J Clin Periodonlol 1994; 21: 281-283 Copyright (C Munk.

-igaard 1994
Primed in Denmark . All rights reserved

Clinical periDdontoiogy
ISSN 0303-6979

R. A. Seymour\ J. S. Ellis\
Amiodipiiie-iiiduced gingival J. M. Thomason^ S. Monkman^ and
J. R. Idle""

overgrowth 'Departments of 'Restorative Dentistry, and

^Pharmacological Sciences, University of
Newcastie-ypon-Tyne, Framiington Place,
Newcastle-upon-Tyne, NE2 4BW, UK

Seymour RA, Ellis JS, Thomason JM, Monkman S and Idle JR: Amlodipine-
induccd gingival overgrowth. J Clin Periodontol 1994; 21: 281-283.
© Munksgaard, 1994.

Abstract. Amlodipine is a calcium channel blocker used in the management of

angina and hypertension. We report 3 cases of gingival overgrowth in adult dentate
patients associated with chronic usage of this drug, Gingival changes occurred
within 3 months of dosage and appeared to be compounded by the patient's
Key words: amiodipine; dihydropyridines; cai-
existing periodontal condition. In all 3 patients, there was sequestration of amlodi- cium channel blockers; ginginai overgrowth.
pinc in their crevieuiar fluid. The significance of this finding in relation to the
pathogenesis of this unwanted effect remains lo be elucidated. Accepted for pjbilcation 27 May 1993

Gingival overgrowth is now a recog-
nised unwanted effect associated with
many of the calcium channel blockers.
Of this large group of drugs, the dihyd-
ropyridines (i,e,, nifedipine. nitrendipi-
ne, felodipine) are the agents most fre-
quently implicated (Seymour, 1991).
However, this may be a reflection on
their widespread usage. Amiodipine is a
comparatively new dihydropyridine cai-
cium channel blocker that is used in the
management of both hypertension and
angina. Unwanted effects associated
with chronic usage of amJodipine are
few and are mainly related to vaso-
dilation. Although gingival overgrowth
does not appear to have been reported
in association with amiodipine, we have
recently observed 3 patients with this
unwanted effect. This report discusses
the clinical and pharmacokinetic fea-
tures of three adults with amlodipine-
induced gingival overgrowth.
Materiai and iVIethods
3 adult patients were referred to the De-
partment of Periodontoiogy for investi-
gation and treatment of their gingival
enlargement. All patients were receiving
amiodipine for treatment of hyperten-
sion and/or angina, A further patient,
medicated with amiodipine, but with no
evidence of gingival enlargement, acted
as a control. Demographic details of the
patients are shown in Table 1,
Periodontal examination
The patient's oral hygiene was assessed
using the visible plaque index (Aina-
mo & Bay 1975) on the lingual, labial
and interproxima! surfaces of all the
teeth. The number of tooth surfaces
where plaque was detected was ex-
pressed as a percentage of the total
number of surfaces.
The gingiva] bleeding index (Aina-
mo & Bay 1975) was used to assess the
patient's gingival condition. Peri-
odonta! probing depths were measured
to the nearest mm using a colour-coded
probe (PC.P, Hu Friedy), All measure-
ments were taken from the crest of the
gingival margin at 4-points around each
tooth (mesial, distal, mid-point buccal
and lingual). The number of sites with
a probing depth > 3 mm, together with
the number of sites which bled on prob-
ing, were recorded and expressed as a
% of the total number of sites measured.
Upper and lower fuil-mouth alginate
impressions were taken for each patient.

Table 1, Patients' demographic and periodontal variables

% sites with
Age Plaque Bleeding index probing depth Hyperplasia
Patient (year) Sex index (%) (%) of > 3 mm index (%) Treatment/outcome

1 66 F 100 11 17 46 gingivectomy and maintenance regimen

2 59 F 59 V ^ change in drug therapy to bendrofluazide: con-

86 siderable improvement in gingival condition

•\ IS M 46 14 29 53 gingivectomy and maintenance regimen

 282 Sevmour et al.
Table 2, Amiodipine dosages and pharmaeokinetics in plasma and gingival crevicular fluid (GCF)
Amiodipine dosage
Patient (mg/day)
no.
I 4
2 5
3 10
HH (control) 5 6
Gingival overgrowth was assessed on
the plaster study models by the method
described by Seymour et al. (1985).
Amiodipine assay
Sample coUcction
Consent was obtained from the patients
lo take a !0 ml venous blood sample
and to harvest crevicular fluid for sub-
sequent analysis in duplicate for amiodi-
pine. Samples were taken consecutively
approximately 1 h after dosage, and col-
lected in a room lit by yellow light in
order lo prevent photodegradation.
Venous blood was centrifuged for 10
min and the plasma removed and frozen
at — 4 C before analysis.
Fig, I. Clinieai views of anterior teeth in pa-
tients exhibiting amlodipine-induced gingival
oveergrowth.
Duration of Plasma coneentration
therapy (/ig/litre)
(months)
13.7
6 11.5
8 12.8
8.7
2 sites were chosen from each patient
for the collection of crevicular fluid.
Sites had a significant probing depth
and exhibited marked gingival enlarge-
ment. Both measures were to ensure an
adequate harvest of fluid. Sites were
carefully dried under a stream of warm
air and isolated with cotton wool roll.
Two filler papers (Periopapers) were in-
serted into the erevice and left unlil a
visible amount of fluid had coHecled.
The filter papers were removed and the
quantity of fluid collected was measured
on a previously calibrated Periotron.
The filter papers were placed in 1 ml of
phosphate buffer and rocked gently for
48 h to ensure maximum extraction of
GCF from the papers.
Samp!e analysis
.A. range of standards were prepared for
plasma and GCF analysis. An internal
standard of nisoldipine was added to
standards and samples which were then
extracted into toluene. Derivitisation
was then carried out using trifluoracetic
anhydride. GCF samples were evapor-
ated to dryness and reconstituted in 100
fi\ of toluene. 0.2 ^1 aliquots of plasma
and GCF standards and samples were
then injected into the gas chromato-
graph.
Concentration of amiodipine in the
patient samples was calculated from the
peak area ratio of the respective stan-
dard curves.
Results
The periodontal and amiodipine phar-
macokinetic variables for the 3 patients
and the control are shown in Tables 1,
2, respeciivcly. The gingival condition
ofthe three responder patients is shown
in Fig. 1. These patients showed both
high plaque scores and % number of
sites with a probing depth > 3 mm. Ail
had a gingival overgrowth index in ex-
cess of 3O'K, which is regarded as clin-
ically significant and thus warrants sur-
gical excision.
Dosages and plasma concentrations
of amiodipine for all patients were
G.C.f. eoncentration Plasma: GCF
(//g/litre) ratio
4000 l:2yO
260 1:19
2730 1:213
none detected
within the normal therapeutic range
(Abernethy 1989). Amiodipine was de-
tected in Ihe crevicular Huid of all three
responder patients, but not in the con-
trol (Table 2). 2 of the responder pa-
tients (nos. 1. 3) exhibited marked
sequestration of the drug in the crevic-
ular fiuid.
Gingivectomy has been completed on
one of the patients and the tissue
showed a hyperplaslic gingivitis,
characterised by a stroma of loose col-
lagen, plump active fibroblasts and an
abundance of ground .substance. The
o\'er!ying epithelium showed acantholy-
tic changes. These features are consist-
ent with the histopathologicai features
of other drug-induced gingival over-
growths.
Discussion
Evidence from the 3 cases suggests that
amiodipine can be included in the lisi of
dihydropyridines which cause gingival
overgrowth. There is no information on
the prevalence of this unwanted effect
and further investigations are required.
Apart from nifedipine, other dihydro-
pyridines which have been implicated in
the unwanted effect of gingival over-
growth include nitrendipine (Browti et
al. 1990, Heijl & Sundin, 1989), oxodip-
ine(Waneretai. 1988, Nyska etai. 1990)
and felodipine(Lombardi etal. 199!).
Previous studies have shown that ap-
proximately 10% of dentate patients
medicated with nifedipine experience
clinieally significant gingival over-
growth (Barclay et al. 1992. Barak et al.
1987), whilst the prevalence reported for
verapamil is approximately 4"A^ (Mil-
ler & Damm, 1992). These findings sug-
gest that the dihydropyridines are more
frequently cited as a cause of drug-in-
duced gingival overgrowth than other
types of calcium channel blockers.
However, this may be a reflection on
the usage of these drugs.
The pathogenesis of amlodipine-in-
duced gingival overgrowth, together
with that of the other dihydropyridines
remains uncertain. All 3 responder pa-

tients had significant periodontal prob-
lems at the time of presentation (Table
1). Tt is thus difficult to establish
whether the high plaque scores obsen'ed
in these patients are the cause or the
consequence of the drug-induced gingi-
val enlargement. A larger cohort of pa-
tients is required to investigate the re-
lationship between the incidence and se-
verity of amiodipine-induccd gingiva]
overgrowth with the patients' peri-
odontal status.
2 of our patients' previous and sub-
sequent drug histories, provide further
insight inlo the problem of amlodipine-
induced gingival overgrowth. One ofthe
patients (EH) had been previously
medicated with nifedipine and during
the course of her treatment with this
drug, she had experienced recurrent gin-
gival overgrowth which required re-
peated surgical excision. As a conse-
quence, her general medical practitioner
was contacted to consider alternative
medication. She was subsequently pre-
scribed amiodipine 5 mg/day. Some 3
months after dosage, the gingival over-
growth had re-occurred. As a conse-
quence ofthe second patient's (AB) gin-
gival changes, her general medical prac-
titioner changed her medication to
bendrofiuazide. At a 3-month recall ap-
pointment, there was considerable resol-
ution o{ her gingival condition.
Amiodipine was detected in the cre-
vicuiar fluid of all 3 responder patients
but not in the control patient (Table 2).
In 2 ofthe patients, there was significant
sequestrations of Ihe drug. These find-
ings are similar to those we reported
with nifedipine (Ellis et al. 1992). How-
ever, with our small sample size, it is
difficult to establish the importance of
such sequestration in the pathogenesis
of this type of drug-induced gingiva!
overgrowth.
Gingival surgery still remains the
treatment of choice for amiodipine and
other dihydropyridine-induced gingival
overgrowth. 2 of the 3 patients required
gingival surgery. A change in drug ther-
apy is desirable, especially if there is a
recurrence of the problem. It is obvi-
ously essential to avoid a further cal-
cium channel biocker in these patients.
One case report has shown that nifedi-
pine-induced gingival enlargement re-
solved when the patient was subjected
to a plaqtie control programme, scaling
Amlodipine-induced gingival overgrowth
and root planing (Hancock & Swan
1992). We would advocate this ap-
proach to the management of these pa-
fients, since a change in their medication
is not always feasible.
We conclude from this study that am-
iodipine is a further dihydropyridine
which is associated with the unwanted ef-
fect of gingival overgrowth. In the 3 pa-
tients described, gingival changes can be
observed as early as 3 months after dos-
age. The drug was detected in the crevic-
ular fiuid of the 3 patients who experi-
enced gingival overgrowth, and in 2 pa-
tients, there was significant
sequestration. The importance of this
finding in relationship to the patho-
genesis of this unwanted effect remains
to be determined.
Zusammenfassung
Am to dip itie indu lierte Ging i vain 'p e rp Ia sie
Amiodipine blockiert die Calcium-Kaniiie
und wird zur Behandlung der Angina pecto-
ris und des Bluthochdruckes verwendet. Wir
berichten von drei Fallen hei eru'achsenen
Patienten. die bezahnt sind und eine Gingiva-
hyperplasie aufweisen, die mit der Verwen-
dung dieses Medikamentes verbunden ist.
Die Veranderungen der Gingiva ereigneten
sieh innerhalb von drei Monaten der Verab-
reichung und schienen mit dem bestehenden
parodontalen Zustand des Patienten asso-
ziierl zu sein. Bei alien 3 Patienten gab es
eine Ausscheidung von Amiodipine in ihrem
Sulkusfluid. Die Bedeutung dieses Ergebnis-
ses in Verhmdung mit der Pathogenese dieser
nichl erwlinschten Wirkung muO noch ge-
kliirt werden.
Resume
Hyperplasie gingivale induite par I'amlodipine
L'amlodipine est un bloquant des canaux du
calcium utilise dans ie traitement de I'angine
de poitrine et de Fhypertension. Nous
tendons ici compte de 3 cas d'hyperplasie
gingivale associee a fusage chronique de ce
medicament, chez des patients aduites denies.
Les alterations gingivaies apparaissaient en
moins de 3 mois de traitement et semblaient
dependre de Petai parodontal existant chez
les patients. Les 3 patients presentaient lous
une sequestration d'amlodipine dans Ie fluide
gingival. II reste a elucider la signification
de ces observations en ce qui concerne la
pathogenie de cet effet indesirable.
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Adress:
R. A. Seymour
Department of Restorative Dentistry
University of Newcastte-upon- Tyne
Framiington Flace
Ne\vca.Ule-upon-Tym NE2 4BW
UK