Journal of Human Hypertension (2014) 28, 10–14

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REVIEW
Calcium channel blocker-induced gingival enlargement
R Livada and J Shiloah

Despite the popularity and wide acceptance of the calcium channel 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: drug-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
medication to prevent recurrence of the lesions. In addition, depending on the severity of the gingival overgrowth, nonsurgical and
surgical periodontal therapy 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; gingivectomy

INTRODUCTION side effects, including tachycardia, facial flushing and, among

The research of calcium channel was pioneered by Fatt and Katz1
with their work on large muscle cells of crab. Subsequent work by
Fleckenstein2 sparked a major therapeutic advance in managing
patients with heart diseases and to a new class of drug: calcium
channel blockers (CCBs).
This class derives its main therapeutic effects by preventing
calcium ion influx through the cell membranes. It binds to
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
relaxation of vascular smooth muscles and vasodilation,
a decrease in myocardial force output (negative inotropy), a
reduction in heart rate (negative chronotropy) and a decrease in
conduction velocity within the heart (negative dromotropy). By
causing vascular smooth muscle relaxation, CCBs decrease
systemic vascular resistance, which in turn reduces arterial blood
pressure. These drugs primarily affect arterial resistance, with only
minimal effects on venous vessels. Because of their dual action on
the heart and blood vessels, CCBs are widely used for managing
hypertension, angina and supraventricular cardiac arrhythmias. As
a class, they ranked eighth in prescription sales in the United
States (Intercontinental Medical Statistics Health Canada), and the
most frequently prescribed CCB among adults is amlodipine3
(Table 1 lists available CCBs in the United States).
The interaction of CCBs with the cell membrane is a complex
process. Three distinctive but allosterically interacting receptors
have been identified on the cell membrane and are blocked
by different chemical compounds—(1) dihydropyridines
(nifedipine-like drugs; for example, amlodipine and isradipine),
(2) phenylalkylamines (verapamil-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
three waves or generations;4 the first one was developed
in the 1970s and included dihydropyridines, phenylalkylamines
and benzothiazepines derivatives. This generation had multiple
others, gingival overgrowth.5The following generations of
dihydropyridines (nitrendipine,6 oxydipine7 and amlodipine8)
were intended to overcome these adverse effects, but were
unable to prevent the drug-induced gingival overgrowth in some
patients.9 The overall objective of this article is to review current
data regarding the impact of CCBs on the gingiva, its clinical
manifestations and management.
GINGIVAL ENLARGEMENT
Despite their popularity and wide acceptance by the medical
community, the oral impact of CCB therapy 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: drug-induced gingival enlargement
or overgrowth. This benign oral condition is a common side
effect of the majority of CCBs. It is characterized by an increase
of the gingival mass and volume, which can range from mild to
extremely severe.
Among calcium antagonists, nifedipine is the most frequently
implicated antagonist in drug-induced gingival overgrowth.10
Lederman et al.11 were the first to report its negative oral
effects in 1984; subsequent studies showed that its prevalence
varied from 14%12 to 83%.13 As for Verapamil14 and amlodipine,
the prevalence was significantly lower (4.2% and 3.3%,
respectively) than that of nifedipine.8 Since then, numerous
reports have associated gingival enlargement with the newer
generation of CCBs, such as felodipine,15 nicardipine,16
manidipine17 and diltiazem.18
CLINICAL FEATURES
The drug-induced gingival enlargement could be detected
clinically as early as 1–3 months following the initial dose of
CCB. Although the overgrowth does not seem to affect edentulous

Department of Periodontology, College of Dentistry, 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: rlivada@uthsc.edu
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
Nisoldipine
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 bacteria that are
Figure 2. Severe gingival enlargement causing esthetic and func-
beyond the reach of a toothbrush or dental floss. These negative tional problems. Patient is unable to achieve optimal oral hygiene.
changes impair optimal oral hygiene and can lead to an increased
host susceptibility to oral infection, caries and periodontal disease.
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 edema, erythema
and bleeding. The latter form is especially seen in patients with
poor oral hygiene. Although CCBs do not directly affect the
underlying alveolar bone, the gingival enlargement may increase
accumulation of bacterial biofilm and prevent adequate oral
hygiene measures, thus inducing inflammation, periodontitis,
bone and tooth 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 phenytoin or cyclosporine. The increase in the
gingival tissue volume is primarily due to a connective tissue
response rather than an epithelial cell proliferation. It is
characterized by an excessive accumulation of extracellular matrix
proteins, such as collagen, amorphous ground substance and of
noncollagenous proteins, such as glycosaminoglycans.21 The
lesion appears highly vascularized and covered by a
parakeratinized epithelium of varying thickness. Epithelial ridges
penetrating deep into the connective tissue could be seen in
some specimens. The chronic inflammatory infiltrate is dominated
by plasma cells and in a lesser degree by lymphocytes.
ETIOLOGY (PATHOGENESIS)
The pathogenesis of drug-induced gingival enlargement is not
fully understood. Several possible mechanisms and pathways have
been proposed over the years. However, there is lack of general
consensus on this issue. Below are some of the most cited causes
and risk factors of gingival overgrowth:
Figure 3. Lobulated appearance of gingival enlargement in a female
patient taking amlodipine. Note the poor hygiene and abundant
microbial plaque.
Role of matrix metalloproteinases
The hallmark of the enlargement is the increase in the amount of
connective tissue matrix dominated by collagen fibers. Collagen
synthesis is controlled by matrix metalloproteinases and the tissue
inhibitor of metalloproteinases. Collagen fibers are degraded via
an extracellular pathway by secretion of collagenases and via an
intracellular pathway via phagocytosis by fibroblasts. CCBs affect
calcium metabolism by reducing the Ca2 þ cell influx, leading
to a reduction in the uptake of folic acid, thus limiting the
production of active collagenase.22 As a result of the reduction in
collagen degradation, increased collagen accumulation occurs.
Other possible pathways for the gingival enlargement is
overproduction of extracellular ground substance characterized
by increased presence of sulfated mucopolysaccharides
(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 cytokines
Proinflammatory cytokines, such as interleukin-1b and interleukin-
6 seem to have a synergistic effect in the enhancement
of collagen synthesis by human gingival fibroblasts.23
Interleukin-6 has been shown to target connective tissue cells,
such as fibroblasts, both by enhancing their proliferation and by
increasing collagen production and glycosaminoglycan
synthesis.24 This highlights the role of the bacterial biofilm
in inducing gingival inflammation, production of cytokines and
gingival enlargement.
Role of fibroblasts
The finding that the majority of patients treated with CCBs does
not develop gingival enlargement lead to the discovery of a
subset of fibroblasts that are susceptible to CCBs. A genetic
predisposition of different fibroblasts phenotypes to CCB may
be related to the human lymphocyte antigen.25 However, there is
a lack of clinical markers to identify susceptibility to CCBs and
patients who are at risk, besides their level of oral hygiene. Other
genetic predisposition could influence the metabolism of CCBs,
as these drugs are metabolized by the hepatic cytochrome
P450 enzymes. Cytochrome P450 genes exhibit considerable
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,
and hence their gingival response.26
RISK FACTORS
Dental plague and oral hygiene level
The oral bacterial biofilm is a common risk factor for all forms
of inflammatory periodontal diseases and its presence exacerbates
CCB-induced gingival enlargement. The severity of gingival
enlargement is well correlated with poor oral hygiene. The
importance of the microbial plaque as a cofactor in the etiology of
drug-associated gingival enlargement has been recognized
in a recent classification system of periodontal diseases by the
American Academy of Periodontology.27 The finding that the
gingival overgrowth is almost exclusively related to dentate areas
suggests that factors attached to the dentition, such as bacterial
dental plaque, have a role in gingival enlargements. Whether
these lesions are preventable by professional toothcleaning and
installation of good oral hygiene habits before prescribing this
class of drug is unknown and requires clinical trials.
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
that a daily dose of 5 mg or higher could be a risk factor for
gingival overgrowth in some patients.8
Journal of Human Hypertension (2014) 10 – 14
PHARMACOKINETICS
Several reports have implicated nifedipine more often than any
other member of this class of drugs for inducing gingival
enlargement. Patients taking nifedipine are at significant
higher risk for developing overgrowth than those taking either
amlodipine or diltiazem.28 These drugs are structurally similar
(dihydropyridines), but amlodipine is more polarized and requires
a complex transport mechanism to penetrate the cell membrane.
In contrast, nifedipine is highly lipophilic and penetrates the
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
possible factor that accounts for the differences between
amlodipine and nifedipine is the variation in their half-lives and
their volume of distribution (amlodipine: 34 h and 21 l kg  1;
nifedipine: 7.5 h and 0.78 l kg  1). Amlodipine’s higher volume
indicates that the majority of amlodipine is tissue bound (hence
‘inactive’) and does not circulate freely in the blood. It has been
suggested that a plasma threshold may exist above which drug-
induced gingival changes are initiated.30 Amlodipine rarely
achieves such threshold levels, unlike nifedipine, which tend to
exhibit pronounced peak plasma levels, possibly affecting drug-
induced gingival enlargement.
TREATMENT OF DRUG-INDUCED GINGIVAL ENLARGEMENT
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.
These include B-blockers, diuretics or angiotensin-converting
enzyme inhibitors. Drug-induced gingival overgrowth has not
been reported with any of these drugs.31 Another option is
substitution with another CCB drug that has a lower risk
of inducing gingival enlargement (for example, verapamil11 or
isradipine32). Despite these options, physicians and patients are
often reluctant to switch to other regimen, especially if the blood
pressure is well controlled or other options have been already
explored. If regimen change is not an option, the lesions should be
managed with or without surgical intervention.
Nonsurgical periodontal treatment
Nonsurgical management of gingival enlargement is usually a
treatment of choice in patients with mild to moderate gingival
overgrowth. Professional mechanical removal of the dental plaque
and calculus, through scaling and root planing, has shown positive
Figure 4. The post-operative appearance of patient in Figure 2
following gingivectomy to remove excess gingival tissue and restore
physiologic architecture.
& 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

gingivoplasty 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 hemostasis. Slower wound healing due
gingivoplasty via used in dentistry for over Used in patient where post-surgical to thermal necrosis.
electrosurgery 70 years. bleeding is Not applicable for all cases.
expected (patients with bleeding Should not be used for patients with
disorders, pacemaker.
anticoagulant 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
Antimicrobial 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
inflammatory component. Good oral hygiene and home care
are pivotal in preventing further inflammation and maintaining
the positive results achieved with dental care and must include
periodic professional tooth cleaning.33 Adjunctive antimicrobial
oral rinses with chlorhexidine gluconate have been recommended
in managing gingival overgrowth.
For patients with mild gingival enlargement, these measures
could reduce the overgrowth to acceptable levels, thereby
making surgical treatment unnecessary. However, in moderate
gingival overgrowth the nonsurgical treatment would shorten
the subsequent surgical intervention and reduce the risk of
post-operative infection.
Surgical periodontal treatment
The main objective of the surgical intervention is resection of the
excess tissue, elimination of pockets and restoration of tissue
contour, appearance and function (Figure 4). The classical surgical
approach is gingivectomy and gingivoplasty. This procedure
could be performed with blades, surgical knives, electrosurgery
or with dental laser. Table 2 summarizes the advantages and
disadvantages of the above surgical methods.
Recurrence
The risk of recurrence of drug-induced gingival enlargement has
been reported in both surgical and nonsurgical methods—
especially if cessation of the offending drug was not an option
or was temporary. Recurrence could occur as early as 3–6 months
following the surgical intervention, and could affect as many as
40% of the patients.34 It appears that the risk of recurrence is
higher in patients with poor oral hygiene or lack of dental care.
SUMMARY
The CCBs are important components of managing patient
populations with hypertension, angina or supraventricular cardiac
arrhythmias. However, a serious and often overlooked side effect
of this class of drugs affects some patients. Gingival overgrowth is
a common oral finding in these patients. Drug cessation and a
substitution to other class of antihypertensive medications is the
best treatment option. Otherwise, these lesions could be managed
by nonsurgical or surgical techniques that only provide a
short-time relief, as recurrence is to be expected if the offending
drug is continued.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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