OCULAR NSAIDS

Sabina Poudel16th BatchB.OptometryMMC, IOM

PRESENTATION LAYOUTInflammatory response

Pharmacologic principle of NSAIDs

Classification of NSAIDs

Common ophthalmic NSAIDs

Indications , contraindications and their side effects

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

source Mediator Main actionCell derived Mast cells, basophils,

plateletsHistamine Increase permeability

Platelets Serotonin Increase permeability

Inflammatory cells prostaglandins vasodilatation

leukotrienes Increase permeability

Lysosomal enzymes Tissue damage

Platelet activating factor Increase permeability

Cytokines Fever

Nitric oxide & oxygen metabolites

Tissue damage

Plasma derived Clotting & fibrinolytic system

Fibrin split products Increase permeability

Kinin system kinin/bradykinin Increase permeability

Complement system AnaphylatoxinsC3a, c4a ,c5a ,c5b –c9

Increase permeability

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 5. Functio laesa: loss of function

Cardinal signs of inflammation

NSAIDS Non steroidal anti-inflammatory drugs

All NSAIDs have three major therapeutic effects:

NSAIDs

Anti-inflammato

ryAnalgesic Anti-pyretic

Cause suppression of signs and symptoms of inflammation but do not eliminate the cause

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

HISTORYSodium 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.

Membrane phospholipid

Arachidonic acid

Chemical and mechanical stimuli

Phospholipase A

cyclooxygenase lipooxygenaseendoperoxidases leukotrienes

Prostacyclin PGI2

PGE2 , PGD2 , PGF2a

Thromboxane A2

glucocorticoids

NSAIDs

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

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.

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, platelets

Induced mainly in sites of inflammation by cytokines

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.•Potent bronchoconstrictor

(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

05/03/2023 17

OCULAR EFFECT OF PROSTAGLANDIN

PROSTAGLANDIN

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

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

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

Membrane phospholipid

Arachidonic acid

Chemical and mechanical stimuli

Phospholipase A

cyclooxygenase lipooxygenaseendoperoxidases leukotrienes

Prostacyclin PGI2

PGE2 , PGD2 , PGF2a

Thromboxane A2

glucocorticoids

NSAIDs

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)

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

BENEFICIAL ACTIONS DUE TO PG SYNTHESIS INHIBITION

Anti-inflammatory effect

Analgesic effect

Anti-pyretic effect

Anti thrombotic effectClosure of ductus arteriosus in new born

ADVERSE EFFECT OF PG SYNTHESIS INHIBITION

Gastric mucosal damage

Bleeding: Inhibition of platelet function

Limitation of renal blood flow

Asthma and anaphylactoid reaction

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/ulceration

Bleeding

NSAIDs inhibit synthesis of proaggregatory (TXA2)

Inhibit synthesis of antiaggregatory PGI2

Inhibit platelet aggregation

Bleeding time prolonged

Hypovolumeia, decreased renal perfusion, Na+ loss Limitation of renal blood flow

induce

Renal PG synthesis which brings intrarenal adjustments byPromoting vasodilatation

Inhibiting tubular Cl- reabsorptionOpposing ADH action

NSAIDs cause:1)COX1 dependent impairment of renal blood flow and

reduction of G.F.R2)Juxtaglomerular COX2 dependent Na+ and water

retention

Certain NSAIDs precipitates:

Anaphylactoid reactionsAsthma Angioneurotic

swelling

Urticaria Rhinitis

CLASSIFICATION OF NSAIDS A) Non selective COX inhibitors 1. Salicylates: Aspirin 2. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen 3. Anthranilic acid derivatives: mephenamic acid 4. Aryl-acetic acid derivatives: Diclofenac, Aceclofenac 5. Oxicam derivative: Piroxicam, Tenoxicam 6. pyrrolo-pyrrole derivative: Ketorolac 7. Indole derivative: Indomethacin, Sulindac 8. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone

B) Preferential COX2 inhibitors: Nimesulide, Meloxicam, Nabumetone

C) Selective COX2 inhibitors: Celecoxib, Etoricoxib, Parecoxib

D) Analgesic- antipyretic with poor anti-inflammatory action: Paracetamol, Metamizol, Propiphenazone, Nefopam

FEATURES OF NONSELECTIVE COX INHIBITORS & SELECTIVE COX 2 INHIBITORS

Action COX-1/COX2 COX-2 inhibitors inhibitors1.Analgesic + +2.Antipyretic +

+3.Antiinflammatory +

+4.Antiplatelet aggregation +

- 5.Gastric mucosal damage +

-6.Renal salt/ Water retention +

+7.Ductus arteriosus closure +

?8.Aspirin sensitive asthma +

- precipitation

Ophthalmic NSAIDs

ROUTES OF ADMINISTRATION

TOPICAL ORAL

Diclofenac Flurbiprofen

Indomethacin

Ketorolac Suprofen Nepafenac

Topical Ophthalmic NSAIDs

COMMON TOPICAL OPHTHALMIC NSAIDSGeneric name

Trade name Formulation

Concentration

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%

Topical NSAIDs in

Preoperative Period

Topical NSAIDs in Anterior Segment

Inflammation

INDICATIONS

TOPICAL NSAIDS IN PREOPERATIVE PERIOD 1. Intraoperative miosis: topical NSAIDs reduce pupillary constriction that occurs during cataract extraction and other intraocular surgeries

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

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

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 including prostaglandins

2. Corneal pain - injury to corneal tissues stimulates prostaglandin synthesis - corneal pain following abrasions, trauma or epithelial erosions, PRK treated with topical NSAIDs

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

Non necrotising scleritis Tab Indomethacin 75 mg BD until inflammation resolves Given in conjunction with topical steroids

Other Indications

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: Voltaren available as

Indications:-Postoperative inflammation -Temporary relief of pain and photophobia in patients undergoing corneal refractive surgery

0.1% ophthalmic solution

FLURBIPROFEN SODIUMTrade name: OcufenAvailable as

Indications:-Inhibition of intraoperative miosis-Post operative inflammation

0.03% ophthalmic solution

KETOROLAC TROMETHAMINETrade name: Acular, Acular PF, Acular LSAvailable asGood 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

INDOMETHACINTrade name: IndocidAvailable as

Indications:Treatment of cystoid macular edema

0.1% ophthalmic solution

SUPROFENTrade name: ProfenalAvailable as 1% ophthalmic

suspension

Indications Prevention of intraoperative miosis

NEPAFENACTrade name: NevanacAvailable as0.1% ophthalmic

suspension

Indications:For pain and inflammation after cataract surgery

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 monthsIndomethacin 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

Ketorolac(non preserved)

1 drop q.i.d for 3 days

ORAL NSAIDS IN OPHTHALMIC USES

Ibuprofen -0ral-trade name: flexon, brufen

Indications:As analgesic in stye, chemical injury

Flexon: ibuprofen 400mg + paracetamol 500mgBrufen: ibuprofen 400mg

1 tab PO TDS

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

CONDITIONS AGGRAVATED BY NSAIDSPeptic ulcer

Hypertension

Congestive heart failure

Renal insufficiency

Hemostatic disorder

DRUG INTERACTIONS WITH NSAIDSβ blockers Decrease antihypertensive

effectACE inhibitors Decrease antihypertensive

effectAnticoagulants Increase risk of G.I bleeding

Cyclosporine Increase nephrotoxicity

Corticosteroids Increase risk of G.I bleeding

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

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

CONTRAINDICATIONS A) Hypersensitivity to any component of formulations

B) Nepafenac and Ketorolac: contact lens wearers

C) 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

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