Drug induced gingival enlargement - DIGO

Drug induced gingival enlargement - DIGO

1. DRUG INDUCED GINGIVAL ENLARGEMENT PRESENTED BY : DR. SHREYA MISHRA MDS 2 nd YEAR

2. CONTENT INTRODUCTION CLASSIFICATION DRUG INDUCED GINIGVAL ENLARGEMENT (A.) INTRODUCTION (B.) EPIDEMIOLOGY (C.) CLINICAL FEATURES (D.) INDICES (E.) PATHOPHYSIOLOGY (F.) ANTI CONVULSANT (G.) CYCLOSPORIN (H.) CALCIUM CHANNEL BLOCKERS 4. CONCLUSION 5. REFERENCES

3. INTRODUCTION American Academy of Oral Medicine describes Gingival Enlargement, also known as gingival hyperplasia or hypertrophy as an abnormal overgrowth of gingival tissues. Increase in size of gingiva or gingival growth ( Carranza 11th Edition ) Gingival enlargement and gingival overgrowth are terms used interchangeably with hyperplasia, hypertrophy and fibrosis.

4. CLASSIFICATION CARRANZA 11th Edition

5. (B.) According to Location & Distribution : Localized : Limited to one or more (group of) teeth Generalized : The gingiva is enlarged in the entire mouth Marginal : Limited to the Marginal gingiva Papillary : Confined to the Interdental papilla Diffuse : Involves all the parts of gingiva Discrete : Isolated sessile or pedunculated tumor -like enlargement CARRANZA 11th Edition

6. According to the Degree of Gingival Enlargement : Grade 0 : No signs of gingival enlargement Grade 1 : Enlargement confined to the interdental papilla Grade 2 : Enlargement involving papilla & marginal gingiva Grade 3 : Enlargement covering three quarters or more of the crown CARRANZA 11th Edition

7. SEQUELE OF GINGIVAL OVERGROWTH

8. DRUG INDUCED GINGIVAL ENLARGEMENT Drug-induced gingival overgrowth (DIGO) also referred to as drug-induced gingival enlargement and previously known as drug-induced gingival hyperplasia, is a side-effect of certain drugs where the gingival tissue is not the intended target organ. The key offending drug classes are anticonvulsants, immunosuppressants and calcium channel blockers . As gingival enlargement develops, it affects the normal oral hygiene practice and may interfere with masticatory functions. It gradually becomes a source of pain and the condition often leads to disfiguration. Tungare S, Paranjpe AG. Drug-Induced Gingival Overgrowth. [Updated 2022 Sep 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan.

9. Overview of identified factors that may contribute to the expression of drug-induced gingival overgrowth Seymour RA, Ellis JS, Thomason JM. Risk factors for drug-induced gingival overgrowth. J Clin Periodontol . 2000 Apr;27(4):217-23

10. OVERVIEW Drug category Anti- convulsants Anti-calcineurins (and immunosuppressants) CCBAs Drugs Phenytoin, carbamazepine, valproic acid Cyclosporin , TAC (azathioprine, mycophenolate mofetil ) Amlodipine, nifedipine, felodipine, nitrendipine, verapimil, diltiazem Therapies Treatment of epilepsy Immunosuppression Anti-hypertensive Incidence of DIGO PHT – 10–83% CsA – 7–80% CCBAs – 10–30% Mechanism Blocking Na+ channels Binding a protein in the cytosol (cyclophilin) through calmodulin Blocking calcium channels Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis. Oral Dis. 2015 Jan;21(1):e51-61

11. EPIDEMIOLOGY DIGE was first reported as far back as 1939 by Kimball , who described the condition in patients using phenytoin for epilepsy. Seymour et al . reported the first case of gingival overgrowth attributed to amlodipine in 1994. Drug-induced gingival overgrowth is most commonly seen in male children and adolescents with a most prevalent location in the anterior gingival tissue with Phenytoin, Cyclosporin and Nifedipine are the most common causes of gingival overgrowth and phenytoin has the highest prevalence of all. Phenytoin-induced overgrowth may be present in 50 to 100% of patients treated with such drug, whereas cyclosporin and calcium channel blocker-induced overgrowths seem to be less common, ranging from 15-85% and 10-30% respectively. Tungare S, Paranjpe AG. Drug-Induced Gingival Overgrowth. [Updated 2022 Sep 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan.

12. CLINICAL FEATURES Firm, painless, nodular enlargement of the interdental papilla, limited to the keratinized portions of the gingiva and extending to the facial and lingual gingival margins. In severe cases, a huge fold of hypertrophied gingival tissue is observed covering the crowns. If no secondary inflammation is present, it appears firm and pale pink, delineated by tissue that does not bleed on touch. If secondary inflammation exists, the gingiva appears smooth, and red or bluish-red. The enlargement is generalized, but it is usually greater in the anterior regions. Typically, it is not seen in edentulous areas. The gingival overgrowth disappears when teeth are extracted. However small differences have been described: in cases due to anti-epileptic drugs, gingiva are firm and pale because of the conspicuous fibrous component, while other drug-induced gingival enlargements are characterised by a nodular lobulated spongy aspect and secondary inflammation that may induce oedema, ulcerations and bleeding on brushing .

13. INDEX FOR DRUG INDUCED GINGIVAL ENLARGEMENT Eva and Ingles (1999) introduced a new index for measuring gingival overgrowth caused due to drugs. In this index for standardization, the buccal and lingual papillae were scored separately. Dubey S, Gattani D, Deotale S, Quazi M. A contemporary review on indices for gingival enlargement. J Adv Med Dent Scie Res 2016;4(4):62-67

14. GRADE 0 No overgrowth (firm adaptation of attached ginigva ) Slight stippling, no granular appearance, Knife edge papilla present No increase in density of gingiva GRADE 1 Mild overgrowth Marked stippling, granular appearance, Tip of papilla is rounded Increase density of gingiva, Probing depth is less than or equal to 3mm GRADE 2 Moderate overgrowth Contour of gingival margin is concave or straight Gingival enlargement has buccolingual dimension upto 2mm Probing depth is between 3-6 mm Increased size of papilla which is somewhat retractable GRADE 3 Marked overgrowth Contour of gingival margin is convex Gingival enlargement has buccolingual dimension upto 3m m or more Probing depth is more than 6 mm Papilla is retractable GRADE 4 Severe overgrowth Profound thickening of the gingiva Large % of clinical crown is covered Probing depth is more than 6 mm Papilla is retractable

15. INDEX To define the extent and degree of severity of phenytoin-induced GE, Seymour et al. (1985) devised an index. They designated vertical and horizontal (i.e., labio -lingual) components to the labial and lingual gingiva. The Seymour index was an indirect and partial mouth index, as study models were used for assessment, and six maxillary and six mandibular anterior teeth are selected for measurement. Hence, there are 20 gingival units in total that are measured in each patient. The sum of vertical and horizontal components provides the score for each gingival unit, which can be a maximum of 5. The sum of the scores for each gingival unit provides the overall score, a maximum of which can be 100, and therefore can be expressed as a percentage. A GO score of 30% or greater is considered clinically significant GE requiring surgical intervention. Tonsekar , P.; Tonsekar , V. Calcium-Channel-Blocker-Influenced Gingival Enlargement: A Conundrum Demystified.  Oral   2021 ,  1 , 236-249

16. VERTICAL COMPONENT : (0) no enlargement of interdental papilla on to tooth surface mild enlargement resulting in a blunted papilla moderate enlargement involving lateral spread of interdental papilla onto the tooth surface of up to a quarter of tooth width marked encroachment of papilla over greater than a quarter of tooth width HORIZONTAL COMPONENT : (0) normal thickness of gingival margin mild increase in thickness less than 2 mm from the normal (2) marked increase in thickness greater than 2 mm from the normal Tonsekar , P.; Tonsekar , V. Calcium-Channel-Blocker-Influenced Gingival Enlargement: A Conundrum Demystified.  Oral   2021 ,  1 , 236-249

17. EVALUATION The diagnosis of drug-induced gingival overgrowth is made by clinical examination and the patient's past medical history . A periodontal examination is necessary to evaluate for the presence of periodontal disease. Full mouth IOPA and OPG are required before beginning any treatment to rule out periodontal disease. Complete blood count (CBC) is indicated in patients with gingival enlargement to rule out anemia and leukemia . Tissue biopsy should be carried out in case the presentation of the disease is unusual or singular. Histopathological examination of persisting overgrowths is mandatory to evaluate malignant changes. Also, Candidiasis and other infections may be ruled out by taking a culture. Tungare S, Paranjpe AG. Drug-Induced Gingival Overgrowth. [Updated 2022 Sep 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan

18. PATHOPHYSIOLOGY Despite their pharmacological diversity, the three major drug groups causing gingival overgrowth have similar mechanism of action at the cellular level, where they inhibit intracellular calcium ion influx. An appraisal of the various investigations into the pathogenesis of drug-induced gingival overgrowth supports the hypothesis that it is multifactorial. The severity of gingival enlargement in patients taking medications correlates well with poor plaque control and is commensurate with the degree of plaque-induced inflammation. Bharti V, Bansal C. Drug-induced gingival overgrowth: The nemesis of gingiva unravelled. J Indian Soc Periodontol . 2013 Mar;17(2):182-7.

19. VARIOUS MECHANISM OF ACTION As suggested by Brown et al in 1991, Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis. Oral Dis. 2015 Jan;21(1):e51-61

20. Na+/ Ca2+ ion Flux Drug Mechanisms Brown et al (1990, 1991a) suggested that it is reasonable to assume that all the three drug categories possess a particular commonality with regard to an inhibitory influence upon cation channels. Brown RS, Beaver WT, Bottomley WK. On the mechanism of drug-induced gingival hyperplasia.  J Oral Pathol Med.  1991a;20:201–209

21. Study Drug Mechanism Jones and Wimbish (1985) PHT Decreases resting fluxes of Na+ ions as well as Na+ currents with respect to action potentials or chemically induced depolarizations Colombani   et al  (1985) CsA Interferes with Ca++ interactions Dretchen  et al  (1986) PHT and CCBAs Inhibition of Ca++ flux into excitable membranes Fugii and Kobayashi (1990) PHT and CCBAs Inhibition of Ca++ uptake within gingival fibroblasts Thomas and Petrou (2013) Anti-seizure drugs Reduction in Na+ channel availability and therefore a decrease in the action potential amplitude. This causes reduced Ca2+ entry and a decrease in Ca2+ activated K+ channels.

22. Plaque Buildup The concentrated drug in GCF or bacterial plaque has a direct toxic effect on the gingival tissue. Dental plaque induces inflammation which causes gingival overgrowth. Inflammation causes the upregulation of TGF-beta 1. Hence, control of dental plaque is needed in the treatment and prevention of DIGO over time. Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis. Oral Dis. 2015 Jan;21(1):e51-61

23. From the above studies, it can be concluded that inflammation secondary to dental plaque is a factor for DIGO and plaque control should be utilized in both DIGO prevention and therapy. Pilatti and Sampaio (1997)  evaluated the effectiveness of 0.12% chlorhexidine (CHX) in the treatment of cyclosporine induced DIGO in a rat study. The combined CsA and CHX group exhibited significantly lower GO compared to the cyclosporin alone treatment group.  Ilgeni et al (1999)  evaluated the effectiveness of periodontal therapy in Cyclosporin and Nifedipine -induced GO. Multiple regression analysis indicated that age, gingival inflammation and attendance at recall appointments were significant factors regarding the recurrence of severe DIGO.  Aimetti et al (2005)  evaluated non-surgical and supportive periodontal treatment on transplant patients with DIGO. They concluded that plaque control appeared to be effective in controlling GO over an extended time period.  Dannewitz et al (2010)  evaluated non-surgical disinfection DIGO therapy. They reported that all clinical parameters improved significantly after therapy.

24. Increased production of GAGs There are a great many studies reporting increased size of connective tissue and proliferation of gingival fibroblasts secondary to the inducing drugs as the primary causation of DIGO ( Brown et al, 1991a; Seymour et al, 1996 ). Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis. Oral Dis. 2015 Jan;21(1):e51-61 Kantor and Hassell (1983)  reported an increased accumulation of sulfated GAGs and noted that it could be related to increased synthesis of inactive collagenase. Nares et al (1996) and Seymour et al (1996)  suggested a defect in collagen breakdown as a possible mechanistic issue with regard to the pathogenesis of DIGO. When the collagen content and composition of human gingiva, enlarged due to drugs were compared to normal and inflamed gingival tissues, the PHT-induced hyperplastic gingiva contained significantly higher amounts of collagen per unit weight ( Hassell et al, 1983) .

25.   Kataoka   et al  (2005)  suggested that DIGO is due to a disruption of homeostasis of collagen synthesis and degradation, predominantly through the inhibition of gingival fibroblastic collagen phagocytosis. They concluded that DIGO is caused by reduced gingival fibroblastic collagen phagocytosis through an alpha-2 beta-1 cell surface integrin. They also noted that the actin-binding protein, gelsolin, may be an important factor, because of it maintains normal tissue integrity through integrin binding affinity to collagens, an important factor for the regulation of collagen phagocytosis. Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis. Oral Dis. 2015 Jan;21(1):e51-61 Mariani   et al  (1996) , in an ultra-structural and histochemical evaluation of DIGO, concluded that that CsA caused an increased amount of GAG deposition and that therefore, increased GAGs appeared to be the main cause of DIGO.

26. Folate cellular uptake Vogel (1977)  was the 1 st to propose that DIGO may be secondary to a localized FA deficiency. Opladen  et al (2010)  reported the effect of anti- convulsant drugs upon the folate receptor 1 (FOLR1)-dependent 5-methyltetrahydrofolate (MTHF) transport. They reported that the metabolic breakdown of anti- convulsants generates ROS. At physiologic MTHF concentrations, the high-affinity FOLR1 represented the predominant mechanism for cellular uptake. Exposure to phenytoin could lead to higher MTHF uptake; however, exposure to superoxide and hydrogen peroxide radicals significantly decreased cellular MTHF uptake. Therefore, it appears that the FOLR1-dependent 5-MTHF transport could also be involved with regard to inhibited folate transport and decreased folate uptake in gingival fibroblasts. Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis. Oral Dis. 2015 Jan;21(1):e51-61

27. Matrix metalloproteinases Kato et al (2005)  examined the effect of phenytoin administration upon collagen degradation. They evaluated gene and protein expressions of MMPs. They concluded that phenytoin causes impaired collagen degradation through MMPs/TIMP-1 through particular cellular signaling pathways of ERK1/2 and nuclear factor kappa B, possibly leading to collagen accumulation resulting in GO. Kato et al (2006)  investigated TNF-alpha (associated with gingival inflammation) and phenytoin with regard to mRNA levels for collagen and MMPs, and TIMPs. They concluded that together TNF-alpha and phenytoin synergistically caused impaired collagen metabolism by suppression of enzymatic degradation with MMPs/TIMP-1 resulting in GO. Vahabi  et al (2013)  recently reported that at least with regard to children, an impaired collagenase activation in DIGO was due to an MMP-1/TIMP pathway. Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis. Oral Dis. 2015 Jan;21(1):e51-61

28. E-cadherin, SMAD, AP-1, TIMP-1, MMP-1, inactive to active collagenase pathway Decreased cellular folic acid leads to decreased E-cadherin and SMAD, which leads to decreased AP-1. Decreased AP-1 results in increased TIMP-1 which leads to decreased MMP-1. As MMP-1 is necessary for the activation of inactivated collagenase to activated collagenase, the result is a decreased amount of activated collagenase. Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis. Oral Dis. 2015 Jan;21(1):e51-61

29. ANTICONVULSANTS Phenytoin has been used to control seizure disorders in patients with epilepsy since its clinical introduction by Merritt & Putnam in 1938 . Within a year of its initial clinical use, reports linking phenytoin to gingival overgrowth appeared in the literature. Despite the widespread availability of anticonvulsant drugs, phenytoin and phenobarbital remain the most commonly prescribed antiepileptic medications. Reports of the incidence of phenytoin-associated gingival overgrowth range from 0% to 84.5%, with an average effect approximating 50%. An increased prevalence of gingival overgrowth has been observed in children and young adults.

30. Pharmacokinetics : Phenytoin selectively depresses the motor cortex of the CNS and is believed to mediate this action by stabilizing neuronal discharge and limiting the progression of neuronal excitation by blocking or interfering with calcium influx across cell membranes. Although the daily dose, duration of use and blood or salivary levels of phenytoin have been related to the presence and degree of overgrowth, several studies have failed to detect any correlation among these factor. In a 2-year longitudinal study, Dahllof & Modeer (1986) observed the clinical onset of gingival overgrowth after 1 month of phenytoin use. Although overgrowth occurred progressively over the study period, it continued at a decreased rate during the second year. Associated gingival overgrowth appears to reach maximum severity 12-18 months after initiating phenytoin treatment. Hallmon WW, Rossmann JA. The role of drugs in the pathogenesis of gingival overgrowth. A collective review of current concepts. Periodontol 2000. 1999 Oct;21:176-96

31. Clinical manifestation : Affected tissues typically present a granular or pebbly surface , with the enlarged papillae extending facially and lingually , obscuring the adjacent tissue and tooth surfaces. Affected papillae may become enlarged to the point of contact, resulting in the clinical presence of pseudoclefts . The facial gingiva of the anteriors is more commonly affected and often results in aesthetic disfigurement. There is no evidence suggesting that sex or race affects the occurrence of phenytoin- associated gingival overgrowth. Also reports of phenytoin-induced gingival overgrowth prior to the eruption of the primary teeth are reported which resulted in delayed eruption. Although considered rare, phenytoin gingival overgrowth has also been observed in edentulous patients and beneath pontics of fixed partial dentures. Hallmon WW, Rossmann JA. The role of drugs in the pathogenesis of gingival overgrowth. A collective review of current concepts. Periodontol 2000. 1999 Oct;21:176-96

32. Histological charateristics : Histologically, tissues from gingival overgrowth biopsies present a thick stratified squamous epithelium with long thin rete pegs that extend deep into the lamina propria . The lamina propria is characterized by proliferation of fibroblasts and increased collagen formation, accompanied by an increase in non-collagenous proteins. Hallmon WW, Rossmann JA. The role of drugs in the pathogenesis of gingival overgrowth. A collective review of current concepts. Periodontol 2000. 1999 Oct;21:176-96

33. Prevention & Treatment : 1. With proper instruction, motivation and reinforcement, oral hygiene may be effectively addressed by the patient during the course of a supportive treatment to control bacterial plaque. In a 15-month longitudinal study by Pihlstrom et al. and another study by Hall et al they studied the effectiveness of a preventive dental program in outpatients who were taking phenytoin for seizure control. All patients received professional preventive care after initiating phenytoin therapy. Although a small increase in gingival enlargement was observed in the first 6 months, no further enlargement occurred. The authors concluded that a preventive dental program could effectively minimize phenytoin- associated gingival enlargement. In a 2-year longitudinal study, Dahllof & Modeer initiated a preventive dental program for 16 children scheduled to begin phenytoin treatment for seizure control. Gingival enlargement was still evident after 1 month and was not prevented by the program.

34. 2. Since phenytoin using patients often experience difficulty with effective oral hygiene maintenance, approaches may need to be modified to meet patient needs. This includes the use of an electric toothbrush and adjunctive antimicrobial sprays or mouthrinses . Shibley et al. prescribed 0.12% chlorhexidine gluconate rinses twice a day in 30 patients exhibiting drug-associated overgrowth. Compared with gingival overgrowth patients using a placebo rinse, the chlorhexidine group had a significant reduction in plaque accumulation, gingival inflammation and gingival overgrowth. 3. Although scaling and root planing effectively reduces accompanying inflammation, surgical treatment is often required to manage the consequences of clinically significant gingival overgrowth. The excessive tissue can be removed using surgical techniques ( gingivectomy / flap), laser gingivectomy or a combination approach. Hallmon WW, Rossmann JA. The role of drugs in the pathogenesis of gingival overgrowth. A collective review of current concepts. Periodontol 2000. 1999 Oct;21:176-96

35. CYCLOSPORIN Cyclosporin A was first isolated in Switzerland in 1970 as a metabolite of the fungus species Tolypocludium influturn Gams. and its first reported use in renal transplantation procedures was by Calne et al . Cyclosporin A has been demonstrated to suppress humoral immunity (B lymphocytes) and to a much greater extent cell-mediated immunity (T lymphocytes) such as allograft rejection, delayed hypersensitivity, graft-versus-host disease and autoimmune diseases. The first cases of gingival overgrowth caused by cyclosporin A medication in the dental literature were reported by Rateitschak-Pluss et al. in 50 kidney transplant patients.

36. Clinical manifestation : Friskopp & Klintmalm indicated that the overgrowth was restricted to keratinized gingiva but could extend coronally and interfere with occlusion, mastication or speech. These enlarged tissues are generally more hyperemic than the gingival tissues associated with phenytoin-induced overgrowth. Also it is noted that there is an absence of overgrown tissue in edentulous patients receiving medication. The enlarged gingival tissues is soft, red or bluish-red, extremely fragile and bleeds easily upon probing. Hallmon WW, Rossmann JA. The role of drugs in the pathogenesis of gingival overgrowth. A collective review of current concepts. Periodontol 2000. 1999 Oct;21:176-96

37. Histological manifestation : The histological features of all drug-induced gingival overgrowth are comparable, consisting primarily of connective tissue with an overlying irregular, multi-layered, parakeratinized epithelium. Epithelial ridges penetrate deep into the connective tissue, creating irregularly arranged collagen fiber bundles. Ultrastructural and immunohistochemical examination of cyclosporine A induced gingival overgrowth shows characteristics of active protein synthesis. The dimensional increase in gingival overgrowth is due to an increased production of amorphous ground substance by the fibroblasts, containing increased numbers of both sulfated and non- sulfated GAG. Hallmon WW, Rossmann JA. The role of drugs in the pathogenesis of gingival overgrowth. A collective review of current concepts. Periodontol 2000. 1999 Oct;21:176-96

38. Prevention & Treatment : 1. Most studies suggest that improving plaque control results in reduction of inflammation and inhibit the development and recurrence of gingival overgrowth. Inflammatory changes in the gingiva caused by plaque enhance the interaction between cyclosporin A and fibroblasts. McGaw et al. have shown dental plaque to act as a reservoir for cyclosporin A, which may account for the suppression of immune response in gingival epithelium of cyclosporin A induced overgrowth patient. Rateitschak-Pluss et al. found a significant improvement in gingival enlargement following initial debridement and stated that strict plaque control was of utmost importance in preventing recurrence. But Seymour et al. found no significant correlation between gingival overgrowth and plaque scores. Also, Daley et al . found only a weak correlation existing between plaque and severity of gingival overgrowth. 2. Removal of local irritants are important in the management of cyclosporin A-induced gingival enlargement. Hallmon WW, Rossmann JA. The role of drugs in the pathogenesis of gingival overgrowth. A collective review of current concepts. Periodontol 2000. 1999 Oct;21:176-96

39. CALCIUM CHANNEL BLOCKERS A group of drugs specifically developed to assist in the management of cardiovascular conditions, including hypertension, angina pectoris, coronary artery spasm and cardiac arrhythmia, has been introduced in recent years. The pathogenesis of CCB-induced GO is not clearly understood and is viewed as being multifactorial. Various risk factors including drug variables (dosage and duration), age, gender, oral hygiene status, and gingival inflammation have been associated with this condition. Tonsekar, P.; Tonsekar, V. Calcium-Channel-Blocker-Influenced Gingival Enlargement: A Conundrum Demystified.  Oral   2021 ,  1 , 236-249

40. Pharmacokinetics : Calcium channel blockers act by inhibiting calcium ion influx across the cell membrane of cardiac and smooth muscle cells, thereby interfering or blocking mobilization of calcium intracellularly. In 1990, Brown et al. reported the first case of gingival overgrowth induced by nitrendipine . At that time, this agent was being used in an experimental protocol to treat hypertension and congestive heart failure. A year later, Lombardi et al . reported gingival overgrowth in a patient taking felodipine to treat hypertension. Tonsekar, P.; Tonsekar, V. Calcium-Channel-Blocker-Influenced Gingival Enlargement: A Conundrum Demystified.  Oral   2021 ,  1 , 236-249

41. Tonsekar, P.; Tonsekar, V. Calcium-Channel-Blocker-Influenced Gingival Enlargement: A Conundrum Demystified.  Oral   2021 ,  1 , 236-249

42. Clinical manifestation : The interdental papillae are initially affected, becoming enlarged and resulting in a lobulated or nodular morphology. These effects are limited to the attached and marginal gingiva, and are more frequently observed anteriorly, especially on the facial surface. As the tissues become progressively larger, plaque control becomes more difficult. Although overgrowth does not appear to affect edentulous areas, nifedipine -induced gingival enlargement has been reported around dental implants. Thomason et al. and Bokenkamp et al . reported increased severity of gingival overgrowth when these two agents were combined, compared with cyclosporin A alone. Tonsekar, P.; Tonsekar, V. Calcium-Channel-Blocker-Influenced Gingival Enlargement: A Conundrum Demystified.  Oral   2021 ,  1 , 236-249

43. Histological manifestation : In a study of 34 biopsies of nifedipine gingival overgrowth, Barak et al. described thickening of the spinous cell layer, slight to moderate hyperkeratosis, fibroblastic proliferation. These changes were accompanied by increased capillary vascularity and slight perivascular inflammation. Similar to other drug-induced gingival overgrowth histological descriptions, the specimen presented long, tubular rete pegs that extended deep into the lamina propria . Tonsekar, P.; Tonsekar, V. Calcium-Channel-Blocker-Influenced Gingival Enlargement: A Conundrum Demystified.  Oral   2021 ,  1 , 236-249

44. Prevention & Treatment : 1. Control of gingival inflammation and maintenance of effective oral hygiene are key factors in preventing and managing gingival overgrowth associated with this class of medications. 2. Surgical reduction of the overgrown tissues is frequently necessary and may consist of conventional gingivectomy and/or laser gingivectomy . 3. Regression of Nifedipine induced gingival overgrowth has been reported following a change in medication to Isradipine , a companion dihydropyridine calcium channel blocker. 4. The use of chlorhexidine mouthrinses and gel has also been suggested as a plaque control adjunct in affected patients. Tonsekar, P.; Tonsekar, V. Calcium-Channel-Blocker-Influenced Gingival Enlargement: A Conundrum Demystified.  Oral   2021 ,  1 , 236-249

45. TREATMENT PROTOCOL Camargo PM, Melnick PR, Pirih FQ, Lagos R, Takei HH. Treatment of drug-induced gingival enlargement: aesthetic and functional considerations. Periodontol 2000. 2001;27:131-8

46. Treatment options: nonsurgical Firstly, consideration should be given to the possibility of discontinuing the drug or of changing medication which should be in conjunction with the patient’s physician. Alternative medications to Phenytoin include Carbamazepine and Valproic acid , which have shown a lower rate of gingival enlargement. For patients on Nifedipine , other CCBs such as Diltiazem and Verapamil may be viable alternatives, since the prevalence of gingival enlargement associated with those drugs is 20% and 4%, respectively. Regression of Nifedipine induced gingival overgrowth has been reported following a change in medication to Isradipine Drug substitution options for Cyclosporin are more limited due to the fact that few of these options exist. Recently, it has been substituted by Tracolimus . There is also preliminary evidence that the antibiotic Azithromycin may aid in decreasing the severity of Cyclosporin -induced gingival enlargement. If any drug substitution is attempted, it is important to allow for 6–12 months to elapse between discontinuation of the offending drug and the possible resolution of gingival enlargement before surgical treatment is implemeted . Camargo PM, Melnick PR, Pirih FQ, Lagos R, Takei HH. Treatment of drug-induced gingival enlargement: aesthetic and functional considerations. Periodontol 2000. 2001;27:131-8

47. 7. The clinician should also emphasize on plaque control along with the treatment of drug induced gingival enlargement. Adequate plaque control may also aid in preventing the recurrence of gingival enlargement in surgically treated cases. Camargo PM, Melnick PR, Pirih FQ, Lagos R, Takei HH. Treatment of drug-induced gingival enlargement: aesthetic and functional considerations. Periodontol 2000. 2001;27:131-8

48. Treatment options: surgical Gingival enlargement may persist, despite drug substitution attempts and good plaque control. These cases need to be treated by periodontal surgery, either gingivectomy or the periodontal flap. In general, small areas (up to six teeth) presenting with DIGE where there is no evidence of attachment loss (and therefore no anticipated need to perform osseous surgery) can be effectively treated with the gingivectomy technique. Larger areas of gingival enlargement (more than six teeth) or areas where attachment loss combined with osseous defects is present should be treated with the periodontal flap. Also, any situation in which the gingivectomy technique may result in the elimination of all keratinized tissue and consequent creation of mucogingival problems should be treated with the periodontal flap. Camargo PM, Melnick PR, Pirih FQ, Lagos R, Takei HH. Treatment of drug-induced gingival enlargement: aesthetic and functional considerations. Periodontol 2000. 2001;27:131-8

49. Maintenance Recurrence of drug-induced gingival enlargement is a reality in surgically treated cases. As stated previously, meticulous home care, chlorhexidine gluconate rinses and professional cleaning can decrease the rate and the degree at which recurrence occurs. Recurrence may occur as early as 3–6 months after the surgical treatment, but in general, surgical results are maintained for at least 12 months. Camargo PM, Melnick PR, Pirih FQ, Lagos R, Takei HH. Treatment of drug-induced gingival enlargement: aesthetic and functional considerations. Periodontol 2000. 2001;27:131-8

50. CONCLUSION Three very different groups of pharmaceutical agents have been associated with the occurrence of gingival overgrowth in susceptible individuals. Despite their pharmacological diversity, they have a similar mechanism of action and clinical manifestation. Although many patients respond favorably to nonsurgical treatment of their gingival enlargement, a significant number require surgical removal of the overgrown tissues to accomplish an aesthetic and functional result. Until the medical community can provide alternative drug therapy with comparable efficacy that does not induce gingival overgrowth, dental prac - titioners will be tasked with the labor intensive management of this unwanted side effect.

51. REFERENCES CARRANZA 11th Edition Tonsekar , P.; Tonsekar, V. Calcium-Channel-Blocker-Influenced Gingival Enlargement: A Conundrum Demystified.  Oral  2021,  1 , 236-249 Hallmon WW, Rossmann JA. The role of drugs in the pathogenesis of gingival overgrowth. A collective review of current concepts. Periodontol 2000. 1999 Oct;21:176-96 Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis. Oral Dis. 2015 Jan;21(1):e51-61 Tungare S, Paranjpe AG. Drug-Induced Gingival Overgrowth. [Updated 2022 Sep 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan Bharti V, Bansal C. Drug-induced gingival overgrowth: The nemesis of gingiva unravelled. J Indian Soc Periodontol . 2013 Mar;17(2):182-7 Dubey S, Gattani D, Deotale S, Quazi M. A contemporary review on indices for gingival enlargement. J Adv Med Dent Scie Res 2016;4(4):62-6 Camargo PM, Melnick PR, Pirih FQ, Lagos R, Takei HH. Treatment of drug-induced gingival enlargement: aesthetic and functional considerations. Periodontol 2000. 2001;27:131-8

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