The CIOMS does not provide a specific code for ADRs associated with oral tissues; however, it does include stomatitis and ulcerative stomatitis under the category of ADRs related to the gastrointestinal system.8 In addition, xerostomia (ranked #28) and taste disturbances (ranked #30) are among the 30 most common ADRs identified with the top 200 drugs dispensed by U.S. community pharmacies.9 Included under this heading are those orally-related ADRs that are of special interest to oral healthcare providers.
Many drugs can cause xerostomia (Box C).13-16 Reduced salivary flow may be related to a drug’s parasympatholytic or antimuscarinic effect in the CNS at parasympathetic and some sympathetic ganglia, or at parasympathetic and some sympathetic effector junctions. Other drugs cause fluid and electrolyte imbalance; glandular vasoconstriction; or alter fluid movement from plasma through acinar cells to the ductal system and, ultimately, into the oral cavity (Figures 1 and 2).
|Antihypertensive agents||Neuroleptic drugs|
Figure 1. Antihistamine-induced Xerostomia.
Figure 2. Neuroleptic Drug-induced Xerostomia.
Many drugs, e.g., chlorhexidine, metronidazole, benzodiazepines, oral hypoglycemic agents, angiotensin converting enzyme (ACE) inhibitors, diuretics, amiodarone, calcium-channel blocking agents, and H1-histamine receptor antagonist have been implicated in dygeusia or taste alterations characterized as bitter or metalic.13-15 The mechanisms of action of these drugs related to taste alterations are poorly understood, but appear to be associated with drug effects on trace metals (e.g., zinc) in plasma membranes.
Stomatitis and ulcerative stomatitis represent cytotoxic reactions to topically applied agents, e.g., LAs; or may result from the systemic administration of cytotoxic drugs, e.g., antineoplastic agents, which damage not only tumor cells, but all rapidly dividing normal cell populations.14,16 The degree of tissue damage depends on the specific agent, dosage, dosage schedule, and patient-related variables. The lesions may appear as erythematous macules, patches, papules, plaques, or diffuse ulcerations (Figures 3 and 4).
Figure 3. Topical ASA-induced Cytotoxic Reaction.
Figure 4. Lidocaine Ointment–induced Cytotoxic Reaction.
Figure 5. Hydrogen Peroxide-induced Cytotoxic Reaction.
Figure 6. Methotrexate-induced Cytotoxic Reaction.
Antibacterial and corticosteroid therapy is often complicated by superinfection with candidal organisms in oral tissues.14,16 Antibacterial agents kill bacteria allowing candidal species to successfully compete for nutrients. Corticosteroids promote gluconeogenesis and a hyperglycemic state facilitates the growth of the opportunistic candida species. Candidiasis may appear as white, raised, cottage cheese-like, or pseudomembraneous lesions that can be scraped off, leaving a red and sometimes hemorrhagic base.
Figure 7. Antibacterial Agent-induced Pseudomembraneous Candidiasis.
Figure 8. Inhaled (Topical) Corticosteroid-induced Hypertrophic Candidosis.
Gingival overgrowth may be associated with the administration of calcium-channel blocking agents, phenytoin, and cyclosporine.13-16 The mechanisms responsible are unclear, but they appear to be related to altered calcium metabolism and concomitant poor oral hygiene-related inflammation.13 While the enlarged tissue is usually firm and painless, it may interfere with mastication; and, with significant inflammation, the patient may report pain and gingival bleeding (Figures 9 and 10).
Figure 9. Calcium-blocking Agent-induced Gingival Overgrowth.
Figure 10. Cyclosporine-induced Gingival Overgrowth.
ASA and other NSAIDs acetylate cyclooxygenase and inhibit platelet thromboxane A2 biosynthesis; clopidogrel inhibits adenosine diphosphate receptor-mediated platelet activity; and other medications such as antineoplastic agents may induce profound thrombocytopenia.13,15 Clinical manifestations of platelet-related bleeding diatheses include petechiae (Figure 11), purpura (Figure 12), ecchymosis (Figure 13), spontaneous gingival bleeding, and increased potential for perioperative bleeding.
Oral anticoagulants (e.g., warfarin which inhibits vitamin K-dependent clotting factors, primarily Factor VII) and the parenteral anticoagulant heparin (which inhibits Factors II and X) reduce clot formation.13 Clinical manifestations of anticoagulant-related bleeding diatheses include hemorrhage, which may be spontaneous or precipitated by trauma. Oral manifestations may include spontaneous gingival bleeding (Figure 14), submucosal bleeding with hematoma formation, and increased peri- and post-operative bleeding.
Figure 11. ASA-related Petechiae.
Figure 12. ASA/clopedigrel-related Purpura.
Figure 13. Warfarin-related Ecchymosis.
Figure 14. Heparin-related Spontaneous Bleeding.
Prevention and treatment of osteoporosis include the administration of antiresorptive agents such as bisphosphonates (BPs). A rare ADR related to BPs is medication-related osteonecrosis of the jaw precipitated by dentoalveolar trauma.17 When BP molecules are released from the bone matrix some are internalized by osteoclasts resulting in inhibition of the mevalonate pathway essential for the synthesis of signaling proteins to activate osteoblast precursors. BPs also inhibit angiogenesis and are toxic to soft tissues.