OTOTOXICITY

AMINOGLYCOSIDES

Agents:

-older agents: streptomycin sulfate, dihydrostreptomycin, kanamycin, and neomycin,

-newer drugs: gentamicin, tobramycin, amikacin, and netilmicin (Matz, 1990)

Cochleotoxic: (ie: more effect on auditory system than vestibular system)

-Dihydrostreptomycin, neomycin, kanamycin, amikacin, sisomycin, livodomycin

Vestibulotoxic: (ie: more effects on vestibular system)

-streptomycin and gentamicin.

Nb: streptomycin selectivity has been used to advantage in the treatment of bilateral active Ménière's disease or to relieve disabling vertigo and preserve hearing in patients with one hearing ear.

Pharmacokinetics and biochemistry

-only 3% of orally administered dose is absorbed from GIT \ give IV.

-tissue concentrations of aminoglycosides are 1/3 of serum concentrations.

-BBB penetration of aminoglycosides is negligible, except in neonates.

-Can cross placenta, \ fetal ear is susceptible to their ototoxic effects.

-excreted almost exclusively by glomerular filtration Þ urinary concentrations may reach levels 10 x’ > serum.

\ Impaired renal function reduces rate of excretion Þ accumulation in blood & inner ear toxicity.

Mechanism for inner ear loss due to ototoxic drugs:

a.-recent experiments Þ an ototoxic metabolite may be formed (Huang and Schacht, 1990).

b.-Henley and Schacht (1988) dispute the concept of perilymph accumulation of aminoglycosides.

-aminoglycoside do not accumulate in perilymph

-perilymph concentrations do not correlate with development of toxicity in experimental animals.

-aminoglycosides do not accumulate in inner ear fluids

-They report ratio of gentamicin in inner ear tissues is significantly lower compared to plasma levels.

c.-Williams (1987) biochemical molecular basis of aminoglycoside toxicity:

- a multistep mechanism of toxicity.

i. binding of aminoglycoside to outer plasma cell membrane.

(This binding is reversible and is antagonized by divalent cations calcium and magnesium).

ii. energy-dependent uptake into cell.

iii. inside the cell they interfere with I/C processes (eg synthesis of polyphosphoinositides).

d.-Anniko et al. (1982), ??? membrane phospholipids in coclea serve as aminoglycoside targets.

e.-energy metabolism may be target in aminoglycoside ototoxicity

f.-aminoglycosides may?? reduce transport of glucose into inner ear. (Garcia-Quiroga et al., 1978).

g.-Takada et al. (1983) Þ gentamicin ototoxicity is not related to glucose uptake or utilization.

h.-Kroese and Van den Bercken (1982)

Þ low concentrations of aminoglycosides may have a dual action on sensory hair cells.

(1) to increase spontaneous afferent nerve activity by affecting hair cell membrane

(2) to cause marked impairment of the mechano-electric transduction process.

i.-Takada and Schacht (1982) aminoglycoside ototoxicity occurs in two stages:

i. an initial effect, a membrane effect on phospholipids, (antagonized by calcium ii. second step that is noncompetitive and irreversible.

j.-role of phospholipids as a target for aminoglycoside ototoxicity:

-experiments have shown the presence of a specific phospholipid in isolated outer hair cells.

-genta has selective & high affinity for this phospholip(phosphatidyl inositol4,5,bisphosphat)

k.-Schacht proposed a molecular mechanism of consisting of several sequential stages:

(1)reversible binding of aminoglycoside to plasma memb, which can be antagonized by calcium ;

(2) energy-dependent uptake of aminoglycosides

(3) intracellular binding to phosphatidylinositol 4,5,-bisphosphate, preventing its hydrolysis and

preventing subsequent formation of the second messenger inositol trisphosphate and the

activation of protein kinase C.

Pharmacokinetics and ototoxicity

-half-life of gentamicin elimination from inner ear tissues increases significantly with chronic treatment.

-Ototoxicity is related to"area under the curve," (approximated by peak & trough levels)

-studies on animals Beaubien et al. (1989) Þ no relationship b/w ototoxicity and plasma level.

Rather the total dose or area under the curve was a much better predictor of amikacin ototoxicity.

-ototoxic effect might be ß if interval b/w doses is long enough for clearance from perilymph.

-delayed onset of ototoxicity

Þ ???redistribution of gentamicin into susceptible cells or cellular compartments.

Þ ???recent studies: toxic metabolite of aminoglycosides Þ ototoxicity.

-Delayed ototoxicity: continuing damage to sensory structures of organ of Corti after termination of treatment

-Degeneration of neurons may occur several years after loss of inner and outer hair cells caused by

kanamycin intoxication so that use of a cochlear implant not usable.

-even if cochlear neurons remain in large numbers, their dysfunction and delayed degeneration may limit the potential benefits of cochlear implants.

-high-affinity binding sites for gentamicin in the organ of Corti & vestibular maculae.

-dissociation constants Þ fourfold greater affinity of gentamicin for vestibule than cochlea,

Þ tendency for gentamicin to cause vestibular toxicity > auditory damage.

-No significant difference in binding of gentamicin to tissues in cochlear apex vs base.

nb: there is a predilection for damage to occur in the basal turn initially.

-potential targets for aminoglycosides are:

-enzyme ornithine decarboxylase.(found in kidney and cochlear.........both inhibited by neomycin)

-acidic glycosaminoglycans (

-nb glutathione pathway in the cochlea may also play a protective role against aminoglycoside ototoxicity

-route by which aminoglycosides reach hair cells from bloodstream is not known.

-Animal studieshave shown that:

(1)direct relationship between degree of aminoglycoside ototoxicity and level of drug reached in perilymph

(2)aminoglycosides perfused directly into perilymph space can induce toxic effects.

Histopathology

drug-induced damage to cochlea parts

Þ selective destruction of type I hair cells of crista ampullaris.

Þ type II hair cells are destroyed later,

Þ selective destruction of outer hair cells in the basal turn of cochlea,

-with greatest number of missing outer hair cells noted in first row facing tunnel of Corti

Þ with progression toward apex as the dose and duration of treatment are increased.

Þ supporting cells tend to remain intact.

Þ Some investigators noted apical inner hair cell injury & rarely supporting cells damage.

Þ damage to structures lining cochlear duct, (including spiral ligament, stria vascularis, vestib memb,

spiral prominence, and pericapillary tissues of the outer sulcus.

Þ stereocilia can change into giant hairs, balloon at base, fuse,& (F) intercellular bridges Þ degenerate Þ normal organs of Corti but had a reduction of cochlear ganglion cells (one third < N cochleas)

-raises possibility that the spiral ganglion may be the target for ototoxicity in some patients.

Þ early loss of hair cells in the basal turn of the cochlea.

Þ more severe damage, this loss extends towards the cochlear apex in an orderly fashion:

-first row of outer hair cells is most susceptible,

-followed by middle row of outer hair cells,

-last the outermost row (Lerner and Matz, 1980).

-Only after most of outer hair cells have been destroyed are changes seen in single row of inner hairs.

-inner hair cell damage is most severe in apex and progresses toward the base.

-Next the tunnel rods as well as other supporting cells of organ of Corti are destroyed.

Þ when auditory damage has progressed to the point at which hair cells are killed, there is no recovery b/c they do not regenerate(Brummett et al., 1978).

-Nb: hair cell damage and auditory dysfunction in patients may be asymmetric.

-histologic picture of drug-induced damage to vestibular parts:

-most obvious effect is loss of hair cells in the utricular, saccular macula & crista of the semicircular canals, which, do not regenerate.

Monitoring

- monitored for two reasons:

(1) to ensure adequate levels for therapy, and

(2) to detect elevated or rising levels that may be associated with ototoxicity and nephrotoxicity

-Renal function best index: creatinine clearance,

serum creatinine level is a good indirect estimate of GFR.

-Suggested schedules (Lerner and Matz, 1979):

1. For normal renal function:

-Peak level on first 1 or 2 days of therapy,

-trough determined within 1 week,

-peak-and-trough levels are determined weekly thereafter.

Nb: Peak levels:1 hour after administration

nb: Trough levels: 15 minutes before next dose.

2. For impaired but stable renal function:

-peak-and-trough levels within first 1 or 2 days of therapy.

-Serum levels daily if renal function remains unstable.

Nb: It has never been established conclusively if occasional Ý serum peak-and-trough levels Þ ototoxicity.

-Routine auditory monitoring of pts taking ototoxic drugs is unnecessary unless they are high-risk:

-impaired renal function, pts who have taken aminoglycoside in past, consistent Ý peak/trough levels -pts with past/present vestib/coch loss, pts in whom a vestib/cochl loss may be debilitating, eg pilots.

Clinical Toxicology

-Normally:

-Humans can hear up to 16,000 Hz, (most audiometers only test up to 8000 Hz).

-patient is not aware of hearing loss until it is >30-dB affecting frequencies as low as 3000-4000 Hz.-

Inc: In most prospective studies the incidence of aminoglycoside ototoxicity is about 10%.

Risk factors for ototoxicity ;

-bacteremia, elevated temperature, liver dysfunction, ratio of serum urea nitrogen to serum creatinine

longer duration of therapy, elevated serum peak and/or trough levels, advanced age, concomitant use of

other ototoxic medications, especially the loop diuretics furosemide and ethacrynic acid.

-nb All potential toxicities are most likely to occur in patients with compromised renal function.

-Acute damage to auditory syst is usually heralded by tinnitus (but ototoxic effects can occur without tinnitus).

-Deafness from these drugs initially affects hi frequ’s but, as damage progresses, lower frequ are also affected.

-Once ototoxicity has been detected clinically, if aminoglycosides are discontinued, ototoxic effects cease.

At least some initial shifts are reversible.

-Ototoxic effects that present 2-3 wks after stopping A/B’s are likely to be permanent (Lerner et al., 1984).

-10% to 15% of patients with aminoglycoside ototoxicity have reversal of the abnormal electronystagmograms and audiograms, thus indicating reversibility of toxicity.

Vertigo is a manifestation of vestibular toxicity.

-Symmetric loss of vestibular fnctn is seen in pts undergoing titrated streptomycin as rx for bilat Meniérè's.

-Some cases, the vestibular effects are reversible although permanent damage usually occurs.

-Rotational vestibular testing Þ initial and most severe vestibular effects to be in lowest frequency range,

with variable extension into higher frequencies.

-nb:Unilateral loss, either of the vestibular or the audiometric system, is possible in aminoglycoside ototoxicity.

Ototopical medications;

-commonly used for bacterial infections are:

neomycin, polymyxin B, and propylene glycol; chloramphenicol

-Morizono (1988) found ototoxic effects in guinea pig from topically used gentamicin eardrops in ME.

-further, propylene glycol (one of the most commonly used carriers of drug otic solutions) is ototoxic.

-ototoxic effect can be reduced in ME if there is profuse ear disease with pus & thick mucosa covering the RW.

-Solut’ns introduced into chronically infected ME of humans are ?? not absorbed into cochlea to significantly. -??due to oblique orientation of the human round window or

-?? due to poor penetration through the chronically infected middle ear mucosa.

\ neomycin and other eardrops should be used with caution in patients with TM perforation.

-Reports of ototoxicity following topical administration of neomycin to large surfaces (eg peritoneal cavities)

-Animal studies Þ cochlear damage by these various preparations (Leach et al., 1990; Morizono, 1988),

but there are anatomic and pathologic differences between the animal model and man.

-Podoshin Þ small (approx 6dB) but statistically significant worsening of hearing in pts treated for (COM)

-concentrated solutions of aminoglycosides (streptomycin, gentamicin) are introduced into ME cavities of pts

with Ménière's disease to unilaterally ablate peripheral vestibular function, Þ significant cochlear ototoxicity -use of otic preparations, esp with TM perforations, should be carefully monitored.

Antifungals

-Cochlear toxicity has been reportd foll top applicat’n of neomycin eardrops to RW memb in guinea pigs.

-Hair cell damage similar to that seen after IV administration of neomycin in guinea pigs has been noted.

-eardrops containing neomycin in humans does not appear to be associated with a high risk of ototoxicity.

-Marsh and Tom (1989), five antimycotic ear-drop preparations were studied.

-25% m-cresyl acetate,

-2% acetic acid,

-1% clotrimazole, and

-1% tolnaftate.

-All the agents studied were clearly ototoxic in guinea pigs.

LOOP DIURETICS

-can Þ bilaterally symmetric SNHL, which may be sudden in onset (Arnold ‘81; Matz, 1990; Schuknt, 1974).

Pharmacokinetics and biochemistry

-act on the loop of Henle to inhibit the reabsorption of Na, K, & Cl ions by a Na-K-2Cl carrier (Greger, 1985).

-most cases of loop-diuretic ototoxicity are temporary and fully reversible

-reversing within 30 minutes to 24 hours of administration (Koegel, 1985).

Risk factors: renal failure, rapid rate of administration, and concomitant aminoglycoside administration

Furosemide

-excreted in the urine.

-half-life for renal elimination of 291 minutes (

-elimination decreases greatly in patients with advanced renal failure.

-plasma half-life is ~ 45 to 92 min in (N) but is prolonged to ~3 hours in pts with renal failure.

-gastrointestinal uptake is high; ( ~65% of an oral dose of furosemide is absorbed)

-Plasma levels > 50 mg/L frequently Þ hearing disturbances.

Biochemical mechanisms of the ototoxic effects of loop diuretics:

-not been fully characterized.

-furosemide is a potent inhibitor of adenylate cyclase isolated from stria,

but not Na-K ATPase at concentrations that inhibit the endocochlear potential.

-loop diuretics influence ion pumps in kidney and cochlear duct.

-loop diuretics block the system that transports potassium chloride out of marginal cells of stria vascularis. This would explain the shrinkage of marginal cell, which may lose water if ions continue to move into the endolymph from it.

-an organic acid transport uptake mechanism may play a role in ototoxicity of furosemide.

-furosemide has been shown to alter active processes in cochlea, Þ reversible alteration of basilar

membrane responses to acoustic stimuli (Ruggero and Rich, 1991).

Best avoided by:

-slow rate by intravenous infusion (less than 15 mg/min) (Matz, 1990),

-decreasing the dosage in the presence of renal failure,

-avoiding the concomitant use of aminoglycosides (Koegel, 1985).

Nb: Once ototoxicity from these agents is established, the only management is drug cessation.

Histopathology

-inner and outer hair cells of animals treated with high doses of furosemide did not show any damage.

-edema & cystic degeneration of stria vascularis has been noted in animals injected with ototoxic doses of both loop diuretics.

-No changes were observed in the cochlear nerve fibers or ganglion cells.

-furosemide Þ stereocilia of outer row of outer hair cells in guinea pig may be splayed.

Þ tip links b/w adjacent stereocilia of outer hair cells may be stretched/broken.

SALICYLATES

Pharmacokinetics and biochemistry

-Orally: absorbed very rapidly in gastrointestinal tract

-half-life of 6 to 15 minutes.

-Absorption is influenced by gastric emptying time and presence of food in stomach.

-Aspirin is hydrolyzed in body to salicylic acid.

-Once absorbed from the serum, salicylates are distributed mainly to the EC water compartments.

-Concentrations of salicylts are higher in liver&kidney VS serum, whereas brain concentn’s are 10% of serum

-quickly enter perilymph after systemic administration.

-perilymph concentration after systemic administration is fourth to one third of blood level.

-concentration in perilymph reaches maximal value ~ 2 hrs after intraperitl injection in animals.

-Other study: relationship between serum and perilymph salicylate level was nearly linear.

-excreted mainly in the urine.

Inc:

-Chinchillas receiving 450 mg/kg IP Þ Ý evoked response threshold of 30 dB, (esp at hi frequencies)

-Guinea pigs receiving salicylates at (450 mg/kg IP) Þ Ý spontaneous activity of neurons in inferior colliculus.

-Humans, serum salicylate concentrations of 20-50 mg/dL Þ hearing losses of up to 30 dB.

-Linear relationship between hearing loss and unbound salicylate concentrations (Day et al., 1989).

-or even below 20 mg/dL...(Day 89).

-salicylate concentrations of 11 mg/dL Þ hearing loss at any given frequency was 12 dB.

Histo:

-tritium-labeled salicylate is detected quickly in blood vessels of stria vascularis & spiral ligament (Ishii 1967). -Within an hour label was found in:

-outer tunnel of organ of Corti

-around outer hair cells

-Rosenthal's canal around the spiral ganglion cells.

Pathog: (NB:most of below are animal studies)

-Salicylates suppress the AP at low but not at high sound intensities

suppress cochlear microphonics (but no effect on summating potential...Puel, 1990).

-??? prostaglandin.......Escoubet et al. (1985) & Jung et al. (1988a):

-controversy whether salicylate effects on cochlea are mediated by prostaglandin metabol..

-??? leukotrienes..... Jung et al. (1991):

-topical application of leukotrienes to RW membrane of chinchilla Þ HL..

-???? inhibition of transaminase and dehydrogenase systems ....Silverstein et al. (1967).

-sodium salicylate selectively reduces (CN VIII) action potential in experimental animals Mitchell (1973).

-??? cochlear blood flow:

-effect of salicylates on cochlear blood flow has been proposed....Hawkins (1973) (Malotte et al., 1990)

-vasoconstriction in capillaries of suprastrial spiral ligament, stria vascularis, tympanic lip & basi memb. but not sufficient to cause loss of sensory cells or changes in the stria vascularis.

Human studies

-no significant cellular alterations were found at the light-microscopic level.

-the site-of-lesion testing of the auditory system in patients suffering from salicylate-induced hearing loss suggests a cochlear pattern (McCabe and Day, 1965),

-histopathologic studies as yet have not pinpointed which cells are altered.

ANTINEOPLASTIC DRUGS

Cisplatin

Pharmacokinetics and biochemistry

-Renal excretion by glomerular filtration.

-There is extensive and strong binding of cisplatin to serum proteins, and this cisplatin-protein complex is inactive against tumor cells.

-not known whether toxic metabolites of cisplatin are formed in inner ear oroutside.

Animal studies:

-cisplatin inhibits the activity of adenylate cyclase in the cochlear tissues.....Bagger-Sjöbäck et al. (1980)

-chinchillas: eightfold increase in prostaglandin levels in perilymph (Jung et al., 1988b).

-tendency for cisplatin to damage outer hair cells.

by initially blocking outer hair cell transduction channels (McAlpine and Johnstone, 1990) causing a reduction in hair cell receptor current and subsequent hearing loss.

-outer hair cells of the basal turn of the cochlea are damaged first, with damage to the more apical cells occurring when the dosage is continued (Fleischman et al., 1975; Stadnicki et al., 1975).

-first row of outer hair cells appears to suffer the greatest damage (Estrem et al., 1981; Moroso and Blair, 1983; Nakai et al., 1982, Schweitzer, 1984, 1986b).

-irregularity of surfaces of stereocilia of both inner and outer hair cells was noted, (esp in apical turns).

-stria vascularis damage only by high dose intravenous cisplatin.

-cisplatin ototoxicity is enhanced by aminoglycosides (Schweitzer and Olson, 1984),

by loop diuretics (Brummett, 1981; Komune and Snow, 1981; McAlpine and Johnstone, 1990), by aminooxyacetic acid (McAlpine and Johnstone, 1990), and by exposure to moderate or high levels of noise (85 to 100 dB SPL in chinchilla) (Boettcher et al., 1989a; Gratton et al., 1990).

Clinical:

-Symptoms that strongly suggest cisplatin ototoxicity: otalgia, tinnitus, subjective HL (Reddel et al., 1982). -Tinnitus in 2% to 36% of patients receiving cisplatin (Moroso and Blair, 1983)

-often transient, lasting from few hours to a week after cisplatin therapy (DeConti et al., 1973).

-Hearing loss:

-incidence in patients treated with cisplatin is b/w 9% (Higby 1974) & 91% (Helson 1978).

-usually bilateral and appears first at high frequencies (6000 and 8000 Hz)

-may experience some degree of reversibility, but when HL is profound, Þ permanent (Hayes 1977). -it may not be detected without audiometry.

-ototoxic critical cumulative dose of cisplatin is 3 to 4 mg/kg body weight

-worse by bolus injection.

-may be minimized by slow infusion and dividing the doses over several months.

-Vestibulotoxicity is especially likely to occur in pts with pre-existing abnormalities of vestibular function.

Nitrogen mustard....(Mechlorethamine)

-massive doses of nitrogen mustard (0.6 to 1.5 mg/kg) Þ mod to severe bilateral SNHL in most patients -generally permanent.

-Histopath in human Þ shrinkage of the organ of Corti without hair cell loss.

Deferoxamine

-an iron-chelating agent

-high-dose Þ acute onset SNHL, often associated with acute onset visual loss (Olivieri et al., 1986).

-mostly involves high frequencies, and usually is permanent (Gallant et al., 1987).

ERYTHROMYCIN

-Mintz 1973 Þ first clinical case of hearing loss related to erythromycin.

-Hi risk pts are elderly individuals with hepatic or renal failure or those with legionnaires' disease.

-Symptoms of ototoxicity include subjective hearing loss, "blowing" tinnitus, and occasionally, vertigo.

-Current recommendations, dose of erythromycin does not need to be altered in renal failure (Bennett 1980).

-hearing loss is usually reversible.

-Schweitzer &Olson 1984; (guidelines for prevention of erythromycin-induced ototoxicity:

1. daily dose should not >1.5 g if creatinine is > 180 mol/L.

2. Pre&post-treatment audiograms (esp in elderly and renal or hepatic insufficiency).

3. Caution in patients already receiving ototoxic drugs, such as furosemide, cisplatin, or an aminoglycoside

VANCOMYCIN

Pharmacokinetics and biochemistry

-nephrotoxic and ototoxic.

-It is important to specify from which phase of the pharmacokinetics curve a blood sample is obtained before meaningful statements that relate blood levels with toxicity can be made (Banner/Ray, 1984).

-Infusion rate can drastically affect "peak" concentrations (Banner and Ray, 1984).

-Elderly patients, (even with normal renal function), have reduced total systemic & renal clearance.

-In premature infants, vancomycin has a significantly longer half-life and volume of distribution.

-vancomycin given during 2nd &2rd trimester of pregnancy does not cause transplacental sensorineural hearing loss or nephrotoxicity in the fetus (Reyes et al., 1989).

Clin:

-Hearing loss in humans occurs at blood levels of vancomycin >30-45 mg/L (Snavely and Hodges, 1984).

Exp:

-Vancomycin to guinea pigs in near-lethal doses was found to be nonototoxic (Brummett et al., 1990). Therefore, Þ appears to have a very small probability of causing ototoxicity.

-Increased incidence of ototoxicity & nephrotoxicity has been observed in humans and animals receiving vancomycin and aminoglycosides in combination (Rybak and Boike, 1983).

CLINICAL ASPECTS OF OTOTOXICITY

-Positional nystagmus, previously reported as a sign of ototoxicity, is a sensitive sign of toxicity.

MONITORING OTOTOXIC DRUGS

-all patients can be questioned regarding auditory and vestibular symptoms on daily records.

-whenever possible, baseline audiometric and vestibular testing should be obtained.

-In several special patient populations, periodic testing during treatment is advisable.

1. Patients with impaired renal function

2. Patients with elevated peak-and-trough serum levels of ototoxic drugs.

3. Patients with pre-existing SNHL, especially those resulting from ototoxic drugs.

4. Patients taking more than one ototoxic drug or those with a previous history of using ototoxic drugs.

5. Patients for whom a treatment course in excess of 14 days is planned.

6. Patients with symptoms suggestive of cochlear/vestibular toxicity that become evident during treatment.

7. Patients over the age of 65.

8. Patients taking any combination of an aminoglycoside antibiotic and a loop diuretic such.

Bibliography:

Cummings, C. Otolaryngology.  chapter 165

Gates Current Therapeutics

Scott Brown, , Otolaryngology

Schucknect, Pathology of the Ear