Ototoxic medications are drugs or pharmaceutical agents which induce ototoxicity. Ototoxicity is defined as the toxic effect on the functioning of the inner ear, which may lead to temporary or permanent hearing loss (cochleotoxic) and balance problems (vestibulotoxic).
There are a wide range of ototoxic medications, including antibiotics, antimalarials, chemotherapeutic agents, non-steroidal anti-inflammatory drugs (NSAIDs) and loop diuretics. While these drugs target different body systems, they also may cause ototoxicity through different mechanisms, such as damage to the cellular tissues of inner ear structures and disturbances of the auditory nervous system. Onset of ototoxicity ranges from taking a single dose to long-term usage of the drugs. Signs and symptoms of ototoxicity include tinnitus, hearing loss, dizziness and nausea and/or vomiting. The diagnosis of medicine-induced ototoxicity is challenging as it usually shows only mild symptoms in early stages. Thus, prospective ototoxicity monitoring would be required when patients are using ototoxic medications. Damage may be permanent or may resolve upon discontinuation of the medication.
Drugs Alcohol is one of the leading substances known to have ototoxic effects. A 2023 systematic review and meta-analysis found that alcohol consumption is associated with an increased risk of hearing loss.
Antibiotics and chemotherapeutic agents The most common classes of ototoxic medications include antibiotics (including aminoglycosides and glycopeptides) and chemotherapeutic agents. Aminoglycosides and some chemotherapeutic agents are associated with both cochleotoxicity and vestibulotoxicity. They are thought to damage the hair cells of the cochlea. Long-term exposure to these drugs may cause damage that progresses to the upper turn of the cochlea, impairing hearing or even causing deafness. Glycopeptides, on the other hand, are rarely associated with ototoxicity.
Aminoglycosides Aminoglycosides are a class of antibiotics. The most frequently used aminoglycosides include gentamicin, amikacin and streptomycin. These antibiotics are usually used in combination with other antimicrobial agents to treat drug-resistant organisms. For example, they are used with β-lactam for bacterial infections in pneumonia. They are usually given either intravenously or intramuscularly due to their poor oral absorption. Aminoglycosides irreversibly inhibit protein synthesis of bacteria, which specifically helps kill the gram-negative bacteria. The drug is first transported into the bacterial cell and it binds to the 30S ribosomal subunit. This action interferes with the reading of codons during mRNA translation, causing misreading and premature termination of the process. This inhibits protein synthesis and ultimately leads to the death of bacterial cells.
All aminoglycosides can cause either reversible or irreversible ototoxicity. Ototoxicity is more frequently observed in individuals who received the treatment for more than five days and those who have renal insufficiency. The mechanism of aminoglycosides-induced ototoxicity is not well understood. It is thought that because cochlear cells are rich in mitochondria, these antibiotics may also target cochlear cells and cause their death. Another hypothesis suggests that these drugs lead to the production of reactive oxygen species which generate oxidative stress and damage the inner ear.
Glycopeptides
Glycopeptides are another class of antibiotics. Vancomycin is the class originator for the glycopeptides. Lipoglycopeptides are a subclass of glycopeptides and they are derived from the structure of vancomycin. Examples are telavancin and dalbavancin. Vancomycin and the lipoglycopeptides have slight differences in their mechanism of actions. Vancomycin inhibits cell wall synthesis of bacteria by preventing the cell wall component of bacteria, peptidoglycan, from elongating and cross-linking. With weakened peptidoglycan, the bacterial cell becomes susceptible to lysis. Lipoglycopeptides, additionally, can increase the membrane permeability of the bacterial cell and disrupt the bacterial cell membrane potential. This class of antibiotics can be used to treat skin or joint infections, where gram-positive bacteria are the pathogens responsible. Vancomycin is also used as an initial empirical treatment agent of community-acquired bacterial meningitis in locations where penicillin-resistant S. pneumoniae is common. This drug has other clinical uses, including endocarditis and respiratory tract infections caused by Methicillin-resistant Staphylococcus aureus (MRSA). Case reports suggested that long-term use of vancomycin has been associated with ototoxicity. However, there is no well-established causal link between vancomycin and ototoxicity. For instance, preclinical studies showed that vancomycin had a low risk of inducing ototoxicity. Despite these findings, literature generally agreed that pre-existing hearing abnormalities, concomitant use of aminoglycosides and renal dysfunction are risk factors for vancomycin-induced ototoxicity.
Chemotherapeutic agents Chemotherapeutic agents are drugs that are used in chemotherapy for the treatment of cancer. Many of these agents are known to have the potential to cause hearing loss. Such agents include cisplatin and bleomycin.
Cisplatin
Cisplatin is known as a platinum coordination complex. Carboplatin and oxaliplatin also belong to platinum coordination complexes, but they are less commonly associated with ototoxicity. These agents are used in the treatment of ovarian, head and neck, bladder, lung and colon cancers. Cisplatin and other platinum coordination complexes work by reacting with various sites on DNA in mainly cancer cells in order to form cross-links. The formed DNA-platinum complexes inhibit replication and transcription, leading to miscoding and cell death. The mechanism of cisplatin in inducing ototoxicity is believed to involve the accumulation of reactive oxygen species, which exert cytotoxic effect on cochlear cells. Some pharmacogenetics research have opened up new perspectives on the contributing factors of cisplatin-induced ototoxicity. They investigated several cancer-inducing genes and genetic polymorphisms. Results showed that some genes are associated with protective effect on ototoxicity, while others may show no effect or even increased effect on ototoxicity.
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