INTRODUCTION
“Early”
bleb failure after glaucoma filtering surgery (GFS) shows a hypercellular
appearance, while “late” failure is associated with thicker collagen
deposition.
Inhibition
of scarring can be achieved at various levels by both physical and
pharmacologic methods.
Decreasing
the size of the operative site and careful hemostasis (which avoids excessive
fibrin and thermal tissue injury) reduce the scope of initial, intra-operative
injury and subsequent fibrosis-stimulating inflammation.
Avoiding
other sources of inflammation, such as combined surgical procedures have the
same effect. Successful egress of aqueous through the sclerostomy serves to
keep the patency of the fistula for a prolonged time.
Characteristics
of patients with increased risk for scarring include:
- Young age
- Black race
- Previous unsuccessful GFS
- Aphakia and pseudophakia
- Neovascular glaucoma
- Uveitic glaucoma
- Iridocorneal endothelial syndrome
- Previous prolonged topical glaucoma therapy
- Conjunctival scarring from conditions such
as alkali burns or pseudopemphigoid.
http://ourgsc.blogspot.com/2017/09/blog-post.html PHARMACOLOGIC AGENTS
Drugs
used in inhibiting fibrosis in the GFS bleb can be categorized into the
following groups=
1. ANTI-INFLAMMATORY
AGENTS
(a) Corticosteroids:
Sugar,
first noted the beneficial effect of topical corticosteroids in prevention of
bleb scarring.
Systemic
steroids did not have any additional effects.
Subconjunctival
steroids have been used at the conclusion of the GFS procedure.
The
presumed mechanism of the anti-fibrosis activity of corticosteroids in GFS is
the inhibition of the inflammatory response, mediated via blockage of the
lipo-oxygenase and cyclo-oxygenase pathways by direct inhibition of
phospholipase A2.
This
results in decreased capillary permeability, chemotaxis inhibition and
suppression of fibrin deposition.
Decreased
fibroblast proliferation occurs at higher concentrations while a stimulatory
effect may be seen at lower concentrations.
(b) Non-steroidal
anti-inflammatory drugs:
NSAIDs,
inhibitors of both lipoxygenase and cyclooxygenase pathways, have demonstrated
suppression of human ocular fibroblast proliferation.
However,
in clinical trials, topical post-operative flurbiprofen 0.03% after GFS
resulted in higher rate of encapsulated blebs and higher final IOP.
2. ANTI-NEOPLASTIC
AGENTS
Many
pharmacologic agents hinder the scarring process via the antimetabolic
activity, typically interfering with one or more phases of the cell replication
cycle of fibroblasts.
(a) 5-Fluorouracil
(5-FU)=
5-Fluororidine
(5-FUR) and 5-FU are pyrimidine nucleotide analogs. Similar to the pyrimidine
analogs, they owe their anti-neoplastic activity to small structural
dissimilarities from endogenous pyrimidines.
These
agents require metabolic conversion to nucleotides to exert cytotoxicity.
Simultaneous catabolism can inactivate these drugs.
5-FU
is a fluorinated pyrimidine with a molecular weight of 130.08.
It
undergoes intracellular conversion to the active deoxynucleotide,
5-fluro-2’-deoxyuridine 5’-monophosphate (FdUMP).
FdUMP
causes competitive inhibition of thymidylate synthetase in the S-phase of the
cell-replication cycle. This hampers conversion of deoxyuridylic acid to
thymidylic acid, thus impeding DNA synthesis.
FdUMP
is also incorporated directly into DNA molecules after conversion by
intracellular kinases to a triphosphate. Such DNA, with flurouracil substituted
for thymine, may be unstable than native DNA.
It
also interfers with RNA processing and function after its conversion to the
ribonucleotide, fluouridine monophosphate (FUMP).
In
GFS, this agent has been used mostly as post-operative subconjunctival
injections.
The
usual single dose is 5 mg (0.1 ml of undiluted bolus at 50 mg/ml).
The
subconjunctival injection is performed 90 to 180 degrees away from the bleb. A
tuberculin syringe with 30-gauge needle is used by going tangentially to the
globe, bevel away from the sclera.
Avoid
the conjunctival vessels to minimize bleeding.
Subconjunctival
diffusion around the wound site may occur, especially through the needle track.
This
elution of the drug into the tear film may encourage epithelial toxicity.
Leakage
can be reduced by tamponade of the injection site by a cotton-applicator; light
massage to move the drug from the track and irrigation of residual undiluted
5-FU from the conjunctiva and eyelids with saline.
The
number of injections can be adjusted by the clinical response and other factors
such as patient access, acceptance, affordability and compliance.
Intra-operative
5-FU implantation using a purified collagen sponge containing 100 µgm of 5-FU
in the quadrant of surgery has also been reported. This leads to a slow release
of the agent and potentially less epithelial toxicity.
Undiluted
5-FU (50 mg/ml) has been used intraoperatively using drug-soaked cellulose
sponges placed under and over the scleral flap and sub-conjunctivally for a
5-minute period followed by copious balanced slat solution (BSS) irrigation.
Toxicity:
Systemic
toxicity is rare as hardly 1-3% of the dose used in anti-cancer therapy enters
the general circulation following ocular 5-FU usage.
Most
of the drug is metabolized through hepatic clearance and elimination by
respiration as carbon dioxide or renal excretion in the form of metabolites or
free drug.
Ocular
toxicity occurs as a consequence of its effect on rapidly dividing epithelial
cells of the cornea and conjunctiva.
The
Fluorouracil Filtering Surgery Study (FFSS) group reported punctate corneal
epitheliopathy in 98% patients, conjunctival epithelial defects and corneal
epithelial defects (64%). This toxicity was also responsible for the large
number of conjunctival wound leaks.
Other
corneal complications were: filamentary keratitis, keratinized corneal plaques,
infectious corneal ulcers and striate melanokeratosis (attributed to
centripetal migration of pigment-laden stem cells from the limbus).
5-FU
was also associated with punctal-canalicular stenosis, cicatricial ectropion
due to lowerlid dermatitis. Contact dermatitis and increased pigmentation of periocular
skin.
The
most devastating complications of 5-FU have been the occurrence of thin, cystic
blebs, with an increased frequency of late bleb leaks, late endophthalmitis and
hypotonic maculopathy (also choroidal effusion and persistent shallow chambers).
5-FU
should be avoided in patients with known corneal diseases that increase the
risk of complications. Such conditions include bullous keratopathy, severe-dry
eye syndrome, preexisting corneal epithelial defects, recurrent erosion
syndrome, corneal melting syndrome, preexisting dellen, conditions associated
with decreased limbal stem cells such as Stevens-Johnson syndrome, pemphigoid,
pseudopemphigoid and old alkali burns.
Epithelial
defects and wound leaks appear dose-related.
Careful
closure of the conjunctival wound is critical to the prevention of early
postoperative wound leaks.
Suturing
with small taper point (round bodied) needles with 8/0-10/0 sutures and
employing a running mattress closure may prevent bleb leaks appreciably.
In
general, antimetabolites are more commonly associated with hyptonic maculopathy
in young and myopic patients.
The
FFSS reported that 5-FU reduced the failure rates of GFS to 49%
postoperatively, compared to 74% in control eyes.
(b) Mitomycin
C (MMC)=
MMC
was isolated by Wakaki and colleagues from Streptomyces
caespitosus.
It
undergoes enzyme activation in tissues and functions as an alkylating agent,
cross-linking DNA.
Although
it is cell-cycle phase non-specific, it is most active in the G and S phases of
cell division.
MMC
is used to treat neoplasms of the stomach, pancreas, bladder, colon, rectum,
lung, cervix and breast.
In
GFS it is used to prevent replication of fibroblasts.
Studies
have shown subconjunctival fibroblast proliferation inhibition to be dependent
on the dose and exposure time.
The
potency of MMC is 100 times greater than 5-FU.
MMC
impedes the future replication of even those cells which are not synthesizing
DNA at the time of exposure.
The
markedly hypovascular blebs following use of MMC is probably due to toxicity to
vascular endothelium and contributes to the decreased scarring.
Toxic
damage to the ciliary body and resulting decreased aqueous production could
also contribute to the lowered IOP.
MMC
has been used in a concentration between 0.1-0.5 mg/ml. it remains stable for 7
days at room temperature and for 14 days when refrigerated.
Non-preserved
MMC should be used within 24 hours.
MMC
is placed on the scleral bed after conjunctival dissection, either before or
after the scleral flap has been fashioned. However, it should never be used
once the coats of the eyeball have a full-thickness entry.
Some
surgeons prefer to place the sponge over the scleral flap.
Care
should be taken to avoid touching the edges of the conjunctival flap to the
sponge, which might encourage postoperative wound leaks.
Toxicity:
MMC
should be avoided during pregnancy due to its potential teratogenic effects.
It
has significant corneal endothelial toxicity.
Scleral
thinning and necrosis has not reported following use of MMC as described here.
MMC
has fewer rates of corneal epithelial toxicity as compared to 5-FU.
Conjunctival
wound leaks and hypotonic maculopathy is dependent on exposure times.
Treatment
options for hypotonic maculopathy include autologous blood injection into the
bleb, cryotherapy, and topical application of trichloracetic acid.
3. OTHER
ANTINEOPLASTIC AGENTS
(a) Antibiotics=
Bleomycin,
daunorubicin, doxorubicin and mithramycin are antineoplastic antibodies
extracted from Streptomyces. These agents have been found to inhibit
fibroblasts.
(b) Pyrimidine
analogs=
Cytosine
arabinoside (Ara-C), trifluorothymidine, 5-fluoroorotate and metabolites of 5-FU
have antiproliferative actions. They inhibit DNA polymerase and impede DNA
synthesis.
(c) Alkaloids=
Some
alkaloids extracted from plants have been found to inhibit fibroblasts. These
include vincristine, vinblastine and taxol.
4. OTHER
ANTIFIBROSIS AGENTS IN GLAUCOMA SURGERY
Interferon-α,
calcium ionophore A23187, β-aminoproprionitrile (BAPN), and D-penicillamine
(DPA) have been studied for their ability to inhibit cellular proliferation,
collagen synthesis and maturation.
Interferon-α
inhibits collagen production, fibroblast proliferation and chemotaxis.
Calcium
ionophore A23187 also inhibits collagen synthesis.
DPA
and BAPN inhibit collagen fibril cross-linking after synthesis, thus,
decreasing tensile strength of scar tissue.
Tissue
plasminogen activators (TPA) is an enzyme that converts plasminogen to plasmin,
which is fibrinolytic. TPA may enhance GFS.
Similarly,
heparin also inhibits proliferation of human scleral fibroblasts. However, it
requires frequent exposure.
