Embed Size (px)
Citation preview
Toxic Responses of the Ocular and
Visual System
Khaled A. Alrasheedi
PharmD, Clinical Toxicologist
Outline INTRODUCTION TO OCULAR AND
VISUAL SYSTEM TOXICOLOGY
EXPOSURE TO THE EYE AND VISUAL SYSTEM
EVALUATING OCULAR TOXICITY AND VISUAL FUNCTION
TARGET SITES AND MECHANISMS OF ACTION: CORNEA
• Acids
• Bases or Alkalies
• Organic Solvents
• Sur actants
TARGET SITES AND MECHANISMS OF ACTION: LENS
TARGET SITES AND MECHANISMS OF ACTION: RETINA
• Retinotoxicity of Systemically Administered
• Retinotoxicity of Known Neurotoxicants
TARGET SITES AND MECHANISMS OF ACTION: OPTIC NERVE AND TRACT
• Acrylamide
• Carbon Disulf de
• Ethambutol
TARGET SITES AND MECHANISMS OF ACTION: THE CENTRAL VISUAL SYSTEM
INTRODUCTION TO OCULAR AND VISUAL
SYSTEM TOXICOLOGY
Environmental and occupational exposure to toxic chemicals,
gases, and vapors as well as side effects resulting from
therapeutic drugs frequently result in structural and functional
alterations in the eye and central visual system.
The retina and central visual system are especially vulnerable
to toxic insult.
EXPOSURE TO THE EYE AND
VISUAL SYSTEM
Ocular Pharmacodynamics and Pharmacokinetics
Toxic chemicals and systemic drugs can affect all parts of the eye.
Factors determining whether a chemical can reach a particular ocular site of action include :
1- physiochemical properties of the chemical
2- concentration
3- duration of exposure
4- movement across ocular compartments
5- barriers.
The cornea, conjunctiva, and eyelids are ofen exposed directly to chemicals, gases, drugs, and particles. The first site of action is the tear film, a three-layered structure with both hydrophobic and hydrophilic properties.
Nanoparticles and Ocular Drug Delivery
The main ocular target sites of importance or disease treatment and neuroprotection are the anterior segment and posterior retina.
There are numerous barriers that restrict bioavailability,
decrease therapeutic efficacy, and increase side effects.
Development of nanoscale preparations or drug delivery is
a new approach to drug delivery which can substantially enhance penetration from the cornea, deliver a wide variety of drugs and molecules, and increase the concentration and contact time of drugs with these tissues
A wide variety of nanoformulations have been considered
including solid lipid nanoparticles containing :
• lipids, phospholipids, and/or metals; liposomes;
nanosuspensions; and emulsions; and the use of biocompatible
coatings such as chitosan.
Metallic particles that enable remote magnetic targeting of
drug delivery also are under development.
Ocular Drug Metabolism
Metabolism of xenobiotics occurs in all compartments of
the eye by well-known phase I and II xenobiotic biotrans
forming enzymes.
Drug-metabolizing enzymes that are present in the tears,
iris ciliary body, choroid, and retina of many different
Species.
Central Visual System Pharmacokinetics
The penetration of potentially toxic compounds into visual
areas of the central nervous system (CNS) is governed by the
Blood brain barrier.
which is differentially permeable to compounds depending on
their size, charge, and lipophilicity.
Compounds that are large, highly charged, or otherwise not
very lipid soluble tend to be excluded from the brain, where as
smaller, uncharged, and lipid-soluble compounds more readily
penetrate into the brain tissue.
Light and Phototoxicity
The most important oxidizing agents are visible light and
UV radiation, particularly UV-A (320 to 400 nm) and
UV-B (290 to 320 nm), and other forms of electromagnetic
radiation.
Light- and UV-induced photooxidation leads to generation of
reactive oxygen species (ROS), and oxidative damage that can
accumulate over time.
Higher energy UV-C (100 to 290 nm) is even more damaging.
The cornea absorbs about 45% of light with wavelengths below
280 nm, but only about 12% between 320 and 400 nm.
The lens absorbs much of the light between 300 and 400 nm and
transmits 400 nm and above to the retina.
Absorption of light energy in the lens triggers a variety of
photoreactions, including the generation of fluorophores and
pigments that lead to the yellow-brown coloration of the lens.
Drugs and other chemicals can mediate photo-induced
toxicity in the cornea, lens, or retina.
This occurs when the chemical structure allows absorption of
light energy and the subsequent generation of activated
intermediates, free radicals, and ROS.
The propensity of chemicals to cause phototoxic reactions can
be predicted using photophysical and in vitro procedures.
EVALUATING OCULAR TOXICITY
AND VISUAL FUNCTION
Evaluation of Ocular Irritancy and Toxicity
The so-called Draize test, with some additions and revisions,
has formed the basis of standard procedures employed or evaluating ocular irritation and safety evaluations.
The procedure involves:
instillation of 0.1 mL of a liquid or 100 mg of a solid into the conjunctival sac of one eye and then gently holding the eye closed or 1 s. The untreated eye serves as a control.
Both eyes are evaluated at 1, 24, 48, and 72 h after treatment.
if there is evidence of damage in the treated eye at 72 h,
the examination time may be extended.
The cornea, iris, and conjunctiva are evaluated and scored according to a weighted scale.
The cornea is scored or both the degree of opacity and area of involvement, with each measure having a potential range from 0 (none) to 4 (most severe).
The iris receives a single score (0 to 2) or irritation, including degree of swelling, congestion, and degree o reaction to light.
The conjunctiva is scored or the redness (0 to 3), chemosis (swelling 0 to 4), and discharge (0 to 3).
The individual scores are then multiplied by a weighting actor: 5 or the cornea, 2 or the iris, and 5 or the conjunctiva.
The results are summed or a maximum total score of 110.
In this scale, the cornea accounts or 73% of the total possible points, in accordance with the severity associated with corneal injury.
Ophthalmologic Evaluations
There are many ophthalmologic procedures or evaluating the
health of the eye.
Examination of the adnexa includes evaluating the eyelids, lacrimal apparatus, and palpebral (covering the eyelid) and bulbar (covering the eye) conjunctiva.
The adnexa and surface of the cornea can be examined initially with the naked eye, a hand-held light, or a slit-lamp biomicroscope, using a mydriatic drug (which causes pupil dilation) i the lens is to be observed.
The width of the reflection of a thin beam of light projected rom the slit lamp is an indication of the thickness of the cornea and may be used to evaluate corneal edema.
Lesions o the cornea can be better visualized with the use of fluorescein dye, which is retained where there is an ulceration of the corneal epithelium.
Examination of the fundus requires use of a mydriatic drug
and a direct or an indirect ophthalmoscope.
An examination of the direct pupillary reflex involves
shining
a bright light into the eye and observing the reflexive pupil
constriction in the same eye.
The absence of a pupillary reflex is indicative of damage
somewhere in the reflex pathway, and differential
impairment of the direct or consensual reflexes can indicate
the location of the lesion.
Electrophysiologic Techniques
Most electrophysiologic or neurophysiologic procedures or testing visual function in a toxicologic context involve stimulating the eyes with visual stimuli and electrically recording potentials generated by visually responsive neurons.
The most commonly used procedures are:
1- The flash-evoked electroretinogram (ERG)
2- Visual-evoked potentials (VEPs)
3- less often , the electrooculogram (EOG).
The flash-evoked electroretinogram (ERG)
ERGs are typically elicited with a brie flash of light and recorded
from an electrode placed in contact with the cornea.
A typical ERG wave form includes an a-wave that reflects
the activation of photoreceptors and a b-wave that reflects the
activity of retinal bipolar cells (BC) and associated membrane
potential changes in Müller cells (MC).
A standard set of ERG procedures includes the recording of
(1) a response reflective of only rod photoreceptor function
in the dark-adapted eye
(2) The maximal response in the dark-adapted eye
(3) a response developed by cone photoreceptors
(4) oscillatory potentials
(5) the response to rapidly flickered light.
Visual-evoked potentials (VEPs)
Flash-elicited VEPs are recorded from electrodes overlying
visual (striate) cortex, and they reflect the activity of the
retinogeniculostriate pathway and the activity of cells in the
visual cortex.
Pattern-elicited VEPs (PEPs), which are widely used in
human clinical evaluations, have diagnostic value.
The electrooculogram (EOG).
The EOG is generated by a potential difference between the front and back of the eye, which originates primarily within the RPE.
The magnitude of the EOG is a function of the level of illumination and health status of the retinal pigment epithelium (RPE) .
Electrodes placed on the skin on a line lateral or vertical to the eye measure potential changes correlated with eye movements as the
relative position of the ocular dipole changes. Thus, the EOG
finds applications in assessing both RPE status and measuring
eye movements. The EOG is also used in monitoring eye movements during the recording of other brain potentials, so that eye movement artifacts are not misinterpreted as brain generated electrical activity.
Color Vision Testing
Color vision deficits are either inherited or acquired.
Hereditary red–green color deficits occur in about 8% of males (X-
linked) whereas only about 0.5% of females show similar congenital
deficits.
Inherited color deficiencies take two common forms:
1- protan, a red–green confusion caused by abnormality or absence
of the long-wavelength (red) sensitive cones (L-type cones).
2- Deutan caused by abnormality or absence of the middle
wavelength sensitive (green) cones (M-typecones).
Most acquired color vision deficits, such as those caused
by drug and chemical exposure, begin with a reduced ability to
perform blue–yellow discriminations.
With increased or prolonged low-level exposure, the color confusion can progress to the red–green axis as well.
Generally, disorders of the outer retina produce blue–yellow
deficits, whereas disorders of the inner retina and ON produce
red–green perceptual deficits.
Bilateral lesions in the visual cortex can also lead to color blindness.
TARGET SITES AND MECHANISMS OF
ACTION: CORNEA
The cornea provides three essential functions.
First, it provides a clear refractive surface and the curvature of the cornea must be correct or the visual image to be focused at the retina.
Second, the cornea provides tensile strength to maintain
the appropriate shape of the globe.
Third, the cornea protects the eye from external actors, including potentially toxic chemicals.
T e cornea is transparent to wavelengths of light ranging
between 310 nm (UV) and 2 500 nm (IR). Exposure to UV light
below this range can damage the cornea. It is most sensitive to
wavelengths of approximately 270 nm. Excessive UV exposure
leads to photokeratitis and corneal pathology, the classic example
being welder’s-arc burns.
Products at pH extremes ≤ 2.5 or ≥ 11.5 can cause severe ocular
damage and permanent loss o vision.
The most important therapy is immediate and adequate irrigation
with large amounts of water or saline.
Acids
The most significant acidic chemicals in terms of the
tendency to cause clinical ocular damage are:
Hydrofluoric acid, Sulfurous acid, Sulfuric acid, and
Chromic acid, followed by Hydrochloric and Nitric acid and
finally Acetic acid.
pH between 2.5 and 7 produce pain or stinging, but with only a brie contact
Mild burns The corneal epithelium may become turbid as the corneal
stroma swells (chemosis).
Rapid regeneration of the corneal epithelium and full
recovery.
Severe burns, The epithelium of the cornea and conjunctiva become
opaque and necrotic and may disintegrate over the course
of a few days
There may be no sensation
o pain because the corneal nerve endings are destroyed
Bases or Alkalies
Compounds with a basic pH are potentially more damaging to
the eye than are strong acids.
The compounds of clinical significance in terms of frequency and severity of injuries are :
1- Ammonia or ammonium hydroxide
2- Sodium hydroxide (lye)
3- Potassium hydroxide (caustic potash)
4- Calcium hydroxide (lime)
5- Magnesium hydroxid
One reason that caustic agents are so dangerous is their ability to rapidly penetrate the ocular tissues.
Organic Solvents
When organic solvents are splashed into the eye, the result is
typically a painful immediate reaction.
Exposure o the eye to solvents should be treated rapidly with abundant water irrigation.
Most organic solvents cause minimal chemical burns to the cornea. In most cases, the corneal epithelium will be repaired over the course of a few days and there will be no residual damage.
Surfactants
These compounds have water-soluble (hydrophilic)
properties
at one end of the molecule and lipophilic properties at the
other end that help to dissolve fatty substances in water and
also serve to reduce water surface tension.
The widespread use of these agents in soaps, shampoos,
detergents, cosmetics. Many of these agents may be
irritating or injurious to the eye.
TARGET SITES AND MECHANISMS OF
ACTION: LENS
The lens of the eye plays a critical role in focusing the visual
image on the retina.
The high transparency of the lens to visible wavelengths of
light is a function of its chemical composition.
The lens is a metabolically active tissue that maintains careful electrolyte and ionic balance.
Cataracts are decreases in the optic transparency of the lens
that ultimately can lead to functional visual disturbances.
Risk actors or the development of cataracts include:
Aging, Diabetes, Low antioxidant levels, and Exposure to
a variety of environmental factors.
Several different mechanisms have been hypothesized to
account or the development of cataracts. These include the
disruption of lens energy metabolism, hydration and/or electrolyte balance, oxidative stress due to the generation of free radicals and ROS, and the occurrence of oxidative stress.
Corticosteroids
There are two proposed mechanisms by which systemic treatment with corticosteroids may cause cataracts.
Corticosteroids alter lens epithelium electrolyte balance, which disrupts the normal lens epithelial cell structure causing gaps to appear between the lateral epithelial cell borders.
Another theory is that corticosteroid molecules react with lens crystallin proteins, producing corticosteroid–crystallinadducts that would be light-scattering complexes.
Naphthalene
Accidental exposure to naphthalene results in cortical
cataracts and retinal degeneration.
The metabolite naphthalene dihydrodiol is the cataract-
inducing agent instead of naphthalene itself .
Subsequent studies showed that aldose reductase in the rat
lens is the enzyme responsible or the ormation of
naphthalene dihydrodiol, and that treatment with aldose
reductase inhibitors prevents naphthalene-induced cataracts.
Phenothiazines
Schizophrenics receiving phenothiazine drugs develop pigmented deposits in their eyes and skin.
The phenothiazines combine with melanin to form a photosensitive product that reacts with sunlight, causing formation of the deposits in lens and cornea.
The amount of pigmentation is related to the dose of the drug, with the annual yearly dose being the most predictive dose metric. More recent epidemiologic evidence demonstrates a dose-related increase in the risk of cataracts from use of nonantipsychoticphenothiazines.
TARGET SITES AND MECHANISMS OF
ACTION: RETINA
The mammalian retina is highly vulnerable to toxicantinduced
structural and/or functional damage due to:(1) The highly enestrated choriocapillaris.
(2) the very high rate of oxidative mitochondrial metabolism.
(3) high daily turnover of rod and cone outer segments.
(4) high susceptibility of the rod and cones to degenerate.
(5) presence of specialized ribbon synapses and synaptic contact
sites.
(6) Presence of numerous neurotransmitter and neuromodulatory systems
(7) presence of numerous and highly specialized gap junctions.
(8) Presence of melanin in the choroid and RPE and also in the iris and pupil.
(9) a very high choroidal blood flow rate.
(10) the additive or synergistic toxic action of certain chemicals with ultraviolet
and visible light
Retinotoxicity of Systemically
Administered Therapeutic Drugs
Cancer Chemotherapeutics.
Ocular toxicity is a common side effect of cancer
chemotherapy
The retina, due to its high metabolic activity and choroidal
circulation, appears to be particularly vulnerable to
numerous cytotoxic drugs such as the alkylating agents
cisplatin, carboplatin, and carmustine
Chloroquine and Hydroxychloroquine
Chloroquine (Aralen) and hydroxychloroquine (Plaquenil)
are 4- aminoquinoline derivatives used as antimalarial and
antiinflammatory drugs that can cause irreversible loss of
retinal function.
Prolonged exposure of the retina to these drugs, especially
chloroquine, may lead to an irreversible retinopathy.
Digoxin and Digitoxin
Digitalis-induced visual system abnormalities include
decreased vision, flickering scotomas, and altered color
vision.
The retina has the highest number of Na+ ,K+ -A Pase sites
of any ocular tissue, which are potently inhibited by digoxin
and digitoxin.
Retinotoxicity of Known Neurotoxicants
Inorganic Lead
Lead poisoning in humans produces amblyopia, blindness, optic
neuritis or atrophy, peripheral and central scotomas, paralysis
of eye muscles, and decreased visual function.
Moderateto to high-level lead exposure produces scotopic and temporal visual system deficits in occupationally exposed factory workers, and developmentally lead-exposed monkeys and rats.
This lead exposure dosage produces irreversible retinal deficits in
the experimental animals.
TARGET SITES AND MECHANISMS OF
ACTION: OPTIC NERVE AND TRACT
The ON consists primarily of RGC axons carrying visual in
formation from the retina to several distinct anatomical
destinations in the CNS. Disorders of the ON may be termed
optic neuritis, optic neuropathy, or ON atrophy, referring to
inflammation, damage, or degeneration, respectively, of the
ON.
Retrobulbar neuritis refers to inflammation or involvement
of the orbital portion of the ON posterior to the globe.
Acrylamide
Acrylamide monomer is used in a variety of industrial and laboratory applications, where it serves as the basis or the production of polyacrylamide gels and other polyacrylamide products.
Exposure to acrylamide produces a distal axonopathy in
large-diameter axons of the peripheral nerves and spinal cord
that is well documented in humans and laboratory animals.
In contrast, middle diameter axons of optic tract are affected,
specifically, RGCs that project to the parvocellular layers of the
LGN.
Carbon Disulfide
Carbon disulfide (CS2) is used in industry to manufacture viscose
rayon, carbon tetrachloride, and cellophane.
CS2 damages both the PNS and CNS, and has profound effects on vision.
In the visual system, workers exposed to CS2 experience loss of visual function accompanied by observable lesions in the retinal vasculature.
Central scotoma, depressed visual sensitivity in the peripheral visual field, optic atrophy, pupillary disturbances, blurred vision, and disorders of color perception have all been reported.
The retinal and ON pathologies produced by CS2 are likely a direct neuropathologic action and not the indirect result of vasculopathy.
Ethambutol
The dextro isomer of ethambutol is widely used as an antimycobacterial drug or the treatment of tuberculosis.
Ethambutol produces dose-related alterations in the visual system, such as blue–yellow and red–green dyschromatopsias, decreased contrast sensitivity, reduced visual acuity, and visual field loss.
TARGET SITES AND MECHANISMS OF
ACTION: THE CENTRAL VISUAL SYSTEM
Lead
In addition to the retinal effects of lead.
Lead exposure during adulthood or perinatal development
produces structural, biochemical, and functional deficits
in the visual cortex of humans, nonhuman primates, and
rats.
Methyl Mercury
Methyl mercury–poisoned individuals experience a striking
and progressive constriction of the visual field (peripheral scotoma).
The narrowing of the visual world gives impression of looking through a long tunnel, hence the term tunnel vision.
The damage is most severe in the regions of primary visual
cortex subserving the peripheral visual field, with relative sparing
of the cortical areas representing the central vision.
Methylmercury–poisoned individuals also experience poor night
vision that is also attributable to peripheral visual field losses.
References
Casarett & Doulls Toxicology The Basic Science of Poisons, 8th Ed.
Thank you
