Corticosteroids Flashcards
Therapeutic Targets for Corticosteroids in Ocular Diseases
-inflammation
-inflammation secondary to injury or surgery
-auto-immune ocular or systemic disease
-edema or ARMD
Systemic Diseases that are Therapeutic Targets for Corticosteroids
auto immune diseases
-rheumatoid arthritis
-psoriasis
-lupus erythematosus (SLE)`
-Crohn’s disease
asthma
allergies
gout
pathological inflammation secondary to infection
Therapeutic Actions of Corticosteroids
-very potent anti inflammatory and immunosuppressive actions
-inhibition of mediator sythesis+
-decrease/slow healing
Corticosteroid Mechanism of Action I
Glucocorticoid receptors: repress of activate gene expression
-steroid is present in bound form
-intracellular receptor is bound to stabilizing proteins
-receptor complex is incapable of activating transcription until it binds to cortisol
-unstable complex and molecules are release
-steroid-receptor complex created and dimerize and enter the nucleus, bind to GRE
Corticosteroid Mechanisms of Action II
-Epigenetic Regulation (Histone Acetylation)
-regulate folding and unfolding of chromatin
-prevents opening of chromatin
Mediators and Bioactions Inhibited by Corticosteroids
- eicosanoids (prostaglandins): vascular, pain, inflammation, host defense
- cytokines: inflammation, lymphocytes, host defense, immune responses, proliferation
- leukotrienes: host defense, smooth muscle, inflammation, leukocytes
- complement components: host defense, antigen presentation
- nitric oxide: vascular tone
- others, e.g. PAF, IgG: Adaptive Immune response, inflammation
- adhesion molecules (selectins, integrins): leukocyte activation and migration
Physiological Anti-Inflammatory Effects of Corticosteroids
- inhibit migration of inflammatory cells
- interfere with lymphocyte activation
- inhibit fibroblast proliferation & activity (reduced fibrosis)
- decrease collagen & proteoglycans synthesis
- decrease mediator synthesis
- reduction in capillary permeability & proliferation
- increased expression of free radical scavenging (SOD)
- inhibit angiogenesis/neovascularization
- increase clearance of leukocytes (phagocytosis)–resolution
Ocular Pharmacological Uses of Corticosteroids
suppress all inflammatory responses
* reduce inflammation in unresponsive &/or severe allergies
* primary inflammations (e.g. uveitis, endophthalmitis)
* secondary (e.g. surgery, trauma)
* Ocular immune responses (e.g., severe dry eye syndrome, graft rejection)
* Allergic conjunctivitis
Most frequently used anti-inflammatory agents
* Provide palliative therapy only
* Degenerative conditions refractory to steroid therapy
* Always contra-indicated for infections
Concerns: Infection, inhibit wound healing, increase IOP
Clinical Considerations for Corticosteroid Choices
-location of inflammation
-penetration ability
-intact or absent epithelium
Corticosteroid Potency - Formulation Interactions
- base-dependence: acetate>alcohol>phosphate
-partly due to altered affinity to receptor
-partly due to altered penetration (PO4 more water soluble) - alcohol form more rapidly metabolized than acetate (fluorometholone)
- ointments generally reach higher concentrations in anterior segment
- not tightly coupled to drug concentration at site of inflammation
Absorption Aqueous Humor
Hydrophilic Drugs – epithelium rate limiting step
Hydrophobic Drugs – stroma rate limiting step
Low molecular weight drugs – penetrate rapidly
Potency Differences across Drugs
- dexamethasone most potent, also long acting
-differences less pronounced between acetate forms
-dexamethasone
-prednisolone (prednisone is prodrug form)
-fluorometholone (alcohol metabolized very rapidly =“soft drug”) - medrysone
-least potent (low affinity), no efficacy in iritis or uveitis
-poor corneal penetration - loteprednol
-soft drug (min. activity in anterior chamber) - rel. systemic & ocular potencies not necessarily matched
General Principles of Ocular Therapy: Inflammatory Disease
Allergies - fluorometholone, rimexolone, loteprednol
Superficial Ocular Inflammation - medrysone
Surroundin Skin - cortisone, metabolized to hydrocortisone
Anterior Segment Inflammation - dexamethasone, prednisolone (acetate), rimexolone, fluorometholone, fluocinolone (implant)
Posterior Segment Inflammation/Edema - triamcinolone (vitreal injection)
General rules of Ocular Therapy
- individualize dosage, maintain close supervision, reevaluate frequently
- therapy should be reduced gradually
- use minimal effective dose for shortest period
- specific type/location inflammation determines site/route of administration:
-local (topical, periocular or intravitreal)
-systemic
-combination
Re-evaluation & Tapering of Corticosteroid Use
Tapering off long-term, high-dose therapy
* necessary because of feedback control of “CORTs”
* combine dose reduction with monitoring
* prevents relapse (rebound inflammation)
* avoid life threatening complications (systemic use)
Adrenal Gland produces 10-20 mg of Cortisol daily
Topical Ocular Administration
Reasons for use
-monocular treatment
-pref for ant. seg disease
-least problem for systemic complications
- epithelial keratopathy from frequent applications
- alternate-day therapy
* 2-day dose given as single dose every other morning
* used only with shorter-acting steroids (e.g. prednisone, not dexamethasone)
* minimizes adrenal suppression & other SEs
