3. INFLAMMATION
Protective response by the body to variety of
infectious or non-infectious agents in order to
eliminate or limit the spread of the injurious agent
Mechanism of acute early response
• Release of mediators
• Vascular changes
• Leucocyte activity
6. 1. Redness (rubor): vasodilation of capillaries to increase
blood flow
2. Heat (calor): due to transfer of internal heat to the
tissue by increased blood flow
3. Pain (dolor): due to sensitization of sensory nerve
endings
4. Swelling (tumor): due to increased vascular
permeability and escape of plasma proteins from the
bloodstream
Cardinal signs of
inflammation
7.
8. NSAIDS
Non steroidal anti-inflammatory drugs
All NSAIDs have three major therapeutic effects:
NSAIDs
Anti-
inflammatory
Analges
ic
Anti-pyretic
Cause suppression of signs and symptoms of
inflammation but do not eliminate the cause
9. Developed as an alternative to steroids in treatment of
inflammatory disease
Most are the organic acid derivatives
Aka non narcotic, non opoid, aspirin like drugs
Do not depress CNS
Act primarily on peripheral pain mechanism
10. 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.
11. Membrane phospholipid
Arachidonic acid
Chemical and
mechanical
stimuli
Phospholipase A
cyclooxygenase lipooxygenase
endoperoxidases leukotrienes
Prostacyclin
PGI2
PGE2 , PGD2 ,
PGF2a
Thromboxane A2
glucocorticoids
NSAIDs
12. Phospholipids : major component of all cell membranes, forms
bilipid layer
Arachidonic acid: polyunsaturated carboxylic acid present in
phospholipids of cell membrane, freed from phospholipid by
phospholipase A2
Prostaglandins: hormone like lipid compounds derived from
fatty acids produced in almost all nucleated cells
Few terminologies
13. Prostacyclin(PGI2): induces vasodilatation,
bronchodilation and inhibits platelet aggregation
Leukotrienes: inflammatory mediators first isolated from
leucocytes.
In body PGs, TXs and LTs are all derived from eicosa
(referring to 20 C-atom) tri/tetra/penta enoic acids. So they
are collectively called eicosanoids.
14. CYCLOOXYGENASE
Enzyme responsible for the formation of prostanoids i.e
prostaglandins, prostacyclin and thromboxane
Two main form of cyclooxygenase
Cyclooxygenase-1 (COX-
1)
Cyclooxygenase -2 (COX-
2)
Produces prostaglandins
that mediate homeostatic
functions
Produces prostaglandins
that mediate
inflammation, pain and
fever
Constitutively expressed
in most tissues like GI,
Induced mainly in sites of
inflammation by
15. FUNCTIONS OF PROSTAGLANDINS
(a) PGE2:
•Vasodilation
•Regulate renal and mucosal blood flow in stomach
•Sensitize afferent nerve endings to pain inducing
chemical stimulus
•Powerful bronchodilator
•Mediate fever
(b) PGF2a:
•Uterine contraction and vasodilation.
16. (d) PGI2:
•Vasodilation
•Inhibition of platelet aggregation
•Regulate renal and mucosal blood flow in stomach
•Sensitize afferent nerve endings to pain inducing
chemical stimuli.
Thromboxane A2: active in platelet aggregation
besides its role as a vasoconstrictor and
bronchoconstrictor
17. 5/22/2016 17
OCULAR EFFECT OF PROSTAGLANDIN
PROSTAGLANDI
N
EFFECT
PGD2 STIMULATES VASODILATATION AND CHEMOSIS
PGE1,PGE2 INFLAMATION , IOP , CAPILLARY PERMEABILITY,
STIMULATES VASODILATION, STIMULATES MIOSIS
PGF2 IOP, MINIMAL EFFECT ON INFLAMATION, MINIMAL EFFECT
ON MIOSIS
18. PROSTAGLANDIN (PGE1, PGE2)
AND MIOSIS
Researcher isolated a substance called “ Irin” from
extracts of the iris tissue, later found to be
prostaglandin
Cause miosis when introduced into the anterior
chamber
Mechanism: not known
Inhibitors: Topical Cycloxygenase blocker
19. MECHANISM OF ACTION OF NSAIDS
1) Anti-inflammatory effect:
due to the inhibition of the enzymes cyclooxygenase
that converts arachidonic acid into prostaglandin,
prostacyclin and thromboxane A2
all NSAIDs reversibly inhibit cyclooxygenase except
Aspirin which inhibit it irreversibly
20. Membrane phospholipid
Arachidonic acid
Chemical and
mechanical
stimuli
Phospholipase A
cyclooxygenase lipooxygenase
endoperoxidases leukotrienes
Prostacyclin
PGI2
PGE2 , PGD2 ,
PGF2a
Thromboxane A2
glucocorticoids
NSAIDs
21. 2) Analgesic effect:
The analgesic effect of NSAIDs is thought to be related
to
• Pripheral inhibition of
prostaglandin synthesis
• Prevent the potentiating action of
prostaglandin on endogenous
mediators of peripheral nerve
stimulation (e.g. bradykinin)
22. 3) Antipyretic effect:
The antipyretic effect of NSAIDs is related to
• Inhibition of production of
prostaglandins induced by
interleukin-1 and IL-6 in the
hypothalamus• Resetting of
themoregulatory system,
leading to vasodilatation and
increased heat loss
23. BENEFICIAL ACTIONS DUE TO PG
SYNTHESIS INHIBITION
Anti-inflammatory effect
Analgesic effect
Anti-pyretic effect
Anti thrombotic effect
Closure of ductus arteriosus in
new born
24. ADVERSE EFFECT OF PG SYNTHESIS
INHIBITION
Gastric mucosal damage
Bleeding: Inhibition of platelet
function
Limitation of renal blood flow
Asthma and anaphylactoid reaction
25. Enchance
acid
secretion
Inhibition of cox-1mediated
synthesis of gastroprotective
PGs (PGE2, PGI2)
Diffusion of H+ ions in
the gastric mucosa
Deficiency of PGs reduces mucus and
HCO3- secretion
Gastric mucosal
damage
Gastric
mucosal
erosion/ulcerat
ion
35. COMMON TOPICAL OPHTHALMIC
NSAIDS
Generic name Trade name Formulation Concentratio
n
Diclofenac Voltaren Solution 0.1%
Flurbiprofen Ocufen 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%
36. Topical NSAIDs in Preoperative Period
Topical NSAIDs in Anterior Segment
Inflammation
INDICATIONS
37. TOPICAL NSAIDS IN PREOPERATIVE
PERIOD
1. Intraoperative miosis:
topical NSAIDs reduce pupillary constriction that occurs
during cataract extraction and other intraocular surgeries
38. 2. Post operative inflammation:
• use of NSAIDs before surery 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
39. 3. Cystoid macular edema:
• prevention of acute aphakic and pseudophakic CME
and treatment of chronic CME
• peak incidence of CME occurs between 4 and 8 weeks
after surgery
40. TOPICAL NSAIDS FOR ANTERIOR
SEGMENT INFLAMMATION
1. 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
41. 2. Corneal pain
- injury to corneal tissues stimulates prostaglandin
synthesis
- corneal pain following abrasions, trauma or
epithelial erosions, PRK treated with topical NSAIDs
42. 3. Episcleritis
- topical NSAIDs may be useful
- oral NSAIDs may be required in recurrent cases
Tab Flurbiprofen 100 mg TDS
Tab Indomethacin 25 mg TDS
43. Non necrotising scleritis
Tab Indomethacin 75 mg BD until inflammation
resolves
Given in conjunction with topical steroids
Other Indications
44. 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
45. DICLOFENAC SODIUM
Trade Name: Voltaren
available as
Indications:
-Postoperative inflammation
-Temporary relief of pain and
photophobia in patients undergoing
corneal refractive surgery
0.1% ophthalmic
solution
46. FLURBIPROFEN SODIUM
Trade name: Ocufen
Available as
Indications:
-Inhibition of intraoperative miosis
-Post operative inflammation
0.03% ophthalmic
solution
47. KETOROLAC TROMETHAMINE
Trade name: Acular, Acular PF, Acular LS
Available as
Good penetrative properties
Indications:
-Allergic conjunctivitis
-post cataract surgery inflammation
-post operative pain and photophobia in radial
keratotomy
-ketorolac 0.5% in treatment of chronic CME
0.5% and 0.4% ophthalmic
solution
51. DOSING REGIMENS OF TOPICAL
NSAIDSIndication 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 q.i.d for at least 1-2 weeks after
surgery
Ketorolac 1 drop q.i.d for at least 1-2 weeks after
surgery
Cystoid macular edema Ketorolac 1 drop q.i.d for at least 3 months
Indomethacin 1 drop q.i.d
Allergic conjunctivitis Ketorolac 1 drop q.i.d for relief of ocular itch during
allergy season
Corneal pain Diclofenac 1 drop preoperatively and 1 drop q.i.d
postoperatively for 3 days
52. ORAL NSAIDS IN OPHTHALMIC
USES
Ibuprofen
-0ral
-trade name: flexon, brufen
Indications:
As analgesic in stye, chemical injury
Flexon: ibuprofen 400mg +
paracetamol 500mg
Brufen: ibuprofen 400mg
1 tab PO
TDS
53. As oral NSAIDs has more systemic side effects (esp.
Gastric mucosal damage), drugs for peptic ulcer is
used
1) H2 antihistamines: cimetidine, ranitidine
2) proton pump inhibitors: omeprazole, pantoprazole,
rabeprazole
Tab Ranitidine 300 mg OD or 150
mg BD
Tab Pantoprazole 40 mg
OD
55. DRUG INTERACTIONS WITH NSAIDS
β blockers Decrease antihypertensive effect
ACE inhibitors Decrease antihypertensive effect
Anticoagulants Increase risk of G.I bleeding
Cyclosporine Increase nephrotoxicity
Corticosteroids Increase risk of G.I bleeding
56. WARNINGS/PRECAUTIONS
1. Increased bleeding of ocular tissues, including
hyphemas in conjunction with ocular surgery
2. Slow or delayed wound healing
3. Cross sensitivity with acetylsalicylic acid
57. 4. 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.
5. 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
58. CONTRAINDICATIONS
A) Hypersensitivity to any component of formulations
B) Nepafenac and Ketorolac: contact lens wearers
C) Flurbiprofen and Suprofen: patients with dendritic
keratitis
59. Adverse Effects:
Systemic absorption minimal in topical NSAIDs
Local effects:
-burning sensation
-stinging sensation upon instillation
-conjunctival hyperemia
60. REFERENCES
1) Essential Of Medical Pharmacology- K.D. Tripathi
2) Clinical ocular Pharmacology- Jimmy D Barlett
3) Ophthalmic Drugs- Graham Hopkins , Richard Pearson
4) Comprehensive Ophthalmology- A.K. Khurana
5) Internet sources
6) Previous presentations
Editor's Notes
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Block the pain sensitizing mechanism induced by bradykinin
PGE2 and PGI2 sensitize afferent nerve endings to pain inducing chemical and mechanical stimuli
ILs are the pyrogenes which induce PG synthesis in hypothalamus during infection which cause fever
