THE INFLUENCE OF DRUGS IN THE VESTIBULOCOCHLEAR SYSTEM IN CHILDHOOD. A special focus on the mechanism of injury

Dr. Paulo Liberalesso. Department of Neurology, Hospital Pequeno Príncipe, Curitiba, Brazil.
Coordinator of Digital EEG Laboratory, Hospital da Cruz Vermelha, Curitiba, Brazil..

Ototoxicoses are iatrogenic diseases caused by drug administration, compromising the auditory function and / or the vestibular system. The ototoxicoses are characterized by neurossensorial hearing loss of more than 25 dB in one or more frequencies in the range of 250 to 8000 Hz, with or without symptoms of dizziness and imbalance. There are numerous drugs with ototoxic capacity and diverse are the mechanisms of injury of the auditory and vestibular system.

The causes of hearing loss in childhood can be divided into two main groups: genetic and nongenetic. The major genetic causes of hearing loss are Treacher-Collins syndrome, Crouzon, Alpert, Usher, Klippel-Feil syndrome, Alport, Hurler, Pendred, Hunter, Edwards, Waardenburg, Down syndrome and osteogenesis imperfecta.

The main nongenetic causes of hearing loss in children can be divided into: (a) prenatal (maternal infection by the rubella virus, CMV, syphilis, herpes and toxoplasmosis, radiation during pregnancy, maternal therapy with ototoxic drugs); ( b) perinatal (prematurity, jaundice, anoxia, birth trauma, use of ototoxic drugs) and (c) post-natal (ear infections, bacterial meningitis, viral encephalitis, measles, mumps, diabetes, ototoxic drugs, acoustical trauma, otosclerosis, tumor of the auditory nerve).

In intensive care units for newborns, the diseases most frequently observed are prematurity, severe jaundice, meconium aspiration, severe hyaline membrane disease, neonatal convulsions, neonatal asphyxia, complications related to birth trauma, neonatal sepsis, necrotizing enterocolitis and surgical diseases. Moreover, the drugs most commonly used in intensive care units for newborns are surfactant, dopamine, dobutamine, ampicillin, gentamicin, amikacin, cefepime, cefazolin, vancomycin, furosemide, amphotericin. Except for the first three medications (surfactant, dopamine and dobutamine) all others can be ototoxic.

In pediatric intensive care units (for children after the first month of life), the most frequently diseases are pneumonia, asthma, diarrhea, severe allergic reactions and complications of surgical diseases. In these units, medications most commonly used are dipyrone, paracetamol, drugs for vomiting, fenoterol, crystalline penicillin, ampicillin, gentamicin, amikacin, chloramphenicol, cephalosporins (third and fourth generation) and vancomycin. Of all these medications, ampicillin, gentamicin, amikacin, chloramphenicol, cephalosporins and vancomycin can be ototoxic.

Currently, in Brazil, there are more than 130 proven ototoxic drugs. Among the best known and most used are the antineoplastic agents (for example cisplatin, carboplatin, carmustine, cyclophosphamide, doxorubicin, melphalan, mitomycin, mechlorethamine, paclitaxel, fluorouracil), antibiotics (amikacin, gentamicin, erythromycin, tobramycin, neomycin, chloramphenicol, cephalosporins, nalidixic acid, vancomycin, ampicillin, polymyxin, colistin, actinomycin, streptomycin, lincomycin), diuretics (furosemide, indapamide, bumetanide), antihypertensives (propranolol, practolol), anti-inflammatory drugs (sodium salicylate, quinine, ibuprofen, indomethacin) and disinfectants (chlorhexidine, benzalkonium chloride, iodine, ethanol, propylene glycol). Several of these medications mentioned are among the most widely used within hospitals.

Ototoxic drugs can cause lesions in different topographies. Diuretics, salicylates and cisplatin can cause injury to the stria vascularis. The amikacin, neomycin, streptomycin, kanamycin, cisplatin and salicylates may cause injury to ciliar cells. Streptomycin, gentamicin and sisomicin can cause injury directly to the vestibular system.

We do not know how many people have symptoms caused by ototoxic drugs each year around the world. The FDA (Food and Drug Administration) has not evaluated whether a new drug is ototoxic before approving its use for the population. Thus, the ototoxicity of new drugs is only detected when a sizable amount of people already showing signs and symptoms of change in the auditory and / or vestibular system.

The main risk factors for ototoxicity are the high serum levels of medication, deficiency on renal and / or hepatic function, concurrent use of potentially ototoxic drugs, high dose of medication, long-term treatment, age (younger children and the elderly), adverse health conditions, hereditary factors that increase the risk of injury to the auditory and vestibular system, previous exposure to noise, neurosensorial hearing loss prior, patients with tinnitus and malnutrition.

It is important to remember that every time we use ototoxic drugs, especially in children with risk factors for injury to the vestibulocochlear system, we must monitor the level of serum medicine, because some drugs even when administered intravenously may have a higher level in cochlear liquid than in his own blood. Another important aspect is that when estimating the serum levels based exclusively on the dose of medication, there is a margin of error of up to 20%.

Another important aspect that we must always remember is about the patients age: the younger child (especially in newborns) and elderly (particularly after the sixth decade of life) the risk of ototoxicity is much higher. We must also remember that during pregnancy, many drugs administered to the mother cross the placenta and indirectly affect the fetus. Fetuses are very sensitive the toxicity of drugs due to immaturity of their vestibulocochlear system.

Cisplatin:
Cisplatin is used as a model for the study of ototoxicity. It is a drug with high antitumor activity, particularly in tumors of the testis and ovary, carcinoma of the head and neck, prostate and bladder. Preliminary data indicate that cisplatin is also active in sarcomas, lymphomas, lung cancer, esophageal cancer, thyroid cancer, neuroblastoma and malignant melanoma.

Cisplatin was identified in 1965 and is used from 1990 as a chemotherapeutic agent. Although it is a drug used for many years, the mechanisms of ototoxicity of cisplatin are not fully known. Initial studies of Harder and Rosenberg in the 1970s showed that the chloride ion in the intracellular environment favored the reaction of platinum with cellular DNA.

For many years it was believed that the mechanisms of cochlear cells injury were mediated by changes in pump sodium-potassium-ATPase, as occurs in cisplatin-induced nephrotoxicity. However, Barron and Daigneault in 1987 showed that in the cells of the cochlea no changes occur in the pump sodium-potassium-ATPase. The molecule of cisplatin inhibits DNA synthesis “in vitro” and “in vivo”, acting in the “S” phase of the cell cycle (during the “S” phase occurs the synthesis of nuclear DNA). In patients with cancer, cisplatin interacts with the DNA of cancer cells forming the cisplatin-DNA complex and thus inhibiting DNA synthesis.

There is evidence that cisplatin can trigger cochlear injury only and not cause injury on the vestibular system. When administered to children, cochlear toxicity of cisplatin varies between 50 to 90%. Mc Alpine and Johnstone in 1990 proved, using techniques of iontophoresis, that hearing loss caused by cisplatin was related to a blockage of ionic channels of ciliar cells and, consequently, a block of mechano-electrical transduction. These authors did not explain exactly how this blockage occurred.

Studies with microscopic analysis showed that in humans the most frequently reported alterations in the auditory system resulting from the use of cisplatin are located in inner and outer ciliar cells, cochlear neurons, stria vascularis and supporting cells of the organ of Corti (or spiral organ). The loss of cells occurs from the base to the apex and the first to the third row of ciliar cells, outer ciliar cells and finally the inner ciliar cells.

In addition to causing changes in cellular DNA, cisplatin can also cause damage to the cell energy system (mitochondrial system) and in the endoplasmic reticulum. These changes may cause loss of stereocilia. The biochemical mechanism of cochlear ototoxicity induced by cisplatin is, probably, the production of free radicals, interference on the antioxidant defense system of the cochlea and the production of proteins of the family of bcl-2 gene that controls apoptosis.

free radicals:

The electron shell of a chemical element are called K, L, M, N, O, P, Q and their sublevels s, p, d, f. The number of electrons in the last layer must always be aware for the element is stable. If there is a reduction reaction (characterized by the gain of electrons) or an oxidation reaction (characterized by loss of electrons) the number of eltrons in the last layer is odd. This new element (after the reactions of reduction or oxidation) becomes a free radical. Quite simply, free radical refers to an atom or a molecule highly reactive that contains an odd number of electrons in its last electronic layer. It is this odd number of electrons in the last layer which confers high reactivity to these elements.

The vast majority of free radical are derived from the oxygen metabolism. In physiological conditions, the cellular aerobic metabolism oxygen undergoes tetravalent reduction to accept 4 electrons leading to the formation of water. During this process free radical is formed, such as superoxide radicals, hidroperoxila, hydroxyl and hydrogen peroxide. Under normal conditions the tetravalent reduction of oxygen occurs within the mitochondria and free radical is neutralized in the same place.

All cellular components are susceptible to the action of free radicals, but the cell membranes are the most affected by the phenomenon of lipid peroxidation, which causes changes in the structure and hence the permeability of cell membranes, altering the ion exchange, leading to release of enzymes hydrolytic lysosomes and culminating in cell death. Lipid peroxidation can occur during natural aging, cancer and toxicity induced by xenobiotics. (Note – xenobiotics are substances which, under physiological conditions, are not produced by the human body and therefore must come from the external environment, such as the drugs).

Cellular antioxidant system

As free radicals are constantly produced in our body, there is a system (the cellular antioxidant system) that also works constantly. While there is a balance between free radical production and operation of the antioxidant system, cell function occurs normally. When some factor increases the production of free radicals, such as the administration of a drug, shall be an excessive amount of free radicals that the cellular antioxidant system is not capable of inactivating, leading to oxidative stress. Oxidative stress is responsible for cell injury law.

To protect against ototoxic drugs the cells of the human body have two defense system. One defense system acts as the agent detoxified before it causes damage to the cell and this system consists of superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), catalase, ceruloplasmin and vitamin E. The other defense system operates repairing the cells that have been damaged by ototoxic drugs, and are part of the system ascorbic acid, glutathione reductase (GSH-Rd) and glutathione peroxidase (GSH-Px).

Antioxidants are substances composed of small molecules that modify the action of free radicals significantly reducing or inactivating the cell injury induced by them. The antioxidant system is composed of small molecules located in the membrane, cytoplasm, and numerous enzymes that participate in the process of oxidation and reduction. The small molecules of the antioxidant system include vitamin C, vitamin E, beta-carotene, glutathione peroxidase, superoxide dismutase and ascorbic acid.

The mechanism of acute injury of cochlear cells occurs through the phenomenon of lipid peroxidation, as previously discussed, and that leads to death of ciliar cells of the cochlea. However, to a mechanism called "subacute mechanism of injury” in which free radicals interact with proteins that make up the mitochondrial DNA leading to complete destruction of mitochondrial DNA or mitochondrial DNA mutations that make the cell energy inactive and trigger the death this cell by energy deficit. The reduction in energy production by mitochondria tends to increase the production of free radical oxygen leading to more cell death and perpetuating the cycle of injury.

ototoxicity induced by aminoglycosides

Aminoglycosides are antibiotics that act against Gran-negative bacteria, and act against tuberculosis and brucellosis. This antibiotic penetrates the cell wall leading to error in the reading of messenger RNA killing bacteria. Importantly, the aminoglycosides are drugs which are not metabolized and are excreted almost exclusively by the kidneys. The concentration in urine can reach levels up to 10 times higher than the levels of the drug in the blood. Thus, children who have impaired renal function may suffer accumulation of aminoglycosides in the blood and tissues, causing ototoxicity. Thus, the dose of aminoglycoside must be adjusted according to the renal function of each child.

Aminoglycosides cross the placental barrier leading to higher levels in the fetus between 30 and 50% of maternal serum. Thus, the use of aminoglycosides in pregnant women increases the risk of injury to the vestibulocochlear system in the fetus and increases the risk of congenital malformations such as cleft palate, skeletal malformations, eye malformations, malformations of the cardiovascular system, genitourinary system and gastrointestinal tract.

Cochlear lesions caused by aminoglycosides are well studied in the literature, but do not know exactly why they occur obeying a certain progression of injury. The progression of injury occurs as follows: (1) inner layer of outer ciliar cells; (2) middle layer of the outer ciliar cells; (3) the outer layer of the outer ciliar cells; (4) only after most of the outer ciliar cells were destroyed is that starts the destruction of the single layer of inner hair cells. With progression of the toxic assault, other cells become committed to supporting cells, cells of stria vascularis and in the end, the nerve cells.

In the vestibular system, ciliar cells are also destroyed by aminoglycosides. Ciliar cells type I are more damaged than the ciliar cells type II. Injury can also occur in otoliths, since studies show reduction in the number of otoliths in the saccule and utricle.

Usually, the first symptom of cochlear injury induced by aminoglycosides is tinnitus (usually of high frequency and continuous), followed by hearing loss, beginning with higher frequencies and then goes to the lower frequencies. The vestibular lesions induced by aminoglycosides usually manifested by dizziness, nausea and vomiting, and with increasing severity of injury can occur oscillometric (feeling objects jumping around the body triggered by head movement).

ototoxicity induced by Erythromycin

Erythromycin is an antibiotic class of macrolide and ototoxicity is very uncommon. The mechanisms of injury induced by erythromycin is not known.  Its main feature of the lesion induced by erythromycin is that as the frequency of human speech are compromised early. Thus, the complaint of hearing loss starts very early, unlike the case with the aminoglycosides, the complaint of hearing loss begins later.

ototoxicity induced by VANCOMICIN

Both studies in experimental animals and humans is not clear the ototoxic effects of vancomycin. However, possibly the vancomycin is a medication that has low ototoxicity. In the studies that showed that its ototoxicity was high, usually the patients had combined use of aminoglycosides. Currently, several authors believe that vancomycin enhances the ototoxic effects of aminoglycosides.

ototoxicity induced by LOOP DIURETICS

The representative of this group of drugs most used in our country is furosemide. The incidence of ototoxicity of furosemide is 6.4% and hearing loss is usually transient and fully reversible. The mechanism of injury (pathogenicity) is the change of potassium transport in cells of stria vascularis of the cochlea. There is a biochemical interaction between loop diuretics and aminoglycosides, so that loop diuretics increase the entry of aminoglycosides in the inner ear, increasing considerably the ototoxicity of aminoglycosides.

ototoxicity induced by SALICYLATE

Aspirin is one of the drugs most used around the world and can cause hearing loss in all frequencies. The mechanism of injury is likely to decrease blood flow to the outer ciliar cells. The reversal of hearing loss is usually complete in 2 to 3 days after discontinuation of medication. However there are cases of permanent hearing loss.

CORTICOSTEROIDS:
The ototoxic effect of corticosteroids is debatable. We do not know the exact incidence of ototoxicity related to this medication, do not know of the possible mechanisms of action and it is unclear whether corticosteroids increase the toxic effects of other drugs.

cochlear mechanisms of self-defense

In 1997, Stengs et al. showed that after injection of cisplatin at a dose of 1.5 mg / kg / day for 8 consecutive days, following the animals with electrophysiological testing, from the eighth week passed occur (a) a progressive improvement electrophysiological examinations, (b) formation of new ciliar cells and (c) repair of damaged ciliar cells. These aspects were observed by means of examinations light microscopy. The data observed by these authors suggest a capacity for spontaneous recovery of damaged ciliar cells, so there are a mechanism for self-defense. The exact mechanism of operation of self-defense system of the cochlea is not fully understood until now.

Otoprotective drugs

Agents otoprotectors been well studied in animal models, but need to be tested in a safe and effective in humans. While studies in animal models show promising results regarding the otoprotection, the only drug tested clinically otoprotective showed unsatisfactory results.

Drugs with the highest level of evidence for otoprotection are thiols (sulfur compounds), metal chelators that act as carriers of intracellular free radicals (sodium thiosulfate and D-methionine). Many of these drugs significantly reduce the main effect of the drug (eg anti-tumor effect). It is very important to consider this aspect because it may influence the efficacy of anticancer treatment.

Some drugs have been used in humans in an attempt to achieve a protective effect for the auditory and vestibular system, such as fosfomycin, sodium thiosulfate, diethyldithiocarbamate, derivatives of melanocortins, D-methionine, L-methionine, L-N –acetylcysteine, sodium salicylate and extract of Ginkgo Biloba.

In conclusion, the main strategies for otoprotection are: (a) prevent the formation of free radicals; (b) reverse the binding of toxic agent with cellular proteins, lipids or DNA; (c) inhibit the production of lipid peroxidation products; (d) use of chelating exogenous free radicals; (e) changes the pH of the cochlea and the fluid coleares and (f) use of a viral vector (HSVnt-3myc/SV40 lac) to inhibit apoptosis.

This text was prepared for a lecture given by Dr. Paulo Liberalesso in the International Symposium on Communication Disorders, held in Curitiba, Brazil, in November 2009.

Recommended reading

Kasse CA, Hyppolito MA, Cruz OLM, de Oliveira JAA. Ototoxicidade e otoproteção. RBM ORL 2008; 3(4): 105-15.

Stengs CHM, Klis SFL, Huizing EH, Smoorenburg GF. Cisplatin-induced Ototoxicity: electrophysiological evidence of pontaneous recovery in the albino guinea pig. Hear Res. 1997 11(1-2):103-113.

Rybak LP, Kelly T. Ototoxicty: bioprotective mechanisms. Otolaryngol Head Neck Surg. 2003 11:328-333.

Mcalpine D & Johnstone BM. The ototoxic mechanism of cisplatin. Hear Res. 1990 47(3):191-203.

Dehne N, Lautermann J, Petrat F, Rauen U, de Groot, H. Cisplatin ototoxicity: involvement of iron and enhanced formation of superoxide anion radicals. Toxicol Appl Pharmacol. 2001 174(1):27-34.

Stengs CHM, Klis SFL, Huizing EH, Smoorenburg GF. Cisplatin-induced Ototoxicity: electrophysiological evidence of pontaneous recovery in the albino guinea pig. Hear Res. 1997 11(1-2):103-113.

Sastry J & Kellie SJ. Severe neurotoxicity, ototoxicity and nephrotoxicity following high-dose cisplatin and aminofostine. Pediatr Hematol Oncol. 2005 22(5):441-445.