Pharmacology of Corticosteroids

Ophthalmic Drugs 1: Anti-Inflammatory Drugs

• Ocular Therapeutic Drugs include anti-inflammatory, anti-infective, dry eye preparations, and anti-glaucoma drugs.
• Part 1 of the lecture covers the pharmacology, indications, and side effects of corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and ciclosporin.
• Part 2 of the lecture covers anti-allergy drugs (antihistamines, mast cell stabilisers).

Corticosteroids

• Corticosteroids are hormones produced by the adrenal cortex.
• These include glucocorticoids and mineralocorticoids.
• Hormone levels are regulated by ACTH from the pituitary gland.
• Glucocorticoids, such as cortisol, maintain blood glucose levels and promote recovery from injury.
• Mineralocorticoids, e.g. aldosterone, affect sodium balance, causing sodium reuptake and water retention, thus influencing blood pressure.

Corticosteroids: Actions

• Glucocorticoids used therapeutically to treat inflammation.
• Glucocorticoids have anti-inflammatory and immunosuppressive effects by reducing the activity of inflammatory mediators (e.g. eicosanoids, platelet-activating factor, and interleukins).
• They also have metabolic effects on carbohydrates, proteins, and fats.
• The steroid-receptor complex binds to glucocorticoid response elements in chromatin, affecting DNA transcription and the production of inhibitory proteins.

Corticosteroids: Action (cont.)

• Corticosteroids inhibit inflammation by impacting inflammatory mediators.
• Inflammatory mediators cause effects such as swelling, redness, heat or pain; corticosteroids interfere with this process
• This process includes chemotaxis as well as cellular migration.

Corticosteroids: Action (cont.2)

• Corticosteroids also inhibit eicosanoid synthesis by preventing the production of eicosanoids such as prostaglandins, thromboxane A2, prostacyclin, leukotrienes, through inhibition of cyclooxygenase and lipoxygenase.

Corticosteroids: Therapeutic Uses (Systemic)

• Anti-inflammatory effects (systemic or topical) for conditions such as asthma, eczema, inflammatory bowel disease, and rheumatic disease.
• Replacement therapy for adrenal gland diseases.
• Chemotherapy for conditions like acute leukaemia and Hodgkin lymphoma.
• Immunosuppression, such as post-transplantation.

Corticosteroids: Adverse Effects

• Adverse effects are common and can be severe, dependent on dose and treatment duration.
• Adverse effects may include impaired glucose tolerance, or diabetes mellitus, osteoporosis, Cushing's syndrome, and immune suppression.

Ophthalmic Corticosteroids: Indications

• Used in the treatment of acute and chronic inflammation, such as anterior uveitis and vernal conjunctivitis.
• Used after surgery, to help reduce inflammation following procedures.
• Intravitreal steroids are used to treat macular oedema and some cases of posterior uveitis.

Ophthalmic Corticosteroids: Indications (cont.)

• There's no official potency hierarchy for topical ocular glucocorticoids; efficacy depends on the salt used (prednisolone acetate is more effective than prednisolone sodium phosphate) and corneal integrity.

Ophthalmic Corticosteroids: Indications (cont.2)

• Prednisolone acetate and dexamethasone are used for severe inflammation, while milder forms use lower strength topical preparations like prednisolone sodium phosphate or hydrocortisone.

• Important to minimise side effects, especially in the presence of viral infections.

Ophthalmic Corticosteroids: Available Preparations

• Betamethasone (Betnesol), Dexamethasone (Maxidex), Fluorometholone (FML), Loteprednol Etabonate (Lotemax), Prednisolone(Predsol, Pred Forte) etc.
• Combination preparations with antibiotics (e.g., Betnesol N, Maxitrol, Tobradex) sometimes needed.
• Intravitreal corticosteroids (e.g., Ozurdex) are used for macular oedema following retinal venous occlusions and non-infectious posterior uveitis.

Ophthalmic Corticosteroids: Adverse Reactions

• Prolonged steroid use increases risk of posterior sub-capsular cataract formation.
• Cataracts are dose-dependent and account for approx. 4% cases, usually in patients on a high dosage over 1+ years.

Ophthalmic Corticosteroids: Adverse Reactions (cont.)

• Raised intraocular pressure (IOP) is a key adverse reaction to short-term use in steroid responsive individuals. This can be caused by topical, inhaled, or systematic use of steroids

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

• Topical NSAIDs provide mild to moderate anti-inflammatory action without the side effects of corticosteroids.
• NSAIDs prevent the formation of eicosanoids.

Biological Actions of Eicosanoids

• Eicosanoids are crucial mediators of the inflammatory response.
• Key eicosanoids are prostaglandins and leukotrienes.
• Ocular effects include vasodilation, increased IOP, miosis, and macular oedema

Biological Actions of Eicosanoids (cont.)

• NSAIDs primarily work by inhibiting cyclo-oxygenase (COX).

Ophthalmic NSAIDs: Indications

• Reduction of intra-operative and post-operative inflammation.
• Use in some centers for post-operative pain management.
• Reduction of pain after corneal trauma—diclofenac sodium is used in some cases.
• Allergic conjunctivitis—diclofenac sodium and others are used in some cases.
• Episcleritis—occasionally used, but is off-license.

Available Topical NSAIDs

• Diclofenac sodium (Voltarol).
• Flurbiprofen (Ocufen).
• Ketorolac trometamol (Acular).
• Nepafenac (Nevanac).
• Bromfenac (Yellox).
• Diclofenac sodium has a licence for post-corneal trauma pain and sometimes also for seasonal allergic conjunctivitis (SAC)(See indications above)

Ciclosporin

• Ciclosporin inhibits cytokine release from T-lymphocytes, thus suppressing the cell-mediated immune response.
• It is licensed for severe keratitis in dry eye disease (usually when other treatments haven't worked).
• Licensed for severe vernal keratoconjunctivitis.

Summary (Ophthalmic Drugs 1 Part 1)

• In the UK, ophthalmic corticosteroids are usually reserved for managing moderate-to-severe inflammation by qualified ophthalmologists and can also be prescribed by independent optometrists.
• Topical NSAIDs are mainly licensed to reduce post-operative inflammation; however, diclofenac is used for seasonal allergic conjunctivitis and pain.
• Ciclosporin is an immunosuppressant, primarily used for severe cases of dry eye and vernal keratoconjunctivitis.

The Ocular Allergic Response

• Eyes are a common site for allergic inflammation.
• The majority of allergic eye conditions affect the conjunctiva.
• Mast cells play a key role in allergic responses.
• Degranulation of mast cells releases substances like histamine.
• Released mediators cause signs and symptoms of ocular allergy.

Allergic Eye Diseases

• Acute allergic conjunctivitis.
• Seasonal/perennial allergic conjunctivitis.
• Giant papillary conjunctivitis.
• Atopic keratoconjunctivitis.
• Vernal keratoconjunctivitis.

Role of Mast Cells in Ocular Allergy

• Mast cells are involved in processing and presenting antigens, producing IgE, and activating inflammation.
• Mast cell degranulation occurs when inflammatory mediators are released.
• Mast cell stabilization involves stopping degranulation, which can be done using mast cell stabilisers.

Anti-allergy Drugs

• Antihistamines, mast cell stabilisers, corticosteroids, NSAIDs, and vasoconstrictors are used to treat allergic eye conditions.

Antihistamines

• Available in topical and systemic forms (many OTC preparations).
• Systemic antihistamines are often used for hay fever and other conditions. The common example of a topical antihistamine is cetirizine. (examples: diphenhydramine and cetirizine).
• Topical antihistamines are a very common treatment for seasonal and perennial allergic conjunctivitis.
• Newer antihistamines also have mast cell stabilizing properties.

Available Anti-allergy Preparations (Topical Antihistamines)

• Antazoline, Azelastine, Epinastine (POM), Ketotifen, and Olopatadine.

Topical Mast Cell Stabilizers

• Block calcium influx to mast cells, preventing degranulation, decreasing the symptoms and signs of allergic reactions.
• Symptom relief takes 7-14 days.
• Effective for moderate to severe allergic eye conditions.

Available Anti-allergy Preparations(Mast Cell Stabilizers)

• Sodium cromoglicate, Lodoxamide, and Nedocromil sodium.

NSAIDs (for allergic conditions)

• Diclofenac sodium (POM) is a licensed, well-tolerated NSAID for allergic eye conditions, particularly SAC, and provides symptomatic relief within 30 minutes of administration.

Vasoconstrictors

• Vasoconstrictors are sympathomimetic drugs, stimulating alpha adrenoceptors to cause constriction of conjunctival blood vessels. Reducing redness and inflammation.
• Vasoconstrictors reduce conjunctival hyperemia and oedema. Examples include: Xylometazoline and Naphazoline.

Summary (Ophthalmic Drugs 1 Part 2)

• Several topical drugs treat allergic eye conditions, including antihistamines, mast cell stabilisers, dual-acting drugs (some over-the-counter), topical NSAIDs and vasoconstrictors.
• Newer antihistamines also have mast cell stabilizing properties.
• Some drugs are available over the counter.
• Topical NSAIDs and vasoconstrictors have a limited role in treating allergic eye conditions.