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Other Topics EXAM 1
Other Topics EXAM 1 - Witt
65
Pharmacology
Graduate
03/13/2012

Additional Pharmacology Flashcards

 


 

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Term
eye drug delivery
Definition
the eye is a specialized sensory organ that is relatively secluded from systemic access by the blood-retinal barrier (separates the neural tissue of the retina from the blood) and blood-aqueous barrier (regulates the exchanges between the blood and the intraocular fluids)

as a consequence, the eye exhibits some unusual pharmacodynamic and pharmacokinetic properties

b/c of its anatomical isolation, the eye offers a unique, organ-specific pharmacological laboratory to study the autonomic nervous system and effects of inflammation and infectious diseases

no other organ in the body is so readily accessible or as visible for observation

however, the eye also presents some unique opportunities as well as challenges for drug delivery
Term
functions of eyelids
Definition
the eyelids serves several functions

foremost, their dense sensory innervation and eyelashes protect the eye from mechanical and chemical injuries

blinking serves to distribute tears over the cornea and conjunctiva

in humans, the average blink rate is 15 to 20 times per minutes

the external surface of the eyelids is covered by a thin layer of skin

the internal surface is lined with the palpebral portion of the conjunctiva which is a vascularized mucous membrane continuous with the bulbar conjunctiva, which is a vascularized mucous membrane continuous with the bulbar conjunctiva

at the reflection of the palpebral and bulbar conjunctivae is a space called the fornix, located superiorly and inferiorly behind the upper and lower eyelids, respectively.

topical medications usually are placed in the inferior fornix, also known as the inferior cul-de-sac
Term
extraocular structures
Definition
[image]

the eye is protected by the eyelids and by the orbit, a bony cavity of the skull that has multiple fissures and foramina that conduct nerves, muscles, and vessels

in the orbit, connective and adipose tissues and six extraocular muscles support and align the eyes for vision

the retrobulbar region lies immediately behind the eye (or globe)

understanding ocular and orbital anatomy is important for safe periocular drug delivery, including subconjunctival, sub-Tenon's, and retrobulbar injections
Term
extraocular muscles
Definition
the EXTRAOCULAR MUSCLES are the six muscles that control the movements of the eye

the actions of the extraocular muscles depend on the position of the eye at the time of muscle contraction

five of the extraocular muscles have their origin in the back of the orbit in a fibrous ring called the annulus of Zinn
Term
lacrimation and drainage
Definition
[image]

the tear drainage system starts through small puncta located on the medial aspects of both the upper and lower eyelids

with blinking, tears enter the puncta and continue to drain through the canaliculi, lacrimal sac, nasolacrimal duct, and then into the nose

the nose is lined by a highly vascular mucosal epithelium; consequently, TOPICALLY APPLIED MEDICATIONS THAT PASS THROUGH THIS NASOLACRIMAL SYSTEM HAVE DIRECT ACCESS TO THE SYSTEMIC CIRCULATION
Term
tear film coating
Definition
TEARS are a liquid process of lacrimation to clean and lubricate the eyes

in humans, the tear film coating the eye has 3 distinct layers, from the most outer surface:

LIPID LAYER
contains oils (sebum) secreted by the MEIBOMIAN GLANDS
the outer-most layer of the tear film coast the aqueous layer to provide a hydrophobic barrier that retards evaporation and prevents tears spilling onto the cheek

AQUEOUS LAYER
contains water and other substances such as proteins secreted by the glands and the lacrimal gland
the aqueous layer serves to promote spreading of the tear film, control of infectious agents and osmotic regulation

MUCOUS LAYER
contains mucin secreted by the conjunctival goblet cells
the inner-most layer of the tear film, it coats the cornea to provide a hydrophilic layer that allows for even distribution of the tear film, as well as mucus covering the cornea
Term
3 types of tears
Definition
BASAL TEARS

in healthy mammalian eyes, the cornea is continually kept wet and nourished by basal tears

they lubricate the eye and help to keep it clear of dust

tear fluid contains water, mucin, lipids, lysozyme, lactoferrin, lipocalin, lacritin, immunoglobulins, glucose, urea, sodium, and potassium

some of the substances in lacrimal fluid fight against bacterial infection as a part of the immune system

REFLEX TEARS

the second type of tears results from irritation of the eye by foreign particles, or from the presence of irritant substances such as onion vapors, tear gas, or pepper spray in the eye's environment

these reflex tears attempt to wash out irritants that may have come into contact with the eye

CRYING OR WEEPING (PSYCHIC TEARS)

the third category, generally referred to as crying or weeping, is increased lacrimation due to strong emotional stress, depression, or physical pain

although most land mammals have a lacrmation system to keep their eyes wet, humans are the only animal generally accepted to cry emotional tears
Term
functions of a healthy tear film
Definition
optical clarity and refractive power

ocular surface comfort (i.e. lubrication)

protection from environmental and infectious insults:
anti-bacterial proteins, antibodies, complement
reflex tears to flush away particles

nutrient environment for corneal epithelium:
necessary electrolytes, correct pH
protein factors for growth and wound healing
Term
anatomy of eye
Definition
[image]

the eye is divided into anterior and posterior segments

anterior segment structures include the cornea, limbus, anterior and posterior chambers, trabecular meshwork, Schlemm's canal, iris, lens, zonule, and ciliary body

the posterior segment comprises the vitreous, retina, choroid, sclera, and optic nerve
Term
anterior anatomy of the eye: cornea
Definition
the cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber, providing most of an eye's optical power

together with the lens, the cornea refracts light, and as a result helps the eye to focus, accounting for approximately 80% of its production to 20% of the lens focusing power

the cornea contributes more to the total refraction than the lens does, but, whereas the curvature of the lens can be adjusted to "tune" the focus depending upon the object's distance, the curvature of the cornea is fixed

the cornea has unmyelinated nerve endings sensitive to touch, temperature, and chemicals

a touch of the cornea causes an involuntary reflex to close the eyelid

because transparency is of prime importance the cornea does not have blood vessels

it receives nutrients via diffusion from the tear fluid at the outside and the aqueous humor at the inside and also from neurotrophins supplied by nerve fibres that innervate it

TRANSPARENCY, AVASCULARITY, AND IMMUNOLOGIC PRIVILEGE MAKES THE CORNEA A VERY SPECIAL ISSUE. THE CORNEA IS THE ONLY PART OF A HUMAN BODY THAT HAS NO BLOOD SUPPLY, IT GETS OXYGEN DIRECTLY THROUGH THE AIR.

the cornea is a transparent and avascular tissue organized into 5 layers: epithelium, Bowman's membrane, stroma, Descemet's membrane, and endothelium

[image]

CORNEAL EPITHELIUM:
a thin epithelial multicellular layer of fast-growing and easily-regenerated cells, kept moist with tears
representing an important barrier to goreign matter, including drugs, the hydrophobic epithelial layer comprises 5-6 cell layers
irregularity or edema of the corneal epithelium disrupts the smoothness of the air-tear film interface, the most significant component of the total refractive power of the eye, thereby reducing visual acuity

BOWMAN'S LAYER:
it is not actually a membrane but a condensed layer of collagen - a tough layer that protects the corneal stroma, consisting of irregularly-arranged collagen fibers
this layer lies beneath the epithelium and is very difficult to penetrate
the difficult access to the Bowman's membrane protects the cornea from injury
but once injured, it resiliently regenerates
it leaves a scar when the injury is deeper
the scar becomes opaque areas, causing the cornea to lose its clarity and luster

CORNEAL STROMA (also substantia propria):
a thick, transparent middle layer, consisting of regularly-arranged collagen fibers along with sparsely populated keratocytes
constituting approximately 90% of the corneal thickness, the stroma, a hydrophilic layer, is uniquely organized with collagen lamellae, synthesized by keratocytes

DESCEMET'S MEMBRANE (also posterior limiting membrane):
a thin acellular layer that serves as the modified basement membrane of the corneal endothelium

CORNEAL ENDOTHELIUM:
a simple squamous or low cuboidal monolayer of mitochondria-rich cells responsible for regulating fluid and solute transport between the aqueous and corneal stromal compartments
these cells maintain corneal integrity by active transport processes and serve as a hydrophobic barrier
endothelial cells are essential in keeping the cornea clear
it pumps this excess fluid out of the stroma, which has the danger of swelling with water
once endothelium cells are destroyed by disease or trauma, they cannot be recovered
too much damage to endothelial cells can lead to corneal edema (swelling caused by excess fluid) and blindness ensues, with corneal transplantation the only available therapy
Term
anterior anatomy of eye: anterior chamber
Definition
[image]

the ANTERIOR CHAMBER is the fluid-filled space inside the eye between the iris and the cornea's innermost surface, the endothelium

aqueous humor is the fluid that fills then anterior chamber
Term
anterior anatomy of the eye: trabecular meshwork
Definition
[image]

the TRABECULAR MESHWORK is an area of tissue in the eye located around the base of the cornea, near the ciliary body, and is responsible for draining the aqueous humor from the eye via the anterior chamber (the chamber on the front of the eye covered by the cornea)
Term
anterior anatomy of the eye: Schlemm's canal (canal of Schlemm, scleral venous sinus)
Definition
[image]

the CANAL OF SCHLEMM is a circular channel in the eye that collects aqueous humor from the anterior chamber and delivers it into the bloodstream

the canal is essentially an endothelium-lined tube, resembling that of a lymphatic vessel

on the inside of the canal, nearest to the aqueous humor, it is covered by the trabecular meshwork, this region makes the greatest contribution to outflow resistance of the aqueous humor

note: another outflow pathway is the UVEOSCLERAL ROUTE (i.e. fluid flows through the ciliary muscles and into the suprachoroidal space), which is the target of selective prostanoids
Term
anterior anatomy of eye: ciliary body
Definition
[image]

the CILIARY BODY is the circumferential tissue inside the eye composed of the CILIARY MUSCLE AND CILIARY PROCESSES

the ciliary body has 3 functions:
accommodation
aqueous humor production
production and maintenance of the lens zonules

the most essential roles of the ciliary processes is the production of the aqueous humor, which is responsible for providing most of the nutrients for the lens and the cornea and involved in wast management of these areas

it is the main target for drugs against glaucoma, as the ciliary body is responsible for aqueous humor production; lowering aqueous humor production will cause a subsequent drop in the intraocular pressure

there are 3 sets of ciliary muscles in the eye, the longitudinal, radial, and circular muscles

they are near the front of the eye, above and below the lens

they are attached to the lens by connective tissue called the zonule of Zinn (i.e. suspensor ligaments), and are responsible for SHAPING THE LENS TO FOCUS LIGHT ON THE RETINA

the ciliary muscles receive parasympathetic innervation from the oculomotor nerve. the accommodate for near-vision, the parasympathetic nerves to the ciliary muscle are activated, causing contraction.

when the ciliary muscle relaxes, it flattens the lens, generally improving the focus for farther objects. when it contracts, the lens becomes more convex, generally improving the focus for closer objects

contraction of the ciliary muscles also puts tractioin on the scleral spur, and hence widens the spaces within the trabecular meshwork. this latter effect accounts for at least some of the intraocular pressure lowering effect of both directly acting and indirectly acting parasympathomimetic drugs
Term
anterior anatomy of eye: aqueous humor
Definition
functions:

1) maintains the intraocular pressure and inflates the globe of the eye; providing magnification power to the cornea

2) provides nutrition for the avascular ocular tissues; posterior cornea, trabecular meshwork, lens, and anterior vitreous

3) carries away wast products from metabolism of the above avascular ocular tissues

4) presence of immunoglobulins indicate a role in immune response to defend against pathogens

aqueous humor is secreted by the ciliary processes and flows from the posterior chamber, through the pupil, into the anterior chamber, and leaves the eye primarily by the trabecular meshwork and canal of Schlemm

from the canal of Schlemm, aqueous humor drains into an episcleral venous plexus and into the systemic circulation

this conventional pathway accounts for 80% to 95% of aqueous humor outflow and is the main target for cholinergic drugs used in glaucoma therapy

another outflow pathway is the uveoscleral route (i.e. fluid flows through the ciliary muscles and into the suprachoroidal space), which is the target of selective prostanoids

[image]
Term
anterior anatomy of eye: lens
Definition
the lens, a transparent biconvex structure, is suspended by zonules, specialized fibers emanating from the ciliary body

the lens is approximately 10 mm in diameter and is enclosed in a capsule

the bulk of the lens is composed of fibers derived from proliferating lens epithelial cells located under the anterior portion of the lens capsule

these lens fibers are continuously produced throughout life

aging, in addition to certain medications, such as corticosteroids, and certain diseases, such as diabetes mellitus, cause the lens to become opacified, which is termed a cataract

the LENS is a transparent, biconvex structure in the eye that, along with the cornea, helps to refract light to be focused on the retina. its function is thus similar to a human-made optical lens

CRYSTALLINS are water-soluble structural proteins found in the lens and the cornea of the eye accounting for the transparency of the structure.
Term
function of the lens
Definition
the principle function of the lens is to change the focal distance of the eye to allow focusing on objects at various distances

this adjustment of the lens is known as ACCOMMODATION

it is similar to the focusing of a photographic camera via movement of its lenses

the ciliary muscle (circular muscle) is innervated by the parasympathetic fibers

the suspensory ligaments are attached to the ciliary muscle and to the margins of the lens in a circular arrangement

the lens of the eye is soft (until the age of ~40 years), like a water-filled plastic bag.

[image]

when the ciliary muscle relaxed (large ring), the suspensory ligaments tug on the margins of the lens to flatten it.

WHEN FLAT, THE REFRACTORY INDEX IS LOW, AND THE LENS IS ADJUSTED FOR DISTANT VISION

to accommodate for near vision, the parasympathetic nerves to the ciliary muscle are activated, causing ciliary muscle to contract and form a smaller ring

AS THE RING BECOMES SMALLER, TENSION ON THE SUSPENSORY LIGAMENTS IS REDUCED AND THE LENS PASSIVELY ASSUMES A ROUNDED (SPHERICAL) SHAPE, INCREASING THE REFRACTORY INDEX AND ACCOMMODATING FOR NEAR VISION

CYCLOPLEGIA - paralysis of the ciliary muscles of the eye that results in the loss of visual accommodation

cycloplegic drugs are generally muscarinic receptor blockers
these include atropine, cyclopentolate, homatropine, scopolamine, and tropicamide
they are indicated for use in cycloplegic refractions and the treatment of uveitis (i.e. inflammation of the iris, ciliary body, and/or choroid)
many cycloplegics are also mydriatic (pupil dilating) agents and are used as such during ophthalmoscopic examinations to better visualize the retina
Term
anterior anatomy of eye: iris and pupil
Definition
CONSTRICTOR MUSCLE (CONSTRICTOR PUPILLAE) = PARASYMPATHETIC

RADIAL MUSCLE (DILATOR PUPILLAE) = SYMPATHETIC

[image]

the IRIS consists of pigmented fibrovascular tissue known as a stroma

the iris contains 2 sets of muscles: CONSTRICTOR MUSCLE (CONSTRICTOR PUPILLAE) and the RADIAL MUSCLE (DILATOR PUPILLAE)

WHEN THE CONSTRICTOR MUSCLES CONTRACT, THE PUPIL BECOMES SMALLER (MIOSIS), LETTING IN LESS LIGHT. THE CONSTRICTOR MUSCLE IS INNERVATED BY CHOLINERGIC PARASYMPATHETIC POSTGANGLIONIC FIBERS.

WHEN THE RADIAL MUSCLE CONTRACT, THE PUPIL BECOMES LARGER (MYDRIASIS), LETTING IN MORE LIGHT. THE RADIAL MUSCLE IN INNERVATED BY SYMPATHETIC NOREPINEPHRINE POSTGANGLIONIC FIBERS.

example of light mediated action:
when the eye is exposed to bright light, a light reflex is activated.
this results in inhibition of the sympathetic pathway to the radial muscle and an increase in firing from the parasympathetic system to the constrictor muscle.
end result: pupil gets small
in terms of neurotransmission: on the parasympathetic side acetylcholine is acting on muscarinic cholinergic receptors on the constrictor muscle causing contraction (miosis).
when bright light is removed and pupillary dilation is desirable parasympathetic firing to the iris decreases and sympathetic activity to the radial muscle increases.
thus, norepinephrine is the neurotransmitter released from the sympathetic postganglionic nerve terminal where it acts on alpha adrenergic receptors of radial muscle to induce contraction and mydriasis

bright light -> release of acetylcholine -> activation of muscarinic parasympathetic system -> constriction of constrictor muscle -> miosis

low light -> release of NE -> activation of alpha adrenergic sympathetic receptors -> contraction of radial muscle -> mydriasis

the PUPIL is the variable-sized, black circular or slit shaped opening in the center of the iris that regulates the amount of light that enters the eye

it appears black because most of the light entering the pupil is absorbed by the tissues inside the eye.
Term
muscarinic agonist (pilocarpine, brimonidine) effect on constrictor pupillae and ciliary muscle
Definition
constrictor pupillae -> contraction -> miosis

ciliary -> contraction -> accomodation (near sight)
Term
muscarinic antagonist (atropine, scopolamine) effect on constrictor pupillae and ciliary muscle
Definition
constrictor pupillae -> relaxation -> mydriasis

ciliary -> relaxation -> cycloplegia
Term
alpha adrenergic agonist (apraclonidine, clonidine) effect on dilator pupillae and ciliary muscle
Definition
dilator pupillae -> contraction -> mydriasis

ciliary -> none
Term
posterior anatomy of eye: vitreous humor
Definition
the vitreous is the transparent, colorless, gelatinous mass that fills the space between the lens of the eye and the retina lining the back of the eye

it contains very few cells (mostly phagocytes which remove unwanted cellular debris in the visual field), no blood vessels, and 99% of its volume is water with salts, sugars, and a network of collagen fibers with hyaluronic acid accounting for the rest

however, the vitreous has a viscosity 2-4 times that of pure water, giving it a gelatinous consistency
Term
posterior anatomy of eye: sclera
Definition
the outermost coat of the eye, the sclera, covers the posterior portion of the globe

the external surface of the scleral shell is covered by an episcleral vascular coat, by Tenon's capsule, and by the conjunctiva

the tendons of the six extraocular muscles insert into the superficial scleral collagen fibers

numerous blood vessels pierce the sclera through emissaria to supply as well as drain the choroid, ciliary body, optic nerve, and iris

the sclera is the opaque (usually white), fibrous, protective, outer layer of the eye containing collagen and elastic fibers
Term
posterior anatomy of eye: choroid
Definition
inside the scleral shell, the vascular choroid nourishes the outer retina by a capillary system in the choriocapillaris

between the outer retina and the choriocapillaris lie Bruch's membrane and the retinal pigment epithelium, whose tight junctions provide an outer barrier between the retina and the choroid

the retinal pigment epithelium serves many functions, including vitamin A metabolism, phagocytosis of the rod outer segments, and multiple transport processes

the choroid is the vascular layer of the eye lying between the retina and the sclera

the choroid provides oxygen and nourishment to the outer layers of the retina
Term
posterior anatomy of eye: retina
Definition
the retina is a thin, transparent, highly organized structure of neurons, glial cells, and blood vessels

the vertebrate retina contains photoreceptor cells (rods and cones) that respond to light; the resulting neural signals then undergo complex processing by other neurons of the retina

the retinal output takes the form of action potentials in retinal ganglion cells whose axons form the optic nerve

several important features of visual perception can be traced to the retinal encoding and processing of light

an area of the retina is the optic disc, sometimes known as "the blind spot" b/c it lacks photoreceptors

the optic disc appears as an oval white area of 3 mm

temporal (in the director of the temples) to this disc is the macula

at the center of the macula is the fovea, a pit that is most sensitive to light and is responsible for our sharp central vision

the FOVEA, also known as the fovea centralis, is part of the eye, located in the center of the macula region of the retina

the fovea is responsible for sharp central vision, which is necessary in humans for reading, watching television or movies, driving, and any activity where visual detail is of primary importance

the retina is made of 8 LAYERS
Term
posterior anatomy of eye: rods (photoreceptors)
Definition
low threshold (low intensity light)

low acuity, but high sensitivity

not present on fovea

monochromatic (RHODOPSIN)

slower response

loss causes night blindness

ROD CELLS, or RODS, are photoreceptor cells int he retina of the eye that can function in less intense light than can the other type of photoreceptor, cone cells.

since they are more light-sensitive, rods are responsible for night vision

named for their cylindrical shape, rods are concentrated at the outer edges of the retina and are used in peripheral vision

there are about 120 million rod cells in the human retina

a rod cell is sensitive enough to respond to a single photon of light, and is about 100 times more sensitive to a single photon than cones
Term
posterior anatomy of eye: cones (photoreceptors)
Definition
high threshold (day vision)

high acuity

3 types of cones (S, M, L)

color vision (PHOTOPSINS)

present on fovea

quick response

loss causes legal blindness

CONE CELLS, or CONES, are photoreceptor cells in the retina of the eye which function best in relatively bright light

the cone cells gradually become more sparse toward the periphery of the retina

cones are less sensitive to light than the rod cells in the retina (which support vision at low light levels), but allow the perception of color

they are also able to perceive finer detail and more rapid changes in images, b/c their response time to stimuli are faster than those of rods

b/c humans usually have 3 kinds of cones, with different photopsins, which have different response curves, and thus respond to variation in color in different ways, they have trichromatic vision

the first responds most to light of long wavelengths, peaking in the yellow region; this type is designed L for long

the second type responds most to light of medium wavelength, peaking at green, and is abbreviated M for medium

the third type responds most to short wavelength light, of a violet color, and is designated S for short

the difference in the signals received from the 3 cone types allows the brain to perceive all possible colors, through the opponent process of color vision
Term
posterior anatomy of eye: optic disc (i.e. optic nerve head)
Definition
location where ganglion cell axons exit the eye to form the optic nerve

1-1.2 million neurons

"blind spot"

small depression in the disc is referred to as the "cup"

the OPTIC DISC or OPTIC NERVE HEAD is the location where ganglion cell axons exit the eye to form the optic nerve

there are no light sensitive rods or cones to respond to a light stimulus at this point

this causes a break in the visual field called "the blind spot" or the "physiological blind spot"

the blind spot (scotoma) is not readily observed as our brains fills in with surrounding detail and with information from the other eye, so the blind spot is not normally perceived

the optic cup is a cup-like area in the center of the optic disc

optic cup to the optic disc (or cup-to-disc ratio) is measured to diagnose glaucoma

glaucoma, in association with increased IOP, produces additional pathological cupping of the optic disc

as glaucoma advances, the cup enlarges until it occupies most of the disc area

the cup-to-disc ratio compares the diameter of the "cup" portion of the optic disc with the total diameter of the optic disc

if the cup fills 1/10 of the disc, the ration will be 0.1

if it fills 7/10 of the disc, the ratio is 0.7

a large cup-to-disc ratio may imply glaucoma or other pathology
Term
pharmacokinetics and toxicology of ocular therapeutics
Definition
formulations PROLONGING TIME OF DRUG ON EYE SURFACE

gels - release drugs by diffusion following erosion of soluble polymers
the polymers used include cellulosic ethers, polyvinyl alcohol, carbopol, polyacrylamide, polymethylvinyl ether-maleic anhydride, poloxamer 407, and puronic acid

ointments (mineral oil and a petrolatum base) - helpful in delivering antibiotics, cycloplegic drugs, or miotic agents

solid inserts - provide a zero-order rate of delivery by steady-state diffusion, whereby drug is released at a more constant rate over a finite period of time rather than as a bolus; the intent is to deliver a sustained dose of medication over several months with reduced spikes in drug delivery independent of patient compliance

soft contact lens

collagen shields

eye drops

several formulations prolong the time a drug remains on the surface of the eye
Term
pharmacokinetics and toxicology of ocular therapeutics: absorption/distribution
Definition
[image]

a number of delivery systems have been developed for treating ocular diseases

most ophthalmic drugs are delivered in solutions, but for compounds with limited solubility, a suspension form facilitates delivery

classical pharmacokinetic theory based on studies of systemically administered drugs does not fully apply to all ophthalmic drugs

although similar principles of absorption, distribution, metabolism, and excretion determine the fate of drug disposition in the eye, alternative routes of drug administration, in addition to oral and intravenous routes, introduce other variables in compartmental analysis

transcorneal and tranconjunctival/scleral absorption are the desired routes for localized ocular drug effects.

the time period between drug instillation and its appearance in the aqueous humor is defined as the lag time

the drug concentration gradient between the tear film and the cornea and conjunctival epithelium provides the driving force for passive diffusion accross these tissues

other factors that affect a drug's diffusion capacity are the size of the molecule, chemical structure, and steric configuration

transcorneal drug penetration is conceptualized as a differential solubility process; the cornea may be thought of as a trilamellar "fat-water-fat" structure corresponding to the epithelial, stromal, and endothelial layers

the epithelium and endothelium represent barriers for hydrophilic stubstances; the stroma is a barrier for hydrophobic compounds

hence, a drug with both hydrophilic and lipophilic properties is best suited for transcorneal absorption

topically administered drugs may undergo systemic distribution primarily by nasal mucosal absorption and possibly by local ocular distribution by transcorneal/transconjunctival absorption

following transcorneal absorption, the aqueous humor accumulates the drugs, which then is distributed to intraocular structures as well as potentially to the systemic circulation via the trabecular meshwork pathway
Term
pharmacokinetics and toxicology of ocular therapeutics: elimination
Definition
nasolacrimal drainage

drug binding to tear proteins

drug metabolism

diffusion across the cornea and conjunctiva

after topical instillation of a drug, the rate and extent of absorption are determined by the time the drug remains in the cul-de-sac and precorneal tear film, elimination by nasolacrimal drainage, drug binding to tear proteins, drug metabolism by tear and tissue proteins, and diffusion across the cornea and conjunctiva

a drug's residence time may be prolonged by changing its formation

residence time also may be extended by blocking the egress of tears from the eye by closing the tear drainage ducts with plugs or cautery

nasolacrimal drainage contributes to systemic absorption of topically administered ophthalmic medications

absorption from the nasal mucosa avoids so-called first-pass metabolism by the liver, and consequently significant systemic side effects may be caused by topical medications, especially when used chronically
Term
glaucoma
Definition
GLAUCOMA is a group of diseases of the optic nerve involving loss of retinal ganglion cells in a characteristic pattern of optic neuropathy

increased intraocular pressure (IOP)

optic nerve ischemia

reduced or dysregulated blood flow

excitotoxicity (excess glutamate?)

auto-immune reactions

associations/causations?
A CLEARLY DEFINED CAUSATION OF GLAUCOMATOUS OPTIC NEUROPATHY IS PRESENTLY UNKNOWN

increased IOP:
>22mmHg = ocular hypertension
>30mmHg = optic nerve damage
determined via aqueous humor (circadian regulation)

worldwide, glaucoma is the second leading cause of blindness

glaucoma affects one in 200 people aged 50 and younger and 1 in 10 over the age of 80

the average IOP in a normal population is 14-16 mmHg; in a normal population pressures up to 20 mmHg may be within normal range

a pressure of 22 (ocular hypertension) is considered to be high

although markedly elevated intraocular pressures (e.g. greater than 30 mmHg) usually will lead to optic nerve damage, the optic nerves in certain patients apparently can tolerate intraocular pressures in the mid-to-high 20s; these patients are referred to as ocular hypertensives
Term
open angled glaucoma
Definition
[image]

open angled glaucoma is believed to be caused by the inability of the cells in the trabecular meshwork to carry out their normal function, or there may be fewer cells present, as a natural result of growing older; others believe it is caused by enzymatic problems

PRIMARY OPEN ANGLED:
bilateral
genetic
60-70% of all glaucoma
90-95% of primary glaucoma
symptoms occur upon substantial visual field constriction

SECONDARY OPEN ANGLED
disease
trauma
surgery
medication
Term
closed angle glaucoma
Definition
[image]

primary closed angle: mechanical blockade of trabecular meshwork by iris

this type of glaucoma is also known as acute glaucoma or narrow angle glaucoma

it is much more rare and is very different from open angle glaucoma in that the eye pressure usually rises very quickly

this happens when the drainage canals get blocked or covered over, like a sink with something covering the drain

with angle closure glaucoma, the iris is not as wide and open as it should be

the outer edge of the iris bunches up over the drainage canals, when the pupil enlarges too much or too quickly; this can happen when entering a dark room

< 5% of primary glaucoma

emergency treatment may be necessary
Term
glaucoma treatment
Definition
decrease production of aqueous humor (ciliary body)

increase outflow (trabecular meshwork or uveoscleral)

[image]

current pharmacotherapies are targeted to decrease the production of aqueous humor at the ciliary body and to increase outflow through the trabecular meshwork and uveoscleral pathways

the goal is to prevent progressive glaucomatous optic nerve damage with minimum risk and side effects from either topical or systemic therapy
Term
glaucoma treatment: beta blockers (first line therapy)
Definition
beta 2 adrenergic receptor blockade in ciliary process produces ocular hypotensive effects via DECREASING AQUEOUS HUMOR

lower IOP 2-30%

5 current drugs with differences in potency, lipophilicity, and intrinsic activity (but general lower IOP equally):
betaxolol (beta-1 selective)
carteolol
levobunolol
metirpranolol
timolol (Timoptic-XE: gel-forming solution)

production of aqueous humor seems to be activated by a receptor medicated cyclic AMP-PKA pathway

blockade blunts adrenergic activity of this pathway by preventing catecholamine stimulation of the receptor, thereby decreasing intracellular cAMP

another hypothesis is that blockers decrease ocular blood flow, which decreases the ultrafiltration responsible for aqueous production

systemic effects are the most important adverse effects of beta blockers

drug absorbed systemically may produce decreased heart rate, reduced blood pressure, negative inotropic effects, conduction defects, bronchospasm, central nervous system effects, and alteration of serum lipids, and may block the symptoms of hypoglycemia
Term
glaucoma treatment: prostaglandin analogs, PGF2alpha analogs
Definition
prostaglandin analogs lower intraocular pressure, theorized by facilitating aqueous outflow through the accessory uveoscleral outflow

ALSO CONSIDERED FIRST LINE (but more expensive)

well tolerated with low systemic impact

altered iris pigmentation

latanoprost, travoprost, bimatoprost, tafluprost

in primates and humans, PGF2 analogs appear to lower intraocular pressure by facilitating aqueous outflow through the accessory uveoscleral outflow pathway

the mechanism by which this occurs is unclear

PGF2 and its analogs (prodrugs that are hydrolyzed to PGF2) bind to FP receptors that link to Gq11 and then to the PLC-IP3-Ca pathway

this pathway is active in isolated human ciliary muscle cells

other cells in the eye also may express FP receptors

theories of IOP lowering by PGF2 range from altered ciliary muscle tension to effects on trabecular meshwork cells to release of matrix metalloproteases and digestion of extracellular matrix materials that may impede outflow tracts

there also is less myocilin protein noted in monkey smooth muscle after PGF2 treatment
Term
glaucoma treatment: carbonic anhydrase inhibitors
Definition
carbonic anhydrase inhibitors reduce IOP by decreasing ciliary body aqueous humor secretion

blockade of Na and bicarbonate ions

topical:
brinzolamide
dorzolamide

systemic:
acetazolamide
methazolamide

[image]

inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion and thus lowers the intraocular pressure in the anterior chamber, presumably by reducing the rate of formation of bicarbonate ions with subsequent reduction in Na and fluid transport; this alleviates the effects of open angle glaucoma

topical CAIs are well tolerated and are indicated for monotherapy or adjunctive therapy of open angle glaucoma and ocular hypertension
relatively specific inhibitors of carbonic anhydrase enzyme II such as dorzolamide and brinzolamide reduce IOP by 15-26%

systemic CAIs are indicated in patients failing to respond to or tolerate maximum topical therapy

systemic and topical CAIs should not be used in combination b/c no data exists concerning improved IOP reduction, and the risk for systemic ADRs is increased
Term
glaucoma treatment: alpha-2 agonists
Definition
alpha-2 agonists reduce aqueous production and may enhance some uveoscleral outflow

reduce sympathetic neurotransmitter release (pre-synaptic)

Gi coupled receptors, decrease cAMP (post synaptic) reducing aqueous humore production

apraclonidine, brimonidine

apraclonidine:
a relatively selective alpha-2 adrenergic agonist that is highly ionized at physiologic pH and therefore does not cross the BBB

brimonidine:
also a selective alpha-2 adrenergic agonist, but is lipophilic, enabling easy corneal penetration

both apraclonidine and brimonidine reduce aqueous production and may enhance some uveoscleral outflow

both appear to bind to pre and post synaptic alpha2 receptors

by binding to the presynaptic receptors, the drugs reduce the amount of neurotransmitter released from sympathetic nerve stimulation and thereby lower IOP

by binding to postsynaptic alpha-2 receptors, these drugs stimulate the Gi pathway, reducing cellular cyclic AMP production, thereby reducing aqueous humor production
Term
glaucoma treatment: parasympathetic (cholinergic) agents
Definition
parasympathetic (cholinergic) agents work by contraction of the ciliary muscle, tightening the trabecular meshwork and allowing increased outflow of the aqueous humor

pilocarpine:
has been used in the treatment of chronic open angle glaucoma and acute angle closure glaucoma for over 100 years
it acts on a subtype of muscarinic receptor (M3) found on the iris sphincter muscle, causing the muscle to contract and produce miosis
this opens the trabecular meshwork through increased tension on the scleral spur
this action facilitates the rate that aqueous humor leaves the eye to decrease intraocular pressure

carbachol:
a choline ester and a positively charged quaternary ammonium compound
it is not well absorbed in the GI tract and does not cross the BBB
it is usually adminstered topically or through intraocular injection
carbachol is a parasympathomimetic that stimulates both muscarinic and nicotinic receptors
in topical ocular and intraocular administration its principal effects are miosis and increased aqueous humor outflow
Term
macular degeneration
Definition
AMD and ARMD (age-related macular degeneration)

leading cause of vision loss and blindness in Americans aged 65 and older

degeneration of the macula

MACULAR DEGENERATION is a medical condition predominantly found in elderly adults in which the center of the inner lining of the eye, known as the macula area of the retina, suffers thinning, atrophy, and in some cases, bleeding

this can result in loss of central vision, which entails inability to see fine details, to read, or to recognize faces

according to the American Academy of Ophthalmology, it is the leading cause of central vision loss (blindness) in the US today for those over the age of 50 years
Term
what causes macular degeneration?
Definition
variant of a gene known as complement factor H (CFH), and increased C reactive protein (inflammatory marker)

oxygen starved cells within the retina -> VEGF-A

abnormal deposits (drusen) in the underlying retinal endothelium, breakdown of the retina

complement factor H (CFH) gene has been determined to be strongly associated with a person's risk for developing macular degeneration (AMD)

people whose genetic makeup includes this variant of the CFH gene are more likely to develop AMD

CFH gene variant may be responsible for about 1/2 of the 15 million cases of macular degeneration in the US

the odds of developing macular degeneration are increased by about 2.5-5.5 times if one has the CFH gene variant

the genes for the complement system proteins factor H (CFH), factor B (CFB), and factor 3 (C3) have been determined to be strongly associated with a person's risk for developing macular degeneration

CFH is involved in inhibiting the inflammatory response mediated via C3b (and the alternative pathway of complement) both by acting as a cofactor for cleavage of C3b to its inactive form, C3bi, and by weakening the active complex that forms between C3b and factor B

C reactive protein and polyanionic surface markers such as glycosaminoglycans normally enhance the ability of factor H to inhibit complement

but the mutation in CFH reduces the affinity for CFH for CRP and probably also alters the ability of factor H to recognize specific glycosaminoglycans

this change results in reduced ability of CFH to regulate complement on critical surfaces such as the specialized membrane at the back of the eye and leads to increased inflammatory response within the macula

vessels in the eye damaged by ischemia may reform abnormally, resulting in damage to retina

during an AMD eye exam, you may be asked to look at an Amsler grid

the pattern of the grid resembles a checkerboards

you will cover one eye and stare at a black dote in the center of the grid

while staring at the dot you may notice that the straight lines in the pattern appear wavy

you may notice that some of the lines are missing

these may be signs of AMD
Term
macular degeneration: dry form
Definition
the cells of the macula slowly begin to break down

diagnosed in 90% of cases

yellow deposits called "DRUSEN" form under the retina between the RETINAL PIGMENTED EPITHELIUM (RPE) and BRUCH'S MEMBRANE which supports the retina

DRUSEN deposits are "debris" associated with comprommised cell metabolism in the RPE and are often the first sign of macular degeneration

eventually, there is a deterioration of the macular regions associated with the drusen deposits resulting in a spottly loss of "straight ahead" vision

the dry form of advanced AMD results from atrophy to the retinal pigment epithelial layer below the retina, which causes vision loss through loss of photoreceptors (rods and cones) in the central part of the eye

NO FDA-APPROVED TREATMENTS ARE AVAILABLE FOR THE DRY FORM OF MACULAR DEGENERATION

A MAJOR NATIONAL EYE INSTITUTE STUDY (AREDS) HAS PRODUCED STRONG EVIDENCE THAT CERTAIN NUTRIENTS SUCH AS BETA CAROTENE (VITAMIN A) AND VITAMINS C AND E MAY HELP PREVENT OR SLOW PROGRESSION OF DRY MACULAR DEGNERATION
Term
3 stages of dry AMD that may occur in one or both eyes
Definition
1) EARLY AMD

people with early AMD have either several small drusen or a few medium sized drusen

at this stage, there are no symptoms and no vision loss

2) INTERMEDIATE AMD

people with intermediate AMD have either many medium sized drusen or one or more large drusen

some people see a blurred spot in the center of their vision

more light may be needed for reading and other tasks

3) ADVANCED DRY AMD

in addition to drusen, people with advanced dry AMD have a breakdown of light sensitive cells and supporting tissue in the central retinal areas

this breakdown can cause a blurred spot in the center of your vision

over time, the blurred spot may get bigger and darker, taking more of your central vision

you may have difficulty reading or recognizing faces until they are very close to you
Term
macular degeneration: wet form
Definition
wet macular degeneration occurs when abnormal blood vessels grow behind the macula, then bleed

there is a breakdown in BRUCH'S MEMBRANE, which usually occurs near DRUSEN deposits and this is where the new blood vessel growth occurs (neovascularization)

these vessels are very fragile and leak fluid and blood (hence "wet"), resulting in scarring of the macula and the potential for rapid, severe damage

"straight ahead" vision can become distorted or lost entirely in a short period of time, sometimes within days

wet macular degeneration accounts for approximately 10% of the cases, however it results in 90% of the legal blindness
Term
who gets macular degeneration?
Definition
WHITE, FEMALE:
higher prevalence

AGING:
significant vision loss accompanying more advanced forms of AMD increases from fewer than 1% among individuals in their 60s to more than 15% among people in their 90s

SMOKING:
smoking is a major risk factor found in one British study to be directly associated with about 25% of AMD cases causing severe vision loss
people living with a smoker double their risk of developing AMD

HEREDITY:
recent studies have found that specific variants of 2 different genes are present in most people who have macular degeneration
studies of fraternal and identical twins may also demonstrate that heredity is a factor in who develops AMD and how severe it becomes

HIGH BLOOD PRESSURE

OBESITY and INACTIVITY:
overweight patients with macular degeneration had more than double the risk of developing advanced forms of macular degeneration compared with people of normal body weight
those who performed vigorous activity at least 3 times weekly reduced their risk of developing advanced AMD compared with inactive patients

LIGHTER EYE COLOR:
the extra pigment found in darker eyes is a protective factor against development of the eye disease during sun exposure
no conclusive evidence has linked excessive sun exposure to development of AMD

PHARMACEUTICS:
chloroquine, phenothiazine, chlropromazine
some cases of macular degeneration can be induced from side effects of toxic drugs such as chloroquine (anti-malarial drug) or phenothiazine
Term
dry macular degeneration treatment
Definition
NO CURRENTLY APPROVED TREATMENT

nutrients:

LUTEIN:

lutein was found to be concentrated in the macula, a small area of the retina responsible for central vision
the hypothesis for the natural concentration is that lutein helps keep the eyes safe from oxidative stress and the high energy photons of blue light

several studies also show that an increase in macula pigmentation decreases the risk for eye diseases such as AMD

only one randomized clinical trial demonstrated a benefit for lutein in macular degeneration and was a small study

lutein and zeaxanthin have identical chemical formulas and are isomers, but they are not stereoisomers

the main difference between them is in the location of a double bond in one of the end rings

this difference gives lutein 3 chiral centers whereas zeaxanthin has 2

ZEAXANTHIN:

one of the 2 carotenoids contained within the retina of the eye

within the central macula, zeaxanthin is the dominant component, whereas in the peripheral retina, lutein predominates

VITAMINS A, C, and E:

vitamin A is required in the production of rhodopsin, the visual pigment used in low light levels; this is why eating food rich in vitamin A is said to allow an individual to see in the dark

OMEGA 3 FATTY ACIDS

ZINC

THE CAROTENOIDS: LUTEIN AND ZEAXANTHIN WERE THE MOST STRONGLY ASSOCIATED WITH REDUCED RISK OF MD

other conclusions from the study were:
1) the intake of retinol (preformed vitamin A) supplements showed no effect on MD
2) vitamin C from food intake had little effect
3) vitamin E actually showed negative effects

in addition to their antioxidant mechanism, lutein and zeaxanthin may help to protect the retina for any or all of the following reasons:
1) they may protect against photodamage of the retina by filtering out blue light which is not stopped by the cornea and lens, and which can damage the retina over time
2) they may protect against peroxidation of fatty acids in the photoreceptor membrane
3) they may protect the blood vessels that supply the macular region

while no treatment is available for this condition, vitamin supplements with high doses of antioxidants, lutein and zeaxanthin, have been demonstrated to slow the progression of dry macular degeneration and in some patients, improve visual acuity

these are obtained primarily from dark green, leafy vegetable such as spinach, collard greens, kale, mustard greens, and turnip greens
Term
wet macular degeneration treatment: ranibizumab (lucentis)
Definition
ranibizumab inhibits all subtypes of vascular endothelial growth factor A (VEGF-A)

ranibizumab is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (avastin)

it is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A

ranibizumab binds to and inhibits all subtypes of VEGF0A

VEGF may trigger the growth of new vessels, which may leak blood and fluid into the eye

these leaky blood vessels may contribute to macular edema and choroidal neovascularization, resulting in the wet type of ARMD

Lucentis is administered through monthly injections into the eye

rare ADRs are associated with the injection itself

complications of treatment can include severe inflammation within the eye (endophthalmitis), increased eye pressure (intraocular pressure), traumatic cataract, or retinal detachment or tear

Avastin should not be used for ocular use

the company, Genentech, cited safety issues as the reason for halting sales of Avastin to compounding pharmaices that have been dividing Avastin into the smaller quantities needed for treating the eye

bevacizumab is a monoclonal antibody against VEGF

it is used in the treatment of cancer, where it inhibits tumor growth by blocking the formation of new blood vessels

bevacizumab was the first clinically available angiogenesis inhibitor in the US
Term
wet macular degeneration treatment: pegaptanib sodium (Macugen)
Definition
pegaptanib is a pegylated anti-VEGF aptamer, a single strand of nucleic acid that binds with specificity to a particular target

pegaptanib specifically binds to VEGF 165

Mucagen is a newer treatment for AMD (pegaptanib sodium) uses a therapeutic molecule to attack a protein that causes abnormal blood vessel growth in the eye

it is administered through injections into the eye, with treatments required every 6 weeks

Macugen also helped slow the rate of vision loss for many macular degeneration patients
Term
wet macular degeneration treatment: verteporfin (Visudyne)
Definition
PHOTOCYNAMIC THERAPY: light activated destruction of new vessel growth

Verteporfin was the 1st drug therapy for treatment of the wet form of the disease

it is only for those patients who have new blood vessel growth (neovascularization) under the retina in a well defined, distinctive pattern known as "predominantly classic"

about 40-60% of new wet AMD patients have this form of macular degeneration

verteporfin therapy is a 2 stage process requiring administration of both verteporfin for injection and nonthermal red light

verteporfin is used as a light activated drug (photosensitizer)

treatment of diseases using photosensitisers and light activation is called photodynamic therapy (PDT)

verteporfin is transported in the plasma primarily by lipoproteins

once verteporfin is activated by light in the presence of oxygen, highly reactive, short lived singlet oxygen and reactive oxygen radicals are generated

light activation of verteporfin results in local damage to neovascular endothelium, resulting in vessel occlusion

damaged endothelium is known to release procoagulant and vasoactive factors through the lipo-oxygenase (leukotriene) and cyclo-oxygenase (eicosancoids such as thromboxane) pathways, resulting in platelet aggregation, fibrin clot formation and vasoconstriction

verteporfin appears to somewhat preferentially accumulate in neovasculature, including choroidal neovasculature

however, animal models indicate that the drug is also present in the retina

therefore, there may be collateral damage to retinal structures following photoactivation including retinal pigment epithelium and outer nuclear layer of the retina

the temporary occlusion of choroidal neovascularization (CNV) following verteporfin therapy has been confirmed in humans with fluorescein angiography
Term
conjunctivitis
Definition
an inflammatory process specific to the mucus membrane of the eye (i.e. conjunctiva)

eye lid: palpebral or tarsal conjunctiva

sclera: ocular or bulbar conjunctiva

eye lide and sclera meet at the fornix conjunctiva

general symptoms:
redness (hyperemia - vascular dilation)
irriation/burning
swelling of conjunctiva (chemosis)
tearing/watering (epiphora)
pus (purulent discharge) often yellowish, brownish-yellow

goblet cells are glandular simple columnar epithelial cells whose sole function is to secrete mucin, which dissolves in water to form mucus
Term
ocular allergies - type I anaphylactic reaction

seasonal vs. perennial allergic CONJUNCTIVITIS
Definition
type I: immediate or anaphylactic hypersensitivity (often known simply as allergy) - occurs in individuals who predominantly exhibit a Th2 rather than a Th1 response to antigen
in these individuals, substances that are not inherently noxious (such as grass pollen, house dust mites, certain food or drugs, animal fur) provoke the production of antibodies of the IgE type
these fix on mast cells, also to eosinophils
subsequent contact with the material cause the release of histamine, PAF, eicosanoids, and cytokines
the effects may be localized to the nose (hay fever), the bronchial tree (the initial phase of asthma), the skin (urticaria), or the GI tract
in some cases, the reaction is more generalized and produces anaphylactic shock (mass/acute degranulation), which can be severe and life-threatening

ALLERGIC CONJUNCTIVITIS:

sometimes requires medical attention

the appropriate treatment depends on the cause of the problem

for the allergic type, cool water constricts capillaries, and artificial tears sometimes relieve discomfort in mild cases

in more severe cases, non-steroidal anti-inflammatory medications and antihistamines may be prescribed

some patients with persistent allergic conjunctivitis may also require topical steroid drops

allergies of the eye, like all allergies, are overreactions of the immune system to foreign substances, which might otherwise be harmless

in people without allergies, the immune response that occurs following exposure to an allergen is controlled, and produces few if any symptoms

in people with allergies, activation of the immune response results in the release of inappropriate, high quantities of chemical mediators - the most common is histamine

1) SEASONAL ALLERGIC CONJUNCTIVITIS (SAC):

primarily outdoor allergens - tree, grass, weeds

peak - spring and fall

with SAC, the symptoms are generally for a short period of time

generally, the symptoms resolve during other times of the year, especially in the winter

2) PERENNIAL ALLERGIC CONJUNCTIVITIS (PAC):

primarily indoor oriented allergens - animal dander, dust mites, molds

milder than SAC

symptoms last throughout the year

seasonal outdoor allergens may worsen the problem
Term
allergic sensitization
Definition
[image]

patients typically consider ocular problems including itch (i.e. pruritus), watering, and redness to be the most important symptoms requiring relief

however, these symptoms are often overlooked by non-eye care practitioners, and many physicians minimize the effects that allergies have on their patient's comfort and well being

1.

mast cells are primarily responsible for the hypersensitivity reaction that occurs in SAC and PAC

in addition to mast cells, eosinophils and T lymphocytes are also involved in VKC, and AKC

2.

allergy symptoms occur after an allergen binds to immunoglobulin E (IgE) on conjunctival mast cells in a sensitized individual

this causes mast cell degranulation, which releases inflammatory mediators such as histamine, leukotrienes, prostaglandins, tryptase, and cytokines

these mediators trigger the acute, or early phase, or an allergic reaction

histamine induces itching, redness, and swelling

PROSTAGLANDINS AND LEUKOTRIENES ARE RESPONSIBLE FOR INCREASED MUCUS SECRETION AND VASCULAR PERMEABILITY

3.

large doses of an antigen can cause the initial allergic reaction to progress to a late phase response

eosinophils and T lymphocytes are responsible for this late pahse reaction

T helper 2 (Th2) cytokines, including IL4, IL5, IL6, IL8, IL13, stem cell factor, platelet activating factor, and tumor necrosis factor can trigger a series of inflammatory events

4.

these events, including the expression of chemokines, protein regulated on activation normal T cell expressed and secreted (RANTES) monocyte chemoattractant protein 1 (MCP1), eotaxin, intercellular adhesion molecule, vascular cell adhesion molecule, and p-selectin lead to the recruitment of eosinophils and neutrophils

this can result in allergy symptoms that persist for up to 24 hours
Term
ocular allergies: mast cells
Definition
[image]

a mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin

although betst known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing and defense against pathogens

mast cells play a key role in the inflammatory process

when activated, a mast cell rapidly releases its characteristic granules and various hormonal mediators

mast cells can be stimulated to degrandulate by direct injury (i.e. physical or chemical), cross linking of IgE receptors, or by activated complement proteins

the molecules thus released into the intercellular environment include:
histamine
proteoglycans, mainly heparin (actiave as anticoagulant)
serine proteases
prostaglandin D2
leukotriene C4
cytokines
Term
ocular allergies: histamine
Definition
released from mast cells by inflammatory or allergic reactions

secretion is initiated by a rise in cytosolic calcium

histamine secretion is inhibited by increased cAMP

triggers for exocytosis: antigen with cell fixed IgE antibodies; interaction of complement components (C3a or C5a) with cell surface receptors

actions of histamine: dilation of blood vessels, increased vascular permeability, itching

histamine is released from mast cells by exocytosis during inflammatory or allergic reactions

stimuli include C3a and C5a that interact with specific surface receptors, and the combination of antigen with cell fixed IgE antibodies

histamine dilates post capillary venules, activates the endothelium, and increases blood vessel permeability

this leads to local edema (swelling), warmth, redness, and the attraction of other inflammatory cells to the site of release

it also irritates nerve endings (leading to itching or pain)

cutaneous signs of histamine release are the "FLARE AND WHEAL" reaction

the bump and redness immediately following a mosquito bite are a good example of this reaction which occurs seconds after challenge of the mast cell by an allergen

the majority of these effects are mediated via the H1-RECEPTOR
Term
ocular allergies: treatments
Definition
topical OTC drops

oral antihistamines

topical antihistamines

topical mast cell stabilizers

topical dual action drugs (antihistamine/mast cell stabilizers)

topical NSAID drops

topical steroid drops
Term
ocular allergies: topical OTC drops
Definition
TETRAHYDROZOLINE:

naphazoline, oxymetazoline, xylometazoline

act as alpha adrenergic agonists

the medication has sympathomimetic properites and thus constricts the blood vessels, via activation of ALPHA ADRENERGIC RECEPTORS and in turn causes a decrease in interstitial fluid accumulation

ZINC SULFATE

an astringent (substance that tends to shrink or constrict body tissues, usually locally after topical application)

PHENIRAMINE MALEATE

an antihistamine with anticholinergic and sedative effects
Term
ocular allergies: topical antihistamines
Definition
the H1 RECEPTOR is a histamine receptor, and thus an important target for clinically important drugs and is likely one of the most important receptors for modulating mammalian circadian cycles

it causes vasodilation, bronchoconstriction, smooth muscle activation, separation of endothelial cells (responsible for hives), and pain and itching due to insect stings; the receptors are also involved in allergic rhinitis symptoms and motion sickness

histamine H1 receptor are metabotropic GPCRs expressed throughout the body, specifically in smooth muscles, on vascular endothelial cells

the H1 receptor is linked to an intracellular Gq which activates phospholipase C and the phosphatidylinositol (PIP2) signalling pathway

antihistamines competitively bind with histamine receptor sites and reduce itching and vasodilation

LEVOCABASTINE:
a topical selective H1 histamine receptor antagonist, is effective in relieving the signs and symptoms of allergic conjunctivitis

EMEDASTINE:
relatively selective antagonist at H1 receptors
following topical ocular administration, emedastine blocks H1 receptors and inhibits histamine stimulated vascular permeability in the conjunctiva
as a result, emedastine relieves the ocular pruitis associated with allergic conjunctivitis
Term
ocular allergies: topical mast cell stabilizers
Definition
PEMIROLAST (ALAMAST):

ophthalmic solution is indicated for the prevention of itching of the eye due to allergic conjunctivitis

symptomatic response to therapy (decreased itching) may be evident within a few days, but frequently requires longer treatment (up to four weeks)

LODOXAMIDE TROMETHAMINE (ALOMIDE):

ophthalmic solution containing a mast cell stabilizer for topical administration to the eye

NEDOCROMIL (ALOCRIL):

a mast cell stabilizer which is available as an ophthalmic solution and oral inhalational aerosol

although nedocromil is similar in some ways to cromolyn, distinct differences exist

neither cromolyn nor nedocromil interfere with the binding of IgE to the mast cell or with the binding of antigen to IgE

nedocromil appears to be equivalent to cromolyn in preventing exercise induced asthma, although cromolyn may be longer acting
Term
ocular allergies: topical NSAID drops
Definition
when applied topically to the eye, NSAIDs inhibit the synthesis of prostaglandins in the iris, ciliary body, and conjunctiva

the degree of ocular inflammatory response is correlated with prostaglandin induced increases in ciliary epithelium permeability

NSAIDs may prevent many of the manifestations of ocular inflammation

ALL OF THE TOPICAL NSAIDS are used association with optical surgery

KEOTROLAC:

given for seasonal allergic conjunctivitis, to reduce pain and inflammation

NEPAFENAC:

ophthalmic suspension is a topical NSAID pro drug for the treatment of the pain and inflammation associated with cataract surgery

nepafenac is the FIRST OPHTHALMIC NSAID PRO DRUG

the pro drug structure of nepafenac allows for rapid penetration to the cornea and distribution to target sites, while minimizing surface accumulation and reducing ocular surface complications

topical nepafenac readily penetrates the cornea and is then metabolized to amfenac, a potent COX1 and COX2 inhibitor

topical nepafenac is also hypothesized to be a potential drug to treat ocular neovascularization
Term
chronic dry eye: keratoconjunctivitis sicca (KCS)
Definition
abnormal or decrease in tear production

stinging or burning eyes

scratchiness

stringy mucus in or around the eyes

eye irritation from smoke or wind

excess tearing

difficulty in wearing contact lenses

photophobia (light sensitivity)
Term
causes of chronic dry eye
Definition
1. ABNORMAL TEAR COMPOSITION

reduced concentration of proteins

cytokine balance shift promoting inflammation

loss of goblet cells = loss of mucin; INCREASED TEAR EVAPORATION, HYPERTONIC TEARS

2. DEFICIENT TEAR PRODUCTION
Term
chronic dry eye predisposing factors
Definition
aging

menopause - decreased androgens (important in lacrimal gland homeostasis)

allergy responses

environmental - contact lens, air pollution, low humidity, lack of sleep

ocular surgery (LASIK)

medications
Term
chronic dry eye: treatments
Definition
1. remove cause if possible

2. artificial tears

3. immunomodulatory agent - cyclosporine (Restasis)
Term
treatment of chronic dry eye: calcineurin inhibitor (i.e. cyclosporine)
Definition
[image]

T cell activation is caused by interactions between T cell receptors, the MHC, cellular adhesion molecules, and costimulatory molecules

among the series of events is calcineurin activation, which ultimately promotes interleukin 2 (IL2) proliferation

after initial T cell activation, the process of clonal expansion and immunologic progression is mediated by cytokines

IL2 is released from T cells and activates T lymphocytes locally and in other regions of the body

cyclosporine induces immunosuppression by inhibiting the first phase of T cell activation

the first phase of T cell activation causes transcriptional activation of immediate and early gene products (IL2, IL3, IL4, TNF alpha, interferon gamma) that allow T cells to progress from the G0 to G1 phases

cyclosporine binds to an immunophilin termed cyclophilin

immunophilins (cyclophilin and FK binding proteins) are immunosuppressant binding proteins that are distribued in all cellular compartments and play an important role in protein regulation

the cyclosporine-byclophilin complex then binds to and inhibits the calcium-calmodulin activated phosphatase calcineurin

the calcineurin enzyme catalyzes critical dephsophorylation reactions necessary for early lymphokine gene transcription, and subsequent early activation of T cells

calcineurin inhibition results in blockade of signal transduction of the nuclear factor of activated T cells (NFAT)

the blockade of signal transduction results in failure to activate NFAT regulated genes

NFAT activated genes include those required for B cell activation including IL4 and CD40 and those required for T cell activation including IL2 and interferon gamma

cyclosporin binds to cyclophilin -> this complex bind to and inhibits the calcium-calmodulin activated phosphatase calcineurin (normally dephosphorylates NFAT) -> T cells are not activated
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