Bioavailability & Pharmacokinetics

o Molecular properties of the drug

o Viscosity of the vehicle

Functional status of the tissue forming the barrier to penetration

three factors influencing drug absorption

nasolacrimal drainage and blinking

Loss of drug from the eye occurs via these two methods

8-10, 30

o Normal tear volume is ____ microliters. The maximum volume that can be held in the eye at a single moment is ____ microliters. Therefore, increasing drop size (normally 50 microliters) has no effect on penetration into the cornea, but does increase systemic load and side effects.

0.5-2.2, increases

Normal tear flow rate is _____ microliters/minute. In dry eye, this rate is at the lower end of normal due to aging or atrophy of the lacrimal ducts and glands. Generally, dry eye ______ drug penetration via increased drug concentration, prolonged contact

tear film drug concentration equals corneal drug concentration

Drug penetration into the cornea ceases when...

dry eye, tear osmolarity

Hypotonic solutions are sometimes used in the treatment of ______ to reduce _____

o Increased drug concentration due to decreased dilution by tears

o Prolonged contact time with the cornea

o Epithelial surface damage allows greater drug penetration

three Influences of Dry Eye on Ophthalmic Drug Administration

Bioavailability

the rate and extent to which an administered drug reaches the systemic circulation. It is dependent on the amount of the drug present at the receptor site.

ED50

the dose level producing a therapeutic response that is 50% of the maximum desired response.

Zero order kinetics

drug kinetics that implies a constant drug release over a period of time. The concentration of the drug release is independent of drug concentration in the body.

Ocusert and lacrisert

two drug release systems used in dry eye that are not commonly used

Retisert

an intravitreal implant that delivers fluocinolone (steroid) for the treatment of noninfectious posterior uveitis. Can administer the drug for about 30 months.

Surodex

an intravitreal implant that delivers dexamethasone (steroid) for the prevention of postoperative inflammation following cataract surgery.

Posurdex

an intravitreal implant that delivers dexamethasone (steroid) in a biodegradable matrix that will degrade completely after about 37 days.

Vitrasert

an intravitreal implant that delivers ganciclovir for the treatment of CMV retinitis. Therapeutic levels can be administered for about 5-8 months following surgical implantation.

First order kinetics

drug kinetics where the rate of drug movement is directly proportional to the drug concentration gradient across the barrier.

Prodrug

a metabolite of a drug that is more active than the parent form at the receptor site. Must be metabolized predictably to the effective drug form before it reaches the receptor site to be therapeutically useful. Its added groups function to aid in the penetration of the drug and the minimization of side effects.

Latanoprost and travoprost

two examples of ocular prodrugs

Vehicle

an agent other than the active drug or preservative added to a formulation to provide proper tonicity, buffering, and viscosity to complement drug action. I.e.) carboxymethylcellulose, petrolatum

§ Increase viscosity

§ Delay washout by tear film

§ Increase bioavailability

High molecular weight polymers used as drug vehicles because they... (3 answers)

o Brimonidine

o Digitalis

o Phenothiazines

o Quinine

four Drugs Toxic to the Retina

o Chloramphenicol

o Ethambutol

o Streptomycin

o Sulfonamides

four Drugs Toxic to the Optic Nerve

Preservatives

found in various drug formulations these can irritate and damage the ocular surface when used at high concentrations. They block normal metabolic processes. Additionally, they are bacteriostatic or bactericidal but act non-selectively against all cells. I.e.) surfactants, iodine, mercurial, alcohols

Oxidative preservatives

a relatively new class of preservatives that can penetrate cell membranes and interfere with essential cellular function but have very low toxicity. Are less detrimental to ocular surfaces than surfactant preservatives because they can be neutralized by cells.

hydrogen peroxide, stabalized oxychlorocomplex (purite), sodium perborate

three oxidative preservatives

Hydrogen peroxide

oxidative preservative that is used as an effective contact lens disinfectant.

Sodium perborate

oxidative preservative that is converted to hydrogen peroxide and then oxygen and water once in the eye.

Surfactants

class of preservatives that are ionically charged molecules that can disrupt the plasma membrane and are usually bactericidal. I.e.) benzalkonium chloride

Benzalkonium chloride

a quaternary surfactant that is known to increase drug penetration. It was previously preferred due to its stability, antimicrobial properties, and long shelf life. It is not commonly used currently because it causes desquamation of the corneal epithelium by arresting cell growth and causing necrosis. Additionally, it has a detergent effect on the tear film.

hypotonic, 290, 0.9, salts, buffering agents, sugars

The combination of the active drug, preservative, and vehicle must be ____, having an osmolarity of about ___ mOsm equivalent to ___% saline. This is achieved by the addition of _____ (3)

temperature, pH, and electrolyte composition

Gel forming systems can be induced by alterations in these three factors

gelrite

a polysaccharide gum that forms a clear gel in the presence of mono or divalent cations seen in tears. This increases corneal penetration and prolongs the action of topically applied ocular drugs

compartment

a region of tissue or fluid through which a drug can diffuse and equilibrate with relative freedom. Is separated by other tissue regions by barriers.

cornea

the major site of absorption for topically applied drugs

lipophilic

does the corneal epithelium allow the penetration of lipophilic or hydrophilic drugs?

1

For a drug to penetrate well, it should have a partition coefficient of about ___ meaning that is it moderately lipophilic and hydrophilic.

hydrophilic

does the corneal stroma allow the penetration of lipophilic or hydrophilic drugs?

lipophilic

do keratocytes found in the corneal stroma serve as a reservoir for lipophilic or hydrophilic drugs?

Descemet’s membrane and corneal endothelium

two layers of the cornea that are not considered major reservoir for drugs. This is because they are very thin layers.

one fifth, extensive vascularization

These two ocular structures are responsible for less than ____ of drug absorption into the iris and ciliary body. Absorption by these structures is limited due to ____ that causes rapid removal of drugs.

large surface area

One benefit of the conjunctiva over the cornea is that is has a _____ for drug administration into intraocular tissues

lipophilic (ie chloroquine)

Do pigment granules found in the iris and ciliary epithelium serve as reservoir for lipophilic or hydrophilic drugs?

tight junctions, nonpigmented epithelium

The ciliary body limits the passage of drugs via ____ located in the ____. It is also the source of major drug metabolizing enzymes.

Tight junctions

____ found in the RPE and making up the outer blood retinal barrier function to prevent the movement of drugs from the blood to the retina and vitreous.

short half life

Drugs which are removed from the eye by both the retinal and uveal vessels exhibit a very...