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

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 patientNSAIDS 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

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..

Classification of NSAID’s NSAID’s are chemically heterogenous groups,grouped in various classes as1]Salicylates2]Fenamates3]Indoles4]Phenylalkanoic Acids5]Pyrazolones6]Phenylacetates7]Para-aminophenolsCommon features shared by all is absence of cholesterol derived steroid nucleus so termed NSAID’sPharmaceutical emphasis is on 3, 4 & 6 b/o instability in solution & high ocular toxicity of 1, 2, 5 derivativesProvide symptomatic relief by suppressing the inflammation but do not modify inflammatory etiology.

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

PGG2

MEMBRANE PHOSPHOLIPID

ARACHIDONIC ACID

12-HPETE

PHOSPHOLIPASE A

CHEMICAL AND MECHANICAL

STIMULIE

5-HPETE

PGH2

ISOMERASE

PGD2 PGE2 PGF2α

THROMBOXANE

SYNTHEASE PROSTACYCLINE SYNTHEASE

TXA2

TXB2

PGI2

LTB4

LTA4

LTC4

LTD4

LTE4LTF4

CYCLOXYGENASE PATHWAY LIPOXYGENASE

PATHWAY

Cyclic endoperoxidase

-ve Corticosteroid’s

-veNSAIDs

-veZileutonType I

inhibitors

Type II inhibitor

s

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 LTE4LTF4---LTC4 & LTD4 are Slow reacting substance of anaphylaxis[SRS-A].

8

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.

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.

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

Comorbid Condition Aggrevated By NSAID’s 1] Peptic Ulcer

2] Hypertension

3] Congestive Heart Failure

4] Renal Insufficiency

5] Haemostatic Disorders

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

+ +

+

+

+

+

+

+

+

+ +

+

_

_

+

+

?

_

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.

Drug interactions with NSAIDs Drugs ResultDiuretics 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

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

Ocular indication of NSAID’s1]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.

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.

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

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%

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 sensationContraidicated 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, KeratitisContraindication in Hypersensitivity to Other NSAID’s.

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.

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.

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.

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.

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

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.

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 includes1) Anterior ischaemic optic neuropathy after bevacizumab inj. 2) Retinal venous occlusion after

bevacizumab inj. 3) Retinal artery occlusions. 4) Haemorrhagic macular infarction.

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.

List of Intravitreal used1)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.

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 360 mOsm/kg, Ph 6 to 7. Binds to Heparin binding domain of VEGF-165.

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.

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.

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.

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.

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.

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.

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 IntravitrealStaphylococcus Cefazolin, Vancomycin (MRSA)Streptococcus VancomycinHaemophillus CholramphenicolPseudomonas Amikacin, CeftazidimeBacillus Clindamycin, Vancomycin, AmikacinMoraxella CeftazidimeEnterococcus VancomycinE. Coli AmikacinProteus Amikacin, CefazolinCorynebacterium Vancomycin, Cefazolin

Recommended Doses of IVAb’sName of Antibiotic Safe Dose (mg/0.1ml) Frequency of Repeat Inj.

(Hrs).1)Cefazolin 2-2.25 242)Ceftazidime 2.0 243)Clindamycin 0.45-1.0 1 week4)Daptomycin 0.2 Single dose5)Dalfopristine/Quinopristine 0.46)Imipenem 0.1-0.57)Piperacillin/Tazobactam 0.258)Linezolid 3.09)Vancomycin 1.0 7210)Amikacin 0.4 24-4811)Gentamycin 0.1 72-9612)Clarithromycin < 1 1213)Ciprofloxacin 0.1 1214)Moxifloxacin 0.05 1215)Chloramphenicol 2 2416)Aztreonam 0.1 12

Preparation of Intravitreal Antibiotics InjectionsAgent Availabilit

yInitial Diluent(ml)

InitialConc.(mg/ml)

Aliquot(ml)

Final Diluent(ml)

Final Conc.(mg/ml)

FinalIntravitrealDose (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

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.

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.

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.

Immunosuppressantsclass Type of agent Name of agentcorticosteroidsAntimetabolites (Cytotoxic agents)

Alkylating agents (Nitrogen mustard)

cyclophosphamide

chlorambucilFolic acid analogs methotrexatePyrimidine analogs 5-fluorouracilPurine analogs Azathioprine

Calcineurin Inhibitors Specific T cell Inhibitors Cyclosporin A Tacrolimus

Antibodies Infliximab, Daclizumab, VEGF-Inhibiting monoclonal antibodies (Bevacizumab, Ranibizumab) & Pegaptanib.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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).

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.

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.

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.

Corticosteroids:-

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.

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.

Xa

Xa

Extrinsic Coagulation

Pathway

Intrinsic Coagulation

Pathway

Prothrombin

Trombin

FbrinogenFibrin

(monomer)

Fibrin (Polymer) soluble

Fibrin Clot

Insoluble

XIIIa

XIII

Ca2+

Ca2+

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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