Intra-vitreals in Ophthalmology

Dr. Atul Dhawan (M.S., F.E.R.C.)Vitreo-Retina Consultant

Dr. Agarwal’s Retina FoundationChennai

• In 1895, Deutschmann injected transplanted rabbit vitreous, and Ohm injected air in the vitreous cavity for the repair of RD.

• Subsequent decades, the use of IVI was limited to administration of saline and air.

• In the 1960s and 1970s, long-lasting gases were developed for the repair of complex RD.

• The modern era of IVI began in the early 1970s with the investigation of the blood ocular barriers .

• The results of these investigations stimulated the use of IVI of antibiotics for treatment of endophthalmitis and steroids for treatment of intraocular inflammation to bypass anatomical barriers in the eye.

This concept heralded the advent:

• Anti-inflammatory and antineoplastic drugs in the 1970s to 1980s

• Antivirals :1980s to 1990s

• Triamcinolone acetonide (TA) and Vascular endothelial growth factor (VEGF) inhibitors in the 2000s.

COMMONLY USED IVI INJECTION

• Anti-infective (antibiotic, antifungal, and antiviral)

• Anti-inflammatory :nonsteroidal antiinflammatory,steroids,immunomodulators

• Gas

• Anti-VEGF

Anaesthesia

Topical anesthesia (66.6%)

Subconjunctival (33.3%)

Procedure• The injection site : infero-temporal

quadrant in the pars plana is 3-4 mm posterior to the limbus.

• The needle aimed at the

midvitreous • The needle is removed with the

application of a cotton-tipped applicator over the sclerotomy site to minimize reflux of material.

• Postinjection course of topical antibiotics typically lasts for 3-7 days.

Post injection check up

Delivery of Anti-infective Agents

Endophthalmitis: for a surgeon

Endophthalmitis

• severe Intraocular inflammation predominantly involving the inner coat e.g. Retina and vitreous

• Intraocular colonization by microorganisms

• Worst complication of ophthalmic surgery

With this event the hopes of the patient vanish, confidence of the operating surgeon is shattered,

and there is always a lurking fear of possible medico-legal implications.

Antibacterial drugs

Aminoglycosides.

• The aminoglycoside antibiotic— streptomycin, gentamicin, kanamycin,

tobramycin, amikacin, and netilmicin.

• Chemical composition of an organic base with amino sugars

• Synthesized : fungal organisms. • Antibiotic activity against both gram-positive and gram

negative bacteria due to interfere with synthesis of ribosomal proteins.

Amikacin

• Amikacin is the aminoglycoside of choice for human endophthalmitis

• DOSE : 400 microgram/0.1 ml

Mechanism of action: Bactericidal

• Bind to 30S/50S/30S-50S interface

• Leads to misinterpretation of code

• Adding of defective protein in cell wall

• Cell wall integrity lost

Vancomycin

Glycopeptides

Vancomycin.

• Intravitreal vancomycin is the drug of choice for endophthalmitis caused by gram-positive organism .

• Dose : 1 mg/0.1 mL

• Inhibit bacterial cell wall synthesis

Mechanism of action: Bactericidal

Always Remember….

• Caution in patients with silicone oil, because nontoxic concentrations of this drug may become toxic after IVI in postvitrectomy, silicone-filled rabbit eyes.

• The threshold for ocular toxicity in rabbits decreased to one quarter of the nontoxic dosage in an unoperated eye compared with silicone-filled eyes.

Cephalosporin

• Ceftazidime and Cefotaxime has more activity against gram-negative organisms but are less active against gram-positive bacteria, especially Staphylococcus.

• Cefazolin is currently not recommended for treatment of

endophthalmitis due to increase in resistant organisms.

• Inhibit cell wall synthesis : bactericidal

AMPHOTERICIN B.

Amphotericin B

fungistatic and fungicidal antibiotic synthesized from Streptomyces nodosus

strains most effective antifungal drug available.

• (0.005 mg in 0.05 mL) is the drug of choice.

Mechanism of action

binds to ergosterol in cell wall of fungi

localized lysis

pores in cell wall

leakage of K+ ions

osmotic imbalance

cellular death

Voriconazole

• newer azole antifungals that contain a third nitrogen on the azole ring

• second-generation synthetic derivative of fluconazole.

• The minimal inhibitory concentration for Candida species, Aspergillus fumigatus, Histoplasma capsulatum,and Fusarium organisms is much lower than others.

Antiviral Agents

• Intravitreal antiviral medications have been used for treatment of viral retinitis.

• Typically occurs in immunosuppressed patients suffering from debilitating illnesses

• Cancer or AIDS or in patients receiving systemic corticosteroids

• Immunosuppressive medications for organ transplantattion.

Acyclovir

Nucleoside Analogs

Acyclovir• Acyclovir is a nucleoside analog.

• Significant activity against herpes simplex viruses Because it is activated in vivo by the virus specific enzymes in infected cells.

• Acyclovir is not toxic to noninfected cells.

• Acyclovir is one of the first antiviral agents to be studied for IVI. to 240 microgram were safe to all ocular structures.

Mechanism of action

Ganciclovir

• The first antiviral agent to be used with IVI against CMV retinitis in AIDS patients.

• A nucleoside analog of acyclovir with a 10- to 100-fold

greater activity against CMV than Acyclovir.

• Mechanism of action: same as Acyclovir

Dose :• induction -2 mg/0.1ml 0.1 ml injected 2 times per week for 3 wks• Maintanance - 2mg/0.1 ml once a week

VITRASERT

VITRASERT• Gancicovir implant.

• Provides local sustained conc. Of the drug with decrease risk of systemic SE without repeated injections.

• Therapeutic levels upto 8 months• 4.5 mg drug in 2.5 mm pellet completely coated by drug

permeable poly vinyl alcohol and incompletely coated with impermeable ethyl vinyl acetate.

• Releases drug at rate of 1 micro gm/hr.

• Mean intravitreal conc. achieved is 4.1 microgm/ml.

Corticosteroids

Specially useful against the inflammatory reaction associated with endophthalmitis

Corticosteroids reduce macular edema in: • Diabetic macular edema (DME)• Pseudophakic CME• Macular edema associated with vein

occlusions

Dexamethasone

• Intravitreal dexamethasone safe to all ocular structures.

• Dexamethasone has a relatively short vitreous half-life thus, it is less likely to cause increased IOP than other steroids

• 0.4 mg 0.1 ml.

Ozurdex® Drug Delivery Technology

O

O

O

O

CH3

CH3O

O

O

O

Sites of hydrolytic cleavage during biodegradation

HO

OH

HO

OH

CH3

O O

Lactic Acid Glycolic Acid

H2O, CO2, and natural metabolites

Polymer DegradationDrug Release

O

O

O

O

CH3

CH3O

O

O

O

Sites of hydrolytic cleavage during biodegradation

HO

OH

HO

OH

CH3

O O

Lactic Acid Glycolic Acid

H2O, CO2, and natural metabolites

Polymer DegradationDrug Release

Lactic Acid Glycolic Acid

Water and Carbon Dioxide

Biodegradable Implant Gradually Transforms Into Water and Carbon Dioxide

• A biodegradable dexamethasone implant

– Drug incorporated into polymer matrix– Sustained medication release – Polymer matrix gradually breaks down into inert

compounds

Ozurdex®

Applicator and NOVADUR™ implant

• Rod shaped tiny implant

• 0.45 mm in diameter and 6 mm in length

• Contains 0.7mg of Dexamethasone (preservative free)

Changes in Polymer Matrix Over Time

After 3 Weeks

Before Implantation

TRIAMCENOLONE ACETATE

• Intermediate acting steroid• Dose 4 mg intraviteal injection

Use:• recalcitrant macular edema• in choroidalneovascularization• to visualize vitreous in clear gel vitrectomy

FLUCINOLONE ACETATE

RETISERT is indicated for the treatment of chronic non-infectious uveitis affecting the posterior seg.

RETISERT

• Implant : one tablet of 0.59 mg of fluocinolone acetonide.

• RETISERT is designed to release fluocinolone acetonide at

initial rate of 0.6 µg/day,

• decreasing over the first month to a steady state between 0.3-0.4 µg/day over approximately 30 months.

Delivery of Anti-VEGF Agents

SITES WHERE WE CAN HIT

MILESTONES IN VEGF

1948–1958

•Michaelson, Ashton, and Wise contribute to “factor X” hypothesis

1989

•Ferrara clones VPF and identifies it as an angiogenesis factor; VPF is rechristened VEGF

1997

•First clinical trials of antiangiogenic therapy in cancer patients initiated

1999

•First anti-VEGF therapy tested in humans with AMD

Properties of VEGF

1. Stimulator of angiogenesis

2. Potent inducer of vascular permeability

3. Proinflammatory effects

4. Neuroprotective effects

Pathologic VEGF activates CNV cascade

Ambati et al, Surv Ophthalmol, 2003; Ferrara et al, Nat Med, 2003; Ishida et al, J Exp Med, 2003; Witmer et al, Prog Retin Eye Res, 2003; Zarbin, Arch Ophthalmol, 2004.

Neovascular AMD

PathologicVEGF

Breakdown of Blood-Retinal Barrier

MonocyteRecruitment

Cytokine and Protease Release

Initiating Stimuli

Angiogenesis

PathologicNeovascularization

63

VEGF in pathologic ocular neovascularization

• Neovascular AMD

• Diabetic retinopathy

• Retinal vein occlusion

• Retinopathy of prematurity

• Corneal neovascularization

• Iris neovascularization

WHAT IS Bevacizumab?

AVASTIN MOLECULE

AVASTIN® (BEVACIZUMAB)

• CLEAR TO SLIGHTLY OPALESCENT

• STERILE SOLUTION

• PH 6.2

• Avastin half life in vitreous =4.32 days

SIDE EFFECTS OF AVASTIN…..

OCULAR SIDE EFFECTS

• RPE TEAR

• LENS INJURY

• CORRNEAL ABRASION

• CHEMOSIS

• OCULAR INFLAMMATION

• INCREASED INTRA OCULAR PRESSURE

SYSTEMIC SIDE EFFECTS

• CEREBRAL INFARCTION• INCREASED SYSTOLIC BLOOD PRESSURE• FACIAL SKIN REDNESS

Ranibizumab

Development of Ranibizumab

72

Affinitymaturation (140x)

rhu Fab v1

Insertion ofmurineanti-VEGF-Asequences into a humanFAb framework

Humanisation

Ranibizumab(48 kDa)

(E. coli vector to mass produce)

Anti-VEGF-AMurine MAb(~150 kDa)

Presta, Cancer Res 1997; 57: 4593 Chen, J Mol Biol 1999; 293: 865

Properties

• Molecular weight : 48 kDa

• Vitreous t1/2 : 9 days

• Effective retinal conc. After one inj. = 1 month

• Serum conc. Are 2000 times less then vitreous

• Dose : 0.5 mg in 0.05 ml

Increased retinal penetration with antibody fragment

IgG

Herceptin150 kDa

Inner retina

Outer retina

The smaller size and lower molecular weight of the antibody fragment allows increased retinal permeability compared to the complete IgG antibody

Mordenti et al, Toxicol Pathol 1999; 27: 536

Fab

RhuFab V148 kDa

Intravitreal Injection of Air and Gases

• The first IVI of gas was performed by Ohm in 1911.

• Ohm punctured the sclera, drained the fluid, and injected air into the vitreous cavity to hold the retina in place, but made a retinal break by administering the injection through the retina. He was successful in two of his four cases.

• In 1938, Rosengrendrainage of subretinal fluid,and IVI of air with postoperative positioning in 256eyes.

• He reported a 77% success rate and that most of the injected air (1.5–2.0 mL) was resorbed within 8 days.

Commonly Used Gases

• Sulfur hexafluoride gasexpands 2.5 times its volume in 48 hours and maintains an effective volume for 7 days to 10 days

• Perfluoropropane (C3F8) expands four times its volume in 96 hours and maintains an effective volume for 35 days.

Pneumatic Retinopexy

Pneumatic retinopexy, a term introduced by Dominguez and Hilton and Grizzard.

Pneumatic Retinopexy

Used to manage RD resulting from either a single break smaller than 1-o’clock hour and located within the superior 8 hours of the ocular fundus or by several small retinal breaks within1-o’clock hour.

• The volume of gas to be injected (0.3– 0.5 mL) is drawn through a millipore filter into a syringe.

• Once the needle is located in the globe, it is pulled back to leave only 2 mm in the vitreous, and the volume of the gas is injected such that only one bubble is formed.

• Paracentesis is commonly performed.

Complications of Intravitreal Injection

The most common adverse effects of IVI are

• Injection site discomfort or pain• Subconjunctival hemorrhage• Temporary elevation of IOP• Floaters• Vitreous or subretinal hemorrhage• Retinal toxicity• RD• Central artery occlusion• Corneal abrasion and lens opacification due to corticosteroid

injections