A presentation on Retinal laser in opthalmology from Dr. Agarwal's Eye Hospital , in Kalpavriksha - 2012 , Chennai

1. Intra-vitreals in Ophthalmology
Dr. Atul Dhawan (M.S., F.E.R.C.)
Vitreo-Retina Consultant
Dr. Agarwal’s Retina Foundation
Chennai

3. • 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.

4. • 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.

5. 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.

6. COMMONLY USED IVI INJECTION
• Anti-infective (antibiotic, antifungal, and antiviral)
• Anti-inflammatory :nonsteroidal
antiinflammatory,steroids,immunomodulators
• Gas
• Anti-VEGF

7. Anaesthesia
Topical anesthesia (66.6%)
Subconjunctival (33.3%)

8. 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.

9. Post injection check up

10. Delivery of Anti-infective Agents

12. Endophthalmitis: for a surgeon

13. Endophthalmitis
• severe Intraocular inflammation predominantly
involving the inner coat e.g. Retina and vitreous
• Intraocular colonization by microorganisms
• Worst complication of ophthalmic surgery

14. 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.

15. Antibacterial drugs

16. 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.

17. Amikacin

18. • Amikacin is the aminoglycoside of choice for
human endophthalmitis
• DOSE : 400 microgram/0.1 ml

19. 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

21. Vancomycin

22. 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

23. Mechanism of action: Bactericidal

25. 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.

26. 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

29. AMPHOTERICIN B.

30. 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.

31. 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

32. 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.

35. 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.

36. Acyclovir

37. 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.

38. Mechanism of action

39. Ganciclovir

40. • 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

41. 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

42. VITRASERT

43. 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.

44. Corticosteroids

45. 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

47. 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.

48. 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
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

49. • A biodegradable dexamethasone implant
– Drug incorporated into polymer matrix
– Sustained medication release
– Polymer matrix gradually breaks down into inert
compounds

50. Ozurdex®
Applicator and NOVADUR™ implant

51. • Rod shaped tiny implant
• 0.45 mm in diameter and 6 mm in length
• Contains 0.7mg of Dexamethasone (preservative free)

52. Changes in Polymer Matrix
Over Time
After 3 Weeks
Before Implantation

53. TRIAMCENOLONE ACETATE
• Intermediate acting steroid
• Dose 4 mg intraviteal injection
Use:
• recalcitrant macular edema
• in choroidalneovascularization
• to visualize vitreous in clear gel vitrectomy

54. FLUCINOLONE ACETATE

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

56. RETISERT

57. • 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.

58. Delivery of Anti-VEGF Agents

59. SITES WHERE WE CAN HIT

61. 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

62. Properties of VEGF
1. Stimulator of angiogenesis
2. Potent inducer of vascular permeability
3. Proinflammatory effects
4. Neuroprotective effects

63. 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
Pathologic
VEGF
Breakdown of
Blood-Retinal Barrier
Monocyte
Recruitment
Cytokine and Protease Release
Initiating Stimuli
Angiogenesis
Pathologic
Neovascularization
63

64. VEGF in pathologic ocular neovascularization
• Neovascular AMD
• Diabetic retinopathy
• Retinal vein occlusion
• Retinopathy of prematurity
• Corneal neovascularization
• Iris neovascularization

65. WHAT IS
Bevacizumab?

66. AVASTIN MOLECULE

67. AVASTIN® (BEVACIZUMAB)
• CLEAR TO SLIGHTLY OPALESCENT
• STERILE SOLUTION
• PH 6.2
• Avastin half life in vitreous =4.32 days

68. SIDE EFFECTS OF AVASTIN…..

69. OCULAR SIDE EFFECTS
• RPE TEAR
• LENS INJURY
• CORRNEAL ABRASION
• CHEMOSIS
• OCULAR INFLAMMATION
• INCREASED INTRA OCULAR PRESSURE

70. SYSTEMIC SIDE EFFECTS
• CEREBRAL INFARCTION
• INCREASED SYSTOLIC BLOOD PRESSURE
• FACIAL SKIN REDNESS

71. Ranibizumab

72. Development of Ranibizumab
72
Affinity
maturation
(140x)
rhu Fab v1
Insertion of
murine
anti-VEGF-A
sequences
into a human
FAb framework
Humanisation
Ranibizumab
(48 kDa)
(E. coli vector to
mass produce)
Anti-VEGF-A
Murine MAb
(~150 kDa)
Presta, Cancer Res 1997; 57: 4593
Chen, J Mol Biol 1999; 293: 865

73. 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

74. Increased retinal penetration
with antibody fragment
IgG
Herceptin
150 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 V1
48 kDa

75. Intravitreal Injection of Air and Gases

77. • 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.

78. • 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.

79. 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.

80. Pneumatic Retinopexy

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

82. 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.

83. • 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.

85. 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