Pharmacological Drugs Inducing Ototoxicity, Vestibular Symptoms and Tinnitus: a Reasoned and Updated Guide
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European Review for Medical and Pharmacological Sciences 2011; 15: 601-636 Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus: a reasoned and updated guide G. CIANFRONE1, D. PENTANGELO1, F. CIANFRONE2, F. MAZZEI1, R. TURCHETTA1, M.P. ORLANDO1, G. ALTISSIMI1 1Department of Otolaryngology, Audiology and Phoniatrics, “Umberto I” University Hospital, Sapienza University, Rome (Italy); 2Institute of Otorhinolaryngology, School of Medicine, Catholic University of the Sacred Heart, Rome (Italy) Abstract. – The present work on drug-in- Introduction duced ototoxicity, tinnitus and vertigo repre- sents the update and revision of a previous The panorama of the pharmacological origin guide to adverse drug reactions for italian physi- iatrogenic noxae able to induce either harmful cians (2005). The panorama of drug-induced side effects causing ototoxicity or symptoms ototoxic effects or just a symptomatology like tin- such as tinnitus or dizziness and vertigo has en- nitus or balance disturbances, without any harm- larged in recent years, thanks to a better knowl- ful consequence, has widened in the last few edge and a more specific attention of pharma- years. The reason for this is the progress of scien- ceutical firms and drug-control institutions. In tific knowledge, the increased awareness of the daily clinical practice, there is a need for the pharmaceutical companies and of the institutions, family physician and the ENT specialist or audi- ologist (also in consideration of the possible which supervise pharmaceutical production. medico-legal implications) to focus the attention Only through continuous updating and experi- on the possible risk of otological side effects. ence sharing it’s possible to offer patients the This would allow a clinical risk-benefit evalua- certainty of receiving the treatment that is appro- tion, weighing the possible clinical advantage in priate, safe and effective and based upon the their field of competence against possible oto- most credited clinical studies. This approach is logical side-effects. The list of active ingredients definitely challenging but necessary in order to and drugs is subdivided in categories based on their audiological and otoneurological side-ef- attain positive effects towards the improvement fects, that have been signaled by the drug com- of patient’s conditions and quality of life. panies and/or ministerial notes. Drugs have also In every day medical practice physicians, oto- been subcategorized with regards to the field in laryngologists and audiologists, need to focus on which they are applied, the therapeutic indica- the risks of otologic side effects, also from a le- tions and the clinical behaviour. They have also gal point of view. It will then be beneficial to been organized in alphabetical order, for an easi- er consultation. have a wider variety of drugs of the same family The guide above, even if initially conceived at hand, therefore, having a wider range of op- for being used in Italy, also presents a more tions meeting the main therapeutic line. Physi- general and international interest, expecially as cians have to daily balance the drug between ef- for as the concepts of pharmacology and the fectiveness and safety; in any case the optimiza- features of the active ingredients are con- tion of the pharmacological/therapeutic ratio has cerned. to be strictly related to the compromise between The guide is, therefore, useful as for as we are concerned to any physician, regardless of clinical advantages and undesired side effects. the country he/she operates in. Today’s work on ototoxic, tinnitus and vertigo induced drugs is a revision and an update of what Key Words: was previously published in 2005, regarding unde- sired side effects of drugs of the otoaudiologic field, Pharmacovigilance, Side-effects, Ototoxicity, Tinni- which has had a positive result and has drawn inter- tus, Vertigo. est from both general and specialized practitioners1. Corresponding Author: Giancarlo Cianfrone, MD; e-mail: [email protected] 601 G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi In the specialised medical practice of otolaryn- ly. The current, sometimes marginal, knowledge gology and audiology there is the need to evalu- of drug behaviours make interactions a delicate ate the patient from a pharmaceutical point of issue. view to assess the potential risks of otologic side The effects of a drug could be affected by the effects. This will allow the evaluation of clinical presence of either of another drug or of food gen- advantages versus otologic adverse events. The erating an interaction that could be dangerous aim is to optimise the drug administration sched- when causing an increase in toxicity or a de- ule in order to obtain a therapeutic improvement crease in effectiveness. Food creates rare and less while sustaining the least number of side effects important clinical interactions by effecting the in the otovestibular apparatus. Sometimes symp- speed and the degree of absorption of a drug. tomatic or harmful effects do not show up imme- Fortunately combinations of drugs to be avoided diately after the first treatment but after a certain are only a handful and many drugs with interac- time, varying from subject to subject. This delay tion issues can be administered simultaneously could be explained by an increase in the organs by taking proper precautions. vulnerability and/or a minimal asymptomatic Pharmaco-dynamic interactions take place event after the first treatment and will later be re- when the effects of a drug are interfered with by vealed by the next dosage. In other instances side the presence of another drug on the action site. effects could be induced by following non-patho- They arise between drugs which share the same genic non-iatrogenic noxae (trauma, noise, infec- or opposite therapeutic effects and that act upon tions, circulatory, metabolic or endocrynologic the same physiologic system i.e. sedatives that disorders) or iatrogenic (oto-surgery). affect brain and respiratory functions. On the contrary, certain drugs could reduce the effective- Pharmacological Action ness of others because they compete for the same Influencing Factors receptors. Factors affecting the pharmacological action Pharmaco-kinetic interactions can take place are: the drug itself (dosage, chemical, physical or at the following levels: physical/chemical properties), the combination with other drugs or substances (interaction and Absorption: affecting bioavailability of a drug other types of interference), pharmaceutical by altering the absorption coefficient or the to- preparation (which affects the bio-availability of tal quantity of the drug absorbed; the active principle) or other factors relating to Distribution: the circulation of a drug can be in the patient using the drug and by the space/time an inactive form, binded to proteins, or in an context in which the drug is administered. active form, not binded; administration of It is well known how the season, the climate, drugs competing for the same proteic linkage the altitude, the temperature etc. may interfere might cause an increase in the “free quota” of with the pharmacological action determining the drug and consequently its activity; sometimes a change from being curative to being Metabolism: interactions can take place between toxic. Ultimately the patient is the factor that drugs metabolized by the same enzymatic sys- most affects the pharmacological action, it de- tem, they can act as enzymatic inductors accel- pends on the general physiological state of the erating the metabolism of the other drug and subject, on the pathological conditions involved, so reducing its effectiveness, or as enzymatic on his capability to metabolise and so eliminate inhibitors slowing down the metabolism of the the drug, on his sensitivity, which could be high other drug creating accumulation and thus an (up to the induction of hyper-sensitivity phenom- increased risk for dosage related side effects; ena both idiosyncratic or allergic) or low. At last Elimination of the drug: interactions can cause factors like gender, age, race, body weight and an alteration of both active tubular separation even social condition and psychological profile and glomerular filtration during renal clear- are also important in determining or influencing ance of certain drugs. the pharmacological action2. We can understand that the problem of drug Interactions interactions during co-administration is impor- An additional consideration has to be given to tant and delicate. As an example, on “Medicines pharmaco-dynamic and pharmaco-kinetic ac- for Children”, the paediatric therapeutic formula- tions between different drugs used simultaneous- ry issued by the Royal College of Paediatricians 602 Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus and Child Health, which is also included in the remain in their system for a longer period of time “Children Drugs User Guide” published by the creating accumulation. The nervous system be- Italian Department of Health3, the combination comes more sensitive with age and many com- of an aminoglycoside like amikacin with vanco- mon drugs like opioid analgesics, benzodi- cymin, ciclosporin, cisplatin, furosemide or am- azepine, anti-psychotics, Parkinson’s disease photericin might increase the risk for ototoxicity drugs have to be used with caution. In a similar and nephrotoxicity, but even the association of way