User:BazzerAHightower/Ototoxicity

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Ototoxicity is the property of being toxic to the ear (oto-), specifically the cochlea or auditory nerve and sometimes the vestibular system (balance and spatial orientation), for example, as an unwanted side effect of a drug. The effects of ototoxicity can be reversible and temporary, or irreversible and permanent depending on the substance, exposure time, exposure dosage, and genetic predispositions. It has been recognized since the 19th century. There are many well-known ototoxic drugs used in clinical situations, and they are prescribed, despite the risk of hearing disorders, for very serious health conditions. Ototoxic drugs include antibiotics (such as gentamicin, streptomycin, tobramycin), loop diuretics (such as furosemide), and platinum-based chemotherapy agents (such as cisplatin and carboplatin). A number of nonsteroidal anti-inflammatory drugs (NSAIDS) have also been shown to be ototoxic. This can result in sensorineural hearing loss, disequilibrium (feeling of unsteadiness or lack of balance), or both. Some environmental and occupational chemicals have also been shown to affect the auditory system and interact with noise to produce additional adverse effects.

Signs and symptoms[edit]
Symptoms of ototoxicity include partial or profound hearing loss, vertigo, and tinnitus.

The cochlea is primarily a hearing structure situated in the inner ear. It is the snail-shaped shell containing several nerve endings that makes hearing possible. It is lined with hair cells that intercept vibrations in the cochlear fluid from the interaction of the ossicles(inner-ear bones) and the tympanic membrane(eardrum), and transmit them to the auditory nerves. Damage to these hair cells, which causes them to "lay down" rather than be erect to receive signals, is what causes hearing cochlea-related hearing loss. Ototoxicity typically results when the inner ear is affected by medication that damages the cochlea, vestibule, semi-circular canals, or the auditory/ vestibulocochlear nerve. The damaged structure then results in the symptoms the patient presents with. Ototoxicity in the cochlea may cause hearing loss of the high-frequency pitch ranges or complete deafness, or losses at points between. It may present with bilaterally symmetrical symptoms, or asymmetrically. '''A symmetrical development indicates that both ears develop symptoms at around the same rate. Asymmetrical development would be if they developed symptoms at different times and rates, or if only one ear developed symptoms. The rate at which symptoms of the condition progress''' vary greatly and symptoms of hearing loss may be temporary or permanent.

The vestibule and semi-circular canal are inner-ear components that comprise the vestibular system. Together, they detect movement of the head in any direction. Two types of otolith organs are housed in the vestibule: the saccule, which points vertically and detects vertical acceleration, and the utricle, which points horizontally and detects horizontal acceleration. The otolith organs together sense the head's position with respect to gravity when the body is static; the head's movement when it tilts; and pitch changes during any motion of the head. The brain receives the information from the saccule an utricle and integrates it to determine where the head is and how and where it is moving.

The semi-circular canals are three bony structures filled with fluid. As with the vestibule, the primary purpose of the canals is to detect movement. Each canal is oriented at right angles to the others, enabling detection of movement in any plane. The posterior canal detects rolling motion, or motion about the X axis; the anterior canal detects pitch, or motion about the Y axis; the horizontal canal detects yaw motion, or motion about the Z axis. When a medication is toxic in the vestibule or the semi-circular canals, the patient senses loss of balance or orientation rather than losses in hearing. Symptoms in these organs present as vertigo, difficulties walking in low light and darkness, disequilibrium, oscillopsia(the sensation that the surrounding environment is constantly in motion when it is, in fact, stationary) among others. Each of these problems is related to balance and the mind is confused with the direction of motion or lack of motion. Both the vestibule and semi-circular canals transmit information to the brain about movement. When these are effected, they are unable to function properly which results in miscommunication with the brain.

When the vestibule and/or semi-circular canals are affected by ototoxicity, the eye can also be affected. Nystagmus (a vision condition in which the eyes make repetitive, uncontrolled movements) and oscillopsia are two conditions that overlap the vestibular and ocular systems. These symptoms cause the patient to have difficulties with seeing and processing images. The body subconsciously tries to compensate for the imbalance signals being sent to the brain by trying to obtain visual cues to support the information it is receiving. This results in that dizziness and "woozy" feeling patients use to describe conditions such as oscillopsia and vertigo.

Cranial nerve VIII is the least affected component of the ear when ototoxicity arises, but if the nerve is affected, the damage is most often permanent. Symptoms present similar to those resulting from vestibular and cochlear damage, including tinnitus, ringing of the ears, difficulty walking, deafness, and balance and orientation issues.

Ototoxic agents[edit]
Main article: Ototoxic medication

Antibiotics[edit]
Antibiotics in the aminoglycoside class, such as gentamicin and tobramycin, may produce toxic effects on the cochlea through a poorly understood mechanism. It may result from antibiotic binding to NMDA receptors in the cochlea and damaging neurons through excitotoxicity. Aminoglycoside-induced production of reactive oxygen species may also injure cells of the cochlea. Once-daily dosing and co-administration of N-acetylcysteine may protect against aminoglycoside-induced ototoxicity. The anti-bacterial activity of aminoglycoside compounds is due to inhibition of ribosome function and these compounds similarly inhibit protein synthesis by mitochondrial ribosomes because mitochondria evolved from a bacterial ancestor. Consequently, aminoglycoside effects on production of reactive oxygen species as well as disruption of the regulation of cellular calcium ion homeostasis may result from disruption of mitochondrial function. Ototoxicity of gentamicin can be exploited to treat some individuals with Ménière's disease by destroying the inner ear, which stops the vertigo attacks but causes permanent deafness. Due to the effects on mitochondria, certain inherited mitochondrial disorders result in increased sensitivity to the toxic effects of aminoglycosides.

Macrolide antibiotics, including erythromycin, are associated with reversible ototoxic effects. The underlying mechanism of ototoxicity may be impairment of ion transport in the stria vascularis (cochlear capillary). Predisposing factors include renal impairment (kidney damage), hepatic impairment (liver damage), and recent organ transplantation. '''This is due to macrolides mechanism of action, the inhibition of protein synthesis. A damage or stressed liver or kidneys cannot properly filter blood. Improper filtration of the blood allows the antibiotics to reach the cochlea and other parts of the ear, where the damage is done. Exposure to macrolide antibiotics comes primarily from being prescribed the medicine through its use in pharmacotherapy(therapeutic use of drugs to treat a condition)'''

Loop diuretics[edit]
'''Diuretics are medicines that reduce fluid buildup in the body. Loop diuretics do this by binding to and affecting the Loop of Henle in the nephrons of the kidneys.''' Certain types of diuretics are associated with varying levels of risk for ototoxicity. Loop and thiazide diuretics carry this side effect. The loop diuretic furosemide is associated with ototoxicity, particularly when doses exceed 240 mg per hour. The related compound ethacrynic acid has a higher association with ototoxicity, and is therefore used only in patients with sulfa allergies. Diuretics are thought to alter the ionic gradient within the stria vascularis. Bumetanide confers a decreased risk of ototoxicity compared to furosemide. Exposure to loop diuretics comes primarily through their prescribed use to tread medical conditions.

Treatments for Multi-Drug Resistant Tuberculosis

'''Second-line injectable drugs used to treat multidrug-resistant tuberculosis, such as amikacin, capreomycin and kanamycin, are advised against use due to their ototoxic effects. Even though hearing loss is no longer thought to be entirely avoidable when treating multi-drug resistant tuberculosis, hundreds of thousands of cases of hearing loss are attributed each year to these drugs. Nephrotoxicity, toxicity to the kidneys, has also been linked to the regimented use of these drugs'''. '''Also, there are no international standards in effect or enforcement to limit use of therapeutic drugs with ototoxic effects. Exposure to these drugs is also primarily through their prescribed use by medical professionals .'''

Chemotherapeutic agents[edit]
Platinum-containing chemotherapeutic agents, including cisplatin and carboplatin, are associated with cochleotoxicity characterized by progressive, irreversible, high-frequency hearing loss with or without tinnitus (ringing in the ears). Ototoxicity is less frequently seen with the related compound oxaliplatin. The severity of cisplatin-induced ototoxicity is dependent upon the cumulative dose administered and the age of the patient, with young children being most susceptible. The exact mechanism of cisplatin ototoxicity is not known. The drug is understood to damage multiple regions of the cochlea, causing the death of outer hair cells, as well as damage to the spiral ganglion neurons and cells of the stria vascularis. Long-term retention of cisplatin in the cochlea may contribute to the drug's potential to damage and cause toxicity to the cochlea. Once inside the cochlea, cisplatin has been proposed to cause cellular toxicity through a number of different mechanisms, including through the production of reactive oxygen species. '''Cisplatin also is known to cause genotoxic effects such as double linkages between base pairs along the chromosomes, thereby causing difficulty for the cells of the cochlea to heal correctly. This increases chances of negative genotypical consequences, which translates to deafness and other forms of ototoxicity'''. The decreased incidence of oxaliplatin ototoxicity has been attributed to decreased uptake of the drug by cells of the cochlea. Administration of amifostine has been used in attempts to prevent cisplatin-induced ototoxicity, but the American Society of Clinical Oncology recommends against its routine use. Similarly, sodium diethyldithiocarbamate, and intratympanic therapy should not be used to reduce ototoxicity caused by cisplatin infusions. It is also suggested that cisplatin infusion schedules should not be altered or lessened with the sole purpose of lessening the chance of harmful ototoxicity .

The vinca alkaloids, including vincristine, are also associated with reversible ototoxicity. '''Vinca Alkaloids are drugs that are used primarily to stop mitosis. They are used accordingly to slow and prevent the division and spread of cancerous cells .'''

'''A cross-disciplinary study has proposed strong evidence that sodium thiosulfate, when administered responsibly, could potentially help limit the development and proliferation of non-metastatic hepatoblastoma in children. The same study recommended that sodium thiosulfate not be used to limit the development of metastatic cancers .'''

Antiseptics and disinfectants[edit]
Topical skin preparations such as chlorhexidine and ethyl alcohol have the potential to be ototoxic should they enter the inner ear through the round window membrane. This potential was first noted after a small percentage of patients undergoing early myringoplasty (surgery performed to repair a hole in the eardrum) operations experienced severe sensorineural hearing loss. It was found that in all operations involving this complication the preoperative sterilization was done with chlorhexidine. The ototoxicity of chlorhexidine was further confirmed by studies with animal models.

Several other skin preparations have been shown to be potentially ototoxic in the animal model. These preparations include acetic acid, propylene glycol, quaternary ammonium compounds, and any alcohol-based preparations. However, it is difficult to extrapolate or apply these results to human ototoxicity because the human round window membrane is much thicker than in any animal model.

Other medicinal ototoxic drugs[edit]
At high doses, quinine, aspirin and other salicylates may also cause high-pitch tinnitus and hearing loss in both ears, typically reversible upon discontinuation of the drug 's therapeutic use. Erectile dysfunction medications may have the potential to cause hearing loss. However the link between erectile dysfunction medications and hearing loss remains uncertain.

Previous noise exposure has not been found to worsen or compound ototoxic hearing loss. The American Academy of Audiology includes in their position statement that exposure to noise at the same time as aminoglycosides may worsen ototoxic effects of the aminoglycosides. The American Academy of Audiology recommends people being treated with ototoxic chemotherapeutics avoid excessive noise levels during treatment and for several months following cessation of treatment. Opiates in combination with excessive noise levels may also have an additive effect on ototoxic hearing loss.

Ototoxicants in the environment and workplace[edit]
Ototoxic effects are also seen with quinine, pesticides, solvents, asphyxiants, and heavy metals such as mercury and lead. When combining multiple ototoxicants, the risk of hearing loss increases. As these exposures are common, hearing impairment and loss can affect many occupations and industries. Examples of activities that often have exposures to both noise and solvents include:

Observed effects/symptoms of occupational exposure to ototoxicants include :
 * Printing
 * Painting
 * Construction
 * Fueling vehicles and aircraft
 * Firefighting
 * Weapons firing
 * Pesticide spraying


 * Compressed loudness: sound distortion.
 * Frequency resolution: the inability to differentiate two sounds with similar frequency.
 * Temporal resolution: the inability to detect time gaps between sounds.
 * Spatial resolution: the inability to localize sound

Industries where ototoxic chemicals are widely present:


 * Fabricated metal
 * Machinery
 * Leather and Allied Product
 * Textile and Apparel
 * Petroleum
 * Paper
 * Chemical (including Paint)
 * Plastics
 * Furniture and Related Product
 * Transportation Equipment (e.g. Ship and Boat Building)
 * Electrical Equipment, Appliance and Component (e.g., Batteries)
 * Solar Cell

Ototoxic chemicals in the environment (from contaminated air or water) or in the workplace interact with mechanical stresses on the hair cells of the cochlea in different ways. For mixtures containing organic solvents such as toluene, styrene or xylene, the combined exposure with noise increases the risk of occupational hearing loss in a synergistic manner. The risk is greatest when the co-exposure is with impulse noise. Carbon monoxide has been shown to increase the severity of the hearing loss from noise. Given the potential for enhanced risk of hearing loss, exposures and contact with products such as fuels, paint thinners, degreasers, white spirits, exhaust, should be kept to a minimum. Noise exposures should be kept below 85 decibels, and the chemical exposures should be below the recommended exposure limits given by regulatory agencies.

Drug exposures mixed with noise potentially lead to increased risk of ototoxic hearing loss. Noise exposure combined with the chemotherapeutic cisplatin puts individuals at increased risk of ototoxic hearing loss. Noise at 85 dBA Sound Pressure Level or above added to the amount of hair cell death in the high frequency region of the cochlea in chinchillas. A similar effect has been seen in the mid to high frequency range of the human cochlea at 90 dBA Sound Pressure Level without an exposure to platinum-containing compounds.

The hearing loss caused by chemicals can be very similar to a hearing loss caused by excessive noise. A 2018 informational bulletin by the US Occupational Safety and Health Administration (OSHA) and the National Institute for Occupational Safety and Health (NIOSH) introduces the issue, provides examples of ototoxic chemicals, lists the industries and occupations at risk and provides prevention information.

'''In many cases, the adverse effects of noise exposure in the workplace or in daily life is potentiated(made worse) by exposure to ototoxic substances. Similarly, ototoxic effects are potentiated by exposure to loud noises. Persons who work in industries where noise exposure and ototoxic substances are present are at significant more risk of occupational hearing loss than employees that work in industries with exposure to excessive noise or ototoxic substances .'''

Additionally, '''hearing loss of any kind is hazardous in the workplace due to its hampering effect on proper communication. Many industries rely on verbal or noise-based communication to ensure safety cooperation and optimize workplace efficiency and safety and health. Workers in these industries are more at risk of industrial accidents due to rapidly changing circumstances. There is also growing concern among health and safety professionals that the effects of ototoxicity in the workplace since it is difficult to assign a cause to occupational hearing loss. This is due to the presence of exposures to both ototoxic substances as well as exposures to excessive noise .'''

Treatment[edit]
No specific treatment may be available, but withdrawal of the ototoxic drug may be warranted when the consequences of doing so are less severe than those of the ototoxicity. Co-administration of anti-oxidants may limit the ototoxic effects. '''Treatment poses a significant challenge because ototoxic effects of toxins are localized on the nerve cells and the hair cells of the cochlea, which transmit information to the auditory nerve. Nerve cells, once damaged, are notoriously difficult, in many cases impossible, for the body to heal .'''

Ototoxic monitoring during exposure is recommended by the American Academy of Audiology to allow for proper detection and possible prevention or rehabilitation of the hearing loss through a cochlear implant or hearing aid. Monitoring can be completed through performing otoacoustic emissions testing or high frequency audiometry. Successful monitoring includes a baseline test before, or soon after, exposure to the ototoxicant. Follow-up testing is completed in increments after the first exposure, throughout the cessation of treatment. Shifts in hearing status are monitored and relayed to the prescribing physician to make treatment decisions.

It is difficult to distinguish between nerve damage and structural damage due to similarity of the symptoms. Diagnosis of ototoxicity typically results from ruling out all other possible sources of hearing loss and is often the generalized explanation for all symptoms. Treatment options vary depending on the patient and the diagnosis. Some patients experience only temporary symptoms that do not require drastic treatment while others can be treated with medication. Physical therapy may prove useful for regaining balance and walking abilities. Cochlear implants are sometimes an option to restore hearing. Such treatments are typically taken to comfort the patient, not to cure the disease or damage caused by ototoxicity. There is, as of yet, no cure or restorative treatment if the cochlear or hair cell damage becomes permanent. Cochlear nerve terminal regeneration has been observed in chickens, which suggests that there may be a way to accomplish this in humans with further research and development.