Endodontic Topics 2003, 4, 9–21 Copyright r Blackwell Munksgaard

Printed in Denmark. All rights reserved ENDODONTIC TOPICS 2003

1601-1538

Drug interactions: a review

and update
B. ELLEN BYRNE

People worldwide rely on medications to prevent, cure, enzyme changes or alterations in active drug transport
or lessen an ever-expanding list of diseases. Drugs can becoming clearer (4). As with any area of complex
be beneficial as well as detrimental. The goal of therapy study, the more one discovers, the more questions one
is to maximize beneficial effects, while trying to may ask. A few drugs are involved in so many
minimize the detrimental effects. Each drug prescribed potentially serious drug interactions that they should
has a risk–benefit ratio. If the benefit of taking the drug be viewed as ‘red flags’. These include warfarin,
outweighs the risk of adverse effects, then the drug cyclosporine, erythromycin, itraconazole, ketocona-
therapy is appropriate. Taking one or more drugs that zole, the HIV protease inhibitors, and the HMG-CoA
interact may change this risk–benefit ratio. What was reductase inhibitors (statins).
once a safe and appropriate drug therapy may now be It must be kept in mind that not all drug interactions
inappropriate due to an increased risk from a drug are clinically significant. The significance of drug
interaction. Studies have shown that when the number interactions can range from theoretical and no effect
of co-administered drugs exceeds four, the risk to life threatening. A drug interaction is considered
associated with such use for the patient increases clinically significant when it occurs between two or
substantially (1). more co-administered agents and results in the need
As the age of an individual increases, so do the for a dosage adjustment of one of the agents or other
number of diseases and the number of drugs an medical intervention (5). The withdrawal of medica-
individual may take. The patient may be taking more tions such as terfenadine, astemizole, cisapride, and
than one drug to treat multiple disorders or they may mibefradil from the market due to fatal drug inter-
be taking multiple drugs to treat a single disorder. actions demonstrates the relevance of drug interactions.
When multiple drug therapies are prescribed, drug Drugs most likely to pose interaction problems are
interactions become an important consideration for those having (6, 7):
the patient and the dentist (2). It is estimated that the ! a narrow therapeutic index (small difference between
incidence of clinical drug interactions ranges from 3 to therapeutic dose and toxic dose);
5% in patients taking (3) a few medications, but ! steep dose–response curve;
increases to 20% in patients receiving 10–20 drugs. In ! high first-pass metabolism (the loss of drug as it
addition, they may be taking over-the-counter drugs or passes through the liver for the first time);
dietary supplements with their prescription medicines. ! a single, inhibitable route of elimination.
Information about drugs continues to increase Pharmacotherapy in dentistry is unique in that a drug is
exponentially. Not only do we have more drugs coming usually administered for a short duration. Many drug
on the market every year, but we also have much more interactions occur after repeated or prolonged dosing.
information about older drugs, as a result of continuing Most of the dental drugs have a large margin of safety
research. Our understanding of drug interactions has and there are a limited number of agents included in
grown many-fold. Knowledge of the mechanisms of drug a practitioner’s armamentarium.
interactions has matured and ideas once held as absolute Drug interactions occur when two or more drugs are
truth are being re-examined. The significance of protein- administered at the same time. The action of one drug
binding displacement has been called into question is altered by the presence of another drug. The power
with new foundations for drug interactions, such as of desirable drug interactions is not always recognized.

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There are many examples of desirable and successfully four basic pharmacokinetic processes: absorption, dis-
used drug interactions to enhance drug efficacy in the tribution, metabolism, or excretion (ADME) of a second
management of infection, pain, and cardiovascular drug (Fig. 1). This type of interaction is measured by a
disorders. Hundreds of other drug interactions are change in one or more of the kinetic parameters, such as
considered to be undesirable. Interaction mechanisms maximum serum concentration, half-life amount of
can be broadly divided into two groups: pharmacody- drug excreted in the urine, area under the concentra-
namic interactions and pharmacokinetic interactions. tion time curve, etc. While it is easy to divide the course
A pharmacodynamic interaction is caused by the of drug therapy into four categories, it must be kept in
concurrent administration of two drugs that have the mind that this process of absorption, distribution,
opposite effect or similar effects. In this type of metabolism, and excretion is a continuum, with these
interaction, there is a change in the patient’s response systems acting in concert to determine the fate of
to the drug without altering the drug’s pharmaco- the drug.
kinetics (absorption, distribution, metabolism, and
excretion). That is, there is a change in drug action
without altering the plasma concentration. The inter-
Alterations in drug absorption
action of drugs having similar effects such as alcohol,
opioids, and sedatives is considered synergistic. In this Drug absorption may be altered in numerous ways,
case, the resultant drug action is greater than the sum of some of which are theoretical and include:
each agent alone. Another synergistic interaction could ! gut motility;
occur in dissimilar drugs sharing a common property ! gut pH;
such as the anticholinergic effects of antidepressants, ! drug
phenothiazines, and antihistamines. Synergistic drug solubility;
interactions may be easier to identify than the inter- ! gut metabolism;
actions of drugs having opposite effects. An example of ! gut flora;
such an interaction with opposite effects would be ! activity of protein carriers.
where a patient with asthma is being treated with a One mechanism involves drug adsorption. This occurs
beta-adrenergic drug such as albuterol for its bronch- when a drug is adsorbed onto a binding agent and the
odilating effects, while also being given a beta- drug is no longer easily absorbed into the blood, and
adrenergic blocking drug as an antihypertensive, which may be therapeutically ineffective. Tetracycline anti-
has bronchoconstricting properties. Pharmacodynamic biotics1polyvalent metal cations (e.g. iron, aluminum,
interactions may result from one drug changing the or calcium as found in antacids) results in a decrease in
environment necessary for the safe and effective use of a serum levels of tetracycline (8). Cholestyramine, an
second drug. An example of this interaction is a loop anionic binding resin binds bile acids and many other
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 benzodia-
zepines 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 Fig. 1. Pharmacokinetics of drug fate.

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 Drug interactions

substances, including the oral anticoagulant warfarin. testes (12–14). P-gp was discovered by Juliano and
This complex decreases the mean plasma warfarin Ling (15) in multi-drug-resistant cancer cells. It was
concentration and hypoprothrombinemic effect of this observed that mammalian cancer cells would actively
drug (9). extrude a wide range of cancer chemotherapeutic
Drug absorption may be altered by drug-induced drugs. P-gp appears to be protective (16). P-gp acts
alterations in gastrointestinal motility. Most drugs are as a pump with drugs and toxins being transported
primarily absorbed in the small intestine. Decreasing or away from tissues, that is, out of the tissue. The drugs
increasing the rate at which the drug reaches this area of are pumped across plasma membranes and into
the gastrointestinal tract may decrease or increase the interstitial fluid or into excretory fluids, such as bile,
rate of drug absorption. Drugs that depress peristalsis thereby limiting absorption (17, 18). This efflux of
(narcotics such as morphine and anticholinergics drugs from the cell membrane or cytoplasm is powered
agents such as atropine) may prolong drug transit time by the energy from the ATP hydrolysis. Because P-gps
in the intestine, thereby increasing the time for block absorption in the gut, they should be considered
absorption. Drugs that are prokinetic (metoclopra- as part of the ‘first-pass effect’. In addition, to prevent
mide) may increase gastric empting and thus increase drugs from reaching the systemic circulation, P-gp
the rate of drug absorption. appears to remove some drugs from the systemic
Changing the pH of the gastrointestinal tract can circulation. P-gp also appears to be the ‘gate-keeper’
alter the absorption of some drugs. Some drugs require for later cytochrome P-450 (CYP) actions. A drug is
an acidic or basic environment in order to dissolve. absorbed by passive diffusion into the enterocyte,
Weak acids would more readily exist in a non-ionized where it may be metabolized by CYP3A and also
(i.e. lipid-soluble form) in an acidic environment, thus subject to active counter-transport by P-gp back into
being more readily absorbed, whereas weak bases the gut lumen. It interacts and works cooperatively
would be more absorbable in a basic environment. with CYP (Fig. 2). The concentration of P-gp in
Drugs that increase gastric pH such as proton pump intestinal enterocytes increases along the length of the
inhibitors and antacids may reduce the absorption of gastrointestinal tract, reaching a maximum concentra-
drugs such as ketoconazole and itraconazole, which are tion in the colon (19). Inhibiting the function of P-gp
absorbed best in an acidic environment (10). would result in an increase in drug absorption and
Food–drug interactions can affect the bioavailability inducing the function of P-gp would decrease absorp-
of a drug. The bioavailability and effect of most drugs tion. Many drugs have now been identified as
are correlated. Food–drug interactions can change the substrates, inhibitors, and inducers of P-gp function.
bioavailability of a drug by a chemical reaction such as Several agents have been identified as P-gp inhibitors:
chelation or by a physiological response to food intake. erythromycin, propranolol, and amiodarone. Some
This would include changes in gastric acidity, bile examples of inducers include: dexamethasone, nefazo-
secretion, and gastrointestinal motility. Food–drug done, and rifampin (16).
interactions that only affect the rate of drug absorption
are common, but rarely of clinical importance (11).

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 oxidation, hydrolysis, or reduction of a drug. These

reactions increase the water solubility of the drug and
Drugs are transported to a site of action or elimination
thus facilitate their elimination from the body. Phase II
bound to serum proteins. Acidic drugs are bound to
metabolism involves the attachment of an additional
plasma albumin and basic drugs are bound to a-acid
molecule to the drug in order to create an inactive
glycoprotein (20). While bound to a plasma protein,
compound and a more water-soluble drug. Phase II
the drug does not contribute to the concentration
processes include glutathione conjugation, glucuro-
gradient, cannot be filtered by the kidney, and in
nidation, sulfation, acetylation, and methylation.
general, is pharmacologically inert. The unbound or
The enzyme that catalyzes this reaction is known as
‘free’ drug is pharmacologically active. Decreasing the
the hepatic CYP. CYP is a complex of protein, heme,
serum concentration of albumin could result in altered
and iron. By using molecular oxygen and NADPH
pharmacokinetics of bound drugs.
(a reduced form of NADP) as a source of electrons, this
From a drug interaction standpoint, a drug with high
cytochrome system catalyzes a series of oxidation–
binding affinity could displace a drug with less affinity,
reduction reactions, which results in the oxidized drug
thereby increasing the free concentration of the drug
product (25). While there are more that 50 different
with less affinity. However, the unbound fraction of the
families of enzymes identified, only three families
drug is not only more available for the site of action, but
CYP1, CYP2, and CYP3 are responsible for the
also is more available for elimination. This principle has
metabolism of most compounds including steroids,
often been applied to highly protein-bound (490%)
prostaglandins, vitamins, other endogenous com-
drugs and to drugs with a narrow therapeutic index,
pounds, and a large number of drugs. Subfamilies
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).

Fig. 3. Phase I and II metabolism.

Drug metabolism
The area of biotransformation, also known as metabo-
lism, is exploding with new information. Recent studies
suggest that the most clinically important drug inter-
actions 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 Fig. 4. Normal metabolism.

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 Drug interactions

within each family are designated by a capital letter and of that drug. This can result in the drug-induced
individual enzymes are named with a final Arabic toxicity. Unlike enzyme induction which takes a while,
number. Thus, the individual enzymes CYP2C9 and this interaction can be rapid and without warning. The
CYP2C19 both belong to the CYP2 family and the antifungal agents ketoconazole and itraconazole, and
CYP2C subfamily. the macrolide antibiotics, such as erythromycin and
Theoretically, any two drugs that are metabolized by clarithromycin (but not azithromycin), are all potent
the same enzyme could produce a drug interaction. inhibitors of CYP3A (6). Certain calcium channel
The two drugs would compete for the same enzyme. blockers, such as diltiazem, nicardipine, and verapamil
One drug could be metabolized and the other drug’s also inhibit CYP3A (28), as does a constituent of
metabolism reduced, resulting in a higher blood level grapefruit juice (10). After ingestion, a substrate in
of the non-metabolized drug. To anticipate a clinically grapefruit juice binds to the intestinal isoenzyme,
significant drug interaction involving the CYP system, impairing first-pass metabolism directly and causes
it is necessary to become familiar with the substrates, a sustained decrease in CYP3A4 protein expression
inhibitors, and inducers of the isoenzymes. The (29). Within 4 h of ingestion, a reduction in the
‘substrate’ refers to that compound known to be effective CYP2A4 concentration occurs, with the effects
metabolized by the isoenzyme. The term ‘inhibitor’ lasting up to 24 h (30). The net result is the inhibition of
denotes a drug known to interfere or compete with the drug metabolism in the intestine and increased oral
isoenzyme, and the term ‘inducer’ describes an agent bioavailability. Because of the prolonged response,
that accelerates the metabolism of a substrate. 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 Drug excretion
decreased based on enzyme induction or enzyme Just as the liver is the primary organ involved in the
inhibition. metabolism of drugs, the kidney is the primary organ
Induction of drug metabolism usually occurs by involved in the excretion of compounds from the body.
enhanced gene transcription following prolonged Other sites of drug excretion include the liver, lungs,
exposure to an inducing agent (Fig. 5). As a result, gastrointestinal tract, saliva, sweat, tears, and breast
the consequences of enzyme induction may take milk. Alterations in renal excretion can occur by several
considerable time to be fully exhibited. The conse- mechanisms, including changes in urinary pH (which
quences of enzyme induction are an increased rate of can alter passive reabsorption of a drug), competition
metabolism, enhanced oral first-pass metabolism, and for the same transport system, changes in active tubular
a reduced bioavailability. All of this results in a decrease secretion, or changes in renal blood flow.
in the drug’s plasma concentration. In contrast, in Acidification of the urine results in an increase in the
drugs that are metabolized to an active or toxic rate of urinary excretion of weak bases. The explanation
metabolite, induction may be associated with an
increased effect or increased toxicity. A well-docu-
mented 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 Fig. 5. Induced metabolism.

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Table 1. Cytochrome P450 substrate, inhibitors, and inducers

Isozyme Substrate Inhibitors Inducers

CYP1A2 Acetaminophen, caffeine, Cimetidine, ciprofloxacin, Barbiturates, cigarettes,

clozapine, amitriptyline, diltiazem, enoxacin, rifampin
tacrine, theophylline fluvoxamine, tacrine

CYP2C9 Fluvastatin, ibuprofen, Amiodarone, cimetidine, Barbiturates, phenytoin,

glipzide, losartan, fluconazole, isoniazid, rifampin
phenytoin, rosiglitazone, metronidazole,
tolbutamine sulfamethoxazole

CYP2C19 Diazepam, citalopram, Esomeprazole, fluconazole, Barbiturates, phenytoin,

esomeprazole, lansoprazole, fluoxetine, fluvoxamine, rifampin
sertraline omeprazole

CYP2D6 Amitriptyline, codeine, Amiodarone, fluoxetine, Rifampin

desipramine, haloperidol, paroxetine,
dextromethorphan, propoxyphene, quinidine,
flecainide, haloperidol, terbinafine, thioridazine
imipramine, metoprolol,
nortriptyline, paroxetine,
propranolol, thioridazine,
timolol

CYP3A4 Amiodarone, alprazolam, Clarithromycin, troleandomycin, Barbiturates, carbamazepine,

buspirone, cisapride, cyclosporin, erythromycin, griseofulvin, phenytoin,
cyclosporin, diltiazem, grapefruit juice rifampin, St John’s wort
erythromycin, felodipine,
indinavir, lovastatin,
midazolam, nifedipine,
pioglitazone, quinidine,
ritonavir, sertraline,
sildenafil, simvastatin,
warfarin, tacrolimus,
triazolam, verapamil,
zolpidem

Italics represent the drugs used in dentistry.

is that a more acidic environment favors the formation was used therapeutically. Penicillin was given with
of the ionized, less lipid-soluble form of the drug, probenecid to increase the plasma level of the penicillin
which would result in a decline in the amount that is to enhance the therapeutics of penicillin.
passively reabsorbed following filtration. Conversely,
renal excretion of weak acids is favored by more alkaline
conditions. Alteration of urine pH does not play a Selected drug interactions
major role in undesired drug interactions. However, it
has been used in the detoxification process to help rid NSAIDs
the body of a drug overdose.
Probenecid serves as a classic example of a drug that NSAIDs + lithium
alters active tubular secretion of drugs from the plasma Several NSAIDs have been shown to increase plasma
into the renal tubular filtrate by competing with other lithium concentrations. The magnitude of the inter-
drugs for active transport sites in the proximal renal action varies with the NSAID and the dose. Evidence
tubular epithelial cells. At one time, this drug interaction for this interaction is available for ibuprofen (31),

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 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 immunosup-

pression

Tacrolimus

Neuropsychiatrics Carbamazepine Drowsiness, ataxia, nausea, respiratory depression

Clomipramine

Antifungal Itraconazole Nausea

naproxen (32), diclofenac (33), flurbiprofen, (34) inhibitors (38). This is probably of most concern with
ketorolac (35), and valdecoxib (36). Sulindac appears long-term dosing of NSAIDs; however, blood pressure
to be an exception (37). Evidence of lithium toxicity increases have been documented after a single dose of
includes nausea, vomiting, diarrhea, anorexia, course an NSAID. A recent report described an increase in
tremor, slurred speech, vertigo, confusion, lethargy, and blood pressure associated with the selective cyclo-
in extreme cases, seizure, coma, and cardiovascular oxygenase-2 (COX-2) inhibitor, rocecoxib (39). The
collapse. While the exact mechanism is unknown, it mechanism of the interaction appears to be related to
appears that the renal clearance of lithium is decreased, the ability of the prostaglandins to reduce the synthesis
possibly by the inhibition of the renal prostaglandins of the vasodilating renal prostaglandins.
(Fig. 6).

NSAIDs 1 methotrexate
NSAIDs 1 angiotensin-converting enzyme
NSAIDs have been shown to decrease the clearance of
inhibitors
methotrexate (23, 24), probably by the same mechan-
NSAIDs have been shown to diminish the antihyper- isms as the other agents and that is by a reduction in the
tensive effect of angiotensin-converting enzyme (ACE) vasodilating renal prostaglandins.

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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, acet-
aminophen 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
Fig. 6. Lithium1NSAIDs interaction. 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
NSAIDs 1 warfarin clinicians should be aware of and monitor closely.

Medications such as aspirin and other NSAIDs can

increase the risk of warfarin-related bleeding by Macrolide interactions
inhibiting platelet function. Aspirin poses the most
The currently available macrolide antibacterials used in
significant risk due to its common use and irreversible
dentistry include erythromycin, azithromycin, and
prolonged effect on platelets. One proposed mechan-
clarithromycin. The primary mechanism by which they
ism of the interaction has been the possibility that these
interact with other drugs is inhibition of hepatic
drugs displace warfarin from plasma protein-binding
microsomal metabolism. An exception is the increase
sites. However, the transient nature of the interaction
in digoxin bioavailability caused by erythromycin’s
makes the significance of this mechanism questionable.
suppression of gut bacteria that normally degrades
Aspirin and NSAIDs also produce gastric erosions that
some digoxin prior to absorption, thus leaving greater
increase the risk of serious upper gastrointestinal
quantities of digoxin to be absorbed (45). This
bleeding.
interaction occurs in only about 10% of the patients
receiving the combination.
The macrolides inhibit the CYP3A-mediated meta-
Acetaminophen 1 warfarin
bolism of a plethora of drugs. Certain macrolide
Acetaminophen is one of the most common drugs used antibiotics, such as erythromycin and troleandomycin
in the United States. Unlike other analgesics, it does are fairly potent inhibitors, while other macrolides,
not cause significant platelet inhibition or gastrointesti- including clarithromycin, are less effective CYP3A
nal bleeding. These characteristics have led to acet- inhibitors, and azithromycin and dirithromycin do
aminophen being the most frequently recommended not appear to cause significant clinical drug interaction
analgesic for use by patients also taking warfarin. (7) (Table 3).
Of all the potential interactions between warfarin and
other drugs, the interaction with acetaminophen is
Tetracycline interactions
probably the most confusing. The published data on
the interaction are conflicting (40–42), but acetami- The bioavailability of tetracycline is reduced by 46–57%
nophen appears to increase the anticoagulant effect of when taken with food, by 50–65% when taken with
warfarin in a dose-dependent manner (43). Approxi- dairy products and up to 85% when taken with iron
mately 30% of patients stabilized on warfarin who supplements. Tetracycline chelates with polyvalent
ingest approximately 2 g of acetaminophen daily can cations (e.g. iron, calcium magnesium, and aluminum
experience an intensification of warfarin response. The in the gut preventing its absorption) resulting in
interaction between acetaminophen and warfarin treatment failures (Fig. 7).

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 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 un-
planned 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.
Fig. 7. Tetracycline chelation interaction.
Rifampin is a potent inducer of the liver CYP enzyme
system and increases the metabolism of the OC
(Fig. 5). except for rifampin, antibiotics do not significantly
OC failure rate with other antibiotics remains less affect the plasma concentration of the OC. However,
clear. Antibiotics that do not induce CYP may reduce due to the existing retrospective case reports, it is
the plasma levels of steroids based on indirect possible that certain individuals may be at risk of this
interference with the enterohepatic circulation of the interaction. In light of this, both the American Medical
estrogen component of the OC. Briefly, the estrogen Association (51) and the American Dental Association
component of the OC is conjugated in the liver and (52) have adopted policies.
excreted in the bile, where the drug would be
eliminated if not for the bacteria in the gut, which is (American Medical Association, June 2001)
thought to deconjugate the estrogen and allow for its 1. Women prescribed rifampin concomitantly with
reabsorption. Antibiotics that kill the gut bacteria OCs faced significant risk of OC failure and should
involved in the deconjugation process can inhibit this be counseled about the additional use of nonhor-
enterohepatic recirculation (50) (Figs 8 and 9). monal contraceptive methods during the course of
However, this mechanism has not been proven, and 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 Rhabdomyolysis, muscle weakness and myalgias

inhibitors: atorvastatin,
cerivastatin, lovastatin

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. Metronidazole is an antibiotic used in dentistry, usually
in combination with penicillin to increase its spectrum
2. Women using combined OCs should be informed
of activity. Metronidazole’s chemical structure contains
about the small risk of interactions with antibiotics
an imidazole ring, which is found in many other drugs
and that it is not possible to identify in advance the
known to inhibit hepatic drug metabolism (e.g.
women who may be at risk of OC failure. Women
cimetidine, ketoconazole, miconazole, and opmepra-
who are not comfortable with the small risk of
zole). Perhaps the most important interaction with
interaction should be counseled about the addi-
metronidazole involves warfarin. Metronidazole
tional use of non-hormonal contraceptive methods.
inhibits the metabolism of warfarin, resulting in
Women who have had previous OC failures or who
accumulation of warfarin and an enhanced antic-
develop breakthrough bleeding during concomi-
oagulant effect. This combination should be avoided
tant use of antibiotics and OCs would be counseled
if possible (53).
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 Epinephrine interactions
women at high risk on contraceptive failure.
Epinephrine 1 beta blockers
(American Dental Association, July 2002) The adrenergic or sympathetic nervous system is
Therefore, it is the opinion of the ADA Council of modulated through alpha (a) and beta (b)receptors.
Scientific Affairs that, considering the possible con- Depending on the type and location of these receptors,
they may have a stimulatory or inhibitory effect. In the
myocardium, beta-receptor stimulation causes excita-
tion that results in a positive inotroptic and chrono-
tropic 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 beta-
receptor 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
Fig. 9. OC fate with antibiotics. vasodilating beta effect of epinephrine and shift the

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 Drug interactions

Fig. 10. Epinephrine receptor action. Fig. 11. Beta-blocker drug interaction.

response to the alpha-mediated vasoconstriction, re- second-line drugs for the treatment of depression after
sulting in marked hypertension followed by reflex the selective seratonin uptake inhibitors. These drugs
bradycardia (Fig. 11). This interaction has been act on the central and peripheral nervous systems to
recognized for years and has been the topic of block the reuptake of certain neurotransmitters, thus
numerous case studies. The most significant report leaving higher concentrations in the synapse. The
was by Foster and Aston, who cited six case studies affected neurotransmitters are thus free to interact
involving plastic surgery (54). No risk appears to be more effectively with their receptors. Epinephrine is
associated with cardioselective beta blockers. subject to the same uptake process and therefore, the
same potentiation. Epinephrine-impregnated gingival
Epinephrine 1 antipsychotics retraction cord is contraindicated because of the large
amounts of epinephrine available for absorption. If
Antipsychotics such as phenothiazine may block the
local anesthetic is used with epinephrine, it should have
peripheral alpha effects of the alpha/beta agonist, leaving
no more than 1 : 100 000 epinephrine and the max-
the beta (vasodilating) effects unopposed (55) (Fig. 11).
imum recommended dose should be reduced by
While this interaction in theory is possible, it appears that
one-third (56).
it does not occur at normal doses and no special
precautions are necessary in ambulatory patients (56).
Summary
Epinephrine1tricyclic antidepressants Dealing with drug interactions can be challenging.
Tricyclic antidepressants such as imipramine, amitripty- New medications are continually being introduced to
line, nortriptyline, desipramine, and doxepin are now the market and dentists should have a fundamental
knowledge of drug interactions. Medication regimens
Table 4. Selectivity of beta-adrenergic receptor- must be routinely screened for potential drug inter-
blocking drugs actions. When assessing potential drug interactions, it
is necessary to consider the result of such interference:
Cardioselective Non-selective
whether this outcome can be adjusted for; and whether
Acebutol Carteolol
the benefit of therapy overrides the risk of such an
Atenolol Nadolol interaction. In many situations, drug interactions are
not seen clinically because the course of therapy of the
Betaxolol Penbutolol
potential offending agent is short (i.e. antibiotics)
Metoprolol Pindolol because of patient characteristics; or because there is a
failure to identify them. New information appears
Propranolol
quickly, especially in the area of drug metabolism.
Timolol Although no one can be expected to know all
drug interactions, good resources are invaluable. (e.g.

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Byrne

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