Drug Interactions

Endodontic Topics 2003, 4, 9–21
Printed in Denmark. All rights reserved

Copyright r Blackwell Munksgaard
ENDODONTIC TOPICS 2003
1601-1538

Drug interactions: a review
and update
B. ELLEN BYRNE
People worldwide rely on medications to prevent, cure,
or lessen an ever-expanding list of diseases. Drugs can
be beneficial as well as detrimental. The goal of therapy
is to maximize beneficial effects, while trying to
minimize the detrimental effects. Each drug prescribed
has a risk–benefit ratio. If the benefit of taking the drug
outweighs the risk of adverse effects, then the drug
therapy is appropriate. Taking one or more drugs that
interact may change this risk–benefit ratio. What was
once a safe and appropriate drug therapy may now be
inappropriate due to an increased risk from a drug
interaction. Studies have shown that when the number
of co-administered drugs exceeds four, the risk
associated with such use for the patient increases
substantially (1).
As the age of an individual increases, so do the
number of diseases and the number of drugs an
individual may take. The patient may be taking more
than one drug to treat multiple disorders or they may
be taking multiple drugs to treat a single disorder.
When multiple drug therapies are prescribed, drug
interactions become an important consideration for
the patient and the dentist (2). It is estimated that the
incidence of clinical drug interactions ranges from 3 to
5% in patients taking (3) a few medications, but
increases to 20% in patients receiving 10–20 drugs. In
addition, they may be taking over-the-counter drugs or
dietary supplements with their prescription medicines.
Information about drugs continues to increase
exponentially. Not only do we have more drugs coming
on the market every year, but we also have much more
information about older drugs, as a result of continuing
research. Our understanding of drug interactions has
grown many-fold. Knowledge of the mechanisms of drug
interactions has matured and ideas once held as absolute
truth are being re-examined. The significance of proteinbinding displacement has been called into question
with new foundations for drug interactions, such as

enzyme changes or alterations in active drug transport
becoming clearer (4). As with any area of complex
study, the more one discovers, the more questions one
may ask. A few drugs are involved in so many
potentially serious drug interactions that they should
be viewed as ‘red flags’. These include warfarin,
cyclosporine, erythromycin, itraconazole, ketoconazole, the HIV protease inhibitors, and the HMG-CoA
reductase inhibitors (statins).
It must be kept in mind that not all drug interactions
are clinically significant. The significance of drug
interactions can range from theoretical and no effect
to life threatening. A drug interaction is considered
clinically significant when it occurs between two or
more co-administered agents and results in the need
for a dosage adjustment of one of the agents or other
medical intervention (5). The withdrawal of medications such as terfenadine, astemizole, cisapride, and
mibefradil from the market due to fatal drug interactions demonstrates the relevance of drug interactions.
Drugs most likely to pose interaction problems are
those having (6, 7):
 a narrow therapeutic index (small difference between
therapeutic dose and toxic dose);
 steep dose–response curve;
 high first-pass metabolism (the loss of drug as it
passes through the liver for the first time);
 a single, inhibitable route of elimination.
Pharmacotherapy in dentistry is unique in that a drug is
usually administered for a short duration. Many drug
interactions occur after repeated or prolonged dosing.
Most of the dental drugs have a large margin of safety
and there are a limited number of agents included in
a practitioner’s armamentarium.
Drug interactions occur when two or more drugs are
administered at the same time. The action of one drug
is altered by the presence of another drug. The power
of desirable drug interactions is not always recognized.

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There are many examples of desirable and successfully
used drug interactions to enhance drug efficacy in the
management of infection, pain, and cardiovascular
disorders. Hundreds of other drug interactions are
considered to be undesirable. Interaction mechanisms
can be broadly divided into two groups: pharmacodynamic interactions and pharmacokinetic interactions.
A pharmacodynamic interaction is caused by the
concurrent administration of two drugs that have the
opposite effect or similar effects. In this type of
interaction, there is a change in the patient’s response
to the drug without altering the drug’s pharmacokinetics (absorption, distribution, metabolism, and
excretion). That is, there is a change in drug action
without altering the plasma concentration. The interaction of drugs having similar effects such as alcohol,
opioids, and sedatives is considered synergistic. In this
case, the resultant drug action is greater than the sum of
each agent alone. Another synergistic interaction could
occur in dissimilar drugs sharing a common property
such as the anticholinergic effects of antidepressants,
phenothiazines, and antihistamines. Synergistic drug
interactions may be easier to identify than the interactions of drugs having opposite effects. An example of
such an interaction with opposite effects would be
where a patient with asthma is being treated with a
beta-adrenergic drug such as albuterol for its bronchodilating effects, while also being given a betaadrenergic blocking drug as an antihypertensive, which
has bronchoconstricting properties. Pharmacodynamic
interactions may result from one drug changing the
environment necessary for the safe and effective use of a
second drug. An example of this interaction is a loop
diuretic that produces potassium wasting and can
increase the cardiotoxic effects of digoxin.
An additional type of interaction involves a blocking
agent that prevents the binding of a drug to a specific
receptor. In the narcotics, the antagonist nalorphine
binds to the receptor and blocks the action of the
opioid agonist drugs such as morphine. The benzodiazepines such as diazepam, lorazepam, etc. also have a
specific antagonist, flumazenil. An antagonist has no
intrinsic activity of its own, but blocks the action of the
agonist. These drugs are used in the treatment of
overdoses by reversing the depression of the central
nervous system and respiratory system depression
associated with the agonist.
A pharmacokinetic (or dispositional) drug interaction
is where one drug alters the rate or extent of any of the

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four basic pharmacokinetic processes: absorption, distribution, metabolism, or excretion (ADME) of a second
drug (Fig. 1). This type of interaction is measured by a
change in one or more of the kinetic parameters, such as
maximum serum concentration, half-life amount of
drug excreted in the urine, area under the concentration time curve, etc. While it is easy to divide the course
of drug therapy into four categories, it must be kept in
mind that this process of absorption, distribution,
metabolism, and excretion is a continuum, with these
systems acting in concert to determine the fate of
the drug.

Alterations in drug absorption
Drug absorption may be altered in numerous ways,
some of which are theoretical and include:
 gut motility;
 gut pH;
 drug
solubility;
 gut metabolism;
 gut flora;
 activity of protein carriers.
One mechanism involves drug adsorption. This occurs
when a drug is adsorbed onto a binding agent and the
drug is no longer easily absorbed into the blood, and
may be therapeutically ineffective. Tetracycline antibiotics1polyvalent metal cations (e.g. iron, aluminum,
or calcium as found in antacids) results in a decrease in
serum levels of tetracycline (8). Cholestyramine, an
anionic binding resin binds bile acids and many other

Fig. 1. Pharmacokinetics of drug fate.

Drug interactions
substances, including the oral anticoagulant warfarin.
This complex decreases the mean plasma warfarin
concentration and hypoprothrombinemic effect of this
drug (9).
Drug absorption may be altered by drug-induced
alterations in gastrointestinal motility. Most drugs are
primarily absorbed in the small intestine. Decreasing or
increasing the rate at which the drug reaches this area of
the gastrointestinal tract may decrease or increase the
rate of drug absorption. Drugs that depress peristalsis
(narcotics such as morphine and anticholinergics
agents such as atropine) may prolong drug transit time
in the intestine, thereby increasing the time for
absorption. Drugs that are prokinetic (metoclopramide) may increase gastric empting and thus increase
the rate of drug absorption.
Changing the pH of the gastrointestinal tract can
alter the absorption of some drugs. Some drugs require
an acidic or basic environment in order to dissolve.
Weak acids would more readily exist in a non-ionized
(i.e. lipid-soluble form) in an acidic environment, thus
being more readily absorbed, whereas weak bases
would be more absorbable in a basic environment.
Drugs that increase gastric pH such as proton pump
inhibitors and antacids may reduce the absorption of
drugs such as ketoconazole and itraconazole, which are
absorbed best in an acidic environment (10).
Food–drug interactions can affect the bioavailability
of a drug. The bioavailability and effect of most drugs
are correlated. Food–drug interactions can change the
bioavailability of a drug by a chemical reaction such as
chelation or by a physiological response to food intake.
This would include changes in gastric acidity, bile
secretion, and gastrointestinal motility. Food–drug
interactions that only affect the rate of drug absorption
are common, but rarely of clinical importance (11).

testes (12–14). P-gp was discovered by Juliano and
Ling (15) in multi-drug-resistant cancer cells. It was
observed that mammalian cancer cells would actively
extrude a wide range of cancer chemotherapeutic
drugs. P-gp appears to be protective (16). P-gp acts
as a pump with drugs and toxins being transported
away from tissues, that is, out of the tissue. The drugs
are pumped across plasma membranes and into
interstitial fluid or into excretory fluids, such as bile,
thereby limiting absorption (17, 18). This efflux of
drugs from the cell membrane or cytoplasm is powered
by the energy from the ATP hydrolysis. Because P-gps
block absorption in the gut, they should be considered
as part of the ‘first-pass effect’. In addition, to prevent
drugs from reaching the systemic circulation, P-gp
appears to remove some drugs from the systemic
circulation. P-gp also appears to be the ‘gate-keeper’
for later cytochrome P-450 (CYP) actions. A drug is
absorbed by passive diffusion into the enterocyte,
where it may be metabolized by CYP3A and also
subject to active counter-transport by P-gp back into
the gut lumen. It interacts and works cooperatively
with CYP (Fig. 2). The concentration of P-gp in
intestinal enterocytes increases along the length of the
gastrointestinal tract, reaching a maximum concentration in the colon (19). Inhibiting the function of P-gp
would result in an increase in drug absorption and
inducing the function of P-gp would decrease absorption. Many drugs have now been identified as
substrates, inhibitors, and inducers of P-gp function.
Several agents have been identified as P-gp inhibitors:
erythromycin, propranolol, and amiodarone. Some
examples of inducers include: dexamethasone, nefazodone, and rifampin (16).

P-glycoprotein
Another mechanism for altering drug absorption
involves the activity of a membrane-bound carrier
protein that is found in many tissues, especially organs
responsible for drug absorption and elimination.
P-glycoprotein (P-gp) is a well-described adenosine
triphosphate (ATP)-dependent carrier glycoprotein in
the plasma membrane responsible for the active
transport of a wide variety of endogenous and
exogenous substrates across various membranes in the
intestines, proximal tubules of the kidneys, brain, and

Fig. 2. P-glycoprotein carrier system.

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Drug distribution
Drugs are transported to a site of action or elimination
bound to serum proteins. Acidic drugs are bound to
plasma albumin and basic drugs are bound to a-acid
glycoprotein (20). While bound to a plasma protein,
the drug does not contribute to the concentration
gradient, cannot be filtered by the kidney, and in
general, is pharmacologically inert. The unbound or
‘free’ drug is pharmacologically active. Decreasing the
serum concentration of albumin could result in altered
pharmacokinetics of bound drugs.
From a drug interaction standpoint, a drug with high
binding affinity could displace a drug with less affinity,
thereby increasing the free concentration of the drug
with less affinity. However, the unbound fraction of the
drug is not only more available for the site of action, but
also is more available for elimination. This principle has
often been applied to highly protein-bound (490%)
drugs and to drugs with a narrow therapeutic index,
where small changes in free drug concentration might
result in significant changes in pharmacological effect.
In practice, protein-binding displacement interactions
do not produce clinically important changes in drug
response (21, 22), except where the displacing drug may
also reduce the elimination of the substrate drug.
A good example of this principle involves interactions
of non-steroidal anti-inflammatory drugs (NSAIDs)
and methotrexate. NSAIDs exhibit varying effects on
the pharmacokinetics of methotrexate. For example,
ibuprofen may decrease methotrexate clearance by 40–
50% (23), possibly by reducing renal perfusion due to a
decrease in renal prostaglandin synthesis (24).

Drug metabolism
The area of biotransformation, also known as metabolism, is exploding with new information. Recent studies
suggest that the most clinically important drug interactions involve pathways of metabolism. Most drugs are
eliminated from the body, at least in part, by being
chemically altered to a less lipid-soluble product. They are
not reabsorbed across a lipid membrane and are excreted
by the kidney or in the bile. While metabolism takes place
in numerous locations including the plasma, intestines,
lungs, and skin, the majority of the metabolism occurs in
the smooth endoplasmic reticulum of the hepatocyte.
Briefly, metabolism can be divided into two phases
(Figs 3 and 4). Phase I metabolism involves the

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oxidation, hydrolysis, or reduction of a drug. These
reactions increase the water solubility of the drug and
thus facilitate their elimination from the body. Phase II
metabolism involves the attachment of an additional
molecule to the drug in order to create an inactive
compound and a more water-soluble drug. Phase II
processes include glutathione conjugation, glucuronidation, sulfation, acetylation, and methylation.
The enzyme that catalyzes this reaction is known as
the hepatic CYP. CYP is a complex of protein, heme,
and iron. By using molecular oxygen and NADPH
(a reduced form of NADP) as a source of electrons, this
cytochrome system catalyzes a series of oxidation–
reduction reactions, which results in the oxidized drug
product (25). While there are more that 50 different
families of enzymes identified, only three families
CYP1, CYP2, and CYP3 are responsible for the
metabolism of most compounds including steroids,
prostaglandins, vitamins, other endogenous compounds, and a large number of drugs. Subfamilies

Fig. 3. Phase I and II metabolism.

Fig. 4. Normal metabolism.

Drug interactions
within each family are designated by a capital letter and
individual enzymes are named with a final Arabic
number. Thus, the individual enzymes CYP2C9 and
CYP2C19 both belong to the CYP2 family and the
CYP2C subfamily.
Theoretically, any two drugs that are metabolized by
the same enzyme could produce a drug interaction.
The two drugs would compete for the same enzyme.
One drug could be metabolized and the other drug’s
metabolism reduced, resulting in a higher blood level
of the non-metabolized drug. To anticipate a clinically
significant drug interaction involving the CYP system,
it is necessary to become familiar with the substrates,
inhibitors, and inducers of the isoenzymes. The
‘substrate’ refers to that compound known to be
metabolized by the isoenzyme. The term ‘inhibitor’
denotes a drug known to interfere or compete with the
isoenzyme, and the term ‘inducer’ describes an agent
that accelerates the metabolism of a substrate.

of that drug. This can result in the drug-induced
toxicity. Unlike enzyme induction which takes a while,
this interaction can be rapid and without warning. The
antifungal agents ketoconazole and itraconazole, and
the macrolide antibiotics, such as erythromycin and
clarithromycin (but not azithromycin), are all potent
inhibitors of CYP3A (6). Certain calcium channel
blockers, such as diltiazem, nicardipine, and verapamil
also inhibit CYP3A (28), as does a constituent of
grapefruit juice (10). After ingestion, a substrate in
grapefruit juice binds to the intestinal isoenzyme,
impairing first-pass metabolism directly and causes
a sustained decrease in CYP3A4 protein expression
(29). Within 4 h of ingestion, a reduction in the
effective CYP2A4 concentration occurs, with the effects
lasting up to 24 h (30). The net result is the inhibition of
drug metabolism in the intestine and increased oral
bioavailability. Because of the prolonged response,
separating the intake of the drug and the juice or whole
grapefruit does not prevent interference (Table 2).

Drugs used in dentistry
The rate of drug metabolism may be increased or
decreased based on enzyme induction or enzyme
inhibition.
Induction of drug metabolism usually occurs by
enhanced gene transcription following prolonged
exposure to an inducing agent (Fig. 5). As a result,
the consequences of enzyme induction may take
considerable time to be fully exhibited. The consequences of enzyme induction are an increased rate of
metabolism, enhanced oral first-pass metabolism, and
a reduced bioavailability. All of this results in a decrease
in the drug’s plasma concentration. In contrast, in
drugs that are metabolized to an active or toxic
metabolite, induction may be associated with an
increased effect or increased toxicity. A well-documented and classic example of enzyme induction
involves the drug rifampin and oral contraceptives
(OCs). Rifampin is an antibiotic used in the treatment
of tuberculosis and a potent metabolic inducer of CYP.
Contraceptive failure is possible due to the altered
metabolism of the OC (26). Other common CYP
inducers include phenytoin, carbamazepine, and the
barbiturates (see Table 1) (27).
A consequence of drug-metabolizing inhibition is an
increase in the plasma concentration of the parent drug
with an exaggerated, prolonged pharmacological effect
from the parent drug and a reduction in the metabolite

Drug excretion
Just as the liver is the primary organ involved in the
metabolism of drugs, the kidney is the primary organ
involved in the excretion of compounds from the body.
Other sites of drug excretion include the liver, lungs,
gastrointestinal tract, saliva, sweat, tears, and breast
milk. Alterations in renal excretion can occur by several
mechanisms, including changes in urinary pH (which
can alter passive reabsorption of a drug), competition
for the same transport system, changes in active tubular
secretion, or changes in renal blood flow.
Acidification of the urine results in an increase in the
rate of urinary excretion of weak bases. The explanation

Fig. 5. Induced metabolism.

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Table 1. Cytochrome P450 substrate, inhibitors, and inducers
Isozyme

Substrate

Inhibitors

Inducers

CYP1A2

Acetaminophen, caffeine,
clozapine, amitriptyline,
tacrine, theophylline

Cimetidine, ciprofloxacin,
diltiazem, enoxacin,
fluvoxamine, tacrine

Barbiturates, cigarettes,
rifampin

CYP2C9

Fluvastatin, ibuprofen,
glipzide, losartan,
phenytoin, rosiglitazone,
tolbutamine

Amiodarone, cimetidine,
fluconazole, isoniazid,
metronidazole,
sulfamethoxazole

Barbiturates, phenytoin,
rifampin

CYP2C19

Diazepam, citalopram,
esomeprazole, lansoprazole,
sertraline

Esomeprazole, fluconazole,
fluoxetine, fluvoxamine,
omeprazole

Barbiturates, phenytoin,
rifampin

CYP2D6

Amitriptyline, codeine,
desipramine,
dextromethorphan,
flecainide, haloperidol,
imipramine, metoprolol,
nortriptyline, paroxetine,
propranolol, thioridazine,
timolol

Amiodarone, fluoxetine,
haloperidol, paroxetine,
propoxyphene, quinidine,
terbinafine, thioridazine

Rifampin

CYP3A4

Amiodarone, alprazolam,
buspirone, cisapride,
cyclosporin, diltiazem,
erythromycin, felodipine,
indinavir, lovastatin,
midazolam, nifedipine,
pioglitazone, quinidine,
ritonavir, sertraline,
sildenafil, simvastatin,
warfarin, tacrolimus,
triazolam, verapamil,
zolpidem

Clarithromycin, troleandomycin,
cyclosporin, erythromycin,
grapefruit juice

Barbiturates, carbamazepine,
griseofulvin, phenytoin,
rifampin, St John’s wort

Italics represent the drugs used in dentistry.

is that a more acidic environment favors the formation
of the ionized, less lipid-soluble form of the drug,
which would result in a decline in the amount that is
passively reabsorbed following filtration. Conversely,
renal excretion of weak acids is favored by more alkaline
conditions. Alteration of urine pH does not play a
major role in undesired drug interactions. However, it
has been used in the detoxification process to help rid
the body of a drug overdose.
Probenecid serves as a classic example of a drug that
alters active tubular secretion of drugs from the plasma
into the renal tubular filtrate by competing with other
drugs for active transport sites in the proximal renal
tubular epithelial cells. At one time, this drug interaction

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was used therapeutically. Penicillin was given with
probenecid to increase the plasma level of the penicillin
to enhance the therapeutics of penicillin.

Selected drug interactions
NSAIDs
NSAIDs + lithium
Several NSAIDs have been shown to increase plasma
lithium concentrations. The magnitude of the interaction varies with the NSAID and the dose. Evidence
for this interaction is available for ibuprofen (31),

Drug interactions
Table 2. Possible interactions between grapefruit juice and drugs metabolized by CYP3A4
Drug class

Drug

Possible adverse effects

Antiarrhythmic

Amiodarone

Arrrhythmias

Anxiolytics

Buspirone

Decreased psychomotor performance,

Diazepam

increased sedation

Midazolam
Triazolam
Calcium channel blockers

Amlodipine

Tachycardia, hypotension

Felodipine
Nifedipine
Nimodipine
HMG-CoA reductase inhibitors

Atorvastatin

Myopathy, headache, rhabdomyolysis

Cerivastatin
Lovastatin
Pravastatin
Simvastatin
Immunosuppressants

Cyclosporin

Renal/hepatic dysfunction, increased immunosuppression

Tacrolimus
Neuropsychiatrics

Carbamazepine

Drowsiness, ataxia, nausea, respiratory depression

Clomipramine
Antifungal

Itraconazole

naproxen (32), diclofenac (33), flurbiprofen, (34)
ketorolac (35), and valdecoxib (36). Sulindac appears
to be an exception (37). Evidence of lithium toxicity
includes nausea, vomiting, diarrhea, anorexia, course
tremor, slurred speech, vertigo, confusion, lethargy, and
in extreme cases, seizure, coma, and cardiovascular
collapse. While the exact mechanism is unknown, it
appears that the renal clearance of lithium is decreased,
possibly by the inhibition of the renal prostaglandins
(Fig. 6).

Nausea

inhibitors (38). This is probably of most concern with
long-term dosing of NSAIDs; however, blood pressure
increases have been documented after a single dose of
an NSAID. A recent report described an increase in
blood pressure associated with the selective cyclooxygenase-2 (COX-2) inhibitor, rocecoxib (39). The
mechanism of the interaction appears to be related to
the ability of the prostaglandins to reduce the synthesis
of the vasodilating renal prostaglandins.

NSAIDs 1 methotrexate
NSAIDs 1 angiotensin-converting enzyme
inhibitors
NSAIDs have been shown to diminish the antihypertensive effect of angiotensin-converting enzyme (ACE)

NSAIDs have been shown to decrease the clearance of
methotrexate (23, 24), probably by the same mechanisms as the other agents and that is by a reduction in the
vasodilating renal prostaglandins.

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Fig. 6. Lithium1NSAIDs interaction.

NSAIDs 1 warfarin
Medications such as aspirin and other NSAIDs can
increase the risk of warfarin-related bleeding by
inhibiting platelet function. Aspirin poses the most
significant risk due to its common use and irreversible
prolonged effect on platelets. One proposed mechanism of the interaction has been the possibility that these
drugs displace warfarin from plasma protein-binding
sites. However, the transient nature of the interaction
makes the significance of this mechanism questionable.
Aspirin and NSAIDs also produce gastric erosions that
increase the risk of serious upper gastrointestinal
bleeding.

Acetaminophen 1 warfarin
Acetaminophen is one of the most common drugs used
in the United States. Unlike other analgesics, it does
not cause significant platelet inhibition or gastrointestinal bleeding. These characteristics have led to acetaminophen being the most frequently recommended
analgesic for use by patients also taking warfarin.
Of all the potential interactions between warfarin and
other drugs, the interaction with acetaminophen is
probably the most confusing. The published data on
the interaction are conflicting (40–42), but acetaminophen appears to increase the anticoagulant effect of
warfarin in a dose-dependent manner (43). Approximately 30% of patients stabilized on warfarin who
ingest approximately 2 g of acetaminophen daily can
experience an intensification of warfarin response. The
interaction between acetaminophen and warfarin

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appears more likely with daily acetaminophen doses of
greater than 2 g daily for a week or more. Occasional
doses of acetaminophen do not appear likely to interact
with warfarin. Acetaminophen is still a valuable drug to
use for patients taking warfarin. Unlike aspirin and
NSAIDs, acetaminophen does not inhibit platelet
function, nor does it cause a significant gastric
irritation, which can lead to bleeding. Faced with a
choice of analgesics for anticoagulated patients, acetaminophen still possesses advantages. Coagulation
parameters should be monitored more frequently, such
as once or twice a week when a patient is starting or
stopping chronic acetaminophen therapy (44). The
mechanism of this interaction is not known; however,
inhibition of CYP has been suggested (44). Regardless
of the mechanism, this is a potential interaction that
clinicians should be aware of and monitor closely.

Macrolide interactions
The currently available macrolide antibacterials used in
dentistry include erythromycin, azithromycin, and
clarithromycin. The primary mechanism by which they
interact with other drugs is inhibition of hepatic
microsomal metabolism. An exception is the increase
in digoxin bioavailability caused by erythromycin’s
suppression of gut bacteria that normally degrades
some digoxin prior to absorption, thus leaving greater
quantities of digoxin to be absorbed (45). This
interaction occurs in only about 10% of the patients
receiving the combination.
The macrolides inhibit the CYP3A-mediated metabolism of a plethora of drugs. Certain macrolide
antibiotics, such as erythromycin and troleandomycin
are fairly potent inhibitors, while other macrolides,
including clarithromycin, are less effective CYP3A
inhibitors, and azithromycin and dirithromycin do
not appear to cause significant clinical drug interaction
(7) (Table 3).

Tetracycline interactions
The bioavailability of tetracycline is reduced by 46–57%
when taken with food, by 50–65% when taken with
dairy products and up to 85% when taken with iron
supplements. Tetracycline chelates with polyvalent
cations (e.g. iron, calcium magnesium, and aluminum
in the gut preventing its absorption) resulting in
treatment failures (Fig. 7).

Drug interactions

Antibiotics 1 OCs
The first report of potential interactions between
antibiotics and OCs appeared in 1971 when Reimers
and Jezek (46) reported an increase of intermenstrual
breakthrough bleeding in 38 of 51 women treated
concomitantly with OCs and the antituberculosis drug
rifampin. Rifampin soon became implicated in unplanned pregnancies (47). After reports of rifampin
interaction appeared, possible links between the use of
other antibiotics and OCs began to appear (48, 49).
Clinical studies show that rifampin significantly
reduces blood levels of the OCs, resulting in ovulation.
Rifampin is a potent inducer of the liver CYP enzyme
system and increases the metabolism of the OC
(Fig. 5).
OC failure rate with other antibiotics remains less
clear. Antibiotics that do not induce CYP may reduce
the plasma levels of steroids based on indirect
interference with the enterohepatic circulation of the
estrogen component of the OC. Briefly, the estrogen
component of the OC is conjugated in the liver and
excreted in the bile, where the drug would be
eliminated if not for the bacteria in the gut, which is
thought to deconjugate the estrogen and allow for its
reabsorption. Antibiotics that kill the gut bacteria
involved in the deconjugation process can inhibit this
enterohepatic recirculation (50) (Figs 8 and 9).
However, this mechanism has not been proven, and

Fig. 7. Tetracycline chelation interaction.

except for rifampin, antibiotics do not significantly
affect the plasma concentration of the OC. However,
due to the existing retrospective case reports, it is
possible that certain individuals may be at risk of this
interaction. In light of this, both the American Medical
Association (51) and the American Dental Association
(52) have adopted policies.
(American Medical Association, June 2001)
1. Women prescribed rifampin concomitantly with
OCs faced significant risk of OC failure and should
be counseled about the additional use of nonhormonal contraceptive methods during the course of
rifampin therapy.

Table 3. Macrolide drug interactions of potential clinical importance
Interacting drug

Comments

Carbamazepine

Two- to four-fold increase in carbamazepine concentration with marked toxicity including
lethargy, weakness, ataxia, dizziness, blurred vision, nystagmus, confusion, tremor

Cyclosporin

Marked increases in plasma cyclosporin following erythromycin and clarithromycin resulting in
reversible renal dysfunction, hepatotoxicity, hypertension

Digoxin

Increased serum digoxin following erythromycin in selected patients (only 10% of the population
appears to be at risk

Feldopine

Case reports suggest that erythromycin increases feldopine adverse effects including hypotension,
tachycardia and edema

HMG-CoA reductase
inhibitors: atorvastatin,
cerivastatin, lovastatin

Rhabdomyolysis, muscle weakness and myalgias

Theophylline

Increased serum theophylline resulting in tachycardia, cardiac arrhythmias, tremor, and seizures

Warfarin

Increased INR with markedly enhanced hypoprothrombinemic response to warfarin

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sequences of an unwanted pregnancy, when prescribing
antibiotics to a patient using oral contraceptives s, the
dentist should do the following:
 advise the patient of the potential risk of the
antibiotic’s reducing the effectiveness of the oral
contraceptive;
 recommend that the patient discuss with her
physician the use of an additional non-hormonal
means of contraception;
 advise the patient to maintain compliance with oral
contraceptives when concurrently using antibiotics.

Metronidazole
Fig. 8. OC fate without antibiotics.

2. Women using combined OCs should be informed
about the small risk of interactions with antibiotics
and that it is not possible to identify in advance the
women who may be at risk of OC failure. Women
who are not comfortable with the small risk of
interaction should be counseled about the additional use of non-hormonal contraceptive methods.
Women who have had previous OC failures or who
develop breakthrough bleeding during concomitant use of antibiotics and OCs would be counseled
about the use of alternate methods of contraception
if they engage in intercourse during the period of
concomitant use, as they may be part of a subset of
women at high risk on contraceptive failure.
(American Dental Association, July 2002)
Therefore, it is the opinion of the ADA Council of
Scientific Affairs that, considering the possible con-

Fig. 9. OC fate with antibiotics.

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Metronidazole is an antibiotic used in dentistry, usually
in combination with penicillin to increase its spectrum
of activity. Metronidazole’s chemical structure contains
an imidazole ring, which is found in many other drugs
known to inhibit hepatic drug metabolism (e.g.
cimetidine, ketoconazole, miconazole, and opmeprazole). Perhaps the most important interaction with
metronidazole involves warfarin. Metronidazole
inhibits the metabolism of warfarin, resulting in
accumulation of warfarin and an enhanced anticoagulant effect. This combination should be avoided
if possible (53).

Epinephrine interactions
Epinephrine 1 beta blockers
The adrenergic or sympathetic nervous system is
modulated through alpha (a) and beta (b)receptors.
Depending on the type and location of these receptors,
they may have a stimulatory or inhibitory effect. In the
myocardium, beta-receptor stimulation causes excitation that results in a positive inotroptic and chronotropic effect. The sinoatrial node conduction velocity is
increased, and the myocardial refractory period is
decreased. The net result of beta-receptor stimulation
on the heart is an increase in cardiac index, cardiac
work, and oxygen consumption. This is the physiologic
basis for many of the therapeutic uses of the betareceptor antagonists better known as beta blockers.
The vascular system has both alpha and beta receptors.
Beta-receptor stimulation causes vasodilatation and
alpha-receptor stimulation causes vasoconstriction.
Epinephrine has both alpha and beta actions (Fig.
10). Non-selective beta blockers (Table 4) block the
vasodilating beta effect of epinephrine and shift the

Drug interactions

Fig. 10. Epinephrine receptor action.

Fig. 11. Beta-blocker drug interaction.

response to the alpha-mediated vasoconstriction, resulting in marked hypertension followed by reflex
bradycardia (Fig. 11). This interaction has been
recognized for years and has been the topic of
numerous case studies. The most significant report
was by Foster and Aston, who cited six case studies
involving plastic surgery (54). No risk appears to be
associated with cardioselective beta blockers.

second-line drugs for the treatment of depression after
the selective seratonin uptake inhibitors. These drugs
act on the central and peripheral nervous systems to
block the reuptake of certain neurotransmitters, thus
leaving higher concentrations in the synapse. The
affected neurotransmitters are thus free to interact
more effectively with their receptors. Epinephrine is
subject to the same uptake process and therefore, the
same potentiation. Epinephrine-impregnated gingival
retraction cord is contraindicated because of the large
amounts of epinephrine available for absorption. If
local anesthetic is used with epinephrine, it should have
no more than 1 : 100 000 epinephrine and the maximum recommended dose should be reduced by
one-third (56).

Epinephrine 1 antipsychotics
Antipsychotics such as phenothiazine may block the
peripheral alpha effects of the alpha/beta agonist, leaving
the beta (vasodilating) effects unopposed (55) (Fig. 11).
While this interaction in theory is possible, it appears that
it does not occur at normal doses and no special
precautions are necessary in ambulatory patients (56).

Summary
Epinephrine1tricyclic antidepressants
Tricyclic antidepressants such as imipramine, amitriptyline, nortriptyline, desipramine, and doxepin are now
Table 4. Selectivity of beta-adrenergic receptorblocking drugs
Cardioselective

Non-selective

Acebutol

Carteolol

Atenolol

Nadolol

Betaxolol

Penbutolol

Metoprolol

Pindolol
Propranolol
Timolol

Dealing with drug interactions can be challenging.
New medications are continually being introduced to
the market and dentists should have a fundamental
knowledge of drug interactions. Medication regimens
must be routinely screened for potential drug interactions. When assessing potential drug interactions, it
is necessary to consider the result of such interference:
whether this outcome can be adjusted for; and whether
the benefit of therapy overrides the risk of such an
interaction. In many situations, drug interactions are
not seen clinically because the course of therapy of the
potential offending agent is short (i.e. antibiotics)
because of patient characteristics; or because there is a
failure to identify them. New information appears
quickly, especially in the area of drug metabolism.
Although no one can be expected to know all
drug interactions, good resources are invaluable. (e.g.

19

Byrne
Lexi-Comp’s Drug Interaction Handbook (57), Drug
Interactions Facts (27) or a pharmacy/hospital drug
information service)
Research is essential in the early stages of drug
development to identify drug interactions, define the
mechanisms of older interactions, and examine the
safety of new drugs from classes that are known to cause
interactions.

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