Ocular NSAIDs and Steroids

Ocular NSAIDs &
Steroids : Uses &
Indications
MODERATOR PRESENTERS
DR. SANJEEV BHATTARAI AAYUSH CHANDAN
SRIJANA LAMICHHANE

Presentation layout
Introduction to inflammation
Introduction to NSAIDs
Mechanism of action
Classification of NSAIDs
Ophthalmic NSAIDs
Indications & contraindications

Inflammation
Part of the complex biological response of body tissues to
harmful stimuli such as pathogens , damaged cells , irritants
& is a protective response involving immune cells , blood
vessels & molecular mediators
Vital part of the immune system’s response to injury &
infection

Cardinal signs of inflammation
1. Redness (Rubor) : Vasodilation of capillaries to increased blood
flow .
2. Heat (Calor) : D/t transfer of internal heat to the tissue by
increased blood flow .
3. Pain (Dolor) : D/t Sensitization of sensory nerve endings .
4. Swelling (Tumor) : D/t increased vascular permeability &
escape of plasma protein from bloodstream .
5.Functio laesa : Loss of Function

Features of inflammatory
response
1. Increased production of prostaglandins & leukotrienes :
Arachidonic Acid is produced by the action of
phospholipase
AA by the enzyme cyclooxygenase converts it into one of
the variety of prostaglandins that have effects on smooth
muscle & mediate some of inflammatory reactions
Lipooxygenase converts AA to leukotrienes which bring
about increase in permeability & oedema

Membrane phospholipid
Phopholipase AGlucocoticoids
ThromboxanePGF2αPGD2PGE2PGI2
Arachidonic acid
Chemical &
mechanical
stimuli
LipooxygenaseCyclooxygenase
Leukotrienes

2. Liberation of histamine from mast cell
Caused by Allergan-Antigen Reaction causing an increase in
influx of Ca++ ions from mast cells
3. Vascular effects
In addition to the action of histamine , other locally active
agents can induce vasodilation & increased capillary
permeability
In the eye , permeability of the blood/aqueous barrier is
increased , leading to a turbid aqueous that contains more
protein than normal

4. Fibroblastic activity
Part of the inflammatory response is to stimulate the
mechanism of wound repair .
e.g. Fibroblast & collagen forming activity
5. Increased Leucocyte Activity
These normally migrate into the site of inflammation to
attack & kill invading cells.

Because the effects of inflammation can be sometimes
excessive & in the eye lead to discomfort & loss of vision , it
is often desirable to limit the extent by the use of
appropriate drugs
Cyclooxygenase inhibiting agents : Steroids & NSAIDs
Interference with release or action of histamine : Mast cell
stabilizers & Antihistamines

NSAIDs
Developed as an alternative to steroids in the treatment of
inflammatory disease
Non-Steroidal Anti-Inflammatory Drugs
All NSAIDs have 3 major therapeutic effects
Anti-inflammatory
Analgesic
Anti-Pyretic
Most are the organic acid derivatives

contd..
Aka non-narcotic , non-opoid , aspirin like drugs or
antipyretic analgesics
There are more than 50 different NSAIDs on the global
market now
Do not depress CNS
Act primarily on peripheral pain mechanism

History
Sodium salicylate was used for pain & fever in 1875 AD.
It’s great success led to the introduction of aspirin in 1899 AD.
Indomethacin was introduced in 1963 AD.
 After the discovery of ibuprofen the mechanism involving
cycloxygenase inhibition was revealed.

Cyclooxygenase
Enzymes responsible for the formation of prostanoids i.e.
prostaglandins , prostacyclins & thromboxane
Two main forms : COX1 & COX2
Recently COX3 also have been isolated (but is not
functional in human)

COX1 COX2
Continuously stimulated by
the body
Induced(normally not
present in cells)
Produces prostaglandin
involved in tissue
homeostatis , gastric
cytoprotection , platelet
aggregation , Renal blood
flow Autoregulation
Produces prostaglandins
that mediate inflammation,
pain and fever
Constitutively expressed in
most tissues like GI, platelets
Induced mainly in sites of
inflammation by cytokines

Prostaglandins
Potent bioactive lipid messengers synthesized from
arachidonic acid mediated by enzyme COX
4 principal bioactive prostaglandins generated in vivo are
Prostaglandin E2 (PGE2)
Prostaglandin F2α(PGF2α)
Prostaglandin I2 (PGI2)
Prostaglandin D2 (PGD2)

1. Prostaglandin E2 (PGE2)
One of the most abundant PGs produced in the body.
Regulation of immune response , BP , gastrointestinal integrity &
fertility.
Involved in processes leading to classical sign of inflammation ,
redness , swelling & pain
Powerful bronchodilator
2. Prostaglandin F2α (PGF2α)
Derived mainly from COX1 in female reproductive system
Plays an important role in ovulation , luteolysis , contraction of
uterine smooth muscle & initiation of parturition
Recent studies also shows that it plays significant role in renal
function , contraction of arteries , myocardial dysfunction , brain
injury & pain

3.Prostaglandin I2 (PGI2)
Regulate cardiovascular homeostasis
Potent vasodilator & inhibitor of platelet aggregation , leukocyte
adhesion
Important mediator of the edema & pain that accompany acute
inflammation
4. Prostaglandin D2(PGD2)
Synthesized in both CNS & peripheral tissue & appear to function in
both an inflammatory & homeostasic capacity
Involved in regulation of sleep
Pain perception
Most predominant in acute allergic response

Thromboxane A2
Mediate platelet adhesion & aggregation , smooth muscle
contraction & proliferation & activation of endothelial
inflammatory responses.

Ocular effects of prostaglandins
Prostaglandin Effects
PGD2 Stimulate vasodilation & chemosis
PGE1 & PGE2 ↑inflammation , ↑IOP , ↑Capillary
permeability , stimulates vasodilation ,
stimulates miosis
PGF2α ↓IOP , minimal effect on
inflammation , minimal effect on
miosis

Mechanism of action of
NSAIDs
1. Anti – Inflammatory effects
Anti-inflammatory actions of NSAIDs are most likely
explained by their inhibition of prostaglandin synthesis by
COX2
Aspirin irreversibly inactivates COX-1 and COX-2 by
acetylation of a specific serine residue.
This distinguishes it from other NSAIDs, which reversibly
inhibit COX-1 and COX-2

2. Analgesic effect
A. The analgesic effect of NSAIDs is thought to be
related to:
 the peripheral inhibition of prostaglandin production
 may also be due to the inhibition of pain stimuli at a
subcortical site
B. NSAIDs prevent the potentiating action of
prostaglandins on endogenous mediators of peripheral
nerve stimulation (e.g., bradykinin).

3.Antipyretic effect
The antipyretic effect of NSAIDs is believed to be
related to:
 Inhibition of production of prostaglandins induced
by interleukin-1 (IL-1) and interleukin-6 (IL-6) in the
hypothalamus
“resetting” of the thermoregulatory system, leading
to vasodilatation and increased heat loss.

Beneficial action due to PG synthesis
inhibition
Anti-inflammatory effect
Analgesic effect
Anti-pyretic effect
Anti-thrombotic effect
Closure of ductus
arteriosus in new born

Adverse effects
1. Gastrointestinal disturbances
Commonest adverse effects of NSAIDs
Result mainly from inhibition of gastric COX-1
Commonly include gastric discomfort , Dyspepsia ,
Diarrhoea , Nausea & vomiting & in some cases gastric
bleeding & ulceration
So, it had been predicted that COX-2 selective agents
would provide good anti-inflammatory & analgesic actions
with less gastric damage

2.Skin Reactions
Rashes are most common
Vary from mild erythematous , urticarial & photosensitivity
reactions to more serious & potentially fatal disease
including Steven Johnson syndrome

3.Adverse renal effect
Decreased Na+ & H20 excretion
Renal failure
Decreased effectiveness of diuretics & antihypertensives
4. Cardiovascular side effects
Potential of NSAIDs when given alone to raise BP &
therefore predispose to adverse cardiovascular events such
as stroke & myocardial infarction

5.others
Bronchospasm
Rhinitis
Nasal polyposis
Delayed parturition
Dystocia

Contraindications to NSAIDs use
H/O ulcer disease
Advanced age
Long duration of NSAIDs therapy
Smoking & heavy alcohol
Patient with renal impairment , heart failure , hypertension
Patient with hypersensitivity reactions to salicylates or any
other NSAIDs
Asthmatics patients

Drug interactions
Drug Result
Diuretics Decrease diuresis
Beta-blockers Decrease antihypertensive
effect
ACE inhibitors Decrease antihypertensive
effect
Anticoagulants Increase of GI bleeding
Cyclosporine Increase nephrotoxicity
Alcohol Increase of GI bleeding

Classification of NSAIDs
A. Nonselective COX inhibitors (traditional NSAIDs)
1. Salicylates: Aspirin
2. Propionic acid derivatives: Ibuprofen, Naproxen,Ketoprofen,
Flurbiprofen.
3. Anthranilic acid derivative: Mephenamic acid
4. Aryl-acetic acid derivatives: Diclofenac, Aceclofenac.
5. Oxicam derivatives: Piroxicam, Tenoxicam.
6. Pyrrolo-pyrrole derivative: Ketorolac
7. Indole derivative: Indomethacin.
8. Pyrazolone derivative: phenylbutazone, Oxyphenbutazone

B. Preferential COX-2 inhibitors
Nimesulide, Meloxicam, Nabumeton.
C. Selective COX-2 inhibitors
Celecoxib, Etoricoxib, Parecoxib.
D. Analgesic-antipyretics with poor anti-inflammatory
action
1. para aminophenol derivatives: Paracetamol
2. Pyrazolone derivative: Metamizol, Propiphenazone.
3. Benzoxazocine derivative: Nefopam

Routes of administration
Topical Oral

Topical Ophthalmic NSAIDs
Indometacin
oxyphenbutazone
Ibuprofen
Diclofenac
Ketorolac
Flurbiprofen
Suprofen
Nepafenac

Common topical ophthalmic
NSAIDS
Generic Trade Formulation Concentration
Diclofenac Igesic Solution 0.1%
Flurbiprofen Eyefen,Flur Solution 0.03%
Ketorolac Acular Solution 0.5%
Acular PF Solution 0.5%
Acular LS Solution 0.4%
Suprofen Profenal Suspension 1.0%
Indomethacin Indocid Solution 0.5%
Nepafenac Nevanac Suspension 0.1%

Indications
Topical NSAIDs in preoperative period
Topical NSAIDs in anterior segment inflammation

Topical NSAIDs in preoperative
period
Intraoperative miosis
Topical NSAIDs reduce pupillary constriction that occur
during cataract extraction and other intraocular surgeries
Post operative inflammation
Use of NSAIDs before surgery prevent the synthesis of
prostaglandin and provide prophylaxis for expected
inflammation
NSAIDs also prevent blood aqueous barrier breakdown and
reduce cells and flare in AC

Cystoid macular edema
Prevention of acute aphakic and pseudophakic CME
and treatment of chronic CME
Peak incidence of CME occurs between 4 & 8 weeks
after surgery

Topical NSAIDs for anterior
segment inflammation
Allergic and non-bacterial conjunctivitis
Most ocular allergies are type I hypersensitivity reaction
mediated by mast cells
Degranulation releases preformed mediators such as
histamine and initiates synthesis of newly formed mediators
including prostaglandins
Corneal Pain
Injury to corneal tissues stimulates prostaglandin synthesis
Corneal pain following abrasions , trauma or epithelial
erosions , PRK , treated with topical NSAIDs

Episcleritis
Topical NSAIDs may be useful
Oral NSAIDs may be required in recurrent cases
Tab Flurbiprofen 100mg TDS
Tab Indometacin 25mg TDS

Other indications
Non necrotizing scleritis
until inflammation resolves
(given in conjunction with topical steroids )
Tab indomethacin 75mg BD

Anterior uveitis
 Systemic Aspirin can be used where steroids are
contraindicated
Phenylbutazone and oxyphenbutazone potent in uveitis
associated with rheumatoid disease
Naproxen is useful in ankylosing spondylitis

Diclofenac sodium
Trade name Igesic
Available as 0.1% ophthalmic solution
Indications  Postoperative
inflammation
 Temporary relief of pain
and photophobia in
patients undergoing
corneal refractive surgery

Flurbiprofen sodium
Trade name Eyefen , flur
Indications  Inhibition of
intraoperative miosis
 Post operative
inflammation

Ketorolac tromethamine
Trade name Acular , Acular PF , Acular LS
Available as 0.5% and 0.4% ophthalmic
solution
Indications  Allergic conjunctivitis
 Post cataract surgery
inflammation
 Post operative pain and
photophobia in PRK
 Ketorolac 0.5% in
treatment of chronic CME

Indometacin
Trade name Indocid
Indications  Treatment of CME

Suprofen
Trade name Profenal
Available as 1% ophthalmic suspension
Indications  Prevention of
intraoperative miosis

Nepafenac
Trade name Nevanac
Available as 0.1% ophthalmic suspension
Indications  For pain and inflammation
after cataract surgery

Dosing regimens of topical
NSAIDs
Indications Drug Regimen
Intraoperative miosis
prevention
Flurbiprofen 1 drop every 30 min , 4 times
before surgery
Ketorolac 1 drop every 30 min , 4 times
before surgery
Suprofen 1 drop every 30 min , 4 times
before surgery
Postoperative inflammation Diclofenac 1 drop QID for at least 1-2
weeks after surgery
Ketorolac 1 drop QID for at least 1-2
weeks after surgery
Cystoid macular edema Ketorolac I drop QID for at least 3
months
Indometacin 1 drop QID
Allergic conjunctivitis Ketorolac 1 drop QID for relief of ocular
itching during allergy season
Corneal pain Diclofenac 1 drop preoperatively and 1
drop QID postoperatively for 3
days
Ketorolac (non preserved ) 1 drop QID for 3 days

Oral NSAIDs in ophthalmic use
Ibuprofen
Trade name Flexon , Brufen `
 Flexon(Ibuprofen
400mg +
paracetamol 500mg)
 Brufen (Ibuprofen
400mg)
Indications As analgesic in stye &
chemical injury
1 Tab PO TDS

As oral NSAIDs has more systemic side effects (esp.Gastric
mucosal damage ) drugs for peptic ulcer is used
H2 antihistamines : Cimetidine , Ranitidine
Proton pump inhibitors : Omeprazole , Pantoprazole ,
Rabeprazole
Tab Ranitidine 300mg OD or 150mg BD
Tab Pantoprazole 40mg OD

Precautions for ocular NSAIDs
Increased bleeding of ocular tissues, including hyphemas
in conjunction with ocular surgery
Slow or delayed wound healing
 Cross sensitivity with acetylsalicylic acid

Topical NSAIDs may cause keratitis: Continued treatment
with ophthalmic NSAIDs may result in epithelial breakdown,
corneal thinning, corneal infiltrates, corneal erosion in
certain susceptible patients
Pregnancy: Due to known effect of NSAIDs on fetal
cardiovascular system including closure of ductus
arteriosus, use of ophthalmic NSAIDs during late pregnancy
should be avoided

Contraindications
Hypersensitivity to any component of formulations
Nepafenac and Ketorolac: contact lens wearers
 Flurbiprofen and Suprofen: patients with dendritic keratitis

Adverse Effects
Systemic absorption minimal in topical NSAIDs
Local effects:
burning sensation
stinging sensation upon instillation
conjunctival hyperemia

PRESENTATION LAYOUT
 Introduction to steroids
 Introduction to adrenal gland
 Inflammatory response
 Pharmacologic principle of steroids
 Common ophthalmic steroids
 Indications, contraindications and side effects of steroids

59
Is a biologically active organic compound
Consist of four rings arranged in a specific molecular configuration
 “Steroid" is a chemical name for any substance that has a characteristic
chemical structure consisting of multiple chemical rings of connected
atoms.
Contains four cycloalkane rings ( core structure) 17 carbon atom
3 rings : cyclohexane
1 ring : cyclopentane
INTRODUCTION TO
STEROID

Hundered of steroids are found in plants, animals and
fungi
Animal steroid
All the human steroids are synthesized from the
cholesterol
Two principle biological function ;
Is an important component of the cell membrane which
alter membrane fluidity
Acts as signaling molecules

CORTISOL DEXAMETHASONE
Some examples of natural steroids
Vitamin D
Cholesterol
Estrogen
Progesterone
Cortisol
Some examples of synthetic steroids
Prednisolone
Dexamethasone
Betamethasone
trimcinolone

ADRENAL GLAND
Two in number, superior and slight
medial to kidneys
Two parts: adrenal cortex (80%)
adrenal medulla (20%)
 Each weight about 4 grams

ADRENAL CORTEX
Comprises 3 zones:
Zona glomerulosa(15%)
Zona fasciculata(75%)
Zona reticularis(10%)

ZONA GLOMERULOSA : Produce mineralocorticoids i.e
Aldosterone
ZONA FASCICULATA : Produce glucocorticoids
e.g Cortisol , corticosterone , small amount of
adrenal androgens and estrogens
ZONA RETICULARIS : Produce androgens
e.g Dehydroepiandrosterone ,small amount
of estrogen and some glucocorticoids

Secretion of mineralocorticoids depend upon extracellular fluid
concentrations of angiotensin II and potassium
Secretion of glucocorticoids is controlled by hypothalmic –
pituitary axis via ACTH(adrenocorticotropic hormone)
Thus secretion pathway of mineralocorticoids and
glucocorticoids does not depend upon each other

HYPOTHALAMO-PITUITARY-ADRENAL
AXIS

The hypothalamic pituitary adrenal (HPA) axis is our central
stress response system.
This system works in a straight forward manner
Any response i.e. stress is characterized by hypothalamic
release of CRH
This CRH binds to receptors of ant.pituitary gland,results in
the release of ACTH
ACTH binds to receptor of adrenal cortex and stimulate
release of cortisol
HPA axis

In response to stressors, cortisol will be released for
several hours after encountering the stressor.
At a certain blood concentration of cortisol this protection
is ostensibly achieved and the cortisol exerts negative
feedback to the hypothalamic release of CRF and the
pituitary release of ACTH (negative feedback). At this point,
systemic homeostasis returns.

FUNCTION OF MINERALOCORTICOIDS
Aldosterone increases renal tubular reabsorption of
sodium and secretion of potassium
Excess Aldosterone increases extracellular fluid volume
and arterial pressure but has only small effect on plasma
sodium concentration
Excess aldosterone causes hypokalemia and muscles
weakness
Deficient aldosterone causes cardiac toxicity

FUNCTION OF GLUCOCORTICOIDS
1.Effect on carbohydrate metabolism i.e stimulation of
gluconeogenesis
Decrease glucose utilization by the cells
Elevate the blood glucose concentration and cause Adrenal diabetes
Cortisol increases the enzyme required to convert the
amino acid into the glucose in liver cells
Cortisol causes mobilization of amino acids from the
extrahepatic tissue mainly from muscles

2.Effect on protein metabolism
•Reduction of cellular protein
•Cortisol increases the liver and plasma protein
Reduction of protein stored in essentially all body cells
except those of liver cells
Decreases protein synthesis and increases catabolism of
protein already present

3.Effect on fat metabolism
Mobilization of fatty acids
Excess cortisol causes obesity
It promotes mobilization of free fatty acids from adipose
tissue
Increases the concentration of free fatty acids in plasma ,
which increases there utilization for energy
Excess deposition of fat in chest and head regions of body
giving a buffalo like torso and rounded moon face

4.Effect in resisting stress
Almost all type of stress ( trauma , infections , intense heat and
cold , surgery ) cause immediate and marked increase
adrenocotical secretion of cortisol
Glucocorticoids cause rapid mobilization of amino acids and
fat from there cellular store , making them immediately
available both for energy and synthesis of other compounds
so the damaged tissues can use the newly formed amino
acids for the maintenance of cellular life

5. Effect on immunity and blood
Decreases activation and migration of leukocytes
Lyse and destroy lymphocytes
Administration of large doses of the cortisol causes significant
atrophy of all lymphoid tissue through out the body
Cortisol increase the count of red blood cells , the cause of which is
unknown , excess causes polycythemia
Deficient leads to anaemia
Inhibit migration of neutrophils to extracellular space and
adherence to vascular endothelium

6.Effect as strong anti-inflammatory agent
Reduce histamine release from basophils induced by IgE
dependent stimulus
Inhibit phospholipase A2 which prevents biosynthesis of
arachidonic acid and subsequent formation of prostacyclin,
prostaglandins and leukotrienes
Decrease capillary permeability and fibroblast proliferation and
the quantity of collagen deposition thus influencing tissue
regeneration and repair
The anti-inflammatory effects are nonspecific, occurring
whether the etiology is allergic, traumatic or infectious

Mode of action
Every tissue has receptor for steroids
Binds to glucocoticoid receptor in nucleus and influence
the gene expression
Because cortisol
is lipid soluble it
can easily diffuse
through the cell
membrane

Transactivation : upregulates the expression of anti-
inflammatory proteins in nucleus
Transrepression : downregulates the expression of
proinflammatory proteins in cytosol

It is better to understand “Increased concentration of drug
better than increased dozes”

Common Ophthalmic steroids
Corticosteroid Derivative Formulation Concentration
Prednisolone Acetate suspension 0.125% or 1%
Prednisolone Sodium
phosphate
solution 0.125% or 1%
Dexamethasone Alcohol Suspension 0.1
Dexamethasone Sodium
phosphate
Solution
Ointment
0.1
0.05
Flourometholo
ne
Alcohol Ointment
Suspension
0.1
0.1
Flourometholo
ne
Acetate Suspension
Suspension
0.25
0.1

Prednisolone
A synthetic analogue of the major glucocorticoid i.e
cortisol or hydrocortisone
Effective for external as well as intraocular inflammation
Commercially formulated as acetate and phosphate ;
acetate derivative being more effective anti-inflammatory
agent
Not available as an ophthalmic ointment.

Available in concentration of 0.5% and 1% W/V
Prednisolone acetate 1% is considered the standard, by which
all other topical ocular corticosteroids are compared
As compared with other topical ocular steroids , 1% prednisolone
acetate is generally considered the most effective anti-inflammatory
agent for anterior segment ocular inflammation

Has the greatest efficacy when compared to all other available
ophthalmic agents
 So,is more likely to elevate IOP and have greater side effects
than its weaker counterparts
Systemic prednisolone recommendation
•Tab. Prednisolone acetate 1 mg/kg of body weight *OD
•Tab. Ranitidine 150 mg *OD * AC
•Tab. Calcium * 500 mg * OD

Dexamethasone
Structurally resemble cortisol
Available as an alcohol or phosphate derivative
0.1% ophthalmic suspension or solution
Alcohol derivative more active than phosphate
Resistant to metabolism after penetration into the
aqueous humor.

Very effective in reducing ocular inflammation
But has the propensity to increase IOP more than any other
topical ophthalmic corticosteroid
Usually limited to shortcourse therapy
 Dexamethasone ointment is very useful for nighttime coverage
in cases of uveitis

Fluorometholone (FML)
Structurally resemble progesterone
 Formulated both as an alcohol and acetate derivative
Relatively weaker corticosteroid
Decreased risk of unwanted complications, such as IOP rise

Treatment of choice in those patients with a history of pressure
rise due to corticosteroid therapy or previously diagnosed
glaucoma
An effective agent in external ocular inflammations , like
conjunctivitis, piguiculitis , scleritis and episleritis
Available as 0.1% drop

Medrysone
Like fluorometholone , a synthetic derivative of
progesterone
Weakest of the available ophthalmic steroids
Useful for superficial ocular inflammations , including
allergic and atopic conjunctivitis
Generally do not respond to intraocular inflammatory
conditions
Elevates IOP minimally or not at all

Betamethasone
Available as 0.1% eyedrop or ointment
Marked anti-inflammatory action
Low dose is enough
So, reduces the risk of side effects

Hydrocortisone
1st corticosteroid used in medicine
Available as 1% eyedrop and 0.5%, 1% or 3% ointment

Rimexolone
Available as a 1% ophthalmic suspension (Vexol)
Effective in suppressing cells, flare, keratin precipitates and
photophobia
Main advantage - more of site-specific action than other
corticosteroids
Less tendency to increase the IOP.

LOTEPREDNOL
Available as 0.2% and 0.5% concentration
 Less potent steroid
Indicated for temporary relief of the signs and symptoms
of seasonal allergic conjunctivitis

Dexamethasone
Prednisolone
Fluorometholone
Medrysone
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BIOAVAILABILITY OF TOPICAL STEROIDS
Fraction of unchanged drug reaching the systemic circulation
Depends upon the ability to penetrate cornea
The ideal steroid should be biphasic i.e solubility in both the
lipid (hydrophobic) layers of the epithelium and endothelium and
the aqueous (hydrophilic) media of the stroma

Acetate and alcohol derivatives more lipophilic i.e fat soluble
 Sodium phosphate and hydrochloride more hydrophilic i.e
water soluble
So, in intact epithelium , penetration of acetate greater while in
absence of epithelium penetration of phosphate greater
Acetate and alcohol derivatives are more effective then the
phosphate derivatives in suppressing corneal inflammation both
in the presence and absence of corneal epithelium

Preparations
LOCAL :
Eyedrops-suspension or solution
Ointments
Injection - subconjuctival , sub-tenon’s
capsule or retrobulbar
SYSTEMIC : Tablets
Injections(intra venous)
-

Routes of administration
TOPICAL SYSTEMIC
Effective in anterior
segment diseases
Effective in posterior
segment diseases
Ease of application, relative
low cost
Difficult application,
relatively high cost
Dosage vary with severity of
disease
Generally single dose daily
Absence of systemic
complications
Systemic complications
present

Ocular indications
Topical Systemic
•Blepharitis
•Uveitis
•Allergic conjunctivitis
•Allergic keratitis
•Viral keratitis
•Pingueculitis
•Inflammation of pterygium
•Cystoid macular edema
•After ocular surgery
• posterior uveitis
•Systemic ophthalmia
•Papillitis
•Retrobulbar neuritis
•Scleritis
•Anterior ischemic optic
neuropathy
•Malignent exopthalmus
•Orbital pseudotumor

Alternate day therapy
Single dose on alternate day, systemic administration of
corticosteroids is as effective as divided daily dose
Permits metabolic recovery and prevents toxic side effects
from accumulating
Patients receives the entire total dose that would be given
over a 2-day period as a sing dose , every other morning
Alternate-day systemic therapy applies only to shorter acting
systemic steroids like prednisone, in case like chronic uveitis

Why steroids dozes tapered ??
Synthetic cortisone medication mimic cortisol,i.e naturally
occuring hormone produced by adrenal gland
Excess production of cortisol – negative feedback
mechanism (HPA axis)
Using large dose for few days or smaller dose for more
than two weeks—prolonged decrease in HPA axis function

So tapering is required i.e continuing the therapy for
several days in reduced dose
Gives time for adrenal glands to return their normal
patterns of secretion
Eliminating doses too quickly can result in adrenal
crisis (a life-threatening state caused by insufficient
levels of cortisol).
Also reduces the chance of recurrence of the disease

Locally (in case of topical) ??
Corticosteroids reduce the leukocyte cells locally
White cells proliferate when therapy stops
Immature cells can produce large quantities of antibodies to
residual antigen in the ocular tissue
Massive polymorphonuclear leukocytic reaction follows
the resultant antigen- antibody reaction

This sequence of events , unless interrupted immediately , can
lead to a recurring , serious necrotizing inflammation
Thus depending upon response and dozes used , topical
therapy should generally be tapered over several days to
weeks
Removal of corneal epithelium caused appearance of
leukocytes in tear fluid within 2-5 hrs which was greatly
reduced by 1% prednisolone and 0.01% flurbiprofen

When to taper the dose??
Shouldn’t be tapered too quickly
Should wait until the inflammation is completely
controlled before tapering
Tapering when the eye is just starting to improve or
stabilize may prolong the inflammation and the therapy

Eyelids
Allergic blepharitis
Contact dermatitis
Herpes zoster dermatoblepharitis
Chemical burns
Neonatal hemangioma

Conjunctiva
Allergic conjunctivitis
Vernal conjunctivitis
Herpes zoster conjunctivitis
Chemical burns
Mucocutaneous conjunctival lesions

Cornea
Immune reaction after keratoplasty
Herpes zoster keratitis
Disciform keratitis
Marginal corneal infiltrates
Superficial punctate keratitis
Chemical burns
Acne rosacea keratitis
Interstitial keratitis

Uvea
 Anterior uveitis
 Posterior uveitis
 Sympathetic ophthalmia
Infectious component : aggressive antibiotic therapy
Intraviteral implant : long term therapy and for advanced
noninfectious posterior uveitis

Sclera
Scleritis
Episcleritis

Retina
Retinal vasculitis
Optic nerve
Optic neuritis
Temporal arteritis
(arteretic anterior ischaemic optic
neuropathy)

Globe
Endophthalmitis
(except fungal endopthalmitis)
Hemorrhagic glaucoma
Orbit
Pseudotumor
Graves’ ophthalmopathy
Extraocular muscles
Ocular myasthenia gravis

Generally contraindicated in:
Peptic ulcer
Osteoporosis
(an increased risk of fracture )
Psychoses
Topical steroids are contraindicated in mechanical
lacerations and abrasions of the eye because they delay
healing and promote the development and spread of
infection

Should be used with caution in
Diabetes mellitus
Chronic renal failure
Congestive heart failure
worsen the condition
Systemic hypertension
Infectious diseases
glaucoma

Patients with prolonged systemic therapy, lack sufficient
adrenal reserve to respond to stress like trauma and surgery , so
require additional corticosteroids to cover the stress.

Adrenal insufficiency
Cushing’s syndrome
Peptic ulceration
Osteoporosis
Hypertension
Muscle weakness or atrophy
Inhibition of growth
Diabetes
Activation of infection
Mood changes
Delay in wound healing
SYSTEMIC SIDE EFFECTS

OCULAR SIDE EFFECTS
Adverse event can occur with all routes of
administration & all preparations currently
available.
Side effects more with long term high doses
therapy.

Posterior subcapsular cataracts
Ocular hypertension or glaucoma
Secondary ocular infection
Retardation of corneal epithelial healing
Keratitis
Corneal thinning or melting
Scleral thinning
Uveitis
Mydriasis
Ptosis
Transient ocular discomfort
OCULAR SIDE EFFECT

Cataract
Occurrence of PSCC
with all routes
High incidence found in
long term systemic therapy
then the topical therapy
Opacity associated with steroid administration resemble with those
produce by ionizing radiation and ocular disease such as uveitis ,
retinitis pigmentosa and retinal detachment

Glucocorticoids enter lens fibres
reacts with lens crystallins
conformational change within cells
release of sulfhydryl groups
Form disulfide bonds protein aggregation
CATARACT
Mechanism

Mechanism
High blood glucose level
High level of sorbitol
Indrawing of water
Swelling of fibers and disruption of
cytoskeletal structures
cataract

mechanism
Corticosteroid induces the production of the new lens fibers
through equatorial region
Which goes and accumulate in posterior sub capsular region
Finally causes cataract

Ocular hypertension or glaucoma
Reversible elevation of pressure with repeated
use of topical steroids.
Steroid induced glaucoma ; a form of secondary
open-angel glaucoma
Recently developments in corticosteroids are aimed at
developing agents with less IOP effect and agents that can
be used intraocularly and periocularly

How steroids increase IOP…..?
GAGs present in the
trabecular meshwork
can not depolimerized
(stabilizing lysosomal
membrane)and they
retain water in
extracellular space lead
to narrowing of
trabecular meshwork
Suppress the
phagocytic activity of
endothelial cells of
trabecular meshwork
leading to collection of
deberies in trabecular
meshwork
Inhibit the
formation of PGE
and PGF leading to
decrease in
aqueous outflow
facility
Obstruction of aqueous outflow

IOP elevation in different steroid
Dexamethasone 0.1% 22.0 +/- 2.9
Prednisolone 1% 10.0 +/-1.7
Fluoromethalone 0.1% 6.1 +/-1.4
Hydrocortisone 0.5% 3.2 +/-1.0
Tetrahydrotriamcenalone 0.25% 1.8 +/-1.3
Medrysone 1% 1.0 +/-1.3
Preparation Avreage IOP rise in MM/Hg
Dexamethasone 0.005% 8.2+/-1.7

Individuals differ in their responsiveness: approximately 4%
develop pressures higher than 31 mm Hg after 6 weeks of
therapy with topical dexamethasone
 Steroid- induce IOP elevation almost never occurs in less than 5
days and rarely in less than 2 weeks
Steroid-induce IOP rises are usually reversible by discontinuance
of therapy if the drug has not been used for more than 1 year ,
but permanent elevations of pressure are common if the therapy
has continued for 18 months or more 1
1 (armaly MF and becker b . Mills DW ARCH OPHTHALMOL 2003)

If IOP rises when we use the steroid ?
1) First stop steroid therapy and may use other anti-
infalmmatory agents like NSAIDs and cyclosporine
2) If IOP persist at higher level then IOP lowering agent can be
used like beta-blocker , carbonic acid inhibitor but
prostaglandin analogue are contraindicated
3) If IOP remains at higher level then we can move to other
surgical procedure

Retardation of corneal epithelial healing
Effect on collagen
synthesis and fibroblastic
activity
Persistent epithelial
staining can be noted

Corticosteroid induce uveitis
Pain
 Photophobia
Blurred vision
 Perilimbal (ciliary)
hyperemia;
Anterior chamber cells
and flare

Mydriasis
Increase in pupillary diameter
approximately 1 mm
Belharoptosis
Due to inhibition of sympathetic
innervation on muller muscle

Other ocular side effects
Transient ocular discomfort
Calcium deposits on cornea ; (Dry eye develop a
calcific band keratopathy)

SOME IMPORTANT FACTS
s Is not s
i.e cotricosteroids are not stored in adrenal gland, they
synthesized from cholesterol in the presence of stimulus
They promote growth of skeletal muscle (anabolic effect) and the
development of male sexual characteristics (androgenic effects)
Drugs used by athletes to boost strength and enhance physical
performance
Anabolic steroid ??

PYRIMON
BETNOR
FML
FML-NEO
OCUPOL-D
PRED-FORTE
Oxop-D
Some topical steroid : Trade name and combination
(Dexamethasone 0.1% + Chloramphenicol 0.1% )
( Betamethasone 0.1% + Neomycin 0.5% )
(Fluromethalone 0.1%)
( Fluromethalone 0.1% + Neomycin 0.5%)
( Each gram contains : Dexamethasone 1 mg +
chloramphenicol 10 mg + polymyxin B sulphate 10000 IU)
(Prednisone acetate 1%)
(Ofloxacin 0.3% + Dexamithasone 0.1% )

Ocular NSAIDs and Steroids

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