Effects of medications on the

periodontal tissues in health and

disease
ROBI N A. SEYMOUR
It is now well recognized that the adult population is
living longer and retaining their teeth into old age. A
major part of this increase in life expectancy is
attributed to an expansion in our understanding of
disease processes and the subsequent explosion in
drug treatments. Some of these drugs will have an
impact on the periodontium and its response to
bacterial plaque. This paper reviews the various
possible interactions between a patients medication
and their periodontium in both health and disease.
The effect of systemic drug therapy on the perio-
dontium can be categorized as follows:
an adverse effect on the periodontal tissues;
affording some degree of protection against peri-
odontal breakdown;
causing an increased risk of periodontal break-
down.
Adverse effects on systemic
medication on the periodontal
tissues
Drug-induced gingival overgrowth remains the most
widespread unwanted effect of systemic medication
on the periodontal tissues. Three drugs are most
frequently implicated; phenytoin, cyclosporine and
the calcium channel blockers. Case reports have
implicated other drugs (e.g. sodium valproate and
erythromycin) but these are rare incidents (60).
Prevalence of drug-induced
gingival overgrowth
The prevalence of drug-induced gingival overgrowth
varies signicantly and, as with most epidemiolog-
ical studies, depends upon the population investi-
gated. Many authors have used hospital-based
patients, which is entirely appropriate for cyclo-
sporine. For phenytoin and the calcium channel
blockers, again many authors have frequently
examined hospital-based patients. Bearing this in
mind, it has nonetheless been estimated that 50%
of dentate patients on phenytoin experience gingi-
val changes, whereas the gures for cyclosporine
and the calcium channel blockers are 30% and
10%, respectively (1, 2, 15, 63).
The above gures do not take into account the
severity of gingival changes and that the term clinical
signicant overgrowth is more appropriate to epi-
demiologic studies. This term is applied to those
patients whose gingival overgrowth requires surgical
excision to correct the gingival contour (59).
Risk factors for drug-induced
gingival overgrowth
A variety of risk factors for drug-induced gingival
overgrowth have been identied and these have been
recently reviewed (59). Essentially, they are age and
other demographic variables, drug variables, con-
comitant medication, periodontal variables, and
genetic factors.
Age and demographic variables
Age is now recognized as an important risk factor for
both cyclosporine- and phenytoin-induced gingival
overgrowth (10, 17, 24, 28, 57). For calcium channel
blockers, age is not applicable since the use of these
drugs is mainly conned to the middle-aged and
elderly. Children and teenagers are more susceptible
to phenytoin and cyclosporine-induced gingival
overgrowth. This could suggest that a hormonal
120
Periodontology 2000, Vol. 40, 2006, 120129
Printed in the UK. All rights reserved
Copyright Blackwell Munksgaard 2006
PERIODONTOLOGY 2000
component contributes to broblast sensitivity to the
challenging drugs. Phenytoin has been shown to
enhance the ability of gingival broblast to meta-
bolize testosterone to the more active 5a dihyd-
rotestosterone (69). Similar results were found for
broblast, obtained from both cyclosporine- and
nifedipine-induced gingival overgrowths (68). Ado-
lescents will have higher levels of circulating andro-
gens which could stimulate further gingival broblast
to increase collagen synthesis and or decrease col-
lagenase activity. There is also the additional action
of increased circulatory sex hormones on the
expression of gingival inammation. Any increase in
inammation will compound the expression of
gingival overgrowth.
Gender
A few studies have investigated whether gender is a
risk factor for drug-induced gingival overgrowth. This
is in part due to a lack of reporting, and as far as
organ transplant patients are concerned, the out-
come is limited by a preponderance of males in the
patient population. Gender does not appear to be a
risk factor for phenytoin-induced gingival overgrowth
(21), but seems to be relevant in cyclosporine and
nifedipine cases (15, 74, 75). Whether such ndings
relate to existing periodontal variables, pharmacolo-
gical factors or a hormonal cofactor remains to be
determined.
Drug variables
There is considerable controversy concerning the
relationship between a variety of drug variables and
expression of drug-induced gingival overgrowth. A
range of pharmacokinetic variables have been stud-
ied and include peak and trough serum concentra-
tion, drug dosage, drug concentration in saliva and
gingival crevicular uid. There is no consistent nd-
ing and, as such, these parameters do not appear to
be a useful prognostic indicator as to how a patients
gingival tissue would respond to one of the implica-
ted drugs (59). Despite these reservations, most
workers would concur that some baseline or thresh-
old concentration of the drug is required to induce
the gingival changes. Such a threshold concentration
may vary from drug to drug and from individual to
individual.
Drug dosage tends to be a poor predictor of
gingival changes (60, 61, 65). It would be more
appropriate to correlate dose with body weight in
order to obtain a more meaningful interpretation of
doses and their relationship to gingival overgrowth.
Phenytoin and calcium channel blockers obtain
steady state therapeutic drug levels 710 days after
the initiation of therapy, thus for these two drugs a
serum sample at any time point is likely to be a
true reection of the drug concentration. Cyclo-
sporine measures are often taken as trough con-
centrations. Whereas such single measures are
useful for checking compliance, the level of anti-
convulsant activity or immunosuppression, they
only reect one aspect of the drugs pharmaco-
kinetic prole. Other pharmacokinetic measures
that may have more potential in relation to the
expression of gingival overgrowth include bioavail-
ability, degree of protein binding, volume of dis-
tribution, and an overall assessment of the drug
concentration in relation to time. This later method
is referred to as an area under the plasma serum
concentration curve (AUC) and measures the total
concentration of the drug over a specic time
period. Such a measurement requires repeated
sampling, which is impractical in large population
investigations. Single serum measures are easy to
obtain and often available as part of the patients
ongoing medical care. Thus the lack of any clear
relationship between blood concentrations of the
drug with the expression of gingival overgrowth
may be a reection of the shortfall of the sampling
technique or a lack of investigation into more
appropriate pharmacokinetic variables.
Concomitant medication
The three major drugs implicated in gingival over-
growth are seldom the only medications prescribed
to the patient. The effect of additional drugs on
the expression of gingival overgrowth has been
investigated with respect to both cyclosporine and
phenytoin.
Nifedipine and other calcium channel blockers are
used extensively in organ transplant patients medic-
ated with cyclosporine. As these drugs also cause
gingival overgrowth, it is not surprising that the pre-
valence of this unwanted effect increases signicantly
in transplant patients (4, 34, 45, 74, 75, 86, 88). It has
been suggested that combined therapy may increase
the prevalence of the condition, but not the severity
(50).
Other drugs taken by organ transplant patients
could likewise inuence the expression of the gin-
gival changes. Prednisolone and azathioprine
appear to afford adult transplant patients some
degree of protection against the development of
121
Periodontal tissues in health and disease
gingival overgrowth (21, 66, 86). The so-called
protective effects of these two drugs on the gingival
tissues may arise from their anti-inammatory
action on plaque-induced gingival inammation
which will be discussed later.
Other anti-epileptics can affect the hepatic
metabolism of phenytoin, which in turn can impact
upon the gingival tissue response. Phenobarbitone,
primidone and carbamazepine induce the hepatic
enzyme P450. The latter has a greater stimulatory
effect on the gingival broblast, which may explain
the increased prevalence of gingival overgrowth in
patients receiving multiple anti-epileptic therapy.
Periodontal variables
Any plaque-induced inammatory changes within
tissues are going to exacerbate the expression of drug-
induced gingival overgrowth. This nding suggests
causality, with a patients oral hygiene being a signi-
cant risk factor for both the development and the
expression of drug-induced gingival overgrowth (15,
30, 49, 66, 7476), althoughreports tothe contrary have
also appeared (57, 63, 87). Furthermore, most of the
evidence supporting the relationship between bac-
terial plaque and drug-induced gingival overgrowth
has been derived from cross-sectional studies, and in
such studies it is difcult to determine whether plaque
is a contributory factor to or a consequence of the
gingival changes. In circumstances where other addi-
tional structures such as orthodontic appliances
interfere withcleaning, the prevalence of overgrowthis
high (11).
Although there may be some debate as to the role
of plaque and gingival inammation in drug-induced
gingival overgrowth, there is no doubt that improving
a patients oral hygiene and reducing the inamma-
tory component in the gingival tissue by nonsurgical
means does have an impact on this unwanted effect.
Despite such measures there still remains a cohort of
patients who develop overgrowth irrespective of their
oral hygiene or periodontal condition (62). In such
patients, other risk factors may be more signicant.
A patients underlying periodontal status may also
be a signicant risk factor for drug-induced gingival
overgrowth (49, 82). Of particular concern is the
extent of inammation present in the gingival tissue
prior to dosing. Organ transplant patients are more
likely to develop overgrowth prior to transplantation
and dosing with cyclosporine when they exhibit sig-
nicant gingival inammation. A similar situation
arises with the calcium channel blockers (6, 40, 72). It
is interesting to note that gingival changes are more
pronounced in patients taking nifedipine for cardio-
vascular disorders than in patients taking these drugs
for other reasons. This may be due to the impact of
other cardiovascular drugs on the gingival vascula-
ture.
Genetic factors
The variable gingival response seen in patients
following drug challenge has been attributed to
broblast heterogeneity. Although this may be a
useful in vitro explanation, it has little value in
determining at-risk patients. Much interest has
focused on drug metabolizing enzymes and the
expression of gingival overgrowth. Phenytoin,
cyclosporine and nifedipine are all metabolized by
the hepatic cytochrome P450 enzymes. Cytochrome
P450 genes exhibit considerable polymorphism,
which results in interindividual variation in drug
levels. This inherited variation in metabolism of
either drug may inuence patient serum and tissue
concentrations and hence their gingival response.
Whereas cytochrome P450 variation may be a risk
factor for drug-induced gingival overgrowth, it is
totally impractical to assess this on a clinical basis
(59). Other studies have investigated P-glycoprotein
drug-transporter MDR1 gene polymorphisim and
CYP2C polymorphism in relation cyclosporine- and
phenytoin-induced gingival overgrowth, respectively
(14, 64). Neither of these investigations showed a
direct correlation between these two genetic
markers and gingival overgrowth.
Other genetic markers for gingival overgrowth have
focused on human lymphocyte antigen expression
(HLA), because HLA phenotype is determined prior
to organ transplantation. There is evidence that
patients who express HLA-DR1 are afforded some
degree of protection against the development of
drug-induced gingival overgrowth, whereas those
who express HLA-DR2 may be more susceptible to
this unwanted effect (7, 48).
Further studies have shown that HLA-A19 expres-
sion may increase susceptibility and HLA-B37 is a
signicant risk factor (34, 75).
The mechanisms that link HLA expression to
gingival overgrowth are unclear. The concept of
molecular mimicry in the wider eld of periodontal
disease (4) has been postulated, via an effect on
lymphocyte function. The apparent HLA associa-
tions may represent nothing more than a tight
linkage disequilibrium between HLA and non-HLA
genes in the MCH region of human chromosome 6
(32).
122
Seymour
Pathogenesis of drug-induced
gingival overgrowth
The main histopathological feature of drug-induced
gingival overgrowth is a brotic or expanded con-
nective tissue with various levels of inammation
and an enlarged gingival epithelium. As a conse-
quence, many of the investigations into the path-
ogenesis of this unwanted effect have been focused
on drug interactions or challenge to various aspects
of connective tissue metabolism. Many investiga-
tions have also considered roles of a variety of
inammatory cytokines and growth factors on the
effect of the drug on gingival broblast. An excel-
lent paper (78) has reviewed the extensive literature
of connective tissue metabolism and gingival over-
growth and little further can be added in this
review.
The pathogenesis of drug-induced gingival over-
growth remains multifactorial, different drugs having
separate impacts on the range of cytokines and
growth factors involved in connective tissue meta-
bolism. It is hoped that a greater understanding of
the pathogenesis of this unwanted effect could lead
to improved management strategies for either its
prevention or its treatment.
Treatment of drug-induced
gingival overgrowth
Gingival surgery (invariably a gingivectomy) remains
the main treatment option for correcting drug-
induced gingival overgrowth. Various different
surgical approaches and techniques have been
employed for removing the excess gingival tissues,
but few studies have demonstrated consistent
advantages over the standard 45 gingivectomy exci-
sion (58). Lasers have also been employed for gingival
excision, but the cost of using these instruments
often precludes their routine use.
Although surgery remains the main option for
treatment of drug-induced gingival overgrowth,
alternative strategies have been investigated to either
prevent the unwanted effect or reduce the incident of
recurrence.
For cyclosporine-induced gingival overgrowth,
attention has focused on the use of systemic or topical
(local) antibiotics to reduce the severity of the
condition or prevent recurrence after surgery. Such
investigation followed on from a small study in
renal transplant patients (89) where four cases of
drug-induced gingival overgrowth responded to a 7-
day course of systemic metronidazole. This uncon-
trolled study did not take into account the patients
underlying periodontal condition, and hence it was
difcult to discern whether the gingival changes were
drug-induced or secondary to underlying gingival
inammation.
Azithromycin is another antibiotic that has been
evaluated in the management of cyclosporine-
induced gingival overgrowth. A review of the clinical
trials that have been completed on the efcacy of the
compound (71) suggests that there are some benets
of systemic azithromycin in the management of
cyclosporine-induced gingival overgrowth. Azithro-
mycin appears to be more effective than metroni-
dazole (8) for this condition. Two investigations have
speculated on the mode of action azithromycin in
cyclosporine-induced gingival overgrowth. A clinical
study (37) concluded that a 7-day course of azithro-
mycin does not affect the remission of drug-induced
gingival overgrowth but does act on concomitant
bacterial over-infection and hence reduces inam-
mation. A study in rats showed that cyclosporine
decreases collagen degradation by lowering phago-
cyte activity of gingival broblasts. Azithromycin
increases this activity (47).
It remains to be determined what are the extent
and benets of azithromycin in the management of
drug-induced gingival overgrowth. Short-term cour-
ses have been employed and such courses may bring
about some reduction in overgrowth. Since drug-
induced gingival overgrowth is a recurrent and con-
tinuous problem, there will be concerns about the
use of repeated doses of antibiotics in the manage-
ment of this unwanted effect, especially in immu-
nosuppressed patients.
There have been other chemotherapeutic applica-
tions in the management of drug-induced gingival
overgrowth, especially to reduce the incidence of
recurrence after surgery. Chlorhexidine mouthwash
(0.2% w v) has been shown to be of benet in pre-
venting phenytoin-induced gingival overgrowth,
especially after surgery (43). Long-term use of this
plaque inhibitory agent has not been evaluated for
this purpose.
Phenytoin inhibits folic acid metabolism, but the
mechanism is uncertain. There is some evidence that
folic acid (1 mg ml mouthwash) appears to be more
efcacious than systemic administration (51). It has
been suggested that topical folate may reduce gingi-
val inammation by binding to the plaque-derived
endotoxins. This action may, in turn, reduce gingival
overgrowth. Patients with a low baseline plasma and
123
Periodontal tissues in health and disease
red blood cell folate show a better gingival response
to topical folic acid than patients with normal levels
(13).
Good plaque control, removal of plaque retentive
factors and treatment of any underlying periodontal
condition will reduce gingival inammation and
hence the severity of any drug-induced gingival
overgrowth. However, in some patients these meas-
ures alone will not reduce the occurrence or recur-
rence of overgrowth and surgical excision remains
the only option.
One obvious solution in the management drug-
induced gingival overgrowth is to change medication.
For many years this was not an option for cyclospo-
rine. However, new immunosuppressant (e.g. tacr-
olimus) alternative medication is now available, and
it has been shown that converting from cyclosporine
to tacrolimus does reduce the severity of overgrowth
and the need for surgical intervention (16, 25).
Although such a change in medication may improve
the gingival tissue, it does not completely resolve the
overgrowth (15).
Although phenytoin usage is declining and there
are more anti-epileptics available, changing the
medication for these patients can be a challenge.
Carbamazepine, ethosuximide and sodium valproate
are alternatives to phenytoin. If a change in anti-
convulsant therapy is contemplated, this should be
accomplished gradually over a period of 23 months.
During this time there should be monitoring of serum
levels of the anti-epileptics and the occurrence of
seizures.
Systemic medication can afford the
patient some degree of protection
against periodontal breakdown
It is well established that activation of the hosts
inammatory and immune responses are pivotal in
the pathogenesis of periodontal breakdown. As a
consequence, systemic medication that affects these
processes are of interest to the periodontist. This
interest is twofold. Firstly, these drugs can be used
as tools to identify the particular roles of immune
and inammatory responses in the periodontal
breakdown process. Secondly, the drugs may have
an additional therapeutic role in the management of
periodontal disease. Drugs that can potentially affect
the periodontium and its response to plaque include
immunosuppressants, corticosteroids and nonster-
oid anti-inammatory drugs. Antibiotics and the
host modulating agent doxycycline will also impact
on the periodontal breakdown process; however,
such drugs will not be considered as part of this
review.
Immunosuppressants
Many studies have investigated the effect of systemic
immunosuppressant medication on the various
parameters of periodontal diseases (60).
Azathioprine and prednisolone reduce the
inammatory responses of the periodontal tissue to
bacterial plaque (56). This nding was conrmed by
Kardachi & Newcomb (29), who compared plaque
scores and gingival indices in renal transplant
patients taking immunosuppressants with those
of otherwise healthy subjects. Both groups had
similar plaque scores, but the gingival index in the
renal transplant patients was signicantly lower
(P < 0.01).
There is evidence to suggest that uraemic patients
are in a state of reduced immunocapacity (5) and the
ndings reported above may be related to the previ-
ous disease, or to the drug therapy or both. In some
of the subsequent studies (3, 44, 77) various perio-
dontal measures were compared in renal transplant
patients taking immunosuppressants, patients on
hemodialysis and healthy controls. Gingival inam-
mation, periodontal destruction and plaque accu-
mulation were similar in all three groups, but in the
transplant group there was again a lack of correlation
between plaque levels and both gingival inamma-
tion and periodontal destruction.
Immunosuppressants do affect the response of
gingival and periodontal tissues to bacterial plaque.
They do not abolish the reaction of the tissues to
plaque, but appear to dampen down inamma-
tory reactions. The specic pharmacodynamics of
immunosuppressants may provide further insight
into the pathogenesis of periodontal inammation
and breakdown.
Corticosteroids
This group of drugs is used in virtually every aspect of
clinical medicine. They are for the most part used for
their anti-inammatory and immunosuppressant
properties (60). Prolonged therapy with corticoster-
oids may favor osteoporosis, which is now regarded
as a risk factor for periodontal disease. Several animal
studies have conrmed that systemic steroids have
adverse effects on the periodontium and its response
to bacterial plaque. Clinical studies are somewhat
124
Seymour
equivocal with respect to a signicant anti-inam-
matory action. An early study in bed-ridden patients
on long-term corticosteroids showed that regardless
of steroid therapy, inammatory changes were more
severe in those subjects with poor oral hygiene.
Therefore, gingival inammation and periodontal
destruction were more dependent on plaque control
than on any anti-inammatory action attributable to
systemic steroids (31). Topical application of corti-
costeroids to inamed marginal gingiva of patients
with periodontal disease resulted in a reduction of
inammation and bleeding with no effect on the
progression of periodontitis (20, 70). However, when
steroids are injected directly into the gingival tissue,
they cause a histological reduction in capillary per-
meability, a reduction in plasma cells and granula-
tion tissue, an inhibition of collagen synthesis and a
clinical improvement in hemorrhagic and hypoplas-
tic gingivitis (26).
The effect of systemic prednisolone upon gingival
inammation and periodontal bone destruction has
been studied in a group of patients suffering from
multiple sclerosis (55). Comparisons were made
between this group, a group of patients who suffered
from neurological disorders but were receiving no
steroids, and healthy controls. There were no differ-
ences between the groups and it was concluded that
long-term systemic steroid therapy had no inuence
on the measures of periodontal disease.
It would appear that despite observations from
animal studies, systemic and topical corticosteroids
have little impact on the periodontuim and its
response to bacterial plaque. The reasons for these
inconsistent ndings may include insufcient dosage
as well as inadequate interactions among the com-
bination of drugs that various patient groups are
taking. Despite their recognized anti-inammatory
and immunosuppressive properties, corticosteroids
have no application in the management of perio-
dontal diseases.
Non-steroidal anti-inammatory drugs
(NSAIDs)
In the early 1970s it was recognized that prostaglan-
dins (PGs) were important mediators in the patho-
genesis of periodontal destruction and activation of
mechanisms of bone resumption (19). At the same
time, Vane and coworkers were identifying the mode
of action of cyclo-oxygenase and subsequent pros-
taglandin synthesis and their inhibition by aspirin
(80). As a consequence of these ndings, a signicant
interest emerged in the possible application of these
drugs in the control and management of periodontal
diseases.
Evidence that such drugs may have an application
in the management of periodontal diseases came
from controlled studies on patients who had been on
long-term NSAID therapy for musculoskeletal rea-
sons (18, 23, 83). In the rst of these studies (83)
patients on long-term NSAIDs had reduced amounts
of gingival inammation and probing depths com-
pared with age- and plaque-matched controls. In a
further study, it was demonstrated that NSAIDs
afforded patients some degree of protection against
alveolar bone loss (18). By contrast, a cross-sectional
study showed no signicant differences for a variety
of periodontal measures between patients on long-
term NSAIDs and a control group (23). However,
patients from the NSAID group had signicantly
lower gingival crevicular uid ow rate than controls.
This was attributed to a possible effect of the NSAID
medication on the vascularity and permeability of
small blood vessels.
Animal studies have conrmed benecial effects of
NSAIDs in ligature-induced periodontitis (41, 42).
Another animal study showed that systemic urbi-
profen signicantly resolved bone loss in beagle dogs
undergoing either surgical or nonsurgical manage-
ment of periodontitis (85).
Clinical studies on NSAIDs when used as adjuncts
in the management of periodontal disease have
been somewhat equivocal with respect to outcomes.
Systemic urbiprofen taken for 12 months reduces
the rate of alveolar bone loss (84) and is benecial
for the resolution of experimental gingivitis (22).
Systemic administration of the drugs in asthmatics
is associated with an increased risk of unwanted
effects including peptic ulceration, interference with
platelet aggregation and increased risk of broncho-
constriction. Concerns over these unwanted effects
directed interest to the topical application of
NSAIDs for adjunctive management of periodontal
disease. Such agents could be delivered in the form
of a mouthrinse or incorporated into toothpaste. A
ketorolac rinse may be of benet in the treatment of
adult periondontitis and appears to have advantages
over systemic urbiprofen in reducing alveolar bone
loss (27). By comparison, a 1% w w urbipropfen
toothpaste was shown to exert a small yet signicant
effect on bone metabolism when used over a 12-
month period as an adjunct to root surface instru-
mentation (22).
Whereas systemic NSAIDs appear to afford a
patient some degree of protection, their use as a
therapeutic measure in the treatment of periodontal
125
Periodontal tissues in health and disease
disease is limited. In part this is due to the high
prevalence of unwanted effects, which subsequently
is encouraging the development of topical prepara-
tions. The success of these agents is also somewhat
limited and their use as a means of controlling peri-
odontal disease has been surpassed by other more
effective compounds.
The new COX-2 inhibitors have all the attributes of
NSAIDs with a reduced risk of unwanted effects.
These drugs have been evaluated as an adjunct to
root surface instrumentation in patients with chronic
periodontitis (81). The results showed little clinical
benet of COX-2 inhibitors in the management of
such patients, but signicant reductions in gingival
tissue levels of PGE
2
and PGF
2
. The recent scare over
the long-term use of these drugs will probably
exclude their use in the management of periodontal
diseases.
Drugs which can increase the
expression of periodontal diseases
Sex hormones
The effects of sex hormones on the gingival tissues
are well established and distinct changes in relation
to puberty and pregnancy are well documented (35).
Such changes are brought about by increased levels
of circulating estrogen and progesterone. Both sex
hormones are constituents of the contraceptive pill
and are also used in hormone replacement therapy.
The oral contraceptive can mimic the gingival and
periodontal changes observed in pregnancy. These
include an increased tendency for gingivitis and
increased probing depths (33, 38, 39), increased
susceptibility to infection (9), decreased neurophil
chemotaxis (52, 67) and an increased number of
periodontopathogens (79). Long-term use of the oral
contraceptive can lead to acceleration in the pro-
gression of periodontal disease, but much would
depend upon the concentration of hormones used in
the pill. However, low doses of estrogen and prog-
esterone are now widely used in contraceptive pills
and these lower doses have little impact on the per-
iodontal tissues and their response to plaque (39).
The impact of hormone replacement therapy on
the periodontium is difcult to dene. It is now
recognized that osteoporosis is a risk factor for peri-
odontal disease and reduction in bone mineral den-
sity is a major health problem in postmenopausal
woman. Estrogen is the main hormone used in hor-
mone replacement therapy and is of value in pre-
venting bone loss and the need for dentures in the
older woman (46). Patients on estrogen replacement
had less tooth loss and hence less need for dentures
than control patients. This would suggest some pro-
tective action of hormone replacement therapy,
possibly medicated by the prevention of osteo-
porosis.
In a further study it was reported that a 2-year
course of estrogen replacement therapy benets a
patients periodontal condition, with reduced levels
of inammation and a reduced frequency of clinical
attachment loss (53). These two studies (46, 53)
suggest that patients on hormone replacement ther-
apy may receive some periodontal benet. Again,
such benets may be medicated via reduction in the
risk of osteoporosis.
Drug-induced desquamative gingivitis
Several drugs can cause oral lichenoid reactions that
can present as desquamative gingivitis. Drugs most
commonly implicated include beta-adrenoceptor
blockers (e.g. propranolol, atenolol), antidiabetic
drugs (e.g. chlorporpamide and tolbutamide), gold
salts and nonsteroidal anti-inammatory drugs. Most
examples have been presented as case reports and a
detailed list of all the drugs implicated in this
unwanted effect can be found in specialized texts
(36). The diagnosis of drug-induced lichenoid erup-
tions (desquamative gingivitis) can be problematic
and often involves stopping the suspected drug and
re-challenging the patient. Most of the drugs fre-
quently implicated can be substituted by an alter-
native medication with the same therapeutic goals.
Drug-induced depression of bone
marrow
Drug-induced depression of bone marrow is the most
serious and potentially life-threatening adverse effect
of systemic medication. Fortunately, this unwanted
effect is rare, but it can result in aplastic anaemia,
agranulocytosis and thrombocytopenia. Again, a list
of drugs that have been implicated in this unwanted
effect can be found in specialist textbooks (12). Drug-
induced depression of bone marrow will affect the
periodontal tissues. There may be a rapid increase in
the rate of periodontal destruction following a
reduction in white blood cell numbers or activity.
Thrombocytopenia will manifest in the gingival tis-
sues, especially if these are inamed. Excessive
bleeding on probing and prolonged bleeding may be
secondary to a drug-induced thrombocytopenia.
126
Seymour
Other unwanted effects that can follow a drug-
induced depression of bone marrow include oral
ulceration, swollen gingiva and an increased risk of
opportunistic infections (e.g. herpes and Candida).
Drug-induced bone marrow often accompanies
chemotherapy used in the treatment of malignant
diseases. Careful monitoring of bone marrow activity
is part of any chemotherapy regimen, but periodontal
manifestation may occur during the course of treat-
ment. Whenever possible, patients about to start
chemotherapy should have a thorough oral screening
and prevention measures should be put in place to
reduce the effect of these drugs on the periodontal
tissues.
Increased bleeding on probing has also been
reported in patients taking aspirin for the prevention
of thrombo-embolic disorders (54). This relates to the
ability of aspirin to reduce platelet aggregation via
blocking cyclo-oxygenase enzymes. The impact of
aspirin upon hemostasis should be taken into
account when assessing the response of the gingival
tissues to gentle probing.
Conclusions
It is evident that periodontal tissue is susceptible to a
range of systemic medications. Such drug therapy
can produce unwanted effects (e.g. gingival over-
growth), and reduce or increase the expression of
periodontal disease. The periodontium may also be
the target of adverse reactions. This emphasizes the
importance of regular medical and drug histories and
thorough oral and periodontal screening for all
patients, especially the elderly.
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