Drug Interactions-Principles, Examples and Clinical Consequences Reply

Institute of Clinical and Experimental Pharmacology at the University Medical Center Schleswig-Holstein.
Deutsches Ärzteblatt International (Impact Factor: 3.52). 08/2012; 109(33-34):546-556. DOI: 10.3238/arztebl.2012.0546
Source: PubMed
ABSTRACT
Background:
Drug interactions can have desired, reduced or unwanted effects. The probability of interactions increases with the number of drugs taken. The high rate of prescribed drugs in elderly patients (65-year-old patients take an average of 5 drugs) increases the likelihood of drug interactions and thus the risk that drugs themselves can be the cause of hospitalization. According to meta-analyses, up to 7% of hospitalizations are drug-related.

Methods:
Selective literature review.

Results:
Drug interactions occur on pharmacodynamic and pharmacokinetic levels. Examples of pharmacodynamic interactions are simultaneous administration of a NSAID and phenprocoumon (additive interaction), or of aspirin and ibuprofen (antagonistic interaction). Pharmacokinetic interactions occur at the levels of absorption (e.g., levothyroxine and neutralizing antacids), elimination (e.g., digoxin and macrolides), and metabolism, as in the competition for cytochrome P450 enzymes (e.g., SSRIs and certain beta-blockers).

Conclusion:
The systematic knowledge of drug interaction, in particular on the level of absorption, elimination, transport and drug metabolism may help to prevent adverse effects. Predicting pharmacodynamic interactions often demands a deeper understanding of the mechanisms of effect. Electronic prescribing systems are helpful.

Full-text

Available from: Ingolf Cascorbi
MEDICINE
CONTINUING MEDICAL EDUCATION
Drug Interactions—Principles, Examples
and Clinical Consequences
Ingolf Cascorbi
SUMMARY
Background: Drug interactions can have desired, reduced
or unwanted effects. The probability of interactions in-
creases with the number of drugs taken. The high rate of
prescribed drugs in elderly patients (65-year-old patients
take an average of 5 drugs) increases the likelihood of
drug interactions and thus the risk that drugs themselves
can be the cause of hospitalization. According to meta-
analyses, up to 7% of hospitalizations are drug-related.
Methods: Selective literature review.
Results: Drug interactions occur on pharmacodynamic and
pharmacokinetic levels. Examples of pharmacodynamic
interactions are simultaneous administration of a NSAID
and phenprocoumon (additive interaction), or of aspirin
and ibuprofen (antagonistic interaction). Pharmacokinetic
interactions occur at the levels of absorption (e.g., levo-
thyroxine and neutralizing antacids), elimination (e.g.,
digoxin and macrolides), and metabolism, as in the com-
petition for cytochrome P450 enzymes (e.g., SSRIs and
certain beta-blockers).
Conclusion: The systematic knowledge of drug interaction,
in particular on the level of absorption, elimination, trans-
port and drug metabolism may help to prevent adverse
effects. Predicting pharmacodynamic interactions often
demands a deeper understanding of the mechanisms of
effect. Electronic prescribing systems are helpful.
Zitierweise
Cascorbi I: Drug interactions—principles, examples
and clinical consequences. Dtsch Arztebl Int 2012;
109(33–34): 546–56. DOI: 10.3238/arztebl.2012.0546
I
ncreasing multimorbidity with age often makes it
necessary to prescribe several drugs for one patient
at a time. As a consequence, the average 65-year-old
patient is on five drugs simultaneously (1). Prescription
peaks in the 75- to 84-year-old group; a European study
showed among patients with a mean age of 81 years
that 34% to 68% were taking six drugs or more (2).
A necessary consequence of this is the danger that
interactions between drugs will lead to serious adverse
effects or will reduce the therapeutic effect of some
compounds. Potential interactions can arise at any age
in life, but the frequency of polypharmacy in older life
increases the risk substantially. Meta-analyses of the
reasons for inpatient admission to medical wards
showed that in 7% of cases serious drug interactions
were the cause for admission or for prolonged hospital
stays (3, e1, e2). Similar conclusions were reached in
an earlier Austrian study of 543 newly admitted elderly
patients (median age: 82 years), who were taking 7.5 ±
3.8 drugs at the time of their admission (4). The authors
regarded 36% of the drugs as unnecessary and 30% as
inappropriate for elderly people (see recommendations
in the PRISCUS list [5]). For 10% of the patients, ad-
verse drug effects were regarded as the reason for their
inpatient admission, and in 18.7% a drug interaction
very probably played a part in these effects (6). Adverse
drug effects are also a—sometimes avoidable—prob-
lem during inpatient treatment. One of the frequent
causes here is incorrect or wrongly adjusted dosages,
especially in patients with reduced kidney function (7).
A British study of 3695 patients demonstrated that al-
most 15% of the patients suffered adverse drug effects
during their stay in hospital, which in a quarter of these
cases prolonged the hospital stay. Once sex, age, and
type of ward (medical, surgical) were taken into ac-
count, the number of simultaneously prescribed drugs
was the only significant predictor (7). In a survey in
Institute of Clinical and Experimental Pharmacology at the University Medical
Center Schleswig-Holstein: Prof. Dr. med. Dr. rer. nat. Cascorbi
Drug interactions
Interactions between drugs can lead to serious
unwanted effects or to a reduction in the thera-
peutic effects of some drug substances.
Polypharmacy, which is common in elderly
patients, increases the risk substantially.
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Sweden, the contribution of drugs to overall mortality
was estimated at 3%; gastrointestinal and central
nervous bleeding alone contributed a third of the inci-
dence (e3).
Knowing about interactions and their causes may
help to avoid them. One study, in which hospital
personnel on an intensive care unit were informed of
drug interactions by written drug information based on
a computerized clinical decision support system, was
very successful, reducing the number of interactions
from 66% to 54% and the number of unwanted events
from 44% to 25% (e4) (Box 1).
Learning goals
This CME article gives examples of interactions at the
pharmacodynamic level, mainly using the example of
nonsteroidal anti-inflammatory drugs (NSAIDs). The
focus is on demonstrating the systematics of pharma-
cokinetic interactions. The learning goals follow from
this: knowledge of important and frequent
pharmacodynamic interactions
pharmacokinetic interactions at the absorption
and excretion levels, and
pharmacokinetic interactions at the drug metab-
olism level, chiefly of cytochrome P450 enzymes
The review article is based on a selective literature
search in PubMed and publicly accessible databases
such as http://medicine.iupui.edu/clinpharm/ddis/. The
clinical manifestation of interactions can vary greatly.
Inadequate lowering of blood pressure and a blood
pressure drop that may be so extreme as to cause hypo-
volemic shock can both result from pharmacodynamic
and/or pharmacokinetic interactions. To avoid serious
consequences so far as possible from the outset, there-
fore, requires the ability to make better predictions
about drug interactions. In some cases, however, de-
sired interactions can improve the therapeutic effect,
e.g., if local bioavailability is increased by inhibition of
the metabolic pathways.
Pharmacodynamic interactions
The term “pharmacodynamic interactions” refers to in-
teractions in which drugs influence each others effects
directly. As a rule, for example, sedatives can potentiate
each other. The same is true of alcohol, which can
potentiate the sedative effects of many drugs.
Often, however, a pharmacodynamic interaction is
actually desired, if mutually potentiating effects in the
same direction (synergistic effects) are aimed at, e.g., in
the use of anti-infectives or in pain therapy. When the
effect of one drug is impeded by another, the effects of
these drugs are antagonistic.
Even barely observable undesired effects can po-
tentiate each other in a dangerous manner. For example,
if fluoroquinolones are combined with macrolides such
as erythromycin, this can result in QT prolongation.
The combination of ACE inhibitors with potassium-
sparing diuretics such as amiloride can increase potass-
ium retention so strongly that life-threatening
hyperkalemia ensues. Interactions of nonsteroidal anti-
inflammatory drugs (NSAIDs) are demonstrated below
as an example of pharmacodynamic interactions.
Pharmacodynamic interactions of NSAIDs
Platelet-related interactions—It is generally known
that simultaneous administration of NSAIDs increases
the COX-1-mediated inhibition of thromboxane syn-
thesis and hence the risk of gastrointestinal bleeding in
a synergistic manner. A particular property of the acidic
anti-inflammatory ibuprofen is its specific, reversible
binding to COX-1, which prevents acetylsalicylic acid
(ASA) from acetylating the serine residue at position
529 of the COX-1 protein. Irreversible and hence long-
lasting inhibition of COX-1-mediated thromboxane A
2
synthesis by ASA can thus be prevented and the cardiac
risk of patients with coronary heart disease can increase
(8).
Long-term clinical observations confirm these ex
vivo observations (e5), which appear also to hold for
naproxen (e6). Accordingly, patients with coronary
heart disease on ASA prophylaxis should not take
ibuprofen or naproxen on a regular basis.
Pharmacodynamic interaction
Pharmacodynamic interactions are those in which
drugs influence each other’s effects directly.
Increased potassium retention
The combination of ACE inhibitors and potassium-
sparing diuretics such as amiloride can increase
potassium retention so strongly that life-threaten-
ing hyperkalemia ensues.
BOX 1
Causes of unwanted drug effects and
interactions
Wrong choice of drug
Failing to take account of renal function
Wrong dosage
Wrong route of administration
Errors in taking the drug
Transmission errors
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Increased gastrointestinal bleeding also occurs when
selective serotonin reuptake inhibitors (SSRIs) such as
citalopram are taken simultaneously with NSAIDs (e7).
SSRIs inhibit the transport of serotonin into the
platelets, leading to further impairment of function and
doubling of the risk of bleeding. The SSRI-mediated
impairment of platelet function can also increase the
risk of bleeding due to vitamin K antagonists such as
warfarin and phenprocoumon (9, e8). SSRIs were as-
sociated with an increased risk of gastrointestinal
bleeding with an odds ratio of 2.6 (95% confidence in-
terval [CI] 1.5 to 4.3), whereas other antidepressants
barely increase the risk. NSAIDs and specific COX-2
inhibitors, on the other hand, also increased the risk of
bleeding, with an odds ratio of 2.6 (95% CI 1.6 to 4.2)
and 3.1 (95% CI 1.4 to 6.7), respectively. These study
results thus indicate that SSRIs increase the risk of
bleeding associated with vitamin K antagonists as
much as NSAIDs do. Since the absolute number of
bleeding events under SSRI treatment is quite low,
however, simultaneous treatment with SSRIs and anti-
coagulants or NSAIDs should chiefly be avoided in at-
risk patients with a known history of bleeding (e7).
Interactions with the vascular system—NSAIDs
can reduce the blood-pressure-lowering effect of ACE
inhibitors. The main mechanism is via a reduction in
glomerular perfusion through a reduction of local pros-
taglandin E
2
synthesis with corresponding reactive se-
cretion of renin. In a controlled clinical study, the blood
pressure of healthy volunteers treated with lisinopril
rose by 7 to 9 mmHg when they were given piroxicam
(e9). It was recently reported that these important inter-
actions of NSAIDs are also true for AT1-receptor
blockers (10). Low-dose ASA, on the other hand,
appears to have no effect on arterial blood pressure
(e10). Nevertheless, doses of 300 mg ASA and higher
can reduce the effects of ACE inhibitors.
Other interactions of inhibitors of the renin–an-
giotensin system (RAAS)—The aldosterone-antagon-
istic effect of ACE inhibitors and AT1-receptor antag-
onists can, in combination with potassium-sparing
diuretics or specific aldosterone antagonists such as
spironolactone and eplerenone, induce dangerous hy-
perkalemia or renal failure. After the introduction of
spironolactone for the treatment of cardiac failure, the
number of hospitalizations for hyperkalemia increased
markedly (11). Apparently there now exists an in-
creased awareness of this potential problem, however;
although, according to the guidelines of the European
Society of Cardiology (ESC), aldosterone antagonists
are the drug of choice for patients with NYHA class II
heart failure, alongside RAAS inhibitors, and conse-
quently are being used more widely, more recent
studies do not show significant hyperkalemia when
they are used in combination with RAAS inhibitors
(e11, e12).
With pharmacodynamic interactions, it is not
possible to demonstrate a simple systematics as it is in
pharmacokinetic interactions; instead, they require a
careful weighing up of which drug groups cause de-
sired and which undesired effects, which can in turn
either potentiate or weaken each other (Table 1).
Pharmacokinetic interactions
Reciprocal influencing of absorption, distribution in the
various compartments, metabolization, and elimination
can affect the effective concentrations at their sites of
action. The causes can be formation of complexes,
competition for uptake transporters, or induction of
metabolizing enzymes and efflux transporters (Figure 1).
Cardiac risk
Patients with coronary heart disease who are tak-
ing prophylactic ASA should not at the same time
be given ibuprofen or naproxen.
Renin-angiotensin system inhibitors
The antihypertensive effect of ACE inhibitors can
be weakened by NSAIDs.
TABLE 1
Examples of typical additive and antagonistic pharmacodynamic interactions
SSRI, selective serotonin reuptake inhibitor;
NSAID, nonsteroidal anti-inflammatory drug
Substance I
Additive interactions
NSAIDs
NSAIDs
ACE inhibitors
SSRIs
Tricyclic antidepres-
sants
Quinolones
Antagonistic interactions
Acetylsalicylic acid
ACE inhibitors
Levodopa
Phenprocoumon
Substance II
SSRI, phenprocoumon
Glucocorticoids
Spironolactone, amiloride
Triptans
Low-potency neuroleptics
Macrolides, citalopram
Ibuprofen
NSAIDs
Classical neuroleptics
Vitamin K
Possible effect
Increased risk of bleeding
Increased risk of gastric
bleeding
Hyperkalemia
Serotonin syndrome
Increased anticholinergic
effects
QT-interval prolongation,
torsade de pointes
Reduced effects
Reduced effects
Reduced effects
Reduced effects
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The systematics are becoming increasingly better
understood, so that some of the interactions of various
drugs can be well predicted, partly with the help of
computer programs, at least for certain drug groups
(12). Quantification of the extent of the interaction,
however, is not usually subject to any simple rule, such
as in dose adjustment of renally eliminated drugs
depending on the patient’s glomerular filtration rate.
Interactions at the absorption level—formation of complexes
Complexes can considerably reduce the bioavailability
of drugs. The bisphosphonates used in osteoporosis,
such as alendronate, have a very low bioavailability of
only 0.5% to 2%. Calcium ions in mineral water or milk
reduce this markedly still further. Multivalent cations
can also form complexes with tetracycline or quinolones
and also reduce the bioavailability of levothyroxine;
simultaneous intake of calcium-containing foods or
neutralizing antacids containing aluminum or magnesium
ions, must therefore be avoided. Recently, a reduction of
the protective properties of alendronate with reference to
avoiding hip fractures was observed when proton pump
inhibitors were given at the same time (13).
Interactions at the absorption level—membrane transport
Multidrug efflux transporters such as P-glycoprotein
(P-gp, ABCB1) were first described as one of the
causes of chemotherapy resistance in tumors. P-
glycoprotein is expressed in many tissue barriers such
as intestine, liver, kidney, and blood–brain barrier, and
in the placenta, testis, lymphocytes, and tumor cells,
and extrudes predominantly lipophilic connections/
bindings from inside the cell via the apical membranes
of epithelial or endothelial cells.
Inhibition of this efflux transporter could therefore
help to overcome chemoresistance. P-gp-mediated
efflux transport also contributes to reducing the respon-
siveness of lymphocytes to HIV protease inhibitors.
Ritonavir, which causes many side effects at high
doses, simultaneously inhibits P-gp and also the drug-
metabolizing cytochrome P450 3A4 (CYP3A4). The
fixed combination of ritonavir with, for example, 200
mg lopinavir improves the bioavailability of the pro-
tease-inhibiting substance and the efflux of lopinavir
out of the lymphocytes, thus reducing the breakdown in
the liver. So far, however, the attempt to overcome the
chemoresistance of tumors by inhibiting efflux trans-
porters, especially by means of P-glycoprotein, has
been unsuccessful.
An example of a typical drug interaction at the P-gp
level is the much higher bioavailability of the cardiac
glycoside digoxin when accompanied by oral adminis-
tration of the calcium antagonist verapamil.
A selection of P-gp substrates, inhibitors, and in-
ducers is shown in Table 2.
P-gp induction can, on the other hand, accelerate
efflux transport and reduce the bioavailability of drugs.
For ciclosporin, this means that simultaneous adminis-
tration of the tuberculostatic rifampicin can lead to
subtherapeutic concentrations. Rifampicin binds
intracellularly to the nuclear receptor PXR, one of the
main regulators of transcriptional control of P-gp
expression (14, e13) (Figure 2). Other PXR ligands,
Aldosterone antagonists
Aldosterone antagonists taken in combination
with RAAS inhibitors can cause hyperkalemia.
Renal function must be taken into account.
Bisphosphonate absorption
The bisphosphonates, used in osteoporosis such
as alendronate, have a very low bioavailability of
only 0.5% to 2%. Calcium ions in mineral water or
milk sharply reduce this still further.
PXR RXR
ABCB1
Transcription Translation
Intracellular Luminal
Inducer
FIGURE 1
Example of induction: P-glycoprotein, the most important efflux
transporter at several interfaces can be induced by rifampicin.
PXR, pregnane X receptor; RXR, retinoid X receptor
BOX 2
Levels of pharmacokinetic
interactions (ADME principle)
Absorption in the bowel
Distribution (crossing between compartments, e.g.,
across blood–brain barrier, plasma protein interactions)
Metabolization (liver and bowel)
Elimination (kidneys)
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and thus inducing drugs, are the anticonvulsants carba-
mazepine (oxcarbazepine to a lesser extent), phenobar-
bital, and phenytoin, and the HIV therapeutic efavirenz.
A case of unexpected clinical significance was one
where ingestion of St. John’s wort extract led to such a
pronounced fall in ciclosporin concentration that an
acute transplant rejection occurred (15). The substance
responsible for this was hyperforin, which is present in
St. John’s wort extract and was identified as another
PXR ligand.
In addition to P-gp, the efflux transporters ABCC2
(MRP2) and ABCG2 (BCRP) are also responsible for
the efflux transport of many medical drugs and can be
subject to interactions with inhibitors.
The opposite also occurs: inhibition of uptake trans-
porters leads to a reduction in bioavailability. An
example is inhibition by repaglinide of the uptake of
metformin via the organic cation transporter OCT1
(e14).
Interactions at the metabolic level
Inhibition of drug metabolism is a frequent cause of
drug interactions. Most metabolic interactions are due
to competition for the cytochrome P450 enzyme
(CYP), which is expressed in the liver and catalyzes the
phase I oxidation of more than half of all medical drugs
(16).
Interactions with CYP3A4 are particularly marked,
since this isoenzyme has a particularly broad substrate
spectrum (e15). Some of the CYP3A4 substrates,
inhibitors, and inducers are identical with those of
P-gp, indicating a synergistic defense mechanism
against foreign matter that has developed in the course
of evolution (Tables 3 and 4).
Anticoagulants—The most relevant interactions are
those relating to drugs with a narrow therapeutic spec-
trum, such as ciclosporin or phenprocoumon. As al-
ready mentioned, vitamin K antagonists can trigger
life-threatening hemorrhage and contribute to the inci-
dence of medical drug-related hospitalizations. The
cause could be interactions with older macrolide anti-
biotics such as erythromycin and clarithromycin, which
inhibit cytochrome P450 3A4, important in the
metabolization of phenprocoumon. Azithromycin
shows almost no interactions with the cytochrome P450
system. The calcium channel blockers verapamil and
azole antimycotics can be highly potent CYP3A4 in-
hibitors. Ketoconazole inhibits the cytochrome P450
system so strongly that it is now used as a standard in-
hibitor in the clinical development of medical drugs, in
order to test interactions with CYP3A4 among others.
Fluconazole is another CYP3A4 inhibitor, although a
weaker one. Bleeding complications during treatment
with fluconazole among others have also been reported
in patients on warfarin anticoagulation therapy. In this
case, the increased bioavailability of warfarin is due to
fluconazole-mediated inhibition of CYP2C9 (e16).
For vitamin K antagonists, however, coadminis-
tration of broad-spectrum antibiotics such as amoxicil-
Example of increased bioavailability through
inhibition of P-glycoprotein
• Central inhibition by loperamide after adminis-
tration of verapamil
Example of reduced bioavailability through
induction of P-glycoprotein
Inefficacy of digoxin after coadministration of
carbamazepine
TABLE 2
Examples of interactions at the intestinal absorption level: selection of rele-
vant substrates, inducers, and inhibitors of P-glycoprotein (ABCB1)
Group
Substrates
Opioids
Antihypertensives
Anticoagulants
Cardiac glycosides
Immunosuppressants
Protease inhibitors
Statins
Antineoplastic agents
Inducers
Anticonvulsants
Tuberculostatics
Antiretroviral
St. John’s wort extract
Inhibitors
Antimycotics
Calcium channel blockers
Macrolide antibiotics
HIV protease inhibitors
Immunosuppressants
Antiarrhythmic drugs
Substance
Loperamide, morphine
Aliskiren, carvedilol
Dabigatran
Digoxin
Ciclosporin, tacrolimus, sirolimus
Indinavir, saquinavir
Atorvastatin, lovastatin, simvastatin
Paclitaxel, anthracyclines, vinca alkaloids, etoposide,
imatinib
Carbamazepine (oxcarbazepine less so), phenytoin,
phenobarbital, primidone
Rifampicin
Efavirenz
Hyperforin
Itraconazole, ketoconazole
Diltiazem; felodipine; nicardipine; nifedipine;
verapamil especially
Erythromycin, clarithromycin, not azithromycin
Indinavir; nelfinavir; ritonavir especially; saquinavir
Ciclosporin
Amiodarone, quinidine, propafenone
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lin (alone or with clavulanic acid) or doxycycline ap-
pears to be a determinant of bleeding events. The cause
is less inhibition of the metabolism, more possibly a
change in coagulation status given the underlying
pyretic infection (17). This case must be carefully
distinguished from a drug interaction.
The flavonoid naringin, contained in citrus fruits
(especially grapefruit), also inhibits CYP3A4 and thus
can increase the availability of a number of other drugs.
In a study carried out in healthy volunteers, the bio -
availability of orally administered midazolam did not
return to normal until 3 days after the subjects drank
one glass of grapefruit juice (e17). The clinical rel-
evance of phenprocoumon is debated, but, at the least,
excessive amounts of citrus fruits should be avoided in
patients receiving anticoagulation treatment with
vitamin K antagonists.
Antidepressants—Selective serotonin reuptake in-
hibitors (SSRIs) are potent inhibitors of CYP2D6
(fluoxetine, paroxetine) (e18) and CYP1A2 (fluvoxa-
mine). This has consequences for the coadministration
of other drugs. In everyday practice, however, one must
also watch out for interactions between antidepressants
and common medical drugs such as certain beta-
blockers. Fluoxetine and paroxetine also inhibit the me-
tabolism of the beta-blocker metoprolol and can thus
cause lowering of blood pressure, bradycardia, and
other undesired effects.
Fluvoxamine, on the other hand, inhibits CYP1A2
and can thus increase the toxicity of theophylline or
clozapine. A fatal interaction between fluoxetine and
clozapine has also been reported (e19).
The inhibition of CYP2D6 can also reduce the
formation of active metabolites of codeine into mor-
phine or tramadol into O-desmethyltramadol. It has
been shown in large studies that the inhibition of
CYP2D6-mediated activation of the anti-estrogen tam-
oxifen to endoxifen through SSRIs is associated with
increased breast cancer mortality (18).
Apart from the pharmacokinetic interactions, an-
other aspect to consider with SSRIs is potentiation of
the serotonergic effects. It is known that simultaneous
administration of moclobemide can trigger serotonin
syndrome and is contraindicated for that reason.
However, other drugs with serotonergic effects such
as tramadol or triptans can increase the risk of
serotonin syndrome. When triptans such as sumatriptan
are used at the same time, there is an additional risk
of coronary artery constriction and hypertension.
Interaction must be expected for several days after
the last administration of SSRIs, because of their long
half-life (Box 3).
Quinolones—Quinolones such as ofloxacin and ci-
profloxacin are primarily inhibitors of CYP1A2, which
is also involved in metabolism of theophylline or cloza-
pine. Simultaneous administration of, for example,
ciprofloxacin and theophylline can lead to a rise in the
plasma concentration of theophylline, with correspond-
ing clinical symptoms of cardiac and gastrointestinal
unwanted effects (19). The bioavailability of quino-
lones themselves can be markedly restricted if they are
given at the same time as bivalent or trivalent cations,
such as are contained in antacids or zinc or iron formu-
lations (Box 4).
Proton pump inhibitors (PPIs)—Proton pump in-
hibitors such as omeprazole, lansoprazole, pantopra-
zole, or rabeprazole inhibit cytochrome P450 2C19
(CYP2C19) to varying degrees. Omeprazole in particu-
lar (esomeprazole less so) is a substrate and inhibitor of
CYP2C19. Recently, a discussion has arisen about the
consequences of its interaction with the platelet aggre-
gation inhibitor clopidogrel. Clopidogrel is a prodrug
that is metabolized to its active metabolites in two
steps, and CYP2C19 plays an essential part in this. Ho
et al. showed a rise from 20.8% to 29.8% in the rate of
deaths or rehospitalization of patients being treated
with clopidogrel for acute coronary syndrome and si -
multaneously with PPIs (adjusted odds ratio 1.25 [95%
CI, 1.11 to 1.41]) (20). A similar association was found
in carriers of the nonactive genetic variants of
Vitamin K antagonists
Vitamin K antagonists can trigger life-threatening
hemorrhage and are one cause of medical drug-
related admissions to hospital.
Inhibitor in citrus fruits
The flavonoid naringin, contained in citrus fruits
(especially grapefruit), is an inhibitor of CYP3A4
and can increase the bioavailability of many
drugs.
Phenprocoumon
Clarithromycin
Risk of bleeding
Inactive metabolites
INR
FIGURE 2
Inhibition of
CYP34A-
catalyzed meta-
bolization of the
vitamin K antag-
onist phenpro-
coumon by the
macrolide anti-
biotic clari-
thromycin. The re-
sult is an increase
in bioavailability, in
turn increasing the
risk of bleeding
Leber_Fotolia abhijith3747
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TABLE 3
Interactions at the cytochrome P450 enzyme level: selection of relevant substrates for which, when used in combination with inhibitors or indu-
cers of the same enzyme, either increased effects and increased occurrence of unwanted effects, or reduced effects or loss of effect must be
anticipated (modified from [24])
* Prodrug
CYP1A2
Clozapine
Imipramine
Mexiletine
Naproxen
Tacrine
Theophylline
CYP2C9
NSAIDs
Celecoxib
Diclofenac
Ibuprofen
Naproxen
Piroxicam
Antidiabetics
Glipizide
Tolbutamide
Angiotensin receptor
blockers
Irbesartan
Lorsartan
Miscellaneous
Cyclophosphamide
Fluvastatin
Phenytoin
Sulfamethoxazole
Torasemide
Warfarin
CYP2C19
Proton pump
inhibitors
Omeprazole
Lansoprazole
Miscellaneous
Amitriptyline
Clomipramine
Clopidogrel*
Cyclophosphamide*
Diazepam
Phenytoin
CYP2D6
Beta-blockers
Metoprolol
Propafenon
Timolol
Antidepressants
Amitriptyline
Clomipramine
Desipramine
Duloxetin
Imipramine
Paroxetine
Venlafaxine
Antipsychotics
Aripiprazole
Haloperidol
Risperidone
Thioridazine
Opioids
Codeine*
Dextromethorphan
Tramadol*
Miscellaneous
Ondansetron
Tamoxifen*
CYP3A4/5
Macrolide antibiotics
Clarithromycin
Erythromycin
Benzodiazepines
Alprazolam
Diazepam
Midazolam
Triazolam
Calcium channel
blockers
Amlodipine
Diltiazem
Felodipine
Nifedipine
Nisoldipine
Nitrendipine
Verapamil
Immunosuppressants
Ciclosporin
Tacrolimus
Sirolimus
HIV protease inhibitors
Indinavir
Ritonavir
Saquinavir
Statins
Atorvastatin
Lovastatin
Simvastatin
Anticoagulants
Apixaban
Rivaroxaban
Phenprocoumon
Miscellaneous
Aripiprazole
Buspirone
Quinidine
Quinine
Ethinylestradiol
Imatinib
Sildenafil
Tamoxifen
Vincristine
CYP2C19 (21, e20). Both the CYP2C19*2-splice-site
variant and the *3 missense variant lead to a complete
loss of effect of the protein. Among white people, 3%
are homozygote CYP2C19*2 carriers, while *3 carriers
contribute to the “poor metabolizer” status of people of
Asian origin. A systematic meta-analysis of follow-up
studies confirmed the association between CYP2C19
polymorphisms and platelet inhibition by clopidogrel,
but clinically no significant effect on the risk of car-
diovascular events was shown (22). The US Food and
Drug Administration (FDA) points out in the safety in-
formation on clopidogrel that the drug will have re-
duced effectiveness in CYP2C19 nonmetabolizers.
With regard to interactions, the FDA recommends
choosing the proton pump inhibitor pantoprazole rather
than omeprazole, if possible. The German drug
information, without mentioning any drugs by name,
advises against the simultaneous use of strong
CYP2C19 inhibitors.
Conversely, omeprazole can inhibit the break -
down of other drugs. An example is citalopram, the
metabolization of which is slowed down by omeprazole
(e21), and the risk of unwanted effects such as
QT prolongation rises. Omeprazole also inhibits
demethylation of the benzodiazepine diazepam. At a
dose of 20 mg, omeprazole results in a 36% increase in
the half-life of diazepam and a 27% reduction in its
clearance; giving 40 mg omeprazole increases the
half-life by 130% and clearance by 54%. Lansoprazole
also inhibits the metab olization of diazepam, although
more weakly; this evidence did not appear for
pantoprazole (e22).
SSRIs and moclobemide
Simultaneous use of moclobemide and SSRIs can
trigger serotonin syndrome and is therefore
contraindicated.
Quinolones
Simultaneous use of, for example, ciprofloxacin
and theophylline, can lead to a rise in plasma
theophylline concentration, with corresponding
cardiac and gastrointestinal adverse effects.
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In addition to inhibiting CYP2C19, omeprazole
leads to reduced induction of CYP1A2 (23, e23).
While lansoprazole is also able to induce CYP1A2,
this interaction was not observed with pantoprazole
(24). Pantoprazole appears to show almost no interac-
tions.
A significant influence of omeprazole on the bio -
availability of the HIV protease inhibitor atazanivir was
observed, not mediated by cytochrome P450, but as a
consequence of the rise in pH. In volunteers receiving
300 mg atazanivir/100 mg ritonavir for 2 weeks, a
reduction in atazanivir C
max
by 48% and of the AUC by
62% was observed during treatment with 40 mg
omeprazole and also during treatment with 150 mg
ranitidine. The kinetics of lopinavir were not changed
by omeprazole or ranitidine (e24). According to the
safety information, increasing the atazanivir dose to
400 mg does not compensate for the impact of omepra-
zole on atazanivir exposure. For this reason, neither
PPIs nor, presumably, H
2
-receptor blockers should be
used simultaneously with atazanivir.
Conclusions
Pharmacokinetic interactions in particular are system-
atic. Knowledge of which enzymatic metabolic path is
clinically relevant to the metabolization of a drug,
whether it is the substrate of a drug transporter, and
whether it inhibits or induces these proteins, makes it
possible to predict pharmacokinetic interactions.
Inhibitors of certain cytochrome P450 enzymes can in-
Proton pump inhibitors
Proton pump inhibitors such as omeprazole, lan-
soprazole, pantoprazole, and rabeprazole inhibit
cytochrome P450 2C19 (CYP2C19) to varying de-
grees.
Omeprazole and clopidogrel
Both these drugs have a low response rate in CYP2C19
nonmetabolizers. With regard to interactions, the FDA
recommends choosing not omeprazole but pantoprazole
if possible.
TABLE 4
Interactions with the most important cytochrome P450 enzymes: inhibitors and inducers (modified from [25])
++, strong inhibition; +, intermediate inhibiton; no +, weak or undefined inhibition
CYP1A2
Inhibitors
Fluoroquinolones
Ciprofloxacin ++
Ofloxacin
Levofloxacin
Miscellaneous
Amiodarone
Cimetidine +
Fluvoxamine ++
Ticlopidine
Inducers
Tobacco smoke
Omeprazole
CYP2C9
Amiodarone +
Fluconazole ++
Isoniazide
Rifampicin
CYP2C19
SSRIs
Fluoxetine
Fluvoxamine
PPIs
Lansoprazole +
Omeprazole +
Miscellaneous
Ketoconazole
Ticlopidine
CYP2D6
SSRIs
Duloxetin +
Fluoxetine ++
Paroxetine ++
Miscellaneous
Amiodarone
Buproprion
Cimetidine
Quinidine ++
Chlorphenamine
Clomipramine
Ritonavir
CYP3A4/5
HIV protease inhibitors
Indinavir ++
Nelfinavir ++
Ritonavir ++
Macrolides
Clarithromycin ++
Erythromycin +
Azole antimycotics
Fluconazole +
Itraconazole +
Ketoconazole ++
Voriconazole
Miscellaneous
Aprepitant +, Amiodarone
Cimetidine +
Diltiazem
Naringin + (in citrus fruits)
Verapamil +
Carbamazepine
(oxcarbazepine less so)
Efavirenz
Hyperforin (in St. John’s wort)
Phenobarbital
Phenytoin
Rifampicin
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fluence the bioavailability of a whole group of drugs
metabolized by the same enzyme, while inducers
usually contribute to a loss of effectiveness. As a gen-
eral principle, drugs that are metabolized more quickly
and have a lower bioavailability carry a higher potential
risk of interactions. Predicting pharmacodynamic inter-
actions often requires a deeper understanding of the
mechanisms of action; but here too a certain system can
be recognized, just as for pharmacokinetic interactions.
Electronic prescribing systems that can alert the user
early on to possible interactions and can assist with
drug selection and dosage are helpful.
Conflict of interest statement
Professor Cascorbi has received fees for preparing medical educational events
from Novartis, MSD, and Sanofi-Aventis.
Manuscript received on 16 May 2012, revised version accepted on 18 July 2012.
Translated from the original German by Kersti Wagstaff, MA.
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BOX 3
Clinical examples of the change in bioavailability of the cytochrome P450
enzymes
Bioavailability can be increased by inhibition of cytochrome P450 enzymes
Risk of renal toxicity with ciclosporin if clarithromycin is given
Risk of bleeding if verapamil is given to patients on phenprocoumon anticoagulation therapy
Myalgia due to simvastatin if fluconazole is also given
Increase in theophylline toxicity if ciprofloxacin is given
Bioavailability can be reduced by induction of cytochrome P450 enzymes
Transplant rejection in patients on ciclosporin for immune suppression who are comedicated with rifampicin
Thrombosis risk in patients on phenprocoumon anticoagulation therapy who are comedicated with carbamazepine
Efficacy of ethinylestradiol contraceptives is at risk if efavirenz is given at the same time.
BOX 4
Quinolone interactions
Inhibition of cytochrome P450 1A2 by quinolones (prin-
cipally pefloxacin and ciprofloxacin, less by ofloxacin,
levofloxacin, or moxifloxacin)
Combination with NSAIDs (except for aspirin) increases
tendency to seizures
Combination with macrolides (prolongation of QT inter-
val with risk of malignant cardiac arrhythmias such as
torsade de pointes)
Potential risk
As a general principle, drugs that are metabolized
more quickly and have a lower bioavailability
carry a higher potential risk of interactions.
Future prospects
Electronic prescribing systems that can alert the
user early on to possible interactions and can
assist with drug selection and dosage are helpful.
554
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ated with concomitant use of clopidogrel and proton pump inhibitors
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morphisms and response to clopidogrel. N Engl J Med 2009; 360:
354–62.
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type, clopidogrel metabolism, platelet function, and cardiovascular
events: a systematic review and meta-analysis. JAMA 2011; 306:
2704–14.
23. Dilger K, Zheng Z, Klotz U: Lack of drug interaction between omepra-
zole, lansoprazole, pantoprazole and theophylline. Br J Clin Pharmacol
1999; 48: 438–44.
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Corresponding author:
Prof. Dr. med. Dr. rer. nat. Ingolf Cascorbi
Institut für Experimentelle und Klinische Pharmakologie
Universitätsklinikum Schleswig-Holstein
Arnold-Heller-Straße 3
24105 Kiel
cascorbi@pharmakologie.uni-kiel.de
Cite this as
Cascorbi, I: Drug interactions—principles, examples and clinical consequences.
Dtsch Arztebl Int 2012; 109(33–34): 546–56. DOI: 10.3238/arztebl.2012.0546
@
For eReferences please refer to::
www.aerzteblatt-international.de/ref3312
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MEDICINE
Please answer the following questions to participate in our certified Continuing Medical Education pro-
gram. Only one answer is possible per question. Please select the answer that is most appropriate.
Question 1
Which drug can increase the platelet inhibiting effect of
NSAIDs?
a) Erythromycin
b) Mirtazapine
c) Citalopram
d) Rifampicin
e) Fluconazole
Question 2
The antihypertensive effect of ACE inhibitors can be
specifically reduced by inhibition of renal prostaglandin
synthesis. Which of the following drugs interacts in this
process?
a) Low-dose ASA
b) Hydrochlorothiazide
c) Verapamil
d) Diclofenac
e) Morphine
Question 3
ASA inhibits platelet aggregation. Which analgesic can
reduce this effect if given at the same time?
a) Ibuprofen
b) Diclofenac
c) Meloxicam
d) Paracetamol
e) Etoricoxib
Question 4
Which drug increases the bioavailability of digoxin by
inhibiting the P-glycoprotein efflux transporter?
a) Dabigatran
b) Hypericin
c) Rifampicin
d) Clarithromycin
e) Morphine
Question 5
Which drugs, if taken at the same time, increase the risk
of gastrointestinal bleeding due to an additive interac-
tion?
a) Paracetamol + triptan
b) Phenprocoumon + NSAID
c) SSRI + paracetamol
d) Quinolone + warfarin
e) Macrolide + NSAID
Question 6
A patient who has received a renal transplant is on ciclosporin therapy.
He says he has been feeling down recently and is therefore taking St.
John’s wort. What could be one effect of the comedication?
a) Increased coagulation time
b) Increased ciclosporin toxicity
c) Hypertrichosis
d) Increased thrombosis risk
e) Transplant rejection
Question 7
A patient who has been taken off the beta-blocker metoprolol is treated
with fluoxetine for depression. What unwanted effect should be ex-
pected?
a) Bradycardia
b) Skin bleedings
c) Increase in blood pressure
d) Anemia
e) Hyperglycemia
Question 8
What is the name of the flavonoid contained in citrus fruits that is an
inhibitor of CYP3A4?
a) Apigenin
b) Naringin
c) Chrysin
d) Luteolin
e) Hesperetin
Question 9
What effect should be expected in a patient taking clopidogrel and
omeprazole simultaneously?
a) Omeprazole increases the side effects of clopidogrel
b) Increased risk of thrombotic-thrombocytopenic purpura
c) Omeprazole raises the plasma concentration of the active clopidogrel
metabolite
d) Reduction of the clopidogrel-mediated inhibition of platelet aggregation
e) Clopidogrel inhibits the breakdown of omeprazole
Question 10
The term “synergy” is used in pharmacodynamics to describe mutual
influencing of the effects of two drugs. What does synergy mean?
a) Mutual strengthening of effect
b) The effect can only be achieved by giving the drugs at the same time
c) An effect that is at least more than the additive effect of both drugs
d) Reduction of the side effects
e) Mutual canceling out (neutralization) of effects
556
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CONTINUING MEDICAL EDUCATION
Drug Interactions—Principles, Examples
and Clinical Consequences
Ingolf Cascorbi
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drug interactions in man. Int J Clin Pharmacol Ther 1994; 32:
385–99.
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Page 12
    • "Neben dem " pharmakokinetischen Genotyp " spielt der " pharmakokinetische Phänotyp " (Abb.durchaus erwünscht, wenn hierdurch gleichgerichtete, sich verstärkende (synergistische) Wirkungen erzielt werden, etwa bei der Anwendung von Antiinfektiva oder in der Schmerztherapie[21]. Eine Übersicht über Grundprinzipien der Pharmakodynamik ndet sich in[9].[22].1A2 "
    [Show abstract] [Hide abstract] ABSTRACT: Die Wirkung eines Neuropsychopharmakons wird durch die physikochemische Interaktion mit seiner Zielstruktur im Gehirn determiniert. Pharmakokinetische Eigenschaften hingegen bedingen, ob ein Pharmakon überhaupt dazu in der Lage ist, in ausreichender Konzentration an seinem Wirkort verfügbar zu sein. Die Höhe des Wirkstoffspiegels ist dabei durch eine Vielzahl unterschiedlicher Einflussfaktoren bedingt. Einerseits ist die Metabolisierung durch die genetische Ausstattung jedes einzelnen Patienten geprägt, andererseits nimmt mit einer zunehmenden Anzahl verordneter Arzneistoffe die Gefahr potenzieller Interaktionen zu. Hierbei können sowohl die Induktion des Arzneimittelmetabolismus als auch eine Inhibition zu einem Therapieversagen und zum Auftreten unerwünschter Arzneimittelwirkungen führen.
    No preview · Article · Feb 2015
  • Source
    • "Cette dernière est une protéine d'efflux qui fait partie des transporteurs de type ATPase et est codée par des gènes appelés gènes MDR (pour multi drug resistance genes) et est responsable du transport transmembranaire de nombreux médicaments dont notamment des antibiotiques comme la cyprofloxacine, l'erythromycine, les quinolones, à côté de médicaments anticancéreux comme le docetaxel, la daunorubicine, le palitaxel entre autres inhibiteurs de protéase et antiémétiques [13]. Les médicaments dont le transport est dépendant de la P-gp sont dits substrats de la Pgp , ceux qui en modifient le fonctionnement sont dit inducteurs ou inhibiteurs, le tableau 1 liste certains substrats, inducteurs et inhibiteurs de ce transporteur [14]. En fonction des cas, la prise concomitante du substrat avec des inducteurs ou des inhibiteurs est susceptible d'augmenter l'absorption du substrat, et conséquemment sa concentration plasmatique, ou de la réduire. "
    [Show abstract] [Hide abstract] ABSTRACT: Among the various types of known drug interactions, those involving pharmacokinetic processes are more complex and dangerous. From digestive pH changes to plasma protein binding and induction or inhibition phenomena ; current data used to define, with precision, the sites of interaction. The enzymes involved in metabolism, the transporters involved in tissue distribution and excretion of drugs and nuclear receptors that regulate the expression of these enzymes and transporters are keys determinants which should be defined for each drug. The clinical relevance of a pharmacokinetic interaction is related to the magnitude of changes in drug’s concentrations and pharmacological properties of these. A good knowledge of the pharmacokinetic properties of drugs and the mechanisms involved in the genesis of these interactions is, then, needed to prevent and avoid theme. Keywords: interactions, pharmacokinetic, induction, inhibition, transporters
    Full-text · Article · Dec 2014
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    • "Prescription of drugs is one of the health care system’s most important methods to treat, relieve and sometimes cure diseases. Nevertheless, prescription drug treatment may carry risks such as adverse drug reactions, interactions and polypharmacy [1], circumstances that may lead to hospital admission [2,3]. Beyond the fact that treatment with prescription drugs may cause patients to suffer from side effects, these unwanted effects are the source of substantial expenses to society. "
    [Show abstract] [Hide abstract] ABSTRACT: It has been reported that there is a difference in drug prescription between males and females. Even after adjustment for multi-morbidity, females tend to use more prescription drugs compared to males. In this study, we wanted to analyse whether the gender difference in drug treatment could be explained by gender-related morbidity. Data was collected on all individuals 20 years and older in the county of Ostergotland in Sweden. The Johns Hopkins ACG Case-Mix System was used to calculate individual level of multi-morbidity. A report from the Swedish National Institute of Public Health using the WHO term DALY was the basis for gender-related morbidity. Prescription drugs used to treat diseases that mainly affect females were excluded from the analyses. The odds of having prescription drugs for males, compared to females, increased from 0.45 (95% confidence interval (CI) 0.44-0.46) to 0.82 (95% CI 0.81-0.83) after exclusion of prescription drugs that are used to treat diseases that mainly affect females. Gender-related morbidity and the use of anti-conception drugs may explain a large part of the difference in prescription drug use between males and females but still there remains a difference between the genders at 18%. This implicates that it is of importance to take the gender-related morbidity into consideration, and to exclude anti-conception drugs, when performing studies regarding difference in drug use between the genders.
    Full-text · Article · Apr 2014 · BMC Public Health
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