the precise mechanism of the action of the corticosteroids within the inner ear is scarcely known .
corticosteroids bind to glucocorticoid receptors on the cell membrane surface , then are transferred into the cell nucleus where transcription is initiated or modulated , influencing cell signalling pathways .
fluid and ionic transfer within the inner ear is influenced by modulation of na / k- atpase activity .
hidro - ionic homeostasis of the inner ear is influenced by means of mineralocorticoid receptor regulated genes induction   and control of aquaporin channels .
dexamethasone has been proved to modulate ionic homeostasis by means of enac epithelial channels in a semicircular membranous channel in primary cultures .
this results in the cationic transport in the vestibular labyrinth and osmotic coupled aquous flow .
a decrease of free radical species production within the inner ear has been shown alongside with the protective effect against proinflamatory cytokines such as the  tumor necrosis factor , after glucocorticoids administration .
inner ear disease glucocorticoid therapy is based most frequently on the supposed immunosupressive and antiinflamatory effects within the cochlea .
thus , a nuclear transcription factor regulates the synthesis of several proinflammatory cytokines involved in the glucocorticoids inhibited general immune response .
systemic innoculation of lipopolisacharides in mice induces the expression of transcription factor mrna in the mouse cochlea .
the process has been suggested to be inhibited by glucocorticoids leading to a reduction of the nuclear factor in different compartments of the inner ear and recovery of hearing loss .
topical administration of corticoids improves the cochlear blood flow . among multiple factors influencing corticoids access to the inner ear structures
, the administration modality ( systemic or intratympanic ) seems to be the most important .
an animal study has compared the concentrations of hidrocortisone , metilprednisolone and dexamethasone in the perilymph , blood and cs fluid after oral , intravenous and intratympanic administration in mice .
plasma concentrations of metilprednisolone and dexamethasone exceeded those in perilymph after oral and intravenous administration .
they include : hidro - ionic disturbances , hydrosaline retention , heart failure in susceptible patients , hypopotassemia , hypertension , muscular atrophy , osteoporosis , vertebral fractures , aseptic necrosis of humeral or femural heads .
gastrointestinal side effects include : peptic ulcer , bowel perforations , pancreatitis and reflux esophagitis .
dermatologic side effects include alteration of the healing processes , thin and brittle skin , bruises and hyperhydrosis .
endocrine problems associated with corticosteroids are menstrual irregularities ; development of cushingoid state ; suppression of growth in children ; secondary adrenocortical and pituitary unresponsiveness , particularly in times of stress ; decreased carbohydrate tolerance ; latent diabetes mellitus ; increased requirements for insulin or oral hypoglycemic agents in patients with diabetes ; and hirsutism .
possible opthalmic complications are posterior cataracts , increased intraocular pressure , glaucoma , and exophtalmos .
other adverse effects include thrombo - embolism , weight gain , increased appetite , nausea , and malaise .
the wide range of adverse effects favors the intratympanic corticosteroids administration as a direct pathway to obtain high therapeutic intracochlear concentrations , devoid of systemic side effects .
the indications for intratympanic corticosteroid therapy include sudden sensorineural hearing loss , meniere disease resistant to salt restriction and medical treatment with diuretics and vasodilators , tinnitus and autoimune inner ear disease .
, there is a strong recommendation for treatment only for salvage therapy in the case of sudden neurosensorial hearing loss after systemic corticosteroid failure .
the treatment strategies , doses and the volume of drug injected intratympanically have been empirically devised .
intratympanic injections are recomended some - times dailly for five days or weekly for up to four consecutive weeks .
the drug solutions are variable , providing a minimal and short - lived exposure of inner ear to corticosteroids .
modern polymer compounds , like dexamethasone based poloxamer oto-104 , seem to have several advantages such as : prolonged exposure of inner ear after single injection , low injection volume , avoidance of a second miringostomy for aeration , few postinjections sequelae due to filling of the middle ear with solution , lack of restriction of the orthostatism , speech and deglutition after injection .
although considered an adverse effect of antiinfectious therapy , ototoxicity has been proved to be useful for the therapy of vertigo related to meniere disease .
surgery ( endolymphatic sac decompression , vestibular neurectomy , labirinthectomy ) and intratympanic therapy are therapeutic alternatives when salt restriction , diuretics and vasodilators fail to decrease the number of vertigo attacks in meniere disease .
intratympanic therapy includes costicosteroids , when the auditive function is preserved , and pharmacologic destruction of the labyrinth with amynoglicoside antibiotics when there is no residual serviceable hearing .
chemical labyrinthectomy with intramuscular streptomicine injections was achieved for the first time in 1948 , by fowler . in 1956 , schuknecht delivered streptomicine injections into the middle ear achieving vertigo control in 63% of the treated patients , with subsequent profound neurosensorial hearing loss in all cases . in 1977 , lange delivered gentamicine intratympanically with hearing preservation in 76% of treated patients .
gentamicine becomes the preferred therapeutic compound due to its higher vestibulotoxicity as compared to its cochleotoxicity . from the middle ear
, gentamicine enters the perilymph of scala tympani by uptake through the round window membrane rather than by diffusion .
thus , the outer layer of this trilaminate membrane comprises cubic cells tightly connected by means of tight junctions , with numerous mithocondria , endoplasmic reticulum and golgi apparatus which suggest intense endocitosis . the molecular weight and the positive electrical charge of the gentamicine molecule favors its entry into the scala tympani perilymph from where it reaches the perilymph in the vestibular scala by means of interscalar carrier systems .
the positive electrical charge prevents gentamicine from entering passively into the scala media due to scala media s positive endocochlear potential .
the amynoglicoside antibiotic seems to reach the cells in the organ of corti through the cochlear blood flow .
aminoglycosides inflict degenerative injuries in the hair cells of the inner ear . in the organ of corti
hair cells are more vulnerable than type 2 hair cells and , from an anatomical perspective , hair cells of the ampular crest are affected in the first place , followed by cells of the utricule and sacule .
the mechanisms of action by which amynoglicosides inflict cell injuries include thermic shock protein 27 expression , increase of production of reactive oxygen species and nitric oxide . nowadays ,
titration protocols of administration are recommended by most of the clinical studies whenever there is indication for supression of the vestibular function by intratympanic gentamicine administration for control of vertigo in meniere disease .
intratympanic gentamicine is administered once a week until either the first symptoms of vestibular hypofunction appear and control of vertigo is achieved or the audition deteriorates . among these protocols ,
long term control of vertigo is similar to that achieved by treatment with daily doses or multiple daily doses .
titration gentamicine therapy controls vertigo in 87% ( between 75 and 100% among different studies ) of patients with unilateral meniere disease , the risk of secondary hearing loss being around 21% ( between 0 and 37% among different studies ) . yet , in one third of the patients , the vertigo can recur .
recurrences can also benefit from intratympanic gentamicine with the same risk of secondary hearing loss .
the main effect of intratympanic gentamicine would be a reduction of vestibular function due to hair cells injury .
optimisation of strategies for therapeutic inner ear perfusion by intratympanic drug delivery for the therapy of cochleo - vestibular symptoms requires a thorough understanding of the intratympanic administration protocols , knowledge of physico - chemical characteristics of intratympanic administered solutions and of round window normal and pathological anatomy , as well as labyrinthine pharmacokinetics advanced studies .
intratympanic corticosteroid therapy is strongly recommended only as salvage therapy in the case of sudden neurosensorial hearing loss after systemic corticosteroid failure .
less frequent dosing regimen of intratympanic gentamicine therapy for control of vertigo in meniere disease results in better hearing preservation .
 intratympanic drug delivery refers to drug administration in the middle ear , the main advantage being direct diffusion of substances in the inner ear through the round window membrane with subsequent high intralabiryntine drug concentration and very low systemic side effects . 
 the article is a review of literature concerning the inner ear barrier systems , the physiology of inner ear fluids , intralabirinthine pharmacokinetics and the commonest drugs applied in the middle ear for the treatment of cochleo - vestibular syndromes . 
Corticosteroids
Amynoglicosides
Conclusions