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Drugs Inducing Hearing Loss, Tinnitus, Dizziness and Vertigo: an Updated Guide

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Drugs Inducing Hearing Loss, Tinnitus, Dizziness and Vertigo: an Updated Guide European Review for Medical and Pharmacological Sciences 2020; 24: 7946-7952 Drugs inducing hearing loss, tinnitus, dizziness and vertigo: an updated guide G. ALTISSIMI1, A. COLIZZA1, G. CIANFRONE2, M. DE VINCENTIIS3, A. GRECO1, S. TAURONE1, A. MUSACCHIO1, A. CIOFALO1, R. TURCHETTA1, D. ANGELETTI1, M. RALLI1 1Department of Sense Organs, Sapienza University of Rome, Rome, Italy 2Associazione Italiana per la Ricerca sulla Sordità, Rome, Italy 3Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Rome, Italy Abstract. – OBJECTIVE: The awareness of Introduction audio-vestibular side effects of drugs, such as hearing loss, tinnitus, dizziness and vertigo, has widely increased in the recent years. The pres- Ototoxicity is an undesirable effect of some ent guide represents an update of the previous drugs that induce reversible and irreversible documents published by the authors in 2005 and damage of the inner ear structures, including the 2011 on drug-induced ototoxicity and vestibulo- cochlea and the vestibule, causing temporary or toxicity. permanent hearing loss, tinnitus and/or balance MATERIALS AND METHODS: The authors alterations1-3. performed a comprehensive analysis of au- Cochlear damage manifests through sensori- dio-vestibular side effects of commercially avail- able drugs based on the British National For- neural hearing loss and tinnitus. Tinnitus can be mulary, a pharmaceutical reference book that associated to hearing loss or appear in the absence contains a wide range of useful information and of clinically evident hearing alterations; tinnitus advice on prescription and pharmacology. may also be a consequence of central drug-in- RESULTS: Commercially available drugs and duced alterations4,5. Vestibular injury may cause their active principles have been classified balance disorders, such as instability, difficulty in based on their audio-vestibular side effects, as maintaining straight posture, unsteadiness, loss of reported by the pharmaceutical companies and/ 6,7 or health agencies. Drugs have been catego- balance and dizziness . Ototoxic effects depend rized based on the field of application, the thera- on duration of therapy, route of administration, peutic indication and the pharmacological prop- infusion rate, dosage, individual sensitivity, ge- erties. netic predisposition and altered renal and hepatic CONCLUSIONS: General practitioners, otolar- functions. Although single administrations may yngology, neurology and audiology specialists have ototoxic effects, long-term therapies have a should be aware of possible audio-vestibular 1-5,8-10 side effects of drugs, such as hearing loss, tin- higher risk of producing ototoxic side effects . nitus, dizziness and vertigo. The present guide represents a practical tool to rapidly identify po- tential audio-vestibular side effects of drugs as Drug Ototoxicity reported by the pharmaceutical companies and/ or health agencies. Ototoxic drugs Drug classes most associated with ototoxicity Key Words: Pharmacovigilance, Side effects, Ototoxicity, Tinni- include antibiotics, such as aminoglycosides, gly- 11-16 tus, Vertigo. copeptides and macrolides ; platinum-based an- titumor drugs5,17-20; loop diuretics, such as furose- 21,22 Abbreviations mide ; antimalarial drugs, such as quinine and NSAIDs: nonsteroidal anti-inflammatory drugs; ADRs: chloroquine23,24; nonsteroidal anti-inflammatory Adverse Drug Reactions; PTA: pure tone audiometry. drugs (NSAIDs) and acetylsalicylic acid10,25,26. 7946 Corresponding Authors: Massimo Ralli, MD, Ph.D; e-mail: [email protected] A review of ototoxic drugs The drug class whose ototoxicity has been fullness, dizziness, and vertigo1-4. These symp- most studied are aminoglycosides and, to date, toms may have a simultaneous or independent their ototoxic effects are well known11,13,15. Some onset, can develop rapidly or gradually and can of these antibiotics tend to cause more damage be reversible or irreversible. Audiological symp- to the cochlear function (Dihydrostreptomycin, toms following ototoxic drug administration are Kanamycin, Neomycin, Amikacin), others to the subject to high interindividual variability due to vestibular function (Streptomycin, Gentamicin, differences in genetic factors, pharmacokinetics, Tobramycin, Sisomicin); sometimes, both func- metabolic status of the individual and co-morbid tions are involved. The risk of ototoxicity increas- medical conditions1,3,5,8,12,18,19,28,36-39. es with the concomitant use of diuretics, in the Sensorineural hearing loss can follow func- presence of renal failure, and for long-term treat- tional impairment and/or cellular degeneration of ments11,13,15. tissues of the inner ear, mainly outer and inner Macrolides and glycopeptides have limited oto- hair cells. Hearing loss may present in the ear- toxicity. Macrolides, such as Erythromycin and ly stages immediately or within 7-10 days from Azithromycin are ototoxic only if used at high drug administration as a bilateral symmetric doses and if administered intravenously27,28. Gly- hearing loss with different paths. Initially, hear- copeptides, such as Vancomycin and Teicoplanin ing loss tends to affect high frequencies followed are ototoxic in the presence of renal failure29. by medium and low frequencies, although the Platinum-derived chemotherapies, such as cis- audiometric aspect may vary and sometimes platin, carboplatin and oxaliplatin have a potent the frequencies affected by the damage are the ototoxic action. These drugs can cause bilateral, middle frequencies, with preservation of the low progressive, non-reversible, dose-dependent sen- and high frequencies2,8,40-42. Hearing loss follow- sorineural hearing loss that may occur immediate- ing ototoxic treatment may resemble that found ly after the first administration or sometimes even in Meniere’s Disease (MD), an idiopathic inner several months after completing treatment. Hearing ear disorder characterized by recurrent vertigo, should be monitored before starting chemotherapy, fluctuating hearing loss, aural fullness and tin- during and after completing treatment. The risk of nitus43-45. Furthermore, drugs used to treat MD hearing loss in patients treated with cisplatin ranges include intratympanic gentamicin, an ablative from 10 to 90% for multiple administrations, while procedure that has been shown46,47 to obtain high it is nearly 30% for a single dose17-20,30,31. rates of vertigo control with dose-dependent risk Other ototoxic drugs include furosemide and of hearing deterioration and healthy-side vestibu- other loop diuretics, that may induce temporary lar hypofunction; recent studies48,49 have demon- or permanent hearing loss if used at high doses strated that intratympanic administration of low- and for prolonged periods21,22; antimalarial drugs, dose gentamicin following a titration protocol can such as quinine and chloroquine23; NSAIDs and produce a satisfactory control of vertigo without acetylsalicylic acid can cause hearing loss and causing significant cochlear damage. generally reversible and dose-dependent tinnitus, Tinnitus following treatment with ototox- especially in long-term treatment10,23,25,32,33. ic drugs may be continuous or, rarely, pulsatile. Ototoxic drugs trigger complex biochemical Tinnitus is mainly low or high pitched, often alterations at the endolymphatic level with conse- associated to hearing loss and matching its fre- quent modification of the endocochlear potential quency50-52. Pulsatile tinnitus can also be found in and cochlear damage. Histopathological alter- patients with ototoxic damage; although it mainly ations have been highlighted in central structures has a vascular origin and not a direct relation to (degenerative phenomena of cochlear and vestib- ototoxicity, it may be indirectly related to drug ular nuclei) and peripheral organs (destruction administration for the effects of these drugs on of sensory cells of maculae, ampullary cupula, the vascular flow or systemic blood pressure. In Organ of Corti and spiral ganglion). Cochlear these cases, normal flow sounds within the body lesions, especially when involving the inner hair are perceived more intensely53. Pulsatile tinnitus cells and spiral ganglion fibers, may be present is usually unilateral, unless the underlying vascu- without a clinically evident hearing loss8,34,35. lar pathology is bilateral, it can have an arterial or venous origin, or it may originate between arter- Main Audiological Symptoms ies and veins53-55. Ototoxicity can present with different symp- Vestibular symptoms of vestibulotoxicity can toms: sensorineural hearing loss, tinnitus, aural be unilateral and bilateral and include oscillop- 7947 G. Altissimi, A. Colizza, G. Cianfrone, M. de Vincentiis, A. Greco, S. Taurone, A. Musacchio et al sia, dizziness, motion sickness, and unsteadi- differentiation of stem cells into functional cells, ness when standing or walking, especially in the and require the evaluation of complex factors, dark14,16,56. Symptoms can range from mild to dis- such as stem cell-type choice, signaling pathway abling, depending on the severity of the vestibular regulations, transplantation approaches, internal toxicity and on the functional integrity of other environment of the cochlea, and external stimu- sensory systems that contribute to the mainte- lation78-80. Recent findings75-77,81 raise hope for the nance of balance and equilibrium14,16,56. future development of stem-cell-based treatment regimens that could be used to repair damages Clinical diagnosis
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