Corticosteroids- an introduction

Corticosteroids- an introduction

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  CORTICOSTEROIDS - AN INTRODUCTION ChristopherFowler Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå Sweden November 2017
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  Synopsis Endogenous glucocorticoid production Glucocorticoidreceptors Pharmacological effects of glucocorticoids Disclaimer Glucocorticoids as anti-inflammatory agents Why dose-tapering after prolonged glucocorticoid treatment?
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  Disclaimer This short presentationis designed to give the pharmacological background to the use of corticosteroids for the treatment of inflammation. It does not give treatment recommendations and should not be used as such. Further, the information is accurate as of November 2017. If you are reading this is in 2022, things may have changed! Christopher Fowler
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  Endogenous glucocorticoid (GC) and mineralocorticoid (MC) production Hypothalamus Anteriorpituitary CRF ACTH Adrenal cortex GC MC + + -- Note the regulatory feedback loops. We’ll get back to those later
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  Glucocorticoid receptors info onthe receptors: http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=625 Non-genomic effects of glucocorticoids also occur. These are responsible for some of the rapid effects of GCs, including translocation of available annexin-1 to the cell surface. GC hsp 70 hsp 90 GR a. b. c. a) glucocorticoids bind to intracellular receptors b) binding removes chaperones and allows for c) translocation to nucleus and modulation of gene transcription
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  Modulation of geneexpresion the way it does this is either directly by binding to glucocorticoid response elements (GREs) in promotor regions of glucocorticoid-sensitive genes (nGREs for repressor responses), or indirectly by affecting the ability of other regulatory proteins (like NFκB) to exert their effects. increased gene expression e.g. annexin-1, ß2-adrenoceptor, IL-1 receptor antagonist decreased gene expression e.g. cytokines like IL-6 and TNFα, cyclooxygenase-2
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  Pharmacological effects ofGCs Many genes regulated → many pharmacological effects • Anti-inflammatory and immunosuppressive actions both acute and chronic inflammation • Metabolic actions ↓ cellular uptake of glucose, ↑ gluconeogenesis protein catabolism, ↓ protein synthesis ↑ lipolysis • Regulatory actions feedback inhibition of endogenous GC production ↓ osteoblast, ↑ osteoclast activity Na+ and water retention As pointed out by Becker (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601727/), ”When supraphysiologic doses are administered, the subsequent pharmacological effects consist essentially of exaggerated physiologic effects”.
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  GCs as anti-inflammatorydrugs Anti-inflammatory Immunosuppressive actions Metabolic actions Regulatory actions §In asthma, inhaled glucocorticoids will not only reach the lungs, but also affect the throat, rendering it sensitive to opportunistic infections (usually Candida). That is why patients should gargle after inhalation, to dilute out the GC that didn’t reach the lungs. 😀 😡 😡 Strategy to minimise unwanted effects: local treatment (when possible) skin (e.g. treatment of eczema) 😡 lungs (treatment of asthma) potent and effective increased sensitivity to infections§ e.g. hyperglycaemia e.g. osteoporosis
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  Why dose tapering after prolongedGC treatment? Hypothalamus Anterior pituitary CRF ACTH Adrenal cortex GC MC + + - - GC exogenous GC (in orange) will turn off endogenous GC production. A sudden end to the GC treatment will leave the patient without GC defences, which is dangerous. That’s why individuals at risk should carry information about their treatment. (see http://www.imperialendo.com/for-doctors/toolkit-for-doctors/steroid-card for an example of a steroid card)