Term
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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 |
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Term
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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 |
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Term
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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 |
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Term
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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 |
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Term
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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 |
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Term
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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 |
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Term
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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 |
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Term
| functions of a healthy tear film |
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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 |
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Term
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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 |
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Term
| anterior anatomy of the eye: cornea |
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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 |
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Term
| anterior anatomy of eye: anterior chamber |
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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 |
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Term
| anterior anatomy of the eye: trabecular meshwork |
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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) |
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Term
| anterior anatomy of the eye: Schlemm's canal (canal of Schlemm, scleral venous sinus) |
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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 |
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Term
| anterior anatomy of eye: ciliary body |
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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 |
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Term
| anterior anatomy of eye: aqueous humor |
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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] |
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Term
| anterior anatomy of eye: lens |
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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. |
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Term
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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 |
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Term
| anterior anatomy of eye: iris and pupil |
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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. |
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Term
| muscarinic agonist (pilocarpine, brimonidine) effect on constrictor pupillae and ciliary muscle |
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Definition
constrictor pupillae -> contraction -> miosis
ciliary -> contraction -> accomodation (near sight) |
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Term
| muscarinic antagonist (atropine, scopolamine) effect on constrictor pupillae and ciliary muscle |
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Definition
constrictor pupillae -> relaxation -> mydriasis
ciliary -> relaxation -> cycloplegia |
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Term
| alpha adrenergic agonist (apraclonidine, clonidine) effect on dilator pupillae and ciliary muscle |
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Definition
dilator pupillae -> contraction -> mydriasis
ciliary -> none |
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Term
| posterior anatomy of eye: vitreous humor |
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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 |
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Term
| posterior anatomy of eye: sclera |
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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 |
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Term
| posterior anatomy of eye: choroid |
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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 |
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Term
| posterior anatomy of eye: retina |
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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 |
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Term
| posterior anatomy of eye: rods (photoreceptors) |
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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 |
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Term
| posterior anatomy of eye: cones (photoreceptors) |
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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 |
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Term
| posterior anatomy of eye: optic disc (i.e. optic nerve head) |
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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 |
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Term
| pharmacokinetics and toxicology of ocular therapeutics |
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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 |
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Term
| pharmacokinetics and toxicology of ocular therapeutics: absorption/distribution |
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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 |
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Term
| pharmacokinetics and toxicology of ocular therapeutics: elimination |
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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 |
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Term
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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 |
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Term
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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 |
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Term
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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 |
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Term
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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 |
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Term
| glaucoma treatment: beta blockers (first line therapy) |
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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 |
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Term
| glaucoma treatment: prostaglandin analogs, PGF2alpha analogs |
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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 |
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Term
| glaucoma treatment: carbonic anhydrase inhibitors |
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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 |
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Term
| glaucoma treatment: alpha-2 agonists |
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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 |
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Term
| glaucoma treatment: parasympathetic (cholinergic) agents |
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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 |
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Term
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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 |
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Term
| what causes macular degeneration? |
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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 |
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Term
| macular degeneration: dry form |
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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 |
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Term
| 3 stages of dry AMD that may occur in one or both eyes |
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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 |
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Term
| macular degeneration: wet form |
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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 |
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Term
| who gets macular degeneration? |
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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 |
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Term
| dry macular degeneration treatment |
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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 |
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Term
| wet macular degeneration treatment: ranibizumab (lucentis) |
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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 |
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Term
| wet macular degeneration treatment: pegaptanib sodium (Macugen) |
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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 |
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Term
| wet macular degeneration treatment: verteporfin (Visudyne) |
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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 |
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Term
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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 |
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Term
ocular allergies - type I anaphylactic reaction
seasonal vs. perennial allergic CONJUNCTIVITIS |
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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 |
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Term
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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 |
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Term
| ocular allergies: mast cells |
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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 |
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Term
| ocular allergies: histamine |
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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 |
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Term
| ocular allergies: treatments |
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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 |
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Term
| ocular allergies: topical OTC drops |
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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 |
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Term
| ocular allergies: topical antihistamines |
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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 |
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Term
| ocular allergies: topical mast cell stabilizers |
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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 |
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Term
| ocular allergies: topical NSAID drops |
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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 |
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Term
| chronic dry eye: keratoconjunctivitis sicca (KCS) |
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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) |
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Term
| causes of chronic dry eye |
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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 |
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Term
| chronic dry eye predisposing factors |
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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 |
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Term
| chronic dry eye: treatments |
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Definition
1. remove cause if possible
2. artificial tears
3. immunomodulatory agent - cyclosporine (Restasis) |
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Term
| treatment of chronic dry eye: calcineurin inhibitor (i.e. cyclosporine) |
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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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