Adverse Drug Interactions in Dental Practice
Drug Interaction Ratings
A series of articles about Adverse Drug Interactions in Dental Practice was published in the Journal of the American Dental Association Vol. 130 Jan thru May editions 1999. These articles were based on a symposium held by the IADR in Minneapolis March 4, 1998 in Minneapolis, MN and was cosponsored by the AADS and the ADA. These articles discussed ways that drug interactions could be classified for their relative importance and the interactions with drugs that dentists commonly use in practice.
The ratings are contingent upon the reader understanding that dental practitioners usually practice in a manner that tends to minimize the likelihood of adverse reactions to drugs. These underlying characteristics are stated below.
Unique Characteristics of Dental Pharmacotherapeutics
1. Therapy usually is in single-dose or short term form
Drugs often administered as a single dose
Therapies are limited to five or 10 days.
2. Most dental drugs have large margins of safety
3. Use of intravenously administered drugs is limited
4. Dental procedures frequently are elective
5. Number of agents in a practitioner's armamentarium is limited
Based on these basic concepts of dental practice the drug interactions associated with dental practice were classified based on the following rating scale
.| Significance Rating | Severity Rating | Documentation Rating |
| 1 | Major | Established, probable or suspected |
| 2 | Moderate | Established, probable or suspected |
| 3 | Minor | Established, probable or suspected |
| 4 | Major or moderate | Possible |
| 5 | Minor All classes |
Possible Unlikely |
| Table from Moore P.A. et. al. Adverse drug
interactions in dental practice : professional and educational implications, JADA, vol.
130, 47-54, Jan 1999 Copyright©1999 American Dental Association. Reprinted with permission of ADA Publishing Co., Inc. |
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The following tables summarize the recommendations from these articles. The complete text of the articles will add considerably to your understanding of the drug interactions listed and is recommended reading.
Adverse Drug Interactions in Dentistry:
Analgesics Used For A Period Of Less Than 5 Days
| Drug Interactions | Signifi- cance Rating |
Clinical Implications |
| Bactericidal antibiotics with bacteriostatic antibiotics | 2 | Theoretically, bactericidal drugs work best when microbes are actively growing. By inhibiting cell growth, bacteriostatic agents may antagonize the bactericidal agent. This interaction is not consistently demonstrated clinically. |
| Tetracyclines with products that contain divalent or trivalent cations | 2 | Tetracycline molecules chelate divalent and trivalent cations, impairing antibiotic absorption. In addition, antiacids can raise the gastrointestinal pH, also impairing absorption. Serum tetracycline can be reduced 20 to 100% leading to poor antibiotic efficacy. |
| Mitronidazole and alcohol | 1 | Metronidazole produces a disulfiram effect by inhibiting the enzyme acetaldehyde dehydrogenase. Acetaldehyde accumulation can lead to facial flushing, headache, palpitation and nausea. |
| Mitronidazole and lithium | 1 | Metronidazole inhibits the renal excretion of lithium, leading to elevated lithium blood concentrations. Lithium toxicity-as manifested by confusion, ataxia and kidney damage-can result. |
| Tetracycline with lithium | 4 | A single case report describes elevated lithium blood concentration and lithium toxicity with concomitant tetracycline administration. Another report and clinical research study did not support the interaction. |
| Erythromycin or tetracyclines with digoxin | 1 | These antibiotics can reduce the gut flora in particular Eubacterium lentum, which metabolizes a significant amount of oral digoxin in 10% of patients taking the drug. Elevated concentration of digoxin can occur in such patients, leading to digitalis toxicity, as manifested by salivation, visual disturbances and arrhythmias. |
| Tetracycline or other broad spectrum antibiotics with warfarin or anisindione | 4 | Broad spectrum antibiotics are hypothesized to reduce the gut flora that normally synthesize vitamin K, a necessary cofactor for clotting. Since warfarin's and anisindione's anticoagulant mechanism involves an antagonism of vitamin K-dependent clotting factors, an increased risk of bleeding may occur. Interaction appears significant only in patients with poor vitamin K intake. |
| Erythromycin, clarithromycin or metronidazole with warfarin or anisindione | 1 | These antibiotics decrease the metabolism of warfarin and anisindione and can significantly increase prothrombin times and increase the risk of serious bleeding in anticoagulated patients. Signs of this adverse interaction include hematuria, bruising and hematoma formation. |
| Table from Hersh, E.. Adverse drug interactions in dental practice : Interactions involving antibiotics, JADA, vol. 130,236-251, Feb 1999, Copyright©1999 American Dental Association. Reprinted with permission of ADA Publishing Co., Inc. | ||
Adverse Drug Interactions in Dentistry: Antibiotics Interaction with P450 isoforms CYP3A4 and CYP1A2 |
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| Erythromycin, clarithromycin, ketoconazole or itraconazole with a host of other drugs that are metabolized by the CYP3A4 and CYP1A2 system in the gut wall and liver | Depends on the interacting drugs (see below) | These antimicrobial agents block the metabolism and thus increase blood levels of a number of drugs. Severity of the reaction depends on the therapeutic index of the interacting drugs. |
| Astemizole, terfenadine or cisapride | 1 | Life-threatening ventricular arrhythmias (torsades de pointes). Metranidazole also increases cisapride blood levels. |
| Alfentanil | 1 | Enhanced and /or prolonged respiratory depression. Ketoconazole not implicated. |
| Bromocriptine | 1 | Increased risk of adverse central nervous system effects, dyskinesias and hypotension. |
| Carbamazepine | 1 | Increased risk of ataxia, vertigo, drowsiness and confusion. Cardiac arrest reported in one child taking erythromycin. |
| Cyclosporine | 1 | Enhanced immunosupression and nephrotoxicity. |
| Felodipine and possibly other calcium-channel blockers | 1 | Increase risk of hypotension, tachycardia, cardiac arrythimias, and edema. |
| Methylprednisolone or prednisone | 1 | Increased risk of Cushings's syndrome and immunosupression. |
| Theophylline | 1 | Increased risk of tachycardia, cardiac arrhythmias, tremors and seizures. Ketoconazole not implicated in this interaction. |
| Lovastatin and possibly other -statins | 2 | Muscle pain and rhabdomyolysis (skeletal muscle lysis). Pharmacokinetic interaction demonstrated for azole antifungal drugs. |
| Triazolam or oral midazolam | 2 | Marked increase in blood levels of both benzodiazepines when taken by mouth, leading to increases in sedative depth and duration. |
| Dysopyramide | 4 | A few clinical reports of arrhythmias or heart block with concurrent erythromycin use. Definitive pharmacokinetics studies are needed. |
| Penicillins, cephalosporins, erythromycin, tetracyclines, metronidazole with combined estrogen and progestin oral contraceptives. | 4 | Sporadic case reports have implicated the concomitant ingestion of antibiotics and oral contraceptives with unwanted pregnancies. It is theorized that antibiotics, by decimating the normal gut flora, can interfere with the enterohepatic recycling of the estrogen component of the oral contraceptive, thereby leading to a subtherapeutic blood levels and ovulation. With the exception of the antituberculosis drug rifampin, clinical studies have failed to demonstrate an interaction. |
| Table from Hersh, E.. Adverse drug interruptions in dental practice : Interactions involving antibiotics, JADA, vol. 130 ,236-251, Feb 1999. Copyright©1999 American Dental Association. Reprinted with permission of ADA Publishing Co., Inc. | ||
Adverse Drug Interactions In Dentistry Involving Analgesics Used For A Period Of Less Than 5 Days |
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| Drug Interactions | Signifi- cance Rating |
Clinical Implications |
| NSAIDs and certain antihypertensives, angiotensin-converting enzyme inhibitors, diuretics, b-blockers (interaction does not apply to calcium channel blockers). | 4 | An NSAID may be coprescribed if required for four days or less. Coadministration should be avoided in patients with severe congestive heart disease. Should be combined cautiously in elderly or black patients. |
| NSAID and lithium | 2 | Toxicity may result; however, evidence is not clear at the present time. Combination should be avoided or NSAIDs should be prescribed for a very short term. Use with elderly patients should be avoided. |
| NSAIDs and anticoagulants | 2 | Gastrointestinal bleeding may result. Combination should be avoided. High-dosage aspirin (more than 3 grams per day) is rated 1. |
| NSAIDs and methotrexate | 1 | Toxicity may result. Combination with high-dosage methotrexate, as used for cancer therapy, should be avoided. Low-dosage methotrexate, as used for arthritis is of little concern. |
| NSAIDs and alcohol | 2 | Predisposes the patient to gastrointestinal bleeding. Combination should be avoided. |
| NSAIDs and digoxin | 2 | Toxicity may result. Combination should be avoided if patient is elderly or has renal disease less concern is necessary if patient’s renal function is normal. |
| NSAIDs and cyclosporine | 4 | Toxicity may result. Combination should be avoided. |
| NSAIDs and other NSAIDs, acetaminophen | 5 | Renal damage may result when given long term. Combination should be avoided if possible. |
| Aspirin and oral hypoglycemics | 2 | Hypoglycemic effect may be increased. Combination should be avoided. |
| Aspirin and anticonvulsants | 4 | Toxicity may result with valproic acid. Combination should be avoided if possible. |
| Aspirin and carbonic anhydrase inhibitors | 3 | Toxicity may result. Combination should be avoided if possible. |
| Acetaminophen and alcohol Acute alcohol ingestion |
5 | Combination may be used if patient has a healthy liver. In alcoholics or those with liver disease, lower maximum dosage(less than 4 g/day) should be used. |
Cessation of alcohol ingestion after chronic intake. |
1 | Liver damage may result. Alcoholic patients should not be told to stop drinking if acetaminophen is used. |
| Opioids and alcohol | 2 | Additive sedation may result. Combination should be avoided. |
| Local Anesthetics with Opioid Sedation mepivacaine with meperidine |
1 | Sedation with opioids may increase the risk of local anesthetic toxicity, particularly with children; local anesthetic dose should be reduced. |
| Meperidine and monoamine oxidase inhibitor's (MAOIs) | 1 | Toxicity may result. Combination should be avoided if patient has taken MAOI in the past 14 days. |
| Table from Daniel A. Haas.. Adverse drug interruptions in dental practice : Interactions associated with analgesics, JADA, vol. 130,397-407, March 1999. Copyright©1999 American Dental Association. Reprinted with permission of ADA Publishing Co., Inc. | ||
| Drug Interactions | Signifi- cance Rating |
Clinical Implications |
Summation interactions with local
anesthetics
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1 | Local anesthetic toxicity is additive when these drugs are given in combination; although combination therapy with local anesthetics is acceptable; total dose should not exceed combined maximum recommended doses or MRDs. |
| Ester Local Anesthetics with sulfonamide
antibiotics procaine with sulfamethoxazole |
5 | Procaine is used infrequently; the procaine metabolite p-amino benzoic acid may transiently reduce sulfonamide antibiotic efficacy. |
| Amide Local Anesthetics with Inhibitors of
Metabolism lidocaine with cimetadine lidocaine with propranolol |
5 | Inhibition of local anesthetic metabolism will have little effect on peak plasma levels of anesthetic when given as a single injection. |
| Local Anesthetics with Opioid Sedation mepivacaine with meperidine |
1 | Sedation with opioids may increase the risk of local anesthetic toxicity, particularly with children; local anesthetic dose should be reduced. |
| Local Anesthetic-induced methemoglobinemia prilocaine with dapsone |
4 | Methemoglobinemia usually results from prilocaine dosing in excess of MRD; increased risk may be possible when similar oxidizing drugs are administered. |
| Table from Paul A. Moore. Adverse drug interactions in dental practice interactions associated with local anesthetics, sedatives and anxiolytics, JADA, vol. 130,541-554, April 1999. Copyright©1999 American Dental Association. Reprinted with permission of ADA Publishing Co., Inc. | ||
Adverse Drug Interactions in Dentistry: Sedatives and Anxiolytics |
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| Example of Adverse Drug Interactions | Significance Rating | Clinical Implications |
| Summation Interactions with Central
Nervous System Depressants diazepam and alcohol antihistamines and barbiturates |
1 | In combination, central nervous system depression is additive for sedatives and anxiolytics; loss of consciousness, respiratory depression and death are possible complications. |
| Chloral Hydrate Interactions | ||
| Alcohol | 1 | Each drug limits the metabolism of the other; depression is greater than additive. |
| Warfarin and dicumarol | 4 | Competition for plasma protein binding of anticoagulant causes hypoprothrombinemia. |
| Furosemide | 2 | Rare reports of diaphoresis, tachycardia, hypertension. |
| Barbiturate Interactions | ||
| Valproic acid and phenobarbital | 3 | Elimination of barbiturate is decreased; sedation is prolonged and enhanced. |
| Warfarin | 5 | Bleeding risk increased when chronic barbiturate therapy is discontinued. |
| Benzodiazepine
interactions Drugs increasing the rate of metabolism. |
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| Rifampin | 3 | Bioavailability of triazolam and oral midazolam is significantly reduced. |
| Carbamazepine | 3 | Bioavailability of triazolam and oral midazolam is significantly reduced. |
Drugs decreasing rate of metabolism |
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| Verapamil and diltiazem | 2 | Level of sedation is increased and prolonged. |
| Cimetidine | 3 | Level of sedation is increased and prolonged |
| Erythromycin and azole antimycotics | 2 | Bioavailability of triazolam and oral midazolam is markedly increased |
| Protease inhibitors: indinavir and nelfinavir |
2 | Bioavailability of triazolam and oral midazolam is markedly increased. |
| Table from Paul A. Moore. Adverse drug interactions in dental practice interactions associated with local anesthetics, sedatives and anxiolytics, JADA, vol. 130,541-554, April 1999. Copyright©1999 American Dental Association. Reprinted with permission of ADA Publishing Co., Inc. | ||
| Example of Adverse Drug Interactions | Significance Rating | Clinical Implications |
| Vasoconstrictor with tricyclic
antidepressant levonordefrin with imipramine |
1 | Sympathomimetic effect may be enhanced. Epinephrine should be used cautiously, use of levonordefrin should be avoided. |
| Vasoconstrictor with nonselective b-adreoceptor antagonist epinephrine with propranolol |
1 | Hypertensive and/or cardiac reactions are possible. Vasoconstrictor should be used cautiously; blood pressure and hear rate should be monitored. |
| Vasoconstrictor with general anesthetic |
1 | Increased possibility of cardiac arrythmias exists with some general anesthetics. Consultations with anesthesiologist is recommended. |
| Vasoconstrictor with antipsychotic or
other a-adrenoceptor blocker epinephrine and chlorpromazine |
4 | Hypotension resulting from overdose of antipsychotic agent may be worsened. Vasoconstrictor should be used cautiously. |
| Vasoconstrictor with adrenergic neuronal blocker | 4 | Sympathomimetic effects may be enhanced. Vasoconstrictor should be used cautiously. |
| Vasoconstrictor with local anesthetic | 4 | Multiple effects on systemic toxicity, which may be self limiting |
| Vasoconstrictor with thyroid hormone epinephrine and thyroxine |
4 | Summation of effects possible when thyroid hormones are used in excess. Vasoconstrictor should be used cautiously if signs of hyperthyroidism are present. |
| Vasoconstrictor with monoamine oxidase
inhibitor epinephrine and phenelzine |
5 | No substantial evidence of an interaction. |
| Table from John A Yagiela. Adverse drug interactions in dental practice: interactions associated with vasoconstrictors, JADA, vol. 130,701-709, May 1999. Copyright©1999 American Dental Association. Reprinted with permission of ADA Publishing Co., Inc. | ||
Note on alcohol and acetaminophen drug interaction.
Alcohol is metabolized by the P450 isozyme CYP2E1. Alcohol, when acting as a substrate for this isozyme, will tend to inhibit this isozyme from metabolizing other drugs which are also substrates for it. Chronic alcohol use can induce (or stabilize) the CYP2E1 enzyme.
Acetaminophen is also a substrate for the CYP2E1 isozyme. CYP2E1 can produce a toxic metabolite of acetaminophen called N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is normally detoxified in the liver by conjugation with glutathione. If this occurs no toxicity results. However, glutathione levels can become depleted. If glutathione levels are insufficient for conjugating all of the NAPQI, then this molecule is substantially hepatotoxoic.
An unfortunate and serious drug interaction can occur when alcoholics, whose CYP2E1 levels have been induced by alchohol; stop drinking alcohol and then take acetaminophen. Under the alcohol withdrawal condition, the induced CYP2E1 can produce more NAPQI and produce more severe liver damage. Because alcohol is also a substrate for CYP2E1, if the alcoholic drinks alcohol, it can reduces the amount of acetaminophen that is metabolized to NAPQI and reduces the likelihood of immediate liver toxicity from acetaminophen. The clinical drug-educational message for an alcoholic to "not drink alcohol when taking acetaminophen" is ill advised and may actually increase the likelihood of hepatotoxicity. The timecourse of the increased NAPQI synthesis is unknown but modeling suggested that metabolism should be close to baseline by about 100 hours after cessation of drinking alcohol. Of course, long term alcohol use is hepatotoxic on its own and alcoholic patients should be counseled to reduce their long term alcohol use.
1 Slattery, JT, Nelson SD, Thummel KE, The complex interaction between ethanol and acetaminophen. Clin. Pharmacol. Ther. 1996,60,241-6.
Compiled by Dr. Vahn Lewis