4) Anti-inflammatory

What are the advantages of corticosteroids as ocular anti-inflammatory agents?

(+) protect delicate ocular structures from irreversible damage (e.g., scarring, neovascularization)

(+) more effective in acute inflammatory states > chronic

What are their non-specific effects of Corticosteroids?

• ❌ don’t act directly to correct a specific underlying cause

• ✅ modify a preexisting or ongoing inflammatory response to foreign or endogenous substances

Give the main injection routes used for steroid treatment of ocular disorders.

• Subconjunctival

• Sub-Tenon’s capsule

• Retrobulbar

What are the ocular tissues to which steroids can be delivered at high concentration by retrobulbar injection?

• sclera

• choroid

• vitreous

• retina

What are the ocular adverse effects due to periocular steroids?

• RD

• Optic nerve atrophy

• Preretinal membrane formation

• ↑ IOP

What are the disadvantages of topical steroid administration?

• occasional adrenal suppression

• occasional conj infections

• dendritic ulcer aggrevation

• white residue formation

• epithelial keratopathy from frequent applications

What steroids are administered intravitreally? Give their clinical uses and adverse effects.

• Triamcinolone acetonide

• Fluocinolone acetonide (Retisert)

• Dexamethasone (Posurdex, Ozurdex)

Clinical uses

• Proliferative vitreoretinopathies

• Exudative AMD

• PDR

• Macular edema, diabetic macular edema

• Retinal vein occlusion (CRVO/BRVO)

• Non-infectious posterior uveitis

Adverse effects

• Ocular HTN

• Intraocular inflammation

• Pseudoendophthalmitis

• Sterile endophthalmitis

• Infectious endophthalmitis

What steroid does Posurdex contain?

Dexamethasone

Give the duration + dose of Fluocinolone delivered to posterior segment.

Delivered via the Retisert implant containing 0.59 mg or 2.1 mg of fluocinolone acetonide, lasting for up to 3 years

What is the advantage of a biodegradable steroid implant?

(+) Combines steroid with a degradable polymer matrix (PLGA) that slowly undergoes hydrolysis → H₂O + CO₂

• doesn’t need surgical implant removal!

What are the advantages and limitations of alternate-day therapy with steroids?

Advantages

• Single dose given every other allows permits metabolic recovery

• Prevents toxic accumulation

• Minimizes growth suppression in children

Limitations

• Applies only to shorter-acting systemic steroids (prednisone)

• Less effective than divided daily doses in severe ocular inflammation

• Adrenal suppression can still occur

Identify the disorders of uvea, sclera, retina and optic nerve that can be treated with corticosteroids.

Uvea: Anterior uveitis, posterior uveitis, sympathetic ophthalmia

Sclera: Scleritis, episcleritis

Retina: Retinal vasculitis

Optic nerve: Optic neuritis, temporal arteritis

What are the problems associated with corticosteroid therapy?

non-bactericidal + ↓ immune resistance → enhanced replication of bacteria, viruses, and fungi while masking signs of infection progression

What is the strength of prednisolone solution prescribed to suppress inflammation?

0.125% and 1.0% concentrations

What are the 2 strengths of dexamethasone formulations available? What form is preferred for ocular disorders?

1. 0.1% (ophthalmic suspension/solution)

2. 0.05% (dexamethasone sodium phosphate ointment)

• Preferred form: Dexamethasone alcohol is superior in anti-inflammatory activity to the sodium phosphate form

Compare the anti-inflammatory activity of alcohol form of fluorometholone to acetate form.

Fluorometholone acetate (Flarex 0.1%) has significantly greater anti-inflammatory activity than the alcohol form (FML 0.1%)

What are the clincal uses of medrysone? List its limitations.

Clincial use -Superficial ocular inflammations (allergic and atopic conjunctivitis) with minimal ↑ IOP risk

Limitations

• Weakest ophthalmic steroid

  • due to limited corneal penetration & ↓ receptor affinity

• doesn’t treat intraocular inflammation

What are the clinical uses of loteprednol etabonate and rimexolone? What are the FDA restrictions for rimexolone?

Loteprednol etabonate

• SAC

• GPC

• Postoperative inflammation

• Acute anterior uveitis

Rimexolone

• postoperative inflammation

• uveitis

** Not FDA-approved for allergies or GPC

Identify 5 major ocular adverse effects of corticosteroids.

1. PSC

2. Ocular HTN/GLC

3. 2er ocular infections

4. Slower corneal epithelial healing

5. Keratitis

How do cytokines induce inflammation of the ocular surface?

Proinflammatory cytokines activate immature APCs + upregulate selectins/adhesion molecules on conj vascular endothelium → leukocyte recruitment

How does chronic ocular inflammation differ from acute ocular inflammation?

Acute inflammation - immediate cytokine-driven response dominated by neutrophils/macrophages

Chronic inflammation - follows when irritants/cytokines persist, involving antigen processing by APCs, T-cell priming in lymph nodes, and long-term tissue damage

Describe the sequence the events happening during acute corneal inflammation.

1. Inflammatory insult

2. Cytokine secretion (TNF-α, IL-6, IL-1)

3. APC activation

4. Upregulation of endothelial adhesion molecules (selectins, VCAM-1, ICAM-1)

5. PMN/macrophage migration

6. Protease release damaging basement membrane

7. Growth & angiogenic factor release

Describe the sequence the events happening during chronic corneal inflammation.

1. Irritant/cytokine persistence

2. Ocular APCs process antigen

3. APCs migrate via lymphatics to lymph nodes/spleen

4. Naïve CD4+ T cells are primed

5. Primed CD4+ T cells return to conj

6. IFN-γ release amplifies inflammation and tissue damage

Differentiate the 2 classes of T helper cells based on cytokines.

Th1 cells - make IL-2, IFN-γ, TNF-α

• associated with dry eye, viruses, graft rejection

Th2 cells - make IL-4, IL-5, IL-13

• associated with allergy & parasites

Describe the sequence the events during an immune-system mediated inflammation.

1. APC infiltration into inflamed tissue

2. Engulfment & peptide processing of antigen

3. Presentation of peptides via MHC II

4. T-cell receptor binding & costimulation (CD80/CD28)

5. Differentiation into Th1 or Th2 cell subsets

6. Effector cytokine release

How do corneal nerves and CNS play a role in tear secretion?

1. Corneal surface free nerve endings sense stimuli

2. Transmit sensory signals via afferent nerves to the CNS

3. CNS sends efferent signals to the lacrimal gland to trigger reflex tear production

How do inflammatory cytokines induce dry eye?

Cytokines (TNF-α, IFN-γ, IL-1, IL-6, IL-8) disrupt neural signaling to the lacrimal functional unit, converting tear composition from "surface supportive" to a "proinflammatory" Th1environment

Briefly describe the different mechanisms of action of corticosteroids.

Genomic

1. Steroid enters cell + releases hsp90 from intracellular receptor

2. Dimerizes

3. Enters nucleus

4. Binds Glucocorticoid Response Elements (GRE) to regulate RNA polymerase 2 transcription

Biochemical - Directly Inhibits Phospholipase A2 → blocks arachidonic acid synthesis

Cellular - Inhibits neutrophil endothelial adherence, macrophage migration, and lymphocyte (B & T cell) activity

What should be the ideal characteristics of steroids for optimum bioavailability?

Must have biphasic polarity (balanced lipophilicity & hydrophilicity) to traverse both the corneal epithelium and stroma

How can salt/derivative form of steroids influence solubility?

Acetate & Alcohol: Lipophilic (formulated as suspensions/ointments)

Sodium Phosphate & Hydrochloride salts: Hydrophilic (formulated as water-soluble solutions)

Which derivatives of steroids are capable of suppressing corneal inflammation?

Lipophilic acetate derivatives (e.g., prednisolone acetate, fluorometholone acetate) penetrate intact corneal epithelium more effectively than hydrophilic phosphate forms

List the 3 therapeutic principles for corticosteroid therapy related to dosage.

1. Initiate therapy ASAP

2. Administer sufficiently high doses at frequent intervals to suppress inflammation

3. Reevaluate dosage frequently and taper chronic high-dose therapy gradually rather than stopping abruptly

What are the ocular disorders treated by topical or systemic therapy with steroids?

Topical: Eyelid, conjunctival, corneal, and iris/ciliary body inflammation (e.g., anterior uveitis, pingueculitis, keratitis)

Systemic: Chorioretinitis, optic neuritis, posterior uveitis, temporal arteritis, sympathetic ophthalmia

What steroids are preferred for oral/IV administration?

1. Prednisone

2. Prednisolone

3. Methylprednisolone

4. Dexamethasone

List 5 main adverse systemic effects due to corticosteroid therapy.

1. Adrenal insufficiency

2. Cushing's syndrome

3. Osteoporosis

4. Peptic ulceration

5. Systemic HTN (or growth inhibition in children)

Identify 2 main steroids with maximum anti-inflammatory activity and no sodium retaining activity.

1. Dexamethasone

2. Betamethasone

Give the unique advantage of EYsuvis formulation.

(+) short-term (up to 2 weeks) dry eye tx where its mucus-penetrating nanoparticle technology enhances tear film residence without significant IOP elevation (<5 mmHg)

How can prolonged use of steroids cause PSC?

abnormal migration of pseudoepithelial cells from the equatorial lens → posterior pole, forming subcapsular lenticular opacities

Compare the IOP increasing effect of dexamethasone, fluorometholone and medrysone.

→ Mean IOP increase after 6 weeks

• Dexamethasone (63.1%) > Fluorometholone (33.8%) > Medrysone (8.3%)

List the 3 systemic disorders for which corticosteroid use is contraindicated.

1. Peptic ulcer

2. Osteoporosis

3. Psychoses

What are the 3 conditions to be monitored for in patients receiving systemic steroid therapy?

1. Systemic HTN

2. GLC

3. Cataracts

What are the 2 cellular homeostatic responses mediated by prostaglandins?

1. Platelet aggregation

2. Renin release

What series of prostaglandins are inflammatory/non-inflammatory?

Series 2 = Proinflammatory

• derived from omega-6/arachidonic acid

Series 1 & Series 3 = Anti-inflammatory

• Series 1 from DGLA

• Series 3 from EPA/omega-3

What are the substrates and end products for cyclooxygenase and lipoxygenase enzymes?

COX: Converts Arachidonic Acid (AA) → Series 2 inflammatory prostaglandins OR EPA → Series 3 anti-inflammatory prostaglandins (PGE3)

Lipoxygenase: Converts EPA → less inflammatory leukotrienes

What are the adverse effects mediated by cyclooxygenase-1 and 2?

COX-1 inhibition: Inhibits thromboxane/platelet aggregation → blood thinning & gastric mucosal bleeding ulcers

COX-2 inhibition: Disruption of hemostatic balance → thrombosis

What is the adverse drug interaction of NSAIDs and warfarin?

↑ clotting times

↓ platelet aggregation (bleeding risk)

What is the main adverse effect of Topical diclofenac?

Keratolysis (corneal melting) in post-surgical pt

Give the clinical uses of NSAIDs.

• Prophylaxis/cystoid macular edema (CME) tx

• Post-cataract pain/inflammation

• Intraoperative miosis prevention

• Refractive surgery analgesia

• Allergic conjunctivitis

Name 2 NSAIDs used for treatment of pseudophakic CME.

1. Ketorolac (Acular-LS)

2. Nepafenac (Nevanac/Ilevro)

Name NSAIDs used for management of pain following cataract surgery.

1. Bromfenac (Prolensa, BromSite)

2. Nepafenac (Nevanac, Ilevro)

3. Ketorolac (Acuvail, Acular)

4. Diclofenac (Voltaren)

   
   

Identify the sequence of events following binding of cyclosporine to its receptor.

1. CsA binds cyclophilin inside T cells

2. CsA–cyclophilin complex inhibits calcineurin

3. Inhibits NF-AT dephosphorylation

4. Blocks cytokines (IL-2, IL-4, IFN-γ, TNF-α) transcription

5. Prevents T-cell activation and tear-secreting epithelial apoptosis

What are the ocular diseases targeted by systemic and topical cyclosporine?

Systemic

• Behçet’s disease

• Uveitis

• Sympathetic ophthalmia

• High-risk corneal graft rejection

• Bird-shot retinochoroiditis

Topical

• Dry eye

• LASIK-induced dry eye

• Severe vernal keratoconjunctivitis

• Thygeson’s SPK

• Graft rejection prophylaxis

Why is Restasis available as an emulsion?

Cyclosporine = highly lipophilic

• so the emulsion formulation allows it to be a suitable vehicle for topical delivery while preventing systemic toxicity

Give the advantage of Cequa formulation over Restasis.

Cequa (0.09% solution) uses nanomicellar (NCELL) technology to overcome solubility barriers allowing it to penetrate the aq layer to release cyclosporine deep into ocular tissue more effectively than Restasis emulsion

Match the brand name with its generic name, concentration, and formulation:

• Alrex

• Eysuvis

• Lotemax ST

• Lotemax

• Inveltys

Alrex: Loteprednol etabonate 0.2% suspension

Eysuvis: Loteprednol etabonate 0.25% suspension

Lotemax ST: Loteprednol etabonate 0.38% gel drops

Lotemax: Loteprednol etabonate 0.5% suspension (or gel/ointment)

Inveltys: Loteprednol etabonate 1.0% suspension

Match the brand name with its generic name, concentration, and formulation:

• Pred Forte

• Pred Mild

• Acular-LS

• Acuvail

Pred Forte: Prednisolone acetate 1.0% suspension

Pred Mild: Prednisolone acetate 0.12% suspension

Acular-LS: Ketorolac tromethamine 0.4% solution

Acuvail: Ketorolac tromethamine 0.45% solution (preservative-free)

Match the brand name with its generic name, concentration, and formulation:

• Prolensa

• Bromsite

• Xibrom

• Nevanac

• Ilevro

Prolensa: Bromfenac 0.07% solution

Bromsite: Bromfenac 0.075% solution

Xibrom: Bromfenac 0.09% solution

Nevanac: Nepafenac 0.1% suspension

Ilevro: Nepafenac 0.3% suspension

Match the brand name with its generic name, concentration, and formulation:

• Restasis

• Cequa

• Voltaren

• Durezol

• Maxidex

Restasis: Cyclosporine A 0.05% emulsion

Cequa: Cyclosporine 0.09% nanomicellar solution

Voltaren: Diclofenac sodium 0.1% solution

Durezol: Difluprednate 0.05% emulsion

Maxidex: Dexamethasone 0.1% suspension

Match the brand name with its generic name, concentration, and formulation:

• Vexol

• FML

• Flarex

• Ocufen

Vexol: Rimexolone 1.0% suspension

FML: Fluorometholone alcohol 0.1% suspension

Flarex: Fluorometholone acetate 0.1% suspension

Ocufen: Flurbiprofen sodium 0.03% solution