The Canadian Journal of Hospital Pharmacy - Volume 47, No. 4, August, 1994 155 Adverse Oral Effects of Systemic Drug Use Douglas Galan and Ruby Grymonpre 1 Ro­ evia­ :es. ABSTRACT RESUME sion­ Individuals may suffer from oral signs and symptoms L 'usage d 'un medicament systemique peut .vhite as a result of systemic drug use. Such oral changes declencher I' apparition de signes et de symptomes ener­ may be varied in their presentation. The pharmacist oraux chez le malade. Les changements oraux :sted. is in a position to assist the prescribing health peuvent varier en apparence. Le pharmacien est en ; last ation professional in correlating drug use with oral mesure d'aider le professionnel de la sante qui a num­ complaints and in offering specialized knowledge prescrit le medicament acorreler I 'usage du produit n the which may be helpful in patient management. aux doleances du malade, et de Lui proposer Les s for Drug-induced oral signs, symptoms, and their connaissances specialisees qui l 'aideront aprendre uble- management are described. en charge son patient. Suit une description des Key words: oral side effects, systemic drugs signes et des symptomes oraux induits par la ished pharmacotherapie et de la maniere de Les regler. st be ssion Mots-cles : effets secondaires oraux, medicaments cript. Can J Hosp Pharm 1994;47:155-64 systemiques ACY INTRODUCTION on the frequency of occurrence of anti-neoplastic drugs2-5 and gold !S for The increasing use of medications oral signs and symptoms, and the salts. 3,6 Patients presenting with d key in the prevention and control of functional significance of these oral ulcerations should be ;ripts ords. disease raises the potential for adverse reactions. This review is investigated by a dentist. A biopsy ude a unwanted side effects, which may not intended to provide an all may be required if an ulcer does :crip- present in the oral cavity. Oral inclusive list of medications not resolve within two weeks after 1 and tctice side effects include a wide variety implicated in adverse oral effects. elimination of the suspected local )due­ of morphological changes, such In addition, only the primary etiologic factors. pro- as ulcerations and swellings, or drug-induced oral side effects will Multiple ulcers or a generalized the production of oral dys­ be discussed. change of the oral cavity is more functions, such as dry mouth supportive of a drug reaction, with !S for (xerostomia), taste disorders Oral Ulcerations many of the lesions being due to a ~cep­ ( dysgeusia), and altered mouth Drug-induced oral ulcerations can drug-induced leukopenia. If the ~ not I for­ movements (dyskinesia). When arise from either topical ulcers create functional problems ords; confronted with individuals applications or systemic use. such as excessive drooling, pain, ~d. experiencing an oral reaction, the Ulcerations may occur exclusively inability to wear dentures, or and pharmacist should not be expected in the mouth or may present with inability to eat, the patient's to provide a definitive diagnosis multi-system involvement. In physician must be informed, and !S for but should attempt to correlate the most cases, single intra-oral ulcers if necessary, the medication o the alua­ oral complaints with a specific are due to mechanical irritation changed. Usually these lesions ed in medication, and provide this (e.g., chipped tooth), a local subside following drug discon­ IQ is- information to the prescribing disease process (e.g., cancer), or a tinuation. Drug-induced erythema dentist or physician. contact hypersensitivity (e.g., multiforme may produce ulcer­ The purpose of this review is to toothpaste hypersensitivity). A ation as an oral manifestation. The .uded provide information for phar­ single oral ulcer secondary to drug oral mucosa shows reddened uthor macists regarding potential use is usually due to topical patches which may rapidly adverse oral effects and the application of an irritant drug such develop into bullae, erosions, or principles involved in their as acetylsalicylic acid. 1 Drugs ulcers (Figure 1). If they occur, management. Drugs selected and commonly implicated as systemic "target lesions" of the skin are iacy included in this report are based ulcerogenic agents include helpful in supporting the diagnosis Douglas Galan, D.M.D., M.Sc. is a Lecturer, Faculty of Dentistry, University of Manitoba, Winnipeg, Manitoba. Ruby Grymonpre, B.Sc. (Pharm), Pharm.D. is an Associate Professor, Faculty of Pharmacy, University of Manitoba. Address correspondence to: Douglas Galan, D.M.D., Faculty of Dentistry, University of Manitoba, 780 Bannatyne Avenue, Winnipeg, Manitoba R3E0W3. 1992 Acknowledgements: The authors wish to thank Dr. S.I. Ahing and Dr. J.B. Perry, Department of Oral Pathology, University of Manitoba - Faculty of Dentistry, for their expertise, and Dr. Charles D. Bayliff of Victoria Hospital, London for his comments and suggestions in the writing and editing of this paper. 156 The Canadian Journal of Hospital Pharmacy- Volume 47, No. 4, August, 1994 Table I: Drugs Associated With Erythema Multiforme Reactions'· 14 Drug Group Drug Antibacterial agents clindamycin tetracycline penicillins sulfonamides Antitubercular agents isoniazid rifampin Anticonvulsants barbiturates carbamazepine phenytoin Antidiabetic agents chlorpropamide Antithyroid agents propylthiouracil Figure 1: Irregular ulcerations (arrows) of ventral surface of tongue in Erythema Cardiovascular agents minoxidil Multiforme (courtesy Dr. J.B. Perry) propranolol Nonsteroidal phenylbutazone antiinflammatory salicylates agents Laxatives phenolphthalein suximide, isoniazid, lithium car­ bonate, quinidine, thiouracil, and 16 17 D-penicillamine. • Gingival Hyperplasia Gingival hyperplasia (enlarged gums) (Figure 4) is principally associated with phenytoin, 18 although cyclosporine19•20 and 22 nifedipine21 • have also been implicated. The reported inci­ dence of phenytoin hyperplasia Figure 2: "Target lesions" of skin characteristic ofErythema Multiforme (courtesy of varies from 3 to 62%, with the Dr. J.W.P. Toole). greater frequency seen in younger individuals. 23 Severity and onset (Figure 2). Although the majority junction with these symptoms, of the hyperplasia is not of erythema multiforme cases are fever, weight loss and lympha­ necessarily related to drug dosage considered idiopathic in origin,7 denopathy may occur. 8 The oral and it decreases with increasing some have been associated with mucosa in 25% of cases have age. 8, 18 The hyperplasia is not drug use (Table 1). 8- 14 Lesions erythematous patches that well correlated with the presence produced are usually self-limiting subsequently break down to form or absence of local irritants. 23 and heal three to four weeks after painful ulcers, often with white Nevertheless, in most cases oral drug withdrawal. A further peripheral striations (Figure 3).3 hygiene plays a role in treatment exposure to the causative agent Most of the drug-induced cases and prevention. Surgical reduction may cause lesion recurrence. resolve upon removal of the of gross tissue overgrowth is often Lupus erythematosus (SLE) causative agents. Drugs primarily necessary to provide a more secondary to drug use, manifests associated with SLE include cleansable environment. Topical itself as a cutaneous rash, with hydralazine and procainamide daily treatments with 0.325% pulmonary, cardiac, muscular, and hydrochloride. 3•15 •16 Other less stannous fluoride or 0.12% abdominal symptoms. 8 In con- prominent drugs include: etho- chlorhexidine gluconate has also The Canadian Journal of Hospital Pharmacy - Volume 47, No. 4, August, 1994 157 Table II: Drugs Frequently Causing 8 25 26 Xerostomia · · Drug Group Drug Anticholinergic trihexyphenidyl agents procyclidine benztropine Antidepressants amitriptyline imipramine doxepin Antiemetics prochlorperazine Antihistamines diphenhydramine orphenadrine Anti psychotics thioridazine chlorpromazine Cardiovascular agents clonidine methyldopa Figure 3: Ulcerations and erythematous plaque of buccal mucosa (arrow) with white prazosin peripheral striations in Lupus Erythematosus (courtesy Dr. S.I. Ahing). disopyramide CNS stimulants mazindol fenfluramine die thy lpropion Muscle relaxants cyclobenzaprine orphenadrine baclofen been shown to be effective in reducing the severity of the hyperplastic response. 24 Effects on Salivary Glands Xerostomia Xerostomia, or dryness of the mouth, is primarily caused by drugs that either stimulate sympathetic activity or depress Figure 4: Enlarged gums (gingiva) secondary to phenytoin (Dilantin) therapy (courtesy of Dr. S.I. Ahing). parasympathetic activity. More than 300 medications are capable of producing xerostomia, but some chewing, swallowing, and speech; brushing with a fluoridated medications are more commonly and infections of the pharynx and dentifrice, regular flossing, 2 27 implicated (Table II).8, 5,26 salivary glands. ·28 fluoride (0.5%) and chlorhexidine Intraorally, the mucosa may Symptomatic management is gluconate (0.12 % ) oral rinses, and appear atrophic, inflamed, usually employed unless the daily fluoride gel applications are fissured, or ulcerated. Often the responsible drug can be identified needed. Since .1cidulated fluorides lesions are associated with a and substituted with one having may aggravate the symptoms, burning sensation, a sore tongue fewer xerostomic side effects. A neutral fluorides should be used or generalized mouth soreness. 27·28 consultation with the patient's wheneverpossible. Alcohol-based Other clinical