Adverse Drug Reactions in the Oro facial Region

In this era an ever-expanding list of medications is linked to pathological reactions in the oral and perioral region. These adverse drug reactions have a broad spectrum of clinical manifestations that can mimic those of other disease states, including both local and systemic conditions. The clinical manifestations of oral reactions to the more commonly prescribed drugs have been discussed in this article.

Well known clinical patterns of adverse drug reactions of the oral cavity include xerostomia, swelling and gingival enlargement , nonspecific ulceration, vesiculobullous or ulcerative mucositis that mimics other immunological disorders , oro-facial pigmentation. A patient who complains of any of these signs and symptoms should be thoroughly questioned regarding medication. If an offending drug can be identified, its alteration or elimination, in consultation with the prescribing clinician, will often result in resolution of the clinical problem.

Drug induced xerostomia

Xerostomia, or dry mouth, is the most common adverse drug-related effect in the oral cavity. To date, xerostomia has been associated with more than 500 medications. The synergistic effects of medications have been recognized and are increasingly common in elderly patients taking multiple medications (polypharmacy). General drug classes that are strongly associated with xerostomia include antidepressants and antipsychotics, antihypertensives, antihistamines, and anticholinergics.



Root caries formed in a patient with drug induced xerostomia



Importantly, patients with xerostomia are also at increased risk for oral candidiasis, a superficial infection that may cause mucosal sensitivity or discomfort, as well as tooth decay that usually affects the cervical (gumline) and root surfaces. Several different mechanisms account for drug-related dry mouth, but an anticholinergic action underlies many: The M3-muscarinic receptors (M3R) mediate parasympathetic cholinergic neurotransmission to salivary (and lacrimal) glands, but other receptors may also be involved.

Antidepressants

Early antidepressant medications such as tricyclic antidepressants (TCAs) unfortunately also blocked histaminic, cholinergic, and alpha1-adrenergic receptor sites, causing dry mouth. Newer antidepressants are essentially serotonin (5-hydroxytryptamine: 5HT) agonists, or block re-uptake of noradrenaline (norepinephrine) and/or serotonin. Members of the newer generation of antidepressants—including the selective serotonin re-uptake inhibitors (SSRIs) and multiple-receptor antidepressants (such as venlafaxine, mirtazapine, bupropion, trazodone, and nefazodone)—target one or more specific brain receptor sites without, in most cases, activating unwanted sites such as histamine and acetylcholine. The SSRI produce no significant changes in salivation, but dry mouth may still be seen (e.g., fluoxetine).

Antipsychotics

Long-term drug treatment of schizophrenia with conventional phenothiazine antipsychotics such as fluphenazine is commonly associated with dry mouth. However, newly developed antipsychotic drugs with more potent and selective antagonistic activity against the dopamine D(2) receptor may not necessarily be associated with a lower incidence of dry mouth. Olanzapine is an atypical antipsychotic which appears to produce dry mouth.

Antihistamines

The therapeutic effects of most of the older antihistamines were associated with sedating effects on the central nervous system (CNS) and antimuscarinic effects including dry mouth. Non-sedating antihistamines—most of which are histamine H1 receptor antagonists, such as acrivastine, astemizole, cetirizine, ebastine, fexofenadine, loratadine, mizolastine, and terfenadine, however—are not entirely free from ADRs, though there may be less dry mouth.

Antihypertensives

The ganglion blockers and particularly the beta-blockers (beta-adrenoceptor antagonists) may cause dry mouth, thought to be associated with activation of CNS and salivary gland alpha 2-adrenergic receptors. Such antihypertensive drugs, or sympatholytics (reserpine, methyldopa, and clonidine), are now little used because of such prominent adverse drug reactions such as dry mouth.  Newer centrally acting antihypertensives, with selective agonist effects on the imidazoline I1 brainstem-receptors in the rostral ventromedulla (RVLM), appear to modulate sympathetic activity and blood pressure without affecting salivary flow: Moxonidine and rilmenidine are examples of this new class.  ACE inhibitors, which block the ACE enzyme in the renin-angiotensin-aldosterone system, known to produce dry mouth.

Unfortunately, these associations are confounded by the fact that xerostomia is a subjective complaint, and some patients who report oral dryness may have apparently normal salivary gland function. Other patients whose mouths appear to be clinically dry may have no complaints. In addition, a certain amount of acinar atrophy and decreased glandular secretions are considered a normal part of the aging process. Also habits such as smoking, alcohol consumption, and even long-term use of caffeinated drinks may contribute to oral dryness or the perception of dryness. Underlying systemic diseases such as in non-insulin-dependent diabetes, saliva secretion is more affected by xerogenic drugs and autonomic nervous dysfunction than in non-diabetic controls Furthermore, the possibility of an underlying autoimmune etiology (eg, Sjögren syndrome) should also be considered in xerostomic patients. The cause for which the drug is being taken may also be important. For example, patients with anxiety or depressive conditions may complain of dry mouth even in the absence of drug therapy or evidence of reduced salivary flow. It is thus important to recognize that some patients complaining of a drug-related dry mouth have no evidence of a reduced salivary flow or a salivary disorder, and there may then be a psychogenic reason for the complaint.

Thus clinical tests to measure salivary flow (at rest and under stimulation) should be used cautiously in assessing a patient with suspected drug-induced xerostomia.

 

Drug related swellings

 

Drug-related gingival enlargement

Gingival enlargement is a well-described oral side-effect of drug therapy. The drugs most commonly implicated in causing this enlargement are phenytoin, ciclosporin and the calcium-channel-blockers, nifedipine, diltiazem, verapamil and amlodipine. Patients receiving therapy with both ciclosporin and calcium-channel-blockers (e.g., post-cardiac or -renal allograft recipients) may be sometimes, but not always, particularly liable to drug-induced gingival enlargement.



phenytoin induced gingival hyperplasia



In general, the gingival enlargement develops within a few months of the commencement of drug therapy, is usually generalized, is only partly associated with poor oral hygiene and local plaque accumulation, and responds variably to improved plaque control and/or withdrawal or reduction of drug therapy. Other drugs that have been occasionally reported to cause gingival enlargement include erythromycin, sodium valproate, phenobarbitone and vigabatrin.

Drug-related lip and mucosal swellings

Drug-induced mucosal swelling predominantly affects the lips and tongue although rare isolated swelling of the uvula [Quinke’s disease] can occur and is typically due to type I hypersensitivity reactions. Among the most common offending agents are ACE inhibitors, penicillin and penicillin derivatives, cephalosporins, barbiturates, aspirin, local anesthetic agents, and other NSAIDs. Affected mucosa typically appears edematous and erythematous within minutes or hours after exposure to the offending drug giving rise to angio-edema. Hypersensitivity to latex is an increasing problem in oral health care and may cause rapid-onset angio-edema in susceptible patients.



Drug induced Angioedema

Non-allergic oral swelling can also arise in response to angiotensin-converting enzyme (ACE) inhibitor therapy. This adverse effect occurs in patients, typically in the early weeks of therapy, although it may occur within a few hours of commencement of treatment, or after long-term therapy. The swelling usually affects the lips, although it can be localized to the tongue, and is occasionally fatal. African-Americans may be at particular risk. The tissue swelling associated with ACE inhibitor therapy may be due to a rise in levels of bradykinins and/or altered levels or function of C1 esterase inhibitor. Plasmacytosis due to ‘tartar control’ toothpastes gives rise to localized enlargements of the gingivae, tongue, and other oral mucosa.

Drug related salivary gland swelling

Some drugs have been related to salivary gland swelling. Painless, usually bilateral, salivary gland enlargement (resembling sialosis) may be an occasional side-effect of phenylbutazone, oxyphenbutazone or chlorhexidine. The bilateral sialadenitis observed in one adult following naproxen therapy was thought to be allergic in origin, since the affected patient also had a cutaneous rash. A similar mechanism has been proposed to underlie the salivary gland enlargement caused by intravenous radiological contrast media. Clozapine, a novel antipsychotic agent, may cause transient salivary gland swelling as well as sialorrhea.



Drug induced parotid swelling



Non specific ulceration and oral mucositis

 

Drug-related oral burns

Epithelial necrosis and ulceration may result from direct application of over-the-counter medications such as aspirin, hydrogen peroxide, potassium tablets, and phenol-containing compounds to the mucosa. Aspirin is often used by patients seeking relief from dental pain.



Aspirin burn



Sodium lauryl sulfate, present in some oral health care products, particularly dentifrices, may cause mucosal irritation or ulceration. The affected mucosa appears whitish and corrugated, with erosion and ulceration of the more severely damaged areas. The associated discomfort can be severe enough to require treatment with a major analgesic and/or a local anesthetic or even discontinuation of the chemotherapeutic agent.

Drug-related aphthous-like ulceration

A number of drugs are implicated in the development of nonspecific ulceration and oral mucositis, and the lesions are often associated with an equally nonspecific histologic appearance at biopsy.



Nicorandil  induced oral ulceration



These include barbiturates, beta-blockers, dapsone, NSAIDs, phenazone derivatives, thiazide derivatives, phenolphthalein, sulfonamides, and tetracyclines. Ulceration of the oral mucosa is a common adverse effect of a wide variety of antineoplastic agents, including methotrexate, 5-fluorouracil, doxorubicin, and melphalan

Fixed drug eruptions

Fixed drug eruptions (contact stomatitis or stomatitis venenata) comprise repeated ulceration

at the same site in response to a particular drug and may be caused by anesthetics, antibiotics, antiseptics, barbiturates, chewing gum, cosmetics, dental materials, dentifrices, mouthwashes, phenacetin, sulphonamides, or tetracyclines. The lesions may be localized to the mouth or can be associated with lesions at other mucocutaneous sites, and manifest as ulceration, bullae, erythematous patches, or superficial erosions.



Fixed drug eruption on the lip



Fixed drug eruption on skin



Initially, the lesions are solitary, but with repeated drug exposure, they may become multiple. these reactions normally resolve with hyperpigmentation and may recur at the same site with reexposure to the drug. Repeated exposure to the offending drug may cause new lesions to develop in addition to "lighting up" the older hyperpigmented lesions. A wide range of drugs may cause fixed drug eruption, particularly paracetamol, barbiturates, phenacetin, pyrazolone derivatives, sulphonamides, and tetracyclines, as may agents such as cinnamon.

Drug-related mucositis

Cytotoxic drugs are very commonly associated with mucositis and ulceration, which arises consistently with many chemotherapy regimens,particularly those involving methotrexate, 5-fluorouracil, doxorubicine, melphelan, mercaptopurine, or bleomycin . Such reactions can be so severe as to be treatment-limiting on occasion. Widespread sloughing and ulceration arise within days of commencement of therapy, the associated pain often requiring opioid therapy and/or alteration or cessation of chemotherapy. The ulceration may be a portal of entry for infection and hence a potential cause of septicemia. Drugs such as phenylbutazone that can cause agranulocytosis may also induce oral ulceration.

Immunosuppressive agents may also cause ulceration. Ulcers in iatrogenically immunocompromised individuals may have a herpesvirus etiology, or occasionally other infective causes. Opportunistic infection secondary to cytotoxic chemotherapy may cause oral ulceration. In particular, herpes simplex virus 1, varicella zoster, and cytomegalovirus give rise to oral ulceration, while, less commonly, ulceration may be due to Gram-negative bacterial infections (e.g., pseudomonas, klebsiella, Escherichia coli, enterobacter, or proteus) or to exogenous bacteria such as tuberculosis, or to fungi such as mucormycosis or even candidosis.

vesiculobullous or ulcerative mucositis that mimics other immunological disorders

Oral drug reactions that bear striking clinical, histopathologic, and even immunopathologic resemblance to idiopathic lichen planus, erythema multiforme (EM), pemphigoid, pemphigus, and lupus erythematosus (LE) are well recognized, and the list of reactions in each category is constantly expanding. Clinically, any oral site can be affected; however, the posterior buccal mucosa (cheeks), the lateral borders of the tongue, and the alveolar mucosa are most commonly involved. Lesions may be isolated, although bilaterally symmetric involvement is not uncommon.

Oral lichenoid reactions

Initially described in association with antimalarial medications, lichen planus–like or lichenoid drug reactions have subsequently been reported in association with many other agents. Both papuloreticular and erosive manifestations may be observed; the latter is characterized by shallow irregular ulcerations or erosions with a peripheral border of fine keratotic striae that often appear to radiate from the center of the lesion. Although drug-induced lichenoid reactions tend to be erosive and unilateral compared with the typical bilateral presentation in idiopathic lichen planus. Currently, NSAIDs and ACE inhibitors appear to be among the most frequently cited offenders.  Interestingly, agents used in the treatment of lichen planus (eg, hydroxychloroquine, dapsone, levamisole) have themselves led to adverse lichenoid eruptions. Lichenoid reactions also may follow the use of HIV protease inhibitors antihypertensive agents, antimalarials, phenothiazines, sulphonamides, tetracyclines, thiazide diuretics, and many others. The exact pathogenic mechanism by which drugs may cause LP-like disease are not known. However, in LP, quite different immunological mechanisms are involved. Histopathological features not significant from idiopathic lichen planus. Thus  the most reliable means to diagnose lichenoid reactions is if the reaction remits with drug withdrawal and returns on rechallenge, but frequently this is not possible because of the need to ensure patient safety.



Oral lichenoid reaction



Dental restorative materials may also be associated with lichenoid lesions. Most patients with OLP have no evidence of any association with dental restorative materials. However, contact with or proximity to restorations involving amalgams or other materials causes some lichenoid reactions that is, lesions that clinically and histologically resemble LP closely, but have an identifiable etiology. These reactions are presumably due to allergic or toxic reactions to compounds released or generated, the Koebner phenomenon, or possibly due to plaque accumulated on the surfaces of the restorations. Some of these oral lesions may improve after substitution of the amalgam by other materials. Composite restorations have also been implicated in oral lichenoid reactions and so the wholesale replacement of amalgams as a possible treatment is not necessarily warranted.

Erythema multiforme (EM)  like reactions

As with idiopathic or virally induced cases (the latter often due to the herpes simplex virus), the disease has a rapid onset with a variable expression that can range from lesions limited to the oral mucosa to widespread mucocutaneous involvement. Drug-induced EM is frequently linked to agents such as sulfonamides, sulfonylureas, and barbiturates, among others. Oral lesions start as erythematous macules or patches that lead to short-lived vesicles or bullae, followed by ragged and shallow ulcerations that may become extensive. Hemorrhagic ulceration and crusting of the labial vermilion zone is common. Any intraoral site can be involved, but the attached gingival and palatal tissues are often relatively spared. Lesional discomfort can lead to decreased fluid intake and dehydration.



Drug induced Erythema multiforme on lips



A variety of lesions, including classic target or bull's eye lesions, can affect the skin.



Target lesions on skin



More severe forms of disease include EM major (Stevens-Johnson syndrome) and toxic epidermal necrolysis (TEN, Lyell syndrome). In addition to the oral and skin lesions, conjunctivitis of the ocular mucosa and urethritis of the genital mucosa are typical findings in patients with EM major. Over three-quarters of EM major cases and virtually all cases of TEN represent adverse drug reactions. In TEN, widespread mucocutaneous epidermolysis results in diffuse bullae formation and subsequent denudation that affects significant proportions of the skin and mucosal surfaces. Severe dehydration, electrolyte imbalances, and secondary infections are potentially life-threatening sequelae, and even with aggressive therapy the mortality rate is greater than 30%.



TEN



Pemphigoid like reactions

Pemphigoid like reactions can be limited to the oral mucosa, or they can affect other mucosal or cutaneous sites. Clinically, lesions appear as relatively sturdy vesicles or bullae that break down into shallow ulcerations. Generalized or multifocal involvement of the gingival tissues may be observed, with marked erythema and erosion of the superficial gingiva, a pattern that has been called desquamative gingivitis. Thiol-containing drugs and sulfonamide derivatives are among the most commonly involved medications, as are the therapeutic classes of NSAIDs, cardiovascular agents, antimicrobials, and antirheumatics .

celecoxib induced vesiculobullous lesion

Circulating autoantibodies to basement membrane components may or may not be detectable. The relatively young age of the patients at onset (the disease affects those younger than 70 y) may help distinguish this disease from idiopathic bullous pemphigoid or idiopathic cicatricial pemphigoid, because these latter conditions typically appear in persons aged 60-80 years. In addition, oral involvement may be more common in drug-induced bullous pemphigoid than in the idiopathic counterpart.

Pemphigus like reactions

Pemphigus like reactions can have features of either pemphigus vulgaris or pemphigus foliaceous, although pemphigus foliaceous is uncommon in the oral cavity.  Traditionally, drugs that are capable of inducing pemphigus are divided into two main groups according to their chemical structure. Drugs containing a sulfhydryl radical (thiol drugs or SH drugs) and non-thiol or other drugs, the latter often sharing an active amide group in their molecules. Thiol-containing drugs are the most common cause of pemphigus like reactions. Pemphigus vulgaris may occasionally be associated with drugs with active thiol groups in the molecule. Drugs implicated include penicillamine, phenol drugs, rifampicin, diclofenac, and, rarely, captopril, other ACE-inhibitors, and other drugs. In drug-induced pemphigus vulgaris, the relatively fragile vesicles are rarely observed at clinical examination, and most cases are characterized by irregular ulcerations with ragged borders that may coalesce to involve large areas of the mucosa. Patients may have circulating autoantibodies to the desmosomal components.

Drug-related Lupoid Reactions

Systemic lupus erythematosus (SLE) may be induced by a wide variety of different drugs. Indeed, over 70 agents have been implicated in causing drug-induced lupus. The most commonly implicated agents of drug-induced SLE are procainamide and hydralazine, although drugs less commonly associated include chlorpromazine, isoniazid, methyldopa, penicillamine, and quinine, as well as whole groups of drugs such as anticonvulsants, beta-blockers, sulphonamides, and others.



Drug induced lupoid reaction in oral mucosa



The possible pathogenesis of drug-related SLE may have an immunogenetic basis, and affected patients have some of the immunological features of classic SLE. Clinically, the oral lesions of drug-induced LE may simulate those of erosive lichen planus, with irregular areas of erythema or ulceration bordered by radiating keratotic striae. These lesions may affect the palate, buccal mucosa, and gingival or alveolar tissues. The rarity of lichen planus on the hard palate may be helpful in differentiating it from drug-induced LE.

Drug related mucosal pigmentation

Drug-related superficial transient discoloration

Superficial transient discoloration of the dorsum of the tongue and other soft tissues and teeth may be of various colors, typically yellowish or brown, and may be caused by some foods and beverages (such as coffee and tea), some habits (such as tobacco, betel, and crack cocaine use), and some drugs (such as iron salts, bismuth, chlorhexidine, or antibiotics), especially if these also induce xerostomia (such as psychotropic agents). When such discoloration noticeably affects the posterior dorsum of the tongue, and the filiform papillae are excessively long and stained dark brown or black, the term ‘black hairy tongue’ is used, but this is less common than other superficial discolorations.

Stomatitis has been reported after the use of proton pump inhibitors (PPIs) such as lansoprazole with amoxicillin , and discolored tongue or glossitis has been recorded after the use of lansoprazole plus antibiotics such as clarithromycin with or without amoxicillin  or lansoprazole alone.

Drug-related intrinsic pigmentation

Localized areas of pigmentation of the mucosa may be due to amalgam, while gingival pigmentation can arise secondary to the gold or metal alloys of crowns. Heavy metal salts were previously reported to cause pigmentation, particularly of the gingival margin. Blue, blue-grey, or brown mucosal pigmentation can be an adverse effect of antimalarials, phenothiazines, and phenytoin. Amiodarone may cause a grey orofacial and oral mucosal pigmentation.

Minocycline has increasingly been reported to cause widespread blue, blue-grey, or brown pigmentation of the gingivae and mucosae. While much of this pigmentation may reflect discoloration of the underlying bone and roots of teeth, there is also inherent pigmentation of the oral mucosa, including the tongue.



Drug induced pigmentation



Oral contraceptives may, albeit rarely, cause melanotic pigmentation, as can cyclophosphamide, busulphan, and ACTH. In HIV disease, drug-induced melanotic pigmentation may arise following therapy with clofazimine zidovudine and/or ketoconazole, the pigmentation being variably diffuse or macular-like Kaposi’s sarcoma of the mouth is a rare complication of immunosuppression, manifesting as a blue, red, or purple macule, papule, nodule, or area of ulceration, typically on the palate or gingivae, but able to affect other oral mucosal sites.