Corticosteroids

Basal secretions Group Hormone Daily secretions Glucocorticoids Cortisol Corticosterone 5 – 30 mg 2 – 5 mg Mineralocorticoids Aldosterone 11- deoxycorticosterone 5 – 150 μg Trace Sex Hormones Androgen Progestogen Oestrogen DHEA Progesterone Oestradiol 15 – 30 mg 0.4 – 0.8 mg From Essential of Pharmacotherapeutics, ed. FSK Barar. P.351

Oestriol Andro-stenedione Oestrone 11- Desoxy- cortisol Cholesterol ACTH Oestriol 17-α- Hydroxy pregnenolone Pregnenolone Dehydro-epi androsterone Progesterone 17- Hydroxy progesterone Andro-stenedione Oestrone 21,β hydroxylase 11-Desoxy-corticosterone 11- Desoxy- cortisol Corticosterone 11,β hydroxylase 18-Hydroxy- corticosterone 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 anti-inflammatory 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 glucose and glycogen) Hepatic actions Peripheral utilization of glucose Glycogen deposition in liver (activation of hepatic glycogen synthase)

Redistribution of Fat Promote adipokinetic agents activity 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

ICP (pseudotumor cerebri) - Rare Actions: CNS Direct: Mood Behaviour Brain excitability Indirect: maintain glucose, circulation and electrolyte balance ICP (pseudotumor cerebri) - Rare

Aggravate peptic ulcer. May be due to: Acid and pepsin secretion 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 1 1.0 0.8 4 5 0.3 Intermediate acting 10 - 15 7 Drug Anti-inflam. Salt retaining Topical Cortisol 1 1.0 Cortisone 0.8 Prednisone 4 Prednisolone 5 0.3 Methylpredni- solone Intermediate acting Triamcinolone Paramethasone 10 - Fluprednisolone 15 7

Preparations Long acting 25-40 10 30 Mineralocorticoids 250 20 Drug Anti-inflam. Salt retaining Topical Long acting Betamethasone 25-40 10 Dexamethasone 30 Mineralocorticoids Fludrocortisone 250 DOCA 20

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: hypertension hypokalaemia growth suppression diabetes mellitus muscle wasting osteoporosis fat redistribution skin atrophy hirsutism acne hypertension hypokalaemia menstrual irregularities adrenal suppression

Unwanted Effects Other: Withdrawal 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 products 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