Ototoxicity

Ototoxicity

1. OTOTOXICITY Presented by DR.R.LATHIKA, MS ENT IIyr Post Graduate . Chapter : 59 Volume :2 Pages :721- 737

2. INTRODUCTION The term ototoxicity is used to refer to the process by which a number of therapeutically useful drugs, certain environmental agents such as industrial solvents, and bacterial toxins cause damage to the peripheral end-organs of hearing and balance. hearing impairment or balance dysfunction through primary action on the respective neural pathways and centres .

3. MODES OF ENTRY OF OTOTOXIC AGENTS TO THE INNER EAR BACTERIAL TOXINS Potentially, bacterial toxins associated with middle ear infections as well as ototoxic drugs may enter the inner ear across the round window. There is evidence that some children who have had otitis media with effusion (OME) may develop extended high-frequency hearing loss , i.e. with a normal audiogram down to about 8 kHz but with significant threshold shifts at higher frequencies loss of both inner and outer hair cells in the most basal regions of the cochlea and this is caused by bacterial endotoxins released in the middle ear effusion crossing the round window membrane to access the basal coils of the cochlea

4. Access to perilymph The permeability properties that determine what will and will not cross these membranes into the inner ear are not known. Access to perilymph is also possible from the middle ear cavity via the membrane covering the round window at the base of the cochlea and that filling the oval window over the vestibule. Access to the perilymphatic compartment of the inner ear via the cochlear aqueduct from (CSF) is possible and this may be a route of entry for bacterial toxins, such as those associated with meningitis.

5. The entry of aminoglycoside antibiotics applied to the middle ear cavity across the round and oval window membranes into the perilymphatic spaces of the inner ear is used as a clinical procedure to ablate hair cells in the vestibular system in cases of severe balance dysfunction in unilateral Meniere’s disease

6. Blood–perilymph barrier Perilymph is not simply an ultrafiltrate of blood plasma, nor does it derive from CSF. The composition of perilymph is different both from CSF and from blood plasma and the composition of perilymph in scala vestibuli differs from that in scala tympani . This indicates that perilymph is produced and circulated locally. Glucose entry, for example, requires facilitated diffusion through glucose transporters Entry to endolymph in the internal compartment of the inner ear is even more restricted and endolymph composition is tightly controlled

7. TIGHT JUNCTIONS -COCHLEA The principal boundaries between endolymph and perilymph, f ormed by selectively permeable membranes and tight junctions between adjacent cells, in the cochlea appear to be Reissner’s membrane, at the level of the basal cells in the stria vascularis , and the network formed by the apical surfaces of the hair cells and adjacent supporting cells in the organ of Corti at the reticular lamina.

8. TIGHT JUNCTIONS-In the vestibular system Level of the tight junctions between hair and supporting cells in the sensory patches and between the epithelial cells that surround the endolymphatic , luminal spaces including Dark cells of the utricle and semicircular canals, the roofs of the utricle and saccule and the semicircular canals.

9. EFFECTS AND ACTIONS OF OTOTOXIC DRUGS The occurrence and extent of ototoxicity is to some extent dependent upon the dosing regime (or exposure conditions) . the status of the patient receiving the drug and multiple drug regimes. Stress produced by infection may increase sensitivity as may malnourishment; the effects of aminoglycosides are more pronounced in nutritionally deprived animals. Individuals under similar conditions and with similar drug-dosing regimes differ in their sensitivity to ototoxic side effects.

10. Drug interactions can also result in much greater damage than would be expected from single drug regimes. A number of ototoxic agents, including aminoglycosides, polypeptide antibiotics and anti- neoplastics , are also nephrotoxic . So that possible damage to the kidney may result in reduced drug clearance and higher serum levels potentially increasing the risk to the inner ear.

11. On this basis,ototoxins can be divided into three broad groups. FIRST - The‘loop ’ diuretics and erythromycin,have acute effects in the stria vascularis resulting in temporaryhearing loss ( temporary ‘threshold shift’ (TTS) SECOND -group, which includes salicylate and quinine, predominantly produce temporary impairment of hair cell function (TTS), often accompanied by tinnitus. These symptoms are completely relieved upon withdrawal of the drug. THIRD -most significant, group of ototoxic agents cause death of the hair cells and permanent hearing loss (permanent threshold shifts (PTS)) and vestibular dysfunction . Aminoglycoside antibiotics and cisplatin ( cis -platinum), as well as organic solvents, fall into this category The sensory epithelia in the inner ear in birds and other non-mammalian vertebrates,the organ of Corti does not spontaneously regenerate hair cells to replace those lost.

12. Agents affecting the ion-transporting epithelia LOOP DIURETICS- Agents whose primary site of action is on the iontransporting epithelia, the stria vascularis (SV) in the cochlea and the vestibular dark cells , adversely affect endolymph composition and, in the case of the SV, the endocochlear potential (EP). The SV has one the highest rates of oxidative metabolism in the body, with oxygen delivered from the intraepithelial blood supply so agents that induce anoxia or ischaemia will affect strial activity. Aminoglycoside antibiotics and cisplatin,may induce permanent strial pathologies although this does not necessarily correlate with effects on EP.

13. Loop diuretics Those diuretics whose principal site of action is in the ascending limb of the loop of Henle , including ethacrynic ( etacrynic ) acid, furosemide( frusemide ), bumetanide and piretanide , produce a transient hearing loss across most of the frequency range. The effects are rapid in onset, within minutes or hours, and persist for some hours but are usually completely resolved within a day if the drug is discontinued. However, a single dose of diuretic when administered closely with a single dose of an ototoxin such as aminoglycoside or cisplatin which has the potential to cause hair cell loss only after chronic repeated treatment, results in rapid devastatingly extensive hearing loss and hair cell death.

14. LOOP DIURETICS

15. Histological studies of the temporal bones from patients who have died while on diuretic treatment-have shown extensive oedema and swelling of the SV. This oedema is also reversible , resolving within about 2–4 hours, prior to complete recovery of EP. Reversible decline in EP , falling from the usual +80 mV to negative values as low as around -40 mV, the K+diffusion potential. The rapid onset of their effects suggests that diuretics gain direct access to their site of action through entry from the strial vasculature into the extracellular spaces of the SV .

16. The development of oedema suggests that diuretics inhibit the ion-transporting processes. Ions accumulating in the extracellular spaces would be confined by the tight junction sealing between basal cells, those between marginal cells and those between capillary endothelial cells,resulting in osmotic uptake of fluid

17. In the kidney, diuretics act on a Na/K/ Cl cotransporter . The same cotransporter , NKCC1, localizes to the basolateral membrane both of vestibular dark cells and of marginal cell of the SV and has been shown to be a target of the diuretics in the SV and vestibular dark cells. In the cochlea, the generation of EP is thereby inhibited and along its entire length such that the consequent hearing impairment resulting from reduction of cochlear amplification is across almost the entire frequency range. (There is no equivalent of EP in the vestibular system so the effects are less pronounced.)

18. Na+/K+-ATPase is also present at high concentration on the basolateral membrane of marginal cells . Inhibition of this might have a similar effect as inhibition of the cotransporter . Potassium cyanide , along with its other actions in the body, causes TTS with a symptomatology similar to that of loop diuretics, thought to result from inhibition of marginal cell Na+/K+-ATPase. Macrolide antibiotics such as erythromycin also produce effects similar to those of diuretics.

19. Agents causing reversible effects on hair cells SALICYLATES COMPLETELY REVERSIBLE Decrease outer hair cellwall stiffness and motility Can increase distortion product OAE. Diminish spontaneous OAE and elctromotility of OHC’s TTSs across most of the detectable frequency range, and tinnitus & dizziness. Affects the motor protein of OHC’s –PRESTIN by inhibiting the CL-ANIONS at anion binding site.

20. Quinine The ototoxic effects of salicylate and quinine thus derive from an ability to cross the blood–perilymph barrier freely. An effect of quinine at the hair cell synapse could also explain vertigo, with its Action at these efferent synapses . It has been found that quinine and its derivatives such as chloroquinine block nicotinic acetylcholine receptors ( nAChR ) Acetylcholine is the predominant efferent neurotransmitter in the cochlea. Primarily they are cochleotoxic Reversible vasculitis and ischemia Causing degenerative changes in stria vascularis and organ of corti Babies born to mother taking quinine and chloroquinine habe B/L SNHL While mothers hearing unaffected.

21. AMINOGLYCOSIDE ANTIBIOTICS- Agents that cause permanent hearing loss and balance disorders They are toxic to hair cells in all inner ear sensory patches in all vertebrate classes. Although all aminoglycosides are potentially both cochleotoxic and vestibulotoxic , the different aminoglycosides exhibit differences in their toxic potential and organ preference. These have indicated that neomycin is the most toxic, gentamicin, kanamycin and tobramycin less so, and amikacin and netilmicin least toxic, but such differential toxicity. Streptomycin and gentamicin are considered more vestibulotoxic than cochleotoxic to humans, whereas amikacin and neomycin are primarily cochleotoxic in the human inner ear.

22. Topical application of a single dose of the drug to the middle ear cavity can almost immediately initiate the progressive damage observed after chronic systemic treatment. The severity of the effects increases progressively with time, continuing after drug,administration has been stopped. The initial effect in the cochlea is a hearing loss confined to the high frequencies,indicating hair cell damage in the most basal region of the cochlea.

23. Location and nature of lesions In the organ of Corti , in line with the pattern of hearing loss, hair cells in the basal (high-frequency)coil are affected first, damage spreading progressively apical wards with time and with increasing dosage . Outer hair cells are more sensitive than inner hair cells . IHCs do not usually appear to die until all the OHCs in their immediate vicinity and may persist for months after there has been complete loss of all OHCs. There is also significant progressive loss of spiral ganglion neurons, the afferent nerves that innervate hair cells . This appears to progress following death of IHCs

24. Preferential uptake of gentamicin! The loss of the terminals is thought to occur by excess release of the neurotransmitter glutamate from the IHCs at synapses with afferent terminals causing excitotoxic damage to the nerve . In the vestibular system aminoglycoside-induced hair cell loss is seen initially in the central regions of the epithelia, i.e. at the crests of the saddle-shaped cristae and across the ‘ striola ’ along the middle of utricular and saccular maculae. Cristae show greater HC loss than the utricle which in turn shows more extensive damage than the saccule . Immunohistochemistry has shown preferential uptake of gentamicin into the type 1 hair cells. The type 1 hair cells predominate on those regions where damage is initiated and are thought to be more susceptible to aminoglycoside induced damage than the type 2 vestibular hair cells.

25. Supporting cells-Saved!! The death of each hair cell is accompanied by expansion of the supporting cells around them to close the lesion and effect tissue repair/are not usually affected by aminoglycosides (or other ototoxins . The replacement hair cells derive from the supporting cell population through initiation of cell division among the supporting cells . And /or through direct non-mitotic transdifferentiation , or ‘phenotypic conversion’ of supporting cells into hair cells.

26. Reorganization of the sensory epithelium !! After hair cell loss and ultimately the crest of cells that normally constitutes the organ of Corti can become replaced by an apparently simple cuboidal-like epithelium across the basilar membrane. In the organ of Corti lost hair cells are not replaced, but there is some evidence for regeneration of hair cells in the mammalian utricle. The extent to which this occurs is limited and only a proportion of the lost hair cells may be replaced by new one.

27. Pharmacokinetics The half-life of aminoglycoside in the inner ear has been estimated as more than 30 days. The peak level reached in perilymph after multiple dosing has been reported to be approximately 50–250 μM . Following systemic administration appears in greater amounts in the scala tympani of the apical turn than in the basal coil. Aminoglycosides also enter endolymph , but only after a prolonged period following entry into perilymph

28. Pharmacokinetics and mechanisms of toxicity The cell death occurs only after some critical concentration of the drug has been reached inside the cell. Aminoglycosides cause death of hair cells by inducing apoptosis There is a linear relationship between serum concentration of aminoglycoside and the perilymph concentration. but aminoglycosides enter perilymph relatively slowly, the peak concentration after extravascular injection-much later in perilymph (about 4 hours) than in serum (about 15–30 minutes

29. APOPTOSIS A programmed cell death pathway in which particular enzymes called caspases play the crucial roles. Gentamicin-induced hair cell death can be prevented by pan- caspase inhibitors , One significant initiator of programmed cell death leading to apoptosis is generation of reactive free radicals. The common feature of all hair cells is the transduction apparatus at their apical poles . Aminoglycosides are one of the few known blockers of the hair cell transduction channel. One of the major routes of entry for aminoglycosides into hair cells is through the mechanotransduction channels at the tips of the stereocilia

30. Why Base is affected more than the Apex? Entry via the transduction channels could provide one explanation for the base-to-apex gradient in hair cell death along the cochlea: the probability of the open state of the transduction channels in OHCs in the basal coil is 50%, but the open state probabilities decrease towards the cochlear apex. Effects of aminoglycosides that lead to the release of free radicals to levels in excess of cellular mechanisms to detoxify them has been considered one potential route through which aminoglycoside-induced hair cell death is triggered.

31. MITOCHONDRIA-> rRna ->ROS Mitochondria are derived during evolution from bacteria and they contain their own distinct set of genes, separate from the genes encoded by the cell’s nuclear DNA. These genes encode some of the mitochondrial proteins and the ribosomal- (r-)RNAs necessary for their translation. Bacterial r-RNAs are the target for aminoglycosides as antibiotics. Damage to mitochondria releases not only ROS but also a number of factors normally resident within mitochondria that regulate the cascade of reactions leading to apoptosis. So,that mutations in mitochondrial genes that encode for mitochondrial rRNAs are associated with enhanced susceptibility to Aminoglycoside induced hearing loss .

32. Effects of aminoglycosides on the stria vascularis The drugs are taken up quite rapidly into marginal cells in the SV. A decrease in the volume of the SV ( strial atrophy) has been observed in human temporal bones obtained within 2 weeks of aminoglycoside treatment. The decrease in the thickness of the stria is due to effects almost exclusively on marginal cells-reduced volume

33. Stria &EP Such alteration expected to affect EP and the ionic profile of endolymph . But EP appears to be maintained at close to normal levels for up to 4 weeks But is reduced by more than half 12 weeks after treatment when there is significant decrease in strial thicknes The stria is less than onethird its normal vol , there is a catastrophic loss of EP. the stria can sustain injury for some time without a noticeable effect on auditory function. If ‘compromised’ state, it might be less able to resist further insults

34. Confounding factors and genetics Mutations in the gene that encodes 12s ribosomal RNA of mitochondria. The ‘A1555G’ missense mutation (an adenosine to guanosine substitution at base position 1555), Thymidine to cytosine mutation at 1095, Cytosine to thymidine missense at 1494 & Cytosine insertion at position 961 Mutations appear to affect only the cochlea’s sensitivity t aminoglycoside; there is no enhanced effect on the vestibular system. ‘Critical -period’ : the time of the onset of auditory function during development in about weeks 18–20 of gestation. Sensitivity to the ototoxic agent is greatest.

35. CONFOUNDING FACTOR NOISE: High sound pressure levels also lead to the generation of a variety of free radical species,which would exacerbate the effects of aminoglycoside-induced cellular stress. LOOP DIURETICS: The SV is also affected, becoming progressively thinner through loss of marginal cells The loop diuretics markedly increase the penetration of aminoglycosides into endolymph and enhance uptake of gentamicin into cochlear hair cells. The reduction in EP to negative values from the normally high positive potential may encourage entry of the cationic aminoglycoside into endolymph . The potentiation of cochleotoxicity

36. CISPLATIN Sites of action and nature of effects Like aminoglycosides, it is nephrotoxic as well as ototoxic. Used to treat various tumours of soft tissue. Cisplatin induces a progressive loss of hair cells, the extent of which correlates with the dose of drug administered

37. Sites of action and nature of effects HairCells in the basal coil of the cochlea are affected with damage spreading progressively apicalwards . Initial high-frequency hearing loss measured by auditory brainstem response (ABR), and suppression of otoacoustic emissions indicating an effect on OHCs. Cisplatin may have direct effects upon the spiral ganglion cells themselves.

38. Effects on SV, Spiral Ganglion ,Basal coil, Spiral ligament Detachment of the myelin sheaths from type 1 spiral ganglion cells (those that innervate IHCs) Progressively increase in extent in parallel with loss of OHCs. Affects- fibrocytes of the spiral ligament Effects in the stria and in the organ of Corti are independent of each other Strial atrophy develops several days or weeks after the end of the chronic treatment. Primarily due to apoptotic death of the marginal cells Cisplatin causes a decline in EP within 1 day of single intravenous high dose and it may become completely lost.

39. Entry via The apical end of the hair cells- mechanotransduction channels Like aminoglycosides, cisplatin gains entry to endolymph from the SV, -an affinity for the hair cell transduction channel . Once inside a cell cisplatin leads to cross-linking of nuclear DNA, which in proliferating cells, such as those of tumours , inhibits DNA synthesis, induces cell cycle arrest, suppresses transcription ultimately leads to apoptosis. Damage to DNA is likely to occur which will activate DNA repair mechanisms. Polymorphisms in genes for two DNA repair enzymes, ERCC2 and XPC= risk factors for cisplatin -induced hearing loss

40. Scavenger of free radicals Cisplatin binds to to sulphhydryl -containing molecules such as metallothineins and glutathione and negatively affects redox balance. Decrease in cochlear glutathione and significant decrease in the activity of glutathione peroxidise & glutathione reductase in cochlear tissues Agents such as d-methionine and 4-methylbenzoic acid , enable maintenance of glutathione levels may be effective in preventing the ototoxic effects of cisplatin .

41. Interactions Noise exposures- Above 70 dB concurrent with cisplatin administration can induce hearing impairments and hair cell loss. Patients who received cisplatin even some years prior to noise exposure-Increased susceptibility to hearing loss has also been reported. Due to long persistence of platinum in the body and prolonged suppression of antioxidant mechanisms Diuretics - Leads to extensive and quite rapid hearing loss and death of OHCs Decline in EP enhancing uptake of the cisplatin into endolymph .

42. ORGANIC SOLVENTS Exposure to high concentrations of organic solvents induce acute, reversible narcosis and neurotoxicity and ototoxic damage. Workers in the chemical Industry and solvent abusers showed a high incidence of hearing loss. The effects of solvents may be exacerbated by concurrent exposure to high noise levels, i.e. noise-induce hearing loss becoming more pronounced with concomitant exposure to certain solvents presenting a significant occupational hazard

43. Aromatic solvents A number of different aromatic solvents have been implicated in ototoxicity. toluene, p-xylene, ethylbenzene , n- propylbenzene , styrene, ά- methylstyrene , trans - β- methylstyrene and allylbenzene . Trichlroethylene has also been reported to be ototoxic- The cell bodies of the afferent neurones may also be a target of trichloroethylene. Characteristic features of toluene are: • It is the mid-frequency ranges of hearing that are affected Rather than the high frequencies, with HC loss in the middle and apical turns of the organ of Corti • There is a distinct spread of damage from the third (outermost) row of OHCs inwards to involve subsequently the second and maybe the first row of OHCs. Additionally, the supporting cells, especially the third (outermost) row of Deiters cells, are affected

44. SV in the middle and apical cochlear turns is affected, perhaps indicating some characteristic of the vascular pathways and blood flow that may influence solvent distribution

45. MODE OF ENTRY Since organic solvents are minimally water-soluble their distribution in the inner ear is unlikely to be determined by entry into the fluid spaces. It is their distribution in the tissue that is significant. The pattern of damage across the organ of Corti , from outside to in , has suggested that the solvents reach the inner ear from the vasculature of the SV or the spiral prominence region just below it and then pass through the tissues to the organ of Corti . The cuboidal cells of the outer sulcus,epithelia of lateral wall to the organ of Corti along the basilar membrane may be a major transport route . Upon reaching the organ of Corti , the supporting cells of the organ of Corti , the Hensen’s cells that form the outer ridge of the sensory epithelium and the Deiters ’ cells that surround the hair cells , may then become injured

46. SUPPORTING CELLS-INJURED!! Deiters ’ cells: the outermost row, - most vulnerable cells in the organ of Corti following styrene administration. Supporting cells: involved in the reuptake of K+ from around the hair cells. Damage to these cells may therefore result in excessive K+ levels around the OHC that would lead to their death

47. The cell-death is principally apoptotic or necrotic Loss of membrane integrity and cell swelling- as a consequence of membrane damage. Death of Deiters ’ cells , unlike that of hair cells, is not prevented by antioxidants , suggesting that different mechanisms of cell death operate in the two cell types

48. OTHER OTOTOXIC AGENTS VIOMYCIN: Reported to be predominantly vestibulotoxic following chronic treatment regimes, Repeated systemic injections of relatively high doses, viomycin causes hair cell death in the vestibular sensory organs . Vancomycin : has been reported to cause transient hearing loss and/or Tinnitus . Polymyxin B: when perfused through the perilymphatic spaces caused an almost immediate decline in cochlear microphonic (CM) followed by a decline in EP , shows Separate effects on both the organ of Corti and the SV. Chloramphenicol : in animals causes irreversible hearing loss following infusion into the middle ear cavity- gaining access to the perilymph following uptake across the round window membrane.

49. Desferrioxamine DFO attenuates aminoglycoside-induced hair cell loss. repeated highdose systemic administration of DFO - cause high-frequency hearing loss in about 20–40% receiving long-term therapy Desferrioxamine ( deferoxamine mesylate (DFO) binds iron and is used in patients with b- thalassaemia to remove excess iron from the serum

50. MONITORING Audiologic monitoring for ototoxicity is primarily performed for two reasons: early detection of hearing status changes presumed to be attributed to a drug so that changes in the drug regimen may be considered, and (2) audiologic intervention when hearing impairment has occurred OTOTOXICITY MONITORING TESTS Three main approaches to audiologic monitoring : basic audiologic assessment, high-frequency audiometry (HFA), and otoacoustic emission (OAE) measurement

51. Ototoxicity monitoring HIGH FREQUENCY AUDIOMETRY The earliest effects of ototoxic drugs are commonly manifested by the outer hair cells (OHCs) of the basal cochlear turn. HFA comprises air-conduction threshold testing for the frequencies above 8 kHz , detection of aminoglycoside-induced or cisplatin -induced ototoxicity long before changes may be detected in the conventional range. HFA usually detects ototoxic change earlier than DPOAEs, and is less affected by otitis media than OAEs . OTOACOUSTIC EMISSION The most commonly used OAEs are transient OAEs (TEOAEs) or distortion product OAEs (DPOAEs). TEOAE responses typically change before hearing threshold in the conventional range, but not before changes in the HFA thresholds DPOAEs may detect ototoxic change earlier than TEOAEs , likely due to the fact that DPOAEs can be measured at higher frequencies

52. Grades of Ototoxicity ASHA The most commonly used criteria was published in 1994 by the American Speech-Language-Hearing Association Retesting must be completed within 24 hours to confirm results . One of the following must be met to identify significant ototoxic change: ● 20 dB or greater decrease in pure-tone threshold at one frequency (20 dB is equivalent to a whisper or rustling leaves) ● 10 dB or greater decrease at 2 adjacent frequencies (10 dB is equivalent to breathing) ● Or loss of response at 3 consecutive test frequencies

53. Adverse event scales for hearing The two most commonly used are the National Cancer Institute (NCI) -Common Terminology Criteria for Adverse Events (CTCAE) Ototoxicity Grades and Brock’s Hearing Loss Grades

54. The Brock’s Hearing Loss Grade test To determine platinum-induced ototoxicity. The grades of hearing loss are assigned based on the standard pure-tone audiologic frequencies at which hearing thresholds equal or exceed 40 dB hearing loss.

55. Patient Education The patient should avoid significant noise exposure during and for several months after taking an ototoxic drug. Patients with hearing aid s should ensure that their power output is carefully monitored to avoid any noise damage. Patients should inform their physician of any changes to hearing, balance, or tinnitus.

56. Journals on prevention of cisplatin induced ototoxicity Intra tympanic dexamethasone Sodium thiosulphate Vitamin E Thank you