This document discusses various topics related to NSAIDs and their use in ophthalmology. It begins by defining NSAIDs as non-steroidal anti-inflammatory drugs and describing their mechanisms of action in suppressing fever, pain, and swelling by inhibiting cyclooxygenase and lipoxygenase enzymes. It then discusses the classification, pharmacokinetics, indications, and adverse effects of various topical NSAIDs commonly used in ophthalmology, including flurbiprofen, ketorolac, suprofen, indomethacin, diclofenac, bromfenac, and nepafenac. The document also briefly mentions intravitreal injections but does not provide details.

1. Newer NSAID's,
Intravitreal,
Immunosuppressant,
Fibrin Glue & Botox.
Nitin Renge.

2. NSAID’S
 NSAIDs means-“Non Steroidal Anti Inflammatory Drugs
 Inflammation-{features are Heat/fever,Swelling,Pain,Redness,Loss of function}
 “Response of the body to injurious stimuli”
 So it is beneficial.
 Is required to be suppressed
Because at times it can be in EXAGGERATED form and can be
Harmful to body
Extremely disturbing to the patient
NSAIDS addresses mainly FEVER[Anti-pyretic effect],PAIN[Analgesic effect] AND
SWELLING[Anti-inflammatory effect].
Redness is not a problem from functional point of view.
Loss of function is usually restored when FEVER , PAIN and SWELLING are taken
care of “if” it is due to those features..
In Ophthalmology primarily used for Anti-inflammatory effects.
2

3. Cont…
 Topical NSAID’S widely used in iatrogenic and other inflammatory conditions of eye.
 Need of Occular NSAID’s felt due to complications associated with corticosteroid therapy as
IOT, progression to cataract , risk of infection, worsening of stromal melting etc..

4. Classification of NSAID’s
 NSAID’s are chemically heterogenous groups,grouped in various classes as
1]Salicylates
2]Fenamates
3]Indoles
4]Phenylalkanoic Acids
5]Pyrazolones
6]Phenylacetates
7]Para-aminophenols
Common features shared by all is absence of cholesterol derived steroid nucleus so termed NSAID’s
Pharmaceutical emphasis is on 3, 4 & 6 b/o instability in solution & high ocular toxicity of 1, 2, 5
derivatives
Provide symptomatic relief by suppressing the inflammation but do not modify inflammatory etiology.

6. Arachidonic acid is further metabolized by….
Cycloxygenase pathway Lipoxygenase pathway
It causes formation of arachidonic acid
Activation of phospholipase occurs
Cell membrane contains phospholipids
Attacks the cell membrane of the cell
Injury/infection/trauma
6

7. 7
PGG2
MEMBRANE
PHOSPHOLIPID
ARACHIDONIC ACID
12-HPETE
PHOSPHOLIPASE A
CHEMICAL AND
MECHANICAL
STIMULIE
5-HPETE
PGH2
ISOMERAS
E
PGD2 PGE2 PGF2
α
THROMBOXA
NE
SYNTHEASE
PROSTACYCLINE
SYNTHEASE
TXA2
TXB2
PGI2
LTB4
LTA4
LTC4
LTD4
LTE4LTF4
CYCLOXYGENASE
PATHWAY LIPOXYGENASE
PATHWAY
Cyclic
endoperoxidase
-ve
Corticoster
oid’s
-ve
NSAIDs
-ve
Zileuton
Type I
inhibitors
Type II
inhibitors

8. Summary of the chart…
 Cycloxygenase pathway generates …
 TXA2- vasoconstriction,platelet aggregation and releasereaction,weak spasmogenic
 PGD2
 PGE2-vasodialation, BP,weak inotropic,reflex cardiac stimulation,bronchi dilation,sensitize afferent nerve to noxious
stimuli,pyrogenic,release ant pituitary harmones,steroids,insulin,TSH like action.
 PGF2α-vasodialation mostly,large vein constrict,little effect on BP,bronchi constriction,spasmogenic
 PGI2- Vasodialation marked and widespread, BP,platelet antiaggregatory,bronchi dialation,sensitize afferent nerve
 How to remember it ?
 Alphabetical order is … DEFGH
 Here first … G & H and then D E F.
 Lipoxygenase pathway generates
 12 HPETE through 12-lipoxygen
 5-HETE through 5-Lipoxygenase
 5-HETE subsequently produces …
 LTA4  LTB4-Potent chemotactic
 LTA4 LTC4  LTD4  LTE4LTF4---LTC4 & LTD4 are Slow reacting substance of anaphylaxis[SRS-A].
8

9. Mechanism of Action of NSAID’s
 As shown in above flow chart MOC of NSAID’s is, by inhibiting COX and Lipo-oxygenase Enzymes
leads to inhibition of PG’s, TX & LT’s.
 PG’s in Eye Causes- miosis , increased vascular permeability, breakdown of blood aqueous barrier,
conjunctival hyperemia, changes in intraocular pressure.
 NSAID’s also suppress PMN chemotaxis, expression of inflammatory cytokines & mast cell
degranulation and also has free radical scavenging activity during inflammation.
 Categorized in two types on basis of step at which action is exerted as Type I & Type II.
 Type I inhibitors - inhibits cox and therefore also Cyclic endoperoxidase activity e.g. Salicylates,
Fenamates, Propionic acid derivatives & indomethacin.
 Type II inhibitors – inhibits isomerases & reductases e.g. pyrazolones
 Apart from Aspirin , Other NSAID’s are Competitive and reversible inhibitors of COX.
 There are two forms of COX- COX-1[Constitutive enzymes found in most cells]& COX-2 [Induced in
inflammatory cells by inflammatory stimulus but Constitutive in Kidney]
 NSAID’s inhibits both COX isoenzymes but they vary in degree of inhibition of each.
e.g.1]Pronounced selective towards COX-1---Aspirin,Indomethacin,Ketoprofen,Piroxicam, Sulindac. 2]
Moderate selectivity towards COX-1----Diclofenac,Ibuprofen,Naproxen. 3] Equal inhibition of COX-1
and COX-2---Etodolac,Meloxicam ,Nimesulide ,Nabumetone. 4] Pronounced selectivity towards COX-
2---Celecoxib.

10. Other Mechanism of Action Of some NSAID’s
 Flubiprofen --- Its (S)(-) enantiomer inhibits COX
nonselectively, but it has been shown in rat tissue to
also affect TNF-α and NO synthesis
 Ketoprofen---inhibits both COX (nonselectively) and lipoxygenase.
 Mephenamic Acid----Inhibits COX as well as Antagonises certain actions of PGs
Exerts peripheral as well as central Analgesic actions
Most important Dose related side effect is Diarrhoea
 Diclofenac sodium---some what COX-2 selective,Antiplatelet action short lasting,Neutrophil
chemotaxis & Superoxide production at inflammatory site reduced
 Aceclofenac---Enchancement of Glycosaminoglycan Synthesis confer Chondroprotective
property
 Piroxicam---also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical
production & inhibits lymphocyte function.
 Indomethacin---may also inhibit phospholipase A and C
Reduce neutrophil migration, and decrease T cell and B cell proliferation.

11. Beneficial Action due to
PG synthesis inhibition
Shared Toxicities due to
PG synthesis inhibition
1]Analgesic – prevention of pain nerve ending
sensitization d/t inhibition of PGE2
2]Antipyresis
3]Anti-inflammatory
4]Anti-Thrombotics
5]Closure of Ductus Arteriosus in New Born
Gastric Mucosal Damage
Bleeding – inhibition of Platelet Function
Limitation of Renal Blood Flow – Na+ & water
retention
Delay / prolongation of Labour
Asthma & Anaphylactoid reactions in susceptible
individuals

12. Comorbid Condition Aggrevated By
NSAID’s
1] Peptic Ulcer
2] Hypertension
3] Congestive Heart Failure
4] Renal Insufficiency
5] Haemostatic Disorders

13. Features of Non-Selective COX & Selective COX-2
Inhibitors
ACTION COX-1/Cox-2 Inhibitors COX-2 Inhibitors
1]Analgesic
2]Antipyretics
3]Anti-inflammatory
4]Antiplatelets aggregatory
5]Gastric mucosal damage
6]Renal Salt/Water retention
7]Dlay/Prolongation of Labour
8]Dutous Arteriosus Closure
9]Aspirin sensitive astma precipitation
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14. Pharmacokinetics
 NSAID’s well absorbed after oral administration & have measurable ocular penetration.
 NSAID’s are 90-99% protein bound and so easily recovered from ocular tissues.
 However Topical NSAID’s appear to penetrate the eye better than oral administration.
 Topical NSAID’s when used stabilize the blood-ocular barriers.
so NSAID’s also used systematically in ophthalmic conditions like CME and Diffuse retinitis.
 Phenyl alkanoic acids are water soluble and formulated as ophthalmic solutions.
 The Pharmaceutical emphasis has been on the Indoles,Phenylacetates,Phenylalkanoic acids
because of instability in solution & hence high ocular toxicity of Salicylates,Fenamates & Pyrazolone
Derivatives
 NSAID’s & their metabolites excreted from body as some by the way of Glomerular Filtration and
Tubular Secretion e.g.Salicylates & some by the way of Bile excretion e.g
Ibuprofen,ketoprofen,Flubiprofen etc..&at last some by both way e.g. diclofenac,piroxicam etc...
 Selective COX-2 Inhibitors Major Adverse effect as no cardioprotection and there is actually
increased MI.

15. Drug interactions with NSAIDs
Drugs Result
Diuretics Decrease diuresis
Beta-blockers Decrease antihypertensive effect
ACE inhibitors Decrease antihypertensive effect
Anticoagulants Increase of GI bleeding
Sulfonylurea Increase hypoglycemic risk
Cyclosporine Increase nephrotoxicity
GCS Increase of GI bleeding
Alcohol Increase of GI bleeding

16. Cont…
 Oral Anticoagulants Metabolism Inhibited
 Sulfonylureas
 Phenytoin Competition for Plasma Protein Binding
 Valproate
So Increases Plasma level of these Drugs
 Digoxin Renal Excretion of
 Lithium
 Aminoglycosides Interacting Drugs
 Methotrexate So Increases Plasma level of these Drugs

17. Ocular indication of NSAID’s
1]Maintenance of intraoperative mydriasis- In surgery like ECCE and in posterior segment
procedures [vitreo-retinal surgery]. NSAID’s commonly used are flubiprofen 0.3%,Suprofen 1% and
Indomethacin 1% suspension or 0.1% ophthalmic solution.
2]Reduction of post-operative inflammation- Surgical injury cause breach in blood aqueous barrier,
so cellular infiltration leading to intraocular inflammation.NSAID’s re-establish blood-aqueous
barrier.Commonly used are Indomethacin 1%,flubiprofen o.o3%,ketorolac 0.5%,diclofenac 0.1%.
3]Prevention & Treatment of Aphakic and Pseudophakic Cystoid Macular Edema- Common
denominator of all CME is mainly PG’s mediated breach of Blood-Retinal Barrier. Both Oral & Topical
NSAID’s are effective.
4]Uveitis- Systemic NSAID’s useful in JRA’s associated Iridocyclitis,Acute nongranulomatous anterior
uveitis,chronic iridocyclitis.For posterior uveitis & Secondary Vasculitis std regime is combination of
topical corticosteroids & oral NSAID’s as initial therapy.
5]Scleritis & Episcleritis- Systemic NSAID’s are choice in treatment of non-necrotising, simple
diffusion & nodular scleritis,when Steroid is needed Dose & Duration can be reduced with adjunctive use
of NSAID’s.
6]Allergic and Giant Papillary Conjunctivitis- ketorolac 0.5% in eye itching associated with allergic
conjunctivitis,1% suprofen in contact lens related GPC,1% acetyl salicylate & 1% piroxicam solution are
effective in treating seasonal allergic conjunctivitis.

18. Cont….
7]Reduction of Discomfort after Refractive Surgery- 0.5% Ketorolac to reduce corneal pain
following Excimer Laser PRK surgery, Combination of 1%Diclofenac & Topical Steroid in controlling
post PRK myopic regression.Topical NSAID’s also used to lessen pain & inflammation after Nd:Yag &
Photocoagulation Laser.Topical 1% Indomethacin to treat symptoms associated with Corneal
scars,edema,infiltrates & erosions.

20. DRUG INDICATION
1]Flubiprofen 0.03%
Solution
Inhibition of intraoperative miosis,Post-operative & Post-Laser
Trabeculoplasty inflammation of Ant.Segment
2]Ketorolac 0.5%
Solution
Seasonal allergic conjunctivitis,Post-Excimer PRK surgery,Chronic
Conjunctivitis,Aphakic & pseudophakic CME,Episcleritis,RD Sugery.
3]Suprofen 1%
Solution
Giant papillary conjunctivitis,iatrogenic inflammation,preventing intra-
operative meiosis. Inhibits release of PGE2,PGF2alpha & TXB2 from
inflamed cornea more effectively.
4]Indomethacin 1%
suspension & 0.1%
Solution
Excellent to treat Aphakic & Pseudophakic CME, For Iatrogenic
inflammation,episcleritis,patient of corneal edema and erosions
5]Diclofenac 0.1to1%
Solution
Iatrogenic & psudophakic inflammation,Aphakic & Pseudophakic CME,Post-
Excimer laser PRK surgery pain,Inhibition of meiosis
6]Bromfenac 0.09%
Solution
Mainly for Post-operative inflammation after cataract extraction
7]Nepafenac 0.1%
Suspension
Post-Operative Pain & inflammation, Iatrogenic Inflammation

21.  Besides above NSAID’s--- other phenylalkanoic acid derivatives used in topical form are
1]Fenoprofen-0.3%
2]Ibuprofen -0.5%
3]Ketoprofen- 1%
4]Naproxen- 0.5%
5]Piroxicam- 1%
Other Indoles Derivatives are
1]Tolmetin- 5%
2]Sulindac- 1%

22. DRUGS ADVERSE REACTION & contraindications
1]Flubiprofen
0.03%
Transient Burning & stinging, minor symptoms of ocular irritations, increase
bleeding tendancy of ocular tissue in conjunction with surgery.
Contraidication in Dendritic Keratitis, on Hypersensitivity to drug &other NSAID’s.
2]Ketorolac
Tromethamine
0.5%
Transient Burning & stinging, ocular irritation, allergic reaction, Superficial ocular
infections & superficial keratitis.
3]Diclofenac
Sodium 0.1 to
1%
Transient localized burning & tingling sensation
Contraidicated in allergic or sensitive to Aspirin or other NSAID’s
4]Bromofenac
0.09%
Transient Burning & stinging, pain, itching, redness, Iritis/Keratitis, Increased risk of
bleeding, Delay healing.
5]Nepafenac
0.1%
Capsular Opacity, Blurring, Foreign body sensation, Increased Intraocular Pressure,
Sticky sensation, Increased Bleeding Time, Keratitis
Contraindication in Hypersensitivity to Other NSAID’s.

23. INTRAVITREAL Intravitreal inj of air was first used by OHM in 1911 for repairing RDs
 Every effort must be made to ensure the preservation of the eye and preinjection vision
 All eyedrops including antibiotics, anesthetic agents & mydriatics be freshly opened just before procedure
 ANEASTHESIA- 1] Local - Currently no method of topical anaesthesia has been proven to eliminate
pain completely 4% lidocaine, 0.5% proparacaine, 2% lidocaine gel, Subconjunctival Xylocaine 2%.
2]Regional – Peribulbar Block with 2% Xylocaine e.g. in Endophthalmitis
It is preferable to have an optimal IOP both before and after procedure specially using
more than one agents e.g. bevacizumab + triamcinolone
Honan IOP reducer used successfully in reducing the IOP before & after procedure. It set
at 30 mm hg for 10 min & procedure performed no later than 5 min after removing it. IOP recorded before,
immediately after, 3 min & 10 min following procedure.
 ANTIBIOTIC DROPS- 1]Preinjection- Current data on preinjection use of topical antibiotics does not find
any significant benefit of their use prior to intravitreal injections of anti-VGEF agents. No any study shows
benefit over standard of care 5% Providone-iodine. Studies favour Vancomycin as most
effective in treating Postinjection Endophthalmitis.
2]Postinjection- According to many studies Postinjection use of antibiotics should be
discouraged even in Diabetic if proper aseptic precautions taken
 PREP- 1] Choose operation theatre setting for procedure
2] 10%Providone-iodine for periocular skin & eyelids.5% providone-iodine for conjunctiva.

24. CONT..
 TECHNIQUE OF INJECTION- 1]Needles- 27 G triamcinolone, 30/31/33G
Bevacizumab/Ranibizumab etc. 27G needle required twice force that off 30 and lesser G
needles.Guarded injection device was developed for withdrawing drug into syringe using 19G
needle & then switching to 33G needle.It has flexible sleeve placed over shaft of
needle.TUNNELED sclera incision is favourable in reducing vitreous reflex
2]SHELL- The intravitreal injection assistant designed by Arnaldo
Gonclaves, MD of the Netharland, is Disposable device that simplifies intravitreal injections. Consist of
a polycarbonate shell that’s placed over eye with guide tube into which syring is placed causing needle
to enter eye 28 Degree angle with reaching a depth of 5.6mm, exactly 3.5mm from limbus.
3] IOP- IF more than 0.05ml of drug or if multiple drugs are injected a
close watch on IOP required & require close observation for 30 min.
 POSTOPERATIVE MONITORING- Extremely important to closely and carefully monitor patient
receiving intravitreal injections. Immediately following inj. see for retinal artery perfusion &
perception of light.

25. Guidline for Intravitreal Inj. Technique
Preoperative Antibiotic (2-3 days prior).
Examination of Eye on the day of Inj. To rule out periocular infection.
Injection to be done in OT.
Perioperative mandatory use of betadine for skin preparation & Drops prior to inj.
Use of Seculum to separate lids.
Postoperative Antibiotic use for 5 days.
Recommended Postoperative Check-Up on Day 1.

27. Complications of Intravitreal
 Complication of Intravitreal inj can be consider under two headings
 1]Related to Technique- A]Acute rise of IOP- Related to volume of drug injected. If there is
vitreous reflux IOP normalizes within 10 min,if no reflux IOP shot up from 15.5 to 45.8 & gradually
decreases over 30 min. IOP rise is more in smaller,Hyperopic eyes than myopic eye.Take longer time
to come down in Pre-existing Glaucoma.More with small bore needles.Adverse effect of such short
term increase unknown but can damage already compromised eyes like with advanced Glaucoma,so
parancentesis can be consider in these eyes. B] Endophthalmitis- Incidence
range from 0.019-1.6% but in recent studies it is decreases to 0.05%.Microbial cause of post-surgical
endophthalmitis is commonly Coagulase negative Staphylococci but in post-inj it is Viridians
Streptococci,a common oral microbe,with poor outcome. Clinical feature are Pain & Reduced VA with
vitritis at presentation and most cases will have Hypopyon in both culture positive & culture negative
cases. Studies favoure TAP alone in management of postinjection endophthalmitis. C]
Rhegmatogenous Retinal Detachment- Overall incidence is low. Etiology proposed to be an
induction of posterior vitreous detachment or incorrect technique of injection. D]Ocular
Heamorrhage- may be Sub-conjunctival, Choroidal or subretinal. Discontinuation of anti-coagulants
for intravitreal injection is not recommended. E]Lens Damage- rare complication may
be result of a wrong technique & cause early progression of cataract.
 2] Related to the Agent Drug- A]Steroids{triamcinolone Acetate & dexamethasone Implant}-
Incidence of IOP elevation with TA seems to be dose dependant.

28. Cont…
With 4 mg TA, duration of OHT is 1 to 9 months with max IOP within 2 weeks & return to baseline
within 4 to 9 months.
With Dexamethasone implants, IOP elevation most commonly observed at 60-day visit & in almost all
cases resolved by 180 days, with most cases successfully managed with observation or topical IOP-
lowering medication.
OHT with flucinolone acetonide implants occur more frequently than with TA & Dexamethasone
implants.
 Risk factors for developing OHT following intravitreal steroids
Risk factors for OHT immediately following Inj. Risk factor for later onset OHT
Phakia Young age
Hyperopia Uveitis
Prior history of POAG Baseline IOP > 15 mm hg
Smaller bore needle Pre-existing Glaucoma
Large volume of inj. Higher steroid dose

29. Recommendation to detect & treat OHT after Steroids
Preoperative & Perioperative check up
• Baseline IOP measurement
• Risk factors
• Paracentesis immediately after inj, if pressure is high
• IOP check-up after 30 min.
Monitor IOP
• 1st postinjection day
• 1 week postinjection for IVTA & 2 weeks Post
Dexamethasone implant
• Then every 2 weeks for 1st month
• Then every month for 6 months
• If IOP is raised at any period of follow-up starting
antiglaucoma medication with close follow-up for disc
& field changes should be done.

30. Cont…
Cataract- Intravitreal steroids increases risk of cataract formation. Incidence increases with higher
doses & with repeated inj. & longer follow-up.
B] Anti-VEGFs {Ranibizumab & Bevacizumab}—
IOP-Recent studies have reported a significant number of intravitreal anti-
VEGF inj is associated with increased risk for IOP elevation. As some eyes with IOP elevation after inj
anti-VEGF need topical or surgical antiglaucoma intervetions, routine monitoring of IOP in all patient
receiving intravitreal anti-VEGF therapy is recommended. Intraocular Inflammation- It is one of
main ocular adverse events with intraocular antiVEGF pharmacologic agents.
Systemic Side Effects– Following intravitreal antiVEGF inj are possible as
detectable levels of the drug have been found in systemic circulation.Pegaptanib has excellent safety
profile, however systemic hypersensitivity reaction following inj has been reported.Serious
Cardiovascular adverse events are classified according to the Antiplatelets Trialists’ Collaboration [ATC]
& including nonfatal myocardial infarction, nonfatal ischaemic stroke, nonfatal hemorrhagic strok or
death owing to vascular or unknown cause. So there is concern with administration to patient with
recent history [<6months] of stroke or myocardial infarction.And it seems prudent to use Ranibizumab
since short systemic T1/2 life.
Rare Ocular & Systemic Side Effects—Rare Ocular event includes
1) Anterior ischaemic optic neuropathy after bevacizumab inj. 2) Retinal venous occlusion after
bevacizumab inj. 3) Retinal artery occlusions. 4) Haemorrhagic macular infarction.

31. Cont…
5) Development or Exacerbation of ocular ischaemic syndrome. 6) Sixth nerve palsy following
bevacizumab inj.
Rare Systemic events include
1) Formed visual hallucinations. 2) Erectile dysfunction. 3) Acute decrease in kidney function.
Adverse Event Consideration in Specific Diseases-- 1) Diabetic retinopathy:-- Intravitreal Bevacizumab
is used as adjunct in the management of PDR. For advanced PDR use of Bevacizumab before
vitrectomy, reported a Development or Progression of Tractional retinal detachment {TRD}. So giving
bevacizumab prior to vitrectomy, it is important to plan the surgery within 10 days after the inj. Ghost cell
glaucoma reported following use of bevacizumab as an adjunct to Vitrectomy for PDR.
There also report of decrease retrobulbar blood flow parameters, retinal arteriolar
vasoconstriction, and worsening of macular ischaemia after inj.of anti-VEGF agents.
2)Age –related Macular Degeneration:-- Several recent publications reported RPE tear associated with
use of intravitreal anti-VEGFs in choroidal neovascular associated with AMD, d/t loss of VEGF mediated
tight junction gene transcription.

32. List of Intravitreal used
1) Anti-VEGF’s Agents– Bevacizumab, Ranibizumab, Aflibercept, Pegatanib {The
VEGF-A APTAMER or Macugen}.
2) Steroids--- Triamcinolone Acetate, Dexamethasone Implants, Flucinolone Acetonide
Implants.
3) Antibiotics--- Vancomycin, Linezolid, Piperacillin/Tazobactum, Imipenem,
Dalfopristine/Quinopristine, Cefazoline, Ceftazidime, Aztreonam, Amikacin, Gentamycin,
clindamycin, Clarithromycin, Daptomycin, Ciprofloxacin, Moxifloxacin, Chloramphenicol.
4) Enzymatic Vitreolysis Agents--- Plasmin, Ocriplasmin, Dispase, Urea (Vitreosolve),
Hyaluronidase, Chondroitinase, Nattokinase.
5) Intraocular Dyes--- Indocyanine Green, Tryphan Blue, Brilliant Blue G.

33. Anti-VEGF Agents---
 VEGF {X factor} discovered 60 year before by Michaelson. VEGF family includes PLGF, VEGF-A,
VEGF-B, VEGF-C, VEGF-D & VEGF-E .VEGF release mainly occurs on basal surface of the RPE.
VEGF-A play crucial role in pathogic Ocular angiogenesis.
 VEGF-A has 9 isoforms –
VEGF121,VEGF145,VEGF148,VEGF162,VEGF165,VEGF165b,VEGF183, VEGF189,VEGF206,
Differ in number of amino acids & heparin-binding affinity.
 VEGF act via two receptors VEGFR-1 & VEGFR-2, primarly present on vascular endothelium.
VEGFR-2 has lower affinity for VEGF than VEGFR-1 but it play more significant role in
neovascularisation processes.
 Hypoxia/ischemia Stimulate production of VEGF & also increased by inflammatory mediator
 Increased VEGF in Ocular fluid found in PDR but not in quiescent or NPDR.
 Neovascularisation is by direct action in endothelial cells, mostly in areas of increased exposure to
VEGF, such as optic nerve head,along vascular arcade or at pupillary border.
 VEGF-A also play crucial role in intra-ocular inflammation by increasing vasopermeability. And
contact time of it for this & break blood-retinal barrier less than for angiogenesis.
 VEGF 121 & 165 found freely diffusible within vitreous & aqueous cavity.
1) Pegatinib--- RNA aptamer directed against VEGF 165. FDA approved in DEC 2004 for
therapeutic use in human. Commercial drug was named Macugen. MW 50 KD, osmolarity 280 to

34. Cont…
Preferred route is intravitreal in humans. Drug Eleminated primarily by RENAL CLEARANCE.
Approved & Recommended dose is 0.3 mg but it is well tolerated even at 10 fold higher doses with
no marked clinical evidence of Systemic VEGF inhibition or Ocular side effects. No dose
adjustment with CLCR >20 ml/min & wt >39 kg needed. Vitreous T1/2 is 10 to 14 days.
2)Bevacizumab(Avastin)-- Recombinant, Full-length, humanized, monoclonal IgG1 Ab directed
against all isoforms of VEGF. It block intraction of VEGF with it’s receptors. MW 149 KD. Produced in
mammalian Chinese Hamster Ovary (CHO) cell. FDA approved for colon cancer treatment in FEB 2004
& In MAY 2005 first patient treated with intravitreal Bevacizumab. Doses range from 1.25 to 2.5 mg
(1.25mg/0.05ml). T1/2 app 4 days & serum level following intravitreal is app 5 ng/ml in animal model,
there is little data in human. Systemic T1/2 is 20 days.
3) Ranibizumab (Lucentis)-- Recombinant, Humanized, Fab fragment of anti-VEGF antibody
& directed against all isoform of VEGF. Molecule lack Fc region. MW 48 KD.Produced by E.coli
expression system. Supplied in preservative free solution. Available as 0.5mg and 0.3mg dose vial.
Vitreous T1/2 is 3 days in animal model. Serum level after monthly inj is range from 0.3ng/ml to
27ng/ml, amount is less than require to inhibit biological activity of VEGF-A by 50%. Systemic t1/2 is
0.09 days.
4) Aflibercept--- High affinity antagonist to VEGF, produced by fusing the immunoglobin domain 2
of human VEGF receptor-1 & domain 3 of VEGF receptor-2 to Fc fragment of IgG1. Binds VEGF-A & B
in tissue & circulation & also bind PLGF. Dose is 2mg/0.05ml. MW 115 KD.

35. Cont..
Recommeded maintenance regimen is one inj every 2 months. Produced in Recombinant Chinese
Hamster Ovary (CHO) cells. Serum conc. after intravitreal inj. Is 0.02mg/ml after 1 to 3 days.
USES--- In Ocular Neovascular conditions as NV-AMD, Diabetic retinopathy & DME, Venous
Occlusion as CRVO & BRVO, ROP, Myopic choroidal neovascular membrane, Macular edema &
choroidal neovascularization in several inflammatory chorioretinal diseases.

37. Steroids--
1) Triamcinolone Acetonide--- Intermediate acting steroid, with Glucocorticoid action 5 times of
cortisol and Zero minralocoticoid action. After IVTA T1/2 in nonvitrectomy eye is 18.6 day
Clinical Application– Use of it broadly classified into antiedematous effect,
antiangiogenic effect & intraoperative use for visualisation.
Antiedematous effects– Can be used for Macular edema associated with DM, CRVO, BRVO,
Cystoid macular edema & other conditions. Diabetic
macular edema– marked reduction of macular edema occur in large majority of cases except cases of
relative or absolute macular ischaemia. Dose—initially 20mg was recommended but later 4mg but use of
2mg dose have documented comparable results. Posterior vitreous detachment, total or partial is
documented effect of drug in macular edema with large cystoid spaces. This Drug can be in cases of diffuse
non-responding tractional macular edema with relative success.
Macular edema with CRVO-- macular edema is major cause of depressed visual acuity in CRVO. This
results in immediate visual improvement but VA returns to pre-treatment level in 3 to 4 months, response to
second inj may not same & 80% cases IOT increases. So prefer to use Anti-VEGF drugs in this cases.
Macular edema with BRVO– Significant improvement in VA but return to baseline VA within 1to2
months.Consider as relative indication.
Pseudophakic CME– Nonresolving post operative CME is eminent indication, causes immediate
improvement of VA & effect is permanent except in significant vitreous traction. Drug can
be used for treating Radiation induced macular edema, CME d/t RP, CME after penetrating corneal graft.

38. Cont…
Antiangiogenic & Antiproliferative effects--- Iris
Neovascularization- Reported to decrease with a fall of IOT but in light of current studies, this is not a
preferred drug for it. Exudative
ARMD-- is a neovascular & edematous disease. A Single 4mg inj well tolerated but higher age group
this of patient progression of cataract is fester & 25% patients develop rise of IOT. VA tends to return to
base level in about 3 to 5 months & repeat inj is needed between 6 to 9 months. Classic subfoveal
neovascularisation tend to do less well. Intravitreal TA for proliferative
Vitreoretinopathy– Some studies indicated reduced postoperative inflammation, reduce pain & reduce
rate of recurrence wih combination of vitrectomy & IVTA. But as on today it is debatable indication for
use of IVTA. Chronic prephthisical ocular hypotony– Relative success in term of
increase of IOT & some improvement in VA has been shown.
Uveitis– IVTA used in therapy resistant cases of chronic uveitis. There is marked reduction of intraocular
inflammation & edema with consistant increase in VA. IVTA reported efficacious in the treatment of
uveitic CME in children & also in children with uveitic cataract the use of TA is even more beneficial.
Intra-operative vitreous visualization with TA– TA crystal adhere to gel vitreous &
delineates gel vitreous. TA residue can also help in delineating the epiretinal membrane or internal
limiting membrane.

39. 2)Dexamethasone Implants or Intravitreal Ozurdex--- Ozurdex is sustained release
700ug Dexamethasone Implants. FDA has approved it for use in Venous occlusions & non-infectious
uveitis. But variety of clinical trials shown it is new treatment option for Persistent Macular Edema
resulting from Diabetic Retinopathy & Irvine-Gass syndrome.
Uses- 1) Macular edema d/t BRVO & CRVO - Found > 15 letter improvement in BCVA from baseline at
2 months after inj.
2) Diabetic macular edema- Found useful in persistent DME that refractory to both laser
photocoagulation & intravitreal anti-VEGF.
3) Non-infectious Uveitis- FDA now approved it for persistent inflammation & CME secondary to
ocular inflammation d/t non-infectious Uveitis with encouraging VA improvement.
4) Adjunct to cataract surgery- In patients with DME & Uveitic macular edema requiring
cataract surgery,it found useful.
5) Exudative ARMD- It found to be useful adjunct therapy with ranibizumab by decreasing
need of ranibizumab inj beyond two mandated treatment.
Adverse Effects-- Most common adverse effect reported in first 6 months are, Raised IOT (25%),
conjunctival haemorrhage (22%), eye pain (8%), conjunctival hyperemia (7%), ocular hypertension (5%),
cataract (5%), Vitreous detachment (2%) & headache (4%). IOP peak at app. Week 8.
Contraindications– 1) Ocular & periocular infections. 2) Advanced Glaucoma & Steroid responder. 3)
Hypersensitivity. 4) Aphakic eye.

40. Antibiotics-
 Effiacy of intravitreal antibiotics is based on how long the intraocular drug exceeds minimal inhibitory
concentration (MIC).
 So aim of repeated Inravitreal inj is to optimize the duration of drug exposure to conc. Above MIC,
rather than aim at higher peak levels.
 Three Repeated inj can be used with a combination of vancomycin, ceftazidime & dexamethasone at
48 hr interval found nontoxic to retina.
 Retreatment with intravitreal antibiotics with or without Vitrectomy should be consider in when
stabilization or improvement not noted in 36 to 48 hrs or sign of worsening appears.
 It is reported that incidence of endophyhalmitis reduced drastically when Gentamycin or vancomycin
is added to cataract infusion solution & then filtered.
 Most commonly combination of two drugs used intravitreally to provide a broad spectrum cover e.g
vancomycin & ceftazidime, Vancomycin & amikacin
 CLEARANCE OF DRUG FROM EYE--- various factor influence like molecular size, solubility, ionic
nature, surgical status & ocular inflammation.
Lage molecules leave predominantly through ant. Route & small from post. Route.
Cationic Drugs like Vancomycin, Aminoglycosides, Erythromycin & rifampicin cleared by passive
diffusion into aqueous & leave via ant.chember with T1/2 about 24 hrs. Anionic drug
like beta-lactams, Cephalosporins & clindamycin cleared by post.route having large surface area and
facilitated by active transport by RPE pump with T1/2 8 hrs.

41. Cont…
Fluroquinolones are zwitterions cleared via both route having shortest T1/2.
Clearance is more rapid through ant.route in Aphakic eye & post.route in vitrectomised eyes.
Inflammation, retards clearance through post.route d/t compromised RPE pump & enchanced through
ant.route.
 Spcific Antibiotic therapy for treatment of bacterial endophthalmitis
Organism Intravitreal
Staphylococcus Cefazolin, Vancomycin (MRSA)
Streptococcus Vancomycin
Haemophillus Cholramphenicol
Pseudomonas Amikacin, Ceftazidime
Bacillus Clindamycin, Vancomycin, Amikacin
Moraxella Ceftazidime
Enterococcus Vancomycin
E. Coli Amikacin
Proteus Amikacin, Cefazolin
Corynebacterium Vancomycin, Cefazolin

42. Recommended Doses of IVAb’s
Name of Antibiotic Safe Dose (mg/0.1ml) Frequency of Repeat Inj. (Hrs).
1)Cefazolin 2-2.25 24
2)Ceftazidime 2.0 24
3)Clindamycin 0.45-1.0 1 week
4)Daptomycin 0.2 Single dose
5)Dalfopristine/Quinopristine 0.4
6)Imipenem 0.1-0.5
7)Piperacillin/Tazobactam 0.25
8)Linezolid 3.0
9)Vancomycin 1.0 72
10)Amikacin 0.4 24-48
11)Gentamycin 0.1 72-96
12)Clarithromycin < 1 12
13)Ciprofloxacin 0.1 12
14)Moxifloxacin 0.05 12
15)Chloramphenicol 2 24
16)Aztreonam 0.1 12

43. Preparation of Intravitreal Antibiotics Injections
Agent Availability Initial
Diluent
(ml)
Initial
Conc.
(mg/ml)
Aliquot
(ml)
Final
Diluent
(ml)
Final
Conc.
(mg/ml)
Final
Intravitreal
Dose
(in 0.1 ml )
Amikacin 500mg/2ml ---- 250 0.1 6.15 4 400 microgram
Ampicillin 1gm 4 250 0.3 1.2 50 5 mg
Cefazolin 500mg 2 225 0.1 0.9 22.5 2.25mg
Chloramphenicol 1gm 10 100 0.1 0.4 20 2mg
Clindamycin 300mg/2ml --- 150 0.1 1.4 10 1mg
Gentamycin 80mg/2ml --- 40 0.1 1.9 2 200 microgram
Kanamycin 500mg/2ml --- 250 0.1 6.15 4 400 microgram
Tobramycin 80mg/ml --- 40 0.1 1.9 2 200 microgram
Vancomycin 500mg 10 50 0.2 0.8 10 1mg

44. Cont…
 Gentamycin is more toxic to Retina than Amikacin.
 Intravitreal Amikacin in Conc. Of 400 microgram in 0.1 ml is non-toxic to Retina.
 Retinal toxicity of Intravitreal Amikacin occurs only in Dose 1500 microgram compared to 400
microgram in Gentamycin & 800 microgram in Tobramycin.
 Most endophthalmitis cases recover with single intravitreal antibiotic administration with or without
vitrectomy.
 Repeat antibiotic injections are required in only few circumstances, termed as Persistent
Endophthalmitis & known to have worse outcome.

45. Enzymatic Vitreolysis Agents---
 Without complete posterior vitreous detachment, intact Posterior hyaloid over macula can cause
macular surface disorders.
 Currently surgery is only way to remove the adhesion & during PVD there can be retinal
detachment, macular puker, macular hole or vitreous haemorrhages.
 Enzymatic Vitreolysis has advantage over surgery like ability to treat haemorrhages earlier, avoids
complications like cataract, endophthalmitis, retinal haemorrhages, tear or detachment.
 Till date only Microplasmin has approved for clinical use in vitreoretinal adhesions & small macular
holes.
 Ocriplasmin (JETREA)– Human recombinant orchiplasmin formerly known as Microplasmin is 1/4th
size of plasmin. Produced by recombinant DNA technology in Pichia pastoris expression.
Recommended dose is 0.125mg ( 0.1ml of dilute solution) administered intravitreal inj
once as a single dose. At 24 hrs postinj. Level in vitreous is below 3% & also detectable level in
systemic circulation are not expected after inj.
Adverse events– Lens subluxation in animal model at 1.4 times higher dose & a
repeat second dose.
OTHER Enzymatic Agents---Plasmin, Dispase, Urea ( Vitreosolve), Hyaluronidase, Chondroitinase,
Nattokinase are in study.
It is very likely that enzymatic vitreolysis will become integral part of Vitreoretinal surgery.

46. Intraocular Dyes---
 When Dye Used on living tissue called Vital Dyes.
 First dye used to identify transparent Vitreous & preretinal tissue during pars plana vitrectomy i.e.
Chromovitrectomy was Sodium Fiuorescein.
 Most frequently used Vitreoretinal stainig agents in vitroretinal interface diseases are ICG, IfCG, TrB
& BBG along with TA though last is not a dye.
 ICG & IfCG-- Stain ILM. TrB– Stain ERM. BBG– Stain ILM & negative stain ERM.
 New Lutein based BBG– Stain vitreous base with Lutein (natural macular pigment) & BBG stain ILM.
 Newer dye in study– As Anthocyanin dye from acai fruit extract stain ILM (and vitreous) best followed
by dyes from Cochineal & Chlorophyll extract from alfalfa.

47. Immunosuppressants
class Type of agent Name of agent
corticosteroids
Antimetabolites (Cytotoxic
agents)
Alkylating agents (Nitrogen
mustard)
cyclophosphamide
chlorambucil
Folic acid analogs methotrexate
Pyrimidine analogs 5-fluorouracil
Purine analogs Azathioprine
Calcineurin Inhibitors Specific T cell Inhibitors Cyclosporin A
Tacrolimus
Antibodies Infliximab, Daclizumab, VEGF-
Inhibiting monoclonal antibodies
(Bevacizumab, Ranibizumab) &
Pegaptanib.

48. Cont…
 Selection of patients
1) Have progressive bilateral vision threatening disease.
2) Failed to responds conventional Corticosteroids therapy Or have unacceptable side effects from
them.
3) Have wegner’s Granulomatosis, PAN or Behcet’s disease( Drug of first choice).
4) Have adequet follow-up.
5) Good compliance about following instructions.
6) Ready to undergo therapy voluntarily with knowledge of potential side effects.
7) May benefit certainly from the use of drugs.
8) Have no primary contraindications like active TB, Toxoplasmosis Or other infectious process.

49. 1)Cyclophosphamide : most potent therapeutic alkylating agent
 A natural product of fungi.
 Mechanism of action: The active metabolites ( aldophosphamide, phosphoramide mustard—by
liver), alkylate purines in DNA and RNA resulting in cross linking which results in cell death. It
decreases the number of activated T lymphocytes.
 More marked effect on B cells & humoral immunity compared to that on T cells & cell mediated
immunity.
 Has a prominent immunosuppressive property.
 Less damaging to platelets.
 Chloramphenicol retards the metabolism of cyclophosphamide.
 Dosage:- 1-2mg/kg/day i.e 150-200mg/day in empty stomach. To monitor WBC on Day 1 & every
2-3 days untill 7 days. To reduce dosage by 25-50mg to stabilize the WBC at about 3000 cells/micro
Lit. Once stabilized to monitor WBC and CBC with differential count weekly and then after a
fortnightly.
 Route :- orally, IV . For controlling ocular inflammation orally dosage is more effective.
 Uses: - 1) Treatment of choice for any patient with ocular manifestations of wegner’s
granulomatosis or polyarteritis nodosa . 2)
Used in Highly destructive form of inflammation in association with rheumatoid arthritis. 3)
Necrotizing scleritis associated with relapsing polychondritis.

50. Cont…
4) Retinal vasculitis associated with sarcoidosis. 5)
Pars planitis associated with multiple sclerosis. 6)
Severe uveitis associated with ankylosing spondylitis, with Reiter’s syndrome, or with inflammatory
bowel disease. 7) Idiopathic
uveitis. 8) Multifocal
choroiditis associated with progressive systemic sclerosis. 9) Other
including posterior uveitis or retinal vasculitis manifestations of Behçet’s disease, Juvenile idiopathic
arthritis, Sympathetic ophthalmia; Vogt-Koyanagi-Harada syndrome; birdshot retinochoroidopathy;
multifocal choroiditis with panuveitis; retinal vasculitis associated with systemic lupus erythematosus.
ADVERSE REACTIONS---
1) Severe bone marrow depression with resultant anemia, leukopenia,thrombocytopenia.
2) Oppurtunistic Infections.
3) GIT disturbances-Anorexia, nausea, vomiting, hemorrhagic colitis, and oral mucosal ulceration;
Jaundice.
4) Renal toxicity, Gonadal suppression, Alopecia & interstitial pulmonary fibrosis.
5) Hemorrhagic Cystitis-- indication for discontinue.
6) Report of increased incidence of Myeloproliferative & Lymphoproliferative malignancy.

51. 2) CHLORAMBUCIL: very slow acting alkylating agent.
 Mechanism of action: DNA to DNA cross linking & DNA to protein cross linking occurs which leads
to interference in DNA replication, DNA transcription and nucleic acid function.
 Suppression of T cell lymphocytes (cell mediated immunity) & to a lesser extent B cells
(antibodies) function i.e active on lymphoid tissue & myeloid tissue is largely spared.
 Has relatively weak immunosuppressant action.
 Dosage:- 0.1-0.2mg/kg/day single daily dose & increase every 3-4 days to a total dosage of 10-
12mg/kg if there is no idiosyncratic reaction.
Monitor WBC, CBC & DC as for cyclophosphamide. Patients
typically require concomitant oral corticosteroids initially & one goal of chlorambucil therapy is to taper &
discontinue oral corticosteroids over a 2 month to 4 month period.
 Used- in retinal vasculitis in Behcet’s ds.
 side effects- are same as cyclophosphamide. (except haemmorhagic cystitis which is a peculiar s/e
of cyclophosphamide and it is not associated with chlorambucil).

52. Monitoring :
 Careful hematologic monitoring is must for use of alkylating agents.
 Avoid depressing:
1) WBC<3000 cells/mm3.
2) Neutrophil <1500 cells/mm3.
3) Thrombocytopenia <75 000 platelets/mm3.
4) CBC and urinalys in every 2 weeks then once in a month.

53. Chlorambucil or Cyclophosphamide and Steroid
Management Module:-
 It involves initial treatment with Prednisolone 1 mg/kg/day along with
cytotoxic drug at appropriate doses.
 Should be continued for 4 weeks until the disease is suppressed then
steroids tapered and stopped over 2 months.
 The cytotoxic drug dosage is adjusted to keep the WBC at 3000-4000
/micro lit and continued for one year to induce remission before being
stopped.
 Monitor the CBC and urine analysis weekly until stable than at every 2
weeks.

54. Azathioprine: Purine analogue (purine antimetabolite).
 More marked Immunosuppressant than antitumour action, may be d/t selective uptake into immune
cells & intracellular convertion to active metabolite 6-mercaptopurine to inhibit purine synthesis &
damage DNA.
 Mechanism Of Action:- It affects the differentiation and function of T cells and inhibits the cell
mediated immunity.
Metabolized by Xanthine oxidase and inhibited by Allopurinol, so dose reduced ¼-1/2 with it.
Toxicity also enchanced in TPMT(thiopurin methyl transferase).
 Dosage- Its dosage starts at 1-2 mg/kg/day gradually increasing to 2.5 mg/kg/day.
The usual dose range is 100-200 mg/day in one or divided doses.
Patient WBC , CBC with differential are taken at regular intervals.
 Absorbed orally.
 Adverse Effects– 1) Main toxic effect is Bone Marrow Depression, develop slowly.
2) Uncontrolled leukopenia, rash, fever, arthralgia & Secondary infections.
3) Thrombocytopenia.
4) Hyperuricemia.
5) GIT disturbances, hepatotoxicity, Anorexia, nausea, vomiting, diarrhea.

55. Cont…
 Clinical Indications–
1) Rheumatoid arthritis, pemphigoid and regional ileitis.
2) Sympathetic ophthalmia and VKH syndrome.
3) Pars planitis and Bechet’s disease.
4) Recalcitrant cases of intermediate uveitis.
5) JIA-associated uveitis that does not respond to conventional steroid
therapy.
6) It also can be effective in the treatment of Cicatricial pemphigoid,
Relapsing polychondritis-associated scleritis. Multifocal choroiditis with panuveitis, Vogt–Koyanagi–
Harada syndrome, sarcoidosis, pars planitis and Reiter’s syndrome-associated iridocyclitis.

56. Methotrexate:- is a folate antagonist
 It is one of the oldest and highly efficient anti neoplastic drugs & potent immunosuppressant.
 Mechanism Of Action:- It inhibits Dihydrofolate reductase which is required convert DHFA to
Tetrahydro folic acid which is an essential Co enzyme required for one carbon transfer in De Novo
Purine synthesis and amino acid conversion.
 It kills cells in ‘S’ phase, inhibits DNA synthesis, also affects RNA and protein synthesis.
 Depresses cytokine & cellular immunity & has anti inflammatory property.
 FOLINIC ACID rapidly reverses the effect of methotrexate.
 Thymidine also counteracts methotrexate property.
 DOSAGE:- Its dosage is variable due to high drug toxicity.
Generally for 1-4 weeks oral,IM or IV dose of 2.5 – 15 mg is given over 36-48 hours until
a therapeutic response is noted.
Maintained as per hematologic (weekly) & renal & hepatic (monthly) monitoring.
 Route : orally , IM, IV, SC, intravitreal.
 Clinical Indication:- 1) It cab be used in Idiopathic cyclitis,sympathetic ophthalmia, ocular
manifestations of rheumatoid arthritis, JIA, Reiter’s syndrome, ankylosing spondylitis,inflammatory
bowel disease, and psoriasis.

57. Cont…
2) 400 microgm intravitreal Mtx is given as a Tt of ref. uveitis & Cystoid Macular Edema.
 Adverse Effects– 1) Exerts major toxicity on Bone Marrow– Low doses repeatedly causes
Megaloblastic Anaemia. High doses produce Pancytopenia. Desquamation & Bleeding may occur in
g.i.t. 2) Leukopenia and Thrombocytopenia.
3)Hepatic and renal toxicity.
4) GIT disturbances.
5) Interstitial pneumonitis.
6) CNS toxicity & Sterility.
 Aspirin & Sulphonamides enchance toxicity of Mtx by decreasing it’s renal tubular secretion.
 Hematological monitoring (WBC, CBC with DC) & LFT should be done in every 4-6wk.
 Leucovorin Rescue may help to reverse some Mtx induced Toxic effects. Concurrent 1mg/day folate
given.

58. 5-fluorouracil :- Pyrimidine analogue
 In body converted to the corresponding nucleotide 5-fluro-2-deoxyuridine monophosphate, which
inhibits thymidylate synthase & block conversion of deoxyuridilic acid to deoxythymidylic acid So
selective failure of DNA synthesis occur d/t non-availability of thymidylate.
 Thus it is toxic to rapidly dividing cells.
 USES:--- The sole opthalmic application of 5-FU is subconjunctival injection after glaucoma filtering
surgery in an effort to prevent subconjunctival fibrosis & bleb failure.
 The primary toxic effect of subconjunctival 5-FU consists of superficial punctate keratopathy and
persistent corneal epithelial defect & wound leak.

59. CYCLOSPORIN A:- Calcineurin inhibitor ( Sp. T Cell Inhib.)
 Mechanism of action:- It is a cyclic polypeptide with 11 amino acids. Selectively inhibits T cell
lymphocyte proliferation, IL-2, other cytokine production & response of inducer T cells to IL-1 without
any effect on suppressor T cells. Lymphocytes are arrested in G0 –G1 phase.
Cyclosporine binds to an intracellular protein “CYCLOPHILIN” and this
complex inhibits Calcium Calmodulin activated enzyme “ CALCINEURIN’’.
Normally after activation this T cell receptor, calcineurin activates the
cytokine gene through Nuclear Factor of Activated T cells resulting in transcription of cytokine genes and
production of IL-2 and other cytokines. These pathways are inhibited by Cyclosporine.
 So it selectively suppresses Cell mediated immunity, Free of toxic effects on BM & RE system.
 And that’s why it Prevents Graft Rejection & Yet leave Receipient with enough immune activity to
combat bacterial infection.
 Dosage:- 2.5-5 mg/kg/day given orally in an olive oil – ethanol solution with milk or juice.
Maximum dose is 10 mg/kg/day.
 INDICATIONS:- 1) Clinical indications– particularly useful in the treatment of various forms of
posterior uveitis, especially when both retina and choroid are involved in the inflammatory process
in:- sympathetic ophthalmia, Vogt–Koyanagi–Harada syndrome, Sarcoid, Birdshot Chorioretinopathy,
multifocal choroiditis with panuveitis, posterior uveitis associated with Behçet’s syndrome (for which
Corticosteroids contraindicated).

60. Cont…
 Relative Indications:- All Non-infective cases of Uveitis unresponsive to maximum tolerated
steroid therapy. 1) Eales Disease.
2) Retinal Vasculitis ( non-infectious).
3) Surpiginous Choroiditis.
4) Anterior segment disease include Pemphigoid, Mooren’s ulcer, High risk
corneal transplant rejection & cataract surgery in uveitis patients.
 In 2003 an ophthalmic formulation, cyclosporine 0.05% emulsion, was approved by the FDA to treat
dry eye disease. It is effective for keratoconjunctivitissicca.
 Topical cyclosporine emulsion has also been investigated for treatment of other ocular surface
disorders that may have an immune-based inflammatory component.
 In these trials, cyclosporine 0.05% emulsion has shown efficacy for management of posterior
blepharitis, ocular rosacea, post-LASIK dry eye, contact lens intolerance, atopic keratoconjunctivitis,
graft-versus-host disease, and herpetic stromal keratitis.
 It was also investigated for the treatment of corneal graft rejection and the results were
disappointing.

61. Cont…
 ADVERSE EFFECTS:- Systemic hypertension.
Partially reversible renal toxicity.
Opportunistics infections.
Hyperuricemia.
Hepatotoxicity.
Precipitates Diabetes.
Anorexia, Gingaval Hyperplasia, Hypertricosis.
Hyperkalaemia, Lithargy, Tremors, Seizures.
 Monthly and if required weekly blood tests (CBC with differential and WBC) should monitor
these effects.
 Combination of steroid and cyclosporin A therapy may augment each other.
 Addition of prednisone ( 10-20 mg/day ) Or Short-term 1 mg/kg/day may allow a lowering of the
cyclosporin A dosage ( 4-6 mg/kg/day ) with no loss of therapeutic efficacy.

62. Tacrolimus:- (FK506)
 A Newer Immunosuppressant. Chemically different from Cyclosporine But same MOA.
 Is 100 times More Potent.
 Mechanism of Action:- Bound to a different Cytoplasmic immunophilin protein labelled FKBP. But
subsequent steps are same i.e. Ihibition of helper T cells via Calcineurin.
 Indications:-The main use for ocular illness is in infectious uveitis.
 Dose: Initial dose of 0.05 mg/kg/day. Oral absorption is variable & decreased by Food.
 Monitoring of blood counts is necessary.
 Adverse Reactions:- Tacrolimus should not be given with cyclosporine because of the similar risks
of renal toxicity.
More likely to Precipitate diabetes, Cause Neurotoxicity, Alopecia & Diarrhoea.
Hypertension, Hirsutism & Gum Hyperplasia are less marked than
Cyclosporine.
Dose limiting toxicity is Renal.

63. Infliximab :- Anti-TNF-alpha Monoclonal Ab.
 Mechanism of action:- It is a chimeric monoclonal antibody directed against tumor necrosis factor –
alpha. It interferes with the binding of TNF to the receptors. TNF enhances leucocyte migration and
activates the pro inflammatory cytokines like interleukin-1 and interleukin – 6.
Infliximab by interfering with the binding of TNF to the receptors, decreases
proinflammatory cytokines.
 Clinical indications in Ophthalmology:--
1) HLA B 27 associated anterior uveitis, Behcet’s disease.
2) Noninfectious Scleritis.
3) Severe Ocular Rheumatoid Disease.
4) Scleromalacia Perforans.
5) Neovascular ARMD.
6) Vogt-Koyanagi-Harda Disease.
7) Retinal Vascular Tumours.
8) Refractory Retinal Vasculitis d/t Sarcoidosis.
9) Diffuse Subretinal Fibrosis Syndrome.
10) Idiopathic Sclerosing Orbital Inflammation ( Myositis).

64. Cont…
11) Sight threatening Thyroid associated Ophthalmopathy.
 Dose: 5mg/kg IV infusion
1st dose on the first day of therapy
2nd dose at the end of 2 weeks &
3rd dose at the end of 6 weeks.
Infliximab is available as 100 mg lyophilized powder which has to be reconstituted with 10 ml sterile
water.
 ADVERSE EFFECTS:-
1) Infusion related Reactions.
2) Hepatitis.
3) Increased risk of infections, particularly tuberculosis & histoplasmosis capsulatum, aseptic
meningitis.
4) The use of infliximab may enhance brain lesions associated with multiple sclerosis.
5) Autoimmunity – Lupus like syndromes.
6) Lymphoma & other Malignancies reported in Children & Adolescent treated with TNF blockers, So
such rare but fatal adverse effect have to be watched out for.

65. Daclizumab:-
 Mechanism of action:- The IL-2 receptor system is a well characterized lymphokine receptor
system that plays a central role in the induction of immune responses. Daclizumab builds to the
alpha chain of IL-2 receptor and blocks the IL-2 mediated responses.
 Indication: Non infectious uveitis.
 Dose: 1 mg/kg two weekly
 Side effects: Cutaneous lesions, Upper respiratory infections, Bronchitis, Herpes zoster infections.

66. Oral retinal S antigen
 Oral tolerance is an approach that has received much clinical interest recently.
 Purpose of study is to evaluate effect & safety of Oral Administration of Retinal Antigen as a
Treatment of Ocular Inflammation.
 Conclusion of Study:- This phase I/II study is the first to test the use of Orally administered S antigen
in treatment of Uveitis. Although not statistically significant, patient given S antigen were more likely to
be tapered off their Chronically administered systemic Immunosuppressive Therapy than were the
other groups tested.
 Dose: 30 mg of S antigen 3 times a week. No specific significant toxic effects attributable to S antigen
therapy has been reported.

67. Corticosteroids:-

68. Fibrin Glue:- A tissuse adhesive
 An Ideal Tissue Adhesive should have following properties:-
1) Must allow sufficient working time before inducing firm Adhesion.
2) Must have adequate tensile strength to maintain wound integrity.
3) Must be Biocompatible.
4) Should be Clear enough to permit Vision.
5) Should be Permeable to fluids & Metabolites to prevent Necrosis.
6) Must not induce Inflammation.
7) Must Disappear eventually to permit healing at the interface.
8) Should not carry the risk of transferring an Infectious Agents.
9) Accessible & Affordable.
 TYPES:-
1) Synthetic- commonest is n-butyl-2-cyanoacrylate
2) Biological- Fibrin Glue.
Newer Adhesives available are- 1) Gelatin & Thrombin products. 2) Albumin &
Glutaraldehyde Products. 3) Polyethylene Glycol Polymers.

69. Fibrin Glue- Blood-Derived product.
 A Blood Derived Product that is Absorbable, Relative Easy to use & can be kept at room Temp. or in
a Refrigerator.
 First Introduce in 1909 But first used in 1944 by Tidrick et al. for Skin Gaft fixation.
 FIBRIN GLUE include Two Component - 1) Fibrinogen & 2) Trombin. Both prepared by Processing
Plasma.
 Unlike Cynoacrylate Glue, it forms a smooth seal along the entire length of wound edge & So
provide greater postoperative Comfort to Patient with fewer complications.
 MOA:---Below pathway is mimicked by fibrin glue to induce
Tissue Adhesion.
XaXa
Extrinsic Coagulation
Pathway
Intrinsic Coagulation
Pathway
Prothrom
bin
Trom
bin
Fbrinogen
Fibrin
(monomer)
Fibrin
(Polymer)
soluble
Fibrin
Clot
Insoluble
XIIIa
XIII
Ca2+
Ca2
+

70. Cont…
 METHODS of PREPARATION:--- Either from Homologous Or Autologous plasma.
Plasma centrifuged to produce a Precipitate containing Fibrinogen & a Supernatant
containing Thrombin. Precipitate is resuspended in a small volume of supernantant & used as Fibrinogen
Component. The Supernatant is further treated by Clotting to convert residual Fibrinogen to Fibrin
followed by filtration to isolate the Fibrin. The resulting Serum is Thrombin Component.
Various methods of Preparation are:-
1) Fibrinogen:- Modified Hartman’s Procedure.
2) Thrombin:- Armand J Quick Method.
3) Fibrinogen Rich Concentrate.
4) Preparartion During Emergency Need.
 Commercially Available Fibrin Glue:-- Tisseel VH Fibrin sealant.
Kit contains the following in separate Vials.
1) Large Blue Bottle:- Sealer Protein Concentrate ( Human ), freeze dried, vapour treated,
containing: Clottable Protein- 75 to 115 mg, Fibrinogen- 70 to 110mg, Plasma Fibronectin- 2 to 9mg,
Factor XIII- 10 to 50 IU, Plasminogen- 40 to 120 micro g.
2) Small Blue Bottle:- Aprotinin Solution, bovine 3000 KIU/ml.

71. Cont…
3) White Bottle:- Thrombin 4 (bovine), Freeze dried reconstituted contains 4 IU/ml.
4) Large Black Bottle:- Thrombin 500 (bovine), Freeze dried reconstituted contains 500 IU/ml.
5) Small Black Bottle:- Calcium Chloride Solution, 40 mmol/L.
1+2 – Fibrin Component.
3+5 – Thrombin Component , Used for Slow Release.
4+5 – Thrombin Component , Used for Rapid Release.
It is Important to maintain the Cold Chain till Use.
 TECHNIQUE FOR APPLICATION:-- TWO - 1) Simultaneous. 2) Sequential.
1) Simultaneous– Two component meet at equal volume at poin of delivery. Rate determined
by concentration of Thrombin. As Thrombin 500 produce clot in 10 sec. while Thrombin 4 in 60
sec.
2) Sequential-- First Thrombin applied on area of interest followed by a thin layer of
Fibrinogen.
In all cases Surgical Field must be Dried meticulously. After application press gently over Glue
for 3 min. for firm adhesion. Put antibiotic drops & P & B.

72. Cont…
 Safety of Fibrin Glue:-- Most but not all viruses can be inactivated by Solvent / Detergent
treatment. Or to ensure FG is Virus Free Prepared it from Homologous FFP from Donor who is
negative for Viral markers at least 6 month after donation.
To further ensure safety, Most Proteinaceous Products are Sterilized by
Gamma Radiation.
 ADVANTAGES:-- 1) Reduce Total Surgical Time.
2) Lower risk of Post-operative wound infections.
3) Well Tolerated & non-toxic to tissue wherever it is applied & has some
antimicrobial activity.
4) Smooth seal along the entire length of wound edges with a Higher Tensile
Strength with Resistant to Greater Shearing Stress.
5) A low incidence of Allergic Reactions however some anaphylactic reactions d/t
Aprotonin Component.
6) FG encourages the formation of Adhesions in Contaminated tissues.

73. Cont…
 DISADVANTAGES:-- 1) Risk of Transmitted disease from pooled & single-donor blood donors.
2) Autologous Preparations is Expensive & require at least 24 hours for
processing. With Variable conc. & unpredictable Performance. Also with Tensile Strength not adequately
determined & precludes Quantification.
 FIBRIN GLUE IN OPHTHALMOLOGY:---------
Used in Europe For more than 25 years in over 9.5 million Surgical Procedures.
1) Conjunctival Surgery-- For Conjunctival closure & Transplant.
In Refractory Conjunctivochalasis for Amniotic Membrane
Transplantation using FG has achieved a Complete/Smooth/Significant Conjunctival Surface in 44-56%
of eyes.
2) In Pterygium Surgery-- Effective for Both attaching Conjunctival AutoGrafts & Amniotic
Membrane Graft fixation in wound closure. Shows Decreased Surgical time & Less post-operative
Discomfort & Inflammation. Except disadvantage of graft dehiscence with eye rubbing.
3) In Strabismus Surgery-- For Conjunctival closure following Stabismus Surgery.
4) In Corneal Surgery-- A) Corneal Perforation & Melt- Found effective in closure of prforation upto
3mm in Diameter. For fixing Amniotic Membrane in Refractory & Perforated Corneal Ulcers. Provides
faster healing & induce less corneal vascularization.

74. Cont…
 B) Amniotic Membrane Transplantation--- Found effective & safety in fixing AM to ocular surface.
Using AM as a Therapeutic Contact Lens in alleviating patient’s pain. For AM transplantation in eye
with Partial Limbal Cell Deficiency. For using freeze dried AM for Ocular Surface Reconstruction.
C) Lamellar Keratoplasty:--- Used successfully in lamellar graft in highly vascularized & infiltrated
Corneas.
D) Deep Anterior Lamellar Keratoplasty:--- FG ideally suited when both receipient bed & donor buttons
are of same size & thickness.
E) Penetrating Keratoplasty:--- In ‘Top Hat’ Keratoplasty FG found more stable mechanically than
suturing. FG provide faster healing & induce significantly less corneal vascularization.
F) Limabal Cell Transplantation:--- FG used effectively & safely to fix donor limbal lenticule on bed of
recipient in cases of Limbal Deficiency.
G) Epikeratophakia:--- Operating time reduced to 50% & Bond srenth is 140 gm/cm.
H) Temporary Keratoprosthesis:--- Aid to stabilize temporarily sutured Keratoprosthesis.
5) Refractive Surgery:--- A) Treating Epithelial Ingrowth:--- Typically in recalcitrant cases of Epithelial
ingrowth. Fg forms a Mechanical Barrier & Prevents epithelial cells from growing underneath flap.
Additional use of FG with debridement may helpful in Preventing Recurrence of Epitelial ingrowth.

75. Cont…
However Major Disadvantage is that FG is fairly Opaque when it Polymerizes & it is
expensive & requires Special equipment & preparation Time.
FG can be used like a Bandage Contact Lens or as an ocular surface bandage. However as
most rapid visual rehabilitation required after LASIK or Epi-LASIK & FG does not form a Good Optical
Surface for Vision, rather forms a rough Band-Aid, It is not advocated in Routine LASIK or Epi-LASIK
surgery.
B) As a Temporary Basement Membrane:--- used on Photorefractive Keratotomy Operated Cornea to
reduce Corneal Haze.
C) In Flap Tear / Traumatic Flap Dislocation:--- Usually flap tear occur secondary to Trauma & induces
some epithelial defect. FG adheres better to denuded surface on or around flap & prevents epithelial
ingrowth.
6) In Glaucoma Surgery:--- A) Conjunctival Closure.
B) Mnagement of Post-operative leaking bleb.
C) In Glaucoma Drainage Device (GDD) Surgery:--- Consider a safe substitute for some of sutures
used in GDD surgery. Indicate that FG is Viable Option for reducing peribulbar filtration & preventing
immediate post-operative hypotony after GDD surgery.
7) Lens Surgery:--- To close Capsular Perforation & Cataract Incision. Prevent post-operative
Astigmatism. Recently it used to Fix the Haptics of IOL to tissue in place of Sutures.

76. Cont…
 8) Vitro-retinal Surgery:--- Used for Conjunctival wound closure.
9) Lid & Adnexal Surgery:--- A) Lid Surgery:--- Used for fixing Autologous Skin Transplants for
covering skin defects. For Lid Split procedure with free Skin Graft for Severe Upper Lid Entropion. In
Lower Lid Trichiasis for fixation of free autologous Conjunctival Transplants from upper fornix.
B) Lacrimal Surgery:--- For reconstructing lacerated canaliculi, in Canaliculocystotomy, in
Canaliculodacryocystorhinostomy, for Microanastomosis between canaliculi & lacrimal sac & for attaching
lacrimal & nasal mucosal flaps.
10) Plastic, Reconstructive & Orbital Surgery:--- To attach soft tissue in Oculoplastic Surgery. To fix
Secondary Orbital Implants in Orbital Surgery.
11) Drug Delivery:--- Use of FG for local delivery of Drug is greatly limited.

77. Botox:--- Botulinum Toxin in ophthalmology.
 Exotoxin Produced by Anaerobic GM+ve Sporulating Bacteria Clostridium Botulinum.
 SCOTT in Early 1980s first use in Ophthalmology.
 PHARMACOLOGY:--- Seven distinct Serotypes A-G.
Potent Neurotoxin molecule synthesized in Single Chain 150 kDa.
To become active cleaved by Bacterial Protease as Zn dependant 50kDa LC
& 100kDa HC fragments.
 MOA:--- LC cleaves specific SNARE proteins in Presynaptic Terminals inhibiting Ach exocytosis
Resulting Chemodenervation of muscle causes a Flaccid Paralysis.
Paralysis is Temporary in Nature d/t noncollateral Sprouting of Nerve Fibres after 2 months.
 DOSAGE:--- Biological effect expressed in units (U). 1U = Mouse LD50.
Onset of Clinical Effect in 1 to 3 days, with full benefit in 4 to 7 days.
May be delayed for 1 to 2 Wks or more & peak effect at 2 to 4 Wks.
Clinical benefit last upto 3 to 4 month in most patients.
Large doses of Toxin type A ( >250 U per session) & administered at < 3 months
intervals are risk factor for Ab’s development & secondary treatment failure.

78. Cont…
 Cotraindications:--- 1) Peripheral Motor Neuropathic Conditions– e.g ALS, Motor Neuropathy.
2) NM junction Disorders--- e.g MG, Eaton-Lambert Syndrome.
3) Pregnancy.
4) Area of Active Infection.
5) Hypersensitivity.
 Indications:---
Common Ophthalmic Indications
Facial Dystonias & Movement Disorders:--- Blepharospasm, Hemifascial Spasm, Myokymia, Meige
Syndrome, Apraxia of Lid Opening.
Other Uses:--- Strabismus, Nystagmus,
Oscillopsia, Eyelid Retraction,
Lower lid Entropion, Gustatory Lacrimation,
Lacrimal Hypersecretion, Chemotarsorrhaphy,
Gustatory Epiphora (Crocodile Tears),
Gustatory Sweating (Frey’s Syndrome).
Esthetic Indications:--- Wrinkle & Frown Line Reduction, Chemical Brow Lift.

79. Cont…
1) Benign Essential Blepharospasm:--- Involuntary Orbicularis Muscle Contraction. Increased
Frequency & Forcefulness of Blinking.
Botox has became treatment of choice & very successful in controlling eyelid spasms.
2) Meige Syndrome:--- Two adjacent Fascial Dystonias as Bening Essential Blepharospasm &
Oromandibular Dystonia, Usually begin with Orbicularis Muscle Spasm.
3) Hemifacial Spasms:--- Recurrent Fasciculation & Twitching of one side of Face.
D/t Mechanical irritation of 7th CN at exit root by a sagging arterial vascular
branch or Aneurysm, demonstrated Radiologically in 85-90% cases.
Medical management with Botox in most cases is highly successful.
4) Apraxia of Lid Opening:-- Refer to non-paralytic inability to Raise Upper lid in absence of
discernible Orbicularis Muscle Contraction or Levator Muscle Injury.
Chemoreduction With Botox of Pretarsal Orbicularis helps eyelid opening.
5) Strabismus:--- Preferred for patient with Acquired Strabismus.
Used to weaken force of Contraction of Specific Opposing Muscles.
6) Nystagmus:--- Shows benefit by inj. Botox directly into Multiple Rectus Muscles.
7) Eyelid Myokymia:--- Involuntary twitching of Orbicularis most commonly Lower lid.

80. Cont…Isolated EM – benign , self limitited disorder.
Stress, Fatigue, Caffeine & Alcohol are triggering factors.
Botox temporarily relax until resolves spontaneously.
8) Corneal Protective Ptosis:--- Temporary Ptosis by Injecting Botox Transconjunctivally or
Transcutaneously into Levator Muscle in Lagophthalmos or in Persistent Epithelial Defect.
9) Gustatory Epiphora:--- Or Crocodile Tears
D/t aberrant regeneration of Secretomotor Fibers to Lacrimal Gland.
Botox inj. In Lacrimal Gland reduce secretion & symptoms.
Disadvantage is Accidental Ptosis.
10) Eyelid Retraction:--- Associated with Thyroid Eye Disease.
Botox inj. Drop lid by 2-3 mm for 8-14 Wks.
Carries Risk 5-10 % of overcorrection, resulting Ptosis & up to 10% Transient
Diplopia.
11) Spastic Entropion:--- Ocular irritation can cause a transient reflex Orbicularis Spasm resulting in
muscle override & Entropion.
Temporary relief by Botox inj. 5-10 U, In Pretarsal & Preseptal Orbicularis in
Lower Eyelid Muscle.

81. Cont…
12) Facial Esthetics:--- Botox Useful for treating Dynamic Rhytids ( Wrinkles produced as a result of
Muscular Contractions.
Some Preferred Sites are Glabellar lines, Forehead Rhytids, Crow’s Feet, Bunny
Lines, Smoker’s Lines.
Botox inj. In Depressors of Brow for a mild Eyebrow Lift.
COMPLICATIONS:--- Most are Transient & Mild. Overall incidence is 30% with Botox-A.
1) Pain, Discomfort at site of inj & Slight Bruising especially in Inj into Orbicularis.
2) Ptosis:-- Most common in Periocular Use. Incidence 0-52.3% with Avrage 13.4%.
Mild & Reversible in 20 – 40 days. Apraclonidine found Useful in reversing.
3) Dry Eye:-- In patient with some predisposing risk factors. Incidence 2.5% ( 0 - 18.2% ).
4) Diplopia:-- Most cases d/t IO paralysis. Symptomatic in 2.1% ( 0 – 17.2% ).
5) Ectropion & Epiphora:-- Theoretical Possibilities especially with medial inj on Lower Lid.
Incidence 0.3% ( 0 – 6.7% ).
6) Mouth Drop:-- in treating Hemifacial Spasm. Incidence 0.9% ( 0 – 4.6% ) when Botox
administered around Orbicularis Alone.
7) Brow Droop:-- In treatment of Forehead Rhytids.

83. THANK
YOU