DOI: 10.15386/cjmed-748 Review

OROFACIAL MANIFESTATIONS OF ADVERSE DRUG REACTIONS: A REVIEW STUDY

SEDIGHEH BAKHTIARI, MARZIYE SEHATPOUR, HAMED MORTAZAVI, MAHIN BAKHSHI

Oral Medicine Department, Dental Faculty, Shahid Beheshti University of Medical Sciences, Islamic Republic of Iran

Abstract

Background. Adverse reaction to medication is common and may have a variety of clinical manifestations in the oral cavity. The present review paper aimed to describe adverse drug reactions (ADRs) which might be encountered by dental practitioners in every discipline. Methods. In this narrative review article, the specialized databases such as PubMed, PubMed Central, MEDLINE, EBSCO, Science Direct, Scopus, and reference books from the years 2000-2016 were used to find relevant documents by using MeSH terms: Adverse Drug Reaction, Drug induced, Medication Related, , Oral Manifestation, , Hard Tissue, Soft Tissue. Results. The data were categorized in 4 groups as follows: and salivary glands involvement, soft tissue (mucosal) involvement, hard tissue involvement, and non specific conditions (taste disorders, halitosis, neuropathies, movement disturbances, and infection). Most articles were about the adverse effect of drugs on the function of salivary glands, which often cause a decrease in saliva secretion. Other reactions were less common; meanwhile, the side effect of bisphosphonate was increasing in the alveolar bone, because of its unlimited prescription. Conclusion. Oral health care providers should be familiar with such events, as they will be confronted with them in their practice.

Keywords: adverse drug reaction, drug induced, medication related, mouth, oral manifestation, tooth, hard tissue, soft tissue

Introduction two subgroups as primary and secondary. Type A primary Different drugs that patients take to prevent or reactions are characterized as an abnormal reaction due to control disease expose them to the risk of developing excessive action of the primary pharmacology of the drug adverse reactions [1]. An adverse drug reaction (ADR) is such as oral mucosal bleeding after the use of anticoagulant defined by WHO as “a response to a drug which is noxious agents, whereas a type A secondary reaction is a secondary and unintended, and which occurs at dose normally pharmacology of the drug such as dysgeusia during the use used in man for the prophylaxis, diagnosis, therapy of of anti hypertention drugs. About 20% of ADRs are caused disease or for the modification of physiological function” by an unpredictable reaction to drug which are known [2]. ADRs have been classified into two types. Type A as type B reactions and are usually non-dose-related. reactions represent about 80% of the cases. They are dose- Type B reactions are also divided into two subgroups, dependent and predictable and are also associated with the immunological and non-immunological reactions. Most pharmacology of drug. Pharmacology can be divided into of these reactions are immune-mediated side effects like hypersensitivity responses. Furthermore, recently other Manuscript received: 10.12.2016 types of drug reactions have been described. For example, Received in revised form: 21.05.2017 Accepted: 16.06.2017 adverse effects may depend on the duration of the treatment Address for correspondence: [email protected] in addition to dose (type C). Delayed adverse reactions Clujul Medical Vol. 91, No. 1, 2018: 27-36 27 Dental Medicine

of the drug are labeled as type D, and those reactions Literature review appearing after many years of treatment are defined as Saliva and salivary glands involvement type E. Finally, reactions occurring after withdrawals Xerostomia are referred to as type F [3]. Since many patients take Xerostomia, the most common adverse drug reaction prescriptions and over-the-counter medications, dentists affecting the oral cavity, is associated with over 500 drugs should be aware of drug-related problems in the orofacial [1,3,5,6]. In a systematic review in USA, xerostomia was regions [4]. The presence and severity of ADRs are related found as a secondary effect in 80-100% of prescribed drugs to patient and drug-dependent factors. Patients’ risk factors [7]. include gender (more common in women), age (frequently In the study by Villa, xerostomia was almost 3 times in neonates and the elderly), underlying disease (more more in adults undergoing medication than those who common in patients with hepatic disease and renal failure), didn’t take any medication. Furthermore, the patients who and genetics. Drug factors include route of administration, took one or more drugs were two times more at the risk of duration, dose, and variation in metabolism [3]. Adverse xerostomia than those who didn’t take any medication [8]. drug events in the oral cavity have a variety of clinical Many middle- aged and older patients are on presentation. Typically, these changes occur within weeks multiple medications (poly pharmacy) that induce dry or months after taking the drugs and may be symptomatic mouth because of synergic effects of these drugs (even with or asymptomatic [1]. The aim of this study is to review the low effects) [1]. literature and highlights the more common and significant Xerostomia is also the most common side effect of adverse oral consequences of drug therapy. salivary gland radiotherapy, chemotherapy, graft versus host disease (GVHD) and some disease like Sjogren Methods syndrome, diabetes and AIDS [5,6]. Smoking, alcohol and The specialized data bases such as PubMed, PubMed caffeine consumption decreases in salivary flow rate [3]. Central, MEDLINE, EBSCO, Science Direct, Scopus, and Different mechanisms exist for drug induced reference books from the years 2000-2016 were used to xerostomia. Some drugs such as cytotoxic agents cause find relevant documents by using of MeSH terms: Adverse dry mouth by direct damage to salivary gland, diuretics Drug Reaction, Drug induced, Medication Related, Mouth, by excreting body liquids and dehydration [2,6]. But this Oral Manifestation, Tooth, Hard Tissue, Soft Tissue. In this side effect of most drugs is due to their anticholinergic or narrative review we took into consideration both medical sympathomimetic effect [3,9,10,11]. and dental journals, including reviews, original papers, Some drugs can decrease salivary flow by causing case reports, and case series. vasoconstriction in the salivary glands [10]. A wide range of drugs may give rise to xerostomia, Results but the most important ones are: We found approximately 100 relative articles, 39 Anti-cholinergics, anti-depressants, anti-histamines, were excluded due to lack of full texts or being written in anti-hypertensive agents, anti-parkinsonian drugs, languages other than English. Finally, 1 textbooks and 60 anti-migraines, anti-neoplastic drugs, anti- psychotics, papers were selected, including 34 reviews, 15 case reports anti-seizures, cytotoxic agents, diuretics, muscle or case series, and 11 original articles. relaxants, sedatives and anxiolytics [1,6,10,12]. Appetite Then, for better understanding, in the present paper, suppressants, supplements, non steroid anti inflammatory oral manifestations of ADRs were categorized into 4 main drugs (NSAIDs), systemic retinoids, anti-retoviral drugs, groups as follows: and medications like cytokines (interferon a, interleukin 2) 1. Saliva and salivary glands involvement: can cause xerostomia as well [1,12-15]. Xerostomia, Ptyalism, Salivary gland enlargement, Complications of xerostomia are taste alternations, Salivary gland pain, Discoloration of saliva , speech disturbance, dental caries, susceptibility 2. Soft tissue (mucosal) involvement: to infections (e.g. candidiasis and ) [5,6]. Lichenoid reaction, Erythema multiform, Drug induced xerostomia is a reversible phenomenon , Lupus erythematous, Fixed drug eruption, and drug-cessation can lead to normal function of salivary , Mucous membrane pigmentation, Drug glands [3]. Pilocarpine, cevimeline, bethanechol, and saliva induced substitute are used for management of this complication [6]. 3. Hard tissue involvement Ptyalism Drug- related , Dental Ptyalism or sialorrhoea is an uncommon condition caries, Dry socket, that increases saliva amount or flow rate and can occur during 4. Non specific conditions menstruation, beginning of pregnancy, tooth eruption, Taste disorders, Halitosis (malodor), Neuropathies, inflammation, gastroesophaghageal reflux disease, heavy Movement disturbance, Infection metal toxicity (like thallium, lead, arsenic, mercury) and neurologic disease (Down syndrome, Parkinson, ,

28 Clujul Medical Vol. 91, No. 1, 2018: 27-36 Review ) [ 4,5]. Soft tissue (mucosal) involvement Ptyalism may result from local irritation such as ill- Lichenoid reaction fitting denture. The most important drugs that can induce Many systemic medications can cause oral lichenoid are para-sympathomimetic drugs such as reactions although the pathogenesis is still unclear. Etiology physostigmin, neostigmine, rivastigmine, cholinergic drugs of lichenoid reactions is related to the contact with specific (bethanechol, pilocarpine, cevimelin), lithium, , agents such as drugs and metallic restorative material. alprazolam, digoxin, and haloperidol [9,10,16,17]. Drug induced lichenoid reaction (LR) is similar to Lichen Mefenamic acid, theophylline, captopril, nifidipin Planus clinically and histopathologically, except that LR and some antibiotic agents like gentamycin, tobramycin, is predominantly unilateral and present with an ulcerative imipenem and kanamycin can increase the salivary flow as reaction pattern [2,5]. Healing of LR after some weeks of well [5,9]. the drug cessation is the most important mean for proper Treatment of drug induced , induced by diagnosis. Time interval between starting the medication drugs, is often symptomatic. Attempts are made to reduce and beginning of lichenoid lesion varies from weeks to the amount of saliva so that the patient can swallow it. It months with an average of 2 to 3 months [4,21]. has been recommended that anticholinergic agents like Drugs that commonly induce LR are: NSAIDs, benztropine, glycopyrrolate and scopolamine could be anti-hypertensive (especially B-blockers, angiotensin useful for management of drooling. Scopolamine skin converting enzyme inhibitors (ACEIs) and anti-retrovirals. patches for transdermal administration and applying Gold is probably one of the most common agents that results Itratripiom spray or increasing adrenergic ton, such as in lichenoid lesions. Gold salt (for treatment of rheumatoid Clonidine patches, can also be employed alternatively. arthritis) induces a range of mucocutaneus lesions; with Botulinum injection into parotid gland in resistant cases oral lichenoid lesions being the first manifestation [3]. has been successfully applied [16,18]. Penicillins, , anti-diabetics (tolbutamide, Salivary gland enlargement glipizide), sulfonamides, HIV protease inhibitors, anti- Salivary gland enlargement has been reported as an malarias, mercury, phenothiazine, anti-leptics (phenytoin, adverse drug reaction. The most common drugs associated carbamazepine), penicillamine, ketoconazole, cyclosporine, with parotid enlargement are iodine containing drugs such prednisolone, indomethacin, pyridoxine, barbiturates, BCG as those used as imaging contrast media [5]..Radioiodine is vaccine, anti-lipid medications (simvastatin, clofibrate), an important therapeutic agent used to treat thyroid cancer; tyrosine kinase inhibitors (imatinib) and alendronate can one of its most common side effects is salivary gland induce these lesions in the oral cavity [1,3,9,5,22-24]. swelling [10]. Biological agents as prescribed for rheumatoid Other agents known to cause salivary gland arthritis and oncology treatment, such as obinutuzumab enlargement include Insulin, methyldopa, phenylbutazone, (anti-CD20 monoclonal antibody) and infliximab (TNF-a oxyphenbutazone, potassium chloride, sulfonamide, inhibitors) can induce lichenoid reaction [25]. sodium warfarin, naproxen, guanidine, nitrofurantoin, Nowadays it is unknown whether lesions in patients clonidine, terbinafine, , and doxycycline. with thyroid disease are due to anti- thyroid agents or are Diazepam can also induce bilateral salivary glands just associated with thyroid disorders [1]. enlargement associated with sialorrhea [4,19]. Erythema multiform In a review study, clonazepam, L-asparginases Erythema multiform (EM) is a hypersensitive and phenylbutazone have been found to induce parotiditis reaction that can affect both skin and mucous membranes. and parotid gland enlargement [20]. In Vinayak study a It can be manifested as papule, macule, vesicle, erosion patient with malignant hypertension who was treated with or ulceration. The lesions can affect any site of oral enalapril developed bilateral parotid swelling 5 minutes mucosa with a little tendency to gingiva, but extensive after injection of the drug. On the basis of many studies, involvement with ulcer and crust can be especially the salivary gland enlargement subsides after cessation of predominant [1,5]. The most common cause of EM is the drugs with or without corticosteroid therapy [10]. infection especially virus (HSV) and less Salivary gland pain commonly Mycoplasma Pneumonia [4,5]. In 18-25% of Anti-hypertensive agents, cytotoxic drugs, anti- cases, drugs such as NSAIDs and anti-leptic agents induce thyroids, chlorhexidine, ganglion blocker agents, iodides, this reaction. It is also resulted from sulfonamides, sulfonyl phenothiazines, sulfonamides, and drugs that induce dry urea and barbiturates [1,26]. mouth can also cause salivary gland pain [4,9]. Antibiotics (like penicillin, cephalosporin, Discoloration of saliva tetracycline, clindamycin and rifampin), estrogen, Clofazimine, levodopa, rifampin, and rifabutins can progesterone, protease inhibitors and homeopathy medicine cause saliva and other body liquids discoloration (orange to can induce EM [2,3,27]. EM is also reported to result from red ) [ 4,9,10,14]. administration of infliximab and adalimumabs [1,28].

Clujul Medical Vol. 91, No. 1, 2018: 27-36 29 Dental Medicine

Pemphigus Fixed drug eruption is a group of life threatening autoimmune The only cause of fixed drug eruption (FDE) is disorders that affect skin and mucous membranes. In 60% medications. Clinically it appears as non-specific diffuse of cases oral lesions represent the first symptom of the erythema to vesicle and ulceration. Symptoms vary from disease and they appear as a bullae that is rapidly disrupted tingling and burning sensation to severe pain of . and leave irregular shallow ulceration. The labial mucosa is most commonly involved [3,5,9]. It Some drugs can induce oral lesions similar recurs at the same site after drug use [3]. FDE is a form of to pemphigus clinically, histopathologically and in delayed hypersensitivity mediated by CD8 Tcell [5]. immunofluorescent aspects [5,29]. These drugs produce In the Ozkara study, naproxen and co-trimoxazole antibodies leading to acantholysis and show symptoms were the main inducers of FDE [35]. similar to pemphigus vulgaris pathogenesis. Drugs capable Barbiturates, dapson, indomethacin, oxyphenbutazone, of inducing pemphigus are divided into 2 groups: meprobamate, salicylates, sulfonamides, tetracycline, Thiol agents (containing sulfidryle) and Non- thiol ibuprofen, clarithromycin and gabapentin can also induce agents that often have active amid groups [3]. fixed drug eruption [4,36,37]. Thiol drugs such as penicillamine, ACEIs (captopril, Angioedema enalapril) are the most common cause of pemphigus like Angioedema is a common clinical manifestation that lesions [3,4]. comes along rapid painless swelling of , tongue, around NSAIDs (diclofenac, ibuprofen and piroxicam), the eye and adjacent area due to contact with an allergen rifampin, phenobarbital, phenylbutazon, propranolol and or specific drug in susceptible patients. If angioedema heroin can also induce pemphigus-like lesions [4,9,29,30]. involves the oropharynx, it may be life threatening. Pemphigoid Swelling continues for 24- 48 hours, after the contact with Drug induced pemphigoid often involves oral mucosa allergen [3,5]. and can also appear as cutaneous lesions. The patients Some medications act directly on the mast cells and suffering from drug-induced pemphigoid are younger than result in their degranulation and release of inflammatory those with autoimmune pemphigoid. Eliminating the special cytokines such as serotonin, histamine, and kinins these drug will make the lesions heal [31]. medications can cause angioedema [3]. Drugs containing thiol and sulfonamide components ACE inhibitors are the most common drugs that are the most common drugs known to induce pemphigoid induce this situation [1]. Other drugs include: penicillins, [4,9]. cephalosporins, local anesthetic agents, aspirin , barbiturates, Anti-arrhythmics, anti-hypertensives (calcium NSAIDs, anti-hypertensive agents (angiotensin receptor channel blockers, ACEIs, beta blockers), anti-diabetics blockers, hydrochlorothiazide, isotretinoin, calcium (tulbutamide), diuretics (furosemide, spironolactone), channel blockers), anti- platelet drugs (clopedigrol) and antibiotics (penicillin, cephalexin, ciprofloxacin), anti-hyperlipidemia (simvastatin, atorvastatin, fluvastatin) anti-rheumatic agents (D-penicillamine), anti-TNF a [1,3,14,38-40]. (adalimumab, etanercept), anti-psychotics and NSAIDs Mucous membrane pigmentation can induce pemphigoid reaction [1,9,32]. Acquired melanocytic pigmentations are drug Lupus erythematous induced in 10 to 20% of cases. This pigmentation can be Oral lesions of lupus erythematous (LE) may be localized, diffuse or multifocal in oral mucosa and is often similar to with irregular areas of erythema seen on the . The lesions are flat, without any swelling or ulceration bordered by radiating keratotic striae. These and nodularity. In most cases discoloration dissolves a few lesions usually involve palate, buccal, gingiva or alveolar months after drug withdrawal; however, pigmentation mucosa [5]. Considering that palate involvement is rare in associated with hormonal drugs may be everlasting. Exact lichen planus is helpful in differentiating from drug induced mechanism is unknown but drugs or metabolites can induce LE [3]. melanogenesis [4,5]. Drug induced LE is a variant of LE that improves Temporary discoloration (yellow to brown) usually within days to months after withdrawal of drug. Nowadays appears on dorsum of the tongue and oral mucosa through up to 70 types of drugs are known can induce LE. The most consumption of some foods and drinks (tea, coffee), or important drugs that cause systemic lupus erythematous is specific habits (smoking, betel, cocaine and crack use), hydralazine and procainamide (20%) [3,5,33]. The other some medications (iron, bismuth, chlorhexidine and drugs with the potential to cause LE are: antibiotics) and psychotropic agents that induce xerostomia All of anti-leptic groups, beta- blockers, sulfonamide, [1,4]. The most important drugs that give rise to melanosis isoniazid, chlorpromazine, methyldopa, penicillamine, are: quinidine, and biologic agents such as anti-TNF inhibitors Anti-malarias (chloroquine, hydroxychloroquine, [1,4,9,5,34]. mepacrine, quinacrine), oral contraceptive (OCP), chlorpromazine, cytotoxic drugs such as cyclophosphamide

30 Clujul Medical Vol. 91, No. 1, 2018: 27-36 Review and busulfan [5,9]. fibrotic consistency [1]. OCP induce by stimulating Mostly, Calcineurin inhibitors (cyclosporine) melanocyte activity [3]. induce gingival hyperplasia. However, tacrolimus can also HIV- patients who are treated with clofazimine, lead to fibrovascular gingival hyperplasia less frequently. zidovudine or ketoconazole may suffer from melanin Fibrovascular hyperplasia manifests as a localized polypoid induced pigmentation. In addition, heavy metal drugs such fibrous tumor involving tongue and buccal mucosa rather as silver, mercury, bismuth and gold may induce gingival than gingiva [1]. Clinically, the Gingival enlargement due pigmentation4]. In 66% of cases anti-malaria drugs lead to cyclosporine has higher signs of inflammation and is to gray-brown to black or yellowish discoloration on the less fibrotic; however, nifidipine and phenytoin are more palate. Also, clofazimine may lead to red color in the fibrotic [5,42]. mucocutanous mucosa [3]. Oral contraceptives (OCP) can cause gingival Some drug metabolites such as , enlargement as well [41]. tetracycline, anti-malaria drugs and clofazimine may Hard tissue involvement deposit in the oral mucosa. These metabolites chelate with Drug-related osteonecrosis of the jaw iron and melanin. Osteonecrosis is a result of temporary or Some drugs affect specific sites. For instance, permanent loss of blood supply to the bone. This is a zidovudine affects the tongue, OCPs involve the serious oral complication from taking bisphosphonates , mandibular gingiva, and chemotherapic agents (BPs), anti-resorptive (denosumab), anti-angiogenic , and (cyclophosphamide, doxorubicin, docetaxel) influence the immunomodulatory medication [1,3,43]. dorsum of tongue and buccal mucosa [1]. Bisphosphonate-related osteonecrosis of the There are many reports about blue, blue-gray or jaw (BRONJ) was first described by Marx in 2003, and brown discoloration of gingiva by minocycline due to commonly result from zolenderonic acid usage [44]. drug interaction with bone, during its formation. However, Osteonecrosis was reported not only for BPs but many of these discolorations may reflect the pigmentation also for anti-angiogenic agents and the distinctive ulcer, of underlying bone and tooth roots [4,9]. caused by mammalian targets of rapamycin inhibitors [1]. Drug induced gingival enlargement Thus the term “medication-related osteonecrosis of the Gingival enlargement is represented by the over jaw” (MRONJ) is more accurate than BRONJ. growth of connective and epithelial tissues that develop Bisphosphonates are non-metabolized analogs of between 1 to 3 months after treatment with some specific pyrophosphate that are located in the bone and prevent or medications. Typically it affects inter dental papilla and may reduce skeletal complications [3]. cover a part or whole of the tooth. Usually it is generalized BPs reduce turnover rate of the bone by inhibiting and involves anterior teeth. Commonly it is painless, but osteoclast activities. They are used in osteoporosis, bone may be traumatized and tender during function. Severity metastatic disease, hypercalcemia due to malignancy, of enlargement is related to drug intake duration, dose and and bone lesions (such as multiple myeloma, osteopenia, patients’ [1,3,9]. osteogenesis imperfecta and Paget disease [19,45]. Most common drugs causing gingival enlargement MRONJ is more common in patients with cancers are as follows [4,41], treated with intravenous BPs, and it is uncommon in Calcium channel blockers (diltiazem, nifidipine, patients on oral administration (0.1- 0.4% in orally taking amlodipine, felodipine, nisoldipine, verapamil) anti- versus 0.8- 12% in IV injection). convulsant drugs (phenytoin, sodium valproate, MRONJ risk is noted to be higher in patients phenobarbitone, vigabatrin, primidone, ethosuximide), and suffering from cancer, since they get the intra venous form immunosuppressants (tacrolimus, sirolimus, cyclosporine). of Bisphosphonates. Intra venous Bisphosphonates are These groups have similar mechanism of action at prescribed to treat cancers and bone problems induced by intracellular level. They inhibit intracellular calcium ion bone metastases, solid tumors, and lytic bone lesions such infusion. as Multiple Myeloma. On the other hand, the oral form Gingival enlargement has been reported in 16 to of Bisphosphonates are prescribed to treat osteoporosis, 94% of patients who take phenytoin. On the other hand, osteopenia, and less common cases in Paget’s disease or other anti-leptic drugs such as valproic acid make less osteogenesis imperfect. MRONJ risk is said to be dependent gingival enlargement [40]. on time in a way that taking venous Bisphosphonates Gingival enlargement was reported as a disease for an average period of 33 months (in patients suffering affect in 8% of the cases taking cyclosporine and in 100% from cancer) and 48 months of the oral form in patients of the patients taking cyclosporine and having kidney with osteoporosis. Tooth extraction, as initiator factor, transplant as well [41]. is considered to be of high importance. In the oral form, Gingival hyperplasia due to calcium channel the risk is 5% and in the venous one, it ranges from 1.6% blockers is diffuse, generalized and often nodular with to about 14%. In patients suffering from cancer, all oral

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cavity mucosa and teeth should be examined before any Tooth discoloration intra venous treatment. Then, any source of infection, Tooth discoloration is classified to extrinsic and pathology and infection risk factors should be removed. intrinsic. Extrinsic types are stains of the outer surface In the following, any teeth with poor prognosis should of the tooth that can be removed by polishing. Poor oral be extracted, and endodontic and prosthodontic treatment hygiene, mouth rinses such as chlorhexidine, excessive should be performed for the teeth with good prognosis. use of tea, coffee, tobacco, and smoking can induce tooth Teeth with three grade mobility should be extracted as extrinsic discoloration. Systemic disease (like Porphyria well. After starting the treatment with Bisphosphonates, the (red), jaundice (brown), erythroblastosis fetalis (gray- patients have to visit the dentists every four or six months brown), and fluorosis (yellow- brown)) can cause intrinsic and panoramic radiography should be done every six to 12 discoloration due to their effect in the developing stage of months in order to diagnose osteosclerosis, or lytic bone, tooth [5]. forca involvment, and periodontal ligament widening. For But some drugs such as antibiotics (minocycline, tooth extraction, antibiotic prescription is essential and penicillin, ciprofloxacin, co-amoxiclave, clarithromycin, teeth should be extracted with minimal trauma. In cases metronidazole) can effect tooth color as well [9,52]. of patients with osteoporosis who are willing to take the Internal discoloration due to taking tetracycline is oral form, it is necessary to be informed about MRONJ prominent when it is used for children under 12. Among problems and symptoms and that taking them for more than , chlortetracycline makes sever discoloration four years predisposes them to this situation [45,46]. with gray-brown hue [3]. Tetracycline, oxytetracycline, Some risk factors that are related to MRONJ and methyl- chlortetracycline create a lower degree included: history of dento alveolar trauma, duration of of color changes (like yellow hue). Also, minocycline taking BPs and its type. Patients with history of dental can affect tooth color and make gray-black hue, but in inflammatory disease are at risk of MRONJ, seven times contrast to tetracycline, it can involve erupted and fully more than others [47]. developed tooth [4]. Other drugs which are related to tooth Yarom stated that patients who took 70 mg alendronate discoloration are as follows, [4,5,52]. in 1 week (for more than 3 years) or 35 mg in 1 week (for Enalapril, Etidronate, Fosinopril, Pentamidine, more than 5 years) are susceptible for BRONJ [48]. Perindopril, Propaferone, Quinapril, Ramipril, Terbinafine, BPs consist of alendronate (fosamax), pamidronate Trandolpril, Zopiclone. (aredia), ibandronate (bonvia), residronate (actonel) and Non specific conditions zolendronate (reclost, zometa) [3]. Taste disorders If tooth extraction is necessary for these patients, Many drugs are associated with taste abnormalities they must stop taking drugs 3 months before and start the which manifest as loss of taste acuity (hypogusia), loss medication 3 months later (after complete healing of tooth of taste sense (agusia), distortion of taste (dysgusia) and socket [43]. bad taste (paragusia) [4]. Sometimes, taste disturbance Dental caries appears in the form of uncommon, bitter or metal taste in Poor oral hygiene, dietary habits and dry mouth are the mouth. The exact mechanism is still unknown, but one risk factors for dental caries. Syrups contain sucrose that of the mechanisms is known to be excretion of drugs or are used for children reduce PH and lead to dental caries. their metabolites into saliva. Another mechanism is related Antifungal (nystatin oral tablet) and antibacterial agents to direct effect of drugs on taste receptors or secondary to have sucrose up to 60g% [49] and increase the risk of hypo salivation. It can affect on physical and psychological dental caries. health or patient’s life style [3]. Furthermore, anti-leptic agents, psychotropic The most common drugs that induce taste substances such as heroin, cocaine, methamphetamine and disturbance are: ACEI inhibitors ,anti- thyroids, beta cannabis can induce dental caries as well [41,49]. lactam, anti-diabetic agents (metformin), chlorhexidine, Dry socket opiates and protease inhibitors, calcium channel blockers Dry socket or is a very painful (nifidipin, diltiazem), antimicrobial drugs (metronidazole, condition that develops between 1 to 3 days after tooth grizofulvine, carbicillin, lincomycin), aspirin, penicillamin, extraction and is one of the common complications after rifampin, lithium and imipramine. Also some drugs like the removal of third molars. It occurs due to removal of the anti-HIV, clarithromycin, lansoprazole, terbinafine and clot within the socket. The prevalence of this phenomenon isotretinoin can cause hypogusia or dysgusia [3,4]. ranges from 0.5 to 5% of cases. OCPs can increase the In the Deco Camila study, the most important oral incidence of dry socket. It may be related to OCP fibrinolytic side effect of anti-diabetic and anti-hypertensive agents effect that interferes with coagulation. Vasoconstrictor in were taste alternation found in 19% of the patients [53]. local anesthetics may contribute to the formation of dry Taking heavy metal drugs cause metal-tasting. socket [14,50,51]. Trauma, smoking, radiotherapy, and Some investigation showed that a lipoic acid can heal taste microorganisms increase the risk of dry socket, too [50]. disturbance relatively. But the most effective way to correct

32 Clujul Medical Vol. 91, No. 1, 2018: 27-36 Review this situation is the elimination or completely discontinuing however, it is socially unpleasant and makes swallowing, such drugs [2,3,53,54]. This state heals 4 months after chewing and speaking difficult. They are seen repeatedly medicine withdrawal [5]. in patients who take dopaminergic antagonists for a long Halitosis (malodor) time [3]. Malodor is the third most frequent reason for The most common drugs that induce people to refer to dental care centers, after and movement disorder are dopamine receptor antagonists gum disease [55]. Poor oral hygiene, dental caries, oral (Chlorpromazine, Haloperidol) and anti-emetics infection, , systemic disease like renal, (Chlorpromazine, Prochlorperazine). Anti-depressants, hepatic, gastrointestinal disease and upper airway infection, anti-psychotics (Phenothiazine), anxiolytics, OCP and some foods or smoking can lead to malodor. Halitosis can Metoclopramide HCL can also result TD [3,14]. be related to indirect effect of drugs which result in dry Phenothiazines may induce involuntary movements mouth, but other drugs like Isosorbide Dinitrate, cytotoxic in the facial muscles 4 days after consumption (grimacing agents, D-methyl sulfoxide, amyl-nitrate, Disulfiram, syndrome). It is accompanied by spasm of facial muscles, Paraldehyde, Chloral hydrate are directly the cause for neck, tongue, abdomen, tetanus like with movement halitosis. Using some vitamins such as B6, can also induce disorder [59]. halitosis. Tetracycline causes malodor and hairy tongue [4]. Benzodiazepines, dopamine agonists and adrenergic Some drugs that cause phantom or real halitosis are lithium agonists are helpful in the treatment [3]. mineral, penicillin, griseofulvin and drugs containing Infection iodine and bismuth [56]. Some drugs which are used locally or systemically Neuropathies may alter the normal flora of the mouth and increase Neuropathy is one of the neurological complications susceptibility to infections. Antibiotics, especially the wide of chemotherapy. Often peripheral neuropathy is spectrum ones, cause secondary infection. The drugs that accompanied by taking taxanes, platinum compound, are capable of inducing infection include Cephalosporin, thalidomide, bortezomib and herbal alkaloids (vincristine, Penicillin, Ciprofloxacin and Griseofulvin. Corticosteroids vinblastine) [1]. also can increase infection susceptibility. Cytotoxic drugs Besides, neuropathies are seen in taking cause bone marrow suppression and increase bacterial, acetazolamide, tricyclic anti-depressants, chlorpropamide, viral, fungal and childhood viral infections (like measles isoniazid, nalidoxic acid, nitrofurantoin, polymixin-B, and chickenpox) [4,9,14,60]. streptomycin, ergotamine, hydralazine, monoamino Long term use of immunosuppressive and anti- oxidase inhibitors (MAOIs), nicotinic acid, tulbutamide rheumatic agents such as methotrexate, abatacept, alefacept and local anesthetics (like articaine and prilocaine) [57-59]. increase herpes virus infection, deep fungal infections and Movement disturbance pseudomambrane candidiasis [1]. Anti-TNF antibody Movement disturbance is divided into 3 main therapy (infliximab, adalimumab) increases the risk groups by symptoms onset: acute, subacute, and tardive. of serious infections [60,61]. Likewise, drugs with the Acute movement disturbance occurs from hours to days potential of inducing dry mouth increase the chance of oral after exposure; subacute one occurs within weeks and infection. tardive one occurs from months to years after medication We show the orofacial related side effects of exposure. Tardive dyskinesia, dystonia, and Parkinson are medication in the Table I. included in this group of disorders [59]. We found that most studies were about the adverse Tardive dyskinesia (TD) is an involuntary, effects of drugs on the function of salivary glands, repetitive, purposeless movement in the body, extremities which often cause a decrease in saliva secretion. Other and orofacial region such as tongue, it happens in the form reactions were less common; meanwhile, the side effect of tongue protrusion, lip smacking, chewing movement, of bisphosphonate was increasing in the alveolar bone, grimacing and puckering. This condition is not painful; because it has being over prescribed.

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Table I. Orofacial related side effects of medication; Saliva and Salivary gland involvement, Soft tissue (mucosal) involvement, Hard tissue involvement, Non specific conditions. Classification Adverse effect Mechanism Clinical findings Related medication Xerostomia Sympathomimetic effect , Difficulties in Anti- cholinergics, Anti- histamine, (Anti-cholinergic) eating, speaking, tasting, Antihypertensive, Anti-depressant, Diuretics Damage to salivary gland swallowing and retention of Saliva and Excreting body liquids (dehydration) removable denture Dysgeusia, Salivary Vasoconstriction in salivary glands Burning sensation gland Sialorrhea Parasympathomimrthic effect Drooling, Choking sensation, Sympathomimetic drugs (pilocarpine, involvement (cholinergic action) May aspirate saliva at night cevimilline), Physostigmine, Heavy metals Salivary gland Hyper sensivity reaction Swelling of salivary glands Radioiodine, Chlorhexidin, Enlargement Oedema (spasm of smooth muscles) Clozapine Lichenoid Delay hypersensivity reaction Similar as lichen planus Anti- hypertensive (B blockers, ACE reaction specially ulcerative form *inhibitors) Anti- hyperglycemic, Anti- leptic, Anti- malaria, NSAIDS**, Gold sulfonamides Erythema Hyper sensivity reaction (immune Mild erythema to painful NSAIDS, Antibiotics, Sulfanamides multiform complex) ulceration, Crusting and bleeding specially on the lips pemphigus Auto immune (Auto antibody versus Shallow irregular erosions and Penicillamine, spinosom layer) ulcers ACEIS (captopril, enalapril) Pemphigoid Auto immune (Auto antibody versus -Desquamative Sulfonamides, Penicillin, basal layer) - Similar as lichen planus Foresmide, Captopril, specially ulcerative form Penicillamine, NSADIS Soft tissue Lupus erythematous Auto immune (by Involving immune -Same as lichen planus Hydralazine, Procainamide (mucosal) complex) -Irregular areas of erythema involvement: or ulceration bordered by radiating keratotic stria Fixed drug eruption Delayed type of hypersensitivity -Diffuse erythema to vesicle Naproxen, Co- trimoxazole, and ulceration Barbiturates, Indomethacin, Salicylates, -Burning sensation to sever Sulfonamids pain in oral mucosa Angioedema Allergy and hypersensitivity reaction(is Painless swelling of lips and ACEIS, Penicilline, Barbiturates, Anti- mediated by inflammatory cytokines orofacial regions hypertensive agents such as serotonin, histamine and kinins) Mucous membrane Stimulatory melanocyte activity, Focal, multifocal or diffuse Anti- malarias, Cytotoxic agents, pigmentation Deposition of drug metabolites in discoloration specially on hard (cyclophosphamide, busulfan), mucosa palate Chlorpromazine Clofazimine, OCP*** Gingival Decrease activity of matrix Over growth of gingiva Calcium channel blockers, enlargement metalloproteinase and failure to activate specially inter dental papilla of Anti- convulsant, collagenase, Dysregulation of cytokines anterior region Immune suppressant and growth factor ( cyclosporine) ,OCP Drug related Loss of blood supply to bone, Reduce Necrosis of bone, Pain, fistula Bisphosphonate, osteonecrosis the rate of bone turn over by inhibiting Anti- angiogenic agents osteoclast activity Dental caries Reduce PH Caries especially in the Antifungal, Antibacterial Anti-leptic agents, cervical tooth Psychotropic substances Hard tissue Dry socket Vasoconstriction, very painful condition Smoking, OCP involvement Interferes with fibrinolytic effect of coagulation Tooth dicoloration Intrinsic: effect in the developing stage Different tooth , yellow- Intrinsic: antibiotics especially; Tetracycline of tooth brown, gray- brown, black, Extrinsic :mouth rinses such as chlorhexidine, Extrinsic: deposition of stains on the brown excessive use of tea, coffee, tobacco, and outer surface of tooth smoking Taste disorder Direct effect to taste receptors, Exertion Loss of taste acuity, Loss of Anti- diabetics, Anti- hypertensive, Anti- of drugs or its metabolites into saliva, taste sense, Bad taste, Metallic thyroids, Secondary to hyposalivation taste Chlorhexidine, Anti- microbial, Opiats Halitosis (malodor) Dry mouth,metabolits Bad breath in the exhale Isosorbide Dinitrate, cytotoxic agents, D- methyl sulfoxide, Amyl- nitrate, Disulfiram, Non specific Paraldehyde, Chloral hydrate conditions Movement Purposeless movement of the Dopaminergic antagonists, Anti- emetics, disturbance tongue, Anti- depressant, anti- psychotics difficulty in the swallowing, (Phenothiazine), anxiolytics, OCP, chewing and speaking Metoclopramide HCL Infection Changes in the normal oral flora Susceptibility to infection such Antibiotics, Corticosteroids, Cytotoxic drugs, as candidiasis, herpetic lesion Immunosuppressive, Anti- rheumatic agents * Angiotensin Converting Enzyme Inhibitor ** Non Steroid Anti Inflammatory Drugs *** Oral Contraceptives

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