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Pharmacokinetics Of Drugs Acting On the Ear

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Mai Hamdy

on 18 November 2013

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Transcript of Pharmacokinetics Of Drugs Acting On the Ear

Pharmacokinetics Of Drugs Acting On the Ear
Is the study of drug absorption, distribution within body, and drug elimination over time.

Drugs administration to ear
classified as related to the route of administration to:
A)Systemic Administration:
Generally, drugs are delivered to the inner ear via the systemic route, but only a few drugs can reach the target site of action at therapeutic concentrations in the inner ear because of the presence of BLB
B) Local administration of drugs to ear
Local delivery:
1)Drugs applied to external ear (ear drops)
2) Drugs applied to middle ear (Intratympanic approaches)
3)Drugs applied to inner ear (Intracochlear administration of drugs)
By: Mai Hamdy & Rania Ebraheem
Supervisor: Dr.Dalia Kamal
Co-ordinator: Dr.Nagwa
-Drug absorption depends on the route of administration
-Drug distribution depends on how soluble the drug molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin)
-Drug elimination is accomplished by excretion into urine and/or by inactivation by enzymes in the liver
- Systemic delivery:
2. Intravenous

Local delivery:
1)Drugs applied to external ear (ear drops)
2) Drugs applied to middle ear (Intratympanic approaches)
3)Drugs applied to inner ear (Intracochlear administration of drugs)
1)Considered as the most convenient method of drug administration to the inner ear.
2)the first line approach in the treatment of inner ear disorders.
3) Easy to use by the patient.
4) Non invasive.
Disadvantages of systemic drugs acting on ear:
In order to achieve therapeutic levels of drugs in the inner ear, high systemic doses are required, which are often associated with undesirable side effects,ranging from minor nuisances to potentially life-threatening situations as follow:

1)Systemic corticosteroids are used in the management of sudden sensorineural hearing loss (SSNHL) and auto immune ear diseases (AIED),
They have side effects such as:
3)Cushing syndrome
4)Organ damage associated with long-term systemic steroid therapy
2)Systemic administration of lidocaine can relieve tinnitus,
but risks of arrhythmia and central nervous system excitation or depression are present.

3) streptomycin and gentamicin used in treatment of severe bilateral Meniere's diseases.
They are Ototoxic.
1) The drug can be administered right where it is needed
2) First pass metabolism doesn't come into play
3) Drug is delivered in a targeted manner, in adequate doses.
4) Toxicity is not common
4) Chronic inflammatory diseases of middle ear cavity causes a certain amount of fibrosis preventing adequate concentrations of systemically administered drug reaching it.

1) Drugs applied to external ear (ear drops):
Ear drops are a form of medicine used to treat or prevent ear infections, especially infections of the outer ear and ear canal (otitis externa).
easily applied b the patient.
less expensive than systemic drugs
Dose is measured in number of drops.
Use care to slowly squeeze the bottle to administer accurately.
Person must remain with treated ear up for 3-5 minutes .
Ciprodex, Gentisone HC, Ciproxin HC, Sofradex,
Also:Aqua Ear (used for swimmer's ear) containing a mixture of substances such as alcohol and acetic acid, to dry the ear and make it difficult for microbes to grow
Delivery of medication directly to the inner ear
It is done by 2 ways : Intra tympanic & Intracochlear
Inner ear drug delivery has been a challenge to physicians in the treatment of inner ear disorders. In the past decade, new biomaterials and drug delivery technologies have been developed for inner ear delivery.
To understand the challenges of drug delivery to the inner ear, the anatomy relevant to inner ear drug delivery is first discussed
Blood labrynthine barrier:
BLB is a major barrier separating the inner ear from systemic circulation with tight junctions, made up of capillary endothelial cells that line blood vessels located in the striavascularis,
It plays an important role in maintaining the microhomeostasis of the inner ear fluid.
Protecting the inner ear integrity similar to the function of the blood brain barrier (BBB) to the brain.
BLB functions not only as a physical barrier but also as a biochemical barrier with efflux pump systems.
The BLB consisting of tight junctions generally permits only the permeation of small lipid-soluble molecules.
but,a number of factors were found to lead to tight junction opening of the BLB,
Including :the presence of ototoxic drugs,noisesand inflammation, It has been reported that aminoglycosides given systemically in combination with diuretics such as furosemide or ethacrynic acid result in hearing loss and inner ear damage faster than that of aminoglycosides alone. This suggests that the diuretics can enhance drug penetration across the BLB.
The Round window membrane
The round window membrane (RMW) is a soft tissue barrier separating the middle ear from the inner ear.
It is the main passage for drug delivery from the middle ear cavity to the inner ear.
The variable RWM thickness and conditions of the membrane across the patient population is believed to be a factor leading to patient-to-patient variability in intratympanic inner ear drug delivery.
The RWM acts like a semipermeable membrane, primarily to low molecular weight molecules such as aminoglycosides & corticosteroids.
While larger molecules like albumin (MW 70,000) cannot diffuse across the RWM easily under normal conditions,
such large molecules have been shown to penetrate the RWM into the inner ear during the early phase of inflammation.
Besides the molecular weights of the drugs and disease states of the ear, other factors including the integrity of the RWM and drug lipophilicities and charges also affect the rates at which the molecules diffuse across the RWM.
In addition, the permeability of RWM is affected by local treatments with anesthetics, endotoxins and exotoxins, histamines, osmotic disturbances, and benzyl alcohol (a commonly used preservative)

How ever as a drawback . In 33% of temporal bones, the round window membrane has been shown to be obstructed with either a pseudomembrane or a fibrous or fat plug, which could prevent the drug from reaching the inner ear
2) Drugs applied to middle ear
(Intratympanic approachs)
i)Cannula-based delivery systems:
Silverstein Microwick .
Round Window Microcatheter.

A). Silverstein Microwick
B). Round Window Microcatheter
The Round Window Microcatheter is a double lumen-sustained microcatheter inserted into the round window.
It is designed to deliver drugs to the inner ear.
The catheter can be inserted into the middle ear and connected to a pump.
The Microwick is a device placed through a tympanostomy opening.
The distal end of wick is in the external auditory canal, where the patients can instill medications several times a day for several weeks. Recent studies have demonstrated the reliability and consistency of gentamicin and methylprednisolone delivery by this device

Advantage of this system:
Delivering drugs to the middle ear continuously for several days to a few weeks.
For example, by using a minipump attached to a microcatheter, gentamicin could be delivered for 10 days.
gentamicin delivery to the RWM to treat the symptoms in Meniere's diseases, patients got relief of their tinnitus and 89–100% patients recovered from vertigo symptoms.
Intratympanic infusion of steroids in patients with sensorineural hearing loss who have failed in the treatment with intravenous steroids and vasodilators.

1) The persistent perforation of the tympanic membrane
2) Risk of infection in the middle ear or external ear
3) Tissue growth in the middle ear leading to cholesteatoma.
4) Presence of anatomic barriers to absorption at the round window membrane & loss of drug down the Eustachian tube
5) Variable or unknown pharmacokinetic profiles of medications currently delivered via this route

2) Drugs applied to middle ear
(Intratympanic approachs)
ii)Sustained-release systems
Gelfoam is a biodegradable gelatin polymer,applied as a delivery vehicle
Their mechanisms are:
1.Slow degradation of the material,
2.Slow drug diffusion,
3.Or a combination of both.
1) Sustained-release drug delivery systems
2) can increase the residence time of a drug in the middle ear
3)provide controlled drug delivery to the inner ear.

basic formulation is a DISOLVABLE MATRIX
releases the medication BY HYDROLYSIS of the matrix or by basic DIFFUSION.
-Disadvantages of hydrogel
1)not ideal for chronic condition
2)CHL if Impacted in middle ear
3) drug take long period to absorb

. Nanoparticles are particles with diameters less than 1000nm and are typically in the size range of 200nm or less when used for drug delivery to the inner ear.
poly-lactic/glycolic acid (PLGA) can house medications

sustained release
They Do not cause hearing loss, cell death or morphological changes in the inner ear for up to 28 days after the application.
Delivery of medications directly to the inner ear
(Intracochlear route)
direct injections,
cochlear implants,
osmotic mini-pumps,
reciprocating perfusion systems.
the injection of drug solution directly into the cochlea through the RWM with a microsyringe and a narrow-gauge needle.
Drug Delivery with Cochlear Implant
Cochlear implant is a device inserted into the ST in the treatment of inner ear disorders.
The basic mechanism is to directly simulate SGNs with electrical pulses through an electrode, overcoming the loss of hair cells in the cochlea

Osmotic mini-pumps
They are used to directly deliver drugs into ST via cannula,
Implantable reciprocating inner ear drug delivery
1) This approach is suggested to be best suited for controlled automatically complex dosing of numerous compounds.
2) The opportunity for timed-sequence release of multiple agents for therapeutic applications that may require complex dosing of numerous compounds

This provides accurate drug delivery for acute drug application to the base of the cochlea.
Direct Injection
1) Electrode insertion deep into the cochlea could destroy the remaining acoustic hearing. Thus, this used for the treatment of severe to profound hearing loss.
2) Great risk of infection.
concurrent use of drugs with implant to reduce trauma to the inner ear or to prevent further degeneration of hearing after implantation, e.g:
Neurotrophics and steroids

1) Inability to deliver varying dosages or dosing intervals of drug
2) The inability to start and stop drug delivery externally (without removing the system),
3) The limited duration of drug delivery requiring the need for surgical access to the device if therapy is planned for a sustained period of time, such as several weeks or months

.1. Gene therapy
. Viral transgenes injected directly into the ST can provide reporter gene expression in SGNs, hair cells, and supporting cells in the organ of Corti.
.2. Stem cell therapy
Stem cell therapy to treat hearing loss has recently received attention due to its potential to replace and/or protect hair cells and SGNs after deafness
. Biotechnology-based approaches of inner ear drug delivery
In spite of these successes, an effective delivery method for stem cells to the inner ear is needed.
It was suggested that the implantation of embryonic stem cells, fetal dorsal root ganglion and otocyst cells in the inner ear could be used to restore damaged hair cells
Injection of gene transfer vehicles directly into SM can result in efficient transduction of hair cells and supporting cells.
On the other hand, the intratympanic route that requires gene delivery across the RWM by diffusion can preserve the cochlear integrity, but offer less efficient transduction in the inner ear cells.
Thank YOU
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