**2. Drug induced gingival overgrowth (DIGO)**

The main drugs associated with GO can be divided into three categories such as anticonvulsants, calcium channel blockers, and immunosuppressants. Few isolated incidences of GO associated with antibiotics and sulphonamides were also reported. Though these drugs have different pharmacologic effect and targets, all of them seem to act similarly on the gingival connective tissue as a secondary target, leading to common clinical and histopathological changes. The gingival overgrowth (GO) is consequent to the alteration of the host tissue response, resulting in an increase in collagen synthesis and cellular changes within the connective tissue. The prevalence of gingival overgrowth varies with different medications, with a reported rate of 50% for phenytoin (anticonvulsant), 25–30% for cyclosporine (immunosuppressant), 5–20% for nifedipine and 3% for amlodipine (CCBs) [2]. The drug associated gingival overgrowth is three times more prevalent among men and can be attributed to the effect of testosterone on fibroblast proliferation and collagen stimulus [3].

The GO appears normally within 1–3 months after administration of these medications (**Table 1**). The gingival enlargement may appear inflamed or more fibrotic depending on the degree of inflammation. Normally the GO is confined to the attached gingiva which might occasionally extend coronally. The enlarged gingiva produces esthetic changes and its clinical symptoms include tenderness, bleeding, interference with speech, dental occlusion problems, and enhanced susceptibility to periodontal diseases [4–6].

Histologically, the drug-induced gingival overgrowth is indistinguishable from other types of gingival enlargement. The enlargement of the gingival tissue occurs as a result of accumulation of extracellular matrix (ECM), although the pathogenesis remains multifactorial. Age, genetic predisposition, pharmacokinetic variables, drug-induced alterations in gingival connective tissue homeostasis, inflammatory changes, drug-induced action on growth factors, etc. are some of the factors that influences the occurrence and severity of the gingival overgrowth.

Genetic factors are important in the pathogenesis of drug associated gingival overgrowth. The drugs are metabolized by cytochrome p450 enzymes, which are characterized by high genetic variability. Research on genes responsible for HLA leukocyte antigen coding confirmed the theory of HLA-DR2 antigen influence, which is found much more commonly in patients with moderate or severe druginduced gingival overgrowth than HLA-DR1 [7]. The drug variables such as dosage, duration of therapy and concentration of drug in plasma and local fluids, like gingival crevicular fluid and saliva, play an important role in DIGO [8].

#### **2.1 Pathogenesis of DIGO**

The exact mechanism behind the pathogenesis of drug-induced gingival overgrowth is not yet fully understood. Each medication has got separate impacts on the range of cytokines and growth factors involved in connective tissue metabolism. Studies revealed that the molecular markers and clinical features of gingival overgrowth differ depending on the drugs. The cytokine and growth factor balances are altered in tissues with GO, including connective tissue growth factor (CTGF), a member of the interesting CCN (cysteine-rich angiogenic protein 61) family of factors [3, 9, 10].

Cytokine dependent alterations in extracellular matrix metabolism appear to be of functional importance to gingival overgrowth. Abnormal differentiation of cells, resulting in accumulation of fibroblasts with a pathologic range of proliferative

**57**

**Table 1.**

need to be elucidated [3, 11].

*Medications causing drug induced gingival overgrowth (DIGO).*

**2.2 Histological features**

*Adverse Effects of Medications on Periodontal Tissues DOI: http://dx.doi.org/10.5772/intechopen.92166*

**Anticonvulsants**

**Immunosuppressants**

**Calcium channel blockers**

**Drugs/groups Incidence/prevalence References**

Phenytoin 13% [17]

Sodium valproate Rare [22] Vigabatrin Rare [23, 24] Carbamazepine None [22]

Cyclosporines 10–85% [25]

Tacrolimus 14.1% [28]

Nifedipine 6.3% [29]

Diltiazem 20% [31] Verapamil 4–19% [32, 33] Amlodipine 3% [34, 35] Felodipine Rare [36]

50.3% [18] 57% [19] 40% [20] 50–60% [21] 53% [22]

30% [26] 8–70% [27] 25–81% [8] 22.4% [28]

50.8% [30] 83% [31]

and synthetic phenotypes, could result from deregulated cytokines. The unique metabolic aspects of gingival extracellular matrix metabolism; and a greater understanding of interactions between and among medications, the innate and acquired immune response, cytokines and growth factors, and gingival epithelial and connective tissue cells providing more detailed molecular and mechanistic information

Histologically, slight to moderate hyperkeratosis, thickening of the spinous layer,

fibrosis of underlying connective tissue with fibroblastic proliferation, increase in the number of capillaries with slight chronic perivascular inflammation is seen. Excessive accumulation of extracellular matrix like collagen with varying amounts of inflammatory infiltrates, predominantly plasma cells are seen. Fibroblastic proliferation may not be evident. Plasma cells are the principal type of infiltrating


#### *Adverse Effects of Medications on Periodontal Tissues DOI: http://dx.doi.org/10.5772/intechopen.92166*

*Oral Diseases*

and collagen stimulus [3].

**2.1 Pathogenesis of DIGO**

factors [3, 9, 10].

susceptibility to periodontal diseases [4–6].

**2. Drug induced gingival overgrowth (DIGO)**

The main drugs associated with GO can be divided into three categories such as anticonvulsants, calcium channel blockers, and immunosuppressants. Few isolated incidences of GO associated with antibiotics and sulphonamides were also reported. Though these drugs have different pharmacologic effect and targets, all of them seem to act similarly on the gingival connective tissue as a secondary target, leading to common clinical and histopathological changes. The gingival overgrowth (GO) is consequent to the alteration of the host tissue response, resulting in an increase in collagen synthesis and cellular changes within the connective tissue. The prevalence of gingival overgrowth varies with different medications, with a reported rate of 50% for phenytoin (anticonvulsant), 25–30% for cyclosporine (immunosuppressant), 5–20% for nifedipine and 3% for amlodipine (CCBs) [2]. The drug associated gingival overgrowth is three times more prevalent among men and can be attributed to the effect of testosterone on fibroblast proliferation

The GO appears normally within 1–3 months after administration of these medications (**Table 1**). The gingival enlargement may appear inflamed or more fibrotic depending on the degree of inflammation. Normally the GO is confined to the attached gingiva which might occasionally extend coronally. The enlarged gingiva produces esthetic changes and its clinical symptoms include tenderness, bleeding, interference with speech, dental occlusion problems, and enhanced

Histologically, the drug-induced gingival overgrowth is indistinguishable from other types of gingival enlargement. The enlargement of the gingival tissue occurs as a result of accumulation of extracellular matrix (ECM), although the pathogenesis remains multifactorial. Age, genetic predisposition, pharmacokinetic variables, drug-induced alterations in gingival connective tissue homeostasis, inflammatory changes, drug-induced action on growth factors, etc. are some of the factors that

Genetic factors are important in the pathogenesis of drug associated gingival overgrowth. The drugs are metabolized by cytochrome p450 enzymes, which are characterized by high genetic variability. Research on genes responsible for HLA leukocyte antigen coding confirmed the theory of HLA-DR2 antigen influence, which is found much more commonly in patients with moderate or severe druginduced gingival overgrowth than HLA-DR1 [7]. The drug variables such as dosage, duration of therapy and concentration of drug in plasma and local fluids, like gingival crevicular fluid and saliva, play an important role in DIGO [8].

The exact mechanism behind the pathogenesis of drug-induced gingival overgrowth is not yet fully understood. Each medication has got separate impacts on the range of cytokines and growth factors involved in connective tissue metabolism. Studies revealed that the molecular markers and clinical features of gingival overgrowth differ depending on the drugs. The cytokine and growth factor balances are altered in tissues with GO, including connective tissue growth factor (CTGF), a member of the interesting CCN (cysteine-rich angiogenic protein 61) family of

Cytokine dependent alterations in extracellular matrix metabolism appear to be of functional importance to gingival overgrowth. Abnormal differentiation of cells, resulting in accumulation of fibroblasts with a pathologic range of proliferative

influences the occurrence and severity of the gingival overgrowth.

**56**

#### **Table 1.**

*Medications causing drug induced gingival overgrowth (DIGO).*

and synthetic phenotypes, could result from deregulated cytokines. The unique metabolic aspects of gingival extracellular matrix metabolism; and a greater understanding of interactions between and among medications, the innate and acquired immune response, cytokines and growth factors, and gingival epithelial and connective tissue cells providing more detailed molecular and mechanistic information need to be elucidated [3, 11].

#### **2.2 Histological features**

Histologically, slight to moderate hyperkeratosis, thickening of the spinous layer, fibrosis of underlying connective tissue with fibroblastic proliferation, increase in the number of capillaries with slight chronic perivascular inflammation is seen. Excessive accumulation of extracellular matrix like collagen with varying amounts of inflammatory infiltrates, predominantly plasma cells are seen. Fibroblastic proliferation may not be evident. Plasma cells are the principal type of infiltrating

inflammatory cell. Parakeratinized epithelium of variable thickness covers the connective tissue stroma. The epithelial ridges may penetrate deep into the connective with columns of interspersed collagen fibers [12].

#### **2.3 Management of drug induced DIGO**

The management of medication induced gingival overgrowth depends on the degree of progression of the disease. Withdrawal or substitution of medication is one of the methods that might resolve the gingival overgrowth. However, not all patients respond to this mode of treatment especially those with long standing gingival enlargement. Professional debridement with scaling and root planning as needed has been shown to offer some remission of the gingival overgrowth in patients. Since the anterior labial gingiva is frequently involved, surgery is commonly performed for esthetic reasons. The classical surgical approach has been the external bevel gingivectomy. However, a total or partial internal gingivectomy approach has been suggested as an alternative. This approach has the benefit of limiting the large denuded connective tissue wound and thereby minimizing postoperative pain and bleeding [13].

The surgical methods include traditional scalpel gingivectomy and periodontal flap surgery. Electrocautery may be used in difficult cases, children, or where the gingiva is fragile and likely to bleed. Excision using laser provides a superior incision margin and improved wound healing due to a coagulated layer along the incision, as well as a reduced incidence of scarring. CO2 laser is very effective in surgery of soft tissues with high water content like the gingiva. Blood vessels up to a diameter of 0.5 mm can be sealed effectively and provides a dry field for better visibility of the surgical field. A laser is preferred over the scalpel as it has strong bactericidal and hemostatic effects [14, 15]. A combined non-surgical and surgical therapy with drug substitution is the most common treatment approach in the management of medication induced gingival overgrowth [16]. In most cases, conservative methods such as professional oral hygiene maintenance, topical anti-inflammatory and antibacterial drugs and a meticulous oral hygiene measures by the patient. Surgical excision is used in cases of where the gingival overgrowth interferes with food intake, causing difficulties in speech and maintaining oral hygiene. Surgical excision is more reliable as it eliminates the hyperplastic tissue and promotes plaque control as well as improves the esthetics.

#### **2.4 Phenytoin**

Phenytoin is an anticonvulsant prescribed for the control of epilepsy and neuralgias. In the present day, phenytoin is not usually prescribed as a first line drug for the management of epilepsy due to the availability of a wide range of newer, more effective anticonvulsant drugs with fewer side effects. The prevalence of drug-induced gingival overgrowth in patients taking phenytoin is reportedly between 15% and 60% [17]. Phenytoin, or its metabolites, probably acts directly on high activity fibroblasts leading to the high levels of production of collagen in the presence of inflammation. This results in gingival enlargement, characteristically originating principally from the interdental papillae (**Figure 1**). The amount or degree of severity of the overgrowth is not related to the dose of the drug. Presence of plaque and gingival inflammation, serum concentrations of the drug are factors which increases the risk of phenytoin-induced gingival overgrowth [37].

The management of this overgrowth is based on obtaining optimal control of plaque. Where the enlargement is unsightly and disfiguring, or even interfering

**59**

**2.5 Cyclosporin**

**Figure 1.**

*Adverse Effects of Medications on Periodontal Tissues DOI: http://dx.doi.org/10.5772/intechopen.92166*

*A case of phenytoin induced gingival overgrowth.*

with chewing, the over-growths should be removed. Gingivectomy appears to be the simplest and best way of achieving good gingival contour as a post-operative result. But optimal plaque control post-operatively is the most important determinant of success. Recent research work suggests that the use of chlorhexidine, especially brushing daily using the gel, can be of valuable assistance in controlling plaque and hence in controlling the overgrowths in the post-surgical phase.

Cyclosporin (CsA) is a cyclic polypeptide with potent immunosuppressive activity used widely to prevent organ transplant rejection and also in the treatment of autoimmune diseases [38, 39]. CsA selectively suppresses helper T-cell function and modulates the network of inflammatory cytokines. However, cyclosporin is associated with several untoward effects like nephrotoxicity, hepatotoxicity, hirsutism and gingival overgrowth [40, 41]. Gingival overgrowth is one of the common side effects of CsA treatment, observed in 13–81% of the patients [6, 39]. The prevalence of gingival overgrowth associated with CsA averages around 30%, with reported rates ranging from 10 to 85% [25]. Studies have shown certain degree of association between GO and potential risk factors, such as age, genetic susceptibility, pharmacokinetic variables, plaque-related inflammation and immunological changes [42–44]. Epidemiological studies have reported wide variation of its occurrence and it accounts for more than 70% of the transplant recipients [4, 45]. The severity of gingival overgrowth is often associated with its prolonged use and further influenced by bacterial plaque and local irritants (**Figure 2**) [46]. The use of other medication, such as calcium channel blockers along with CsA increases the prevalence of gingival overgrowth and subsequently the risks [11]. The condition can interfere with the mastication, speech and oral hygiene maintenance and has a

The most prominent pathologic manifestation of the gingival overgrowth is an excessive accumulation of extracellular matrix, predominantly type I collagen. Many studies have shown increased transcriptional and translational levels of type I collagen in both tissue and fibroblast cultures derived from CsA-induced gingival overgrowth [9, 10, 47]. Though the exact mechanism is not clearly understood, studies also have shown increased expression of specific cytokines, especially transforming growth factor-beta (TGF-β), in drug-induced gingival overgrowth. This suggests that TGF-β, an inflammatory mediator that regulates cell proliferation and differentiation, plays a

role in enlarging the extracellular matrix in hyperplastic gingival tissue [48].

psychological impact in the affected individual [5].

*Adverse Effects of Medications on Periodontal Tissues DOI: http://dx.doi.org/10.5772/intechopen.92166*

**Figure 1.**

*Oral Diseases*

inflammatory cell. Parakeratinized epithelium of variable thickness covers the connective tissue stroma. The epithelial ridges may penetrate deep into the connective

The management of medication induced gingival overgrowth depends on the degree of progression of the disease. Withdrawal or substitution of medication is one of the methods that might resolve the gingival overgrowth. However, not all patients respond to this mode of treatment especially those with long standing gingival enlargement. Professional debridement with scaling and root planning as needed has been shown to offer some remission of the gingival overgrowth in patients. Since the anterior labial gingiva is frequently involved, surgery is commonly performed for esthetic reasons. The classical surgical approach has been the external bevel gingivectomy. However, a total or partial internal gingivectomy approach has been suggested as an alternative. This approach has the benefit of limiting the large denuded connective tissue wound and thereby minimizing

The surgical methods include traditional scalpel gingivectomy and periodontal flap surgery. Electrocautery may be used in difficult cases, children, or where the gingiva is fragile and likely to bleed. Excision using laser provides a superior incision margin and improved wound healing due to a coagulated layer along the incision, as well as a reduced incidence of scarring. CO2 laser is very effective in surgery of soft tissues with high water content like the gingiva. Blood vessels up to a diameter of 0.5 mm can be sealed effectively and provides a dry field for better visibility of the surgical field. A laser is preferred over the scalpel as it has strong bactericidal and hemostatic effects [14, 15]. A combined non-surgical and surgical therapy with drug substitution is the most common treatment approach in the management of medication induced gingival overgrowth [16]. In most cases, conservative methods such as professional oral hygiene maintenance, topical anti-inflammatory and antibacterial drugs and a meticulous oral hygiene measures by the patient. Surgical excision is used in cases of where the gingival overgrowth interferes with food intake, causing difficulties in speech and maintaining oral hygiene. Surgical excision is more reliable as it eliminates the hyperplastic tissue and promotes plaque

Phenytoin is an anticonvulsant prescribed for the control of epilepsy and neuralgias. In the present day, phenytoin is not usually prescribed as a first line drug for the management of epilepsy due to the availability of a wide range of newer, more effective anticonvulsant drugs with fewer side effects. The prevalence of drug-induced gingival overgrowth in patients taking phenytoin is reportedly between 15% and 60% [17]. Phenytoin, or its metabolites, probably acts directly on high activity fibroblasts leading to the high levels of production of collagen in the presence of inflammation. This results in gingival enlargement, characteristically originating principally from the interdental papillae (**Figure 1**). The amount or degree of severity of the overgrowth is not related to the dose of the drug. Presence of plaque and gingival inflammation, serum concentrations of the drug are factors which increases the risk of phenytoin-induced gingival

The management of this overgrowth is based on obtaining optimal control of plaque. Where the enlargement is unsightly and disfiguring, or even interfering

with columns of interspersed collagen fibers [12].

**2.3 Management of drug induced DIGO**

postoperative pain and bleeding [13].

control as well as improves the esthetics.

**2.4 Phenytoin**

overgrowth [37].

**58**

*A case of phenytoin induced gingival overgrowth.*

with chewing, the over-growths should be removed. Gingivectomy appears to be the simplest and best way of achieving good gingival contour as a post-operative result. But optimal plaque control post-operatively is the most important determinant of success. Recent research work suggests that the use of chlorhexidine, especially brushing daily using the gel, can be of valuable assistance in controlling plaque and hence in controlling the overgrowths in the post-surgical phase.

#### **2.5 Cyclosporin**

Cyclosporin (CsA) is a cyclic polypeptide with potent immunosuppressive activity used widely to prevent organ transplant rejection and also in the treatment of autoimmune diseases [38, 39]. CsA selectively suppresses helper T-cell function and modulates the network of inflammatory cytokines. However, cyclosporin is associated with several untoward effects like nephrotoxicity, hepatotoxicity, hirsutism and gingival overgrowth [40, 41]. Gingival overgrowth is one of the common side effects of CsA treatment, observed in 13–81% of the patients [6, 39]. The prevalence of gingival overgrowth associated with CsA averages around 30%, with reported rates ranging from 10 to 85% [25]. Studies have shown certain degree of association between GO and potential risk factors, such as age, genetic susceptibility, pharmacokinetic variables, plaque-related inflammation and immunological changes [42–44]. Epidemiological studies have reported wide variation of its occurrence and it accounts for more than 70% of the transplant recipients [4, 45]. The severity of gingival overgrowth is often associated with its prolonged use and further influenced by bacterial plaque and local irritants (**Figure 2**) [46]. The use of other medication, such as calcium channel blockers along with CsA increases the prevalence of gingival overgrowth and subsequently the risks [11]. The condition can interfere with the mastication, speech and oral hygiene maintenance and has a psychological impact in the affected individual [5].

The most prominent pathologic manifestation of the gingival overgrowth is an excessive accumulation of extracellular matrix, predominantly type I collagen. Many studies have shown increased transcriptional and translational levels of type I collagen in both tissue and fibroblast cultures derived from CsA-induced gingival overgrowth [9, 10, 47]. Though the exact mechanism is not clearly understood, studies also have shown increased expression of specific cytokines, especially transforming growth factor-beta (TGF-β), in drug-induced gingival overgrowth. This suggests that TGF-β, an inflammatory mediator that regulates cell proliferation and differentiation, plays a role in enlarging the extracellular matrix in hyperplastic gingival tissue [48].

**Figure 2.** *A case of cyclosporin A induced gingival overgrowth.*

The management of cyclosporin associated gingival overgrowth includes removal of local irritants and plaque and maintenance of adequate oral hygiene. Invasive procedures, such as gingivectomy is done in severe cases [49]. Currently the use of antibiotics has shown reduction in the GO associated with the drug usage. Azithromycin, a semi synthetic antibiotic, derived from the macrolide erythromycin has shown reduction in gingival overgrowth [50]. Roxithromycin, a macrolide antibiotic with similar characteristics of azithromycin, is also found to be effective in the reduction of gingival overgrowth in renal transplant recipients on CsA [25]. Gingival overgrowth can be prevented by intensive plaque-control practices including meticulous brushing, although critically ill patients receiving CsA may not be the ideal candidates for such intensive procedures. A combination of chlorhexidine or normal saline mouth rinses and mechanical cleaning was found to be effective in controlling the management of such patients [51, 52].

#### **2.6 Calcium channel blockers**

Drugs including diuretics, alpha and beta blockers, angiotensin converting enzyme inhibitors, angiotensin II type 1 receptor blockers and calcium channel blockers (CCBs) have been used to manage hypertension [53]. They are administered either alone or in combination, depending on the needs of the patient. The calcium channel blockers are the most frequently prescribed antihypertensive agents which is comprised of two subclasses, dihydropyridines and non-dihydropyridines. Although their mechanism of action is the same, they have varied pharmacological effects. While the dihydropyridines are potent vasodilators, the non-dihydropyridines produce more negative inotropic effects. The dihydropyridines such as nifedipine, amlodipine and felodipine are significantly associated with gingival overgrowth. The non-dihydropyridines such as diltiazem and verapamil are less commonly associated with gingival enlargement [54].

#### *2.6.1 Nifedipine*

Nifedipine, a drug that belongs to a pharmacological agent group known as calcium channel blocker was introduced in 1972 and has been used widely in the management of hypertension and angina pectoris. Lederman et al. [55] was the first to describe nifedipine-induced gingival overgrowth in patients treated with this drug. The prevalence of nifedipine-induced gingival overgrowth is between 30 and 50% and was found to be 3 times likely to develop in males [29]. The overgrowth

**61**

**Figure 3.**

*Adverse Effects of Medications on Periodontal Tissues DOI: http://dx.doi.org/10.5772/intechopen.92166*

forming growth factor-beta (TGF-β) [62].

*A case of nifedipine induced gingival overgrowth.*

*2.6.2 Amlodipine*

appears 1–9 months after administration of the drug and the most common sites affected included the labial anterior gingiva of both jaws [56, 57]. A multifactorial pathogenesis has been suggested including environmental, genetic, immunological and inflammatory factors [58]. The interdental papilla becomes more grossly enlarged followed by the marginal and the attached gingiva (**Figure 3**). Presence of gingival periodontal disease and dental plaque has been reported as significant risk factors in the development of gingival enlargement. Several hypotheses have been put forward to explain the phenomena of the gingival overgrowth. The interaction between nifedipine and gingival fibroblasts contain increased sulfated mucopolysaccharides which are precursors of ground substance, leading to the overproduction of collagen and extracellular ground substance [59]. A genetically specific predetermined subpopulations of fibroblasts are identified which are sensitive to nifedipine and cause an increase in the production of collagen [60]. The dose of nifedipine is important and it was found that its presence in gingival crevicular fluid is 15–316 times higher than plasma. The higher concentration of nifedipine in the gingival crevicular fluid could increase the severity of gingival enlargement.

Amlodipine is a third-generation dihydropyridine calcium channel blockers (CCB) that is used in the management of both hypertension and angina. The prevalence of gingival overgrowth associated with amlodipine is between 1.7% and 3.3% [35]. Though the etiopathology of this adverse reaction is not clearly understood, mechanisms such as inflammatory and non-inflammatory pathways have already been hypothesized. The non-inflammatory mechanisms involves a defective collagenase activity due to decreased uptake of folic acid, blockage of aldosterone synthesis in the adrenal cortex and consequent increase in Adrenocorticotropic hormone level, and up-regulation of keratinocyte growth factor [61]. The inflammatory pathway develops as a result of direct toxic effects of concentrated drug in gingival crevicular fluid and bacterial plaques leading to the up-regulation of several cytokine factors such as trans-

The gingival overgrowth normally begins at the interdental papillae and is more frequently found in the anterior segment of the labial surfaces. Subsequently gingival lobulations that develop might appear as inflamed or fibrotic in nature depending on the degree of contributing factors (**Figure 4**). Normally the fibrotic enlargement is confined to the attached gingiva which might advance coronally and *Adverse Effects of Medications on Periodontal Tissues DOI: http://dx.doi.org/10.5772/intechopen.92166*

appears 1–9 months after administration of the drug and the most common sites affected included the labial anterior gingiva of both jaws [56, 57]. A multifactorial pathogenesis has been suggested including environmental, genetic, immunological and inflammatory factors [58]. The interdental papilla becomes more grossly enlarged followed by the marginal and the attached gingiva (**Figure 3**). Presence of gingival periodontal disease and dental plaque has been reported as significant risk factors in the development of gingival enlargement. Several hypotheses have been put forward to explain the phenomena of the gingival overgrowth. The interaction between nifedipine and gingival fibroblasts contain increased sulfated mucopolysaccharides which are precursors of ground substance, leading to the overproduction of collagen and extracellular ground substance [59]. A genetically specific predetermined subpopulations of fibroblasts are identified which are sensitive to nifedipine and cause an increase in the production of collagen [60]. The dose of nifedipine is important and it was found that its presence in gingival crevicular fluid is 15–316 times higher than plasma. The higher concentration of nifedipine in the gingival crevicular fluid could increase the severity of gingival enlargement.

#### *2.6.2 Amlodipine*

*Oral Diseases*

**Figure 2.**

The management of cyclosporin associated gingival overgrowth includes

Drugs including diuretics, alpha and beta blockers, angiotensin converting enzyme inhibitors, angiotensin II type 1 receptor blockers and calcium channel blockers (CCBs) have been used to manage hypertension [53]. They are administered either alone or in combination, depending on the needs of the patient. The calcium channel blockers are the most frequently prescribed antihypertensive agents which is comprised of two subclasses, dihydropyridines and non-dihydropyridines. Although their mechanism of action is the same, they have varied pharmacological effects. While the dihydropyridines are potent vasodilators, the non-dihydropyridines produce more negative inotropic effects. The dihydropyridines such as nifedipine, amlodipine and felodipine are significantly associated with gingival overgrowth. The non-dihydropyridines such as diltiazem and verapamil

Nifedipine, a drug that belongs to a pharmacological agent group known as calcium channel blocker was introduced in 1972 and has been used widely in the management of hypertension and angina pectoris. Lederman et al. [55] was the first to describe nifedipine-induced gingival overgrowth in patients treated with this drug. The prevalence of nifedipine-induced gingival overgrowth is between 30 and 50% and was found to be 3 times likely to develop in males [29]. The overgrowth

are less commonly associated with gingival enlargement [54].

removal of local irritants and plaque and maintenance of adequate oral hygiene. Invasive procedures, such as gingivectomy is done in severe cases [49]. Currently the use of antibiotics has shown reduction in the GO associated with the drug usage. Azithromycin, a semi synthetic antibiotic, derived from the macrolide erythromycin has shown reduction in gingival overgrowth [50]. Roxithromycin, a macrolide antibiotic with similar characteristics of azithromycin, is also found to be effective in the reduction of gingival overgrowth in renal transplant recipients on CsA [25]. Gingival overgrowth can be prevented by intensive plaque-control practices including meticulous brushing, although critically ill patients receiving CsA may not be the ideal candidates for such intensive procedures. A combination of chlorhexidine or normal saline mouth rinses and mechanical cleaning was found to be effective in controlling the

management of such patients [51, 52].

*A case of cyclosporin A induced gingival overgrowth.*

**2.6 Calcium channel blockers**

**60**

*2.6.1 Nifedipine*

Amlodipine is a third-generation dihydropyridine calcium channel blockers (CCB) that is used in the management of both hypertension and angina. The prevalence of gingival overgrowth associated with amlodipine is between 1.7% and 3.3% [35]. Though the etiopathology of this adverse reaction is not clearly understood, mechanisms such as inflammatory and non-inflammatory pathways have already been hypothesized. The non-inflammatory mechanisms involves a defective collagenase activity due to decreased uptake of folic acid, blockage of aldosterone synthesis in the adrenal cortex and consequent increase in Adrenocorticotropic hormone level, and up-regulation of keratinocyte growth factor [61]. The inflammatory pathway develops as a result of direct toxic effects of concentrated drug in gingival crevicular fluid and bacterial plaques leading to the up-regulation of several cytokine factors such as transforming growth factor-beta (TGF-β) [62].

The gingival overgrowth normally begins at the interdental papillae and is more frequently found in the anterior segment of the labial surfaces. Subsequently gingival lobulations that develop might appear as inflamed or fibrotic in nature depending on the degree of contributing factors (**Figure 4**). Normally the fibrotic enlargement is confined to the attached gingiva which might advance coronally and

**Figure 3.** *A case of nifedipine induced gingival overgrowth.*

**Figure 4.** *A case of gingival overgrowth in a patient on amlodipine.*

interfere with esthetics, mastication, or speech [63]. Management of amlodipine induced gingival overgrowth includes substitution of the drug and controlling the other risk factors with meticulous mechanical and chemical plaque control. Surgical management of the overgrowth is advised in cases to accomplish an esthetic and functional outcome [64].
