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90
S. McCarthy and A. Fleming
codynamic drug interactions are saw palmetto,
echinacea, feverfew, kava, goldenseal, and turmeric.
Concomitant use of any herbal medication with
regular or short-term prescribed medications should
involve screening for drug–herb interactions.
6 Drug–Food Interactions
Drug–food interactions typically result from
reduced gastrointestinal absorption or motility.
Chelation between some drugs and foods (e.g.,
iron-, calcium-, magnesium-containing foods
and certain medications) can reduce GI absorption
and is usually countered by spacing out administration times by a specied period of time.
Grapefruit juice inhibits intestinal CYP3A4 and
can increase levels of CYP3A4 substrates (e.g.,
simvastatin). It is a CYP3A4 inhibitor (mainly
intestinal) and a drug transporter protein inhibitor
and can interact with felodipine and some statins.
MAOIs (e.g., tranylcypromine, selegiline) inhibit
the breakdown of tyramine. When MAOIs are
taken with foods high in tyramine content (e.g.,
chocolate, red wine, cheese, smoked sh/meat,
fermented foods), tyramine accumulation can
occur, resulting in hypertensive crisis (symptoms
include severe headache, dizziness, ushing,
sweating, nausea, vomiting). Cranberry juice has
been reported to increase International
Normalized Ratio (INR) levels when taken with
warfarin. Warfarin is a vitamin K antagonist,
which inhibits the enzyme vitamin K epoxide
reductase, thus reducing the synthesis of vitamin
K-dependent blood clotting factors by the liver.
Fluctuations in dietary intake of vitamin K1 (e.g.,
cruciferous vegetables such as broccoli, brussels
sprouts, cabbage) may impact warfarin levels. If
the intake of dietary vitamin K1 increases, then
the synthesis of the blood clotting factors begins
to return to normal [4].
Table 4.4 lists some examples of herb–drug
and food–drug interactions, which may have
clinical signicance [67–72].
Table 4.4 Examples of reported drug–herb and drug–food interactions
Herb Drug Mechanism Effect
Black cohosh (Actaea
racemosa, Cimicifuga
racemosa)
Garlic (Allium sativum) Paracetamol
Ginkgo (Ginkgo biloba) Warfarin
Ginseng (Panax
ginseng)
St. John’s wort
(Hypericum perforatum)
Liquorice (Glycyrrhiza
glabra)
Glucosamine Warfarin, anticoagulants,
Cannabidiol Anticonvulsants
Statins CYP3A4 inhibition Elevated statin levels, resulting in
raised liver enzymes
P-gp induction Changes in pharmacokinetic
Warfarin
Saquinavir
Amiodarone
Some chemotherapy,
antiretrovirals, antidepressants,
antihypertensives, statins
Oral contraceptive pill,
warfarin, digoxin, tacrolimus,
benzodiazepines, statins
Monoamine oxidase inhibitors
(MAOI)
Diuretics
direct anticoagulants,
antiplatelets
Phenytoin
Antiplatelets/anticoagulants
Antiplatelet effect
CYP3A4 inhibition
CYP3A4 induction Reduced effectiveness of the drug
CYP3A4 induction
P-gp induction
MAOI activity
Sodium and water
retention
Anticoagulant effect Increased bleeding risk
CYP2 C19 inhibition
Inhibition of platelet
aggregation
variable
Increased INR
Decreased concentration
Increased bleeding risk
Increased toxicity risk
Reduced effectiveness of the drug
MAOI toxicity
Exacerbated hypokalemia
Increase in drug concentration;
increase in liver function tests of
some anticonvulsants
Increased plasma phenytoin
concentration
Increased bleeding risk
4 Drug Interactions andTheir Management
Table 4.4 (continued)
Food Drug Mechanism Effect
Grapefruit/grapefruit
juice
Green vegetables (e.g.,
cabbage, broccoli,
brussels sprouts)
Milk and dairy products Ciprooxacin, tetracycline,
Hard cheese MAOIs, linezolid Accumulation of
Digoxin
Dihydropyridine calcium channel
blockers, amiodarone, simvastatin,
tacrolimus
Warfarin High vitamin K content
levothyroxine, bisphosphonate
P-gp induction
CYP3A4 inhibition
interferes with warfarin
action
Chelation with the drug Reduced absorption and
monoamine oxidase
Reduced effectiveness
of digoxin
Increased effectiveness
of the drug
Reduced anticoagulant
effect of warfarin
effectiveness of the
drug
Increase in blood
pressure, headaches
– Beta-blockers taken for heart disease or hyper-
7 Drug–Disease Interactions
tension can worsen a patient’s asthma [73].
– Metformin and heart failure: Metformin
Drug–disease interactions are situations where
the pharmacotherapy used to treat a disease
causes a worsening of another preexisting disease
or condition in a patient [73]. Similarly, the presence of a particular disease condition could inuence the action of a specic drug, altering its
ADME or pharmacodynamic response and
resulting in altered effectiveness and/or safety.
Older patients are particularly at risk of drug–disease interactions due to the coexistence of comorbidities and risk of polypharmacy. The American
Geriatrics Society has identied drug–disease
interactions as a key element of care for older
persons with multimorbidity [74].
A systematic examination of recommenda-
should be avoided in patients with heart failure and renal impairment due to the risk of
lactic acidosis [74].
– Bisphosphonates and renal impairment: The
patient’s renal function and bisphosphonate
dose and duration of therapy due to the risk of
further renal impairment should be reviewed
[74].
– Anticholinergic drugs and dementia can result
in delirium [75].
– Aspirin taken when a patient has peptic ulcer
disease could result in gastrointestinal bleeding [76].
– Nonsteroidal anti-inammatory drugs
(NSAIDs) can worsen heart failure [77].
tions in 12 United Kingdom national clinical
guidelines reported a number of potentially serious drug–disease interactions between drugs recommended for type 2 diabetes mellitus,
depression, and heart failure, particularly when a
patient has comorbid chronic kidney disease
[14].
Patients with diabetes mellitus are at risk of
hypoglycemia, polypharmacy, and drug–drug
and drug–disease interactions [74]. This risk is
exacerbated or results in potentially greater clinical risk when the patient has multimorbidity.
Examples of drug–disease interactions with
potential clinical consequences include the
following:
It must also be noted that drug-induced renal
or hepatic impairment may impact the elimination of another drug. Liver and cardiac diseases
that affect hepatic blood ow can affect drug
metabolism. In some cases, patients present with
conditions that are exacerbated by drug–disease
interaction. For example, a patient with fatigue
may feel more fatigued if they are prescribed a
beta-blocker to slow the heart rate or if they experience unstable blood glucose levels (e.g., risk of
hypoglycemia with sulfonylureas).
When prescribing for patients with multimorbidity and polypharmacy and for older
patients, a comprehensive assessment of the
91
92
S. McCarthy and A. Fleming
patient’s risk factors (e.g., comorbidities, renal
function, hepatic function, concomitant medications) must be conducted. The use of clinical
decision support tools and guidelines developed
for patients with multimorbidity is recommended to support safe prescribing for patients
with multimorbidity and polypharmacy [78].
Screening tools such as the Beers criteria,
Screening Tool of Older Persons’ Prescriptions
(STOPP) and Screening Tool to Alert to Right
Treatment (START) criteria, and the Screening
Tool of Older Persons’ Prescriptions in Frail
Adults with Limited Life Expectancy (STOPPFRAIL) are supportive tools to improve appropriate and safe prescribing for older persons
[79–81]. In the Netherlands, pharmacies use
clinical decision support implemented in their
pharmacy information system that generates
alerts for drug-related problems, such as drug
hypersensitivity, drug–drug interactions, and
drug–disease interactions [82]. This system was
rst developed by a multidisciplinary expert
panel who created a panel of recommendations
for drug–disease interactions for 57 diseases,
which were embedded into the clinical decision
support system [83]. This system supports pharmacists and physicians as a point-of- care signal
to support medication safety.
8 Drug–Laboratory Test
Interactions
Drugs may impact the interpretation of laboratory
test results. Drug–laboratory test interactions
(DLTIs) represent a source of diagnostic and/or
therapeutic errors; this is a well- recognized and
well-evidenced issue in clinical practice [84].
DLTIs are categorized as either physiological
(pharmacological, biological, invivo) or analytical
(methodological, in vitro) [84]. Analytical drug–
test interactions occur when a drug alters the test
specimen or interferes with the test reagent.
Laboratory testing and diagnostic methodologies
are continuously being improved in terms of accuracy and sensitivity; however, a margin of error
exists for all tests, with drugs presenting a source
of error [85]. DLTIs may result in the need for an
additional test, inaccurate diagnosis, and inaccurate treatment, potentially resulting in morbidity or
mortality. A review of all the US Food and Drug
Administration (FDA)-approved drug labels found
that 134/1368 (9.8%) single-ingredient prescription drugs interfere with at least 1 clinical laboratory test, 31 drug labels (2.3%) listed that the drug
did not interfere with laboratory tests, and 4 drug
labels listed that there was no available information [85]. The review reported that antibacterial
agents, psychotropic drugs, and contrast media
were the classes of drugs reported as most likely to
lead to DLTIs. Despite DLTIs being an important
clinical issue, many drug monographs do not
include information on them [86].
One of the most common examples of DLTIs
are with urine specimens due to drugs interfering
with the chemical components of the urine, e.g.,
cephalosporins may interfere with urine glucose
and ketone tests [86].
Other examples of drugs and DLTIs are the
following [84]:
– Fluoxetine leads to increased reported triglyc-
eride levels.
– Simvastatin, atorvastatin, and rosuvastatin
lead to increased reported glucose levels.
– Daptomycin can falsely prolong or elevate
reported prothrombin time and the INR [87].
Measures to prevent and minimize the clinical impact of DLTIs include reminder or notication systems on laboratory test programs to
screen for DLTIs based on a patient’s prescription medications. Other recommendations
include the reporting of DLTI studies during
post-marketing surveillance and in clinical
practice to improve the recording and awareness of DLTIs. There are online databases that
contain DLTI information such as the DailyMed
website, where FDA- approved drug interactions with laboratory or diagnostic testing are
listed [88]. A review of the licensed drug monograph is recommended in the event that a laboratory result is not congruent with the clinical
picture. However, in the event of no information being included in the monograph, healthcare and laboratory professionals should
consider a repeat test or testing using another
assay method [86].
4 Drug Interactions andTheir Management
93
9 Prevention andManagement
ofDrug Interactions
inPractice
Prescribing and medicine management is increasing in complexity, with an ever-growing number
of medications on the market, and rising polypharmacy. It must be acknowledged that it is not possible to remember all DDIs that are clinically
relevant. DDIs are the responsibility of all healthcare professionals involved in the prescribing, dispensing, and administration of medications, which
includes doctors, dentists, pharmacists and pharmacy staff, and nurses, in all health-care settings.
The risk of a DDI becoming clinically signicant can depend on both patient and medication
factors. A recent point prevalence study
(n=1466 patients) of Irish data has found that
one-quarter of older adults (≥70-years-old) were
potentially exposed to one “severe” cardiovascular or central nervous system DDI. Those prescribed warfarin, escitalopram, atorvastatin,
furosemide, or clarithromycin had the highest
burden of potential exposure to DDIs [10]. The
therapeutic index of the drug, the concentration
of the interacting drug, and the clearance of the
drug all have an impact on the clinical signicance of an interaction; this is variable from
patient to patient. Recommendations on how to
reduce the risk of DDIs occurring are presented
in Table 4.5.
When co-prescribing medications, the impact
of one on the other, additive clinical effect (pharmacodynamic interaction), and the risks and benets to patients should all be considered. Patients
should be monitored for signs of DDIs or toxicity, and patient involvement and education to
support this is important [90]. Certain DDIs that
have been associated with negative clinical outcomes include the following:
– Warfarin and aspirin/other interacting medica-
tions: GI bleeding [91]
– NSAIDs and aspirin: GI adverse effects [91]
– Diuretic combinations: Renal failure [92]
– Diuretics and angiotensin-converting enzyme
inhibitor (ACEIs): Renal failure [92]
– Digoxin and interacting medications: Digoxin
toxicity [93]
Table 4.5 Interventions to minimize the risk of potential
drug–drug interactions
Factor Action
High-risk
patients
Medication
history
Drugs with a
narrow
therapeutic index
High-risk
medications
Combinations of
medications
Genetic
polymorphisms
Patient
monitoring
Carefully monitor older patients,
patients with polypharmacy,
comorbidities, renal/hepatic disease,
and impact on pharmacokinetics and
pharmacodynamics
Conduct a thorough and detailed
medication history (include
prescribed regular and as required
medications, OTC medications,
herbal medications, supplements,
certain foods (e.g., grapefruit juice,
calcium-containing foods).
Conduct thorough medication
reconciliation at transitions of care
Monitor drugs in this class (e.g.,
warfarin, phenytoin, antiepileptics,
direct oral anticoagulants, digoxin,
antineoplastic drugs). Consider the
impact when prescribing other
medications for patients on narrow
therapeutic index medications
Be aware of commonly prescribed
enzyme inducers (e.g., phenytoin,
carbamazepine, rifampicin) and
enzyme inhibitors (e.g., azole
antifungals, HIV protease inhibitors,
macrolide antibiotics, selective
serotonin reuptake inhibitors)
Be aware of the potential risks of
combining high-risk medications, and
consider the potential for increased
risk of pharmacodynamic interactions
Pharmacogenetic testing can guide
individualized dosing for patients
with gene mutations impacting drug
metabolism and increasing DDI risk
(e.g., CYP2C19 testing for patients
on venlafaxine requiring
co-trimoxazole treatment) [89]
Where medications that have the
potential for DDI are being used,
ensure that patient monitoring is
conducted to ensure appropriate
clinical response and any signs of
adverse effects or toxicity
Anticoagulants, including warfarin and direct
oral anticoagulants (DOACs), have a narrow
therapeutic index and are susceptible to DDIs,
increasing the risk of bleeding or thrombosis
[94]. Particular care must be given when coprescribing other medications with these agents,
especially CYP450 inducers (e.g., CYP3A4
94
S. McCarthy and A. Fleming
inducer rifampicin) or inhibitors (e.g., CYP3A4
inhibitor clarithromycin). DOACs are P-gp substrates and at risk of DDI with P-gp inducers
(e.g., carbamazepine, phenytoin) and P-gp inhibitors (e.g., clarithromycin, uconazole).
Lithium, prescribed for mood disorders, has a
narrow therapeutic index and is susceptible to several clinically relevant interactions, mainly due to
an interacting drug altering renal function, particularly glomerular ltration rate and tubular reabsorption. ACEIs, angiotensin receptor blockers,
nonsteroidal anti-inammatory drugs, and diuretics have a high risk of reducing lithium excretion,
resulting in clinical toxicity [95]. Prescribers and
pharmacists must be alert to the potential for interaction and patient harm, and increased monitoring
of lithium blood levels is required if an interacting
drug is prescribed. A change in patients’ status
(e.g., renal or hepatic function) may necessitate a
medication review, which should consider the
potential for any clinically relevant DDIs [96].
Patient education and highlighting the importance and risk of drug–drug, drug–herb, and, in
some cases, drug–food interactions are vital to
inform patients about the risks of taking new
medications, especially nonprescription overthe- counter/herbal medications or supplements.
When a drug interaction occurs, there are several
courses of action that may be taken. In all cases,
clinical judgment and knowledge of the patient’s
medical and medication history are advised as well
as discussion with the patient’s physician as appropriate. Some possible actions to take to avoid negative clinical consequences for a patient with a
potential or actual DDI include the following [4, 73]:
– Discontinue one or both of the interacting
agents (including food, herbal, supplementary
medicines, etc.).
– Consider an alternative medication.
– Carefully monitor the patient without chang-
ing therapy.
– Adjust the dose or dosing schedule of one or
both drugs.
– Change the route of administration.
Preventive measures and system processes to
identify and prevent DDIs from occurring are
essential. Electronic prescribing systems and
pharmacy dispensing software systems with DDI
alerts are an important measure to alert healthcare professionals to DDIs. Sources of medication information such as the British National
Formulary and Stockley’s Drug Interactions
(book or online subscription via Medicines
Complete), manufacturers’ licensed product
information, and various online sources are available to screen for DDIs and assess the clinical
risk of a DDI.Examples of specic online sources
of DDI information are listed below:
– Lexicomp Drug Interactions: Available with
subscription
– Micromedex: Available freely online at https://
www.merckmanuals.com/professional/druginformation/drug- interactions
– CredibleMeds: Information on medications
that prolong the QT interval
– Medscape Drug Interaction Checker:
Primarily based on medications licensed in
the United States
– HIV Drug Interactions Checker: Operated by
the University of Liverpool
– Cancer Drug Interactions: Operated by the
University of Radboud, The Netherlands, and
the University of Liverpool
– Hepatitis C Drug Interactions: Operated by
the University of Liverpool
Health-care professionals, including doctors,
nurses, and pharmacists, should be encouraged to
report drug–drug/drug–herb/drug–food interactions, which result in patient adverse events to
their national medicinal products regulator, e.g.,
USFDA, United Kingdom Medicines and
Healthcare Products Regulatory Agency
(MHRA), etc.
9.1 Patient Involvement
Patients frequently request information on their
medications, including any interactions that their
medications may have with each other. DDI management involves a complex risk–benet assessment, in which patient preferences should be
considered [97]. Patient empowerment is impor-
4 Drug Interactions andTheir Management
95
tant for patients to feel condent in managing
their medications. It is important to provide
appropriate medicine information to patients to
support their understanding and medication
adherence [98]. Online information for patients
to explain what DDIs are and how to avoid them
is available; however, there is less guidance on
how to provide tailored information at an individual patient level [99, 100]. A recent scoping
review of providing DDI services for patients has
found that there are numerous online and digital
DDI services available; however, large variations
in quality have been reported, which could potentially lead to safety issues [101]. Although there
is a demand for online DDI checkers, the use of
these by patients poses a safety risk and could
undermine the patient’s condence in their medications or result in patients changing their regime
without rst consulting with a health-care
professional [98]. A focus group with patients
exploring their preferences for the management
of DDIs found that emotional, cognitive, situational, and personal factors such as fear, trust,
risk perception, and openness to change inuenced their needs [97]. Shared decision-making
involves more than just information provision,
and patient values and preferences must be considered in the health-care professional–patient
communication on DDIs. Future research should
investigate the impact of communication models
and tools to provide DDI information on patient
outcomes, such as their levels of condence and
risk perception, and on clinical outcomes, such as
medication adherence.
10 Areas forFuture Research
Identifying DDIs is a key area for researchers and
practitioners alike. For any newly approved drug,
the post-marketing phase is key to identifying
any potential DDIs. In this phase, the new drug is
taken by many more patients, with multiple
comorbidities and medications and thus previously unknown interactions may occur. A challenge for the pharmaceutical industry and
researchers is the ability to detect any new DDIs
in a timely manner. More recent research has
focused on the ability of machines to detect DDIs
in large real-world datasets and to predict DDIs
that may occur before a drug comes to the market
[102]. This area of research, which is progressing
rapidly with more powerful and sophisticated
models utilizing the power of articial intelligence to detect and predict DDIs, holds tremendous potential to advance drug safety assessment,
facilitate proactive risk mitigation strategies, and
ultimately contribute to the safe use of
medicines.
11 Summary andConclusions
This chapter provides health-care professionals
with an overview of drug interactions, the mechanisms by which they occur, and the impact they
can have on treatment efcacy and patient safety.
• The rst step for health-care professionals is
prevention, and, thus, when starting a medica-
tion for a patient, a thorough history should be
obtained, which should include all medica-
tions (including all prescribed, OTC, and
herbal or alternative medicines). It is impor-
tant to be aware of any drugs with a narrow
therapeutic index (e.g., warfarin).
• Health-care professionals should be aware of
medications that are commonly associated with
drug interactions such as antimicrobials (macro-
lides, azoles) and ASMs (e.g., carbamazepine,
sodium valproate). Health-care professionals
should consider the possibility that any new
symptom a patient presents with could be due to
a DDI and manage it appropriately. This is par-
ticularly relevant for patients at high risk of
DDI, including older patients, patients with
polypharmacy, and patients with comorbidities
such as renal and hepatic disease. Providing
patients with information on their medications
and the potential for interactions could help
empower them to identify and avoid DDIs.
• Finally, health-care professionals should be
aware of reference resources available to
review DDIs, which can support them when
making clinical decisions on the management
of DDIs in patients.
96
S. McCarthy and A. Fleming
12 Case Studies
12.1 Case Study 1
A 73-year-old male was experiencing symptoms
of cough and sputum production. On a Friday
evening, he phoned an out-of-hours physician
service and discussed with the physician (not his
regular physician) his symptoms. The patient is
usually t and well. His medical history included
high blood pressure and type 2 diabetes; his current medications included ramipril, amlodipine,
bendroumethiazide, spironolactone, metformin,
and atorvastatin.
The physician made a diagnosis of bronchitis
and considered appropriate antibiotics, given the
patient’s age and comorbidities. The physician
prescribed clarithromycin 500 mg twice a day
orally for 5days.
The prescription was sent to the late-night
pharmacy (not his regular pharmacy), and the
patient’s daughter collected the prescription for
him that night. The patient started the antibiotic
on Saturday morning. On Monday morning, the
patient felt dizzy and faint. He visited his regular
physician who noted his blood pressure as
92/38mmHg and pulse rate as 43bpm. His physician arranged for the patient to be transferred to
a hospital.
In the emergency department, the patient was
assessed for septic shock, cardiogenic shock, and
hypovolemic shock; however, all parameters
linked to these diagnoses were normal. On conducting a medication reconciliation, the pharmacist determined that the patient had recently
started a course of clarithromycin and, therefore,
the hypotension was likely drug-induced.
Following supportive treatment at the hospital,
the patient’s condition stabilized and he was discharged 6days later.
1. What is the pharmacokinetic basis for the
drug–drug interaction(s) in this case?
Clarithromycin and amlodipine:
(a) Clarithromycin is a macrolide anti-
bacterial, which is commonly used for
the treatment of various infections,
including lower respiratory tract
infections.
(b) As discussed earlier in this chapter,
clarithromycin is a potent inhibitor of
CYP3A4, the enzyme largely responsible for the metabolism of the calcium
channel blocker amlodipine.
(c) It can also inhibit the organic anion-
transporting polypeptides OATP1B1
and OATP1B3 [103].
Clarithromycin and atorvastatin:
(d) Another possible interaction could
have occurred between clarithromycin
and atorvastatin.
(e) Clarithromycin, through not only its
effects on CYP3A4 but also its effect
as an inhibitor of hepatic statin uptake
transporters, increases the systemic
exposure to most statins, the extent to
which varies depending on the type of
statin used [104].
2. What clinical impact does this interaction
have on the patient?
Clarithromycin and amlodipine:
(a) In this case, inhibition of CYP3A4 led
to increased concentration of amlodip-
ine and increased blood pressure-low-
ering effect.
(b) This situation arose for this patient
because of the interaction between
clarithromycin and amlodipine, the
effects of which were likely enhanced
by the multiple antihypertensives
prescribed.
Clarithromycin and atorvastatin:
(c) In this patient’s case, it is considered
that an interaction and adverse effects,
such as myopathy and rhabdomyoly-
sis, are possible with atorvastatin and
clarithromycin coadministration [4].
4 Drug Interactions andTheir Management
97
3. How could a situation like the one experi-
enced by this patient be avoided?
We need to consider the factors that con-
tributed to this case.
(a) Both the physician and the pharmacist
who dispensed the medication were
unfamiliar with the patient, likely did
not have access to the patient’s medical/medication records, and therefore
may not have had an accurate picture of
the patient’s risk factors.
(b) The patient was an older man and had
signicant medical comorbidities and
polypharmacy.
To prevent this from occurring again:
(c) Therefore, the rst step when prescrib-
ing or dispensing medication is to
ensure that an accurate history of all
medications is known.
(d) This includes all prescribed medica-
tions (considering that multiple pre-
scribers may be involved in the care
of a patient), medication recently
started or stopped, medication that the
patient may purchase over the coun-
ter, herbal, or other preparations, and
also consider whether patients are
taking all medications prescribed, as
issues with adherence, if not consid-
ered, may lead to additional medica-
tions being prescribed.
(e) The perpetrator drug in this case is
clarithromycin, a drug well-docu-
mented for causing DDIs. Although it
is impossible for health-care profes-
sionals to know every single potential
DDI, they should be familiar with
some of the commonly implicated
drugs, such as clarithromycin. If clar-
ithromycin is indicated for a patient,
then a thorough check for possible
interactions should be undertaken.
4. What action should be taken when these inter-
actions occur?
(a) How to deal with an interaction will
depend on the nature of the interaction
and the potential for harm to the patient,
and the long-term impact of the action
chosen, and the decision and action taken
should involve the patient’s doctor.
(b) In some cases, a drug–drug combina-
tion will be contraindicated and an
alternative will be required, e.g.,
changing clarithromycin to another,
appropriate, antimicrobial agent.
(c) A temporary discontinuation of a drug
may be a suitable course of action and
should be discussed with the patient’s
doctor (e.g., putting atorvastatin on
hold when taking clarithromycin). The
clinical impact of this needs to be carefully considered.
(d) Sometimes a change in dose or change
in administration timing may be sufcient to avoid adverse effects.
(e) There are many reputable sources
available to support health-care professionals to determine the best course of
action to take to minimize the risk of
harm from DDIs, as discussed above,
such as those listed previously.
12.2 Case Study 2
A 78-year-old lady presents to a hospital emergency department following referral by her family physician. She presents with a history of
increasing disorientation, tremor, and drowsiness, and she also says that she has been experiencing “racing heart beat” or palpitations. She
has a history of chronic lower back pain for
which she takes morphine 10mg twice daily and
amitriptyline 10mg once daily. She recently had
a fall at home and her back pain has worsened,
for which she was prescribed a combined analgesic with paracetamol 325 mg and tramadol
37.5mg, one tablet four times a day, 5days ago.
She was admitted, and, over the course of her
initial day in hospital, she became increasingly
unwell, with sweating, fever, worsening confusion, and muscular rigidity. There was no evidence of infection upon examination, and blood
samples were sent to the laboratory for
investigation.
98
S. McCarthy and A. Fleming
Her laboratory results reported elevated serum
creatinine kinase and transaminases.
Following review of her medications, history,
and assessment, the multidisciplinary team
stopped all medications and administered supportive care. Within 24h, her condition stabilized
and her symptoms were resolving. The team
diagnosed SS as a result of the interaction
between amitriptyline and the newly prescribing
tramadol.
1. What is the basis for the drug–drug inter-
action(s) in this case?
Amitriptyline and tramadol:
(a) Amitriptyline is a tricyclic antidepres-
sant, often prescribed for pain, which
increases noradrenergic or serotonergic
neurotransmission by blocking the noradrenaline or serotonin transporter at
presynaptic terminals.
(b) Tramadol is an atypical opioid analge-
sic with weak μ-receptor agonism and
central reuptake inhibition of serotonin
and noradrenaline. Although it is a less
potent opioid analgesic than morphine,
it poses safety risks of its own.
(c) Tramadol has been reported to contrib-
ute to a signicant number of cases of
SS, either when prescribed by itself or
in combination with other serotonergic
medications [105].
(d) Patients with comorbidities, those tak-
ing high doses of tramadol, and those
taking other serotonergic medications
are at an increased risk of SS.
(e) SSRIs, serotonin noradrenaline reup-
take inhibitors (SNRIs), MAOIs, and
tricyclic antidepressants have all been
shown to cause or contribute to SS.
Other medications such as tramadol,
diphenhydramine (a rst-generation
antihistamine that may also inhibit
serotonin reuptake), and linezolid (a
weak, reversible, nonselective monoamine oxidase A and B inhibitor) have
also been implicated in cases of SS
[106].
2. What clinical impact does this interaction
have on the patient?
(a) SS can be diagnosed using Sternbach’s
criteria or Hunter Serotonin Toxicity criteria [59].
(b) Sternbach’s criteria diagnoses SS on
presentation of at least three of the
following:
• Mental status changes (confusion,
hypomania)
• Agitation
• Myoclonus
• Hyperreexia
• Diaphoresis
• Tremor
• Diarrhea
• Incoordination/ataxia
• Fever
(c) Hunter Serotonin Toxicity criteria are a
presentation of any of the following:
• Spontaneous clonus
• Inducible or ocular clonus and agitation or diaphoresis
• Tremor and hyperreexia
• Hypertonia and hyperpyrexia (temperature exceeding 38°C) and ocular/inducible clonus
3. How could a situation like the one experi-
enced by this patient be avoided?
We need to consider the factors that con-
tributed to this case.
(a) The patient was at risk as she was an
older patient and was prescribed a
combination of medications posing a
risk of DDI.
(b) She was prescribed a combination of
medications, several of which had a
central nervous system effect and a
serotonergic effect.
To prevent this from occurring again:
(c) The rst step when prescribing or dis-
pensing medication is to ensure that an
accurate history of all medications is
known.
(d) A risk–benet assessment to consider
the risk and potential clinical conse-
quences of a DDI should be conducted
4 Drug Interactions andTheir Management
99
by the prescriber, supported by information from DDI information checkers.
(e) When the acute phase has passed, the
patient should be informed about what
occurred and the risks of DDIs
explained clearly and how to avoid
them. The patient should be informed
of the risk of combining any medications with her long-term amitriptyline
medication, and all medication decisions should be made with her physician and/or pharmacist. She should
ensure in the future that all health-care
providers are aware of her
medications.
(f) In some patient groups, the risk of SS
posed by combining medications with
recreational drugs such as ecstasy and
LSD (lysergic acid diethylamide)
should be highlighted.
(g) Patients on medications with a seroto-
nergic effect should be taught how to
recognize the signs and symptoms of
SS, which is at an increased risk if a
medication dose is being increased or a
new medication is prescribed.
(h) Useful information is provided for
patients such as an infographic developed by Foong etal. [107].
4. What action should be taken when these inter-
actions occur?
(a) The management of SS involves dis-
continuation of serotonergic medications and implementing supportive
care.
(b) Vital signs (blood pressure, tempera-
ture, pulse) and renal function should
be monitored.
(c) Intravenous uids may be required
to replace uid loss or correct
hypotension.
(d) Diazepam or lorazepam may be admin-
istered for convulsions or agitation. In
most mild cases, symptoms usually
resolve within 24 h of discontinuing
the serotonergic medication(s); however, symptoms may persist in cases
involving medications with long
half-lives.
(e) High-dependency unit care may be
needed for more severe cases.
(f) Cyproheptadine (a histamine-1 recep-
tor antagonist with nonspecic
5- hydroxytryptamine (5-HT)1A and
5-HT2A antagonistic properties) has
been used in certain cases, but denitive
evidence of its effectiveness is lacking
[58].
References
1. World Health Organization. Life tables.
Global Health Observatory; 2022. https://
www.who.int/data/gho/data/themes/
mortality- and- global- health- estimates/
ghe- life- expectancy- and- healthy- life- expectancy.
2. Masnoon N, Shakib S, Kalisch-Ellett L, Caughey
GE.What is polypharmacy? A systematic review of
denitions. BMC Geriatr. 2017;17(1):230. https://
doi.org/10.1186/s12877- 017- 0621- 2.
3. Maher RL, Hanlon J, Hajjar ER. Clinical consequences of polypharmacy in elderly. Expert Opin
Drug Saf. 2014;13(1):57–65. https://doi.org/10.151
7/14740338.2013.827660.
4. Baxter K, Preston CL.Stockley’s drug interactions
[Online]. London: Pharmaceutical Press; 2022.
https://www- medicinescomplete- com.ucc.idm.oclc.
org/#/content/stockley/x01- 3201?hspl=additive&hs
pl=or&hspl=synergistic&hspl=interactions.
5. Alvim MM, da Silva LA, Leite ICG, Silvério
MS. Adverse events caused by potential drugdrug interactions in an intensive care unit of a
teaching hospital. Revista Brasileira de Terapia
Intensiva. 2015;27(4):353–9. https://doi.
org/10.5935/0103- 507X.20150060.
6. Lexicomp Online. 2023. https://online.lexi.com.
7. Lopez-Gonzalez E, Herdeiro MT, Figueiras
A.Determinants of under-reporting of adverse drug
reactions. Drug Saf. 2009;32(1):19–31. https://doi.
org/10.2165/00002018- 200932010- 00002.
8. de Oliveira LM, do Amaral Carneiro Diel J, Nunes
A, da Silva Dal Pizzol T. Prevalence of drug interactions in hospitalised elderly patients: a systematic
review. Eur J Hosp Pharm. 2021;28(1):4–9. https://
doi.org/10.1136/ejhpharm- 2019- 002111.
9. Zheng WY, Richardson LC, Li L, Day RO,
Westbrook JI, Baysari MT.Drug-drug interactions
and their harmful effects in hospitalised patients:
a systematic review and meta-analysis. Eur J
Clin Pharmacol. 2018;74(1):15–27. https://doi.
org/10.1007/s00228- 017- 2357- 5.
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