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EFFECT OF DRUGS ON ORAL

MUCOSA AND THEIR


MANAGEMENT

By:-

Rajsandeep Singh

Roll no.71

4th year

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Introduction

About 10% of ambulant outpatients may be having systemic drug treatment. Though not
a common source of difficulties, some drugs can complicate dental management,
occasionally catastrophically. Drug addicts are also a growing clinical problem The
effects of systemically administered drugs on dental management are varied.

Significance of drug treatment to dental management.

• Drugs may complicate dental treatment itself.

• Drugs may react with drugs given for dental purposes.

• Drugs may cause stomatitis or have other oral effects.

Etiology and Pathogenesis of Oral Adverse Drug Reactions

Although the skin is more commonly involved in adverse reactions to drugs, the oral
mucosa is also frequently affected. Virtually any drug has the potential to cause an
untoward reaction, but some have a greater ability to do so than others. Pathogenesis of
drugs are mediated by the immune system and are drug allergies. Three mechanisms have
been proposed for drug allergies. Firstly, IgE-mediated reactions occur when the drug
reacts with IgE antibodies bound to mast cells. Secondly, drug allergies can involve a
cytotoxic reaction in which an antibody binds to a drug that is already attached to a cell
surface. The third mechanism in a drug allergy involves circulation of the antigen for
extended periods allowing sensitization of the patient’s immune system and production of
a new antibody. Nonimmunologic drug reactions are not antibody dependent and may
directly affect mast cells causing the release of chemical mediators. Also some
nonimmunologic drug-induced result from a drug overdose or toxicity.

Clinical Features of Oral Adverse Drug Reactions


Manifestations of drug reactions are dependent on the type of drug, dose and individual
patient differences. These reactions can be seen either rapidly or several days after drug
use. Acquired angioedema is an IgE-mediate drug allergy that is commonly observed as
drug and food reactions. Other cutaneous manifestations of drug reactions include
urticaria, maculopapular rash, erythema, vesicles, ulcers, and target lesions. An unusual
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form of drug reaction is known as fixed drug reaction during which an erythematous
lesion appears in the same location with each antigenic challenge. Oral manifestations of
drug reactions may be erythematous, vesicular, or ulcerative in nature. They may also
mimic erosive lichen planus known as lichenoid drug reactions.

Histopathology of Oral Adverse Drug Reations

Histologic features or findings of drug reactions include nonspecific features as


spongiosis, apoptotic keratinocytes, lymphoid infiltrates, eosinophils, and ulceration.
Also, mononuclear of pllymorphonuclear infiltrations in a subepithelial or perivascular
distribution, basal cell destruction, edema, and keratinocyte necrosis are seen.

Diagnosis of Adverse Drug Reactions

The diagnosis of drug reactions requires a high index of suspicion and careful history
taking. Recent use of a drug is important. Withdrawal of the suspected drug should result
in improvement, and reinstitution of the drug should exacerbate the patient’s condition.
The clinical expression of lesions in drug reactions is generally allergic in nature that can
help with the diagnosis.

BRIEF DESCRIPTION OF DRUGS HAVING DENTALLY RELEVANT


ADVERSE REACTIONS

I) Tetracyclines

These are a class of antibioties having a nucleus of 4 cyclic rings. They are
obtained from soil actinomycetes.

These are primarily bacteriostatic. They interfere with a attachment of


aminoacyl-t-RNA to the mRNA – ribosome complex by binding to 30S
ribosomes in susceptible organisms.

Indications :

a) Empirical therapy or in mixed infections although combination of B-


lactams & an aminoglycocide or 3rd generation cephalosporin on
flouroquinolone are preferred.

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b) Many organisms have developed resistance however they are still
preferred for Venereal diseases like lymphogranuloma venereum &
granuloma inguinale, ataypical pneumonia caused by mycoplasma,
cholera, brucellosis, plague, relapsing fever (cause by B recurrentis),
Rickettseal infections like typhus, rocky fever, Q-fever.

Effect on oral mucosa : It causes superinfection as they cause marked


suppression of the resident flora causing the more virulent organism to flare
up.

II) Chloramphenicol:

It is synthesized chemically and it inhibits bacterial protein synthesis by


interfering with transfer of the elongating peptide chain to the newly attached
aminoacyl - tRNA to acceptor site at the ribosome-mRNA complex.

Indications :

It is never used for infections treatable by other agents. It is however used for
the following purposes:

• In enteric fever caused by sensitive strains

• H.influenzae meningitis

• Anaerobic infections caused by Bact.fragilis and others(wound


infections, pelvic and brain abscesses).

• Intraocular infections

Effects on oral mucosa:

• Bone marrow depression: This leads to opportunistic infections, necrotizing


gingival diseases or purpuric spots on the mucosa.

• Hypersensitivity reactions may cause atrophic glossitis, angiodema.

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• Superinfections similar to the ones caused by tetracyclines are seen but are less
common as compared to tetracyclines.

• When high doses are given to neonates it causes grey baby syndrome ashen-grey
cyanosis which is also manifested in the oral mucosa.

III) Penicillin

These are chemically β-lactams and one of the first antibiotics to be used
clinically.

These in a bit transpiptidases and therefore destroy the cell wall repair mechanism
of organisms.

Indications :

a) Streptecocal infection

b) Meningococal infection

c) Gonorrhoea

d) Syphilis

e) In diphtheria & tetanus as adjuvant therapy

f) Prophylactic uses for Rheumatic fever, gonorrhoea / syphilis, Bacterial


Endocarditis, surgical infections.

Effect on oral mucosa: It causes type1 hypersensitivity reactions. There is


generalized slight oedema of face, rashes, pallor and may cause angiodema.

IV) Nefedipine

It is a calcium channel blocker and is a potent vasodilator & anti-anginal drug. It


causes preferential dilatation of coronary vessels & increases coronary blood

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flow. It also exerts a potent vasodilator effect on arterial bed & produces
reduction in both systolic & diastolic blood pressure & causes reflex tachycardia.

Indications:

Vasospastic angina, chronic stable angina, hypertension, hypertrophic


cardiomyopathy, peripheral vascular diseases, congestive heart failure, acute
myocardial infarction, myocardial preservation, during surgery, migrane,
oesophageal sparsm, exercise induced bronchial asthma.

Effect on oral mucosa – gingival hyperplasia

V) Diltiazem:

It is a less potent vasodilator thannefedipine & has a modest direct negative


chronotropic, inotropic, dromotropic effect. It produces a modest fall in bp
with no change in heart rate. Large doses decrease total peripheral resistance
markedly & elicit reflex cardiac effects. It is a potent coronary dilator.

Indications: Angina pectoris due to coronary spasm & chronic stable angina.

Effect on oral mucosa:

Gingival hyperplasia.

VI Phenytoin

Most outstanding action is abolition of tonic phase of maxima electro shock


seizures, with no effect / prologation of chronic phase. It stabilizes neuronal
membranes & therefore, limits spread of seizure activity & is also effective in
neuralgias & cardiac arrythmias.

Indications :

• Grandmal, cortical focal & Psychomotor epilepsy.

• Migraine

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• Trigeminal neuralgia

• Cardiac arrythmias especially diagoxin induced.

Effects on oral mucosa & perioral structures:

Gingival hyperplasia, neutropenia, DLE, Rashes, megaloblastic anaemia.

VII Aspirin

It is acetyl salicylic acid which is a potent anti-inflammatory & a good analgesic.


It is rapidly converted to salicylic acid which is responsible for most of its actions.
Other actions result from acetylation of macromolecules like COX.

Indications:

• Analgesic (headache, backache, myalgia, joint pain, tooth ache,


neuralgias, dysmenorrhoea).

• Antipyretic

• Acute Rheumatic fever

• Rheumatoid arthritis

• Osteoarthritis

• Post myocardial infarction & post stroke patients, transient ischemic


attacks.

• Coronary bypass, Trans-luminal angio-plasty

Effects on oral mucosa:

Potentiation of any haemorrhagic tendencies, avoid in children because of risk of


Reye’s syndrome.

VIII Other NSAIDs occasionally cause lichenoid drug reactions

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IX Hypnotics & sedatives cause potentiation of general anaesthetics & other
sedating drugs.

X Barbiturates

They are known as minor tranquilizers. They are general depressants for all
neurons and produce dose dependant effecys on CNS ranging from sedation to
coma. They besides acting on the CNS act on the CVS. They have a dual mode of
action on skeletal muscles acting directly on them & also by acting on
neuromuscular transmission.

Indications: Except for thiopentone in anesthesia and phenobarbitone in epilepsy


they are rarely used now. As hypnotics and anxiolytics they have been superseded
by BZDs.

Effects on oral mucosa :

They cause Erythema multiforme which may progress to toxic epidermal


necrolysis.

XI Phenothiazine antipsychotics

These are called ‘major tranquilizers’

Indications:

• Psychoses (Schizophrenia, Mania, organic brain syndromes)

• Anxiety

• As antiemetics

• To potentiate Hypnotics, analgesics, anaesthetics

• Intractable hiccoughs

• Tetanus

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• Alcoholic hallucinosis, huntington’s diease, Gilles de la Tourette’s
syndrome.

Effects on oral mucosa:

• Dry mouth in due to their anti cholinergic properties, however, clozapine causes
hypersalivation due to its central actions.

• They also cause rigidity, tremos, hypokinesia and mask like facies.

• Acute Myotonias: Bizarre muscle spasms, mostly involving linguo-facial muscles.


Which cause grimacing, torticollis, locked jaw and occur within few hours of a
single dose or at the most in the first week of therapy.

• Tardive dyskinesia occur late in therapy include constant chewing, pouting,


puffing of cheeks, lip licking, choreoathetoid movements.

XII Metoclopramide:

It is a prokinetic drug & acts by D2 antagonism 5HT4 agonism & 5HT3


antagonism.

Indications: It is used as an anti-emetic, gastrokinetic, in dyspepsia and in


GERD.

Effects on oral mucosa:

Can cause muscle dystonias. Can lead to clenching of jaws.

XIII Tricyclic antidepressants (eg. Amitryptyline)

They inhibit the active uptake of biogenic amines(NA & 5-HT3) into their
respective neurons and thus potentiate them.

Effec on oral mucosa :

They cause a dry mouth and bad taste. In the perioral tissues sweating and fine
tremors can be seen.

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XIV MAO inhititors:

They as the name suggest, inhibit mitochondrial oxidative deamination of


biogenic amines and potentiates their effects. Therefore is used in various forms
of depression.

Effect on oral mucosa:

• They cause dry mouth.

• Opiod therapy particularly with pethidine is contra indicated because it


causes high fever, sweating, excitation, detirium, convulsions & sense
respiratory depression. This is because MAO inhibitors retard hydroysis of
pethidine but not its demethylation. Thus norpethidine accumulates.

XV Antihistamines:

These have histamine antagonist, antiallergic, CNS depressant & anti –


cholinergic actions.

Indications: they are used in various allergic disorders, as pruritides, common


cold, motion sickness and vertigo.

Effect on oral mucosa:

They cause a dry mouth

Other dentally relevant adverse effects are drowsiness & potentiation of sedatives.

XVI Corticosteroids

They have glucocorticoid & mineralocorticoid actions, however, they are mainly
used for their glucocorticoid actions. They are catabolic in most of their functions
except they promote gluconeogenesis, glycogenesis. They increase the destruction
of lymphocytes(t-cells primarily). However their main action is anti-
inflammatory. The action is non-specific and covers all components and stages of
inflammation.

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Indications:

• Replacement therapies

• Arthritides

• Collagen diseases

• Severe allergies reactions

• Autoimmune diseases

• asthma

Effect on oral mucosa:

• They progressively bring down the systemic & local immune defenses &
causes opportunistic infections in the mouth(e.g.candida)

• It decreases wound healing.

• Foetal abnormalities: Cleft palate and other defects are produced in


animals, but have never been encountered in clinical use in pregnant
women.

XVII Other immunosuppressive & cytotoxic drugs

• Methotrexate causes oral ulceration.

• Cisplatin causes grey gingival line.

• Vincristine can cause jaw pain & weakness of facial muscles.

• Besides all of these would cause opportunistic infections.

XVIII Cyclosporin

It is a cyclic polypeptide obtained from a fungus & is a highly selective


immunosuppressant. It profoundly & selectively inhibits T lymphocyte
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proliferation, IL2 and other cytokine production and response of inducer T-cells
to IL-1 without any effect on suppressor T-cells. Lymphocytes are arrested in G0-
or G1 phase.

Indications: It is the most effective drug for preservation and treatment of graft
rejection reaction. It is routinely used in renal, hepatic, cardiac, bone marrow &
other transplantations.

Effect on oral mucosa:

Gum hyperplasia

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IMPORTANT TYPES OF ORAL DRUG REACTIONS

I Local reactions to drugs

• Chemical irritation

• Interference with the oral flora

II Systemically mediated reactions

• Depression of marrow function

• Depression of cell mediated immunity

• Lichenoid reactions

• Erythema multiforme (Stevens-Johnson syndrome)

• Fixed drug reactions

• Toxic epidermal necrolysis

III Other effects

1. Gingival hyperplasia

2. Pigmentation

3. Dry mouth

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LOCAL REACTIONS TO DRUGS

1. Chemical burns. The best known example is that of aspirin tablets held against the
mucosa close to an aching tooth. This causes superficial necrosis and a white patch.

Other irritant chemicals are acid etchants or phenol dropped on oral mucosa
during dental treatment.

2. Interference with the oral flora: superinfection. Prolonged therapy use of


antibiotics(particularly tetracyclines) in the mouth kills off sensitive organisms and
allows resistant ones, particularly Candida albicans , to proliferate , causing thrush. In
susceptible patients use of a topical antibiotic may precipitate candidal infection within
48 hours

SYSTEMICALLY MEDIATED REACTIONS

1) Depression of marrow function. Few drugs significantly depress red cell


production alone, though any drug which causes anemia might give rise to oral
signs. E.g. phenytoin which, in susceptible patients, can occasionally cause severe
aphthous stomatitis.

Management: Response promptly follows administration of folate, and the blood


picture returns to normal.

Necrotizing Ulcerative Gingivitis: White cell production is depressed by a variety


of drugs. Leucopenia can be severe enough to produce a picture of agranulocytosis,
with necrotizing ulceration of the gingivae and throat which can go onto a severe
prostrating illness and septicaemia if untreated. Drugs which may have this effect
are:

• Antibacterials, particularly co-trimoxazole, chloramphenicol.

• Analgesics, particularly amidopyrine(obsolete in most countries)

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• Phenothiazines

• Anti-thyroid drugs

When the main effect is on granulocytes, the low-grade pathogens, particularly of


the gingival margins, are able to overcome local resistance and produce necrotizing
ulceration.

Oral manifestatrions:

• It has a rapid and acute onset.

• First symptoms include excessive salivation, a metallic taste, and sensitivity


of the ginivae

• This is followed by extremely red and painful gingivae with punched out
crater like ulcerations usually on the on the inter-dental gingivae but any
part of the marginal gingivae can be involved.

• There is accompanying malodor and gingival bleeding.

Management:

This is directed towards supportive care and pain control, definitive treatment and
identification of predisposing factors.

Definitive treatment consists of gentle debridement of as much plaque and calculus as


possible; bets accomplished under local anesthesia.

Use of chlorhexidine mouth washes is very helpful.

In extensive cases antibiotics against gram –ve bacteria (β-lactams)are essential.


Metronidazole though ineffective against spirochetes is helpful.

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necrotizing ulcerative infection in neutreopenic patient

Other drugs may affect haemostasis and cause oral purpura. Drug induced purpura is an
early sign of aplastic anemia caused by drugs like chloramphenicol. It can produce severe
gingival bleeding or blood blisters or extensive submucosal ecchymoses.

2) Aphthous Stomatits:

Aphthous stomatitis is commonly observed and is mediated by the immune system.


Lesions usually appear as painful, tiny, discrete, or grouped papules and vesicles. These
vesicles are small in diameter with round, shallow ulcerations predominantly seen over
the buccal and labial mucosa. The ulcers seen are usually of minor type. The reactions
usually heal without scarring in 10-14 day, however, recurrence is common.

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recurrent aphthous stomatitis

Drugs with potential to cause aphthous stomatitis

Azathiopurine Losartan

Captopril NSAIDs

Cyclosporine Fluoxetine

Penicillamine Gold compounds

Sertaline Indinavir

Sulphonamides Interferones

Management:

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In mild cases with two or three small lesions, use of a protective emollient such as
Orabase or Zilactin, a topical anesthetic is all that’s necessary. Pain can be relieved by
topical anesthetic agent or topical diclofenac.

In more severe cases a high potency topical steroid preparation, such as fluocinonide,
betamethasons, or clobetasol is necessary which shortens healing time and reduces the
size of the ulcers.

3) Depression of cell-mediated immunity:

Immunosuppresion by drugs as corticosteroids is induced in patients having organ


transplants or with immunologically mediated diseases. Viral and fungal infections of
the mouth are common in patients and can be severe. Recurrences of childhood
infections like measles and chicken pox are possible.

4) Lichenoid reactions:

Etiology and pathogenesis:

• It has been postulated that DLIRs may result from poor drug metabolism because
genetic variation of the major cytochrome p-450 enzymes

• As the clinical and histopathological picture resembles a delayed type


hypersensitivity reaction, it has been suggested that drugs or their metabolites act
as haptens and trigger a lichenoid reaction against the cell components.

Drugs with potential to cause LIchenoid Eruptions

penicillin gold sulfonamides

Merciry(amalgam) allopurinol ACE inhibitors

methyldopa Arsenical compounds NSAIDs

Β-blockers palladium Bismuth

penicillamine chloroquine Primaquine

Cholera vaccine HBV vaccine Quinine

quinidine .hydroxychloroquine Chlorpropamide.


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Propranolol Phenothiazines furosemide

streptomycin tetracyclines Lithium carbonate

BCG vaccine captopril Carbamazepine

griseofulvin ketoconazole Interferon-{157}

metformin Protease inhibitors Oral contraceptives

Clinical findings:

It has been suggested that they are predominantly unilateral and present with an
ulcerative reaction pattern. However, these findings are not consistant and not enough to
differentiate them from lichen planus.

They show a homogenous well demarcated white plaque often but not always surrounded
by striae, appearing similar to lichen rubber planus, and may be severely pruritic.

Management:

Discontinuance of the drug and symptomatic treatment with topical steroids is usually
enough. The patient should be properly educated about the responsible drug to prevent
future DILRs.

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The picture shows a lichenoid reaction following 1 month of medication with a
cholestyramine-containing drug. The adjacent picture shows regression following
withdrawl.

5) Acute erythema multiforme

Erythema multiforme is an acute, self-limited, inflammatory mucocutaneous disease that


manifests on skin and often oral mucosa, although other mucosal surfaces are also may
involved.

In general, EM is classified as EM minor if less than of skin involvement is there and


there is minimal to no skin involvement.

It is classified as major if it has more extensive but characteristic skin involvement, with
the oral mucosa and other mucosal surfaces involved.

Etiology and pathogenesis:

EM is an hypersensitivity reaction and the most common enticing factors are infection,
particularly with HSV, or drug reactions to NSAIDS, anticonvulsants, or other drugs.

It has been postulated that these agents incite a t-cell mediated delayed hypersensitivity
reaction that generates interferon-γ, with the amplified immune response recruiting more
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T-cells to the area. Cytotoxic T cells, natural killer cells, and/or cytokines destroy the
epithelial cells.

Clinical features:

Episodes usually last several weeks

There is a prolonged prodrome of fever, malaise, headache.

Skin lesions rapidly appear over few days starting usually from hands and spreading
centripetally to the trunk. Skin lesions take several forms and hence the name multiforme.

Typical target lesions of the hand

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target lesions if the leg

• Oral findings range from mild erythema and erosions to painful ulcerations.

• When severe, ulcers may be large and confluent, causing difficulty in eating,
drinking, and swallowing.

• Patients with severe EM may drool blood-tinged saliva.

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Intra oral lesions of EM in an 18-year old

Management:

There are no specific laboratory tests that are useful but diagnosis is made primarily on
clinical findings.

• Mild EM can be managed with systemic or topical analgesics for painand


supportive care as the disease is self-limiting and resolves within a few weeks.

• More severe cases are treated with systemic corticosteroids.

• Topical corticosteroids may also help resolve the lesions.

Dugs with potential to cause erythema multiforme

NSAIDS carbamazepine phenytoin Sulphonamides

barbiturates Iodine containing chlorpropamide rifampicin


mouth washes

Combination of anti Estrogens/progestins clindamycin Tetracyclines


malarials-

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chloroquine and
sulfadoxine-
pyrimethamine

6) Toxic epidermal necrolysis:

This which probably represents the extreme end of the spectrum of erythema multiforme,
is one of the most dangerous a severe forms of drug reactions.

Mucosal involvement is common and causes widespread erosions due to epithelial


destructions. Oral ulcerations may precede the dermal changes, and cause the patient to
seek treatment for extreme soreness of mouth.healing of the lesions may leave a pattern
of lichen planus.

Causative drugs: metals such as gold salts are important causes but phenylbutazone,
barbiturates have also been implicated.

Because of the severity of the disease, treatment is generally with high doses of systemic
corticosteroids., intravenous immunoglobulins, and thalidomide.

7) Fixed drug eruptions:

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These consist of sharply circumscribed skin lesions recurring in the same site or sites
each time the drug is given. Involvement of the oral mucous membrane has been
described but is exceedingly rare. Phenolphphthalein, a component of purgatives is most
commonly implicated.

• Oral mucosal membranes may be the sole site of involvement, or they may be a
part of a more generalized skin reaction to the offending drug.

• The main type of hypersensitivity reaction that affects oral mucosa is a delayed
reaction mediated by sensitized T-lymphocyte.

• Stomatitis medicamentosa, or fixed drug eruption, occurs with systemic drug


usage and stomatitis venenata appears with contact hypersensitivity.

• Lesions associated with fixed drug eruption are erythematous in mild cases and
appear ulcerated in severe cases.

• The reactions usually appear in 24 hours post-ingestion of the drug. Delayed


reaction (up to two weeks) has been noted after use of ampicillin. Withdrawal of
the causative drug results in resolution of the lesions.

Other drugs implicated are:

Barbiturates Lidocaine Chlorhexidine Penicillamine

Gold Salicylates Indomethacin Sulphonamides

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Fixed eruption on the tongue

OTHER DRUG EFECTS

1) Gingival hyperplasia:

The growth starts as a painless, beadlike enlargement of the interdental papilla and
extends to the facial and lingual gingival margin. The enlargement is usually generalized
throughout the mouth but is more severe in the maxillary and mandibular anterior
regions.

Etiology and pathogenesis:

It is hypothesized that in non-inflamed gingiva, fibroblasts are less active or even


quiescent and do not respond to circulating drugs; fibroblasts within inflamed tissue are
in an active state as a result of inflammatory mediators and the endogenous growth
factors. It is known that causative drugs inhibit Ca2+ uptake on gingival fibroblasts that
correlates with the rate of fibroblast proliferation. Drug variables, plaque-induced
inflammatory changes in the gingival tissues, and genetic factors should be considered.
The last determines the heterogeneity of the gingival fibroblast and could also influence
drug pharmacokinetics and pharmacodynamics.

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Phenytoin, cyclosporine-A, calcium channel blockers, and oral contraceptives are the
main causative agents of gingival hyperplasia. Several mechanisms have been suggested
for drug-induced gingival hyperplasia.

• Cyclosporine-A has been shown to increase the fibroblast production of collagen


and protein, leading to extra cellular collagen and matrix formation and to
decrease collagenase activity. The increased levels of interlukin-6 and TGF-ß and
the decreased levels of gamma-interferon observed during cyclosporine-A therapy
may favor the fibroblast synthesis of collagen. Also, it has been reported the
keratinocyte growth factor receptor is up-regulated by cyclosporine-A25, and
there is evidence that cyclosporine-A regulates cytokine expression in gingival
tissue.
• There is evidence that mast cell mediated androgen action in the gingiva in
response to phenytoin could contribute to gingival overgrowth The incidence of
phenytoin-induced gingival overgrowth is approximately 50 percent, but it is
higher in both teenagers and institutionalized epileptics. Gingival overgrowth
usually becomes apparent during the first 3 months after starting phenytoin and is
most rapid in the first year. Unlike phenytoin hyperplasia, cyclosporine-induced
hyperplasia is reversible following cessation of drug use
• Nifedipine, the most commonly used calcium channel blocker, induces gingival
enlargement in 20% of the cases. Amlodipine, diltiazem, felodipine, nitrendipine,
and verapamil also induce gingival overgrowth. The dihydropyridine derivative
isradipidine does not induce gingival overgrowth. Inhibition of apoptosis by
nifedipine and resultant epithelial hyperplasia has been reported There is also
evidence that nifedipine inhibits both adherence- and lipoploysaccharide-
stimulated macrophage-induced death of fibroblasts which results in gingival
overgrowth Nifedipine is frequently prescribed to organ transplant patients to
reduce the nephrotoxic effects of cyclosporine and, thus, an additive effect on the
gingival tissues is usually observed
• The incidence of gingival overgrowth by oral contraceptives is not rare and
resolves when the drug is withdrawn. There is evidence the accumulation of
metabolic products of the naturally occurring sex hormones in gingiva is an
important factor in the pathogenesis of chronic gingivitis. The prevalence and
percentage of incidence is uncertain. Maintenance of adequate plaque control is
important for gingival health during the administration of oral contraceptives.

Other drugs with potential to cause gingival hyperplasia are listed below

Other drugs with potential to cause gingival hyperplasia


Cotrimoxazole Phenobarbital
Cyclosporine Primidone
Erythromycin Sertraline

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Ethosuximide Sodium valproate
Ketoconazole Topiramate
Lamotrigine Vigabatrin
Lithium

Management:

Plaque removal and good oral hygiene may benefit in a fast recovery and limits the
severity of the lesion but the lesion does not completely resolve. Extreme cases need
surgery and long term oral hygiene maintenance is essential.

cases of drug induced gingival hyperplasia

2) Pigmentation:
• Heavy metals such as mercury, bismuth and lead can cause black or brown deposits
in the gingival sulcus by interaction with bacterial products to form sulphides.
The blue lead line may be particularly sharply well defined and indicate the floor of
the pocket.
• Cisplatin, a cytotoxic drug, can cause a blue line.
• Topical antibiotics and antiseptics can cause dark pigmentation.

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.Black Hairy Tongue (Lingua villosa nigra)

In this condition there is an elongation of the filiform papillae of the tongue to form hair-
like overgrowth that becomes stained brown or black due to proliferation of chromogenic
microorganisms. Black hairy tongue can be seen with the administration of oral
antibiotics, poor dental hygiene, and excessive smoking in adults. Drugs and chemicals
with potential to cause black tongue include those listed in below.

Drugs and chemicals with potential to cause black tongue


Amitriptyline Lansoprazole
Benztropine Methyldopa
Cephalosporines Maprotilline
Chloramphenicol Nortriptyline
Clarithromycin Penicillins
Clomipramine Streptomycin
Clonazepam Sulfonamides
Corticosteroids Tobacco
Desipramine Tetracyclines
Fluoxetine Thiothixene
Griseofulvin Tranylcypromine
Imipramine Vegetable dyes

Black hairy tingue

3) Effect on salivary glands:

The salivary glands are under control of the autonomic nervous system, mainly the
parasympathetic division. Salivary gland function can be affected by a variety of drugs
that can produce xerostomia or ptyalism. It is suggested this is due to both the reduced
salivary flow rate and to a decrease in salivary calcium and phosphate concentration
caused by such drugs as amphetamines. Submandibular and parotid glands, the major
salivary glands of the body, have important roles in maintaining the health of the oral
29
cavity and gastrointestinal tract. Altered salivary flow rate and levels of secretory
proteins or enzymes may cause destructive effects on oral and dental health and wound
healing rates directly through lower levels of specific growth factors being present. It is
known that salivary mucins and growth factors are involved in the maintenance of
mucosal integrity due to their ability to trap water, thereby, preventing injury through
desiccation; growth factors may assist in tissue regeneration. The epidermal growth
factor that is secreted from salivary glands has a potential role in oral wound healing.
Common oral manifestations resulting from decreased salivary flow include increased
dental caries, fungal infections, bacterial infections, aphthous lesions, and dysphagia.
Systemic drug therapy can also produce pain and swelling of the salivary glands. The
following table lists drugs and chemicals with potential to inhibit the function of salivary
glands.

xerostomia

Drugs and chemicals with potential to inhibit the function of salivary glands including
secretion of proteins and enzymes into saliva
Benzodiazepines Morphine
Cadmium Nifedipine
Cyclosporine Nitric oxide inhibitors
Diltiazem Ofloxacin
Gentamicin Rubidium
Lead Verapamil
Lithium
Drugs that can cause dryness of mouth
Amphetamine Omeprazole
Anticholinergics Ondansetron
Antihistamines Selective serotonin reuptake inhibitors
Antineoplastic drugs Thiabendazole
Anti-HIV protease inhibitors Tramadol
Didanosine Tricyclic antidepressants
Levodopa

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Drugs that can cause sialorrhea
Alprazolam Levodopa
Amiodarone Lithium
Bethanechol Mefenamic Acid
Buspirone Mercurial salts
Clozapine Niridazole
Diazoxide Pentoxifylline
Edrophonium Pilocarpine
Gentamycin Risperidone
Guanethidine Rivastigmine
Imipenem/Cilastatin Succinylcholine
Iodides Tacrine
Kanamycin Tobramycin
Ketamine Venlafaxine
Lamotrigine Zaleplon
Drugs that have potential to cause swelling and/or pain in salivary
Bretylium Naproxen
Catecholamine inhalation Nifedipine
Chlorhexidine Nitrofurantoin
Cimetidine Phenytoin
Clonidine Ranitidine
Deoxycycline Ritodrine
Famotidine Sulfonamides
Iodine Trimipramine
Methyldopa Warfarin
Sjogren's Syndrome includes parotid swelling. However, parotid enlargement in Sjogren’s
Syndrome occurs relatively late in the course of rheumatoid arthritis. Its sudden
appearance in the early stages of the disease may well indicate an adverse reaction to an
anti-inflammatory drug since the H2–receptor antagonists have been reported to aggravate
the disease. The swelling is quite common in rheumatoid arthritis, for which NSAIDs are
frequently used, therefore, salivary gland swelling could be part of the disease rather than
a complication of its treatment. Sjogren's Syndrome is often (30%) seen in association
with other autoimmune rheumatic diseases.

4) Muscular and Neurological Disorders

Tardive dyskinesia that affects the elderly, particularly women, taking antipsychotic
drugs for many years, is an uncommon and sometimes unrecognized cause of orofacial
pain. Tardive dyskinesia is a painless syndrome in itself, but secondary orofacial pain

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can result from chronic mild trauma between a denture-bearing mucosa and dentures with
abnormal movement.

Facial pain has also been reported following the use of a controlled–release theophylline
preparation. The following table lists drugs reported to cause sensation of numbness,
tingling, or burning in the face or mouth.

Drugs reported to cause sensation of numbness, tingling, or burning in


the face or mouth
Acetazolamide Nicotinic acid
Amitriptyline Nitrofurantoin
Chlorpropamide Pentamidine
Ergotamine Polymyxin B
Gonadotropin-releasing-hormone Propranolol
analogues
Hydralazine Streptomycin
Isoniazid Tolbutamide
Nalidixic acid

5) Taste Disturbance

Many drugs induce abnormalities of taste by processes not yet fully understood. The
alteration in taste may be simply a blunting or decreased sensitivity in taste perception
(hypogeusia), a total loss of the ability to taste (ageusia), or a distortion in perception of
the correct taste of a substance, for example, sour for sweet (dysgeusia). A wide-range of
drugs give rise to dysgeusia or hypogeusia either by interfering in chemical composition
or flow of saliva, or, more specifically, affecting taste receptor function or signal
transduction. Sulfhydryl compounds are a common cause of taste disturbance. Drugs
with the potential for affecting taste are listed in Table 15.

Drugs with potential to cause ageusia


Acarbose Dicyclomine Pentamidine
Acetazolamide Enalapril Phenytoin
Amitriptyline Etidronate Propantheline
Aspirin Fluoxetine Propylthiouracil
Atrovastatin Fluvoxamine Rifabutin
Captopril Indomethacin Ritonavir
Ceftirizine Isotretinoin Rivastigmine
Cisplatin Levodopa Spironolactone
Clidinium Losartan Sulfadoxine
Clomipramine Methimazole Topiramate

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Cocaine Penicillamine Venlafaxine
Diazoxide
Drugs with potential to cause dysgeusia
Acetaminophen Dipyridamole Minoxidil
Acetazolamide Donepezil Naratriptan
Acyclovir Dorzolamide Nifedipine
Albuterol Doxepin Nortriptyline
Alendronate Deoxycycline Ofloxacin
Allopurinol Enalapril Olanzapine
Alprazolam Etidronate Omeprazole
Amiloride Famotidine Pamidronate
Amiodarone Fenfluramine Penicillamine
Amitriptyline Fentanyl Penicillins
Amlodipine Flecainide Pentazocine
Amoxicillin Fluconazole Pentoxifylline
Aspirin Fluorouracil Pergolide
Atrovastatin Fluoxetine Perindopril
Atropine sulfate Flurazepam Phytonadione
Baclofen Fluvastatin Pilocarpine
Benztropine Fluvoxamine Potassium iodide
Bromocriptine Gancyclovir Procainamide
Buspirone Gemfibrozil Propantheline
Busulfan Glyburide Propranolol
Calcitonin Gold compounds Propylthiouracil
Captopril Granisetron Pyrimethamine
Carbamazepine Griseofulvin Quinidine
Cephalosporines Hydrochlorothiazide Ranitidine
Celecoxib Hydroxychloroquine Ribavirin
Chlorhexidine Imipenem/Cilastatin Riluzole
Chlorothiazide Imipramine Risperidone
Cholestyramine Indinavir Ritonavir
Ciprofloxacin Interferons Rivastigmine
Citalopram Isotretinoin Saccharin
Clarithromycin Ketoprofen Selegiline
Clidinium Ketorolac Serteraline
Clindamycin Labetalol Simvastatin
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Clofazimine Lamotrigine Sulfonamides
Clofibrate Lansoprazole Sumatriptan
Clomipramine Leuprolide Tacrine
Clonazepam Levodopa Tamoxifen
Clonidine Lisinopril Terbutaline
Clozapine Lithium Timolol
Codeine Loratadine Tocainde
Cotrimoxazole Losartan Tolazamide
Cromolyn Lovastatin Tolbutamide
Cyproheptadine Maprotilline Tolmetin
Dacarbazine Mesalamine Topiramate
Dantrolene Mesna Tramadol
Desipramine Metformin Triamteren
Dexfenfluramine Methamphetamine Trimipramine
Dextroamphetamine Methimazole Ursodiol
Diazoxide Methocarbamol Vancomycin
Diclofenac Methotrexate Venlafaxine
Dicyclomine Metoprolol Vinblastine
Dihydroergotamine Metronidazole Vincristine
Diltiazem Midazolam Zidovudine

6) Halitosis

Halitosis is the offensive breath resulting from poor oral hygiene, dental or oral
infections, ingestion of certain foods, use of tobacco, and some systemic diseases.
Disulfiram and sublingual isosorbide dinitrate can cause halitosis. Drugs causing
xerostomia, discussed earlier, may indirectly cause or aggravate this problem.

7) Alveolar Osteitis (Dry Socket)

The use of contraceptives has been associated with a significant increase in the frequency
of dry sockets (alveolar osteitis) after removal of impacted lower third molars. The
probability of dry sockets increases with the estrogen dose in the oral contraceptive. The
dry sockets can be minimized by carrying out the extractions during days 23-28 of the
tablet cycle.

Conclusion
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Since most drug reactions occur within 1 to 2 weeks following initiation of therapy,
reactions seen after 2 weeks are less likely to be due to medication use. Some reactions
are dependent on dosage or cumulative toxicity. The majority of drug-induced oral
reactions are moderate in severity. However, severe reactions necessitate rapid
withdrawal of the suspected drug. In most cases, the oral reaction will be resolved by
symptomatic treatment. Readministration of the offending drug helps to establish whether
the oral eruption is drug-induced. Reactions after rechallenge may be more severe and,
therefore, rechallenge should not be performed without medical supervision. Many
clients take multiple medications; therefore, dentists must be aware of the issues related
to drug use including indications, interactions, and adverse drug effects. The ability to
evaluate these issues is necessary to accurately assess client status and prevent situations
that compromise client safety. Oral side effects interfere with client function and increase
risks for infection, pain, and possible tooth loss. It has been reported the most frequent
side-effects of drugs are xerostomia, dysgeusia, and stomatitis.

As a final note, rapid progress in pharmacotherapeutics requires clinicians to constantly


update their knowledge of drugs used by their patients. Attention must be paid to their
toxic and unwanted effects that in many cases may be similar to characteristics of
common diseases.

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