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Corticosteroids

The document discusses corticosteroids, detailing their production from the adrenal cortex and medulla, and their physiological regulation via the hypothalamus-pituitary-adrenal axis. It covers various physiological and pharmacological effects, therapeutic uses, side effects, and contraindications associated with corticosteroids, along with their classification into natural and synthetic forms. The document also highlights their application in treating conditions like Addison's disease, Cushing's syndrome, and various inflammatory and autoimmune disorders.

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Corticosteroids 04/30/19 1PATKI
The hormones produced from three zones of adrenal cortex Adrenal medulla : Epinephrine (adrenaline) Zona glomerulosa (outer) : Mineralocorticoids Zona fasciculata (middle) : Glucocorticoids Zona reticularis (inner) : Adrenal androgens Acute stress Chronic stress 04/30/19 2PATKI
Acute stress Chronic stress 04/30/19 3PATKI
4 Hypothalamus + CRH Anterior pituitary + ACTH Adrenal cortex Hydrocortisone secretion __ __ __ CRH: corticotropin releasing hormone; ACTH:ACTH: adrenocorticotrophic hormoneadrenocorticotrophic hormone ●Physiological regulation mechanism of glucocorticoids secretion (Hypothalamus-pituitary-adrenal gland axis) plasma
DIAGNOSTIC USES (ACTH) 1. Adrenal insufficiency Primary insufficiency No increase in cortisol level Secondary insufficiency Increase in cortisol level 2. Cushing syndrome ACTH injected 04/30/19 5PATKI
THERAPEUTIC USES Replacement therapy: Tumour in anterior pituitary To stimulate the adrenal gland inactivated by steroid therapy Both uses are expensive & inconvenient similar to that of steroids. Being a foreign protein, ACTH may produce anaphylactic reactions. Side effects and contraindications 04/30/19 6PATKI
Corticosteroids History Synthesis Pharmacological Actions Pharmacokinetics Preparations Therapeutic principles Dosage schedule & Steroid withdrawal Uses: – Therapeutic – Diagnostic Adverse reactions Contraindications Precautions during therapy Glucocorticoid antagonists 04/30/19 7PATKI
History 1855 – Addison's disease 1856 – Adrenal glands essential for life 1930 – Cortex > medulla 1932 – Cushing’s syndrome 1949 – Hench et al (Steroids in rheumatoid arthritis) 1952 – Aldosterone 04/30/19 8PATKI
CORTICOSTEROIDS • Adrenal cortex essential for survival • Adapt for changing environment • Organ of par excellence -homeostasis • Zona glomerulosa-aldosterone • Zona fasciculata- glucocorticoids • Zona reticulata- sex steroids • Regulatory control from the hypothalamus and pituitary. 04/30/19 9PATKI
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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 Trace From Essential of Pharmacotherapeutics, ed. FSK Barar. P.35104/30/19 12PATKI
Cholesterol Pregnenolone Progesterone Corticosterone 11-Desoxy- corticosterone 18-Hydroxy- corticosterone ALDOSTERONE 17-α- Hydroxy pregnenolone 11- Desoxy- cortisol 17- Hydroxy progesterone 21,β hydroxylase CORTISOL 11,β hydroxylase Dehydro-epi androsterone Andro- stenedione Oestrone Oestriol TESTOSTERONE OESTRADIOL ACTH 04/30/19 13PATKI
  CLASSIFICATION OF ADRENOCORTICOSTEROIDS   Natural   Synthetic   Glucocorticoids   Hydrocortisone (cortisol) Cortisone  Prednisone, Prednisolone Methyl-prednisolone Triamcinolone Betamethasone, Dexamethasone     Mineralocorticoids   Aldosterone Desoxycorticosterone (DOC)     Fludrocortisone 04/30/19 14PATKI
Classification • Natural- mineralocorticoid & glucocorticoid aldosterone hydrocortisone • Synthetic : 1.Short acting: hydrocortisone (8-12hrs.) Cortisone 2. Intermediate acting: prednisolone, (12-36hrs.) triamcinolone 3. long acting (36-72hrs) dexamethasone, betamethasone 4. Inhalation: fluticasone, budesonide , beclamethasone 5. Topical: clobetasol, mometasone desonide 6. Mineralocorticoid: fludrocortisone 04/30/19 15PATKI
Steroid (free form) Cytoplasmic protein receptor Steroid receptor complex Modulation of Gene Protein synthesis Response Response 04/30/19 16PATKI
Mechanism of actions • Steroid receptor- 70 amino acid domain –Zinc finger (steroid responsive elements) • Genomic & non-genomic effects • Regulate the expressions of responsive genes • Changes the level of array of proteins • Action manifest after several hours • Membrane receptor related effect immediate • Aldosterone increase membrane protein level 04/30/19 17PATKI
Dynamics • Numerous actions & wide ranging effect • Endows capacity to resist noxious stimuli. • Synthesized and released as needed • Act at multiple sites • Permissive role- presence normal functions • Physiologic actions • Pharmacological effects • Life saving 04/30/19 18PATKI
Actions • Metabolic; • Catabolic • Mineralocorticoid • Anti-inflammatory • Anti-immune • Anti-allergic • Anti-growth • Anti-stress • Gastric acid secretion • Preservation of CVS • Skeletal muscle • Anti-vitamin-D • Renal system • CNS- neurosteroids • Delays wound healing • On blood • Uricosuric 04/30/19 19PATKI
Metabolic actions • Carbohydrate: profound effects • Protect glucose dependent tissues, brain & heart from starvation • Anti-insulin effects • Increase gluconeogenesis • Reduce glucose uptake & utilization • Steroid induces diabetes mellitus • Lipid: Cushingoid habitus increase lipolysis • Protein: catabolic action- negative nitrogen balance 04/30/19 20PATKI
Electrolyte & water excretion • Act on distal tube & collecting tubule • Retains sodium & promote K+ & H+ excretion • Reduce Ca++ level- increase excretion, reduce absorption –Anti-vitamin-D action • Fludrocortisone - synthetic potent mineralocorticoid uses: adrenocortical insufficiency severe orthostatic hypotension 04/30/19 21PATKI
CVS function • Hyperaldosterinism: Increase BP, athersclerosis, cerebral hemorrhage, stroke, hypertensive cardiomyopathy • Enhance vascular reactivity to vasoactive substances, increase cardiac fibrosis • Increase expression of adrenergic receptor in vascular wall • Hypoaldosteronism: decrease BP vascular collapse 04/30/19 22PATKI
Action on lymphocytes • Increase apoptosis • IL-1,2,3,6 TNF-alpha, Gm-CSF inhibited • Inhibit phospholipase-A2 & COX-2 • Cytokines production & release blocked • Hodgkin's lymphoma • Inextricably linked to suppression of inflammation • Multiple mechanisms 04/30/19 23PATKI
Steroidal anti-inflammatory • Inextricably linked to immunosuppressive effect • Multiple mechanisms are involved • Decreased release of vasoactive and chemoattractive factors • Reduce extravasations of leukocytes 04/30/19 24PATKI
Anti-inflammatory & immunosuppressive effect • Suppress both early & late phases • Affect pro-inflammatory cytokines generation • Synthesis –lipocortin & macrocortin • Inhibits Phospholipase- A2- C20 acid release • PGs, IL-1, Il-6, TNF- alpha , Gm-CSF • Reduce vasoactive chemoattractant release • Inhibits fibroblast proliferation-reduce fibrosis • Reduce collagenase enzymatic activity 04/30/19 25PATKI
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On skeletal muscle & blood • Muscle function – permissive concentration • Steroid myopathy- high doses • Enhance lymphocyte apoptosis • Stimulate erythropoietin secretion • Diminish destruction of erythrocytes in autoimmune hemolytic anemia • Causes polycythemia in Cushing's syndrome 04/30/19 27PATKI
Corticosteroids are Gene-Active 04/30/19 28PATKI
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.04/30/19 29PATKI
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.).04/30/19 30PATKI
Pharmacological Actions 1. Carbohydrate 2. Protein 3. Lipid 4. Electrolyte and H2O 5. CVS 6. Skeletal Muscle 7. CNS 8. Stomach 9. Blood 10. Anti-inflammatory 11. Immunosuppressant 12. Respiratory system 13. Growth and Cell Division 14. Calcium metabolism 04/30/19 31PATKI
Stress and The Adrenal Glands 04/30/19 32PATKI
Actions: Carbohydrate and protein metabolism • Gluconeogenesis – Peripheral actions (mobilize aas and glucose and glycogen) – Hepatic actions • Peripheral utilization of glucose • Glycogen deposition in liver (activation of hepatic glycogen synthase) Negative nitrogen balance and hyperglycemia 04/30/19 33PATKI
• Redistribution of Fat • Buffalo hump • Moon face • Promote adipokinetic agents activity (glucagon, growth hormone, adrenaline, thyroxine) Actions: Lipid metabolism 04/30/19 34PATKI
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 04/30/19 35PATKI
• Restrict capillary permeability • Maintain tone of arterioles • Myocardial contractility Actions: Cardiovascular system Mineralocorticoid induced hypertension ?? Na+ sensitize blood vessels to the action of catecholamines & angiotensin 04/30/19 36PATKI
Addison's disease: weakness and fatigue is due to Prolonged use: Actions: Skeletal Muscles Needed for maintaining the normal function of Skeletal muscle inadequacy of circulatory system Steroid myopathy 04/30/19 37PATKI
• Direct: – Mood – Behaviour – Brain excitability • Indirect: – maintain glucose, circulation and electrolyte balance Actions: CNS ICP (pseudotumor cerebri) - Rare 04/30/19 38PATKI
Immunosuppressive and anti-allergic actions • Suppresses all types of hypersensitivity and allergic phenomenon • At High dose: Interfere with all steps of immunological response • Causes greater suppression of Cell-mediated immunity (graft rejection and delayed hypersensitivity) • Transplant rejection: antigen expression from grafted tissues, delay revascularization, sensitisation of T lymphocytes etc. 04/30/19 39PATKI
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• Inhibit cell division or synthesis of DNA • Delay the process of healing • Retard the growth of children Actions: Growth and Cell division 04/30/19 41PATKI
• Intestinal absorption • Renal excretion • Excessive loss of calcium from spongy bones (e.g., vertebrae, ribs, etc) Actions: Calcium metabolism 04/30/19 42PATKI
• Not bronchodilators • Most potent and most effective anti-inflammatory • Effects not seen immediately (delay 6 or more hrs) • Inhaled corticosteroids are used for long term control Actions: Respiratory system 04/30/19 43PATKI
Preparations Drug Anti-inflam. Salt retaining Topical Cortisol 1 1.0 1 Cortisone 0.8 0.8 0 Prednisone 4 0.8 0 Prednisolone 5 0.3 4 Methylpredni- solone 5 0 5 Intermediate acting Triamcinolone 5 0 5 Paramethasone 10 0 - Fluprednisolone 15 0 7 04/30/19 44PATKI
Preparations Drug Anti-inflam. Salt retaining Topical Long acting Betamethasone 25-40 0 10 Dexamethasone 30 0 10 Mineralocorticoids Fludrocortisone 10 250 10 DOCA 0 20 0 04/30/19 45PATKI
Kinetics • PO, PR, i.v., im. topical, intra-articular, inhalation, instillation, epidural, intranasal, intra-lesional • Binds to transcortin 90% synthetic congeners have low affinity • Sulfate & glucuronide conjugation 04/30/19 46PATKI
Guidelines for steroid therapy • Largely empirical neither specific nor curative except replacement therapy • Dose to be determined by trial & error method and reevaluate periodically • Careful patient assessment is mandatory • A single large dose is virtually without harmful effects & be reserved for life threatening conditions • A short course therapy is unlikely to be harmful • Abrupt withdrawal may be fatal 04/30/19 47PATKI
Therapeutic uses • Diagnostic: Dexamethasone suppressant test • Replacement therapy- Addison’s disease • Life saving indications: acute Addisonian crisis, anaphylactic shock, SLE, pemphigus vulgaris, status asthmatics • Rheumatic diseases • Renal disorders • Allergy, skin, git, hepatic, ocular, malignancy 04/30/19 48PATKI
Steroids for Rheumatic diseases • Serious inflammatory disorders • SLE • Polyarteritis nodosa • Wegener's granulomatosis- granulomatosis • Churg Strauss syndrome- allergic angitis • Giant cell arteritis • Arthritis • Osteoarthritis 04/30/19 50PATKI
Steroids in Renal Ocular & Skin diseases • Nephrotic syndrome • Membranous glomerulonephritis • Ocular indications • topical as anti inflammatory effect not more than 2 weeks • Skin diseases • Pemphigus vulgaris 04/30/19 51PATKI
Prednisolone for malignancy • Acute lymphocytic leukemia & lymphoma • Rationale • Anti –inflammatory • Immunosuppressant • Stimulate erythropoietin release • Reduce hematological toxicity of co- administered cytotoxic drugs • Mild euphoria 04/30/19 52PATKI
Therapeutic uses contd… • Transplantation surgery • Auto immune hemolytic anemia • Sarcoidosis • Thrombocytopenia • Spinal cord injury • Shock? • Cerebral edema? 04/30/19 53PATKI
Therapeutic uses .. cont. • Chronic ulcerative colitis • Crohn's disease • Auto immune hepatitis • Cerebral edema 04/30/19 54PATKI
Adverse reactions • Two types:1) due to sudden withdrawal 2) due to supra physiological doses • Steroid withdrawal acute adrenal insufficiency • Malaise, fever, arthralgia, myalgia. • Pseudotumor cerebri - increased intracranial pressure with papilledema • Steroid replacement 04/30/19 57PATKI
Steroid toxicity • Cushing’s syndrome • Hypertension, Electrolyte abnormalities • Hyperglycemia, glycosuria • Supra-infection, prone for infection • Osteoporosis, avascular/aseptic osteo- necrosis, spontaneous fracture • Myopathy • Psychoses • Glaucoma, cataract 04/30/19 58PATKI
Adverse reactions….contd • Peptic ulcer • Growth arrest • Acne, hirsutism • Topical –loss of skin collagen • Inhalation: hoarseness of voice • Teratogenicity: cleft palate, altered neuronal development • Reactivation of TB 04/30/19 60PATKI
Antagonists of Adrenocortical Agents A. Synthetic inhibitors and glucocorticoid antagonists 1. Metyrapone – inhibits 11-hydroxylation, interfering with cortisol and corticosterone synthesis (0.25g BID to 1g QID) - used in tests of adrenal function (300-500mg q 4hrs. X 6doses, fed by urine collection - treat hypercorticotism: 4 g/day 04/30/19 61PATKI
2. Aminoglutethimide – blocks the conversion of cholesterol to pregnanelolone and causes a reduction in the synthesis of all hormonally active steroids; breast Ca and Cushing’s syndrome due to adrenocortical Ca: 250 mg every 6hrs. - enhances metabolism of dexamethasone 3. Trilostane - inhibits 3beta hydroxysteroid dehydrogenase 04/30/19 62PATKI
3. Ketoconazole – an antifungal imidazole derivative; potent, non-selective inhibitor of adrenal and gonadal steroid synthesis; tx of Cushing’s syndrome (200-1200mg/d) 4. Mifepristone (RU 486) – 11β-aminophenyl-substituted 19-norsteroid; has strong anti-progestin activity; blocks glucocorticoid receptor 04/30/19 63PATKI
B. Mineralocorticoid Antagonists 1. Spirinolactone – diagnosis of aldosteronism (400-500mg/day fro 4-8 days); preparing for surgery (300-40mg/day x 2 wks to reduce the incidence of arrhythmias); hirsutism in women (androgen antagonist 50-200mg/d x 2-6 mos); diuretic 2. Eplerenone 3. Drospirenone – progestin in a new oral contraceptive, antagonizes the effect of aldosterone 04/30/19 64PATKI
PATKI Drug interactions • Estrogens may decrease prednisone metabolism. • Phenobarbital, phenytoin, and rifampicin may increase metabolism of glucocorticoids • May cause digitalis toxicity secondary to hypokalemia. • Monitor for hypokalemia with co-administration of diuretics 04/30/19 65
PATKI Fludrocortisone • It is the only mineralocorticoid given orally. • It has a very great mineralocorticoid plus a significant glucocorticoid activities. • It has a long duration of action Fludrocortisone is preferred in: - Replacement therapy in Addison's disease. - to preserve sodium and treat hypotension as in cases of interstitial nephritis and autonomic neuropathy. 04/30/19 66
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