DRUG-RELATED GINGIVAL ENLARGEMENT
Heterogeneity of the gingival response depends on several variables, including the drug in question, plaque-induced inflammatory changes in the gingival tissues, genetic factors, and other factors known to influence drug pharmacokinetics and pharmacodynamics (Charles et al., 2012). It has been reported that good oral hygiene practices can mitigate the degree of gingival enlargement associated with drugs (Khzam, Bailey, Yie, & Bakr, 2016). The enlargement is generally greater in inflamed tissue because less active or quiescent fibroblasts in non-inflamed gingiva do not respond to circulating systemic drugs, whereas inflammatory mediators and endogenous growth factors cause fibroblasts in inflamed tissue to be active and exhibit an exaggerated response to drug therapy. Researchers have described drug-specific pathogenic processes for gingival enlargement (Zoheir, & Hughes, 2020). For example, cyclosporine A increases production of collagen and protein by fibroblasts, which results in formation of extracellular collagen and matrix and reduction in the activity of the enzyme collagenase. In addition, increased levels of cytokines, such as interleukin-6, and reduced levels of gamma-interferon may promote fibroblast synthesis of collagen (Murai et al., 2011). Phenytoin-induced gingival overgrowth has been attributed to activity of hormones in the gingiva (Agrawal, 2015). Although the presentation of drug-specific gingival overgrowth may be similar, the etiology of these conditions can be different on a molecular level. Nifedipine is a commonly prescribed calcium channel blocker that has been implicated in causing gingival enlargement. Other calcium channel blockers, such as amlodipine, diltiazem, felodipine, nitrendipine, and verapamil, may also precipitate this condition (Aral, Dilber, Aral, Sarica, & Sivrikoz, 2015). Researchers have linked the pathogenesis of nifedipine-linked gingival hyperplasia to the inhibition of apoptosis (planned cell death) with consequent epithelial hyperplasia (Cohen & Bhattacharyya, 2008; Trackman & Kantarci, 2015; Zoheir, & Hughes, 2020). In addition, gingival enlargement has been attributed to nifedipine’s inhibition of both the adherence- and macrophage-induced death of fibroblasts (Fujimori, Maeda, Saeki, Morisaki, & Kamisaki, 2001; Trackman & Kantarci, 2015, Zoheir, & Hughes, 2020). Gingival enlargement induced by oral contraceptives is common and has long been reported (Domingues et al., 2012; Pearlman, 1974; Sumanth, Bhat, & Bhat, 2007). Both estrogen and progesterone, which are used in oral contraceptives, are known to increase gingival exudate, edema, and inflammation. It has been shown that women who take oral contraceptives exhibit greater periodontal destruction than a control group of comparable age and oral hygiene (Domingues et al., 2012). Although it does not prevent gingival enlargement, practicing good oral hygiene can limit response severity (Kalmar, 2016). The exact role played by bacterial plaque in drug-induced gingival enlargement is unclear, but good oral hygiene and professional plaque removal have been shown to decrease the amount of gingival enlargement. One study involving transplant patients exhibiting cyclosporine A-related gingival enlargement reported that a strict plaque control program lowered inflammatory infiltrate and changed connective tissue composition (Aimetti, Romano, Marsico, & Navone, 2008; Zoheir, & Hughes, 2020). Treatment for drug-induced gingival enlargement should be tailored to the patient and the causative medication as well as the clinical presentation of each particular case (Kalmar, 2016; Mohan et al., 2013). Initially, the clinician should
Enlargement of the gingiva is a well-recognized side effect of drug therapy, especially with medications such as anticonvulsants (e.g., phenytoin, phenobarbital, ethosuximide), oral contraceptives, immunosuppressants (e.g., cyclosporine), and calcium channel blockers (e.g., nifedipine, amlodipine; Kalmar, 2016; Raizada, Varghese, Bhat, & Gupta, 2016; Sarda & Rathod, 2015; Seymour & Rudralingham, 2008). Table 2 lists the drugs with potential to cause gingival enlargement. Table 2: Drugs with Potential to Cause Gingival
Enlargement • Amlodipine • Candesartan • Captopril • Clopidogrel • Eprosartan • Losartan • Midodrine
• Nicarpidine • Nifedipine • Nitrendipine
• Phenytoin • Valsartan • Verapamil
Note. Adapted from “Cardiovascular Drugs-Induced Oral Toxicities: A Murky Area to be Revisited and Illuminated,” by P. Balakumar, M. Kavitha, and S. Nanditha, 2015, Pharmacological Research, 102 , pp. 81-89; and “Drugs, Medications and Periodontal Disease,” by P. A. Heasman and F. J. Hughes, 2014, British Dental Journal, 217 (8), pp. 411-419. Diffuse, non-neoplastic enlargement of the gingival tissues was initially recognized in patients using phenytoin (Chen et al., 2015). Calcium channel blockers (members of the dihydropyridine class of medications) and cyclosporine have also been associated with this reaction. In the calcium channel blocker family, nifedipine, diltiazem, verapamil, and amlodipine are among the most commonly reported causative agents (Charles, Ramesh, Babu, & Premalatha, 2012). However, drug-related gingival enlargement is not observed in all patients. The prevalence ranges between 25% and 50%, with no clear relationship between the dose of the drug and the severity of the overgrowth (Kalmar, 2016). Drug-induced gingival enlargement was previously termed gingival hypertrophy or gingival hyperplasia because of an increased number of fibroblasts in gingival connective tissue on histological analysis (Mohan, Rastogi, Bhushan, & Verma, 2013; Teoh, Moses, & McCullough, 2019). However, the terms hypertrophy and hyperplasia inaccurately reflect the histological composition of enlarged gingiva. It is not the increased proliferation of gingival fibroblasts, but the accumulation of extracellular matrix, particularly collagenous components, within the gingival connective tissue that is responsible for gingival enlargement. Although it is known that the pathogenic process of drug-related gingival enlargement is characterized by chronic inflammation and accumulation of extracellular matrix within the gingival connective tissue, the exact mechanism is still being investigated (Trackman & Kantarci, 2015). Clinically, gingival enlargement typically occurs 1 to 3 months after initiation of drug therapy and starts as a beadlike enlargement of the interdental papilla (Mohan et al., 2013). Over time, this painless enlargement extends to the facial and lingual gingival margins. Although the enlargement is usually generalized throughout the mouth, enlargement in the anterior regions is frequently more severe.
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