2 The adrenal cortex secretes a number of steroid hormones into circulation: Glucocorticoids: cortisol (hydrocortisone).Mineralocorticoids: aldosterone.Sex hormonesI. CortisolThe major glucocorticoid in humans.controlled by ACTH secreted from the anterior pituitary.circadian rhythm peaks in early morning & troughs at midnight.95% of Cortisol circulates in blood bound to globulin; Corticosteroid binding globulin (CBG).
3 II. AldosteroneMost important mineralocorticoid (inhibits Na+ excretion & stimulates K+ & H+ excretion) with minimal glucocorticoid activity.Very important in regulating blood volume & pressure.Control of Aldosterone Secretion1. Renin-angiotensin system activation by hypovolemia & hyponatremia (most important).2. Hyperkalemia.
4 Pharmacokinetics :cortisol is bound to corticosteroid binding globulin [CBG].CBG is increased by oestrogen, decreased in cases of liver cirrhosis and nephrosis of kidney,t 1/2 is min,Metabolised in the liver,Excreted by kidneys as water soluable reduced conjuagates, about 10% is excreted as ketosteroids.
5 Mechanism of Action of Corticosteroids They enter cells where they combine with steroid receptors in the cytoplasm forming a macro molecular complex which enters the nucleus where it interacts with chromosomal constituents and alters gene expression effects on organs and tissues.
6 Pharmacological Actions Adverse Effects & Precautions I. Metabolic EffectsCarbohydrates: ↑ blood glucose: Gluconeogenesis, ↓ glucose utilization.- Hyperglycemia → diabetes.CI: diabetes.Fat Metabolism:- redistributes fat from extremities to face, abdomen & shoulders.( increase lipolysis, hyperglycemia → ↑insulin secretion →fat dep.- Moon face.- ↑ abdominal fat.- Buffalo hump - obesity.Proteins MetabolismCatabolic (↑protein breakdown) in lymphoid , connective tissues, muscle and bone (except in liver).- Muscle wasting: thin arms & legs.- Thinning of skin.- Retardation of growth (children).- Osteoporosis (↓ protein & Ca2+).Salt and Water Metabolism-↓ Ca2+ absorption from GIT.-Weak mineralocorticoid action:- ↑ Na+ reabsorption.- ↑ K+ excretion. - Osteoporosis (CI).- Edema - ↑ weight.- Hypertension - heart failure (CI).- Hypokalemic alkalosis.
7 II. Anti-inflammatory & immunosupressive ↓ VD & edema & redness of acute inflammation. *↓ Healing - ↓ fibrosis.Mechanism: ↓ Ab-Ag reaction↓ Eosinophils, macrophages, monocytes & lymphocytes conc., migration & function.Inhibit cytokine release.Inhibit phospholipase A2 → ↓ PGs, LTs, PAF.↓ COX 2 expression- Mask manifestations of inflammation.-Delay healing of wounds.- Spread of infection.CI: severe infection, e.g. TB.III. Adrenal suppressionProlonged use of high doses → ↓ ACTHSudden withdrawal → acute adrenal insufficiencyIV. GIT: ↑ HCl & pepsin - ↓ mucus.Peptic ulcer (CI).V. CNS: euphoria- behavioral changes.Psychosis - depression (CI).VI. Other effects:Glucoma, cataract, hirsutism, acne
8 Preparations of Corticosteroids A. Preparations with Primarily Glucocorticoid ActivityI. Cortisol (hydrocortisone)Disadvantages of Cortisol1. Mineralocorticoid activity.2. Short duration: (t½ dramatically in liver insufficiency).3. Poorly absorbed through normal skin (but readily absorbed through inflamed skin & mucus membrane).II. Synthetic PreparationsPrednisone - prednisolone – dexamethazone.Advantages over Cortisol1. Mineralocorticoid activity is less with prednisolone & absent with dexamethazone.2. Longer duration of action.3. More absorption through skin.
9 B. Preparations for Bronchial Asthma Beclomethazone, budesonide, fluticasone inhalationAdvantages in Asthma1. Readily penetrate airway.2. Very short half lives after entering the blood (if swallowed while being inhaled) due to extensive 1st pass metabolism so that systemic effects and toxicity are greatly reduced.
11 A. Acute Adrenal Insufficiency (Addisonian Crisis) Therapeutic UsesI. Adrenal DisordersA. Acute Adrenal Insufficiency (Addisonian Crisis)1. Saline & 5% glucose maintain fluid & salt balance & blood sugar.2. IV hydrocortisone hemisuccinate.3. Fluodrocortisone is started when total cortisol dose is to 50 mg/d.4. Treat precipitating factors, e.g. antibiotics for infection.B. Chronic Adrenal Insufficiency (Addison’s disease)1. Oral hydrocortisone: dose is during stress or surgery.2. Fluodrocortisone (orally): maintains Na+ balance & BP.
12 B. Immunosuppressants in: II. Nonadrenal DisordersA. Anti-allergic1. Bronchial asthma. 2. Allergic conditions: skin, eye, GIT.B. Immunosuppressants in:1. Autoimmune diseases: systemic lupus - rheumatoid arthritis.2. Organ transplantation, skin grafts.III. Other Uses1. Cerebral edema: VD - exudation of fluids.2. leukemia - lymphomas: lymphocytes.3. Antistress in: bleeding - trauma - septic & anaphylactic shock ( VC effect of CA - glucose level, providing energy to counteract stress).4. Hypercalcemia: vit. D activation in liver Ca2+ absorption).5- Respiratory distress lung syndrome (stimulatin of lung maturation in the fetus by stimulation of surfactant production
13 Precautions of use of glucocorticoids: I-Avoid adrenocortical suppression by using smallest doses, alternate dayschedule and gradual withdrawal.2- The dose should increased during periods of stress in chronic therapy.3- Diet should contain low Na+, high K+, high Ca++ and high proteins.4- regular examination of blood pressure, blood glucose and body weight.5-X ray spine every 6 months to detect osteoporosis.6- anabolic steroid may be given to counteract catabolic effects.7 - Never stop therapy suddenly to avoid acute adrenocortical insufficiency
14 2- Deoxycorticosterone (DOC( Mineralocorticoids1- Aldosterone:2- Deoxycorticosterone (DOC(it is potent mineralocorticoid with no glucocorticoid action used in hypoadrenal states by IM injection or as DOCA pellet sc.3-FluodrocortisoneSynthetic prep. with potent mineralocorticoid & glucocorticoid activity.used for replacement therapy in hypoadrenal states, e.g. after adrenalectomy.
15 AgentMechanismUses & SE1-Aminoglutethimideblocks the conversion of cholesterol to pregnenolone It inhibits syn. of all ster. H.with metyrapone or ketoconazole in Cushing's syndrome due to adrenocortical cancer3-Metyrapone:inhibitor of steroid 11-hydroxylation, interfering with cortisol and corticosterone synthesisdiagnostic test.Cushing disease*adverse effects are salt and water retention and hirsutism.4-Trilostane:dehydrogenase inhibitor that interferes with the synthesis of adrenal and gonadal hormonesGIT upset5-Abiraterone:blocks 17 -hydroxylase and 17,20-lyase and reduces synthesis of cortisol and gonadal steroidsrefractory prostate cancer6-Mifepristone:antiprogestin activity. High doses of mifepristone blocking the gluc. receptorinoperable patients with ectopic ACTH secretion or adrenal carcinoma7-Mitotane:cytotoxic on adrenal cortexin patients with adrenal cancer.Side effects diarrhea, nausea, vomiting, depression, somnolence,skin rashes.