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Therapeutics Update - Steroids Gary E. Oliver, O.D., F.A.A.O.

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General Steroid Pharmacokinetics A. B. C. D. E. Steroids are synthetic glucocorticoids designed to produce similar antiinflammatory effects to endogenous glucocorticoids secreted by adrenal cortex Inhibit prostaglandin production Block enzyme phospholipase A2 Inhibit chemotaxic agents - prostaglandins, thromboxanes, leukotrienes, etc. Prevent mast cell degranulation

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Ocular Steroid Pharmacologic Effects A. B. C. D. E. F. G. H. I. Reduce capillary permeability Reduce cellular infiltration & exudation Suppress macrophage and neutrophil migration Inhibit fibroblast activity Inhibit mast cell degranulation Reduce overall quantity of inflammatory mediators Inhibit production of inflammatory mediators - prostaglandins, thromboxanes, leukotrienes, etc. Suppress lymphocyte proliferation Inhibit cell-mediated immune response (T-cells greater than B-cells)

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General Therapy Considerations and Principles A. B. C. D. E. F. G. H. I. J. Assess risks/benefits/alternatives before treatment Treatment is nonspecific Treatment goal - rapid reduction of inflammation Ocular treatment goal - prevent vision threatening complications Type and location of inflammation determines proper route of administration 1. Topical vs. systemic treatment Type and clinical severity of inflammation determines the appropriate dosage Clinical severity determines the appropriate dosage Initial dose should be adequate to suppress the inflammatory process Steroid dosage regulated by both the drug concentration and application frequency Steroid formulation indicated is determined by the inflammation site and need for 1

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tissue penetration May need to treat aggressively, particularly anterior uveitis Pulse vs. standard dosing techniques

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Steroid Dosage Protocols A. Pulse dose 1. Effective for type I or IV hypersensitivity reactions and traumatic iridocyclitis 2. High initial dose followed by immediate, rapid taper of steroid 3. Short therapeutic course (typically 5-7 days) Standard dose 1. Effective for most inflammatory processes including uveitis, systemic disease related inflammation, or other more complex inflammatory reactions 2. Initial dose dependent upon severity of inflammation 3. Initial dose maintained for minimum of 72 hours, monitor for clinical improvement 4. Continue initial dose for 3-4 days after clinical improvement is noted 5. Taper steroid in step down fashion over several weeks

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Ocular Steroid Therapy Principles A. B. C. D. E. F. Steroid dosage regulated by both drug concentration and application frequency Steroid formulation determined by inflammation site and need for tissue penetration Normal vs. inflamed tissue Always continue therapy for 3-4 days after signs and symptoms begin to resolve Always taper steroids Steroid tapering techniques 1. Reduce frequency of steroid dose 2. Reduce steroid concentration of initial medication 3. Adjust steroid potency by changing medications 4. Consider nonsteroidal anti-inflammatory agent for long term tapering Role of NSAIDS for treatment of ocular inflammation 1. Generally not as potent or as clinically effective as steroids for reduction of ocular inflammation 2. May be useful for long term tapering of anti-inflammatory agents

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Adverse Effects from Topical Ocular Steroid Therapy 2

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Elevation of intraocular pressure Secondary or reactivation of infection Masking of clinical signs Delayed wound healing Transient discomfort - burning, stinging Dry eye syndrome Posterior subcapsular cataract

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Contraindications for Topical Ocular Steroids A. B. Presence of active infection examples may include bacterial disease, corneal ulcer, Herpes simplex Steroid responders use with caution, use steroid with less risk of increasing intraocular pressure, monitor IOP carefully, may need concurrent IOP lowering medication

VIII. Topical Steroid Agents A. B. C. D. E. F. G. 0.125%-1% prednisolone acetate 0.125%-1% prednisolone phosphate 0.1% fluorometholone acetate 0.1% fluorometholone alcohol 0.2%-0.5% loteprednol etabonate 1% rimexolone 0.1% dexamethasone alcohol

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Steroid Efficacy A. B. C. Potency of agent Tissue penetration of agent Dosage

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Relative Steroid Anti-Inflammatory Activity A. Steroid Potency - decrease in inflammation after 48 hours of therapy 3

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1% prednisolone acetate 51% 0.1% dexamethasone alcohol 40% 0.1.% fluorometholone acetate 31% 1% rimexolone, 0.5.% loteprednol may be equivalent to 1% prednisolone acetate but dosage considerations are important Steroid Dosage - decrease in inflammation after 48 hours of therapy with 1% prednisolone acetate one drop q1h 51% one drop q2h 30% one drop q4h 11% Treatment Protocols 1. External disease - minimal initial dose typically q4h 2. Anterior uveitis - minimal initial dose typically q2h

XI. Clinical Management Pearls A. Have an expected time frame for resolution of inflammation 1. External disease - expect improved symptoms in 24-48 hours, clinical signs 48-96 hours depending on the clinical entity 2. Anterior uveitis - expect improved symptoms 48-72 hours, early improvement of clinical signs by one week If not responding as expected 1. Consider if diagnosis is correct 2. Question patient compliance 3. Is dosage correct, may need to increase dosage 4. Change medication 5. Referral for second opinion Mistakes in steroid therapy 1. Under-prescribing the medication 2. Can always taper, more difficult to increase dosage 3. Undertreated cases usually are more difficult to manage 5. Steroid therapy in presence of active infectious ocular disease 6. Not monitoring intraocular pressure

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Systemic Steroid Therapy A. B. C. Indicated for very severe anterior uveitis (adjunctive therapy) Indicated for posterior uveitis, scleritis, (possibly optic neuritis) Systemic prednisone usually not necessary for anterior segment disease due to ability to build high steroid titers from topical therapy

XIII. Nonsteroidal Anti-Inflammatory Agents (NSAIDS) A. Nonsteroidal anti-inflammatory drugs are synthetic agents designed to achieve a similar anti-inflammatory effect to the endogenous glucocorticoids secreted by the adrenal cortex 1. Inhibit the production of prostaglandins by reversibly blocking the action of the enzyme cyclooxygenase in the prostaglandin pathway 2. Most have no direct effect on leukotriene production and do not prevent mast cell degranulation 3. Inhibit platelet coagulation General Pharmacological effects 1. Analgesic 2. Anti-Inflammatory 3. Antipyretic 4. Anticoagulant Ocular Pharmacological Effects Topical Therapy 1. Improves blood-aqueous barrier 2. Prevent vasodilation 3. Reduce capillary permeability 4. Prevent migration of some inflammatory mediators 5. Reduce mild to moderate pain Adverse Effects Topical Therapy 1. Transient burning or stinging 2. Secondary or reactivation of infection 3. Masking of clinical signs 4. Headache 5. Possible central nervous system effects, such as dizziness, seizures, syncope, short term memory loss, decreased attention span General Contraindications for NSAIDS usage these are systemic principles but may have implications for topical NSAIDs depending on systemic absorption from topical application 1. Upper gastrointestinal disease 2. Bronchial asthma 3. Hypersensitivity history 4. Bleeding disorders 5. Anticoagulant therapy 6. Immediate post-op period following invasive surgery 7. Chronic renal or hepatic disease 8. Congestive heart disease 9. Pregnancy

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XIV. Additional Anti-Inflammatory Agents A. 0.05% cyclosporine 1. Inhibits cytokine induced inflammation 2. Inhibits some T-cell activity 3. Increases goblet cell activity 4. Promotes rejuvenation of lacrimal gland tissue which can increase tear production Adverse Effects 1. Transient burning or stinging 2. Transient blurred vision 3. Secondary or reactivation of infectious disease, i.e. Herpes simplex

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Clinical Grand Rounds