Periodontology 2000, Vol. 40, 2006, 120129 Printed in the UK.

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Copyright Blackwell Munksgaard 2006

PERIODONTOLOGY 2000

Effects of medications on the periodontal tissues in health and disease

R O B I N A. S E Y M O U R
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 periodontium can be categorized as follows: an adverse effect on the periodontal tissues; affording some degree of protection against periodontal breakdown; causing an increased risk of periodontal breakdown. gated. Many authors have used hospital-based patients, which is entirely appropriate for cyclosporine. 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 gingival 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 epidemiologic studies. This term is applied to those patients whose gingival overgrowth requires surgical excision to correct the gingival contour (59).

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).

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, concomitant 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

Prevalence of drug-induced gingival overgrowth

The prevalence of drug-induced gingival overgrowth varies signicantly and, as with most epidemiological studies, depends upon the population investi-

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component contributes to broblast sensitivity to the challenging drugs. Phenytoin has been shown to enhance the ability of gingival broblast to metabolize testosterone to the more active 5a dihydrotestosterone (69). Similar results were found for broblast, obtained from both cyclosporine- and nifedipine-induced gingival overgrowths (68). Adolescents will have higher levels of circulating androgens which could stimulate further gingival broblast to increase collagen synthesis and or decrease collagenase 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 outcome 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, pharmacological factors or a hormonal cofactor remains to be determined.

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. Cyclosporine measures are often taken as trough concentrations. Whereas such single measures are useful for checking compliance, the level of anticonvulsant activity or immunosuppression, they only reect one aspect of the drugs pharmacokinetic prole. Other pharmacokinetic measures that may have more potential in relation to the expression of gingival overgrowth include bioavailability, degree of protein binding, volume of distribution, 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.

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 studied and include peak and trough serum concentration, drug dosage, drug concentration in saliva and gingival crevicular uid. There is no consistent nding 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 implicated drugs (59). Despite these reservations, most workers would concur that some baseline or threshold 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

Concomitant medication
The three major drugs implicated in gingival overgrowth 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 medicated with cyclosporine. As these drugs also cause gingival overgrowth, it is not surprising that the prevalence 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 gingival changes. Prednisolone and azathioprine appear to afford adult transplant patients some degree of protection against the development of

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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.

pronounced in patients taking nifedipine for cardiovascular disorders than in patients taking these drugs for other reasons. This may be due to the impact of other cardiovascular drugs on the gingival vasculature.

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 expression 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 associations may represent nothing more than a tight linkage disequilibrium between HLA and non-HLA genes in the MCH region of human chromosome 6 (32).

Periodontal variables
Any plaque-induced inammatory changes within tissues are going to exacerbate the expression of druginduced gingival overgrowth. This nding suggests causality, with a patients oral hygiene being a signicant risk factor for both the development and the expression of drug-induced gingival overgrowth (15, 30, 49, 66, 7476), although reports to the contrary have also appeared (57, 63, 87). Furthermore, most of the evidence supporting the relationship between bacterial 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 additional structures such as orthodontic appliances interfere with cleaning, the prevalence of overgrowth is 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 inammatory 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 signicant gingival inammation. A similar situation arises with the calcium channel blockers (6, 40, 72). It is interesting to note that gingival changes are more

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Pathogenesis of drug-induced gingival overgrowth

The main histopathological feature of drug-induced gingival overgrowth is a brotic or expanded connective tissue with various levels of inammation and an enlarged gingival epithelium. As a consequence, many of the investigations into the pathogenesis of this unwanted effect have been focused on drug interactions or challenge to various aspects of connective tissue metabolism. Many investigations have also considered roles of a variety of inammatory cytokines and growth factors on the effect of the drug on gingival broblast. An excellent paper (78) has reviewed the extensive literature of connective tissue metabolism and gingival overgrowth and little further can be added in this review. The pathogenesis of drug-induced gingival overgrowth remains multifactorial, different drugs having separate impacts on the range of cytokines and growth factors involved in connective tissue metabolism. 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 druginduced 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 excision (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 7day course of systemic metronidazole. This uncontrolled 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 cyclosporineinduced 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. Azithromycin appears to be more effective than metronidazole (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 azithromycin does not affect the remission of drug-induced gingival overgrowth but does act on concomitant bacterial over-infection and hence reduces inammation. A study in rats showed that cyclosporine decreases collagen degradation by lowering phagocyte 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 courses have been employed and such courses may bring about some reduction in overgrowth. Since druginduced gingival overgrowth is a recurrent and continuous problem, there will be concerns about the use of repeated doses of antibiotics in the management of this unwanted effect, especially in immunosuppressed patients. There have been other chemotherapeutic applications 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 preventing 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 gingival inammation by binding to the plaque-derived endotoxins. This action may, in turn, reduce gingival overgrowth. Patients with a low baseline plasma and

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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 measures alone will not reduce the occurrence or recurrence of overgrowth and surgical excision remains the only option. One obvious solution in the management druginduced gingival overgrowth is to change medication. For many years this was not an option for cyclosporine. However, new immunosuppressant (e.g. tacrolimus) 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 anticonvulsant 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.

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 previous disease, or to the drug therapy or both. In some of the subsequent studies (3, 44, 77) various periodontal measures were compared in renal transplant patients taking immunosuppressants, patients on hemodialysis and healthy controls. Gingival inammation, periodontal destruction and plaque accumulation were similar in all three groups, but in the transplant group there was again a lack of correlation between plaque levels and both gingival inammation 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 inammatory reactions. The specic pharmacodynamics of immunosuppressants may provide further insight into the pathogenesis of periodontal inammation and breakdown.

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 nonsteroid anti-inammatory drugs. Antibiotics and the

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 corticosteroids 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

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equivocal with respect to a signicant anti-inammatory 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 corticosteroids 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 permeability, a reduction in plasma cells and granulation tissue, an inhibition of collagen synthesis and a clinical improvement in hemorrhagic and hypoplastic 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 differences 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 combination of drugs that various patient groups are taking. Despite their recognized anti-inammatory and immunosuppressive properties, corticosteroids have no application in the management of periodontal diseases.

Non-steroidal anti-inammatory drugs (NSAIDs)

In the early 1970s it was recognized that prostaglandins (PGs) were important mediators in the pathogenesis 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 prostaglandin 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 reasons (18, 23, 83). In the rst of these studies (83) patients on long-term NSAIDs had reduced amounts of gingival inammation and probing depths compared 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 longterm 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 urbiprofen signicantly resolved bone loss in beagle dogs undergoing either surgical or nonsurgical management 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 bronchoconstriction. 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 12month period as an adjunct to root surface instrumentation (22). Whereas systemic NSAIDs appear to afford a patient some degree of protection, their use as a therapeutic measure in the treatment of periodontal

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disease is limited. In part this is due to the high prevalence of unwanted effects, which subsequently is encouraging the development of topical preparations. The success of these agents is also somewhat limited and their use as a means of controlling periodontal 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 PGE2 and PGF2. The recent scare over the long-term use of these drugs will probably exclude their use in the management of periodontal diseases.

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 protective action of hormone replacement therapy, possibly medicated by the prevention of osteoporosis. 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 therapy 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 eruptions (desquamative gingivitis) can be problematic and often involves stopping the suspected drug and re-challenging the patient. Most of the drugs frequently implicated can be substituted by an alternative medication with the same therapeutic goals.

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 progression of periodontal disease, but much would depend upon the concentration of hormones used in the pill. However, low doses of estrogen and progesterone are now widely used in contraceptive pills and these lower doses have little impact on the periodontal 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 periodontal disease and reduction in bone mineral density is a major health problem in postmenopausal woman. Estrogen is the main hormone used in hormone replacement therapy and is of value in pre-

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). Druginduced 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 tissues, especially if these are inamed. Excessive bleeding on probing and prolonged bleeding may be secondary to a drug-induced thrombocytopenia.

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Other unwanted effects that can follow a druginduced 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 treatment. 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.

7.

8.

9.

10.

11.

12. 13.

14.

Conclusions
15.

It is evident that periodontal tissue is susceptible to a range of systemic medications. Such drug therapy can produce unwanted effects (e.g. gingival overgrowth), 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.

16.

17. 18.

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