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Corticosteroids Basal secretions Group Hormone Daily secretions 5 – 30 mg 2 – 5 mg 5 – 150 μg • Cortisol • Corticosterone Mineralocorticoids • Aldosterone • 11- deoxycorticosterone Trace Sex Hormones •Androgen • DHEA 15 – 30 mg •Progestogen • Progesterone 0.4 – 0.8 mg Trace •Oestrogen • Oestradiol Glucocorticoids From Essential of Pharmacotherapeutics, ed. FSK Barar. P.351 Cholesterol ACTH Oestriol Pregnenolone 17-α- Hydroxy pregnenolone Dehydro-epi androsterone Progesterone 17- Hydroxy progesterone Androstenedione 11-Desoxycorticosterone 21,β hydroxylase Oestrone 11- Desoxycortisol Corticosterone 11,β hydroxylase 18-Hydroxycorticosterone ALDOSTERONE CORTISOL TESTOSTERONE OESTRADIOL Glucocorticoid Analogues Pharmacological Actions • Direct (Intended) Actions Anti-inflammatory Anti-allergy Anti-immunity • Permissive Actions • Lipolytic effects • Effect on bp • Effect on bronchial muscles • (e.g.,sympathomimetic amine) Pharmacological Actions • Negative feedback mechanism. • Steroids and drugs designed to mimic them are directly gene-active. • Glucocorticoids (e.g., prednisolone) used to suppress inflammation, allergy and immune responses. • Anti-inflammatory therapy is used in many illnesses (e.g., RA, UC, BA, eye and skin inflammations). -Useful in, say, tissue transplantation and lymphopoiesis (leukemias and lymphomas). • Striking improvements can be obtained, but severe adverse, but highly predictable, effects are ensue. Pharmacological Actions • For most clinical purposes, synthetic glucocorticoids are used because they have a higher affinity for the receptor, are less activated and have little or no salt-retaining properties. • Hydrocortisone used for: orally for replacement therapy, i.v. for shock and asthma, topically for eczema (ointment) and enemas (ulcerative colitis). • Prednisolone the most widely used drug given orally in inflammation and allergic diseases. Pharmacological Actions • Betamethasone and dexamethasone: very potent, w/o salt-retaining properties; thus, very useful for high-dose therapies (e.g., cerebral edemas). • Beclometasone, diproprionate, budesonide: pass membranes poorly; more active when applied topically (severe eczema for local antiinflammatory effects) than orally; used in asthma, (aerosol). • Triamcinolone: used for severe asthma and for local joint inflammation (intra-articular inj.). Stress and The Adrenal Glands Actions: Carbohydrate and protein metabolism Negative nitrogen balance and hyperglycemia • Gluconeogenesis – Peripheral actions (mobilize aas and – Hepatic actions glucose and glycogen) • Peripheral utilization of glucose • Glycogen deposition in liver (activation of hepatic glycogen synthase) Actions: Lipid metabolism • Redistribution of Fat • Buffalo hump • Moon face • Promote adipokinetic agents activity (glucagon, growth hormone, adrenaline, thyroxine) Actions: Electrolyte and water balance • Aldosterone is more important • Act on DT and CD of kidney – Na+ reabsorption – Urinary excretion of K+ and H+ • Addison’s disease ?? • Na+ loss • Shrinkage of ECF • Cellular hydration • Hypodynamic state of CVS • Circulatory collapse, renal failure, death Actions: CNS • Direct: – Mood – Behaviour – Brain excitability • Indirect: – maintain glucose, circulation and electrolyte balance ICP (pseudotumor cerebri) - Rare Actions: Stomach Aggravate peptic ulcer. May be due to: – Acid and pepsin secretion – immune response to H.Pylori Actions: Calcium metabolism • Intestinal absorption • Renal excretion • Excessive loss of calcium from spongy bones (e.g., vertebrae, ribs, etc) Preparations Drug Cortisol Anti-inflam. Salt retaining Topical 1 1.0 1 0.8 0.8 0 Prednisone 4 0.8 0 Prednisolone 5 0.3 4 Methylprednisolone 5 0 5 5 0 5 Paramethasone 10 0 - Fluprednisolone 15 0 7 Cortisone Intermediate acting Triamcinolone Preparations Drug Anti-inflam. Salt retaining Topical Long acting Betamethasone 25-40 Dexamethasone 30 Mineralocorticoids Fludrocortisone 10 DOCA 0 0 0 10 10 250 20 10 0 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 anti-inflammatory actions and duration of effect eg as parenteral AIA NaRet products 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