**Ototoxicity**

#### **Chapter 13 Provisional chapter**

#### **Ototoxicity: Old and New Foes Ototoxicity: Old and New Foes**

Agnieszka J. Szczepek Agnieszka J. Szczepek

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/66933

#### **Abstract**

Drug-induced ototoxicity has been known for centuries. Already in the seventeenth century, hearing loss was described to be a side effect of quinine. The post- World War II pharmaceutical industry boomed with the production of aminoglycoside antibiotics followed by diuretics and cytostatic drugs. Wide-spread and long-term usage of these medications brought the knowledge about their unwanted ototoxic effects. In the last decades, several new drugs appeared on the shelves of pharmacies and the hearing loss or tinnitus have been among the side effects of many of them. However, the awareness of community about new ototoxic medications is still not sufficient. New ototoxic drugs may belong to the class of phosphodiesterase-5 (PDE5) inhibitors, used to improve microcirculation and to treat erectile dysfunction. Moreover, interferons used for the therapy of hepatitis B and C, common painkiller paracetamol and hydrocodone, synthetic opioid methadone and the inhibitors of reverse transcriptase were demonstrated to induce adverse effects on hearing. Lastly, hearing loss linked to immunosuppressive drugs was documented in patients undergoing organ transplantation. Making the patients aware of adverse drug reactions and offering them audiological monitoring and intervention should be considered by respective therapists.

**Keywords:** ototoxic drugs, viral infections, reverse transcriptase inhibitors, interferons, PDE5 inhibitors, immunosuppressants, hearing loss, adverse reactions

### **1. Introduction**

The sense of hearing is fundamental to the communication and proper reaction to dangerous situations. Moreover, recent studies indicated that the hearing loss increases significantly the risk of dementia [1]. Unfortunately, people's ability to hear deteriorates with time, as the human auditory epithelium is post-mitotic and unable to regenerate. In other

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© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, words, the few thousand of auditory hair cells with which we are born have to last our entire life. There are several causes of hearing loss such as noise, aging, infections, tumors, neuronal degeneration or cardiovascular diseases. Another important cause of hearing loss is ototoxicity.

In this chapter, we will concentrate on medications that are known to induce hearing loss as an adverse effect. These medications are also known as ototoxic medications.

Clinical signs of ototoxicity may include at least one of the following symptoms:


First signs of ototoxicity usually develop during or shortly after receiving particular medication. Majority of ototoxic drugs induces irreparable damage translating into permanent hearing loss; however, **aspirin and derivatives** belong to drugs that cause most of the times **reversible hearing loss** [2]. In fact, aspirin-induced ototoxicity in form of tinnitus was used for decades by rheumatologists to adjust the maximal therapeutic dose of salicylates in the patients. This practice was abandoned because of poor correlation between salicylate blood levels and ototoxicity symptoms [3] and because of development of new drugs used for the treatment of rheumatic diseases. Nevertheless, even today there are patients occasionally admitted to the emergency room because of the salicylate-induced ototoxicity [4]. The ototoxicity of salicylate has been attributed to its capacity to bind and inhibit the action of cochlear protein **prestin**, expressed by the outer hair cells [5, 6]. In addition, salicylate can induce **death of spiral ganglion neurons** as well as cause **dysregulation in the central auditory pathway** [7].

Other groups of well-known ototoxic drugs that frequently cause **hearing loss** include:


Platinum-based cytostatics (**cisplatin**, **carboplatin** and **oxaliplatin**) are used as single agents and in combination with other drugs for the treatment of various types of cancer (e.g., testicular carcinoma, lung carcinoma, ovarian carcinoma, head and neck carcinomas, melanomas, lymphomas and neuroblastomas) [8]. The platinum-based drugs bind DNA and induce irreversible changes that prohibit tumor cell division. However, common adverse effects of platinum-based drugs include nephrotoxicity and ototoxicity. This toxicity is being attributed to an excessive production of reactive oxygen species that leads to death of auditory hair cells [9–11]. Clinically, patients develop **permanent bilateral hearing loss that originates in high frequencies** [12]. In addition, patients may have **difficulties with speech understanding in noise** [13].

words, the few thousand of auditory hair cells with which we are born have to last our entire life. There are several causes of hearing loss such as noise, aging, infections, tumors, neuronal degeneration or cardiovascular diseases. Another important cause of hearing loss

In this chapter, we will concentrate on medications that are known to induce hearing loss as

First signs of ototoxicity usually develop during or shortly after receiving particular medication. Majority of ototoxic drugs induces irreparable damage translating into permanent hearing loss; however, **aspirin and derivatives** belong to drugs that cause most of the times **reversible hearing loss** [2]. In fact, aspirin-induced ototoxicity in form of tinnitus was used for decades by rheumatologists to adjust the maximal therapeutic dose of salicylates in the patients. This practice was abandoned because of poor correlation between salicylate blood levels and ototoxicity symptoms [3] and because of development of new drugs used for the treatment of rheumatic diseases. Nevertheless, even today there are patients occasionally admitted to the emergency room because of the salicylate-induced ototoxicity [4]. The ototoxicity of salicylate has been attributed to its capacity to bind and inhibit the action of cochlear protein **prestin**, expressed by the outer hair cells [5, 6]. In addition, salicylate can induce **death of spiral ganglion neurons** as well as cause **dysregulation in the central auditory** 

Other groups of well-known ototoxic drugs that frequently cause **hearing loss** include:

Platinum-based cytostatics (**cisplatin**, **carboplatin** and **oxaliplatin**) are used as single agents and in combination with other drugs for the treatment of various types of cancer (e.g., testicular carcinoma, lung carcinoma, ovarian carcinoma, head and neck carcinomas, melanomas,

an adverse effect. These medications are also known as ototoxic medications.

Clinical signs of ototoxicity may include at least one of the following symptoms:

is ototoxicity.

234 Advances in Clinical Audiology

• tinnitus

• vertigo.

**pathway** [7].

• loop diuretics

• hearing loss (unilateral or bilateral)

• platinum-based cytostatic drugs

• aminoglycoside antibiotics

Aminoglycosides are a group of antibiotics used to treat gram-negative bacterial and mycobacterial infections. Clinically used aminoglycosides include amikacin and kanamycin (primarily cochleotoxic) as well as gentamicin, streptomycin and tobramycin (primarily vestibulotoxic) [14]. Similar to the ototoxic mechanism of platinum-based drugs, aminoglycosides induce excessive formation of free oxygen species followed by apoptosis of sensory hair cells [10, 15]. The aminoglycoside-induced hearing loss **is bilateral and permanent and starts in the high frequencies**. Precisely because of its ototoxic properties, gentamicin is frequently used for the treatment of Ménière's disease in the form of intratympanic injections to deplete the vestibular hair cells and thus, to prevent frequent vertigo attacks.

**Of note:** About 30% of the world population is infected with *Mycobacterium tuberculosis* [16]. The treatment of tuberculosis (especially that caused by **multiple-drug resistant** *Mycobacterium tuberculosis*) includes intravenous administration of so-called ond-line antibiotics–amikacin, kanamycin and streptomycin–leaving at least 20% of the patients with serious permanent hearing impairment [17].

Loop diuretics are a group of drugs that inhibit renal reabsorption of sodium, chloride and potassium. They are often used to treat kidney insufficiency or heart failure. Loop diuretics include furosemide, bumetanide, ethacrynic acid and torsemide. Their ototoxic mechanism involves inhibition of potassium resorption occurring in the stria vascularis and consequent **decrease in the endocochlear potential** [18]. The hearing loss induced by loop diuretics is **bilateral and usually reversible;** however, since loop diuretics are known to synergize with platinum-based drugs or with aminoglycosides in their ototoxic action, in patients receiving drugs from both groups, loop diuretics may worsen the degree of permanent hearing loss [19–21].

There is a growing number of case reports and larger studies indicating that the family of ototoxic drugs is growing and embraces newly developed medications. Although the ototoxic properties of several pharmacological drugs were recently compiled in an excellent review written by Cianfrone et al. [22], the clinical information changes and requires update.

In this chapter, we review selected group of frequently used, contemporary pharmacological drugs (phosphodiesterase-5 blockers and antiviral drugs (see **Table 1**), painkillers and immunosuppressants) in aspect of audiologically important adverse reactions including hearing loss and tinnitus.


Although in the industrialized countries, the hepatitis C and B therapy with pegylated or non-pegylated interferons and ribavirin is being replaced by other pharmacological regimes, one should not ignore the fact that not all countries and hospitals have adopted the new routine and that the interferons are still in use, possibly contributing to drug-related hearing loss.

**Table 1.** Summary of clinical reports describing hearing loss in PDE5- and interferon-treated patients.
