Case report on low dose of Cilnidipine: A fourth-generation calcium channel blocker-induced gingival overgrowth.

Drug-induced gingival overgrowth is a frequently observed adverse effect of antihypertensive drug calcium channel blockers (CCBs). Gingival enlargements are more common with the dihydropyridine class of CCBs. The fourth-generation dihydropyridine CCB Cilnidipine was introduced in 1995 and is used as an antihypertensive agent for patients in the Indian subcontinent. This is the first report in literature to document an isolated case of generalized gingival overgrowth induced by the long-term use of low dose of cilnidipine in an elderly female patient who is under antihypertensive therapy. Gingival overgrowth is an adverse drug reaction of new-generation CCB Cilnidipine when administered even as low-dose antihypertensive therapy agent. Physicians and dentists should identify such late changes in susceptible individuals.

INTRODUCTION

Drug-induced gingival overgrowth (DIGO) is an adverse effect of anticonvulsants, immunosuppressants, and calcium channel blockers (CCBs).[12] CCBs are a class of widely used antihypertensive agents. DIGO is more common with the dihydropyridine class of CCB. The first- and second-generation dihydropyridines (nifedipine, verapamil, diltiazem, and amlodipine) are associated with DIGO.[34] The prevalence of nifedipine-induced gingival overgrowth ranges from 20% to 83%, while for other CCBs such as diltiazem, amlodipine, and verapamil, the prevalence is around 74%, 3.3%, and 21%, respectively.[34]

The fourth-generation dihydropyridine CCBs are now in common use as antihypertensive agents. Cilnidipine is a promising fourth-generation CCB that came into market in 1995 and is widely used as an antihypertensive agent in India. So far, only one case of fourth-generation dihydropyridine-induced gingival overgrowth has been reported in literature.[4] It was a report of a Japanese patient who had a combination therapy of Cyclosporin A and Cilnidipine. Interestingly, DIGO is a known adverse effect of the immunosuppressant Cyclosporin A.[1] Our case report could be the first report in literature to document the gingival overgrowth as an adverse effect of the long-term use of low-dose Cilnidipine alone.

CASE REPORT

A 55-year-old female patient, taking once-daily dosage of Cilnidipine – 5 mg, was referred by her physician to the Periodontics division of our Dental College, for improving her oral hygiene [Figure 1a-c]. She was under antihypertensive treatment for 6 years. She gave a history of slowly progressing enlargements on her gums for 1 year. She also reported discomfort while brushing the teeth due to bleeding from gums in the last 6 months after which the size of the swelling enlarged rapidly.

Figure 1

(a) Frontal view of the patient demonstrating the drug-induced gingival enlargement, complicated by secondary inflammatory changes; (b) left lateral view; (c) right lateral view

Intraorally, the gingiva was enlarged in relation to maxillary and mandibular teeth, and it was firm, diffuse, and lobulated and characteristically appears to project from beneath the gingival margin, with Grade II to Grade III gingival overgrowth according to Buchner et al.'s grading criteria. In the maxillary arch, the overgrowth extended labially from 22 to 27; it was localized around 12. In the mandibular arch, the overgrowth extended labially from the distal aspect of 33–43 regions and localized around 46. There was minimal involvement of the palatal or lingual areas. Few areas showed signs of secondary inflammatory changes. Teeth in the involved area had plaque and calculus. The Oral Hygiene Index score was 2 (fair oral hygiene). The presence of the enlargement made plaque control difficult, resulting in secondary inflammatory changes especially in the mandibular teeth, which complicated the gingival overgrowth caused by the drug. Since she was undergoing antihypertensive therapy and no other known drugs which could induce gingival overgrowth were prescribed, the case was clinically diagnosed as drug-induced (Cilnidipine) gingival overgrowth with secondary inflammatory changes which was confirmed histologically.

Histologically, there was pronounced hyperplasia of the connective tissue and epithelium. There was acanthosis of the epithelium and elongated rete pegs were extending into the connective tissue, along with densely arranged collagen bundles, many fibroblasts and new blood vessels, and few inflammatory cell infiltrates [Figure 2].

Figure 2

Histopathologic view

Clinical management

She was advised to undergo a full-mouth periodontal rehabilitation along with drug modification after consulting her physician. Unfortunately, 1 week later, we lost the patient as she succumbed to massive cardiac arrest. A limitation of this case report is that radiographs could not be obtained, and importantly, we could not deliver dental treatment for her.

DISCUSSION

DIGO is an adverse effect of anticonvulsants, immunosuppressants, and CCBs [12] with some common clinical characteristics such as genetic predisposition, more prevalent in anterior gingiva, younger individuals, and onset within 3 months of use.[5678]

CCBs are drugs that were developed for the treatment of various cardiovascular conditions. These drugs are the dihydropyridine derivatives, the benzothiazine derivatives, and the phenylalkylamine derivatives. The first- and second-generation dihydropyridines (e.g., nifedipine, verapamil, diltiazem, and amlodipine) are associated with DIGO.[34] CCBs inhibit the intracellular Ca2+ uptake and stimulate the gingival fibroblasts. There exists a functional heterogenicity in the gingival fibroblasts in response to various stimuli.[1] Only susceptible patients receiving the same drug develop DIGO. Individuals with DIGO may have fibroblasts with an abnormal susceptibility or fibrogenic response to the drug.

Several factors may be involved in the pathophysiology of CCB-induced gingival overgrowth. Age and genetic predisposition of the host, alteration in gingival connective tissue homeostasis, pharmacokinetic variables, inflammatory changes, and drug action on growth factors are few of the factors. The pathogenesis of DIGO involves both noninflammatory and inflammatory pathways. The noninflammatory pathway includes (1) defective collagenase activity which could be due to decreased uptake of folic acid, (2) the blockage of aldosterone synthesis in the adrenal cortex and consequent feedback increase in adrenocorticotropic hormone level, and (3) upregulation of keratinocyte growth factor. Inflammation may develop as a result of (1) the direct toxic effects of the concentrated drug in the crevicular gingival fluid and/or (2) bacterial plaques which upregulate several pro-inflammatory cytokines such as transforming growth factor-β1, interleukin 1 (IL-1) β, and IL-6.[1] Many studies have shown an association between the oral hygiene status and severity of DIGO.[12] In the present case, the poor plaque control had worsened the existing gingival enlargement and therefore further complicated the oral hygiene maintenance.

Many reports have shown that Amlodipine 10 mg/day caused DIGO within the first 6 months of use.[123] Interestingly, there are only few reports on DIGO induced by short-term administration of low-dose Amlodipine (5 mg).[9] For the first time in literature, this is a case report on Cilnidipine alone-induced gingival enlargement. In contrast to the available knowledge on CCB-induced gingival overgrowths, our case is unique since it highlights (1) a fourth-generation CCB cilnidipine-induced gingival enlargement, (2) low-dose drug-induced changes, and (3) long-term adverse effect of the drug. The structural similarity of cilnidipine with other dihydropyridines can be hypothesized to be the probable reason for this adverse drug reaction (ADR).

The ADR Probability Scale often referred to as the Naranjo Scale is a method to assess whether there is a causal relationship between an identified untoward clinical event and a drug using a simple questionnaire to assign probability scores.[10] This scale was developed to help standardize assessment of causality for all ADRs except drug-induced liver injury [Table 1]. According to this ADR scale, a “probable” causal relationship with Cilnidipine was assessed by Naranjo score (score = 4). Furthermore, a “possible” causal relationship is assessed using the World Health Organization-Uppsala Monitoring Centre scale for causality assessment [Table 2].[11] More cases of DIGO caused by Cilnidipine need to be diagnosed and assessed after treatment to confirm the causal relationship.

Table 1

Calculation of adverse drug reaction for Cilnidipine based on Naranjo adverse drug reaction probability scale

Question	Yes	No	Don’t know	Score
Are there previous conclusive reports on this reaction?	+1	0	0	0
Did the adverse event appear after the suspected drug was administered?	+2	−1	0	+2
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+1	0	0	0
Did the adverse event reappear when the drug was readministered?	+2	−1	0	0
Are there alternative causes (other than the drug) that could on their own have caused the reaction?	−1	+2	0	+2
Did the reaction reappear when a placebo was given?	−1	+1	0	0
Was the drug detected in blood (or other fluids) in concentrations known to be toxic?	+1	0	0	0
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
Was the adverse event confirmed by any objective evidence?	+1	0	0	+1

Total score >9 - Definite ADR; 5-8 - Probable ADR; 1-4 - Possible ADR; 0 - Doubtful ADR. ADR–Adverse drug reaction

Table 2

The World Health Organization-Uppsala Monitoring Centre causality assessment scale

Causality term	Assessment criteria (all points should be reasonably complied)
Certain	Event or laboratory test abnormality; with plausible time relationship to drug intake Cannot be explained by disease or other drugs Response to withdrawal plausible(pharmacologically, pathologically) Event definitely pharmacologically or phenomenologically (ie; an objective and specific medical disorder or a recognized pharmacological phenomenon) Rechallenge satisfactory; if necessary
Probable /Likely	Event or laboratory test abnormality; with reasonable time relationship to drug intake Unlikely to be attributed to disease or other drugs Response to withdrawal clinically reasonable Rechallenge not required
Possible	Event or laboratory test abnormality; with reasonable time relationship to drug intake Could also be explained by disease or other drugs Information on drug withdrawal may be lacking or unclear
Unlikely	Event or laboratory test abnormality; with a time to drug intake that makes a relationship improbable (but not impossible) Disease or other drugs provide plausible explanation
Conditional/ Unclassified	Event or laboratory test abnormality More data for proper assessment needed , or Additional data under examination
Unassessable /Unclassified	Report suggesting an adverse reaction Cannot be judged because information is insufficient or contradictory Data cannot be supplemented or verified

Adapted from Syed AZ. Adverse drug reactions and causality assessment scales - Letter to the Editor. Lung India 2011;28:152-3.

To summarize, gingival overgrowth is an ADR of new-generation CCB Cilnidipine when administered even as low dose (5 mg). Physicians and dentists should identify such late changes in susceptible individuals. Interdisciplinary approaches in them need to be focused on terminating or modifying the offending drug along with effective oral hygiene maintenance measures.

CONCLUSION

For the first time in the literature on DIGO case reports, this is a case report of cilnidipine-alone-induced gingival enlargement with some unique characteristics: (1) A fourth-generation CCB cilnidipine-alone-induced gingival hyperplasia, (2) low-dose-induced changes, and (3) long-term adverse effect of this antihypertensive drug. Interdisciplinary approaches focused on terminating or modifying the offending drug along with effective oral hygiene maintenance measures.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.