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80
S. McCarthy and A. Fleming
identied many serious interactions between
drugs recommended by guidelines in each of the
three index conditions and drugs recommended
for 11 other conditions. Therefore, clinicians
who may be prescribing within the recommendations of a condition-specic guideline may be
unintentionally putting their patients at risk of
DDIs.
3 Types ofDrug–Drug
Interactions
DDIs can be classied based on their mechanisms of action as either pharmacokinetic or
pharmacodynamic.
3.1 Pharmacokinetic Drug
Interactions
Pharmacokinetics describes what the body does
to a drug; pharmacokinetic DDIsoccur when one
drug alters the rate or extent of absorption, distribution, metabolism, or excretion (ADME) of
another drug. Pharmacokinetic DDIs can alter
drug concentrations, thus affecting clinical
response [15]. We will review howDDIs occur at
each of the stages of ADME and some common
examples.
3.1.1 Absorption
The oral route is the most common route of
administration as it is a noninvasive, convenient
route for drug delivery [16, 17]. However, many
factors can inuence the absorption of drugs
administered orally, including gastric pH, volume and composition of gastric uids, and gastric emptying time, leading to variability in drug
absorption [17]. This variability can occur due to
physiological causes (e.g., in pediatrics and the
elderly), due to medical conditions (e.g., postbariatric surgery), and due to the presence of drug
interactions [17]. We will now consider the
mechanism by which some of these absorption
drug interactions can occur. It should be noted
that for drugs administered via the intravenous
route, absorption is complete.
Change inGastric pH
Most drugs are administered orally and thus need
to be absorbed through the gastrointestinal (GI)
mucosa. The movement of drugs by simple passive diffusion relies on the extent to which they
exist in the non-ionized lipid-soluble form,
which, in turn, depends on factors such as the
drug pKa and the pH of the GI tract [4]. If a drug
alters the gastric pH, for example, in the case of
proton pump inhibitors (PPIs), which reduce acid
secretion and increase gastric pH, then this has
the potential to change the kinetics of the coadministered drugs. An example of this is the interaction between PPIs and certain tyrosine kinase
inhibitors, used in the treatment of solid and
hematological malignancies [18].
Adsorption andOther Complex
Mechanisms
Certain drugs such as cholestyramine, ions such
as calcium (found in dairy products), aluminum
and magnesium (often found in antacids), and
iron compounds can affect absorption by binding
to and forming complexes with medications. This
can then reduce the absorption of the medication.
This pharmacokinetic interaction is the basis of
using activated charcoal as an adsorbing agent in
case of an overdose. These types of interactions
can often be overcome by separating the administration time of the doses by 2–3hours [4], and,
so, patient education is an important aspect of
managing and minimizing the potential effects of
such interactions.
Inhibition or Induction ofDrug
Transporter Proteins
Drug transporter proteins serve to transport drugs
into and out of cells, which affect systemic drug
concentration [19]. One of the key drug transporter proteins is the permeability glycoprotein
or P-gp, a member of the adenosine triphosphate
(ATP)-binding cassette (ABC) family of transporters, which is located in various parts of the
4 Drug Interactions andTheir Management
81
body, including the luminal membrane of the
small intestine and blood–brain barrier, and the
apical membranes of excretory cells of the liver
and kidneys [20]. P-gp plays a role in intestinal
absorption of drugs, in addition to limiting the
entry of drugs into the central nervous system,
and in biliary and urinary excretion of drugs [20].
Drugs can be substrates of P-gp and are thus
transported by P-gp across membranes, can act as
inhibitors of P-gp and thus impair the actions of
P-gp, and can act as inducers of P-gp and thus
enhance P-gp activity [19].
Examples of drugs that are P-gp substrates are
digoxin, losartan, ciclosporin, tacrolimus, diltiazem, verapamil, ondansetron, morphine, phenytoin, doxorubicin, ritonavir, erythromycin,
dabigatran, apixaban, rivaroxaban, and edoxaban
[21]. If two of these drugs are prescribed together,
then they can compete for the P-gp transporters
and lead to an alteration in their absorption,
excretion, and tissue distribution at sites where
the P-gp transporter is expressed.
Drugs that inhibit P-gp can cause DDIs, for
example, the cardiovascular drug verapamil, a
calcium antagonist, inhibits the activity of P-gp,
which can increase concentrations of P-gp substrates such as digoxin [4]. Clarithromycin inhibits P-gp and may reduce the renal clearance of
digoxin, thus increasing the risk of digoxin toxicity [21]. The expression of P-gp can be induced
by drugs such as the antituberculosis drug rifampicin, which, in the presence of digoxin, reduces
its plasma concentration [4]. Many of the drugs
that are affected by P-gp interactions are also
affected by interactions affecting the cytochrome
P450 system, in particular CYP3A4, which we
will look at later in this chapter.
Changes inGastric Motility
The movement of drugs through the gastrointestinal tract to the main site of absorption, the small
intestine, can be altered by drugs that alter gastric
motility. One such drug is the prokinetic agent
metoclopramide, which exhibits activity on
dopamine and 5-hydroxytryptamine (5-HT)
receptors in the gastrointestinal tract [22]. By
accelerating gastric emptying, metoclopramide
can increase the rate of absorption of several
drugs, including paracetamol (acetaminophen),
an interaction which is taken advantage of when
the two drugs are used in combination for the
treatment of migraine, a condition often accompanied by delayed gastric emptying [22].
3.1.2 Distribution
The next step in the process is the distribution
of the drug through the body’s blood and
tissues.
Displacement fromProtein-Binding Sites
Several factors can impact drug distribution,
including plasma-binding proteins, particularly
the albumins. Some drugs are highly proteinbound meaning that a large proportion of the
drug is reversibly bound to the protein and only
the unbound molecule is available for passive diffusion to extravascular or tissue sites where it can
exert its pharmacological action [4]. Drug interactions may arise from displacement from plasma
protein-binding sites, but such effects are typically of limited clinical signicance since the
metabolism of the displaced drug generally
increases alongside the increased concentration
of unbound drug. However, it may have importance and should be considered for highly bound
drugs having a narrow therapeutic window, a
high hepatic extraction ratio (if administered
intravenously), or a high renal extraction ratio
[23]. Awareness of this interaction with narrow
therapeutic drugs is important as it can alter the
interpretation of therapeutic drug monitoring.
This is the information provided in the reference
included. For example, if the antiepileptic drug
phenytoin was displaced from its binding site,
then the amount of free phenytoin would initially
increase, but, through metabolism and excretion,
the amount of free phenytoin would reduce back
to the original level. However, the total amount of
phenytoin would be reduced as a result, and, thus,
interpretation of this reduced level, without consideration of the interaction, may lead a clinician
82
S. McCarthy and A. Fleming
to incorrectly increasing the dose of phenytoin
[4].
Inhibition or Induction ofDrug
Transporter Proteins
In addition to their role in drug absorption, drug
transporter proteins, including P-gp, inuence
drug distribution by limiting penetration into several sensitive tissues such as the brain [24]. DDIs
that inhibit or induce drug transporter proteins
could therefore affect the uptake of drug substrates to areas such as the brain.
3.1.3 Metabolism
Drug metabolism is the process by which a drug is
chemically changed so as to facilitate its excretion
from the body. The liver is the primary site for
drug metabolism, although metabolism can occur
in other areas of the body, including the skin,
lungs, intestines, kidneys, and plasma [4, 25]. In
the liver, drugs are metabolized through either
phase I reactions (oxidation, reduction, hydrolysis
reactions) or phase II reactions (glucuronidation,
acetylation, sulfation reactions) or both, with the
aim of converting lipid-soluble to more watersoluble compounds for excretion [25]. Phase I
reactions are catalyzed by a family of enzymes
within the liver microsomes called cytochrome
P450, comprising 18 families and 44 subfamily
members [26]. However, the most clinically relevant CYP isoenzymes for drug metabolism are
CYP1A2, CYP2C9, CYP2C19, CYP2D6,
CYP2E1, and CYP3A4/5, which account for 90%
of metabolic activity [27]. The liver is also a key
site for DDIs to occur, notably through induction
and inhibition of CYP enzymes.
Induction
Drugs that are inducers increase the synthesis of
a CYP450 enzyme, resulting in increases in
enzymatic activity. This leads to a decrease in
serum concentrations of other drugs metabolized
by the same isoenzyme. Induction reactions tend
to be delayed in their onset and their resolution,
the effects dependent on the half-life of the inducing drug, the dose of the inducing drug, and the
rate of turnover of the enzyme being induced [4,
28]. Examples of inducers include the antiepilep-
tic drugs carbamazepine and phenytoin and the
antituberculosis drug rifampicin [4]. Induction
reactions can often be overcome by increasing
the dose of the affected drug; however, this
requires careful monitoring, including ensuring
that the dose is modied if the interacting drug is
stopped.
Inhibition
The most common mechanism leading to DDIs
is inhibition of the CYP450 system [29]. This
occurs when a drug (precipitant drug) inhibits
the CYP450 isoenzyme that is responsible for
the metabolism of another drug (object drug),
resulting in an increase in the plasma concentration of the object drug. There are several
ways in which inhibition can occur: reversible
inhibition, which includes competitive and
noncompetitive inhibition, and irreversible or
mechanism-based inhibition [29]. Competitive
inhibition occurs when two drugs that are substrates for the same enzyme compete for the
same active site of the CYP450 enzyme. A substrate with a stronger afnity to the binding
site can displace the weaker substrate from the
active site, thus resulting in increased plasma
concentration and the potential for an adverse
event to occur [29]. The effect of this type of
competitive inhibition is almost immediate in
contrast to induction interactions, which are
slower at onset. Noncompetitive inhibition
occurs when the precipitant drug binds to the
allosteric site of the enzyme and thus does not
prevent the object drug from also binding to
the enzyme at the active site. However, by
binding to the allosteric site, a conformational
change occurs at the active site, and it loses its
afnity toward the object drug. Similar to competitive inhibition, the effect of noncompetitive
inhibition is almost immediate [29]. There are
also examples of mixed inhibition, whereby a
drug can act in both a competitive and noncompetitive way, binding at the active site and
at the allosteric site of the enzyme; these drugs,
such as the azoles, tend to be potent inhibitors
[29]. Irreversible and quasi-irreversible inhibitions are together known as mechanism-based
inhibition; this involves the metabolism of the
4 Drug Interactions andTheir Management
83
inhibitor drug into a reactive metabolite, which
modies the CYP enzyme, leading to irreversible loss of enzymatic activity [30]. Examples
of drugs that interact in this way include the
macrolides, clarithromycin and erythromycin,
and the proton pump inhibitor omeprazole [4,
29]. Health-care professionals should recog-
nize when an inhibition interaction has
occurred or has the potential to occur and take
appropriate steps to avoid adverse effects to the
patient.
The CYP3A4 enzymes are also expressed in
the intestine, with their expression level varying
across the intestine, with high levels in the duodenum. These enzymes are responsible for a
signicant number of DDIs as they are involved
in the metabolism of many drugs. Determining
specic DDIs with 3A4 enzymes can be challenging as they are also present in the liver. An
example of such a DDI is the inhibition of intestinal 3A4 by itraconazole, which leads to
increased gut oral bioavailability of midazolam
[31].
Table 4.1 presents some common CYP450mediated drug–drug interactions.
3.1.4 Excretion
The nal step in the pharmacokinetic pathway
is the removal of drugs from the body. Excretion
of drugs can occur through different mechanisms, including the lungs, sweat, saliva, and
milk; however, the main routes of excretion are
through involvement of the kidneys (which
accounts for more than two-thirds of drug
excretion) and the liver through excretion via
the bile [32]. Hydrophilic drugs are typically
excreted directly by the kidneys, whereas
hydrophobic drugs require biotransformation
(most often by the liver) before excretion by the
kidneys.
Urinary pH
Urinary pH can impact excretion of drugs by the
kidneys. If a drug exists in its ionized lipidinsoluble form, it cannot undergo passive reabsorption into the tubule cells and so will be removed
from the body in the urine. For drugs that are weak
acids with a pKa between 3 and 7.5, this situation
will arise at high pH values, whereas for drugs that
are weakly basic with a pKa between 7.5 and 10.5,
this situation arises at low pH values. Changes in
Table 4.1 Examples of substrates, inducers, and inhibitors of cytochrome P450 enzymes
Substrates Inducers Inhibitors
CYP3A4:
Apixaban, rivaroxaban, atorvastatin,
simvastatin, calcium channel blockers,
ciclosporin, codeine, benzodiazepines,
oral contraceptives, verapamil,
R-warfarin
CYP2D6:
Beta-blockers, codeine, donepezil,
ecainide, tricyclic antidepressants,
tolterodine, risperidone
CYP2C9:
Aspirin, most NSAIDs, diazepam,
selective serotonin reuptake inhibitors,
S-warfarin, statins
CYP1A2:
Caffeine, clozapine, imipramine,
olanzapine, theophylline, tricyclic
antidepressants, R-warfarin, duloxetine
CYP2C19:
Citalopram, clopidogrel, diazepam,
lansoprazole, omeprazole, voriconazole
Disclaimer: This table is not exhaustive
CYP3A4:
Barbiturates,
carbamazepine,
dexamethasone,
rifampicin, St. John’s
wort
CYP2D6:
Carbamazepine,
rifampicin
CYP2C9:
Barbiturates, rifampicin,
phenytoin
CYP1A2:
Omeprazole,
lansoprazole, phenytoin,
tobacco smoke
CYP2C19:
Carbamazepine,
rifampicin, omeprazole
CYP3A4:
Amiodarone, diltiazem, clarithromycin,
erythromycin, cimetidine, uconazole,
itraconazole, uoxetine, sertraline,
venlafaxine, grapefruit juice, tamoxifen,
tricyclic antidepressants
CYP2D6:
Amiodarone, chlorpheniramine, uoxetine,
paroxetine, sertraline, tricyclic
antidepressants, venlafaxine, ketoconazole,
haloperidol
CYP2C9:
Cimetidine, uoxetine, omeprazole,
metronidazole, uconazole, voriconazole
CYP1A2:
Amiodarone, cimetidine, quinolones,
uvoxamine
CYP2C19:
Cannabidiol, esomeprazole, uconazole,
uoxetine
84
S. McCarthy and A. Fleming
urinary pH can alter the amount of drug excreted;
however, this interaction appears to be only clinically signicant in a small number of cases [4].
One such example is urine alkalinization with
methotrexate. Methotrexate is poorly soluble at an
acidic pH, which can result in it and its metabolites
precipitating in the renal tubules, leading to acute
kidney injury. Administration of urine alkalinizers,
such as sodium bicarbonate, to achieve a urinary
pH of 7 increases the solubility of methotrexate and
reduces the risk of crystal formation [33].
The Role ofDrug Transporters
Various drug transporters, including P-gp, organic
anionic transporters (OATs), and organic cationic
transporters (OCTs), are predominantly expressed
in the renal proximal tubules and function to eliminate drugs into the urine from the circulation [34].
Drugs that inhibit renal drug transporters can
decrease renal clearance, which can lead to
increased plasma drug concentrations and consequent adverse effects. The interaction can also lead
to drug-induced nephrotoxicity due to accumulation of the drug in the proximal tubule cells [34].
An example of this interaction occurs with the
drug probenecid, a uricosuric agent used in the
treatment of gout, which inhibits OATs. Probenecid
inhibits OAT1 and OAT3, leading to the inhibition
of renal excretion of methotrexate, which can lead
to toxic effects of methotrexate [4].
Biliary Excretion
Biliary excretion occurs when drugs, either
unchanged or conjugated, are excreted into bile,
ready for removal from the body. The hepatobiliary elimination process is complex involving multiple processes and many different transporter
proteins, including P-gp, OATs, and OCTs [4].
Drugs that induce or inhibit the activity of these
transporter proteins can alter the pharmacokinetics of the victim drug [35]; however, the clinical
relevance of these drug interactions is unclear [4].
3.2 Pharmacodynamic Drug
Interactions
Pharmacodynamics is concerned with what a
drug does to the body to elicit a physiological
response [32]. Pharmacodynamic DDIs occur
when the pharmacodynamics of one drug is
altered by that of a coadministered drug.
Pharmacodynamic DDIs can be classied as
additive, synergistic, or antagonistic [36]. In
addition, pharmacodynamic DDIs can be used
intentionally for benecial effects (e.g., combinations of drugs to lower blood pressure) or can be
unintended and lead to adverse effects (e.g.,
selective serotonin reuptake inhibitors [SSRIs] in
combination with the analgesic tramadol with the
potential to cause serotonin syndrome [SS]).
3.2.1 Additive Pharmacodynamic
Drug Interactions
An additive pharmacodynamic DDI occurs
when the interaction produces an effect equal to
the sum of the pharmacological effects of each
drug involved [36]. An example of this interaction is the coadministration of the antidiabetic
medications liraglutide and insulin detemir,
which produce an additive glucose-lowering
effect [37].
3.2.2 SynergisticPharmacodynamic
Drug Interactions
A synergistic pharmacodynamic DDI occurs
when the combination of two drugs results in an
effect, which is greater than the sum of the effects
of each drug individually [32]. An example of
this is the synergism between volatile anesthetics
and opioids in which the dose requirements of
various anesthetics, including desurane, propofol, and thiopental, might be lower after opioid
use [4]. Another example involves the combination of the antibacterial drugs sulfamethoxazole
and trimethoprim, as the preparation cotrimoxazole, in which both drugs work synergistically to inhibit steps along the folic acid
biosynthetic pathway [38].
3.2.3 Antagonistic Pharmacodynamic
Drug Interactions
Antagonisticpharmacodynamic DDIs occur when
one drug, the perpetrator, inhibits the effect of the
second drug, the victim drug. An example of this
interaction for benecial purposes is the use of
naloxone and umazenil to counteract the effects
of opioids and benzodiazepines, respectively. An
4 Drug Interactions andTheir Management
85
unwanted antagonistic DDI occurs if a non-cardioselective beta-blocker can oppose the bronchodilator effects of beta-agonist bronchodilators,
which can lead to serious bronchospasm [4].
4 Clinically Relevant Drug–
Drug Interactions
The following section provides an overview of
commonly encountered, clinically relevant DDIs.
It should be noted that this is not an exhaustive
list.
4.1 Antimicrobial Drug–Drug
Interactions
Antimicrobial stewardship, which aims to ensure
that antibiotics and antifungal therapies are used
appropriately and responsibly, can be negatively
impacted by antimicrobial–drug interactions.
The risk of patient toxicity increases if they are
prescribed medications that can interact with
antimicrobial therapy. Some antibacterial medications interact with many other medications,
and the increasing burden of chronic disease and
polypharmacy increases the risk of DDIs involving antimicrobials. Macrolides (e.g., clarithromycin, erythromycin, azithromycin) interact
with statins, potentially leading to life- threatening
rhabdomyolysis and resulting in acute kidney
injury. Macrolides are CYP3A4 inhibitors and
statins are CYP3A4 substrates; concomitant use
of both medications can increase the systemic
exposure to statins [39].
Fluoroquinolones (e.g., ciprooxacin, levooxacin) interact with some antiarrhythmic
agents, resulting in torsade de pointes, due to QT
(the duration of ventricular electrical systole)
interval prolongation [4]. Multivalent cations
(e.g., antacids, supplements, or feeds containing
calcium, iron, magnesium, zinc, sucralfate, bismuth) bind to uoroquinolones and reduce their
absorption from the gastrointestinal tract. If used
together, administration times must be spaced
apart [4].
Antifungal medications pose a particular challenge with a high degree of risk and serious drug
interactions, which can occur between antifungal
medications and many other medications [40,
41]. Most of these interactions occur due to
CYP450 interactions, with some new interaction
pathways, e.g., organic anion-transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein pathways (BCRPs). Interactions
with antifungals can lead to life-threatening
adverse effects, e.g., QT interval prolongation,
neuromuscular toxicity, and death [42].
Antifungal agents inhibit key metabolizing cytochrome P450 enzymes (e.g., CYP3A4) and
membrane- bound transport systems (e.g., P-gp),
thus affecting the absorption, metabolism, and
excretion of coadministered drugs. DDIs may
preclude the use of rst-line antifungal agents
(e.g., anti-mold azoles may be problematic in
patients on concurrent chemotherapy or antiretrovirals due to unpredictable drug interactions).
Azole antifungals and phenytoin can interact in a
bidirectional manner; azole rst inhibits the
CYP-mediated metabolism of phenytoin, which
is followed by the phenytoin- induced, CYPmediated metabolism of azoles. This can result in
phenytoin toxicity and/or treatment failure with
the azole antifungal [43].
The Antifungals Interaction Database is a single central resource, which holds interactions
data, and is a useful source of information for
health-care professionals on drug interactions
with antifungal agents [44]. Some commonly
encountered drug and antifungal interactions are
outlined in Table4.2 [45].
4.2 Antiretroviral Drug–Drug
Interactions
Antiretrovirals (ARVs) have complicated and
unpredictable DDIs, leading to toxicity and treatment failure, including human immunodeciency
virus (HIV) treatment failure. There isan increasing number of ARVs available for treating HIV
and coupled with the increasing life expectancy
of patients living with HIV, the risk of DDIs
increases. Absorption of ARVs can be impacted
86
S. McCarthy and A. Fleming
Table 4.2 Examples of drug interactions with antifungal
medications
Antifungal
agent Interacting drug Comment
Fluconazole,
Miconazole
(oral gel)
Fluconazole,
itraconazole
Caspofungin Rifampicin
Disclaimer: This table is not an exhaustive list of all drug
interactions with antifungal agents. Please check product
summary of product characteristics for comprehensive
information
Statins
(simvastatin,
atorvastatin)
Direct
anticoagulants
(apixaban,
dabigatran,
rivaroxaban,
edoxaban)
Warfarin Increased risk of
Clopidogrel Reduced antiplatelet
Domperidone QT interval
Benzodiazepines Increased and
Ciclosporin,
tacrolimus
Phenytoin
Carbamazepine
Dexamethasone
Tacrolimus Increase in
Increased risk of
myopathy and
rhabdomyolysis.
Check statin
summary of product
characteristics for
detailed information
Fluconazole can
increase bleeding
risk
bleeding due to
raised International
Normalized Ratio
(INR); also risk with
miconazole oral gel
activity; increased
bleeding risk
prolongation
prolonged sedative
effects
Increased risk of
toxicity; renal
impairment
Reduced
caspofungin plasma
concentration
tacrolimus levels.
Monitor levels and
adjust as needed.
by gastric pH; for example, lansoprazole and
omeprazole can reduce the absorption of atazanavir and rilpivirine. Drugs that increase or slow the
rate of gastric emptying can impact ARV absorption. Polyvalent cations (e.g., calcium, iron, magnesium, zinc) can chelate with integrase inhibitors
(e.g., dolutegravir, raltegravir) and reduce
absorption.
Most ARVs are hepatically metabolized by
the CYP450 system or by glucuronidation via
uridyl- diphosphate- glucuronosyl-transferase
1A1 (UGT1A1) (dolutegravir and raltegravir)
[46]. CYP3A4 has a signicant impact on ARV
metabolism. From a clinical perspective, treatment of other conditions in HIV is challenging.
For example, rifampicin, which is a potent
CYP450 enzyme inducer and UGT1A1 inducer,
and indicated for treating tuberculosis, poses
challenges in HIV patients, resulting in reduced
levels of ARVs such as raltegravir [47].
Prescribing and reviewing of ARV medications is a specialized area, and health-care professionals should seek expert advice in this area
before changing medication regimens. ARVs can
be substrates, inhibitors, and inducers of CYP450
and drug transporter systems. DDIs with ARVs
can impact HIV treatment and treatment of other
conditions. Caution should be exercised when
managing patients on drugs with a narrow therapeutic index and interactions with ARVs. Further
information can be sourced online at www.hiv- -
druginteractions.org [48] and https://clinicalinfo.
hiv.gov/en/guidelines/hiv- clinical- guidelinesadult- and- adolescent- arv/drug- interactionsoverview?view=full provided by the Ofce of
AIDS Research in the National Institutes of
Health in the United States [49].
4.3 Anti-Seizure Medication
Drug–Drug Interactions
Interactions between Anti-Seizure Medications
(ASMs) are complex and can increase the risk of
side effects and toxicity, usually as a result of
hepatic enzyme inhibition or induction. Patients
with epilepsy are often prescribed a number of
medications, including other ASMs, which
increases the risk of DDIs. The potent enzyme
inducers phenytoin and carbamazepine carry a
risk of DDIs with many drug classes, including
statins, antidepressants, and neuroleptics [50].
Sodium valproate is an inhibitor of CYP450
enzymes and contributes to several pharmacokinetic interactions. When co-prescribed with
lamotrigine, it can increase its half-life and lead
4 Drug Interactions andTheir Management
87
to reduced lamotrigine clearance. Adjustment of
the existing lamotrigine dose may be required if
it is co-prescribed with sodium valproate.
Carbamazepine is a potent CYP450 inducer,
which leads to signicant drug interactions. One
interaction of note is with the estrogen and progestogen components of the contraceptive pill, which
can result in contraceptive failure [4]. Levetiracetam
is an ASM with fewer interactions and is often chosen for this reason, if clinically appropriate.
ASMs are at risk of DDIs due to antimicrobials
in the uoroquinolone and macrolide class
(CYP3A4 inhibition). Phenytoin and carbamazepine are older ASMs, which are enzyme inducers,
and may reduce the levels of antimicrobials, thus
reducing their therapeutic effect. An example of
bidirectional DDI exists between the antifungal
voriconazole and several ASMs. Voriconazole is
metabolized and is a strong inhibitor of CYP3A4,
CYP2C9/10, and CYP2C19. Phenytoin has been
shown to induce voriconazole metabolism with
possible loss of its efcacy, whereas voriconazole
increases the levels of phenytoin [51].
In the process of prescribing medications for
patients taking ASMs, care should be taken to
screen for DDIs, adjust the medication dose as
appropriate, conduct therapeutic drug monitoring, and carry out clinical monitoring to reduce
patient adverse consequences [52]. It should be
noted that some antimicrobials (e.g., uoroquinolones, monobactams, cephalosporins, isoniazid) have epileptogenic properties due to
disturbing gamma-aminobutyric acid (GABA)
neurotransmission [52].
4.4 Drug Interactions andQT
Prolongation
QT interval prolongation can be caused by congenital and acquired causes, common of which is druginduced QT interval prolongation [53]. QT
prolongation is a risk factor for torsade de point and
ventricular arrhythmias and results in cardiac death.
DDIs can increase the risk of QT interval prolongation, a) if more than one QT- prolonging medication
is prescribed (pharmacodynamic interaction), b) if
its metabolism is inhibited by another medication
(pharmacokinetic interaction), c) if a medication,
which disturbs electrolytes, is prescribed, then this
increases the risk of QT prolongation [54].
When prescribing a drug that may cause QT
prolongation, it is important toassess the risks and
benets for the patient, andtheir individual factors
should be considered. Individual patient factors
such as female sex, age over 65years, thyroid disease, cardiac disease, bradycardia, congenital long
QT syndrome, and electrolyte disturbances can
increase the risk of QT interval prolongation [54].
An extensive list of medications associated
with QT prolongation is available on www.credi-
blemeds.org [55]. The list is frequently updated
and categorizes the medications according to the
risk of QT prolongation. There is a particular section of this online resource, which highlights
clinically relevant, common drug–drug interactions, e.g. amiodarone and quinolones.
The risks and benets of QT-prolonging medications must be evaluated on a case-by-case basis.
If a QT-prolonging medication is recommended,
then an electrocardiogram (ECG) at baseline and
regular monitoring could be considered [53, 54].
As it would not be practical to request an ECG
each time a QT-prolonging drug is prescribed, an
algorithm is presented in Fig. 4.1 [53]. Patients
prescribed QT-prolonging medications who present with palpitations, light- headedness, and dizziness should be investigated.
A systematic review summarizing and comparing tools for assessing safety risks with QT
interval-prolonging medications reported on
nine risk assessment tools, mostly applying risk
scores, with risk assessment included in a clinical decision support system or computerized
physician order entry [56]. Most studies were
conducted in hospital in-patient settings, and
risk assessments were primarily designed for use
by physicians and pharmacists. An intervention
study conducted in 20 community pharmacies in
the Netherlands introduced a clinical decision
support (CDS) prediction tool to support the risk
management of QT interval DDIs [57]. The
study did not report a statistically signicant difference in the proportion of QT interval DDIs
where a pharmacist intervention was conducted
after implementation of the CDS; however, phar-
88
S. McCarthy and A. Fleming
Correct modifiable risk factors & keep potassium closer to the higher end of the range (e.g.
correct hypokalaemia/hypomagnesaemia, stop medicines that are not needed)
Drug with low risk of QTc prolongation
No concurrent QTc
prolonging drugs
prescribed.
No patient risk factors.
No monitoring is
required.
Monitor baseline ECG
reaches steady state.
Concurrent QTc
prolonging drugs
prescribed and/or
Patient risk factors
present.
& repeat once drug
Drug with high risk of QTc prolongation
Avoid in patients
with pre-existing
QT prolongation
No concurrent QTc
prolonging drugs
prescribed.
No patient risk
factors.
Check baseline ECG.
May repeat once drug
reaches steady state. No
regular ECG monitoring
is needed if patient is
asymptomatic.
(e.g. high risk patients,
suspected symptoms).
Concurrent QTc
prolonging drugs
prescribed and/or
Patient risk factors
present.
Check baseline ECG.
Repeat once drug
reaches steady state.
Regular ECG
monitoring as needed
For patients with congenital long QT syndrome, seek alternative drugs
All patients who present with palpitations, light headedness or dizziness whilst on a medication with the
Fig. 4.1 Management of QT prolongation in practice. (Reproduced with permission from Khatib etal. [53])
macists reported that less time was spent on the
management of these DDIs when tool was used.
potential to prolong the QT interval should be offered an ECG
sweating, ushing, tachycardia, hyper- or hypotension), and altered mental status (e.g., agitation, confusion, delirium); however, not all are
present in all cases [58]. There are a wide range
4.5 Drug Interactions
andSerotonin Syndrome
of drugs that contribute to SS (Table 4.3), and
over- the- counter, herbal medicines, and drugs of
abuse can also contribute [59] to it. Many cases
Serotonin syndrome (SS) is the clinical manifestation of excess serotonin in the body, resulting
from therapeutic use or overdose of serotonergic
medications. The clinical features of SS range on
a spectrum from minor symptoms to death and
present as neuromuscular excitation (e.g., shivering, tremor, tooth-grinding, myoclonus, hyperreexia), autonomic effects (e.g., diarrhea,
occur due to the use or combined use of seroto-
nergic medications or when one serotonergic
medication is stopped and another is started.
CYP3A4 and CYP2D6 inhibitors may also con-
tribute by inhibiting the metabolism of serotoner-
gic medications, leading to SS [60]. Table 4.3
presents examples of drugs contributing to SS
[59].
4 Drug Interactions andTheir Management
89
Table 4.3 Drugs causing serotonin syndrome
Mechanism Drugs involved
Increase in
serotonin
production
Inhibition of
serotonin
metabolism
Increase in
serotonin release
Inhibition of
serotonin
reuptake
Serotonin
receptor agonism
Disclaimer: This table is not exhaustive
-Tryptophan
Monoamine oxidase inhibitors (e.g.,
phenelzine, moclobemide)
Selegiline
Linezolid
Amphetamines
Aminoindanes (e.g., MDAI
(5,6-methylenedioxy-2aminoindane))
Benzofurans (e.g., benzofury)
3,4-Methylenedioxymethamphetamine
(MDMA—“Ecstasy”)
Methylphenidate
Selective serotonin reuptake
inhibitors (e.g., escitalopram)
Tricyclic antidepressants (e.g.,
amitriptyline, imipramine)
Serotonin norepinephrine reuptake
inhibitors (e.g., venlafaxine,
duloxetine)
Opioid analgesics (e.g., fentanyl,
pethidine, tramadol)
St. John’s wort (Hypericum
perforatum)
Buspirone
Sumatriptan
Lithium
Tryptamines (e.g.,
alpha-methyltryptamine—AMT)
Prevention of SS requires clinical awareness
of the toxic potential of serotonergic medications and avoiding combined use of these medications. Patients should be educated about taking
their medications as prescribed and to be aware
of the signs of SS. Prescribers should minimize
the unnecessary use of serotonergic medications
and observe safe wash-out periods when transitioning patients between antidepressant medications to prevent overlap [61]. Taking particular
care to follow the manufacturer’s summary of
product characteristics is needed when changing
from an SSRI to a monoamine oxidase inhibitor
(MAOI), and vice versa. SSRIs with a long halflife, e.g., uoxetine, need to have an appropriate
wash-out period before another serotonergic
medication is started.
5 Drug–Herb Interactions
Health-care professionals must be alert to the
potential of herb–drug interactions. There can be
misperceptions that herbs are harmless, as they
are perceived to be natural. However, there is
potential for signicant clinical impact, for
example, traditional Chinese medicine herbs or
herbal products may exhibit steroidal activity
[62]. Herbal medicinal products and supplements
are largely unregulated by medicinal products
regulators. Studies have found that up to onethird of patients do not disclose complementary,
herbal, or supplement use to health-care professionals [63, 64]. Drugs with a narrow therapeutic
index (e.g., warfarin) raise a safety concern when
taken concomitantly with herbal products.
Pharmacokinetic herb–drug interactions can
occur via mechanisms affecting drug absorption,
induction and inhibition of metabolic enzymes,
and transport proteins, which can be countered
by changing the drug dose [64]. For example,
ginseng (Panax ginseng) can increase/decrease/
have no effect on warfarin efcacy and, as such,
extreme caution is needed. Less common pharmacodynamic herb–drug interaction mechanisms
due to the intrinsic pharmacological properties of
herbal supplements acting on drug sites/receptors
can result in synergistic, additive, and/or antagonistic effects of the concomitant drug without
alteration of its level and are also unlikely to be
countered by a change in drug dosage [64]. Of
interest in recent years has been the increasing
use of cannabis-based medicinal products containing cannabidiol (CBD) and tetrahydrocannabinol (THC). Both THC and CBD have been
found to inhibit CYP1A1, CYP1A2, and CYP1B1
enzymes in invitro studies [65]. CBD is a potent
inhibitor of CYP2C19 and CYP3A4 [66].
Concurrent use of other medications that induce,
inhibit, or are metabolized by CYP3A4 may
require a dose adjustment to avoid treatment failure or increased risk of adverse effects. There
may be enhanced sedation with central nervous
system depressants such as benzodiazepines,
opioids, and phenobarbital.
Several other commonly used herbal medicines
with the potential for pharmacokinetic and pharma-
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