<<

Journal of Human (2014) 28, 10–14 & 2014 Macmillan Publishers Limited All rights reserved 0950-9240/14 www.nature.com/jhh

REVIEW -induced

R Livada and J Shiloah

Despite the popularity and wide acceptance of the blockers (CCBs) by the medical community, their oral impact is rarely recognized or discussed. CCBs, as a group, have been frequently implicated as an etiologic factor for a common oral condition seen among patients seeking dental care: -induced gingival enlargement or overgrowth. This enlargement can be localized or generalized, and can range from mild to extremely severe, affecting patient’s appearance and function. Treatment options for these patients include cessation of the offending drug and substitution with another class of antihypertensive to prevent recurrence of the . In addition, depending on the severity of the gingival overgrowth, nonsurgical and surgical periodontal may be required. The overall objective of this article is to review the etiology and known risk factors of these lesions, their clinical manifestations and periodontal management.

Journal of Human Hypertension (2014) 28, 10–14; doi:10.1038/jhh.2013.47; published online 6 June 2013 Keywords: calcium channel blockers; gingival enlargement;

INTRODUCTION side effects, including , facial flushing and, among 5 The research of calcium channel was pioneered by Fatt and Katz1 others, gingival overgrowth. The following generations of 6 7 8 with their work on large muscle cells of crab. Subsequent work by dihydropyridines (, oxydipine and ) Fleckenstein2 sparked a major therapeutic advance in managing were intended to overcome these adverse effects, but were patients with and to a new class of drug: calcium unable to prevent the drug-induced gingival overgrowth in some 9 channel blockers (CCBs). patients. The overall objective of this article is to review current This class derives its main therapeutic effects by preventing data regarding the impact of CCBs on the gingiva, its clinical calcium ion influx through the membranes. It binds to manifestations and management. L-type calcium channels, which are located on vascular smooth muscles, cardiac myocytes and cardiac nodal tissue (sinoatrial and atrioventricular nodes). Through this blockage, CCBs cause GINGIVAL ENLARGEMENT relaxation of vascular smooth muscles and , Despite their popularity and wide acceptance by the medical a decrease in myocardial force output (negative inotropy), a community, the oral impact of CCB therapy is rarely recognized or reduction in (negative chronotropy) and a decrease in discussed. CCBs, as a group, have been frequently implicated as an conduction velocity within the heart (negative dromotropy). By etiologic factor for a common oral condition seen among patients causing vascular relaxation, CCBs decrease seeking dental care: drug-induced gingival enlargement systemic vascular resistance, which in turn reduces arterial or overgrowth. This benign oral condition is a common side pressure. These primarily affect arterial resistance, with only effect of the majority of CCBs. It is characterized by an increase minimal effects on venous vessels. Because of their dual action on of the gingival mass and volume, which can range from mild to the heart and blood vessels, CCBs are widely used for managing extremely severe. hypertension, and supraventricular cardiac . As Among calcium antagonists, is the most frequently a class, they ranked eighth in prescription sales in the United implicated antagonist in drug-induced gingival overgrowth.10 States (Intercontinental Medical Statistics Canada), and the Lederman et al.11 were the first to report its negative oral most frequently prescribed CCB among adults is amlodipine3 effects in 1984; subsequent studies showed that its (Table 1 lists available CCBs in the United States). varied from 14%12 to 83%.13 As for Verapamil14 and amlodipine, The interaction of CCBs with the is a complex the prevalence was significantly lower (4.2% and 3.3%, process. Three distinctive but allosterically interacting receptors respectively) than that of nifedipine.8 Since then, numerous have been identified on the cell membrane and are blocked reports have associated gingival enlargement with the newer by different chemical compounds—(1) dihydropyridines generation of CCBs, such as ,15 ,16 (nifedipine-like drugs; for example, amlodipine and ), manidipine17 and .18 (2) phenylalkylamines (-like drugs) and (3) benzothiaze- pines (diltiazem-like drugs)—that have been developed to specifically bind with these sites. CCBs came into the market in CLINICAL FEATURES three waves or generations;4 the first one was developed The drug-induced gingival enlargement could be detected in the 1970s and included dihydropyridines, phenylalkylamines clinically as early as 1–3 months following the initial dose of and benzothiazepines derivatives. This generation had multiple CCB. Although the overgrowth does not seem to affect edentulous

Department of , College of , University of Tennessee Health Science Center, Memphis, TN, USA. Correspondence: Dr R Livada, Department of Periodontology, College of Dentistry, University of Tennessee Health Center, 875 Union Avenue, Memphis, TN 38163, USA. E-mail: [email protected] Received 23 April 2013; revised 1 May 2013; accepted 1 May 2013; published online 6 June 2013 CCB-induced gingival enlargement R Livada and J Shiloah 11 Table 1. Common calcium channel blockers

Generic drug name

Amlodipine Diltiazem Felodipine Isradipine Nicardipine Nidefipine Verapamil Figure 1. A patient with a severe gingival overgrowth affecting the natural dentition but not the edentulous area. areas,19 nifedipine-induced gingival enlargement has been reported around dental implants20 (Figure 1). The enlargement could be localized or generalized, affecting the entire mouth, and it could range from mild increase of the interproximal gingival papillae to severe enlargement of both marginal and papillary tissues. In its initial stages, the gingival enlargement may appear as a firm nodular enlargement of the interdental papillae, and its prevalence in the mouth is varied. It affects more the anterior rather than the posterior teeth, and is more pronounced on the facial/buccal than the palatal/lingual surfaces.21 In severe cases the entire papillae and the surrounding tissues are enlarged, giving the gingival tissues a lobulated appearance. The enlargement could extend vertically (coronally) and interfere with mastication and speech. It can also create esthetic problems if the anterior teeth are involved (Figures 2 and 3). The overgrown tissue creates pockets that harbor pathogenic that are Figure 2. Severe gingival enlargement causing esthetic and func- beyond the reach of a or dental floss. These negative tional problems. Patient is unable to achieve optimal . changes impair optimal oral hygiene and can lead to an increased susceptibility to oral , caries and periodontal . The clinical manifestations of gingival overgrowth have a wide spectrum of presentations. They range from noninflamed, firm and fibrous gingiva to one that is dominated by , erythema and . The latter form is especially seen in patients with poor oral hygiene. Although CCBs do not directly affect the underlying alveolar , the gingival enlargement may increase accumulation of bacterial biofilm and prevent adequate oral hygiene measures, thus inducing inflammation, periodontitis, bone and loss, and halitosis.

HISTOLOGICAL FEATURES The microscopic appearance of CCB-induced gingival enlarge- ments is not diagnostic and cannot be clearly distinguished from other forms of gingival enlargements caused by other classes of drugs, such as or cyclosporine. The increase in the Figure 3. Lobulated appearance of gingival enlargement in a female patient taking amlodipine. Note the poor hygiene and abundant gingival tissue volume is primarily due to a microbial plaque. response rather than an epithelial cell proliferation. It is characterized by an excessive accumulation of extracellular matrix proteins, such as , amorphous ground substance and of Role of matrix metalloproteinases 21 noncollagenous proteins, such as . The The hallmark of the enlargement is the increase in the amount of appears highly vascularized and covered by a connective tissue matrix dominated by collagen fibers. Collagen parakeratinized of varying thickness. Epithelial ridges synthesis is controlled by matrix metalloproteinases and the tissue penetrating deep into the connective tissue could be seen in inhibitor of metalloproteinases. Collagen fibers are degraded via some specimens. The chronic inflammatory infiltrate is dominated an extracellular pathway by secretion of and via an by plasma cells and in a lesser degree by lymphocytes. intracellular pathway via by fibroblasts. CCBs affect calcium by reducing the Ca2 þ cell influx, leading to a reduction in the uptake of folic acid, thus limiting the ETIOLOGY (PATHOGENESIS) production of active .22 As a result of the reduction in The pathogenesis of drug-induced gingival enlargement is not collagen degradation, increased collagen accumulation occurs. fully understood. Several possible mechanisms and pathways have Other possible pathways for the gingival enlargement is been proposed over the years. However, there is lack of general overproduction of extracellular ground substance characterized consensus on this issue. Below are some of the most cited causes by increased presence of sulfated mucopolysaccharides and risk factors of gingival overgrowth: (glycosaminoglycans).19

& 2014 Macmillan Publishers Limited Journal of Human Hypertension (2014) 10 – 14 CCB-induced gingival enlargement R Livada and J Shiloah 12 Role of inflammatory Proinflammatory cytokines, such as -1b and interleukin- Several reports have implicated nifedipine more often than any 6 seem to have a synergistic effect in the enhancement other member of this class of drugs for inducing gingival of collagen synthesis by human gingival fibroblasts.23 enlargement. Patients taking nifedipine are at significant Interleukin-6 has been shown to target connective tissue cells, higher risk for developing overgrowth than those taking either such as fibroblasts, both by enhancing their proliferation and by amlodipine or diltiazem.28 These drugs are structurally similar increasing collagen production and (dihydropyridines), but amlodipine is more polarized and requires synthesis.24 This highlights the role of the bacterial biofilm a complex transport mechanism to penetrate the cell membrane. in inducing gingival inflammation, production of cytokines and In contrast, nifedipine is highly lipophilic and penetrates the gingival enlargement. cell membrane rather quickly. It appears that these structural differences in drug/cell interaction have a major role in the pathogenesis of drug-induced gingival enlargement. Another Role of fibroblasts possible factor that accounts for the differences between The finding that the majority of patients treated with CCBs does amlodipine and nifedipine is the variation in their half-lives and not develop gingival enlargement lead to the discovery of a their volume of distribution (amlodipine: 34 h and 21 l kg À 1; subset of fibroblasts that are susceptible to CCBs. A genetic nifedipine: 7.5 h and 0.78 l kg À 1). Amlodipine’s higher volume predisposition of different fibroblasts phenotypes to CCB may indicates that the majority of amlodipine is tissue bound (hence 25 be related to the human lymphocyte . However, there is ‘inactive’) and does not circulate freely in the blood. It has been a lack of clinical markers to identify susceptibility to CCBs and suggested that a plasma threshold may exist above which drug- patients who are at risk, besides their level of oral hygiene. Other induced gingival changes are initiated.30 Amlodipine rarely genetic predisposition could influence the metabolism of CCBs, achieves such threshold levels, unlike nifedipine, which tend to as these drugs are metabolized by the hepatic cytochrome exhibit pronounced peak plasma levels, possibly affecting drug- P450 enzymes. genes exhibit considerable induced gingival enlargement. polymorphism, which results in interindividual variation in enzyme activity. This inherited variation in metabolism of the offending drug may influence the patient’s serum and tissue concentrations, TREATMENT OF DRUG-INDUCED GINGIVAL ENLARGEMENT 26 and hence their gingival response. The most effective treatment of these lesions is cessation of the offending medication and a substitution with another class, or a cocktail, of antihypertensive drugs by the medical provider. RISK FACTORS These include B-blockers, or angiotensin-converting Dental plague and oral hygiene level enzyme inhibitors. Drug-induced gingival overgrowth has not 31 The oral bacterial biofilm is a common risk factor for all forms been reported with any of these drugs. Another option is of inflammatory periodontal diseases and its presence exacerbates substitution with another CCB drug that has a lower risk 11 CCB-induced gingival enlargement. The severity of gingival of inducing gingival enlargement (for example, verapamil or 32 enlargement is well correlated with poor oral hygiene. The isradipine ). Despite these options, physicians and patients are importance of the microbial plaque as a cofactor in the etiology of often reluctant to switch to other regimen, especially if the blood drug-associated gingival enlargement has been recognized pressure is well controlled or other options have been already in a recent classification system of periodontal diseases by the explored. If regimen change is not an option, the lesions should be American Academy of Periodontology.27 The finding that the managed with or without surgical intervention. gingival overgrowth is almost exclusively related to dentate areas suggests that factors attached to the dentition, such as bacterial Nonsurgical periodontal treatment , have a role in gingival enlargements. Whether Nonsurgical management of gingival enlargement is usually a these lesions are preventable by professional toothcleaning and treatment of choice in patients with mild to moderate gingival installation of good oral hygiene habits before prescribing this overgrowth. Professional mechanical removal of the dental plaque class of drug is unknown and requires clinical trials. and , through , has shown positive

Age and gender Age has not been identified as a risk factor for CCBs, as these drugs are usually prescribed to middle-aged and older patients, preventing any attempt to stratify them.28 However, both human29and animal30 studies have suggested that a gender- related factor may have a role in drug-induced gingival overgrowth; males are more susceptible than females. Nifedipine has been shown to affect androgen metabolism by increasing the conversion of testosterone to 5a-dihydrotestosterone when added to cultured gingival fibroblasts.29 The active androgen metabolite appears to target subpopulations of fibroblasts and induces collagen synthesis or decreases its degradation. Ishida et al.30 suggested that a serum threshold above which overgrowth occurs exists and that this level was lower in males.

Dose There is lack of a clear correlation between dosage of nifedipine and gingival overgrowth.22 Some reports on amlodipine suggest Figure 4. The post-operative appearance of patient in Figure 2 that a daily dose of 5 mg or higher could be a risk factor for following gingivectomy to remove excess gingival tissue and restore gingival overgrowth in some patients.8 physiologic architecture.

Journal of Human Hypertension (2014) 10 – 14 & 2014 Macmillan Publishers Limited CCB-induced gingival enlargement R Livada and J Shiloah 13 Table 2. Surgical management of drug-induced gingival enlargement

Procedure Description Advantages Disadvantages

Gingivectomy/ ‘Traditional’ external Predictable results. Risk for intrasurgical and with blades bevel incision. Does not require specialized surgical post-surgical bleeding especially in highly or surgical knives armamentarium. inflamed gingiva. Gingivectomy/ This technique has been Provides adequate . Slower due gingivoplasty via used in dentistry for over Used in patient where post-surgical to thermal . electrosurgery 70 years. bleeding is Not applicable for all cases. expected (patients with bleeding Should not be used for patients with disorders, pacemaker. drug regimen and so on). Cannot be used around teeth with metal restorations. Gingivectomy/ Various types of dental Accuracy in cutting. Lengthy procedure. gingivoplasty with dental lasers can be used (CO2 Provides adequate hemostasis Use of laser require further training. lasers or Nd:YAg or Ar). Minimal post-operative pain and Laser equipments are expensive. edema. Cannot be used around teeth with metal action. restorations. Flap surgery Used in cases where Removal of excess gingival tissue and More technically demanding. bone needs to be reshaping Lengthier procedure. modified. of both soft and hard tissue can be Requires suturing. achieved concurrently. Less post-operative hemorrhage. Less post-surgical discomfort of patient. Antimicrobial action.

effects in reducing gingival enlargement by eliminating its substitution to other class of antihypertensive is the inflammatory component. Good oral hygiene and home care best treatment option. Otherwise, these lesions could be managed are pivotal in preventing further inflammation and maintaining by nonsurgical or surgical techniques that only provide a the positive results achieved with dental care and must include short-time relief, as recurrence is to be expected if the offending periodic professional tooth cleaning.33 Adjunctive antimicrobial drug is continued. oral rinses with gluconate have been recommended in managing gingival overgrowth. For patients with mild gingival enlargement, these measures CONFLICT OF INTEREST could reduce the overgrowth to acceptable levels, thereby The authors declare no conflict of interest. making surgical treatment unnecessary. However, in moderate gingival overgrowth the nonsurgical treatment would shorten the subsequent surgical intervention and reduce the risk of REFERENCES post-operative infection. 1 Fatt P, Katz B. The electrical properties of crustacean muscle fibers. J Physiol 1953a; 120: 171–204. 2 Fleckenstein A. History of calcium antagonists. Circ Res 1983; 52: 13–16. Surgical periodontal treatment 3 Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of The main objective of the surgical intervention is resection of the medication use in the ambulatory adult population of the United States: excess tissue, elimination of pockets and restoration of tissue The Slone Survey. JAMA 2002; 287: 337–344. contour, appearance and function (Figure 4). The classical surgical 4 Toyo-Oka T, Nayler WG. Third generation calcium entry blockers. Blood Press 1996; 5(4): 206–208. approach is gingivectomy and gingivoplasty. This procedure 5 Dougall HT, McLay J. A comparative review of the adverse effects of calcium could be performed with blades, surgical knives, electrosurgery antagonists. Drug Saf 1996; 15(2): 91–106. or with dental laser. Table 2 summarizes the advantages and 6 Brown RS, Sein P, Corio R, Bottomley WK. Nitrendipine-induced gingival hyper- disadvantages of the above surgical methods. plasia. Oral Surg Oral Med Oral Pathol 1990; 70: 593–596. 7 Nyska A, Waner T, Pirak M, Galiano A, Zlotogorski A. Gingival in rats induced by -a . J Periodontal Res 1990; 25: Recurrence 65–68. The risk of recurrence of drug-induced gingival enlargement has 8 Jorgensen MG. Prevalence of amlodipine-related gingival hyperplasia. been reported in both surgical and nonsurgical methods— J Periodontol 1997; 68: 676–678. especially if cessation of the offending drug was not an option 9 Guidelines Subcommittee. 1999 World Health Organization-International Society or was temporary. Recurrence could occur as early as 3–6 months of Hypertension Guidelines for the Management of Hypertension: Guidelines following the surgical intervention, and could affect as many as Subcommittee. J Hypertens 1999; 17(2): 151–183. 34 10 Butler RT, Kalkwarf KL, Kaldahl WB. Drug-induced gingival hyperplasia: phenytoin, 40% of the patients. It appears that the risk of recurrence is cyclosporine, and nifedipine. J Am Dent Assoc 1987; 114:56–60. higher in patients with poor oral hygiene or lack of dental care. 11 Lederman D, Lumerman H, Reuben S, Freedman PD. Gingival hyperplasia asso- ciated with nifedipine therapy: Report of a case. Oral Surg Oral Med Oral Pathol 1984; 55: 620–622. SUMMARY 12 Barak S, Engelberg IS, Hiss J. Gingival hyperplasia caused by nifedipine. Histo- The CCBs are important components of managing patient pathologic findings. J Periodontol 1987; 58: 639–642. 13 Fattore L, Stablein M, Bredfeldt G, Semla T, Moran M, Doherty-Greenberg JM. populations with hypertension, angina or supraventricular cardiac Gingival hyperplasia: a of nifedipine and diltiazem. Spec Care Dent arrhythmias. However, a serious and often overlooked side effect 1991; 11: 107–109. of this class of drugs affects some patients. Gingival overgrowth is 14 Miller CS, Damm DD. of verapamil-induced gingival hyperplasia in a a common oral finding in these patients. Drug cessation and a dental population. J Periodontol 1992; 63: 453–456.

& 2014 Macmillan Publishers Limited Journal of Human Hypertension (2014) 10 – 14 CCB-induced gingival enlargement R Livada and J Shiloah 14 15 Lombardi T, Fiore-Donno G, Belser U, DiFelice R. Felodipine-induced gingival 25 Pernu HE, Knuuttila MLE, Huttenen KRH, Tiilikainen ASK. Drug-induced gingival hyperplasia: a clinical and histologic study. J Oral Pathol Med 1991; 20: 89–92. overgrowth and class I1 major histocompatibility . Transplantation 1994; 16 Seymour RA. Calcium channel blockers and gingival overgrowth. Br Dent J 1991; 57: 1811–1813. 170: 376. 26 Seymour RA, Ellis JS, Thomason JM. Risk factors for drug-induced gingival over- 17 Ikawa K, Ikawa M, Shimauchi H, Iwakura M, Sakamoto S. Treatment of gingival growth. J Clin Periodontol 2000; 27: 217–223. overgrowth induced by administration. A case report. J Periodontol 27 Armitage GC. Development of a classification system for periodontal diseases and 2002; 73: 115–122. conditions. Ann Periodontol 1999; 4: 1–6. 18 Brown RS, Beaver WT, Bottomley WK. On the mechanism of drug-induced gingival 28 Ellis J, Seymour R, Steele J, Robertson P, Butler T, Thomason JM. Prevalence of hyperplasia. J Oral Pathol Med 1991; 20: 201–209. gingival overgrowth induced by calcium channel blockers: a community based 19 Lucas RM, Howell LP, Wall BA. Nifedipine-induced gingival hyperplasia. study. J Periodontol 1999; 70: 63–67. A histochemical and ultrastructural study. J Periodontol 1985; 56(4): 29 Sooriyamoorthy M, Gower DB, Eley BM. Androgen metabolism in gingival 211–215. hyperplasia induced by nifedipine and cyclosporin. J Periodont Res 1990; 25(1): 20 Silverstein LH, Koch JI, Lefkove MD, Garnick JJ, Singh B, Steflik DE. Nifedipine- 25–30. induced gingival enlargement around dental implants: a clinical report. J Oral 30 Ishida H, Kondoh T, Kataoka M, Nishikawa S, Nakagawa T, Morisaki I et al. Factors Implant 1995; 21: 116–120. influencing nifedipineinduced gingival overgrowth in rats. J Periodontol 1995; 66: 21 Marshall RI, Bartold PM. A clinical review of drug induced gingival overgrowth. 345–350. Aust Dent J 1999; 44: 219–232. 31 Torpet LA, Kragelund C, Reibel J, Nauntofte B. Oral adverse drug reactions to 22 Barclay S, Thomason JM, Idle JR, Seymour RA. The incidence and cardiovascular drugs. Crit Rev Oral Biol Med 2004; 15: 28–46. severity of nifedipine-induced gingival overgrowth. J Clin Periodontol 1992; 19: 32 Westbrook P, Bednarczyk E, Carlson M, Sheehan H, Bissada N. Regression of 311–314. nifedipine-induced gingival hyperplasia following switch to a same class calcium 23 Johnson RB, Zebrowski EJ, Dai X. Synergistic enhancement of collagenous protein channel blocker, isradipine. J Periodontol 1997; 68: 645–650. synthesis by human gingival fibroblasts exposed to nifedipine and interleukin- 1- 33 Mavrogiannis M, Ellis JS, Thomason JM, Seymour RA. The management of drug beta in vitro. J Oral Pathol Med 2000; 29: 8–12. induced gingival overgrowth. J Clin Periodontol 2006; 33: 434–439. 24 Duncan MR, Berman B. Stimulation of collagen and glycosaminoglycan produc- 34 Ilgenli T, Atilla G, Baylas H. Effectiveness of periodontal therapy in patients with tion in cultured human adult dermal fibroblasts by recombinant human inter- drug induced gingival overgrowth. Long—term results. J Periodontol 1999; 70: leukin- 6. J Invest Dermatol 1991; 97: 686–689. 967–972.

Journal of Human Hypertension (2014) 10 – 14 & 2014 Macmillan Publishers Limited