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Drugs and Eye Disorders

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Stephanie Chu

on 25 May 2016

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Transcript of Drugs and Eye Disorders

PD: pharmaco
dynamics,
mechanism of action,
most drug act by binding to regulatory macromolecules

i.e.: agonist or antagonist to a receptor; activator or inhibitor at the enzyme level

Delivery Routs
Locally:
Eye drops
Ointment
Periocular Injection
Intraocular Injection
Systemically:
Oral
IV injection
Agents for glaucoma
Mydriatics & Cycloplegics
Classification
Agents for glaucoma
Mydriatics and Cycloplegic
Anti-inflammatory agents
Anti-infectives
Anti-allergic
Dry eye medication
Anti-angiogenesis
Miscellaneous /Diagnostic
Ocular Surface
Eyelid:
e.g. acetaminophen, allopurinol..etc.
- erythema multiform

prostaglandin:
elongation of eyelash and darkening of skin

targeted therapy, e.g.: gefitinib (Iressa) for lung cancer:
curling of the eyelash

Ocular Drug Delivery & Barriers
Ocular Drugs
Drug Related Eye Disorders
Drugs and Eye Disorders
Outline
Ocular Drug Delivery and Barriers
Common Ocular Drugs
Drug Induced Eye Disorders
PK and PD
PK: pharmaco
kinetics,
the
absorption, distribution, metabolism,
and
excretion
of a drug
Anatomy of The Eye
Eye Drops
one drop = 50-75 uL
average tear volume of cul-de-sac = 7-10 uL, turn over rate 16% per minute
during drug instillation, maximal volume of cul-de-sac = 30uL, tear turn over rate increased to 30% per minute
blinking + drainage + tear turn over
only < 5% of topical dosage can be absorbed with most of the drug loss to drainage in the first 15-30 sec.
Barriers of Topical Drops
Cornea:
Epithelium
- tight junction, lipophilic
Stroma
- hydrophilic
Endothelium
- loose for macromolecules
Conjunctiva:
Epithelium
- tight junction
Non productive
loss of drugs to systemic circulation via vessels and lymphatics
Sclera
Collagen fibers
the permeability of drug across sclera is inversely related to the molecular radius
Factors influencing topical drug penetration
Drug concentration / Solubility
Viscosity:
addition of
methylcellulose
and
polyvinyl alcohol
increases drug penetration by increasing contact time with the cornea and altering corneal epithelium
Lipid solubility:
the higher, the better penetration of corneal epithelium
Factors influencing topical drug penetration
Preservatives:
alter cell membrane of the corneal epithelium, thus increase the drug permeability e.g.
benzylkonium
and
thiomersal
PH:
normal tear PH is 7.4, if the drug PH is much different, will cause reflex tearing
Ointment
Increase the contact time
of the medium to ocular surface thus better effect
Disadvantage
of vision blurring
The drug has to be
high lipid soluble with some water solubility to
have the maximum effect as an ointment
Periocular Injection
Drug can reach the posterior segment via trans-scleral pathway, systemic circulation through choroid, and anterior through conjunctiva, aqueous humor, vitreous
Reach behind the iris-lens diaphragm
better than topical application
Bypass the corneal and conjunctival epithelial barriers, which is
good for drugs with low lipid solubility
(e.g. penicillin)
Also steroid and local anesthetics can be applied this way
Periocular Injection
Subconjunctiva
Subtenon
Peribulbar
Retrobulbar
Systemic: Oral or IV drugs
Barriers:
Blood-aqueous barrier (BAB)
Blood-retinal barrier (BRB)
Factors influencing systemic drug penetration
Lipid solubility of the drug:
more penetration with high lipid solubility
Protein biding:
more effect with low protein binding
Eye inflammation:
more penetration with ocular inflammation / also rapid turn over rate
Intraocular Injection
Intracameral
Intravitreal

Frequent applications:
steroid for intraocular inflammation
antibiotics for intraocular infection
antiviral medication
chemothearpy for intraocular lymphoma
Anti-inflammatory
Corticosteroid
NSAID
Alpha-2 agonist
e.g. Brimonidine, apraclonidine
Mechanism:
decrease aqueous production
Local side effects:
local allergy, lid reaction
Systemic side effects:
oral dryness, drowsiness
Contraindication:
infants
Beta Blocker
Non-selective:
timolol, carteolol, levobunolol, metipranolol
Selective:
betaxolol
Mechanism:
decrease aqueous production
Local side effects:
irritation
Systemic side effects:
bronchospasm (less in betaxolol), cardiac impairment (arrhythmia)
Carbonic Anhydrase Inhibitor
acetazolamide, brinzolamide, dorzolamide, methazolamide, dichlorphenamide
Mechanism:
decrease aqueous production
Local side effects:
myopia
Systemic side effects:
parasthesia, anorexia, GI upset, headache, altered taste, metabolic acidosis, renal stone
Contraindication:
sulpha allergy
Cholinergic Agonist
pilocarpine
Mechanism:
increase aqueous outflow
Local side effects:
myopia shift, meiosis and difficulty in eye exam
Systemic side effects:
Headache, GI upset
Prostaglandin Analogs
bimatoprost, lantanoprost, travoprost, unoprostone
Mechanism:
increase uveoscleral outflow
Local side effects:
irritation, darkening of iris, lengthening and thickening of eyelashes, intraocular inflammation
Osmotic Agents
e.g. Glycerol 50% syrup; Mannitol 20% IV
Mechanism:
dehydrate vitreous body which significantly lower ocular pressure
Systemic side effects:
syrup-nausea, hyperglycemia; mannitol-fluid overload and contraindicated in renal/heart failure patients
Anti-Infectives
Antibacterial
Antiviral
Antifungal
Antiprotozoal
Antiallergic
Anesthetic
Anti-angiogenesis
Anti-VEGF (monoclonal antibody)
bevacizumab
pegaptanib
ranibizumab
aflibercept

Verteporfin
Dry Eye Medication
sympathetic +
parasympathetic +
Cholinergic Antagonist
tropicamide, cyclopentolate, atropine, homatropine, scopolamine
Mechanism:
paralyzing the sphincter muscle and the ciliary muscle
Local side effects:
allergic reaction, blurred vision
Systemic side effects:
N/V, constipation, urinary retention,
in children,
may cuase flushing, fever, tachycardia, delirium
Adrenergic Agonist
alpha-1 agonist:
epinephrine, depevefrin (pro-drug)
Mechanism:
iris radial muscle contracture
Local side effects:
conjunctival adrenochrome
Systemic side effects:
headache, arrhythmia, increased blood pressure
Local use Steroid
fluorometholone, betamethasone, prednisolone, dexamethasone, remixolone
Mechanism:
inhibition of arachidonic acid release from phopholipids by inhibiting phospholipase A2
Local side effects:
immunosuppresion, glaucoma, cataract, ptosis, scleral melting, skin atrophy
Systemic Steroid
prednisolone, methylprednisolone
Mechanism:
same as local steroid
Local side effects:
cataract, glaucoma, central serous retinopathy
Systemic side effects:
immunosuppression, hyperglycemia, osteoporosis, peptic ulcer, psychosis
Topical NSAIDs
ketorolac, diclofenac, flurbiprofen
Mechanism:
inactivation of cyclo-oxygenase
Local side effects:
stinging, allergy, corneal melting
Antifungal
Polyenes
(natamycin, amphotericin B)
Mechanism:
damage cell membranes of susceptible fungi
Local side effects:
epithelial toxicity
Systemic side effects:
nephrotoxicity
Antibacterials
Penicillins
Cephalosporin
Sulfonamides
Tetracyclines
Chloramphenicol
Aminoglycosides
Fluoroquinolones
Vancmycin
topical:
surgical prophylaxis
oral:
preseptal cellulitis, scleral involved ulceration
iv:
orbital cellulitis
ivi:
endophthalmitis
Commercial Antibacterial
Sulfamethoxazole (OSMD)
chloramphenicol
Tetracycline
/Erythromycin ointment
Gentamycin
eye drops & ointment
Neomycin sulfate, polymyxin B ointment
Levofloxacin /ciprofloxacin/ gatifloxacin/moxifloxacin

Mechanism:
same as iv form
Local side effects:
ocular surface toxicity (relative low in newer generation FQs)
Antiviral
Acyclovir / Gancyclovir / Trifluridine
Mechanism:
synthesized analogue, interact with viral kinase
Local side effects:
irritation, epithelial toxicity
Systemic side effects:
renal impairment, hematological side effects
Anti Allergy
Antihistamine:
antazoline, pheniramine, levocabastine
Decongestants:

tetrahydrozoline, naphazoline, phenylepherine
Mast cell stablizer:
cromolyn, lodoxamide, pemirolast, nedocromil, olopatadine
NSAIDs
Steroids
Combination:
ketotifen (anti-histamine + mast cell stabilizer); allergopos (anti-histamine + vasocongestant)
Gel and Ointment
polyacrylic acid
polyacylene glycol
petrolatum, anhydrous liquid lanolin, mineral oil
Artificial Tears
Preserved
Non-preserved
mixed emulsified lipid with tear
Others
topical cyclosporin:
anti-inflammation
hydroxypropyl cellulous ophthalmic insert (Lacrisert):
slow release, water soluble, non-preserved ocular lubricant
Retinopathy of Prematurity
Diagnostic
Fluorescein:
drops, strips, and iv form. Used for stain corneal abrasions, detecting wound leakage and fluorescein angiography

Indocyanine green (ICG):
used for determining cardiac output, hepatic function, and for ophthalmic angiography

Miscellaneous
Azapentacene polysulfonate sodium (Quinax):
binding with SH radical, may retard cataract progression

Neostigmine methylsulfate (O.N.S.D.):
acetylcholine esterase inhibitor, muscle relaxant for eye strain

Imidazoles
(ketoconazole, itraconazole, miconazole)
Mechanism:
increase fungal cell membrane permeability
Local side effects:
less than polyenes
Systemic side effects:
hepatotoxicity
Flucytocine
Mechanism:
inhibiting DNA synthesis
Anti-protozoal
BIguanide:
Chlorhexidine, Polyhexamethylene biguanide, PHMB
Mechanism:
interacts with cytoplasmic membrane, resulted in loss of cell components. Amoebicidal and cysticidal.
Diamides:
propamidine, desomedine
Mechanism:
increase cell permeability
Local side effects:
cataract, iris atrophy, and peripheral corneal ulceration
proparacaine, xylocaine, bupivacaine
different onset and duration
local side effect:
corneal toxicity, allergic reaction
Uveal Tract
Sulfa drug (e.g. Topiramate for epilepsy, weight loss)
idiosyncratic reaction, choroidal effusion and anterior rotation of iris diaphragm may induced glaucoma and myopia.

Alpha-1 adrenergic antagonist (e.g. tamsulosin for prostate hypertrophy) :

relax of bladder neck but also iris. Cause floppy iris syndrome and complicated intraocular surgery.

Glaucoma
Open angle glaucoma:
corticosteroid
impaired trabecular meshwork

Angle closure glaucoma:
epinephrine
for anaphylactic shock,

sulbutamol
for COPD, resulted in pupil dilatation

Cataract
Glucocorticosteroid
Phenothiazine:

antidepressant
Busulfen:

antineoplasm, alkylating agent
Statin:

lipid lowering agents

Retina
Anti-estrogen (eg. Tamoxifen):
axon degeneration induced crystalline maculopathy

Hydroxychloroquine:
bull-eye maculopathy

Optic Nerve
Ethambutol:

chelates copper in neuron cells, affect the mitochondrial oxidase activity, cause toxic neuropathy
Erectile dysfunction drug (sildenafil, tadalafil, vardenafil):

ischemic optic neruopathy
Linezolid:
antibiotics for VRE, unknown mechanism, partial reversible

Conjunctiva:
prostaglandin, topical antibiotics etc.:
conjunctival injection
adrenergic agonist:
adrenochrome

Cornea
topical anesthetics/NSAIDs:

corneal melting
preservatives as benzalkonium chloride (BAK), thiomersal:
induced cell apoptosis of corneal epithelium: medicamentosa
amiodarone/chloroquines:
vorticillate keratopathy (drug deposits)

Tear Secretion
Visual Disturbance
Digitalis:

chromatopsia, yellow hue


Drug & Optic neuropathy
Methanol
(fake alcohol)

Ethylene glycol (antifreeze)
Chloramphenicol
Isoniazid
Ethambutol
Digitalis
Chloroquine
Streptomycin
Amiodarone
Quinine
Vincristine and methotrexate (chemotherapy medicines)
Sulfonamides
Melatonin with Zoloft (sertraline)
high-protein diet
Carbon monoxide
Lead
Mercury
Thallium (alopecia, skin rash, severe vision loss)
Malnutrition with vitamin B-1 deficiency
Pernicious anemia (vitamin B-12 malabsorption
phenomenon)
Radiation (unshielded exposure to >3,000 rads).
Lacrimal Functional Unit
Ocular Blood Supply
Vitreous
eyelid
conjunctiva
cornea
tear film
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Any Questions?
Systemic drug induced cataract: periphery

Topical drug induced cataract: anterior

Operation/ocular inflammation induced cataract: posterior
Full transcript