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Clinical Pharmacology of Corticosteroids Joe Collier Aims • The session will describe: the class of corticosteroids generally how corticosteroids bring about their effects how corticosteroids can be used to: treat patients with deficiency or to modify disease the key pharmacokinetic and pharmacodynamic properties of corticosteroids the main unwanted effects of corticosteroids and ways in which these may be avoided Clinical Pharmacology of Corticosteroids • Objectives - At the end of the session you should be able to: describe the actions of corticosteroids (prednisolone, hydrocortisone, betamethasone, dexamethasone), explain, where possible, the pharmacokinetics and pharmacodynamics of these drugs; describe and explain their interactions and unwanted effects and how these can be avoided; describe, briefly, the principles of their use Examples of Corticosteroids available • • • • • • hydrocortisone prednisolone dexamethasone beclomethasone budesonide fluticasone Uses • Corticosteroids are used: to reduce inflammation (asthma, arthritis) and swelling (cerebral oedema) to suppress the immune response (systemic lupus erythematosis) to reduce nausea and vomiting (as in cancer chemotherapy) to reduce terminal pain (associated with cancer) as replacement therapy (in Addisons disease) Unwanted Effects • Metabolic: – – – – – – – – growth suppression diabetes mellitus muscle wasting osteoporosis fat redistribution skin atrophy hirsutism acne – – – – hypertension hypokalaemia menstrual irregularities adrenal suppression Unwanted Effects • Other: – infection – emotional disturbances (psychosis, depression, mania) – cataract, glaucoma – GI bleeding, perforation • Withdrawal – – – – Addisonian crisis raised intracranial pressure arthralgia/myalgia pustular rash How corticosteroids work • Gross (metabolic) actions: – glucose: diabetogenic » (glucose uptake and utilisation; gluconeogenesis) – fat: Cushing’s syndrome » (redistribution, lipolysis) – protein: muscle wasting » (catabolism, anabolism) – minerals: hypertension (mineralocorticoid effect) How corticosteroids work • Cellular (nuclear)* level: – anti-inflammatory and immunosuppressive actions: » number and activity of leucocytes, » proliferation of blood vessels, » activity of mononuclear cells, » activity of cytokine secreting cells, » production of cytokines, » generation of eicosanoids and PAF, » complement components in blood, » histamine release *Effect through gene transcription (lipocortin synthesis, inhibition of COX-2 synthesis). THIS TAKES TIME! Avoiding unwanted effects of corticosteroids • Modification of dose/dose regimen Use short courses/low doses if possible Use steroid sparing drugs Withdraw ‘chronic’ steroids slowly Give dose once daily and in morning Give on alternate days if possible Give prophylactics if possible Give product locally Remember contraindications Enrol help of patient Avoiding unwanted effects of corticosteroids • Steroid Selection: – remember, their effects can differ with regard to their mineralocorticoid and antiinflammatory actions and duration of effect eg as parenteral products AIA NaRet Hydrocortisone 1 1 Prednisolone 5 1 Dexamethasone 35 <1 Fludrocortisone <<1 20 or as topical products (creams) • hydrocortisone - mild • clobetasone but. moderately potent • betamethasone - potent • clobetasol prop. - very potent Giving products locally can still cause problems! • systemic dosing can occur • local toxicity can develop – skin: infection, thinning, bruising. – eye: viral infection, cataract, glaucoma. – inhalation: fungal infection, hoarseness – joints: infection, necrosis