ADRs Affecting Oral Tissues

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.¹⁴ In addition, xerostomia (ADR #28) and taste disturbance (ADR #30) were among the 30 most common ADRs identified with the top 200 drugs dispensed by U.S. community pharmacies in 2008.¹⁵ 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).^20-24 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).

Figure 1. Antihistamine-induced Xerostomia.

Figure 1. Antihistamine-induced Xerostomia.

Figure 2. Neuroleptic Drug-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 taste disturbances or dysgeusia characterized as bitter or metalic.^21,22,24 The mechanisms of action of these drugs related to taste disturbance 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.^22,24 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 3. Topical ASA-induced Cytotoxic Reaction.

Figure 4. Lidocaine Ointment–induced Cytotoxic Reaction.

Figure 4. Lidocaine Ointment–induced Cytotoxic Reaction.

Figure 5. Hydrogen Peroxide-induced Cytotoxic Reaction.

Figure 5. Hydrogen Peroxide-induced Cytotoxic Reaction.

Figure 6. Methotrexate-induced Cytotoxic Reaction.

Figure 6. Methotrexate-induced Cytotoxic Reaction.

Antibacterial and corticosteroid therapy is often complicated by superinfection with candidal organisms in oral tissues.^21,22,24 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 typically presents as its pseudomembranous form characterized by the cottage cheese- or milk curd-like lesions that can be scraped off, leaving a red and sometimes hemorrhagic base.

Figure 7. Antibacterial Agent-induced Pseudomembranous Candidiasis.

Figure 7. Antibacterial Agent-induced Pseudomembranous Candidiasis.

Figure 8. Inhaled (Topical) Corticosteroid-induced Pseudomembranous Candidiasis.

Figure 8. Inhaled (Topical) Corticosteroid-induced Pseudomembranous Candidiasis.

Gingival enlargement may be associated with the administration of calcium-channel blocking agents, phenytoin, and cyclosporine.^20-22,24 The causative mechanisms are unclear, but they appear to be related to altered calcium metabolism and concomitant poor oral hygiene-related inflammation.²⁰ 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 Enlargement.

Figure 9. Calcium-blocking Agent-induced Gingival Enlargement.

Figure 10. Cyclosporine-induced Gingival Enlargement.

Figure 10. Cyclosporine-induced Gingival Enlargement.

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.²⁰ 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.

The oral anticoagulants such as warfarin, the directs acting anticoagulants (DOACs), and heparin inhibit clot formation.²⁰ Warfarin which inhibits vitamin K-dependent clotting factors, primarily Factor VII. DOACs such as apixaban and rivaroxaban competitively block Factor Xa and heparin inhibits Factors II and X.²⁰ 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 11. ASA-related Petechiae.

Figure 12. ASA/clopidogrel-related Purpura.

Figure 12. ASA/clopidogrel-related Purpura.

Figure 13. Warfarin-related Ecchymosis.

Figure 13. Warfarin-related Ecchymosis.

Figure 14. Heparin-related Spontaneous Bleeding.

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 (MRONJ) precipitated by dentoalveolar trauma.²⁵ 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.