Anti-Inflammatory Drugs Amy J. Rankin Diplomate ACVO Associate Professor Ophthalmology Kansas State University • Corticosteroids • NSAIDs Corticosteroids • Adrenal gland • Glucocorticoids – Zona fasciculata – Zona reticularis – Anti-inflammatory – Metabolic – Immune • Mineralocorticoids – Zona glomerulosa www.news-medical.net – Electrolyte & water balance Riviere & Papich, Veterinary Pharmacology & Therapeutics, 10th Ed Glucocorticoids • Anti-inflammatory – Inhibition of angiogenesis – Reduces leukocyte migration – Decreased capillary permeability – Decreases WBC degranulation • Effects on tissue regeneration – Decreased fibroblastic & collagen formation – Increased collagenolytic activity – Decreased wound healing • Loewenberg et al.,Trends Molec Med, 2007 Loewenberg et al., Trends Molec Med, 2007 Glucocorticoids-Transrepression • GC binds to receptor in cytoplasm • GC-receptor translocates to nucleus • Binds to negative GRE • Down regulation of pro-inflammatory proteins (IL-1 & IL-2) Glucocorticoids-Transrepression • GC binds to receptor in cytoplasm • GC-receptor interacts with transcription factors (TF) NF- ĸβ, AP-1 • GC-receptor complex or TFs do not bind to pro- inflammatory GREs • Down regulation of pro-inflammatory and immune stimulation factors Glucocorticoids-Transrepression • GC binds to receptor in cytoplasm • GC-receptor translocates to the nucleus • GC-receptor binds to nuclear coactivators – AP-1 • Inhibition of pro-inflammatory protein proteins Glucocorticoids-Transactivation Stahn et al., Molecular and Cellular Endocrinology, 2007) • GC diffuses through cell membrane • GC binds to receptor in cytoplasm • GC-receptor translocates to nucleus • Binds to GC response element (GRE) in target gene • Up-regulation of anti-inflammatory, immunomodulatory, and metabolic processes Non-genomic MOA • High dose therapy • Rapid onset of clinical effects – Anti-inflammatory – Immunosuprression Non-genomic MOA • GC interact with cellular membranes – Reduced Ca and Na transport across membranes of immune cells – Rapid immunosuppression Non-genomic MOA University of Tokyo • GC-receptor binding causes protein complex dissociation so GC-receptor translocates to nucleus • Heat shock proteins & kinases that are released mediate various rapid intracellular effects • GC-receptor inhibits release of AA from plasma membrane via transcription-independent mechanism Non-genomic MOA • GC effects mediated by a membrane- bound GC receptor • Upregulation of membrane GC receptor during immunostimulation • GC-induced membrane bound GC receptor-mediated apoptosis Anti-inflammatory Effects of Glucocorticoids • Inhibition – Pro-inflammatory transcription factors • AP-1 • NF- ĸβ • STAT – Expression of pro-inflammatory cytokines • IL1-6, IL 11-13, IL 16, & IL 17 • Interferon –γ • TNF • GM-CSF Anti-inflammatory Effects of Glucocorticoids • Synthesis – Anti-inflammatory proteins • Lipocortin – Inhibits phospholipase A2 • IL-10 • Annexin-1 • Mitogen-activated protein kinase phosphatase-1 – Decreased transcription of pro-inflammatory genes Immunosuppressive Effects of Glucocorticoids • Decrease number and function of B &T cells – Inhibition of NF-ĸβ • Induction of TGF-β expression – Blocks cytokine synthesis and T-cell activation • Inhibition of humoral immunity – Decreased synthesis of IL-2 & IL-2 receptors • Inhibition of cell-mediated immunity – Inhibition of multiple interleukins (IL-1, IL-2, IL-3, IL-6) GC Side Effects • Systemic – Gluconeogenesis – Breakdown of muscle – Effects on psyche – Diabetogenic – Suppression of HPAA – Osteoporosis – PU/PD • Inhibition of ADH release and action GC Side Effects • Ophthalmic – Cataract – Ocular hypertension – Decreased wound healing – Potentiate infection – Corneal lipid deposition GC-Induced Cataract • Humans posterior subcapsular cataracts • Oral, topical, cutaneous, inhalation... • Dose and duration dependent • Children more sensitive • Reported prevalence 22% – 0-90% GC-Induced Cataract • Not well documented in SA • Experimentally-induced cats – Topical dexamethasone NaP or prednisolone – Subscapular cataracts after 40 days of therapy Zhan et al., Experimental Eye Research, 1992 Etiology of GC-Induced Cataract • Etiology of GC-induced cataract – Unknown – Decrease in lens enzymes – Alterations in lens hydration • Modulation of NaKATPase – Aberrant posterior LEC migration – Alteration in ocular growth factors? GC Ocular Hypertension • Systemic, periocular, topical, inhalational routes... • High responder – 15 mmHg increase • Moderate responder – 6-15 mmHg increase Phulke S et al., J Curr Glaucoma Practi 2017 Becker B, Invest Ophthalmol, 1965 Becker B & Chevette L, Am J Ophthalmol, 1964 Becker B & Hahnka L, Am J Ophthalmol, 1964 GC Ocular Hypertension • Generally reversible • Risk factors in humans: – Glaucoma suspects (30%) – POAG patients (90%) – High myopia – History of refractive surgery – Bimodal age distribution (<10 years and older adults) – Diabetes mellitus – Genetics Morales J & Good D, J Cataract Refract Surg, 1998 Podos SM et al., Am J Ophthalmol, 1966 Armaly MF, Arch Ophthalmol, 1963 Becker B, Am J Ophthalmol, 2971 Etiology of GC Hypertension • Decrease in outflow facility • Accumulation of extracellular material in the TM • Increased expression laminin & myocilin TM cells • Activation of GC receptors in TM • Increased type IV collagen, heparin sulfate proteoglycan, fibronectin Clark AF et al, Invest Opthalmol Vis Sci, 2001 Johnson et al., Arch Ophthalmol, 1997 Dickerson JE et al, Exp Eye Res, 1998 Tawara A et al., Glaucoma, 2008 GC Ocular Hypertension-Dogs • Beagles with POAG – 2 weeks topical 0.1% dex QID – Mean IOP increase 5 mmHg – Returned to baseline within 1 week • Normal dogs – Oral hydrocortisone 3.3 mg/kg TID 5 weeks – No significant increase in IOP Gelatt KN & Mackay EO, J Ocul Pharmacol Ther, 1998 Herring IP et al., Vet Ophthalmol, 2004 GC Ocular Hypertension Normal Cats – Topical 0.1% dex or 1% prednisolone TID for 4 weeks – Significant increase in IOP with 2-3 weeks – Mean IOP increase 4.5 mmHg greater than control cats – IOP values quickly returned to normal Bhattacherjee P et al., Arch Ophthalmol, 1999 – Topical 1% dex NaP BID or TID or 1% prednisolone acetate BID – Significant increase IOP that was reversible Zhan G et al., Exp Eye Res, 1992 GC Ocular Hypertension - Cats • 0.1% dexamethasone or 1% prednisolone BID • Normal cats (n=5) – 2/5 increased IOP compared to contralateral eye (maximum 6.4 mmHg) • Feline congenital glaucoma cats (n=11) – 8/11 increased IOP compared to contralateral eye (maximum 56 mmHg) • Mild 3 cats (<15 mmHg) • Moderate 2 cats (15-25 mmHg) • Marked 3 cats (>25 mmHg) • Values returned to baseline within 7-10 days Gosling et al., Vet Ophthalmol, 2016 GC Ocular Hypertension • Normal cows (Herford and Brahman X) • 1% prednisolone TID 7 wks • 100% of cows increased IOP after 3 weeks of therapy (maximum 15 mmHg) • Normal sheep (Corriedale) • 0.5% prednisolone TID 3-4 wks • 100% of sheep increased IOP after 2 weeks (~16 mmHg difference) Gerometta R et al., Arch Ophthalmol, 2004 Gerometta R et al., Inves Ophthalmol Vis Sci, 2009 GC Ocular Hypertension - Cows • Normal cows (Herford and Brahman X) • 1% prednisolone TID • Altered gene expression in TM • Expression of 258 genes upregulated 187 genes downregulated in TM • Genes coding for cytoskeletal proteins, enzymes growth & transcription factors, immune response proteins Danias J et al., Invest Ophthalmol Vis Sci, 2011 GC Corneal Wound Healing • Increase lytic action of collagenase • Delay wound healing • Decreased collagen deposition • Decreased stromal keratocyte proliferation • In vitro dexamethasone phosphate less cytopathic effect on cultured epithelial cells than prednisolone Hendrix DH et al., Vet Ophthalmol, 2002 GC Systemic Side Effects • Suppression of HHAA – Dogs 1% prednisolone QID 2 weeks • Adrenal suppression & liver changes – 0.1% dexamethasone QID OU • Mean 0.03mg/kg of body weight/day • Suppression of ACTH-stimulated cortisol – 2 subconjunctival injections 10 mg methylprednisolone (3 weeks) • Iatrogenic Cushing's disease Eichenbaum J et al., J Am Anim Hosp Assoc,1988 Roberts et al, Am J Vet Res, 1984 Glaze et al., J Am Vet Med Assoc, 1988 Regnier, Res Vet Sci, 1982 Murphy, J Am Animal Hosp Assoc, 1990 GC Systemic Side Effects • Humans topical dexamethasone – Diabetics significant increase in BG at 1 month • Diabetic dogs topical 1% prednisolone acetate – No significant difference in BG curves, fructosamine or clinical scores between diclofenac or prednisolone • Diabetic rats & humans subconjunctival injection dexamethasone – Increased BG Bahr, Curr Eye Res, 2007 Rankin AJ et al., Proc ACVO, 2017 Faukushima, Eye, 2001 Fukushima, J Cataract Refract Surg, 2001 GC Side Effects • Calcific band keratopathy – Humans & horses • Lipid keratopathy?? – Dogs • Bilateral exophthalmos – Calves parenteral dexamethasone – 30 mg/kg BID noted after 28 days Berryhill et al., Vet Ophthalmol, 2017 Brooks, Equine Vet J, 2012 Taravella et al., Arch Ophthalmol, 1994 Townsend et al., Vet Ophthalmol, 2003 Minimize GC Side Effects • Long-circulating liposomal GC • Selective GCR agonists (SERGAs) • Selective GCR modulators (SEGMs) • Sustained action of steroids • Decreased dose • Less frequent dosing interval Liposomal Glucocorticoids • Liposomes – Phospholipid bilayer – GC in lumen – PEG polyethylene glycol • Modification of surface to increase stability and t1/2 • Medial applications – Cancer, RA, asthma, Parkinson’s dz... Liposomal Prednisolone • Human colon carcinoma T-84 cell lines – Direct antiproliferative effect