DRUG INDUCED GINGIVAL ENLARGEMENT / dental crown & bridge courses

DRUG INDUCED GINGIVAL
ENLARGEMENT
www.indiandentalacademy.com

INDEX
 Introduction
 Definition
 Types
 Grades
 Risk factors
 Drugs causing GE
 Other drugs
 Management
 Conclusion

INTRODUCTION
 Gingival contour within the normal physiology is described as
“Scalloped and knife edged”.
 The significance of which is that it enhances the self cleansing
mechanism of the gingiva against various local irritants.
 Any increase in the gingival size alters the physiologic contour, which
in turn acts as a nidus for the accumulation of local irritant leading to
the further destruction and in many cases to the attachment loss.
 Gingival enlargement adversely affects, function, esthetic and
phonetics progressively and dynamically and also may lead to
periodontal pathology.

 Cause of fibrotic gingival enlargement may be iatrogenic
or idiopathic. The most common iatrogenic cause is by
use of certain drugs, which are used to treat certain
medical conditions.
 The oral cavity can be the site of an adverse drug reaction
either as primary singular allergic or toxic reaction or as
one of a number of untoward effects of a particular drug
or drug group.

 Therefore the aim is to understand pathogeneses,
6alteration in drug induced gingival enlargement at
early stage so as to provide adequate treatment before
occurrence of periodontal changes at preventive and
therapeutic level based on current knowledge and
investigative observations.
GM= gingival
margin, BC= bone
contact. SD=
sulcus depth, JE=
junctional
epithelium,
CTC=connective
tissue contact.
BW=biologic width
= SD+JE+CTC.

DEFINATION
 HYPERPLASIA: Increase in the size of the tissue or an organ
produced by an increase in the number of its component.
 HYPERTROPHY: Enlargement or overgrowth of an organ or part
due to increase in the size of its constituent cells in order to meet in
creased functional requirement for useful work.
Gingival hyperplasia is a more appropriate term to designate gingival
enlargement, as there is increase in the number of components cells.

ACCORDING TO LOCATION AND
DISTRIBUTION GINGIVAL ENLARGEMENT
IS DESCRIBED AS :-
 Localized: Limited to gingiva adjacent to a single
tooth or group of teeth.
 Generalized: Involving the gingiva throughout the
mouth.
 Marginal: Confined to the marginal gingiva.

 Papillary: Confined to the interdental papilla.
 Diffuse: Involving the marginal and attached
gingivae and papillae.
 Discrete: An isolated sessile or pedunculated tumor
like enlargement.

 BASED ON THE SEVERITY, THE DEGREE
OF GINGIVAL ENLARGEMENT CAN BE
SCORED AS FOLLOWS (BOKENKAMP ET
AL 1994)
 Grade 0: - No signs of gingival enlargement.
 Grade I: - Enlargement confined to interdental
papilla.
 Grade II: - Involves papilla and marginal gingiva.
 Grade III: - Enlargement covers ¾ or more of the
crown.

 DRUGS ASSOCIATED WITH GINGIVAL
OVERGROWTH

RISK FACTORS FOR DRUG-INDUCED
GINGIVAL OVERGROWTH
 Differences in the prevalence of the drug-induced
gingival enlargement suggests that there is a variable
gingival response in patients taking these drugs.
 Indeed the term responders and non-responders appears
in the literature.
 Futhermore , within the group of patients that develop
this unwanted effect, there appears to be variability in
the extent and severity of the gingival changes.

 Identifiable factors can be considered under the
following headings:
1. Age and other demographic variables.
2. Drug variables.
3. Periodontal variables.
4. Genetic factors.
5. Concomitant medication

AGE AND OTHER DEMOGRAPHIC
VARIABLES
 Age has been considered an important risk factor for drug-
induced gingival overgrowth with particular reference to
phenytoin and cyclosporine.
 Early studies on prevalence of phenytoin induced gingival
overgrowth identified that teenagers were at high risk.
 It was reported that younger age and poor oral hygiene
seemed to predispose to the severest level of gingival
involvement.

 Also in cyclosporine induced gingival overgrowth, in various
studies, number of children with clinically significant
gingival overgrowth was higher (52%) when compared to
adults.
 Age is not an applicable risk factor for the calcium channel
blockers since the use of these drugs is usually confined to the
middle aged and older adult.

 One possible explanation for this association may reside with an
interaction between circulating androgens and gingival fibroblast.
Such cells can readily metabolize testosterone to the active
metabolite 5- a- dihydrotestosterone.
 Phenytoin enhances this metabolism and excised tissue from both
cyclosporine and nifedipine induced gingival enlargement exhibits
a similar increase in androgen metabolism.

 Circulating androgen level will be higher in adolescents
and teenagers.
 The active metabolite could act on gingival fibroblasts
and cause an increase in collagen synthesis.

OTHER DEMOGRPHIC VARIABLES
 Very few studies have investigated whether gender is a risk
factor for drug-induced gingival overgrowth.
 Gender and race were not important risk factors for the
expression of Phenytoin induced gingival overgrowth.
 Many of cyclosporine studies have a significant male bias,
since organ transplantation (especially heart transplant) is
more frequently carried out on men.

 Males were at greater risk from developing this
unwanted effect than females and severity of changes
greater in males.
 Similarly males were shown to be three times more likely
than females to develop clinically significant gingival
changes when medicated with calcium channel blocker.

 It was suggested that there existed a serum threshold above which
overgrowth occurs, and that this level was lower in males.
 There is an increasing evidence with respect to both cyclosporine and
Calcium channel blockers that males are more prone to developing
gingival overgrowth than females and that gingival changes are more
severe. Whether this relates to existing periodontal factors,
pharmacological variables or a hormonal co-factor remains to be
determined.

DRUG VARIABLES
 The relationship between the extent and severity of overgrowth and a
variety of drug variables (i.e. dose,duration,serum and salivary
concentrations) remains an area of controversy.
 Most of the researchers would agree that some baseline or threshold
concentration of the drug is required to initiate the gingival changes
and that such a threshold concentration may vary from individual to
individual.

 Seymour and Jacobs in 1992 reported that drug doses tend to
be a poor predictor of gingival changes. They suggested that
it would be more appropriate to relate dose to the patient's
body weight to obtain a more meaningful interpretation of
dosage and its relationship to overgrowth.

 Many studies have also investigated the relationship
between serum concentrations of the implicated drug and
the expression of overgrowth.
 Both Phenytoin and Calcium channel blockers obtain
steady state therapeutic drug levels at 7-10 days after the
initiation of therapy. Thus for these two drugs serum
sample at any time point is likely to be a true reflection
of the drugs concentration.

 Other pharmacokinetic measures that may be more pertinent in relation
to gingival overgrowth include bioavailability , degree of protein
binding, volume of distribution, and an overall assessment of drug
concentration in relation to time.
 Wondimu et al in 1996 reported that the type of cyclosporine
preparation may well have some impact on the development of gingival
overgrowth in organ transplant patients. In this study cyclosporine
was given as a solution (mixed with milk) or in capsule form.
 The effects of both preparations on the gingival tissues were compared
during one year longitudinal study. Gingival overgrowth was observed
in 37% of the patients taking the cyclosporine solution, compared to
43% dosed with capsules

 However, the solution patients showed an earlier onset of gingival
changes and more extensive overgrowth than those medicated with
capsules. It was concluded that changing a patient's cyclosporine
medication from a solution to capsule might minimize the
development of gingival overgrowth.
 This different effect of the two cyclosporine preparations on the
gingival tissues may be related to subsequent changes in the drugs
pharmacokinetics, in particular bioavailability and time to
maximum blood concentration.

 Significant sequestration of both nifedipine and amlodipine has
been observed in patients who exhibit significant gingival changes
arising from these drugs. Despite the high levels of nifedipine
sequestered in the GCF only the plasma concentration of nifedipine
was identified as the risk factor for the severity of the gingival
changes.
 As such the mechanism of drug sequestration and its relationship
to the gingival changes remains unknown.

PERIODONTAL VARIABLE
 Plaque scores and gingival inflammation appear to exacerbate the expression
of drug induced gingival overgrowth, irrespective of the initiating drug.
 Patients’ oral hygiene is a significant risk factor for the expression of drug
induced gingival overgrowth.
 Most of the evidence to support a relationship between bacterial plaque and
gingival overgrowth has been derived from cros-sectional studies and it is not
clear whether plaque is a contributory factor or a consequence of gingival
changes. However, in circumstances when other additional structure such as
orthodontic appliances impede cleaning then the prevalence of overgrowth is
high.

 The effect of oral hygiene programme on cyclosporine-induced gingival
overgrowth was examined in study by Seymour and Smith 1992.
 Both the oral hygiene group and control group developed significant
gingival changes over the six month post transplant investigation
period, although the magnitude of the changes in the oral hygiene group
was less marked. They concluded that oral therapy while of some
benefit to the patient failed to prevent the development of gingival
overgrowth.
 Somacarrera et al 1994 in a study of 100 organ transplant patient
found improvement in oral hygiene group but overgrowth was still seen
in 43% of cases.

 Taking the findings as a whole, it would be reasonable to
suggest that proper oral hygiene might be expected to
minimize the severity of gingival overgrowth , possibly by
eliminating the inflammatory component of the lesion .
 Improved oral hygiene in itself would not appear to prevent
overgrowth.

 A more recent study Vargar et al 1998 has evaluated the impact of a
patient's periodontal condition prior to organ transplantation and the
development of gingival overgrowth post transplant.
 Their result showed that patient who exhibited hyperplastic gingivitis
prior to transplant where highly likely to develop gingival change post
transplant.
 This would suggest a “susceptibility" of gingival tissues (or fibroblasts)
to both plaque-induced inflammatory changes and cyclosporine.
 Periodontal variables in particular plaque and gingival inflammation
are also important risk factors for the expression of gingival
overgrowth.

GENETIC FACTOR
 Fibroblast heterogenicity remains one of the key factors
used to explain the variable response of gingival tissues
to the various gingival overgrowth inducing drugs.
However, while these may be used in vitro explanation, it
has limited clinical value in identifying "at risk patients”.
There is no clinical marker of gingival fibroblast
phenotype.

 A genetic predisposition could influence the metabolism of Phenytoin,
cyclosporine and nefidipine, since all three drugs are metabolised by
hepatic cytochrome P450 enzymes. Cytochrome P450 genes exhibit
considerable polymorphism which results in inter-individual variation
in enzyme activity.
 This inherited variation in metabolism offending drug may influence
the patient’s serum and tissue concentrations and hence their gingival
response. While cytochrome P450 variation may be a risk factor the
Drug-induced gingival overgrowth.

 The one genetic marker that has been investigated in relation to drug-
induced gingival overgrowth is the human lymphocyte antigen
expression (HLA).
 Investigation of this marker has been confined to the organ transplant
patients since their HLA phenotype is determined prior to
transplantation.
 One study reported that patient who expressed HLA DR1 are
afforded some degree of protection against gingival overgrowth while
HLA DR2 may increase the development of this unwanted effect.

 To date only HLA-B37 has been identified in patients who are protect
in some way from the effect of gingival overgrowth (Thomason et al
1996).
 The mechanisms that may tie HLA antigens to gingival overgrowth are
unclear.
 The effect of lymphocyte function have also been postulated.

CONCOMITENT MEDICATION
 The effect of polypharmacy has been studied in relation to both
Cyclosporine and Phenytoin induced gingival overgrowth.
 There is now a evidence that the combination of nifedipine and
cyclosporine in organ transplant patients produces more gingival
overgrowth than if either drug was used singularly.It has been
suggested that combined therapy may increase the prevalence of
condition but not the severity.
 And combination therapy was significant risk factor for progression
and recurrence of lesion after treatement.

 In organ transplant patients, dosage of both Prednisolone and
azathioprine appeared to afford the patients some degree of
protection against the development of gingival overgrowth, both
drug also reduces the severity of drug induced gingival overgrowth
 The so-called protective effect of these two drugs on gingival
overgrowth may arise from their anti-inflammatory actions on
plaque induced gingival inflammation.

 Polypharmacy can have an effect on Phenytoin induced gingival
overgrowth.
 Phenytoin is metabolized in the liver by P-450 enzymes to 5-4-
hydroxyphenyl-5-phenylhydantoin (4-HPPH).This metabolite has
been shown to induce gingival overgrowth.
 Anticonvulsants such as phenobarbitone, primidone and
carbamazepine have been shown to induce hepatic P450 isoenzyme
and if given in conjunction with Phenytoin will increase serum
concentration of 4-HPPH.This may explain the increased
prevalence of overgrowth in patients receiving multiple anti
convulsant therapy.

PHENYTOIN INDUCED GINGIVAL
ENLARGEMENT Phenytoin has been the drug of choice in grandmal epilepsy for over
50 years and was first described by Putham and Meritt in 1937.
 Enlargement in association with drug use was first recognized in
1939 by Glickman et al (1941) reported incidence varying from 3%
to 84.5 %.

 Effect of drug on gingiva is dose related but available evidence
suggests that minimal serum level of each specific drug must be present
in order to induce gingival overgrowth. Serum drug levels higher than
this minimal may not always lead to concomitant increase in tissue
enlargement.
 Gingival overgrowth occurs in about half of the individuals who ingest
Phenytoin on a chronic regimen as their sole antiepileptic medication.
 However the prevalence of gingival overgrowth is much higher when
Phenytoin is taken in combination with other antiepileptic agents.

 Prevalence of gingival overgrowth associated with various
antiepileptic drug regimens:-
Antiepileptic drug Regimen
Prevalence Of Gingival
Overgrowth (%)
Phenytoin alone 52 %
Phenytoin + sodium valproate 56 %
Phenytoin + Carbamazepine 71 %
Phenytoin + Carbamazepine +
Phenobarbital
83 %
Phenytoin + Polypharmacy 88 %

PREPARATION AND DOSAGES
 Phenytoin Sodium
 Trade Name: Dilantin
Diphenylan
Epileptin
 Phenytoin - 100mg/2ml lnj.
 Available as: 30 & 100 mg capsule
50 mg/ml solution
 Initial daily dosage for adults is 3-5mg/kg once daily or divided dosage.
Increments in the dosage may be made at 1-week interval at low
dosage but at 2 weeks interval when dosage exceeds 300 mg daily.

CLINICAL FEATURES
 Inflammation is a prerequisite for the development of enlargement.
 Phenytoin induced hyperplasia may occur in mouth devoid of local
irritants and may be absent in mouth in which local irritants are
profuse.
 Both sexes and all races are susceptible to Phenytoin induced gingival
overgrowth.
 Not all patients receiving Phenytoin have gingival hyperplasia.
Reported incidences ranges from 10-50 %.
 Teenagers & young adults to about 30 years age are affected more
frequently than the middle – aged or elderly persons.

 Hyperplasia is more severe in the maxillary & mandibular anterior
regions.
 Generally occurs in the area where teeth are present, not in
edentulous spaces & the enlargement disappears in areas from
which teeth are extracted.
 Enlargement is chronic & slowly increase in size.
 The earliest clinical signs of gingival change are soreness &
tenderness & may occur 2-3 weeks after initiation of Phenytoin
therapy.

 The first common sign of hyperplastic tissue responses is an
enlargement of the interdental papillae which starts as a painless,
bead-like enlargement gradually extending labially or lingually.
 Gingival overgrowth often becomes clinically apparent during first 6-9
months of therapy as interdental papillae overgrow & extrude, forming
firm, mobile, triangular tissue masses.
 The enlargement characteristically appears to project from beneath the
gingival margin from which it is separated by a linear groove.
 As the conditions progresses, the marginal & papillary enlargements
unite; they may develop into massive tissue fold covering a considerable
portion of the crowns & they may interfere with occlusion.

 Occlusal gingival involvement can impair speech & mastication.
Interfere with normal tooth eruption and may cause tooth migration.
 In uncomplicated cases of gingival hyperplasia the tissue is dense,
resilient & insensitive with little tendency to bleed.
 Mostly oral hygiene becomes extremely difficult, results in plaque
accumulation with gingival inflammation & enamel cervical caries.
 Secondary inflammation however can change the appearance. Changes
add to the size of lesion, obliteration of lobulated surface demarcations.
 The tissue may become dark as red / bluish discoloration, edematous,
spongy, friable, ulcerated & bleed easily.

 The attached gingiva also exhibits firm nodules with a granular
appearance of labial surface.
 There is rarely apical migration of junctional epithelium.
 Thus deep pseudopockets are created as the accumulation of the tissue
continues.
 Halitosis is common.

PATHOGENESIS
 The enlargement is basically a hyperplastic reaction initiated by drug with
inflammation being a secondary complicating factor.
 The exact mechanism of the gingival hyperplastic reaction in the patient
taking Phenytoin is unknown.
 Tissue culture studies showed a direct stimulatory effect by Phenytoin on
fibroblast proliferation & morphologic structure.
 Shafer in 1960 showed a twofold growth of human fibroblast incubated in 5
mgml of Phenytoin. This in vitro study showed Phenytoin acting to
proliferate gingival fibroblasts resulting in increased collagen synthesis.

 Nuki & cooper in 1972 suggested that both gingival inflammation
& local irritants were prerequisite for gingival enlargement.
 They reported that in absence of irritants, no enlargement occurs.

 Anglopoulos in 1975 suggested that Phenytoin has a direct effect on
the gingival mast cells, resulting in degranulation & release of
histamine, heparin & hyaluronic acid into the surrounding tissues.
 He added that these substances are taken up & metabolized by
fibroblasts, which in turn are stimulated to produce collagen, these
building up connective tissue.
 He concluded that the combined influences of Phenytoin & local
irritating factors on the gingival mast cells result in gingival
hyperplasia.

 Hasell et al in 1976, 1982 & 1983 stated that Phenytoin causes
gingival overgrowth in genetically susceptible individuals by enhancing
proliferation of fibroblasts that produce elevated quantities of collagen
& ground substance.

 Phenytoin elicits a folic acid deficiency in a large percentage of
patients, which can cause degenerative changes in sulcular
epithelium, the main physical barrier against local irritants.
 These local irritants may produce an exaggerated inflammatory
response in the gingiva.
 A high incidence of folic acid deficiency is associated with
pregnancy & use of oral contraceptives, two conditions frequently
showing gingival hyperplasia.

 Sooryamoorthy et al 1986 reported that receptors for 5 -
dihydrotestosterone (DHT) – The principle biologically active
metabolite of testosterone are present in gingival fibroblast & to a
great extent in hyperplastic tissue.
 Phenytoin stimulated conversion of testosterone to DHT, which
may affect Phenytoin induced gingival hyperplasia.
 Die et al 1993 proposed that Phenytoin increases production of
Platelet Derived Growth factor that would mediate gingival
overgrowth.

HISTOPATHOLOGY
 At light microscopic level, stratified squamous epithelium convering the
Phenytoin induced hyperplastic gingiva shows moderate epithelial
acanthosis with a thin, keratinised layer.
 Rete pegs are long & thin.
 Basic changes in the C.T. are proliferation of fibroblasts & increased
formation of collagen fiber bundles, which are abundant, tortuous &
non-oriented.
 The collagen fibers appear thinner &
shorter with an increased amount
of ground substance.

 Fibroblast to collagen ratio is equal to that of normal gingival
from normal individuals.
 Oxytalin fibers are common along the sulcular surface of the
gingiva.
 Increased number & thickness of Oxytalin fibers adding tensile
strength to C.T. have been reported.
 There is an influx of inflammatory cells, mainly lymphocytes &
plasma cells in most cases. Vascularity is not a feature of tissue.

 Kantor et al, 1983 reported increased proteoglycans &
glycosaminoglycans in excised gingiva & cultured cells from
phenytoin related overgrowth gingiva.
 Hence, the excess gingival tissue that results from Phenytoin
ingestion represents neither hypertrophy nor hyperplasia, nor it is a
true fibrosis, it is best described as “Gingival overgrowth”

DRUG INTERACTIONS
 Several drugs are known to interact adversely with Phenytoin.
 Diazepam, estrogens, chloramphenicol, dicumrol, isoniazide, cimetidine
& alcohol intake can increase serum level of Phenytoin ( concentration
of Phenytoin in plasma) by decreasing its rate of metabolism.
 Certain drugs which cause inhibition or inactivation (decrease
Phenytoin serum level) of Phenytoin are – salicylates, Tolbutamide,
Carbamazepine & chronic alcohol abuse.
(American Hospital Formulary service Drug information 1985)

OTHER EFFECTS ON THE
BODY Megaloblastic Anemia
 Osteomalacia
 It can inhibit insulin release & cause hypoglycemia
 If used during pregnancy, act as teratogen & can produce FETAL
HYDANTOIN SYNDROME.
A condition consisting of abnormal fingernails, hypoplasia of
distal phalanges, retardation of growth, mental deficiency & characteristic craniofacial
anomalies including short nose with low nasal bridge, hypertelorism, and cleft palate.

REFERENCES
 J. Mark Thomason, Robin A. Seymour. Determinants of gingival
overgrowth severity in organ transplant patients an examination
of the rôle of HLA phenotype. Journal of Clinical Periodontology.
1996:(23)7;628 - 634.
 Nishikawa S, Nagata T. Pathogenesis of drug-induced gingival
overgrowth. A review of studies in the rat model. J Periodontol.
1996 May;67(5):463-71.
 Barbara Anne Taylor. Management of drug-induced gingival
enlargement Aust Prescr 2003;26:11-3.

 Seymour et al. Risk factors for drugs induced gingival overgrowth.
J Clic Periodontology 2000;27. 217-223.
 Butler et al. Drug induced gingival hyperplasia. Phenytoin,
Cyclosporine and nifedipine. JADA. 1987: 56-60.
 Carranza's clinical periodontology . By Newman, Takei and
Carranza 10th
edition.

 Valsecchi R, Cainelli T. Gingival hyperplasia induced by
erythromycin. Acta Derm Venereol. 1992;72(2):157

Thank you

DRUG INDUCED GINGIVAL ENLARGEMENT / dental crown & bridge courses

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Viewers also liked

Viewers also liked (20)

Similar to DRUG INDUCED GINGIVAL ENLARGEMENT / dental crown & bridge courses

Similar to DRUG INDUCED GINGIVAL ENLARGEMENT / dental crown & bridge courses (20)

More from Indian dental academy

More from Indian dental academy (20)

Recently uploaded

Recently uploaded (20)

DRUG INDUCED GINGIVAL ENLARGEMENT / dental crown & bridge courses