Drug induced ge 2 final/ dental crown & bridge courses

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

GINGIVAL OVERGROWTH INDUCED BY
CALCIUM CHANNEL BLOCKER
 Calcium channel blockers are a group of drugs specifically developed and
extensively used in the management of cardiovascular condition.
 Chemically, the calcium antagonists can be classified as
 Dihydropyridines - Nifedipine
 Benzothiazine - Diltiazem
 Phenylalkylamine - Verapamil

 Gingival overgrowth has been reported in 15% to 30 % (composite average
= 42.5%) of patients taking nifedipine, approximately 21 % taking diltiazem
and about 4% taking verapamil.
 Minimum blood level of 800 mg/ml of nifedipine resulted in gingival
overgrowth in a rat model and that the degree gingival overgrowth
depended on Increased concentration above this threshold value.
 In a report amlodipine was detected in the GCF of each individual, all of
whom were long term recipients of the medication.

 There is increased severity of gingival overgrowth when nifedipine &
cyclosporine A were used in combination, compared with cyclosporine A
alone.
 The principle action of nifedipine to inhibit the influx of extracellular
Calcium ions across the membranes of cardiac and vascular smooth muscle
cells, without changing serum calcium concentration.
 By inhibiting calcium influx, nifedipine inhibits the contractile process
thereby dilating the main coronary and systemic arteries.

DOSAGE & TRADE NAME
 Trade Name: Calcigard
 Depin
 Nifetal
 Procardia
 Dosage: - 10- 40 mg orally BD
5 mg sublingually repeatedly 6 hourly.

DRUG INTERACTIONS
 If Nifedipine used with diuretics, no additional
antihypertensive action of diuretic is seen.
 If Nifedipine used with hydralzine, pattern of
haemodynamic action is seen

CLINICAL FEATURES OF CALCIUM CHANNEL
BLOCKER INDUCED GINGIVAL OVERGROWTH
 Clinical features are similar among all agents of this class.
 The interdental papilla is initially affected becoming enlarged resulting in a
lobulated or nodular morphology and this growth then spread across the
tooth surface.
 There is generalized marked lobulated enlargement of facial and lingual
gingiva.
 The growth is limited to the attached and marginal gingiva and are more
frequently observed especially on the facial surface.

 In one case where gingival hyperplasia appeared 1-2 months after
nifedipine therapy began at a dose of 90 mg/day.
 Within a week after withdrawl of the drug, the hyperplasia decreased with
symptomatic improvement.
 When nifedipine was reinstituted for increasing chest pain, the gingival
hyperplasia was exacerbated and regressed when the drug was
discontinued a second time.

 Enlarged gingival tissues are often, accompanied by inflammatory changes
associated with poor plaque control.
 The enlarged gingiva may extend coronally and partially or completely
obscured the teeth, presenting aesthetic & functional difficulties for
affected patients.
 There are reports of nifedipine induced gingival overgrowth around dental
implant.

PATHOGENESIS
 Despite unrelated pharmaceutical effects, the calcium channel
blockers & Phenytoin have a common mechanism of action.
 It is suggested that gingival overgrowth results from
overproduction of extracellular ground substance
characterized by increased presence of sulphated
mucopolysaccharides and collagen & abundant active
fibroblasts.

 Collagenolytic effects of inflammatory cells and synthesis of collagenase are
calcium dependent cellular events.
 Nifedipine may interfere with calcium transport and calcium dependent
processes.
 These agents may reduce calcium levels in gingival fibroblasts and T- cell
thus interfering with T cell proliferation or activation and collagen by
gingival fibroblasts.

HISTOPATHOLOGY
 There is similar histological findings as the other drug
associated gingival overgrowth.
 The overlying stratified squamous epithelium was
parakeratotic with slight to moderate hyperkeratosis.
thickening of the spinous cell layer elongated thin rete pegs.
 Numerous fibroblasts and fibrosis of lamina propria with
increased in the extracellular ground substance was present.

THERAPEUTIC USES
 Angina pectoris, chronic .stable angina
 Hypertension
 Arrhythmias
 Congenital Heart Failure.

ADVERSE EFFECTS
Frequent side effects are:
 Palpitation
 Flushing
 Ankle edema
 Hypotension
 Nausea.

CYCLOSPORIN INDUCED GINGIVAL
ENLAGEMENT
 Cyclosporin is a potent immunosuppressant that is used extensively in
organ and bone marrow transplant recipient and in a variety of systemic
diseases.
 It is a cyclic polypeptide comprise of 11 amino acid and is produced as a
metabolite of the fungus tolypoclodium inflatum gams by Borel in 1972 as
an antifungal agent.
 Its advantage as an immunosuppressive agent is to not to depress the bone
marrow processes when therapeutic levels of the drug are used.
 The mechanism of action is via its

 Specific and reversible inhibition of lymphocytes.
T-lymphocytes are preferentially
inhibited and it is this suppression of cellular immune response
and the subsequent sparing of the humoral response and bone
marrow that make cyclosporine an ideal agent to use in the
prevention of allograft rejection.

Associated gingival overgrowth was
first reported in 1983 and occurs approximately in
8%-70% of patients taking the medication, with an
overall incidence of approximately 25%.

 Cyclosporin is often used in combination with calcium channel blockers
which are also capable of inducing gingival overgrowth, thus complicating
the situation.
 Usually occurs within 3 months of cyclosporine dosage. However cases
have been demonstrated to occurs as early as 1 month after starting
therapy.
 Cyclosporine dose > 500 mg/day induce gingival overgrowth.
 Gingival overgrowth was more likely to develop when plasma
concentration of cyclosporine exceeded 400 ug/ml.

PREPARATION AND DOSAGE
 Cyclosporin is available as :
 For oral administration- as solution containing 100mg/ml.
 For IV - 50mg/ml.
Dosage : 10-15 mg/kg body wt. 4-12 hr. before
procedure and continue 1-2 week.

 Trade Name: Sandimmune.
Sandimmune neoral
Imusporin
Zymmure

 Maintainance : 2-6 mg/kg body wt.

CLINICAL FEATURES OF CYCLOSPORIN INDUCED
GINGIVAL OVERGROWTH
 Hyperplasia induced by cyclosporine is similar to that induced by
Phenytoin.
 Growth starts in the interproximal papillae, more frequently in the
anterior facial areas, partially covering the crown.
 Tissue is pink , dense and resilient with a stippled or granular surface and
little bleeding tendency.
 In some cases it may be of more inflammatory character, enlarged gingival
tissue were soft, red or bluish red , extremely fragile and bleed easily upon
probing.
 Severe hyperplasia is noted in patients with external irritants and having
plaque, calculus, defective restorations, appliances and mouth breathing.

 There is positive correlation between the degree of
cyclosporine-induced hyperplasia, dental plaque index and a
gingivitis index.
 The gingival overgrowth was restricted to keratinized gingiva
but could extend coronally and interfere with occlusion,
mastication and speech.
 Cyclosporine-induced hyperplasia has not been observed on
the alveolar ridges of edentulous area.

PATHOGENESIS
 A fewer than 50% of patients taking cyclosporine-A develops gingival
enlargement, the terms "responders" and ‘nonresponders’ have been used
in the literature to identify these individual differences and perhaps a
genetic predisposition.
 Gingival overgrowth was related to sensitivity of individuals to the drug or
its metabolites.
 Cyclosporine A and its major metabolites OL-17 could react with a
phenotypically distinct subpopulation of gingival fibroblasts
 Causing an increasing protein synthesis and rate of cell proliferation.

HISTOPATHOLOGY
 Most of the features are similar to the phenytoin induced gingival
overgrowth. An increased proportion of cells termed myofibroblasts have
been found which are modified fibroblasts.
 Hyperplastic epithelium with acanthosis and focal spongiosis is present.
The elongated rete pegs have a tendency to form " forked endings" .
 The underlying connective tissue consist of focal areas made up of dense
collagen which are alternated with areas of myxomatous change.

 Abundant amorphous substance is found with marked plasma cell infiltrate
in the gingival tissues.
 Basal and spinous layers of epithelium showed distinct dilatation of the
intercellular spaces characterstic of diseases related overgrowth.

DRUG INTERACTIONS
 Accelerated clearance of cyclosporine has been
demonstrated in patients receiving
 Phenytoin
 Phenobarbital
 Trimethoprim
 Sulfamethoxazole

 Decreased clearance of cyclosporin has been associated
with concurrent administration of :
 Erythromycin
 Ketoconazole
 Amphotericin-B
 Cimetidine

ADVERSE EFFECTS :
 Hepatotoxicity
 Nephrotoxicity
 Tremors
 Hirusutism
 Neurotoxicity

GINGIVAL OVERGROWTH ASSOCIATED WITH
OTHER DRUGS
1. SEX HORMONES (ORAL
CONTRACEPTIVES)
The ability of male and female sex
hormones to induce hyperplastic , edematous gingivitis has
been recognized for many years in associations with puberty
in both sexes and pregnancy among women.

 Administration of androgenic hormones such as
testosterone and /or estrogen and/or progesterone
has been occasionally associated with gingival
enlargement in adults.
 Most frequently reported associations occur with the
use of oral contraceptives among women.

2. CANNABIS
Excessive use of marijuana has been associated with gingival
enlargement.
 Layman 1978 stated gingival enlargement being reported in
individuals using cannabis to excess.
 This may resemble other forms of drug induced gingival
overgrowth and may be accompanied by gingivitis and alveolar
bone loss.
 The incidence and causative mechanism is unknown.

3. ERYTHROMYCIN
 One well described case report identified gingival enlargement
in association with administration of erythromycin in a six
years old boy being treated for tonsillitis.
 Overgrowth became evident one week after initiation of the
drug. Overgrowth involved the anterior facial interdental
papillae and the palatal and mandibular lingual gingival.
 Lesions remitted on discontinuance of the drug and recurred
when erythromycin was again prescribed.

MANAGEMENT OF DRUG-INDUCED GINGIVAL
OVERGROWTH
 Despite of greater understanding of the pathogenesis of drug-
induced gingival overgrowth, its treatment still remains a
challenge for the Dentist.
 The problem is compounded by the high recurrence rate
arising from chronic usage of the listed medications and
persistence of other risk factors.

From the treatment standpoint, the
clinician should be particularly concerned with cases where
there is evidence of gingival enlargement on patient taking one
or more of these drugs because:
-It poses a plaque control problem
-It may affect mastication
-It may alter tooth eruption
-It may interfere with speech and
-It may cause aesthetic concerns

Examination of drug-induced gingival
overgrowth cases reveals that the enlarged tissue have 2
components :
1. Fibrotic-which is caused by the drug and
2. Inflammatory one is induced by bacterial plaque.
 The management strategies can most simply be categorized
as either non-surgical or surgical approaches.

NON-SURGICAL APPROACHES
 The primary aim of non-surgical approaches is to reduce the
inflammatory component in the gingival tissues and thereby
avoid the need for surgery.
 Ideally preventive programme should be instituted before the
initiation of drug therapies implicated in drug-induced gingival
overgrowth but is often impractical.
 Improving the patient's standard of self maintained oral
hygiene in absence of other therapeutic measures can
influence the development of gingival overgrowth.

 The nature of the relationship between plaque and the expression of
gingival overgrowth is unclear and controversy exists as to whether
plaque accumulation is the cause of gingival changes or the
consequence of it.
 Oral hygiene therapy while of some benefit to the patient failed to
completely prevent the development of gingival overgrowth which
include :-
 Effective oral hygiene measures
 Professional tooth cleaning
 Scaling and root surface instrumentation.

 For some patients these measure alone could reduce the
gingival overgrowth to acceptable levels, for others , it could
make surgical correction easier.
 Local environmental factors that enhances plaque
accumulation such as faulty restorations, broken teeth or
carious lesions should be eliminated and any fixed or
removable prostheses should be designed to minimize plaque
retention.

ANTISEPTIC MOUTHWASHES
 Adjunctive chemical plaque removal has also been used in the management
of drug-induced gingival overgrowth.
 In human chlorhexidine has, to date, only been evaluated in the
management of Phenytoin-induced gingival overgrowth, when regular use
of his mouthwash helps to reduce the recurrence rate after surgery
 However, the unwanted effects of chlorhexidine of bacterial resistance and
taste disturbance limit its long-term use.
 Other antiseptic mouthwashes have not been investigated in either the
prevention of drug-induced gingival overgrowth or reducing the rate of
recurrence.

SYSTEMIC ANTIBIOTICS
 There is evidence to suggest that a combination of oral hygiene
reinforcement and systemic antibiotics may be beneficial in the
management of Drug-induced gingival overgrowth.
 Complete remission of cyclosporine induced gingival overgrowth has been
reported in four renal transplant patients after 7-day course of
metronidazole.
 No details were provided of the patient's periodontal condition before
medication with metronidazole and a small number of patient and lack of a
control group somewhat limits the significance of these findings. In,
addition metronidazole is known to reduce the hepatic metabolism of
cyclosporine leading to the potential risk of nephrotoxicity.
 Benefits of metronidazole on the gingival tissues may have resulted simply
from a change in the subgingival biofilm and an associated reduction in
tissue inflammation.

 Azithromycin appear to be more effective than metronidazole in the
management of this unwanted effect (Chand et al 2004) and that systemic
administration of the drug appears to be more effective in reducing
overgrowth than a local delivery preparation.
 There are two suggested mechanism by which azithromycin may act.
-Firstly by reducing concomitant bacterial infection and hence
inflammation
-secondary by increasing the phagocytic activity of gingival
fibroblasts. Thereby reversing the ability of cyclosporine to decrease
collagen degradation (only been demonstrated in rats.)

 All studies have used short-term courses which may
have brought about some reduction in overgrowth.
 However as Drug-induced gingival overgrowth is
recurrent and continuous problem there are
concerns regarding the use of repeated doses of
antibiotics in the long-term management of this
unwanted effect, especially in immunosuppressed
patients.

CHANGE IN MEDICATION
 One obvious solution in the management of Drug-induced gingival
overgrowth is to change medication.
 For many years, this was not an option for cyclosporine. However, with
the advent of new immunosuppressant i.e. Tacrolimus, alternatives are
now available. Azithromycin 500mg OD for 5 days followed by 250mg
OD for 3 days gives good result after 4 weeks.
 The prevalence and severity of Drug-induced gingival overgrowth in adult
transplant patient, tacrolimus has been shown to be approximately half
that of cyclosporine and it does reduce the need for surgical intervention.

 It does not necessarily lead to complete resolution of overgrowth .
 Different calcium channel blocker such as verapamil has been substituted
for nifedipine but more usually where substitution is made by a structurally
different antihypertensive drug, such as the angiotensin-converting enzyme
inhibitor, enalapril ; the B-blocking drug, atenolol or thiazide diuretics.
 Phenytoin usage is now declining, partly due to its adverse effect profile
and also the introduction of new antiepileptics.
 However, changing antiepileptic medication can be a challenge & a gradual
staged approach is required. This may take 2-3 months during which time
serum levels of the antiepileptic requires monitoring along with the
frequency and severity of seizures occurrence.
 Carbamazepine, ethosuximide and sodium valproate are alternatives to
Phenytoin which have been shown not to cause drug-induced gingival
overgrowth

 For the calcium channel blockers, there is a greater range of alternative
medications which achieve the same therapeutic goals. Prevalence and
severity of overgrowth has been shown to be very different even with
drugs of a similar chemical structure for e.g. nifedipine and amlodipine are
both dihydropyridines and yet the amlodipine has a prevalence of severe
gingival overgrowth of half that of nifedipine (3.3% compared with 6.3%)
 Change in medication should only be considered for those patients where
the new medication can offer some advantage for control of their
hypertension, which present with clinically significant overgrowth and are
at high risk from either corrective surgery or recurrence after
gingivectomy.

OTHER AGENTS
 Phenytoin has been shown to inhibit folic acid metabolism
although the mechanism by which this occurs is uncertain.
 There is some evidence that a folic acid mouthwash (1 mg/ml)
may be efficacious in reducing the recurrence of phenytoin-
induced gingival overgrowth and that a mouthwash is more
effective than systematic administration.
 It has been suggested that topical folate may reduce gingival
inflammation by binding to the plaque-derived endotoxins.
This action, in turn reduces gingival overgrowth.

SURGICAL MANAGEMENT
 Although the variety of non-surgical measures have been shown to be of
some value in management of drug-induced gingival overgrowth , surgical
correction of gingival overgrowth is still the most frequent therapy.
 Such therapy is only advocated only when overgrowth is severe.
 From the patient's prospective, surgical correction of drug-induced gingival
overgrowth should result in little or no post-operative pain or sequel,
good aesthetics and a reduced risk of recurrence.
 Currently, the surgical management of drug-induced gingival overgrowth
includes the scalpel gingivectomy, electrosurgery and laser excision.

SCALPEL GINGIVECTOMY
 The surgical treatment of choice is the gingivectomy, which was first
advocated for drug-induced gingival overgrowth in 1941
 The soft tissue wall of the pocket is excised.
 Gingivectomy presents with the advantage of technique simplicity and
quickness.
 With this approach the increased bulk of the tissue can be removed, the
soft tissue pockets are eliminated and the crowns of the teeth exposed.
This procedure improves access to any faulty restoration or calculus
deposits, facilitating their elimination.
 The procedure is used extensively and the technique is straight forward,
accurate and causes minimal damage to the surrounding tissues.
 Peri-operative hemorrhage is the main disadvantage of scalpel excision and
this can be significant in highly vascularised and inflamed overgrowth
gingival tissues

 Also this technique will not allow for osseous recontouring
and may sacrifice keratinized tissue.
 Also gingivectomy results in healing by secondary intention
which causes discomfort and increased chances of post-
operative bleeding.
 In general, small areas (up to six teeth) presenting with drug-
induced gingival overgrowth where there is no evidence of
attachment loss (and therefore no anticipated need to
perform osseous surgery) can be effectively treated with the
gingivectomy technique.

ELECTROSURGERY
 Electro surgery techniques have been used in dentistry for the
past 70 years. Although such techniques produces adequate
haemostatic, they have the disadvantage of causing a
surrounding zone of thermal necrosis, which may impede
wound healing.
 Reports in the literature have confirmed delayed healing of
electro surgery wound when compared with scalpel wound
healing.
 This is probably due to the production and accumulation of
excessive latent heat, which can be significant if electro
surgery is performed inappropriately.

 Nevertheless, surgical intervention using conventional
means (scalpel) may sometimes be technically difficult
and/or impractical for eg. in children or mentally
handicapped , or in patients suffering from impaired
haemostasis. In these situations the use of
electrosurgery may be advantageous

LASER GINGIVECTOMY
 The dental laser may be another useful alternative treatment
to conventional gingivectomy techniques.
 Lasers have remarkable cutting ability and they also generate a
coagulated tissue layer along the wall of laser incision which
promotes healing.
 Other advantage of use of laser in correcting drug-induced
gingival overgrowth includes a relative bloodless operative and
post-operative field, greater accuracy in making incisions,
sterilization of operating field, minimal swelling and scarring,
vaporization and cutting with much less post-operative pain.

 The haemostasis provided by the laser may also avoid the
need for a periodontal dressing.
 Lasers can also be used for re-contouring the gingiva, for
tissue welding, and to minimise the need for sutures.
 The laser gingivectomy may be particularly useful in patients
on anticoagulant therapy or for whom problems with
haemostasis are anticipated.

 There are now many different types of lasers available to
Dentist.
 The ND: YAG laser has been used for the variety of intraoral
soft tissue procedures and can be used without anesthesia.
 The CO2 laser has been used for the removal of phenytoin-
induced gingival overgrowth.

MAINTENANCE
 Recurrence of drug-induced gingival overgrowth is a reality in
the surgically treated cases.
 As stated previously, meticulous home care, chlorhexidine
gluconate rinses and professional cleaning can decrease the
rate and degree at which recurrence occurs.
 Recurrence may occur as early as 3-6 months after the
surgical therapy, but in general, surgical results are maintained
for at least 12 months.

CONCLUSION
 The gingiva as treated may be enlarged in response to
various interactions between the host and the
environment.
 The enlargement may be result primary due to
inflammatory response against local irritant and
secondary due to certain drugs consumptions such as
anti-convulsants, Calcium channel blockers and
immunosuppresants and many others.

 For a Dentist appropriate and perfect knowledge in
concerned with pharmacokinetics of drugs, etiology,
clinical features, pathogenesis, histologic features
regarding specific type of drug-induced gingival
enlargement is of utmost importance and prime
significance so as to reach to perfect diagnosis and
provide adequate treatment both at therapeutic and
preventive levels to prevent further destruction of
periodontium.

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

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