Periodontology 2000, Vol. 44, 2007, 15–28  2007 The Authors.

Printed in Singapore. All rights reserved Journal compilation  2007 Blackwell Munksgaard
PERIODONTOLOGY 2000

Drug interactions important for

periodontal therapy
P A M E L A J. S I M S & K E V I N M. S I M S

Predicting and preventing adverse drug–drug inter- chostimulants such as Concerta or Adderall XR.
actions is important in optimizing desirable Although Concerta and Adderall XR are used to
pharmacological responses to medications and min- control the attention deficit or hyperactivity of an
imizing the risk of adverse or toxic reactions to those individual, a side-effect is central nervous system and
medications. Mechanisms or types of drug–drug cardiovascular stimulation, causing a patient to be
interactions can be categorized into five major areas: more difficult to sedate. In these situations, patients
• additive or synergistic pharmacological responses, require careful monitoring and titration of doses of
• antagonistic pharmacological responses, the sedating medication to achieve optimal results.
• incompatibility, If two drugs that are incompatible are administered
• common pharmacokinetic pathways, to patients, the patient may receive little or no benefit
• altered defense mechanism of the host. from either of the administered medications. Drug
The simplest mechanism of a drug interaction oc- incompatibilities can be the result of two drugs
curs when two or more drugs are administered that that are physically or chemically incompatible and
produce the same or similar pharmacological re- therefore result in degradation or precipitation of the
sponses in a patient. The response may be the de- drugs. When the antibiotic vancomycin is adminis-
sired pharmacological response or a side-effect of the tered parenterally through the same intravenous line
medications. For example, when opioid analgesics as the antibiotic ceftazidime, a cephalosporin, whe-
such as hydrocodone or oxycodone are prescribed for ther administered before or after the ceftazidime, a
pain and phenothiazine anti-emetics such as pro- precipitate will be formed which may occlude the
methazine are prescribed for nausea, each causes line. In this case, the incompatible drugs should not
sedation and will have at least an additive and be mixed together before administration or admin-
possibly a synergistic effect of potentially excessive istered in close proximity of time or route of
sedation. To minimize the risk to the patient of a drug administration to the patient. In the above example,
interaction resulting from an additive pharmacolo- the ceftazidime should be administered first and the
gical response, the prescriber should reduce the do- intravenous line should then be flushed before
ses of the interacting medications or choose alter- administering the vancomycin. Other drugs are
native medications that do not have similar desired incompatible because they form insoluble complexes
effect or side-effect pharmacology. when they are mixed together before administration
When two or more medications that produce or are given in close temporal proximity by the same
opposing or antagonistic pharmacological responses route of administration (23). Tetracycline antibiotics
are administered to patients, the desirable effects of such as doxycycline form insoluble complexes called
the medication may be difficult to achieve while chelates with divalent cations, such as calcium or
administering safe doses. Again, the opposing or magnesium (23). Therefore, if doxycycline is taken
antagonistic pharmacology may be the desired ef- with milk, other dairy products or antacids, a chelate
fects or a side-effect of the medications. For example, will form and the calcium and doxycycline will not be
patients treated for attention deficit disorder or absorbed in the gastrointestinal tract but will be
attention deficit and hyperactivity disorder may be eliminated in the feces. In this case, the medication
more difficult to sedate with benzodiazepines such as administration should be separated by an adequate
midazolam because of the stimulant effects of psy- amount of time or the medications should be

15
Sims & Sims

administered by different routes of administration. to cause these ventricular arrhythmias. These drug–
Tetracyclines, such as doxycycline, should not be drug interactions are the most difficult to manage
administered within 2 h of calcium sources such as and at times contraindicate the co-administration of
milk, other dairy products, calcium-fortified food or the medications.
beverages or antacids. Finally, some medications can alter conditions in
Drugs that utilize the same pharmacokinetic the patient which will cause the patient to respond
pathway or process for absorption, distribution, differently to other medications which they take or
protein binding, biotransformation, or excretion are are administered. The consequences are not the re-
at risk of drug–drug interactions. These pharmaco- sult of a direct drug–drug interaction, but are the
kinetic pathways include absorption of drugs from result of the condition of the patient being altered,
the site of administration to the bloodstream to be resulting in unwanted responses to other medica-
transported to the site of action; distribution of the tions. Patients taking antibiotics frequently experi-
drug from the bloodstream to the site of action; ence mild gastrointestinal disturbances, often the
protein binding of the drug, which affects the amount result of alterations in the normal gut flora. Those
of free (unbound) drug available in the body; meta- flora are necessary for the absorption of vitamin K.
bolism or biotransformation of the drug by the liver Therefore patients taking antibiotics frequently have
or other site in the body; and excretion of the drug by reduced absorption of vitamin K. As a result, if the
the kidney or other site in the body. If two medica- patient also takes the oral anticoagulant warfarin
tions compete for the same pharmacokinetic path- (Coumadin) they may experience increased bleed-
way, the pathway will process one drug and not the ing. Warfarin works as an anticoagulant by inhibiting
other, resulting in an altered response in the patient. the vitamin K-dependent clotting factors in the clot-
For example, the drug probenecid was designed to ting cascade. If patients have a reduced absorption of
occupy the tubular secretion site for organic acids in vitamin K as a result of antibiotic administration, this
the kidney. By administering probenecid to a patient, may result in increased anticoagulation when war-
their kidneys did not tubularly secrete other organic farin is administered. This interaction could lead to
acids such as penicillins, prolonging the length of hemorrhage. At times the co-administration of the
time that the penicillin stayed in the body. This drug two medications may be contraindicated and at
interaction was utilized to preserve the small supplies times the interaction may be managed by modifying
of penicillin antibiotics when treating the wounded the doses of the medications and carefully monitor-
during World War II and may be used today to pro- ing the patient. In the above example, a patient
long the effects of medications like Tamiflu, which should be cautioned to watch for increased bruising
is used to treat influenza. In addition, some medi- and bleeding and possibly to have increased monit-
cations can alter a pathway affecting the way in oring by their physician of their International Nor-
which the body would normally process another malized Ratio.
drug, causing the affected drug to disappear more Drug–drug interactions can occur when the inter-
quickly or to persist for a longer time in the body, acting medications are administered in more than
again altering the expected pharmacological one medication. The interacting medications may be
response in the patient. The non-sedating antihista- administered in a practice setting, prescribed, or
mines, terfenadine (Seldane) and astemizole (His- obtained over-the-counter or as a nutritional sup-
minal) were withdrawn from the market after plement or herbal remedy. The greater the number of
patients taking these medications concurrently with doses of different medications a patient takes, the
macrolide antibiotics such as erythromycin and greater the risk of drug–drug interactions. Drug–drug
clarithromycin (Biaxin) experienced dangerous and interactions have resulted in significant patient
sometimes fatal ventricular arrhythmias. Erythromy- morbidity, both toxicity and treatment failures, pa-
cin and clarithromycin are irreversible inhibitors of tient mortality, and product recall. The significance
cytochrome 3A4, an enzyme responsible for meta- of drug–drug interactions is greater for drugs with a
bolizing terfenadine and astemizole (30, 46). The narrow therapeutic range where the difference be-
increased and prolonged concentrations of the ter- tween efficacy and toxicity is very small; for those
fenadine and astemizole caused the arrhythmic drugs whose toxicities are more dangerous, or for
side-effects of those compounds to be pronounced. those drugs in which a therapeutic failure places the
In patients not taking interacting drugs, the terfena- patient at a great risk. A thorough understanding of
dine and astemizole were metabolized more effi- the mechanisms of and potential for drug–drug
ciently and did not reach the concentrations required interactions provides the practitioner with the

16
 Drug interactions important for periodontal therapy

greatest ability to optimize their patient’s care while

Table 2. Suggested prophylaxis regimens for ortho-
preventing untoward drug responses (5, 51, 75).
pedic patients (1, 18, 39, 43, 80)
When patients seek treatment from a periodontist,
three important times exist for the periodontist and Patients not allergic Patients allergic
to penicillin to penicillin
staff to determine the risk for and manage potential
drug–drug interactions. The first occurs when provi- Cephalexin, cephradine Clindamycin
ding pre-treatment prescriptions for antibiotic pro- or amoxicillin 600 mg orally 1 h
2 g orally 1 h before before the dental
phylaxis, pain control, or steroid therapy. The second procedure procedure
occurs during treatment of the patient in the office
setting. The third occurs when the patient is dis-
charged home with prescriptions for medications
used in the post-operative management of the pa- nutrients, vitamins and drugs. When those flora are
tient. diminished, patients experience a range of mild
gastrointestinal disturbances, such as nausea and
diarrhea, as well as a decreased ability to produce
Antibiotics, antifungals, and other vitamin K and enterohepatically recycle and absorb
anti-infective agents certain hormones, such as estrogen. As a result,
patients taking one or more doses of antibiotics are
Antibiotics are commonly prescribed before treat- at a risk of decreased absorption of vitamin K and
ment for periodontal patients undergoing invasive a resultant decreased production of vitamin
procedures who are at risk of developing endocar- K-dependent clotting factors, VII, IX, X, and possibly
ditis (13, 16, 67, 70), those who have had a recent V. This decline in clotting factors places the patient
orthopedic joint replacement (1, 18, 39, 43, 72, 80), at an increased risk of bleeding. This risk of bleeding
and those who have received a solid organ trans- is of particular significance if that patient is con-
plant. The prophylactic guidelines for at-risk patients currently taking the anticoagulant warfarin (Coum-
for endocarditis and recent orthopedic joint adin), which produces anticoagulation by reducing
replacement patients are listed in Tables 1 and 2, the production of those vitamin K-dependent clot-
respectively. Antibiotics are also administered during ting factors (4, 27, 78). This is an example of one
treatment and are prescribed following periodontal drug, the antibiotic, altering the condition of the
therapy. Antibiotics, in general, have the potential to patient, placing the patient at risk of adverse effects
alter normal gut flora. Those flora, Lactobacillus ac- from another drug, warfarin. Therefore, when pre-
idophilus and Proteus vulgaris, are important in scribed an antibiotic, patients taking warfarin should
preventing the overgrowth of opportunistic infec- be advised to monitor themselves for increased
tions in the gastrointestinal tract and are essential bruising and bleeding and notify you and their
for the production and/or absorption of certain treating physician immediately should this occur.
The longer the course of antibiotic therapy, the
greater the risk to the patient.
Table 1. Endocarditis prophylactic regimens for
dental procedures (13, 16, 70) A more controversial interaction is the potential
interaction of antibiotics with estrogen-containing
Standard general Amoxicillin Adults: 2.0 g products, including oral contraceptives. Reports
prophylaxis Children: 50 mg/kg
supporting and disputing this interaction exist (15,
1 h before procedure
19, 83). The proposed mechanism involves the en-
Allergic to Clindamycin Adults: 600 mg terohepatic recycling of the conjugated estrogen ex-
penicillin Children: 20 mg/kg
creted in the bile, reactivated by the gastrointestinal
1 h before procedure
flora and reabsorbed as active drug. Because today’s
Cephalexin* or Adults: 2.0 g oral contraceptives are low-dose or very-low-dose
cefadroxil* Children: 50 mg/kg
estrogen products, it is theorized that even small
1 h before procedure
decreases in estrogen absorption could render the pill
Azithromycin Adults: 500 mg
ineffective. Until this controversy is resolved, many
or Children: 15 mg/kg
clarithromycin 1 h before procedure pharmacologists and attorneys encourage practi-
tioners to inform patients of the potential for this
*Do not administer a cephalosporin to a patient who has a rapid hyper- interaction and to provide the patient with informa-
sensitivity reaction to penicillins.
tion that another form of contraception might be

17
Sims & Sims

indicated during any oral contraceptive cycle that has with penicillin treating the aerobic component, clin-
been interrupted by antibiotic therapy. damycin may be used alone as an alternative to treat
Certain antibiotics and antifungals prescribed by those mixed infections. Table 3 provides a more
periodontists have particular drug-interaction risks complete listing of these interacting medications and
for patients. The macrolide antibiotics, erythromycin recommendations for treatment.
and clarithromycin (Biaxin) are potent, irreversible Two groups of antibiotics, tetracyclines and
enzyme inhibitors of the important cytochrome quinolones, form chelates with divalent or trivalent
P-450 enzymes 3A4 and 1A2 (28, 46). Several of the cations found in the diet (23, 62, 74). These chelates
quinolone antibiotics including ciprofloxacin are are insoluble and therefore unable to be absorbed
reversible inhibitors of 3A4 and 1A2 (63, 66, 68, 76). across the mucosa into the bloodstream from the
The azole antifungals, ketaconazole and fluconazole, gastrointestinal tract, and are instead excreted in the
are also potent inhibitors of 3A4 and additionally 2C feces. As a result, the patient receives no benefit from
(28, 46, 71). Metronidazole is a weaker inhibitor of the antibiotic or the mineral. Tetracycline antibiotics
both 3A4 and 2C (28, 46). Inhibition of these enzymes such as tetracycline, doxycycline, and minocycline
has resulted in several fold increases in the concen- chelate with divalent cations such as calcium, mag-
tration of concurrently administered medications, nesium, and divalent iron (23, 62). Therefore, tetra-
which are metabolized by those enzymes. Inhibition cycline antibiotics should be taken by patients either
of the interacting drug’s metabolism results in in- 2 h before or 2 h after food, nutrients, mineral sup-
creased and prolonged drug concentrations and plements or antacids containing calcium, magnes-
therefore drug effects, which could result in increased ium or divalent iron. The importance of calcium in
adverse effects or toxicity. Interacting medications the diet of children for proper growth and develop-
with inhibitors of 3A4 include benzodiazepines such ment of their bones and teeth and in that of women
as midazolam and triazolam which periodontists may to prevent osteoporosis is greatly stressed by today’s
use for intravenous or oral sedation of patients; most health-care community. As a result many foods today
calcium channel blockers taken by patients for are fortified with calcium, causing the potential for
hypertension or arrhythmias; 3-hydroxy-3-methyl- this food–drug interaction to be very prevalent.
glutaryl-coenzyme A reductase inhibitors such as Quinolone antibiotics, such as Cipro (Ciprofloxa-
atorvastatin, lovastatin, and simvastatin used to treat cin), form chelates with trivalent cations such as zinc
hypercholesterolemia; cyclosporin and tacrolimus and iron. Studies conducted in hospitalized patients
used as immunosuppressants in the management of receiving nutrition through enteral tube feeding
patients following solid organ transplant or to treat found that when those patients were administered
autoimmune disorders such as rheumatoid arthritis quinolone antibiotics through the feeding tubes, very
or psoriasis; opioid analgesics which periodontists little to no antibiotic could be measured in the
may use during intravenous sedations or to manage bloodstream (14, 39, 40, 41, 62, 74). Therefore the
moderate to severe post-operative pain; and protease administration of quinolone antibiotics such as
inhibitors, the antiviral agents used in the manage- Cipro must be separated from the ingestion of
ment of human immunodeficiency virus infection mineral supplements containing zinc and iron by at
and acquired immune deficiency syndrome, such as least 2 h.
idinavir, nelfinivir, ritonavir, and saquinavir (46).
Interacting medications with inhibitors of 1A2 in-
Local anesthetics
clude theophylline used in the treatment of asthma
(46, 53, 63, 64, 68, 76). The macrolide antibiotic Studies show that the most common time for an
azithromycin (Zithromax) does not inhibit hepatic emergent or adverse event to occur in a dental office
enzymes and is a safe alternative in patients taking is around the time of the administration of the local
these interacting medications. Inhibition of 2C re- anesthetic. Local anesthetic carpules used in dentis-
sults in increased concentrations of the anticonvul- try frequently contain a vasoconstrictor in addition to
sant, phenytoin, and the anticoagulant, warfarin (46, the local anesthetic (10, 11, 26, 42, 84). Table 4 pro-
73, 78). Nystatin may be used as an alternative anti- vides a summary of currently available local anes-
fungal for mild oral fungal infections in patients who thetic solutions. The presence of the vasoconstrictor
are not immunocompromised, but true therapeutic provides the greater source for potential drug–drug
alternatives do not exist for treatment with the azole interactions than does the local anesthetic (25, 26, 29,
antifungals. Because metronidazole is generally used 34, 35, 38, 45, 50, 56, 57, 77, 81, 82). The vasocon-
to treat the anaerobic component of oral infections strictor is present to localize the injection to the site

18
 Drug interactions important for periodontal therapy

Table 3. Inhibition of cytochrome P450 enzymes by antibiotics, antifungals and anti-infectives which increase
interacting drug effects (46, 53, 58, 71)
Cytochrome Inhibitor Interacting drug
3A4 Macrolide antibiotics Benzodiazepines
Erythromycin Midazolam
Clarithromycin Triazolam
Azole antifungals Calcium antagonists
Ketaconazole Amlodipine
Fluconazole Diltiazem
Metronidazole Felodipine
Nifedipine
Verapamil
Cholesterol-lowering agents
Atorvastatin
Cervistatin
Simvastatin
Immunosuppressants
Cyclosporin
Tacrolimus
Opioid analgesics
Alfentanil
Antivirals
Idinavir
Nelfinivir
Ritonavir
Saquinavir
1A2 Macrolide antibiotics Theophylline
Erythromycin Antidepressants
Clarithromycin Amitriptyline
Clomipramine
Fluvoxamine
Imipramine
Antipsychotics
Clozapine
Haloperidol
2C Azole antifungals Anticonvulsant
Ketaconazole Phenytoin
Fluconazole Anticoagulant
Metronidazole Warfarin

Table 4. Local anesthetics

Trade name Generic name Available concentration Volume (ml)
Septocaine Articaine 4% with 1 : 100,000 epinephrine 1.7
Marcaine Bupivicaine 0.5% with 1 : 200,000 epinephrine 1.8
Sensorcaine
Xylocaine Lidocaine 2% with 1 : 50,000 epinephrine 1.8
2% with 1 : 100,000 epinephrine
Carbocaine Mepivicaine 3% (plain) 1.8
2% with 1 : 20,000 levonordefrin
Citanest Plain Prilocaine 4% (plain) 1.8
Citanest Forte 4% with 1 : 200,000 epinephrine

19
Sims & Sims

of administration and to decrease bleeding in the

Table 5. Interacting antidepressants (2, 21, 36, 50,
area. These effects are provided by the vasoconstric-
57, 79, 81, 82)
tor’s stimulation of the a-adrenergic receptors in the
peripheral vasculature. The two vasoconstrictors Norepinephrine/serotonin Selective
reuptake inhibitors norepinephrine
commonly used in dentistry are epinephrine
reuptake
and levonordefrin. Each of these agents stimulate inhibitors
both a- and b-adrenergic receptors, but to differing
Tricyclic antidepressants Atomoxetine
degrees. Epinephrine stimulates both a and b (both (Strattera)
b1 and b2) receptors equally (50/50) and levonor-
Tertiary amines Herbals
defrin stimulates a receptors three times as much as
b1 receptors (75/25). Stimulation of the a receptor Amitriptyline (Elavil) St John’s Wort
provides peripheral vasoconstriction while stimula- Clomipramine (Anafranil)
tion of the b receptors in the heart (b1) increases
Doxepin (Adapin, Sinequan)
heart rate, and stimulation of b2 receptors in the
peripheral blood vessels causes peripheral vasodila- Imipramine (Tofranil)
tion. Therefore, epinephrine has a greater effect on Trimipramine (Surmontil)
heart rate than levonordefrin. The drug interactions Secondary amines
with the vasoconstrictors are based upon the
Amoxapine (Asendin)
presence of other medications which also affect these
a- and b-adrenergic receptors and occur with drugs Desipramine
in four categories: other central nervous system (Norpramin, Pertofrane)
stimulants; antidepressants; antipsychotics and b- Maprotiline (Ludiomil)
adrenergic antagonists (35, 45, 49, 50, 56, 57, 81, 82). Nortriptyline (Aventyl, Pamelor)
Over-the-counter and prescription oral decon-
Protriptyline (Vivactil)
gestants, prescription appetite suppressants, oral
stimulants used to treat fatigue and psychostimulants Miscellaneous
used in the treatment of attention deficit disorder, Amoxapine (Asendin)
attention deficit hyperactivity disorder and narco-
Mirtazapine (Remeron)
lepsy all have additive effects with the stimulant
properties of the vasoconstrictors. Most of these or- Venlaxafine (Effexor)
ally administered sympathomimetic agents act indi-
rectly or act in a mixed manner (having both direct
and indirect actions). Indirect agents, such as
amphetamines, cause the release of norepinephrine mias and hypertension. With levonordefrin, the pri-
from the nerve terminal while mixed acting agents, mary effect is a prolongation of peripheral vascular
such as the herbal ephedrine, have some effect on the resistance resulting in hypertension. The herbal
receptors and cause some release of norepinephrine. product St John’s Wort often may also have this ef-
Because norepinephrine has a greater effect on a fect. Strattera (Atomoxetine) is a new agent used in
than b receptors (90/10), indirect agents cause the treatment of attention deficit disorder and
an increase in blood pressure, as a result of vaso- attention deficit hyperactivity disorder. Atomoxetine
constriction, which is more pronounced when works by selective inhibition of the presynaptic re-
levonordefrin is administered compared to the uptake of norepinephrine. As a result the interaction
administration of epinephrine (50, 81, 82). of atomoxetine with the vasoconstrictor epinephrine
Antidepressants work by blocking the reuptake of is more profound than the interaction of other anti-
norepinephrine and/or serotonin at the nerve syn- depressants because it selectively inhibits the reup-
apses. As a result, patients taking antidepressants take of norepinephrine and not serotonin and results
which block the reuptake of norepinephrine experi- in a greater risk of elevations in heart rate and blood
ence prolonged effects of epinephrine and levonor- pressure. Again, the interaction of atomoxetine with
defrin administered in the local anesthetic (2, 31, 36, levonordefrin is less profound because it is the result
50, 56, 57, 79, 81, 82). In the case of epinephrine, this of the more predominant peripheral vasoconstriction
results in increased and prolonged elevation of heart and has less effect on cardiac rate and contractility.
rate, cardiac contractility, and peripheral vascular Interacting antidepressants and herbals are listed in
resistance. This places the patient at risk of arrhyth- Table 5.

20
 Drug interactions important for periodontal therapy

One of the pharmacological effects of antipsych- hypertensive crisis or a cerebrovascular accident. In

otics and phenothiazine anti-emetics is the blockade patients receiving selective b-adrenergic antagonists
of a receptors, the receptors responsible for periph- the effects are less pronounced with epinephrine, but
eral vasoconstriction. As a result, when patients tak- may still persist with levonordefrin, as levonordefrin
ing antipsychotics are administered vasoconstrictors, does not stimulate the b2 receptors responsible for
particularly epinephrine, the b-adrenergic agonist producing peripheral vasodilation to balance the
effects predominate, causing an increased heart rate a-mediated peripheral vasoconstriction (48, 50, 56,
and cardiac contractility accompanied by peripheral 57, 81). Selective and non-selective b-adrenergic
vasodilation. This results in the patient experiencing antagonists are listed in Table 7. Vasoconstrictors
orthostatic hypotension and reflex tachycardia (50, should be used with caution in patients treated with
56, 57, 81, 82). If the patient is also being treated with these agents.
antihypertensive agents, the effects of those antihy- Historically, it has been reported that vasocon-
pertensive agents on the patient’s blood pressure will strictors should not be administered to patients who
be potentiated. Because these antipsychotic and anti- are taking monoamine oxidase inhibitors, such as the
emetic agents block the a receptors responsible for antidepressants, phenelzine (Nardil), Traylcypro-
the effectiveness of the vasoconstrictor for dental mine (Parnate), and the antiparkinson drug selegi-
surgery, utilizing vasoconstrictors in patients taking line (Eldepryl) (56, 57). More recent research has
these agents may be poorly effective. Interacting anti- demonstrated that the enzyme monoamine oxidase
psychotics and anti-emetics are listed in Table 6. is responsible for metabolizing indirect and mixed-
b-Adrenergic antagonists are used in the treatment acting sympathomimetic compounds, not the direct
of hypertension, arrhythmias, migraine prophylaxis, acting agents used as dental vasoconstrictors, there-
and mitral valve prolapse. The primary pharmacolo- fore inhibition of monoamine oxidase does not cause
gical effect is achieved through blockade of b recep- a significant increase in or prolong the presence of
tors. Non-selective b-adrenergic antagonists block the vasoconstrictor (50).
both b1 and b2 receptors, while selective b-adrener-
gic antagonists block primarily b1 receptors. When
epinephrine or levonordefrin are administered to Behavior-modifying agents
patients receiving non-selective b-adrenergic antag-
onists, those vasoconstrictors cause unopposed a Many periodontists employ behavior-modifying
receptor mediated peripheral vasoconstriction (48, agents in the treatment of their patients. These
50, 56, 57, 81). This results in an initial hypertensive agents are used to assure that the patient is calm,
episode in the patient followed by bradycardia. If relaxed and, if necessary, can co-operate with the
pronounced enough, these effects can lead to a procedure being performed. The majority of agents

Table 7. Interacting b-adrenergic antagonists (21, 50,

Table 6. Interacting antipsychotics and antiemetics 56, 57, 81, 82)
(21, 50, 57, 81, 82)
Selective b-1 Non-selective
Phenothiazines Miscellaneous antagonists b-antagonists
Acetophenazine (Tindal) Thiothixene (Navane) Acebutolol (Sectral) Carteolol (Cartrol)
Chlorpromazine (Thorazine) Haloperidol (Haldol) Atenolol (Tenormin) Carvedilol (Coreg)
Fluphenazine (Prolixin) Clozapine (Clozaril) Betaxolol (Kerlone) Nadolol (Corgard)
Mesoridazine (Serentil) Loxapine (Loxitane) Bisoprolol (Zebeta) Penbutolol (Levatol)
Perphenazine (Trilafon) Molindone (Moban) Metoprolol (Lopressor) Pindolol (Visken)
Prochlorperazine (Compazine) Risperdal (Risperidone) Propranolol (Inderal)
Promazine (Sparine) Zyprexa (Olanzapine) Sotalol (Betapace)
Promethazine (Phenergan) Seroquel (Quetiapine) Timolol (Blocadren)
Thioridazine (Mellaril) Labetalol
Trifluoperazine (Stelazine) (Trandate, Normodyne)

21
Sims & Sims

used for oral or intravenous behavior modification or

Table 8. Inhibitors of CYP3A4 that reduce the
sedation are benzodiazepines. These agents provide
metabolism of benzodiazepines and increase their
anxiolysis, sedation, skeletal muscle relaxation with effect (32, 46, 53, 58, 71)
some degree of anterograde amnesia. Accompanying
Grapefruit juice Cannabinoids
the depression of the central nervous system is the
risk of respiratory depression (12). Benzodiazepines Azole antifungals Nefazodone
are metabolized by the cytochrome P450 enzymes, Fluconazole Selective serotonin
Itraconazole reuptake inhibitors
primarily 3A4 and 1A2 and are therefore susceptible Ketoconazole Fluoxetine
to pharmacokinetic drug interactions (28, 45, 46, 50). Miconazole Fluvoxamine
As a result, agents that induce those enzymes will Sertraline
reduce the effectiveness of the benzodiazepines and Metronidazole Zafirlukast
agents that inhibit those enzymes will increase the
Antiarrhythmics Quinolones
effects, possibly leading to toxicity. The most
Amiodarone Norfloxacin
common inducers of both 3A4 and 1A2 are the Mibefradil
older anticonvulsants, phenytoin, phenobarbital and
Macrolides Antiviral (protease inhibitors)
carbamazepine, used in the treatment of seizure Erythromycin Indinavir
disorders and neurogenic or neuropathic pain as well Clarithromycin Nelfinavir
as antibiotics used in the treatment of tuberculosis, Troleandomycin Ritonavir
rifampin, and rifabutin (46). In addition, smoking is Siquinavir
the most common inducer of 1A2 (46). Therefore,
patients treated with these anticonvulsants or anti-
biotics or those who smoke will require higher doses
of benzodiazepines to achieve adequate behavior gastrointestinal problems are all at risk of increased
control. The use of benzodiazepines with longer half- and prolonged effects of benzodiazepines and may
lives may be beneficial. Benzodiazepine doses must require substantially smaller doses. These interac-
be carefully titrated and the patient closely monit- tions are listed in Table 8.
ored, preferably with pulse oximetry and automated Any pharmacological agent which is used by the
non-invasive blood pressure monitoring, for exces- periodontist to calm or sedate a patient will have the
sive sedation and respiratory depression. Because potential to be additive in effect with any other
benzodiazepines can block the hypercapneic drive, medications that the patient takes which also cause
oxygen saturations <90% should be avoided. If sedation. Other sedating agents include the sedating
patients become compromised they should be awa- antihistamines, antidepressants, antipsychotics,
kened and oxygenated and if non-arousable or per- anxiolytics, anticonvulsants, sedative/hypnotics, and
sistently compromised, treated with flumazenil (Ro- cough suppressants (45, 50). The herbals, kava and
mazicon), which is the benzodiazepine reversal valerian, can also increase sedation. Therefore, pa-
agent. Medications that inhibit these enzymes will tients who are administered nitrous oxide, oral, or
increase and prolong the effects of the benzodiaze- intravenous conscious sedation should be carefully
pines, placing the patient at risk for excessive seda- interviewed regarding other sedating medication or
tion and/or respiratory depression (20, 45). As herbals they may be taking. If other sedative medi-
discussed previously, the macrolide antibiotics cations are being taken by the patient, the doses of
erythromycin and clarithromycin and the azole behavior-modifying agents should be reduced and
antifungals itraconazole, ketaconazole, and flucon- the patient should be closely monitored.
azole are potent inhibitors and metronidazole is a
less potent inhibitor of the metabolism of ben-
zodiazepines, resulting in an increased and Opioid and central analgesics
prolonged response. In addition, patients who are
treated with the selective serotonin reuptake inhib- Patients managed with opioid analgesics during
itor antidepressants such as fluoxetine (Paxil) and conscious sedation or those prescribed opioid
fluvoxamine (Luvox), as well as the antidepressant analgesics following treatment to manage post-pro-
nefazodone (Serzone); patients treated with the cedural pain, are at risk of serious drug–drug inter-
protease inhibitor antivirals, indinavir, nelfinavir, ri- actions (24, 44). Fentanyl, frequently administered
tonavir and squinavir; and patients taking prescribed with midazolam for intravenous sedation, is meta-
or over-the-counter cimetidine or omeprazole for bolized by the cytochrome P450 enzyme 3A4 (28, 46).

22
 Drug interactions important for periodontal therapy

Fentanyl metabolism is inhibited by the protease include the cognitive-behavioral symptoms of con-
inhibitors, indinavir, nelfinavir, ritonavir, and squin- fusion/disorientation (51%) and agitation/irritability
avir, as well as the H1 antagonist, cimetidine, (34%); autonomic nervous system symptoms of
resulting in increased and prolonged effects. For hyperthermia (45%), diaphoresis (45%), sinus
these patients, fentanyl doses should be reduced and tachycardia (36%), and hypertension (35%); as well
titration should be carefully conducted with thor- as neuromuscular symptoms of dilated pupils (28%),
ough patient monitoring. Rifampin induces the tachypnea (26%), and nausea (23%) (9, 52, 65). The
metabolism of fentanyl, shortening and reducing its most profound interactions occur in patients taking
effects, resulting in patients requiring higher doses. the selective serotonin reuptake inhibitors, fluvox-
Again, patients should be titrated carefully and amine (Luvox), fluoxetine (Prozac), paroxetine
monitored closely. Most of the opioid analgesics (Paxil), sertraline (Zoloft), citalopram (Celexa)
including codeine, fentanyl, hydrocodone, meperi- and escitalopram (Lexapro) and depend upon the
dine, methadone, oxycodone, propoxyphene, and the dose and duration of therapy of the interacting drugs.
central analgesic, tramadol, are metabolized by 2D6 Other agents that block the reuptake of both sero-
(28, 46). Inhibition of their metabolism by the 2D6 tonin and norepinephrine can invoke the syndrome
inhibitors ritonavir or cimetidine increases the to a lesser degree and include most antidepressant
opioid’s effect. PatientsÕ opioid doses should be de- medications and the herbal preparation St John’s
creased. Inducers of 2D6 including the anticonvul- Wort. Treatment of serotonin syndrome requires re-
sants, carbamazepine, phenobarbital, phenytoin, moval of the interacting drug, in this case discon-
primidone, and the antibiotic rifampin decrease the tinuation of meperidine, and supportive therapy for
opioid’s efficacy (46). For these patients, opioid doses the patient (9, 65). In addition to this, meperidine is
may need to be higher. These opioid–drug interac- contraindicated in patients taking monoamine oxid-
tions are listed in Table 9. ase inhibitors within 14 days. The monoamine oxid-
Meperidine, when administered to patients ase inhibitors currently on the market include the
receiving other serotonergic medications, including antidepressants, phenelzine (Nardil), traylcypro-
most antidepressants and many other medications mine (Parnate) and the antiparkinson drug selegi-
used to treat behavior disorders, can produce sero- line (Eldepryl). If meperidine is administered to a
tonin syndrome (8, 37, 47, 52, 59, 65, 66). Serotonin patient within 14 days of taking a monoamine oxid-
syndrome is the result of excessive production and ase inhibitor, a serious and life-threatening condition
maintenance of serotonin at the nerve synapses. It is called hyperphenylalaninemia can occur.
characterized by a constellation of symptoms in three Opioid and central analgesics have additive seda-
broad categories: cognitive-behavioral, those invol- tive and respiratory depressant effects with other
ving the autonomic nervous system, and those which central nervous system depressants such as seda-
are neuromuscular. The most prevalent symptoms ting antihistamines, antidepressants, antipsychotics,
anxiolytics, anticonvulsants, sedative/hypnotics, and
cough suppressants (44, 61). The herbals, kava and
Table 9. Inhibitors of CYP2D6 that reduce the valerian can also increase the sedation by opioids.
metabolism of opioids and increase their effect (46, Opioid analgesics have several additive to synergistic
53, 58, 71)
effects with phenothiazines, used as antipsychotics,
Cimetidine Selective serotonin antihistamines or antiemetics. In addition to the
reuptake inhibitors central nervous system and respiratory depression,
Fluoxetine which is synergistic rather than additive in this
Paroxetine
combination, the a receptor blockade caused by the
Sertraline
phenothiazines and the peripheral vasodilation
Antiarrhythmics Antidepressants caused by the opioid analgesics result in profound
Amiodarone Clomipramine
Mibefradil Desipramine
orthostasis in patients, placing them at risk of pos-
Propafenone tural instability and resulting falls. Should a patient
Quinidine experience respiratory depression and arrest on this
Antipsychotics Antivirals combination, resuscitation may be difficult because
Fluphenazine Ritonavir of the inability of pressor agents to affect the a re-
Haloperidol ceptors and reverse the profound peripheral vasodi-
Thioridazine lation. Periodontists should consider this interaction
when prescribing opioids in combination with phe-

23
Sims & Sims

nothiazines for the management of post-operative

Hydrochlorothiazide (Hydrodiuril, Esidrix, Oretic)

Trichlormethiazide (Metahydrin, Naqua, Diurese)

pain and nausea as separate agents or in the mar-
keted combination of meperidine and phenergan,
Mepergan Fortis. Table 10 lists the interacting

Methyclothiazide (Enduron, Aquatensen)

Hydroflumethiazide (Diucardin, Saluron)
phenothiazines.

Bendroflumethiazide (Naturetin)

Metolazone (Zaroxolyn, Mykrox)

Non-selective non-steroidal

Quinethazone, (Hydromox)
anti-inflammatory drugs

Chlorothiazide (Diuril)

Polythiazide (Renese)
Benzthiazide (Exna)

Indapamide (Lozol)
Selective (cyclo-oxygenase II inhibitors) and non-

Thiazide diuretics
selective non-steroidal anti-inflammatory drugs are
frequently used in the management of the mild to
moderate pain and inflammation associated with
periodontal procedures. All non-steroidal anti-
inflammatory drugs reduce renal blood flow and
therefore have the potential to reduce the efficacy of
drugs used to treat hypertension that act through a

Ethacrynic acid (Edecrin),

renal mechanism. Caution should be used in pre-

Torsemide (Demadex)
Bumetanide (Bumex),
scribing non-steroidal anti-inflammatory drugs for

Furosemide (Lasix),
Table 11. Antihypertensive agents whose effects are reduced by nonsteroidal antiinflammatory drugs
patients whose hypertension is being treated by

Loop diuretics
angiotensin-converting enzyme inhibitors such as
benazapril, captopril, enalapril, lisinopril, etc., b-
adrenergic antagonists such as atenolol, metoprolol,
propranolol, etc., loop diuretics such as bumetanide,
furosemide, etc., thiazide diuretics such as hydro-
chlorothiazide, and the new angiotensin II receptor

Labetalol (Normodyne,
(Lopressor, Toprol XL)
antagonists such as candesartan, eprosartan, iresar-

Propranolol (Inderal)

Timolol (Blocadren),
Atenolol (Tenormin)

Penbutolol (Levatol)
tan, losartan, etc. The most significant interaction
Acebutolol (Sectral)

Bisoprolol (Zebeta)
Betaxalol (Kerlone)

Carteolol (Cartrol)

Sotalol (Betapace)
Nadolol (Corgard)

Pindolol (Visken)
occurs in patients taking angiotensin converting
enzyme inhibitors or angiotensin II receptor antag-
Metoprolol

Trandate)
b-blockers

onists or in patients on those medications in com-

bination with other antihypertensives. Table 11 lists
the interacting drugs.
Angiotensin II receptor

Candesartan (Atacand)

Telmisartan (Micardis)
Eprosartan (Teveten)
Irbesartan (Avapro)

Valsartan (Diovan)
Losartan (Cozaar)

Table 10. Interacting phenothiazines

Acetophenazine (Tindal)
antagonists

Chlorpromazine (Thorazine)
Fluphenazine (Prolixin)
Mesoridazine (Serentil)
Lisinopril (Prinivil, Zestril)

Perphenazine (Trilafon)
Angiotensin converting

Prochlorperazine (Compazine)
Fosinopril (Monopril)
Benazepril (Lotensin)

Trandolapril (Mavik)
Quinapril (Accupril)
Captopril (Capoten)

Moexipril (Univasc)
Enalapril (Vasotec)
enzyme inhibitors

Promazine (Sparine)
Ramipril (Altace)

Promethazine (Phenergan)
Thioridazine (Mellaril)
Trifluoperazine (Stelazine)

24
 Drug interactions important for periodontal therapy

This non-steroidal anti-inflammatory drug-medi- Acetaminophen

ated reduction in renal blood flow also reduces the
clearance of lithium, methotrexate, and cyclosporin – Acetaminophen is one of the most commonly self-
increasing their concentrations in the patient administered and prescribed medications. As an over-
frequently resulting in serious toxicities (7, 17, 69). the-counter product, acetaminophen is taken for pain
Non-steroidal anti-inflammatory drugs should gen- and fever, and in combination products for discom-
erally be avoided in those patients. forts related to colds, allergies, and sinus problems.
Non-selective non-steroidal anti-inflammatory Acetaminophen is most commonly prescribed in
drugs, through their effects on cyclo-oxygenase I, combination products with opioid analgesics. For
inhibit platelet aggregation, reducing clot forma- several decades reports of interactions between acet-
tion. These agents are contraindicated in patients aminophen and warfarin have been reported but the
taking other anti-platelet drugs such as dipyrida- mechanism has not been understood (3). Recent re-
mole (Persantine), ticlodipine (Ticlid), anagr- ports indicate that acetaminophen causes a dose-
elide (Agrylin), clopidogrel (Plavix), and dependent increase in the International Normalized
celostazol (Pletal) or anticoagulants such as Ratio of patients taking warfarin (6, 22, 33). Hemor-
warfarin (Coumadin), anissindione (Miradon), or rhages may result according to the intensity of anti-
dicumarol, because of the risk of increased bleeding coagulation, particularly when the International
(44, 54, 55, 60). Non-selective non-steroidal anti- Normalized Ratio is greater than 4.0. Patients ingesting
inflammatory drugs should be used cautiously in 9,100 mg acetaminophen per week were 10 times
patients taking aspirin or other salicylates because more likely to have an International Normalized Ratio
those medications also inhibit platelet aggregation greater than 6 (22). Potential mechanisms include the
and therefore reduce clot formation. Herbal saturation of cytochrome P450 enzymes responsible
products, including dong quai, garlic, gingko, and for metabolizing warfarin by the higher prolonged
ginseng, have anti-platelet effects and may also concentrations of acetaminophen resulting from these
potentiate the platelet inhibition of non-steroidal large doses. For this reason, acetaminophen alone or
anti-inflammatory drugs. Interacting antiplatelet in combination with opioids should be used cautiously
and anticoagulant drugs and herbals are listed in in warfarin anticoagulated patients. Periodontists
Table 12. should be familiar with the acetaminophen content of
opioid combination products and prescribe the lowest
dose possible in warfarin anticoagulated patients.

Table 12. Non-steroidal anti-inflammatory drugs

potentiate bleeding when administered with the fol- Emergencies in the dental office
lowing agents

Potentiates the effects of anticoagulants Patients who are taking medications which enhance
sexual performance such as Viagra, Cialis, and
Warfarin (Coumadin)
Levitra, and who experience chest pain while in the
Anisindione (Miradon)
dental office, should not be treated with nitroglycerin
Dicumarol
or nitroglycerin-containing products. Viagra (silde-
Potentiates the effects of other antiplatelet drugs nafil citrate), Cialis (tadalafil), and Levitra (vardenafil)
Dipyridamole (Persantine) work by vasodilation. When nitroglycerin is admin-
Ticlodipine (Ticlid) istered, it increases the vasodilation causing a preci-
Anagrelide (Agrylin) pitous fall in blood pressure that can result in death.
Clopidogrel (Plavix) Patients taking Viagra within the previous 24 h, Cialis
Cilostazol (Pletal) within the previous 4 days or Levitra within the pre-
vious 24 h who experience chest pain while in the
Potentiates the antiplatelet effects of some herbs
dental office should not be administered nitroglyc-
Dong quai erin products but may be administered oxygen and
Garlic opioids, if necessary, for pain, and should be trans-
Gingko ported immediately by the emergency medical ser-
Ginseng vices to the nearest hospital emergency room for
treatment. In addition, the metabolism of Viagra,

25
Sims & Sims

Cialis, and Levitra by the cytochrome P450 enzyme 12. D’Eramo EM. Morbidity and mortality with outpatient
3A4 is inhibited by several drugs used by periodon- anesthesia: the Massachusetts experience. J Oral Maxillo-
fac Surg 1992: 50: 700–704.
tists. These 3A4 inhibitors include the azole antifun-
13. Dajani AS, Taubert KA, Wilson W, Bolger AF, Bayer A,
gals such as Diflucan (fluconazole) and Nizoral Ferrieri P, Gewitz MH, Shulman ST, Nouri S, Newburger
(ketoconazole), the macrolide antibiotic erythromy- JW, Hutto C, Pallasch TJ, Gage TW, Levison ME, Peter G,
cin and Biaxin (clarithromycin), the quinolone Zuccaro G. Prevention of bacterial endocarditis. J Am Med
antibiotic, Cipro (ciprofloxacin), the tetracycline Assoc 1997: 277: 1794–1801.
14. Depperman KM, Lode H. Fluoroquinolones: interaction
antibiotic doxycycline and the non-steroidal anti-
profile during enteral absorption. Drugs 1993: 45(Suppl. 3):
inflammatory, Voltaren (diclofenac). 65–72.
15. Derossi SS, Hersh EV. Antibiotics and oral contraceptives.
Dent Clin North Am 2002: 46: 653–664.
Conclusion 16. Durack DT. Antibiotics for prevention of endocarditis
during dentistry: time to scale back? Ann Intern Med 1998:
129: 829–831.
The prescribing of antibiotics, analgesics, or anti-
17. Ellison NM, Servi RJ. Acute renal failure and death fol-
emetics and the administration of local anesthetics lowing sequential intermediate-dose methotrexate and
and behavior-modifying agents to patients place the 5-FU: a possible adverse effect due to concomitant indo-
periodontist in a situation where drug–drug interac- methacin administration. Cancer Treat Rep 1985: 69: 342–3.
tions may have an important impact on the success 18. Fitzgerald RH, Jacobson JJ, Luck JV, Nelson CL, Nelson JP,
Osmon DR, Pallasch TJ. Antibiotic prophylaxis for dental
of that drug therapy and on patient treatment and
patients with total joint replacements. J Am Dent Assoc
care. A complete understanding of the interacting 1997: 128: 1004–1008.
drugs and the mechanisms for those interactions is 19. Gibson J, McGowan DA. Oral contraceptives and antibiot-
important for the periodontist to optimally manage ics: important considerations for dental practice. Br Dent J
their patient (51, 75). 1994: 177: 419–422.
20. Goho C. Oral midazolam–grapefruit juice drug interaction.
Pediatr Dent 2001: 234: 365–366.
21. Goulet JP, Perusee R, Turcotte JY. Contraindications to
References vasoconstrictors in dentistry: Part III, Pharmacologic
interactions. Oral Surg Oral Med Oral Pathol 1992: 74:
1. American Dental Association; American Academy of 692–697.
Orthopaedic Surgeons. Advisory statement antibiotic pro- 22. Greer M, Ross M. Acetaminophen may intensify warfarin
phylaxis for dental patients with total joint replacements. anticoagulation. Samford University Global Drugs Infor-
J Am Dent Assoc 1997: 128: 1004–1008. mation Service’s Current Literature and Information for
2. Anderson LD, Reagan SE. Local anesthetics and vasocon- Pharmacists 1998: 2: 1–2.
strictors in patients with compromised cardiovascular 23. Gugler R, Allgayer H. Effects of antacids on the clinical
systems. Gen Dent 1993: 41: 161–164. pharmacokinetics of drugs. An update. Clin Pharmacokinet
3. Antlitz AM, Mead JA, Tolentino MA. Potentiation of oral 1990: 18: 210–219.
anticoagulant therapy by acetaminophen. Curr Ther Res 24. Haas DA. Adverse drug interactions in dental practice:
1968: 19: 501–507. interactions associated with analgesics, Part III in a series.
4. Bandrowsky T, Varano AA, Borris TJ, Marcaning HW. J Am Dent Assoc 1999: 130: 397–407.
Amoxicillin-related postextraction bleeding in an antico- 25. Haveles EB. Local anesthetics a review. Dent Hyg News
agulated patient with tranexamic acid rinses. Oral Surg 1994: 7: 3–7.
Oral Med Oral Pathol Oral Radiol Endod 1996: 82: 610–612. 26. Hersh EV. Local anesthetics in dentistry: clinical consid-
5. Becker DE. Drug interactions in dental practice: a summary erations, drug interactions, and novel formulations. Com-
of facts and controversies. Compendium 1994: 15: 1228– pend Contin Educ Dent 14: 1020–1030.
1244. 27. Hersh EV. Adverse drug interactions in dental practice:
6. Bell WR. Acetaminophen and warfarin, undesirable syn- interactions involving antibiotics, Part II of a Series. J Am
ergy. J Am Med Assoc 1998: 279: 702–703. Dent Assoc 1999: 130: 236–251.
7. Bier JA. Letters, An abstract error? J Am Dent Assoc 1993: 28. Hersh EV, Moore PA. Drug interactions in dentistry, the
124: 10–12. importance of knowing your CYPs. J Am Dent Assoc 2004:
8. Bodner RA, Lynch T, Lewis L, Kahn D. Serotonin syndrome. 135: 298–309.
Neurology 1995: 45: 219–223. 29. Hersh EV, Helpin ML, Evans OB. Local anesthetic mortal-
9. Brown TM, Skop BP, Mareth TR. Pathophysiology and ity: report of case. J Dent Child 1991: Nov–Dec: 489–491.
management of the serotonin syndrome. Ann Pharmac- 30. Honig PK, Wortham DC, Zamani K, Cantilena LR. Com-
other 1996: 30: 527–533. parison of the effect of the macrolide antibiotics erythro-
10. Ciancio SG. Drugs in dentistry, local anesthetics: the mycin, clarithromycin and azithromycin on terfenadine
amides. Dent Manage 1991: May: 16–18. steady state pharmacokinetics and electrocardiographic
11. Ciancio SG. Drugs in dentistry, local anesthetics: the esters. parameters Drug Invest 1994: 7: 148–156.
Dent Manage 1991: April: 50–51.

26
 Drug interactions important for periodontal therapy

31. Huangfu D, Goodwin WB, Guyenet PG. Sympatholytic ef- 53. Nix DE, DeVito JM, Whitbread MA, Schentag JJ. Effect of
fect of tricyclic antidepressants: site and mechanism of multiple dose oral ciprofloxacin on the pharmacokinetics
action in anesthetized rats. Am J Physiol 1995: 268: R1429– of theophylline and indocyanine green. J Antimicrob
R1441. Chemother 1987: 19: 263–269.
32. Hulisz D, Miller K. Update on quinolone drug interactions. 54. O’Callaghan JW, Thompson RN, Russell AS. Combining
Am Pharm 1990: NS30: 34–36. NSAIDs with anticoagulants: yes and no. Can Med Assoc J
33. Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. 1984: 131: 857–859.
Acetaminophen and other risk factors for excessive war- 55. O’Reilly RA, Levy G. Pharmacokinetic analysis of potenti-
farin anticoagulation. J Am Med Assoc 1998: 279: 657–662. ating effect of phenylbutazone on anticoagulant action
34. Janowsky EC. Pharmacologic aspects of local anesthetic of warfarin in man. J Pharmaceut Sci 1970: 59: 1258–
use, anesthesiology. Clin North Am 1990: 8: 1–25. 1261.
35. Jastak JT, Yagiela JA. Vasoconstrictors and local anesthesia: 56. Perusse R, Goulet JP, Turcotte JY. Contraindications to
a review and rationale for use. J Am Dent Assoc 1983: 107: vasoconstrictors in dentistry: Part I. Oral Surg Oral Med
623–630. Oral Pathol 1992: 74: 679–686.
36. Keene Jr JJ, Galasko GT, Lanam F. Antidepressant use in 57. Perusse R, Goulet JP, Turcotte JY. Contraindications to
psychiatry and medicine: importance for dental practice. vasoconstrictors in dentistry: Part II. Oral Surg Oral Med
J Am Dent Assoc 2003: 134: 71–79. Oral Pathol 1992: 74: 687–691.
37. Kline SS, Mauro LS, Scala-Barnett DM, Zick D. Drug 58. Polk RE. Drug–drug interactions with ciprofloxacin and
experience, serotonin syndrome versus neuroleptic malig- other fluoroquinolones. Am J Med 1989: 87: 76S–81S.
nant syndrome as a cause of death. Clin Pharm 1989: 8: 59. Reynolds RD. Serotonin syndrome: what family physi-
510–514. cians need to know. Am Fam Physician 1995: 52:
38. Levy SM, Baker KA. Considerations in differential diagnosis 1263–1271.
of adverse reactions to local anesthetic: report of case. J Am 60. Rhodes RS, Rhodes PJ, Klein C, Sintek CD. A warfarin–
Dent Assoc 1986: 113: 271–274. piroxicam drug interaction. Drug Intell Clin Pharm 1985:
39. Little JW. Managing dental patients with joint prostheses. 19: 556–558.
J Am Dent Assoc 1994: 125: 1374–1379. 61. Robinson EM. Death in the dental chair. J Forensic Sci 1989:
40. Lomaestro BM, Bailie GR. Quinolone–cation interactions: a 34: 377–380.
review. DICP 1991: 25: 1249–1258. 62. Romankiewicz JA. Effects of antacids on gastrointestinal
41. Lomaestro BM, Bailie GR. Absorption interactions with absorption of drugs. Prim Care 1976: 3: 537–660.
fluoroquinolones. 1995 update. Drug Saf 1995: 12(5): 63. Rybak MJ, Bowles SK, Chandrasekar PH, Edwards DJ.
314–333. Increased theophylline concentrations secondary to
42. Malamed SF. Local anesthetics: dentistry’s most important ciprofloxacin. Drug Intell Clin Pharm 1987: 21: 879–881.
drugs. J Am Dent Assoc 1994: 125: 1571–1576. 64. Schwartz J, Jauregul L, Lettierl J, Bachmann K. Impact of
43. Mason JC, Dollery CT, So A, Cohen J, Bloom SR, Bulpitt C, ciprofloxacin on theophylline clearance and steady-state
Russell-Jones R, Oakley DM. An infected prosthetic hip, is concentrations in serum. Antimicrob Agents Chemother
there a role for prophylactic antibiotics? BMJ 1992: 305: 1998: 32: 75–77.
300–302. 65. Sporer KA. The serotonin syndrome, implicated drugs,
44. Meechan JG. Polypharmacy and dentistry: 2. Interactions pathophysiology and management. Drug Saf 1995: 13:
with analgesics and antimicrobials. Dent Update 2002: 29: 94–104.
382–388. 66. Sternbach H. The serotonin syndrome. Am J Psychiatr
45. Meechan JG. Polypharmacy and dentistry: I. Introduction 1991: 148: 705–713.
and interactions with local anaesthetics and sedative drugs. 67. Strom BL, Abrutyn E, Berlin JA, Kinman JL, Feldman RS,
Dent Update 2002: 29: 325–330. Stolley PD, Levison ME, Korzeniowski OM, Kaye D. Dental
46. Michalets EL. Update: clinically significant cytochrome and cardiac risk factors for infective endocarditis, a popu-
P-450 drug interactions. Pharmacotherapy 1998: 18: 84–112. lation-based, case–control study. Ann Intern Med 1998:
47. Mills KC. Serotonin syndrome. Am Fam Physician 1995: 52: 129: 761–769.
1475–1482. 68. Thomson AH, Thomson GD, Hepburn M, Whiting B.
48. Mito RS, Yagiela JA. Hypertensive response to levonordef- A clinically significant interaction between ciprofloxacin
rin in a patient receiving propranolol: report of case. J Am and theophylline. Eur J Clin Pharmacol 1987: 33: 435–436.
Dent Assoc 1988: 116: 55–57. 69. Thyss A, Kubar J, Milano G, Namer M, Schneider M. Clin-
49. Moore PA. Preventing local anesthesia toxicity. J Am Dent ical and pharmacokinetic evidence of a life-threatening
Assoc 1992: 123: 60–64. interaction between methotrexate and ketoprofen. Lancet
50. Moore PA. Adverse drug interactions in dental practice: 1986: February: 256–258.
interactions associated with local anesthetics, sedatives 70. Van Scov RE, Wilkowske CJ. Prophylactic use of anti-
and anxiolytics. Part IV of a series. J Am Dent Assoc 1999: microbial agents in adult patients. Mayo Clin Proc 1992: 67:
130: 541–554. 288–292.
51. Moore PA, Gage TW, Hersh EV, Yagiela JA, Haas DA. Ad- 71. Von Moltke LL, Greenblatt DJ, Duan SX, Harmatz JS,
verse drug interactions in dental practice, professional and Shader RI. In vitro prediction of the terfenadine-ketocon-
educational implications. J Am Dent Assoc 1999: 130: 47–54. azole pharmacokinetic interaction. J Clin Pharmacol 1994:
52. Nierenberg DW, Semprebon M. Clinical pharmacology 34: 1222–1227.
rounds, the central nervous system serotonin syndrome. 72. Wahl MJ. Myths of dental-induced prosthetic joint infec-
Clin Pharmacol Ther 1993: 53: 84–88. tions. Clin Infect Dis 1995: 20: 1420–1425.

27
Sims & Sims

73. Wahl MJ. Dental surgery in anticoagulated patients. Arch 79. Wynn RL. Antidepressant medications. Gen Dent 1992:
Intern Med 1998: 158: 1610–1616. May–June: 192–197.
74. Wallis SC, Charles BG, Gahan LR, Filippich LJ, Bredhauer 80. Wynn RL, Meiller TF. Guidelines for antibiotic prophylaxis
MG, Duckworth PA. Interaction of norfloxacin with diva- for dental patients with joint replacements. Gen Dent 1998:
lent and trivalent pharmaceutical cations. In vitro com- Mar–April: 140–146.
plexation and in vivo pharmacokinetic studies in the dog. 81. Yagiela JA. Adverse drug interactions in dental practice:
J Pharm Sci 1996: 85: 803–809. interactions associated with vasoconstrictors. Part V of a
75. Weinberg MA, Fine JB. The importance of drug interactions series. J Am Dent Assoc 1999: 130: 701–709.
in dental practice. Dent Today 2001: 20: 88–93. 82. Yagiela JA, Duffin SR, Hunt LM. Drug interactions and
76. Wijnands WJA, Vree TB, Van Herwaarden CLA. The influ- vasoconstrictors used in local anesthetic solutions. Oral
ence of quinolone derivatives on theophylline clearance. Surg Oral Med Oral Pathol 1985: 59: 565–571.
Br J Clin Pharmacol 1986: 22: 677–683. 83. Zachariasen RD. Effect of antibiotics on oral contraceptive
77. Wilde JA. Gentle anesthetic: the greatest of practice build- efficacy. J Dent Hyg 1991: 65: 334–338.
ers. Dent Today 1993: Aug: 70. 84. Zinman EJ. Letters to the editor, Toxicity and mepivicaine.
78. Wood GD, Deeble T. Warfarin: dangers with antibiotics. J Am Dent Assoc 1976: 92: 858.
Dent Update 1993: 20: 350–353.

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