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Adverse reactions of systemic drugs in the oral cavity

Davide Bartolomeo Gissi1*
  • 1 University of Bologna, Department of Biomedical and Neuromotor Sciences, Italy

An adverse drug reaction (ADR) is defined by WHO as “a response to a drug which is noxious and unintended, and which occurs at dose normally used in man for the prophylaxis, diagnosis, therapy of disease or for the modification of physiological function" (1972). ADRs have been classified into two types. Type A reactions represent about 80% of the cases. They are dose dependent and predictable and are also associated with the pharmacology of drug. Pharmacology can be divided into two subgroups as primary and secondary. Type A primary reactions are characterized as abnormal reactions due to excessive action of the primary pharmacology of the drug. Oral mucosal bleeding after the use of anticoagulant agents is an example of primary reaction, whereas dysgeusia during the use of anti-hypertension drugs is a classical type of a secondary reaction related to drug intake. About 20% of ADRs are caused by an unpredictable reaction to drug which are known as type B reactions and are usually non-dose-related. Type B reactions are also divided into two subgroups, immunological and non-immunological reactions. Most of these reactions are immune-mediated side effects like hypersensitivity responses (Bakhtiari et al., 2018). A wide spectrum of drugs can sometimes give rise to numerous adverse reactions in the oral cavity (Scully and Bagan, 2004). For example, Medication-related osteonecrosis of the jaw (MRONJ) is a typical example of a widely described ADR in the orofacial region, for which dose and time are known to be relevant risk factors (Nicolatou-Galitis et al., 2018). A classification of ADRs in the oral cavity is difficult to generate due to the multiplicity of involved classes of drugs and substances, the variety of involved tissues and functions, the different type of lesions and the complexity of pathogenetic mechanisms (Lo Russo et al., 2012). For example, Xerostomia is considered the most common adverse drug reaction affecting the oral cavity but is associated with over 500 drugs (Sultana N.;Yuan and Woo, 2015). Indeed, in a systematic review in USA, xerostomia was found as a secondary effect in 80-100% of prescribed drugs (Zavras et al., 2013). Different authors classified ADRs in the oral cavity or in orofacial region into 4 main groups as follows (Bakhtiari et al., 2018): 1. Saliva and salivary glands involvement: Xerostomia, Ptyalism, Salivary gland enlargement, Salivary gland pain, Discoloration of saliva 2. Soft tissue (mucosal) involvement: Lichenoid reaction, Erythema multiform, Pemphigoid, Lupus erythematous, Fixed drug eruption, Angioedema, Mucous membrane pigmentation, Drug induced gingival enlargement 3. Hard tissue involvement: Medication-related osteonecrosis of the jaw, Dental caries, Dry socket, Tooth discoloration 4. Non-specific conditions: Taste disorders, Halitosis (malodor), Neuropathies, Movement disturbance, Infection. Furthermore, several orofacial adverse reactions related to target therapies have been recently reported in literature (Watters et al., 2011;Georgakopoulou et al., 2018). Indeed, over the past decade, as cancer treatment protocols evolve, Target therapies have significantly changed the treatment of cancer. These drugs are now a component of therapy for many common malignancies including breast, colorectal, lung, and pancreatic, cancers, as well as lymphoma, leukemia and multiple myeloma (Harris, 2004;John et al., 2004;Basu and Eisen, 2010;Moon et al., 2010;Mukai, 2010). Targeted therapies owe their name to their ability of targeting specifically dysregulated signaling pathways in cancer cells. These treatments include anti-tumor monoclonal antibodies (mAbs), small molecules, signal transduction receptor inhibitors, and cancer vaccines (Harris, 2004;Watters et al., 2011). The enhanced discrimination of target therapies between tumor and normal cells is a more promising and efficacious approach to cancer treatment than conventional cytotoxic chemotherapy. Indeed, conventional cancer chemotherapeutics are designed to destroy malignant cells but also harms normal proliferating tissues mainly in bone marrow and mucocutaneous sites, with a heavy toxicity burden. Nevertheless, targeted therapies are not free from side effects, and some manifest in the oral cavity (Zavras et al., 2013;Vigarios et al., 2017;Georgakopoulou et al., 2018). Adverse reactions of target therapies are considered to be mild to moderate and in most cases are substantially less damaging than conventional cancer chemotherapy. Interestingly, the majority of oral adverse events related to target therapy were unexpected in the preclinical setting. ADRs of target therapy actually have been mainly reported in case reports and case series (Watters et al., 2011;Georgakopoulou and Scully, 2015). Initial studies have indicated as oral complications of target therapy mucosal inflammation and ulceration, dry mouth and taste change. Prospective studies with patient reported oral symptoms and function using validated instruments and specific clinical evaluation of the oral cavity and oral function are thus warranted. Risk factors related to appearance of an ADR The presence and severity of ADRs are related to patient and drug-dependent factors (Lo Russo et al., 2012). Patient’s risk factors include gender (more common in women), age (frequently in neonates and elderly), underlying diseases (more common in patients with hepatic disease and renal failure) and genetics. Drug factors include route of administration, duration, dosage and variation in metabolism. An important factor related to the appearance of an ADR was the drug-drug interaction in patients with multiple medications (poly pharmacy). For example many authors demonstrated that middle-aged and older patients with multiple medications may develop a common adverse reaction as dry mouth because of synergic effects of these drugs (Femiano et al., 2008). Finally, it is important to remember that an ADR may be the result of a drug-drug interaction between medicines and herbal or traditional remedies, recreational drugs, drug of abuse, as well as cosmetics and foods (Edwards and Aronson, 2000). Management of ADR Any symptom in a pharmacotherapy and polipharmacotherapy should be considered an adverse drug reaction until proved otherwise (Edwards and Aronson, 2000). Due to the great number of drugs related to a single adverse drug reaction, a very accurate medical history is mandatory, and it must include medicines as well as products that may not be routinely thought of as medicines. Once medical history is meticulously and clearly completed a link between the appearance of a lesion/disturbance and the single drug taken by the patient should be established. Alternatively, in case of polypharmacotherapy, only a correct clinical record allows the identification of which medicine/s among many alleged responsible causative agents could be responsible of the adverse events. If one or more drugs could be related with appearance of ADR, the non-essential medicines should be withdrawn first, preferably one at a time. If the patient is getting better, alternative medicines for the basic disease can be administered, if necessary, otherwise, the next most likely agent should be withdrawn, and the process repeated. If a selected drug is essential for the patient, it should be reintroduced, or, if suspected to be causative, substituted with another drug. In poli-pharmacotherapy essential medicines should be reintroduced one at a time, starting with the one least likely to be causative of the reaction. If we suspect that an ADR is related to a modification of dosage, treatment adjustment should be considered with respect to suspension of therapy. Database of suspected adverse drug reaction reports The European database of suspected adverse drug reactions (http://www.adrreports.eu/it/index.html) and the FDA Adverse Event Reporting System (FAERS) Public Dashboard (https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm070093.htm) are two examples of databases where health-care professionals can consult and/or report information about suspected ADRs that they detect, especially if the link between drug and ADR is uncertain.

References

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Keywords: Adverse Drug Reaction, Saliva, Oral soft tissue, Oral hard tissue, FDA adverse event reporting system (FAERS), Systemic drugs

Conference: 5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine., Ancona, Italy, 19 Oct - 20 Oct, 2018.

Presentation Type: oral presentation

Topic: Oral Diseases

Citation: Gissi D (2019). Adverse reactions of systemic drugs in the oral cavity. Front. Physiol. Conference Abstract: 5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine.. doi: 10.3389/conf.fphys.2019.27.00077

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Received: 27 Nov 2018; Published Online: 09 Dec 2019.

* Correspondence: Dr. Davide Bartolomeo Gissi, University of Bologna, Department of Biomedical and Neuromotor Sciences, Bologna, Emilia-Romagna, 40126, Italy, marcomascitti86@hotmail.it