Drug Interactions in Dentistry: Pharmacology

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DentalPharmacology

Robin A Seymour

Drug Interactions in Dentistry


Abstract: An increasing number of our patients are on medication of various types. This increase in prescribed medicines also raises
the significant issue of potential drug interactions between those drugs used in dental practice and those taken by the patient. This
article addresses those interactions and, where appropriate, puts them into perspective and attempts to quantify the risk. Mechanisms of
relevant drug interactions are also discussed. Certain categories of drugs are more likely to be involved in interactions and again these are
highlighted. Drug interactions relevant to dentistry can for the most part be prevented. A careful drug history should be taken from each
patient and updated on a regular basis.
Clinical Relevance: This article highlights drug interactions that can arise in dental practice and how they can be avoided and managed.
Dent Update 2009; 36: 458–470

Drug interactions are quite simply an


interaction between two or more medications
that the patient may be prescribed. In
the dental setting, such interactions may
occur between those drugs prescribed or
administered in dental practice and the
patients’ current medication.
It is now widely recognized
that our patients are living longer and
retaining their teeth into old age. One major
contribution to this increase in life expectancy
is improved medication and a greater choice
of drugs to treat the frequent age-related
illnesses. It has been estimated that 75% of
the population over the age of 55 are taking
medication in order to sustain various bodily
functions.1 As the number of patients taking
one or more drugs increases, the risk of drug
interactions between the patients’ medication Figure 1. Interaction between tetracyclines and various metallic ions found in antacids.
and those drugs commonly prescribed in
dental practice, will also increase. As new
drugs are developed and come into clinical
practice, the risk of drug interactions should a variety of mechanisms and their tested. The therapeutic index of a drug
always be considered. significance can relate to certain gives some idea of its margin of safety.
categories of drugs and/or their A drug with a low (narrow) therapeutic
pharmacological properties. For example, index is potentially less safe than a drug
Broad principles of drug a drug with a low therapeutic index, with a high (wide) therapeutic index (eg
interactions that is also extensively protein bound, warfarin and digoxin).
Drug interactions can involve is susceptible to drug interactions. The Other principles of
therapeutic index of a drug is a measure drug interaction can be considered
of the ratio of the median lethal dose in terms of pharmacokinetic and
Robin A Seymour, Professor of (LD50) to the median effective dose pharmacodynamic properties.
Restorative Dentistry, School of (ED50). The lethal dose is the dose of drug Pharmacokinetic interactions can be
Dental Sciences, Newcastle University, required to be lethal for 50% of a group further categorized under the headings
Framlington Place, Newcastle upon Tyne of animals. ED50 is the dose required to of absorption, distribution, metabolism
NE2 4BW, UK. produce a response in 50% of subjects and excretion.
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Pharmacokinetic interactions of ‘free’ or pharmacologically active drug. The problem with warfarin is
This is illustrated by the anticoagulant drug compounded by its low therapeutic index.
Drug absorption
warfarin, which has a low therapeutic index Warfarin is 99% protein-bound, with only
Most drugs are absorbed in the
and is 98−99% protein-bound. Aspirin and 1% available to affect blood coagulation. If
upper part of the gastro-intestinal tract.
other non-steroidal inflammatory drugs are a further drug is administered that reduces
Absorption depends upon factors such as
also extensively protein-bound. If aspirin is warfarin binding from 99−98%, then the
a drug’s ability to survive the low gastric
given to a patient on warfarin, then more amount of free or active warfarin increases
pH, the effect of food, and the formation
of the anticoagulant will be displaced from from 1−2%. This is a 100% increase in
of irreversible complexes with other drugs
the binding site, causing an increase in the the amount of pharmacologically active
or constituents of food. Benzylpenicillin
free, pharmacologically active warfarin. warfarin, which will raise the patient’s INR.
is deactivated by gastric acid and so can
The result of such an interaction is an All drugs which exhibit
only be given by injection. The pH of the
increase in the patient’s INR and a serious more than 90% protein binding are at
stomach affects the absorption of the
haematological risk (see later). This type of a significant risk from drug interactions.
antifungal agent ketoconazole, where the
drug interaction is illustrated in Figure 2. Within this category are, in addition
acidic conditions aid dissolution prior to
absorption. Drugs which reduce the acidity
of the stomach, such as antacids, H2–receptor
blockers (ranitidine) and proton-pump
inhibitors (omeprazole) will reduce the a
absorption of ketoconazole.2
Tetracyclines form chelates with
divalent and trivalent cations (eg Al3+, Bi2+,
Ca2+, Fe2+, Mg2+, Zn2+) (Figure 1). Chelated
tetracyclines are poorly absorbed, resulting
in reduced antimicrobial activity. Salts of
aluminium, calcium and magnesium are
the main ingredients of antacids; also the
ACE-inhibitor quinapril contains magnesium
carbonate. These drugs should be avoided
if a patient is prescribed tetracyclines.
In addition, some food substances
contain calcium ions, especially dairy
products, and hence patients prescribed
tetracyclines should be advised not to take
milk, indigestion remedies or medicines
containing iron or zinc at the same time of b
day. Incompatible preparations should be
taken 2−3 hours apart. Ideally, tetracyclines
should be taken on an empty stomach or 60
minutes before or after food.3

Drug distribution
When a drug is absorbed
from the gastrointestinal tract it is often
distributed in the bloodstream bound
to plasma protein. The bound portion is
considered pharmacologically inert, whereas
the so-called free or unbound portion may
interact with the receptor binding site. The
number of binding sites is limited and other
drugs compete for the protein binding
site, resulting in an increase in the free
pharmacologically active portion.
Displacement of one drug
from its binding site by another drug that Figure 2. (a) Aspirin and warfarin in terms of protein binding. (b) Diagram to show the interaction
competes for the same binding site will between aspirin and warfarin in terms of competition for protein-binding sites.
have a significant effect on the amount
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to warfarin, oral anti-diabetic drugs Erythromycin Rifampicin


(chlorpropamide and other sulphonylureas), (enzyme inhibitor) (enzyme inducer)
and the anti-epileptic drug, phenytoin.

Drug metabolism
Many drugs are metabolized
(biotransformed) in the liver, rendering
the drug inactive, or changing its physico-
chemical properties to make it easier to
excrete. The liver also biotransforms inert pro-
drugs to more active metabolites. This is the
case with codeine, the metabolite morphine
being more pharmacologically active than the
parent drug.
Drugs biotransformed in the liver DMEs
LIVER
by enzymes are collectively known as drug
metabolizing enzymes (DME). Of the various
DMEs, the ones most frequently the target of
drug interactions are the cytochrome P450
isoenzyme system.4 The cytochrome P450 Simvastatin
nomenclature is as follows: CYP stands for Contraceptive pill
cytochrome P. This is followed by a number
representing the subfamily and then another
number representing the individual gene.
The cytochrome enzymes most frequently
involved in drug interaction include CYP1A2,
CYP2C9, CYP2C19, CYP2D6, CYP2E1 and
CYP3A4.
These CYP45O enzymes can be
induced or inhibited by drugs. For example, Increased risk of Reduced plasma
although not particularly relevant to dentistry, simvastatin-induced concentration
the anti-tuberculosis drug rifampicin induces myopathy of the
the CYP450 enzyme that metabolizes the
contraceptive
pill, increasing
oral contraceptive, leading to pill failure.5
the risk of pill
By contrast, the antibiotic erythromycin
failure
is an enzyme inhibitor for CYP3A4, which
includes the enzyme responsible for the Figure 3. Schematic diagram to illustrate the effect of drug interactions involving hepatic drug
biotransformation of simvastatin and metabolizing enzymes (DMEs).
atorvastatin.6 This interaction can potentially
increase the risk of statin-induced myopathy
(Figure 3).
It should also be recognized that healthy adult, this could be problematic in a Of dental relevance under this
other substances, which may not be regarded child or a medically compromised patient. category is the ability of non-steroidal anti-
by patients as drugs, can also have an effect inflammatory drugs, such as ibuprofen or
on the cytochrome P450 group of enzymes. Drug excretion diclofenac, to inhibit the renal excretion of
Alcohol, smoking, various recreational drugs The kidney is the main site of lithium.8 Lithium has a narrow therapeutic
and even char-grilled meats have been drug excretion. Renal excretion of drugs index and a raised serum concentration can
identified as enzyme inducers. Grapefruit juice often involves an energy-dependent, multi- lead to severe renal and CNS toxicity.
has been shown to be an enzyme inhibitor. drug efflux pump known as P-glycoprotein. Competitive inhibition is a
Grapefruit juice consumption prior to oral As with drug metabolizing enzymes, certain further process of drug interactions involving
midazolam sedation could be problematic. drugs can induce or inhibit P-glycoprotein. excretion. Weak acids, such as the penicillins,
Taking 200 ml of grapefruit juice two hours An inducer of P-glycoprotein will result in may compete with methotrexate in the renal
before oral midazolam can double the plasma more drug excretion, whilst the converse will tubules for excretion, so that there is an
concentration of this benzodiazepine.7 Whilst apply to an inhibitor. The latter will raise serum increase in serum methotrexate and increased
such high levels of midazolam should not concentration and increase the risk of toxic toxicity. NSAIDs inhibit the synthesis of
present a serious problem in an otherwise effects. prostaglandins, which results in a fall in renal

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Antibiotic Interacting drug Mechanism Outcomes and recommendations

Erythromycin Theophylline, aminophyline Inhibition of CYP3A4 Increase in plasma concentrations of theophylline


(systemic broncho-dilator) leading to tachycardia, dysrythmias, tremors-
seizure. Avoid prescribing erythromycin.

Erythromycin Simvastatin Inhibition of CYP3A4 Increase in plasma concentration of simvastatin


leading to increased risk of myalgias,
rhabdomyolysis and renal failure. Avoid prescribing
erythromycin or, if the antibiotic is essential , then
stop taking simvastatin.

Erythromycin Ciclosporin and tacrolimus Inhibition of CYP3A4 Increase in plasma levels of both
immunosuppressives leading to excessive
immunosuppression and increased risk of renal
toxicity. Avoid prescribing erythromycin if possible.

Erythromycin Warfarin Inhibition of CYP3A4 Increase in plasma concentrations of warfarin leading


to a raised INR and increased risk of bleeding.
Concurrent use need not be avoided as
erythromycin-induced inhibition of CY3PA4 is
somewhat unpredictable.

Erythromycin Carbamazepine Inhibition of CYP3A4 Increase in levels of carbamazepine leading to


increased risk of drowsiness, ataxia and confusion.
Avoid erythromycin.

Erythromycin Midazolam Inhibition of CYP3A4 Increase in plasma concentration of midazolam


leading to excessive and prolonged sedation. Avoid
erythromycin for some 12 hours before iv sedation
with midazolam.

Metronidazole Alcohol Blocks enzyme Increase in levels of acetaldehyde which produces


acetaldehyde flushing, headache, nausea and palpitations. Avoid
dehydrogenase which alcohol consumption during metronidazole therapy
converts acetaldehyde and for at least 2-3 days after completing course.
to acetic acid

Metronidazole Warfarin Inhibition of CYP3A4 Increase in plasma concentrations of warfarin


leading to a raised INR and increased risk of
bleeding. Avoid metronidazole.

Erythromycin Calcium channel blocks, Inhibition of CYP3A4 Increase in plasma concentration of nifedipine
eg nifedipine resulting in severe risk of hypotension and oedema
formula. Avoid erythromycin.

Table 1. Possible drug interactions arising from antibiotic prescribing.

perfusion. This could lead to a rise in serum are those where the action of one drug is interactions include the antiplatelet action
methotrexate level and likewise increased enhanced by the action of another. These of aspirin and the anticoagulant effect of
toxicity. actions may be additive or synergistic, warfarin, atropine and tricyclic antidepressants
where the pharmacological effect is greater (antimuscarinic effect), and opioid analgesics
than the simple sum of either drug alone. and alcohol (sedative CNS effect). More recent
Pharmacodynamic drug Pharmacodynamic interactions occur at evidence has shown that non-steroidal anti-
interactions the site of drug action, often at receptor inflammatory drugs, such as ibuprofen and
Pharmacodynamic interactions level. Examples of pharmacodynamic drug diclofenac, interact with selective serotonin
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reuptake inhibitors (eg Prozac). As both drugs


have an effect on platelet aggregation, this
interaction increases the risk of a NSAID-
induced gastrointestinal bleed.9

Drug interactions that are


significant in dental practice
Dental practitioners prescribe
relatively few categories of drugs and this
section will focus only on three widely used
categories:
„ Antibiotics;
„ Analgesics; and
„ Local anaesthetic solutions.

Drug interactions involving


antibiotics
A synopsis of possible drug
interactions relating to antibiotic prescription
is shown in Table 1.
Some of the drug interactions
involving antibiotics are worth highlighting.
Figure 4. Interaction between broad spectrum antibiotics and COC.

Metronidazole, erythromycin and warfarin


Both antimicrobials inhibit liver Bacteriostatic Bactericidal
enzymes CYP2C9 (metronidazole) and CYP3A4 Tetracyclines Penicillins erythromycin and the tetracyclines. Antibiotics
(erythromycin). These enzymes are involved Erythromycin Cephalosporins used in dentistry will affect the gut flora.
in the metabolism of warfarin (especially Clindamycin Metronidazole Although numerous case reports
CYP2C9) and their inhibition will lead to Table 2. Classification of antibiotics used in den- have appeared in the literature indicating
an increase in plasma concentrations of tistry by their mode of action. that systemic antibiotic therapy has resulted
warfarin, leading to an increased INR and risk in ‘pill’ failure, evidence from controlled trials
of bleeding.10 If either antibiotic is essential are lacking. Following initial absorption
in the management of a patient’s infection, of the oestrogen component of a COC, it
then control of the infection should take the efficacy of the bactericidal drug. For undergoes conjugation with glucuronic
precedent. It would be worthwhile informing example, tetracycline or erythromycin should acid in the liver. Once conjugated, the
the patient’s physician before prescribing not be prescribed to a patient taking penicillin oestrogen is pharmacologically inactive and
metronidazole. An antibiotic-induced change or metronidazole. However, clinical evidence is excreted via the bile into the gut. In normal
in hepatic metabolism of warfarin, and hence to support this is not strong. There is no circumstances, the conjugate is hydrolysed by
an increase in INR, is likely to be of short rationale for using such a combination in colonic bacteria, which releases the oestrogen
duration. Despite this, it is essential to check dentistry for the management of odontogenic to be reabsorbed for the suppression of
the patient’s INR if he/she has recently (within infections. ovulation. This process is illustrated in Figure
two to three days) completed a course of 4. Thus a viable gut flora is thought to be
either metronidazole or erythromycin. necessary for oestrogen metabolism and pill
Antibiotics and oral contraceptives efficacy. As progestogen does not undergo
Bactericidal and bacteriostatic antibiotics An oral contraceptive pill enterohepatic recycling, POPs are not affected
Antibiotics have two modes of contains a combination of oestrogen and by antibiotics. Many antibiotics reduce the
action against bacteria; they either destroy progestogen (combined oral contraceptive, gut flora and thereby there is, in theory, an
them (bactericidal) or stop them dividing COC) or progestogen alone (progestogen only increased risk of pill failure. As there is no
(bacteriostatic). Table 2 provides a list of pill, POP). There are two ways in which oral easy way of determining the effect of the
antibiotics used in dentistry categorized contraceptives can be affected by antibiotics: gut flora in reducing circulating levels of
according to their mode of action. Bactericidal first, their metabolism can be induced leading oestrogen, all women taking the COC pill
antibiotics are more effective if the bacteria to lower levels of the circulating hormones should be considered at risk from pill failure
that they are targeting are dividing. and thus failure of effect. This can occur if prescribed systemic antibiotics. The overall
Theoretically, therefore, administration of a with the antibiotic rifampicin; secondly, by failure rate of oral contraceptives in women
bacteriostatic agent will reduce significantly their effect on the gut flora, eg amoxicillin, taking systemic antibiotics may be no greater

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than when taking oral contraceptives alone.


It is recommended that all female patients
taking the pill are warned of the risk of pill
failure if prescribed systemic antibiotics and
to use additional methods of contraception
during the antibiotic therapy, and for at least
one week after the last antibiotic dose.11 If
these seven days run beyond the end of a
packet, the next packet should be started
immediately without a break.

Drug interactions involving


analgesic agents
In dental practice, analgesics
are frequently prescribed as short 3−5 day
courses for the management of post-operative
pain after a dental or oral surgical procedure.
Drug interactions involving analgesics are
summarized in Table 3.
Combinations of non-steroidal
anti-inflammatory drugs (NSAIDs) to
control post-operative pain will not result in
additional analgesia, however, it will increase
the risk of adverse effects. For example, using
both aspirin and ibuprofen to treat post-
operative pain increases the risk of gastro-
intestinal problems and ulceration. There is
also an interaction between ibuprofen or
other NSAIDs and low dose aspirin taken for
vascular and cerebrovascular protection.12 A
single dose of ibuprofen 400 mg, when taken
before aspirin, has been shown to reduce
aspirin’s antiplatelet effect by up to 50%. If
ibuprofen is taken after aspirin, the effect on
aspirin-induced antiplatelet activity is minimal.
If ibuprofen or other NSAIDs are prescribed
to a patient taking low dose aspirin, then the
patient should be advised to take the aspirin
before the NSAID.13
NSAIDs, aspirin and selective
serotonin re-uptake inhibitors (SSRIs) can
interact to increase the risk of bleeding. SSRIs,
eg fluoxetine (Prozac), citalopram, paroxetine,
and sertraline also inhibit serotonin re-uptake
in platelets. Serotonin is normally released
from platelets as a response to injury and
has an important role in regulating the
haemostatic response by potentiating
platelet aggregation. NSAIDs and aspirin
also affect platelet aggregation by blocking
thromboxane synthesis and release. This
interaction is illustrated in Figure 5. The major
significant risk from this interaction is a
gastro-intestinal bleed; when both drugs are
Figure 5. Schematic diagram to illustrate interaction between aspirin and NSAIDs with SSRIs leading to
used concurrently the risk of a bleed increases
an increased risk of bleeding.
15−16 fold.14 This increased risk of a GIT bleed
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Analgesic Interacting drug Outcome and recommendation

Paracetamol Alcohol Increased risk of paracetamol toxicity and liver damage. Daily
(acetaminophen) dose of paracetamol should not exceed 4000 g (8 tablets) and
for alcoholics this should not exceed 2000 g (4 tablets).

Aspirin and other non-selective Alcohol Increased risk of gastro-intestinal toxicity. Analgesic intake and
cyclo-oxygenase inhibitors, eg alcohol consumption should be separated by 12 hours.
ibuprofen

Non-steroidal anti-inflammatory Antihypertensive drugs, NSAIDs can affect renal function and causes salt and water
drugs, eg ibuprofen especially beta-blockers retention which can antagonize antihypertensive drugs. This
(atenolol), ACE inhibitors only becomes a clinical problem if such analgesics are
(lisinopril) and diuretics prescribed for more than 5 days. Limit analgesic usage to this
timeframe for patients on antihypertensives.

NSAIDs, eg ibuprofen Methotrexate The effects of NSAIDs on renal perfusion are described above.
This increases the risk of methotrexate toxicity. Avoid NSAIDs
whenever possible in patients taking methotrexate.

NSAIDs, aspirin Selective serotonin Both drugs affect platelet function and increase the risk of post-
reuptake inhibitors, eg operative bleeding and bleeding from the gastro-intestinal tract.
fluoxetine Avoid concomitant use.

Aspirin Warfarin Increased risk of bleeding: displacement of warfarin from


protein-binding sites and both drugs affect haemostasis. Avoid
aspirin in patients taking warfarin.

Aspirin Clopidogrel Both drugs affect platelet function and therefore increase risk of
bleeding. Avoid analgesic doses of aspirin.

Aspirin, NSAIDs Systemic corticosteroids Both categories of drugs are ulcerogenic and increase the risk
of gastro-intestinal bleeding. Avoid aspirin and NSAIDs in
patients on systemic corticosteroids unless they are taking anti-
ulcer drugs.
Table 3. Synopsis of drug interactions with commonly prescribed analgesics.

should be compared with a 4−5 fold increase an excellent safety record. Most of the Adrenaline and B-adrenoreceptor blockers (Beta
when NSAIDs are used alone. In view of the concerns with local anaesthetic agents -blockers)
significance of this interaction, NSAIDs should and drug interactions reside with the Beta-blockers are widely
be prescribed with caution to patients taking vasoconstrictor component, in particular, used for the treatment of a range of
SSRI. The addition of a gastroprotective agent, adrenaline. This vasoconstrictor is an cardiovascular problems, in particular
eg a proton pump inhibitor (omeprazole), agonist at both A-1 and B2 adrenergic hypertension, angina and disorders of
should be considered if this combination receptors. A-1 stimulation causes cardiac rhythm. They are categorized as
is essential. Paracetamol can be used as an vasoconstriction in the skin and mucous being either selective (block B1 receptors
alternative. membranes, whilst B2 activity results in only) or non-selective, blocking both B1
vasodilatation in skeletal muscles. These and B2 receptors. Potential interactions
actions of adrenaline are short lived owing between adrenaline and beta-blockers
Drug interactions involving local to its short half-life in the bloodstream. depend upon the type of beta-blocker
anaesthetic agents A considerable amount of and the systemic absorption of adrenaline.
The three main local anaesthetic conjecture has surrounded many possible For example, an intravenous infusion of
drugs used in dental practice are lidocaine, drug interactions involving adrenaline adrenaline (0.016−0.032 μg), when given
prilocaine and articaine. All are amide agents and related compounds and these will be to hypertensive patients on propanolol
and, when used at normal doses, have discussed below. therapy (a non-selective beta-blocker),

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cause a significant rise in both systolic have a significant effect, notably in the patients at every visit. Many patients know
and diastolic blood pressure.15 The cardiovascular system, leading to an their drugs only by the trade name and it
dose of adrenaline used in this study increase in blood pressure. must then be checked in the Formulary.
is equivalent to 1−2 cartridges of Animal experiments have If in doubt, contact the patient’s general
adrenaline-containing local anaesthetic shown that such an interaction can occur, medical practitioner. There are certain
solution (25−50 μg). By contrast, when but only if the adrenaline dose exceeds categories of drugs that are more likely to
the same group of patients were treated the equivalent of seven cartridges of local be involved in drug interactions, notably
with a cardio-selective beta-blocker anaesthetic solution.19 It is recommended those that are extensively protein-bound,
(atenolol), there was only a slight rise in that no more than three cartridges of those with a low therapeutic index, and
blood pressure. adrenaline-containing local anaesthetic those drugs metabolized by the CYP450
Whilst these findings solution should be given at any one time enzymes. Drug interactions can be
were in hypertensive patients, similar to patients on tricyclic antidepressants.20 minimized in the dental setting by taking
observations have been found in health There is also a suggestion that chronic a full drug history and using alternative
volunteers; selective beta-blockers, such dosing of tricyclic antidepressants can drugs where indicated, or dose reductions.
as atenolol, metoprolol, and acebutolol, result in desensitization in response to
can block an adrenaline-stimulated adrenaline as a consequence of down
increase in blood pressure.16 regulation of post synaptic receptors.21 References
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important and can lead to significant
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inflammatory drug interactions. J Clin
at central synapse. The excess of and, for the most part, these are safe.
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9. Loke YK, Trivedi AN, Singh S. Meta-
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