one of the most clinically relevant CYP isoforms, appears to exhibit
greater activity in females [32]. In addition,
important factors such as conjugation, absorption, protein binding, and renal elimination may
all have some sex-based differences [10].
Furthermore, sex- specic hormonal effects or
interaction with signaling molecules that can
affect drug safety are important [30]. Men and
women also show different pharmacodynamic
responses to a variety of drugs, particularly with
cardiac and psychotropic medications [10, 30].
Unique issues in women, such as menopause,
pregnancy, oral contraceptive use, and physiological and hormonal changes during the menstrual
cycle, can also have signicant effects on drug
metabolism, which can be clinically important
[30, 31]. It is likely that a variety of physiological
changes that occur during pregnancy may affect
the pharmacokinetics of drugs. Drug distribution
and protein binding are changed by pregnancy.
While some drug-metabolizing enzymes demonstrate an increase in activity, others exhibit an
apparent decrease in activity. Pregnancy alters
the apparent activities of multiple drug transporters, resulting in changes in the net renal secretion
of drugs. The higher serum concentrations of
digoxin reported in pregnant patients may be
caused by increased bioavailability due to
decreased gastric emptying time during pregnancy [33].
Sex can inuence the amount and type of
medications used. Women use a signicantly different range of drugs than do men, particularly
drugs associated with oral contraception, menopause, and pregnancy. Oral contraceptives can
both affect the metabolism of and be affected by
a wide range of other therapeutic drugs. For
example, paracetamol is conjugated more in
women taking an oral contraceptive compared
with controls [34]. A number of conditions,
including urinary tract infections, arthritis,
depression, and anxiety disorders, are also more
prevalent in women, and, accordingly, the use of
medications for managing these conditions differs [10]. In general, not only do women use
more sex-specic drugs, they may also use more
general medications [35]. Additionally, factors
such as the difference, if any, in the promptness
in seeking medical attention when medical complications arise, and the importance placed on illness between sex have been suggested to be
responsible for the possible difference in the
prevalence of ADRs based on sex [36].
There are certain ADRs that appear to be more
common in women. It is generally established
that women experience more severe ADR outcomes compared to men, such as hepatic ones
[30]. Impairment of concentration and psychiatric adverse events associated with meoquine are
more common in females [22]. Females are more
susceptible to drug-induced torsade de pointes, a
ventricular arrythmia, which is considered to be
due to their longer QTc interval (duration of ventricular electrical systole (QT) corrected for heart
rate) compared to men [22]. Estrogen seems to
reduce the density of IKr potassium channels (IKr
type; inward rectier potassium current), which
results in slower repolarization and prolongation
of the QT interval [37].
Rodenburg etal. conducted a large study in
the Netherlands to understand the sex-related differences in hospital admissions attributed to
ADRs. In all different drug classes, signicant
54
J. Jose and F. J. de Abajo
differences existed between the sexes in ADRrelated hospital admissions, with cardiovascular
drugs accounting for the most pronounced differences. Overall, the number of ADR-related hospital admissions conrmed the higher risk of
women to be hospitalized due to an ADR. Instead,
the risk of ADR-related hospitalizations attributed to antirheumatic drug use was higher in
men. Diabetes due to glucocorticoids and hypoglycemic coma due to insulin and antidiabetic
agents were more frequent in men. Men were
more frequently hospitalized for ADRs following
antibiotic use. Admission for osteoporosis due to
adrenal cortical steroids was more frequent in
women [29].
4.1.3 Ethnicity
Ethnicity may be associated with a higher prevalence of certain genetic variants of human leukocyte antigens (HLAs), crucial for some
hypersensitivity reactions (see Sect. 4.1.4), and
may also be associated with polymorphisms
affecting some drug metabolic routes, such as
cytochrome P450, which can explain the greater
susceptibility to ADRs of some ethnic groups
[22]. Moreover, social behaviors and lifestyle
factors can be linked to ethnicity. Although the
study results were limited by multiple factors, a
systematic review conducted by Baehr etal. [38]
to assess the racial and ethnic disparities in ADRs
identied the following ndings. Asians may be
at particular risk of anticoagulant-related ADRs,
Blacks may be at increased risk of diabetic agentrelated ADRs, and Whites may be at increased
risk of opioid-related ADRs. It was reported in a
pharmacogenomic study by Takahashi etal. that
VKORC1 and CYP2C9 polymorphisms contribute to interpopulation differences in warfarin
doses among the three studied populations:
Caucasians, Japanese, and African Americans
[39].
McDowell etal. [40] systematically reviewed
the evidence for increased susceptibility to
adverse reactions to cardiovascular drugs in certain ethnic groups. Although their study had
reported limitations, it provided valuable details
as presented below. The relative risk (RR) of
angioedema associated with angiotensin-
converting enzyme (ACE) inhibitors was higher
in Black patients compared with White patients,
and the risk of cough was enhanced in patients
from East Asia (i.e., China, Korea, or Japan),
compared with White patients. In Black patients,
thrombolytic therapy was associated with an
increased risk of moderate or severe bleeding and
also with intracranial hemorrhage [40]. Individual
studies of hypertensive therapy reported an
increased risk of depression with hydrochlorothiazide and with all hypertensive therapy in
Blacks compared with Whites. Digitalis therapy
was also associated with an increased risk of hospital admission for ADRs in Black patients compared with White patients [41]. Pharmacokinetic
studies suggest greater plasma concentrations of
some statins or their active metabolites in subjects of East Asian ethnicity compared with
Whites due to differences in the prevalence of
variant alleles coding for statin-metabolizing
enzymes and membrane transporters. Chinese
patients appear to be more susceptible to myopathy induced by simvastatin [42]. The most obvious difference in statin pharmacokinetics in East
Asians is in terms of rosuvastatin [43].
4.1.4 Genetic Factors
Most pharmacokinetic processes are mediated by
proteins, such as drug-metabolizing enzymes or
membrane drug transporters. Moreover, many
drug targets are proteins themselves such as ion
channels, enzymes, or receptors. Thus, their
functionality is genetically determined and a
variation in the genes that encode them may
increase the probability of experiencing an ADR
of type A or, on the other hand, it may reduce the
efcacy of the drug [44, 45]. Moreover, some
ADRs of type B can be genetically mediated,
such as those linked to some enzymatic decits
that control critical physiological processes (e.g.,
hemolytic anemia induced by oxidative drugs in
patients with a glucose-6-phosphatase dehydrogenase deciency) or those triggered by immunogenic mechanisms in susceptible populations
(e.g., hypersensitivity reactions) [46–48].
Depending on the underlying mechanism, we can
envision ve categories of genetically determined
ADRs: (1) variant drug-metabolizing enzymes;
3 Predisposing Factors forAdverse Drug Reactions
55
(2) variant drug transporters; (3) variant drug targets (enzymes, channels, receptors); (4) variant
human leukocyte antigens (HLAs); and (5) variant enzyme-governing processes not related to
the drug’s own pharmacokinetics or pharmacodynamics (which predispose to the so- called
idiosyncratic reactions). The rst three induce
ADRs of type A and the last two ADRs of type
B. Table3.3 provides some examples in which
there is consistent information of a genetic basis.
The identication of a genetic variation as a predisposing factor for some ADRs may lead to the
clinical use of biomarkers to predict the ADR and
help minimize the risk in the population.
However, showing an association between an
ADR and a genetic variation is not enough. For a
predictive genetic test to be included in clinical
practice, the following criteria should be consid
Table 3.3 Types and examples of genetic variants as predisposing factors for ADRs
Drug Mechanism Genetic factor ADR (type)
Abacavir
b,c,d
Hypersensitivity
reaction
HLAB*57:01
Hypersensitivity
reactions, DRESS
syndrome (type B)
Allopurinol
Amoxicillin–clavulanic
acid
b,c,d
e,f
Hypersensitivity
reaction
Hypersensitivity
reaction
HLAB*58:01
HLADRB1*15:01
SJS/TEN (type B) Yes, for information (in
DILI (type B) No
HLADQB1*06:02
HLAA*02:01
HLA-
B*18:01
Antiarrhythmic classes
IA and III
e
Variant drug target
(cardiac K channel)
KCNQ1
KCNH2
Arrhythmias (TdP) in
patients with cLQTS
(type A)
Azathioprine
c
Variant drugmetabolizing
TPMT
NUDT15
Myelosuppression
(type A)
enzyme
Carbamazepine
Carbamazepine
Flecainide
Flucloxacillin
Irinotecan
b,c
b,c
e
d,e,f
c,d
Hypersensitivity
reaction
Hypersensitivity
reaction
Variant drug target
(cardiac Na channel)
Hypersensitivity
reaction
PK-drugmetabolizing
HLA-
SJS/TEN (type B) Yes, highly recommended
B*15:02
HLA-
B*31:01
DRESS, SJS/TEN
(type B)
SCN5A Brugada syndrome
(type A)
HLA-
DILI (type B) No
B*57:01
UGT1A1 Neutropenia, severe
diarrhea (type A)
enzyme (UGT1A1)
Oxidant drugs
(sulfonamides,
chloroquine,
quinolones)
d,e
Idiosyncratic
reaction
In patients with
G6PDH deciency
G6PDH Hemolytic anemia
(type B)
Genotyping included in
drug label (FDA)
a
or
SmPC (EU)
Yes, mandatory to all
patients before treatment
Han Chinese, Thai,
Korean)
No
Yes, mandatory or highly
recommended.
Alternatively, consider
phenotype testing for
TPMT
in Han Chinese and Thai
populations (Malaysian
and Indian)
Yes, for information (in
European descendants and
Japanese populations)
No
Yes, for information
No
(continued)
56
Table 3.3 (continued)
Drug Mechanism Genetic factor ADR (type)
Simvastatin
Warfarin
Warfarin
Abbreviations: cLQTS congenital long QT syndrome, CYP cytochrome P450, DILI drug-induced liver injury, DRESS
drug reaction with eosinophilia and systemic symptoms, G6PDH glucose-6-phosphate dehydrogenase, K potassium,
EMA European Medicines Agency, FDA Food and Drug Administration, Na sodium, OATP1B1 organic anion trans-
porter polypeptide family member 1B1, SLCO1B1 solute carrier organic anion transporter family member 1B1, SmPC
summary of product characteristics, SSJ/TEN Stevens–Johnson syndrome/toxic epidermal necrolysis, TdP torsade de
pointes, TPMT thiopurine methyltransferase, UGT1A1 UDP glucuronosyltransferase family one member A1, VKORC1
vitamin K epoxide reductase complex type 1
a
A updated list can be found at https://www.fda.gov/drugs/science- and- research- drugs/table- pharmacogenomic-
biomarkers- drug- labeling
b
EMA/CHMP/281371/2013: A guideline on the key aspects of the use of pharmacogenomics in the pharmacovigilance
of medicinal products, 2015
c
Pratt etal., Medical Genetics Summaries, National Center for Biotechnology Information (US), 2021
d
Wang etal. [44]
e
Micaglio etal. [46]
f
Böhm and Cascorbi [48]
c,d
b,c,d
b
Variant drug
transporter
(OATP1B1)
Variant drug-
metabolizing
enzyme
Variant drug target
(enzyme)
SLCO1B1 Myopathy (type A) Yes, for information
CYP2C9 Bleeding (type A) Yes, for information
VKORC1 Bleeding (type A) Yes, for information
J. Jose and F. J. de Abajo
Genotyping included in
drug label (FDA)
SmPC (EU)
(recommended if high
doses)
a
or
ered [49]: (1) medical need; (2) clinical validity
and utility of testing (low probability of falsepositive and false-negative results and a low
number of patients needed to screen to prevent
the event); (3) relative ease of use; and (4) existing choice of treatments. It is advisable to refer to
Chap. 23 for further details on the inuence of
genetics on drug safety.
4.1.5 Immunological Considerations
ADRs that involve a specic drug-induced
immune response are referred to as drug hypersensitivity reactions. Although induction of a
drug-induced immune response is the main event
involved in drug hypersensitivity, induction of an
antibody response alone is not the pathological
process. Taking into consideration that many
patients with antidrug antibodies or drug-induced
autoantibodies remain asymptomatic, it is highly
likely that there are individual risk factors associated with the translation of an immune response
into tissue damage. All drug hypersensitivity
reactions involve several sequential steps, each of
which may provide sources of interindividual
variation [15].
4.2 Factors Related
totheUnderlying Diseases
Concomitant host disease or comorbidities may
inuence susceptibility to ADRs. The best example is human immunodeciency virus (HIV) disease, which increases the frequency of toxicity
with co-trimoxazole. It is reported that adverse
reactions to co-trimoxazole increase from
approximately 2–8% in the general population to
more than 43% among HIV-positive individuals
to approximately 69% in subjects with acquired
immunodeciency syndrome (AIDS) [50]. The
reasons behind this increased frequency of ADRs
with co-trimoxazole are likely to be more complex than only changes in drug-metabolizing
capacity; immune dysregulation may also play a
3 Predisposing Factors forAdverse Drug Reactions
57
part [51]. Another classical example of the inuence of specic disease is infectious mononucleosis (due to Epstein–Barr virus), which greatly
increases the risk of rash in patients administered
amoxicillin [21].
Usual doses of drugs produce higher-thannormal serum drug concentrations in patients
with kidney or liver disease, especially for drug
or drug metabolites that are highly dependent on
the kidneys or liver for elimination. This requires
special consideration, particularly for drugs with
a narrow therapeutic index, which might result in
an exaggerated response [10]. Reductions in
renal and hepatic function can alter drug handling, and this has implications for practical therapeutics, including an increased risk of ADRs
[21]. Reduction in hepatic blood ow as a consequence of acute myocardial infarction or heart
failure may decrease the elimination of drugs that
are normally highly extracted by the liver.
Hypothyroidism may be associated with a
decrease in both hepatic and renal drug clearances, resulting in an exaggerated response [10].
Table 3.4 provides examples of few specic
drug–disease interactions, which increase the
risk of ADRs.
4.3 Factors Related
toEnvironmental Factors
4.3.1 Lifestyle Factors
Both the pharmacokinetics and pharmacodynamics of drugs may be altered by lifestyle factors
such as alcohol and caffeine consumption.
Alcohol can exaggerate the CNS depressant
effects of drugs, including benzodiazepines, phenothiazines, tricyclic antidepressants, opiates,
and some antihistamines. Caffeine has a potentially dangerous stimulant effect when taken with
ephedrine in herbal weight loss and athletic
performance- enhancing supplements [55].
Cigarette smoking is known to increase the
metabolism of many drugs via inducing CYP1A2
(e.g., clozapine, olanzapine, caffeine, R-warfarin,
erlotinib) [56, 57], CYP2B6 (e.g., methadone)
[56], and uridine diphosphate (UDP)glucuronyltransferase (UGT) (e.g., clozapine,
mirtazapine) [57].
4.3.2 Food–Drug Interactions
Food–drug interactions can also have negative
outcomes. The salt, protein, or vitamin content of
a diet may affect the renal excretion of drugs. An
Table 3.4 Disease effects on drug pharmacokinetics and pharmacodynamics and inuence on safety
Drug–disease interaction End effect Mechanism
Cefepime and kidney disease [52] Life-threatening cefepime induced
neurotoxicity in patients with acute
kidney failure
Opioids and liver [53] Patients with liver disease have an
unusual sensitivity to opioids such
that even small doses can precipitate
encephalopathy
Digoxin and hypothyroidism [54] Increased risk of digoxin toxicity Hypothyroidism increases serum digoxin
Digoxin and electrolyte imbalance
(hypokalemia) [54]
Increased risk of digoxin toxicity Potassium competes with digoxin for
Cefepime is highly dependent on the
kidneys for elimination, and, hence, dose
reductions are highly critical in patients
with severe kidney disease
Increased density and afnity to opioid
receptors in the brain is the proposed
explanation
concentration by decreasing the
glomerular ltration rate and volume of
distribution of digoxin. The myocardium
of patients with myxoedema may have a
reduced tolerance to digoxin
myocardial receptor-binding sites, and
hypokalemia results in an increase in
myocardial digoxin uptake, a decrease in
sodium–potassium pump activity
(increased digoxin binding to the sodium
potassium pump), and a decrease in
tubular secretion of digoxin
58
J. Jose and F. J. de Abajo
example is when a patient taking lithium initiates
a low-salt diet for treatment of hypertension or
heart failure, he/she excretes less lithium, which
may result in higher serum lithium concentrations and potential toxicity [58]. A further example is a low-protein diet that is associated with
decreased renal clearance of oxypurinol (the
active metabolite of allopurinol) [59].
Concomitant administration of grapefruit juice
can increase the plasma concentration of numerous drugs in humans, and such elevations of drug
plasma concentrations have, on occasion, resulted
in adverse clinical effects. Increased concentrations are primarily mediated by chemicals in
grapefruit juice, which inhibit the CYP 3A4 drugmetabolizing enzyme in the small intestines [60].
A classic example is the interaction between
grapefruit juice and cyclosporine, which has been
shown to cause an increase in both parent and
metabolite proles, indicating an alteration in the
disposition of cyclosporine and metabolites. This
interaction is of potential clinical importance in
terms of mechanism, side effects, and dosing [61].
Similarly, a sudden decrease in vitamin K intake
from dark-green vegetables can increase the risk
of bleeding in patients using warfarin [62].
4.4 Drug-Related Factors
It is important to note that while the dose and duration of treatment are, obviously, factors linked to
ADRs (in particular to type A), they are dimensions of the drug itself and thus cannot be formally
considered predisposing factors. According to the
denition provided in Sect. 2, a predisposing factor should be “a third variable, different from the
drug itself and the indication for which the drug is
taken.” Thus, in this section, we will consider other
factorsthat may modify the effect of thedrug such
asinteractions, polypharmacy, and pharmaceutical
factors that may alter its bioavailability.
4.4.1 Drug–Drug Interactions
Altered pharmacokinetics or pharmacodynamics
as a result of drug–drug interactions may contrib-
ute to ADRs. The most frequent contributing factors are those drug interactions that affect
bioavailability and drug elimination. Most commonly, drug-induced inhibition of cytochrome
P450 enzymes can result in the reduced metabolism of certain drugs, resulting in increased concentration of the affected drugs and resultant
ADRs. P-glycoprotein, a protein expressed on the
luminal surface of intestinal epithelial cells, biliary hepatocytes, and renal tubular cells transports
the drug from within the cell to the intestine, bile,
or urine, respectively. Inhibition of P-glycoprotein
by certain drugs can increase the bioavailability
and decrease the renal and biliary excretion of
their substrates, thus increasing their serum concentrations [63].
Displacement of a drug from plasma proteins
by another drug results in only transient
increases in the free and active drug and hence
does not generally result in adverse effects [64,
65]. However, there may be signicant interac-
tions when the affected drugs have a narrow
therapeutic margin; an example is drug interactions with warfarin, which can result in displacement of warfarin from the protein-binding
site and in an increase in free warfarin plasma
concentration.
Pharmacodynamic mechanisms could also be
behind drug–drug interactions. They arise when
the pharmacological effect of one drug is affected
by that of another. Pharmacodynamic drug–drug
interactions are typically categorized as synergistic, additive, or antagonistic [66]. Examples
include serotonin syndrome caused by adding
tramadol to a selective serotonin reuptake inhibitor (SSRI) [67] or excessive reduction in blood
pressure and symptomatic hypotension by addition of ACE inhibitors in patients who have been
sodium and/or volume depleted by thiazide or
loop diuretics [68].
The information available regarding drug
interactions from various resources has certain
limitations. The value of these tools could be
diminished if too many minor or clinically
insignicant interactions are included, which
leads to the phenomenon of alert fatigue where
Соседние файлы в папке Библиотека им академика М.И. Перельмана