**5. Pharmacokinetics and pharmacodynamics**

384 Hearing Loss

interesting application of intratympanic medication was reported by Bryan in 1973, when he described the use of intratympanic steroids in a patient with facial paralysis (8). Itoh (9), in 1991, used steroids for Meniere's disease. Silverstein (10) in 1996, used steroids for

The cochlea can be thought of as a long coiled tube looking much like a snail shell (11). It is composed of three compartments. The middle compartment is the scala media, which is filled with endolymph. The lower and upper fluid compartments respectively are the scala tympani and scala vestibuli, both of which are filled with perilymph. These two compartments communicate with each other at the apex of the cochlea through the helicotrema. The round window is a membranous opening in the bone within the scala tympani. It sits at the base of the scala tympani and is very compliant, capable of bulging into the middle ear. It separates perilymph from the middle ear space. The oval window, in the scala vestibuli, contains the footplate of the stapes, one of the middle ear bones, that

Most of the structures of the cochlea are protected from the systemic circulation by the presence of a blood-cochlear barrier (or blood-labyrinthine barrier), similar to the bloodbrain barrier. There is exchange between the different compartments of the inner ear: between tympanic perilymph and vestibular perilymph and between endolymph and perilymph. But also between the inner ear fluids and cerebrospinal fluid and between the inner ear fluid and plasma (12) (13). Exchanges between endolymph and plasma are through the stria vascularis and between perilymph and plasma through the capillaries perilymphatic. At this level makes a pass filtering products: blood-labyrinthine barrier

This blood–inner ear barrier consist of tight junctions and other mechanisms that limit access of molecules to inner ear targets. In fact the endothelial cells are connected with tight junctions and without fenestrations (14). This network of tightly coupled endothelial cells is the dominant component of the blood-cochlear barrier which make this solid barrier impermeable to macromolecules. In addition to this physical barrier, there is a chemical barrier between blood and endolymph/perilymph wich has a selectivity to electrolytes and

In the fluid of the inner ear, there are other obstacles to the spread of drugs administered systemically: Because the scala media has a relatively high positive charge due to the endocochlear potential, the charge the drug carries will be a significant factor in its ability to

The relatively high protein content of perilymph will tend to bind drugs (16). Protein interactions with drugs are as important in the perilymph as in blood. Albumin levels are high and can bind acidic drugs, and acid glycoproteins can bind basic drugs (16). Partition coefficients of drugs with these proteins will determine free concentration of the drug. The

enter the scala media, with positively charged drugs at a disadvantage (13).

free fraction of the drug binds to the sensory cells and exerts its effect (13).

transmits acoustic vibrations from eardrum to the inner ear.

Sensorineural Hearing Loss.

**3. Anatomy** 

**4. Physiology** 

water-soluble molecules (15).

(13).

Treatment given by intratympanic will diffuse in liquid of the inner ear. There are 3 practical entry points: 1) through round window membrane RWM (at the base of the cochlea on the scala tympani side), 2) through or near the oval window (at the base of the cochlea on the scala vestibuli side), 3) through the bone of the cochlea via application in the middle ear. This infusion is mainly through the round window.

The RWM has three layers (18): an outer epithelial layer on the middle ear side, a middle fibrous layer, and another epithelial layer facing the inner ear. The outer epithelial layer contains some microvilli and abundant mitochondria, suggesting that it may be able to absorb substances and carry out metabolic activities. The inner epithelial layer has areas of discontinuous basement membrane that may provide space for substances to traverse the membrane.

Plontke (19), and colleagues have extensively modeled the distribution of drugs applied at the RWM. They suggest that in addition to diffusion along the length of the cochlea, diffusion through the tissue of the cochlea from one scala to another must be considered as well.

Some factors facilitate the passage of molecules through the round window membrane: low molecular weight, water-soluble nature, the ionic charge, histamine, prostaglandins, leukotrienes, endotoxin of E. coli, Staphylococcus exotoxins (20). The contact time with the round window membrane has the most important effect. Wang (21) demonstrates that the inner ear pharmacokinetic profile of steroids administered intratympanically is dependent upon the nature of the vehicle as well as the physicochemical properties of the steroid drug itself. In fact the degree of aqueous solubility of the drug has a major impact on its residence time and exposure in the inner ear (21).

Glucocorticoid receptors have been identified in the inner ear and are more abundant in the cochlea (22). The presence of glucocorticoid receptors in the inner ear provides a cellular means by which circulating glucocorticoids can directly affect the inner ear physiology. Corticosteroids have been used extensively for inner ear disease because of their antiinflammatory effects but also affect the vascularity of the inner ear. Corticosteroids have many effects : they prevent a decrease in cochlear blood flow, reduce degeneration of the stria vascularis and have an antioxidant effect (23).
