Adrenocorticotropic hormones

Adrenocorticotropic hormones

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  ADRENOCORTICOTROPIC HORMONES DR. RUPALI A.PATIL ASSOCIATE PROFESSOR, PHARMACOLOGY DEPARTMENT GES’S SIR DR. M. S. GOSAVI COLLEGE OF PHARMACEUTICAL EDUCATION & RESEARCH, NASHIK
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  ADRENAL GLANDS ▪ Itis located at the top or above the kidney ▪ Adrenalin, the hormone it produces. ▪ TWO PARTS ▪ Inner part :“medulla” ▪ Medulla is the source of epinephrine(adrenalin) and Non- epinephrine. Epinephrine raises blood sugar levels, cause nervousness and perspirations on acute emergencies. ▪ Sympathetic neurons innervate ▪ Outer part “cortex” ▪ Cortex releases cortisone which is essential for adapting to stress and maintaining blood sugar level and aldosterone that regulates thesalt and water balance of the body. 1
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  CortexMedulla Zona glomerulosa Zona Fasciculata Zona Reticularis Mineralocorticoids Aldosterone Glucocorticoids cortisol Sex Hormones Androgens& estrogen 2
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  ADRENAL HORMONES – Mineralcorticoids •Mostly aldosterone (retain Na+, secrete K+) – Glucocorticoids • Secreted in response to ACTH • Cortisol (hydrocortisone) is most important – Stimulate gluconeogenesis (fat and protein catabolism) – Also glycolysis – Stress response – Suppresses immune system 3
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  Hormones of theAdrenal Medulla • Hormones synthesized in adrenal medulla are: • dopamine • adrenaline/ noradrenaline (epinephrine/norepinephrine) • 80% of released catecholamine is epinephrine • Hormones are secreted & stored in the adrenal medulla & released in response to appropriate stimuli 4
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  Tyrosine (1) Tyrosine hydroxylase Dopa PLP CO2 (2)Dopa decarboxylase Dopamine (3) Dopamine hydroxylaseCu++ Vit C Norepinephrine SAM (4) N-METHYL TRANSFERASE SAH Epinephrine SAM (5) Catechol-O-methyl transferase SAH Metanephrine (6) Mono amino oxidase VMA (Vanillyl mandalic acid) (+)O2 5 Synthesis of catecholamines
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  Mechanism of Action •receptor mediated – adrenergic receptors • peripheral effects are dependent upon the type & ratio of receptors in target tissues Receptor   Norepinephrine ++++ ++ Epinephrine ++++ ++++ 6
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  DIFFERENCES BETWEEN EPINEPHRINE& NOREPINEPHRINE Epinephrine >> norepinephrine – in terms of cardiac stimulation leading to greater cardiac output ( stimulation). Epinephrine < norepinephrine – in terms of constriction of blood vessels – leading to increased peripheral resistance – increased arterial pressure. Epinephrine >> norepinephrine –in terms of increasing metabolism Epi = 5-10 x Norepinephrine 8
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  Effects of Epinephrine Metabolism: -glycogenolysis in liver and skeletal muscle • can lead to hyperglycemia - mobilization of free fatty acids - increased metabolic rate • O2 consumption increases 9
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  PHEOCHROMOCYTOMA •a catecholamine-secreting tumourof chromaffin cells of the adrenal medulla adrenal pheochromocytoma (90%) • paraganglioma – a catecholamine secreting tumour of the sympathetic paraganglia extra-adrenal pheochromocytoma 12
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  Signs and Symptomsof Pheochromocytoma • Treatment resistant hypertension (95%) • Headache • Sweating • Palpitations • Chest pain • Anxiety • Glucose intolerance • Increased metabolic rate classic triad 13
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  Diagnosis and Treatment •Diagnosed by high plasma catecholamines & increased metabolites in urine • No test for adrenal or extra-adrenal • Treatment is surgical resection 14
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  Hormones of Adrenalcortex 15
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  A. GLUCOCORTICOIDS CORTISOL :95% OF TOTAL GLUCOCORTICOID ACTIVITY 16
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  GLUCOCORTICOIDS - CORTISOL •a steroid hormone - plasma bound to corticosteroid binding globulin (CBG or transcortin) • essential for life (long term) 2hr • the net effects of cortisol are catabolic - prevents against hypoglycemia 17
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  18 Mechanism of actionof glucocorticoids
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  REGULATION OF CORTISOLRELEASE • Cortisol release is regulated by ACTH • Release follows a daily pattern - circadian • Negative feedback by cortisol inhibits the secretion of ACTH & CRH • Release increase by: • physical trauma • infection • extreme heat and cold • exercise to the point of exhaustion • extreme mental anxiety 20
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  Control of glucocorticoidsecretion 2 4 5 hypothalamus 1 3 22
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  PHARMACOKINETICS • Well absorbed& effective by oral route, except DOCA. • Absorption into systemic circulation occurs from topical sites of application as well, but the extent varies depending on the compound, site, area of application & use of occlusive dressing. • Water soluble esters, e.g. Hydrocortisone hemisuccinate, Dexamethasone sod. phosphate • i.v. / i.m., act rapidly & achieve high concentrations in tissue fluids. • Insoluble esters, e.g. Hydrocortisone acetate, Triamcinolone acetonide • cannot be injected i.v., slowly absorbed from i.m. site & produce more prolonged effects. 23
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  Metabolism The corticosteroids aremetabolized primarily by hepatic microsomal enzymes. Pathways are— (i) Reduction of 4, 5 double bond & hydroxylation of 3-keto group. (ii) Reduction of 20-keto to 20-hydroxy form. (iii) Oxidative cleavage of 20C side chain (only in case of compounds having a 17-hydroxyl group) to yield 17- ketosteroids. These metabolites are further conjugated with glucuronic acid or sulfate and are excreted in urine. 24 • Hydrocortisone : high first pass metabolism, has low oral: parenteral activity ratio. • Oral bioavailability of synthetic corticoids is high. • 90% bound to plasma protein - cortisol-binding globulin (cbg; transcortin) as well as to albumin. • Transcortin : increases during pregnancy & by oral contraceptives—corticoid levels in blood are increased but hypercorticism does not occur, because free cortisol levels are normal.
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  25 Steroid
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  26 • Plasma t½of hydrocortisone : 1.5 hours. • Biological t½ is longer because of action through intracellular receptors & regulation of protein synthesis—effects that persist long after the steroid is removed from plasma. • Synthetic derivatives are more resistant to metabolism & are longer acting. • Phenobarbitone & phenytoin induce metabolism of hydrocortisone, prednisolone & dexamethasone, etc. to decrease their therapeutic effect.
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  Actions of cortisoldepends on its plasma level: 1. Permissive Actions Its presence even at small amounts permits certain processes to occur Glycogenolysis: Glucagon & catecholamines 2. Physiological Actions Effects of the normally present hormone levels in plasma 3. Pharmacological Actions Effects of the high levels of hormone in plasma 27
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  Gluconeogenesis Glucose glycogen Glycogen 2 Glycogen phosphorylase synthase eGlucose 6-PO4 3 Glycolysis pyruvate Lipolysis Fat (T.G.) FA Glycerol Blood glucose Blood FFA 1 a.a. 28 2. Physiological actions
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  I. Effect onmetabolism II. Effect on CNS Required for normal EEG pattern III. Weak mineralocorticoid effect IV. Anti-stress effect V.C.catecholamines Permissive action Blood glucose Plasma a.a. Plasma FFA 29
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  Physiological Actions ofCortisol • promotes gluconeogenesis • promotes breakdown of skeletal muscle protein • enhances fat breakdown (lipolysis) • suppresses immune system • breakdown of bone matrix (high doses) 30
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  1. Anti-inflammatory actions 2.Anti-allergic actions Mast cell 31 3. Pharmacological actions
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  NORMAL RANGES • Aldosterone: 6 – 20 ng/ml • Corticosterone : 130- 820ng/dl • Cortisol : 9 AM 5 - 25 microgram/dl midnight 2 - 5 microgram/dl • Progesterone : 12- 30 ng/ml • Epinephrine : 10- 100pg/ml • Non-epinephrine : 70-700pg/ml 33
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  34 Pharmacological Actions 1. Metabolism 1.Carbohydrates 2. Protein 3. Lipids 2. Calcium 3. Water excretion 4. CVS 5. Skeletal muscles 6. CNS 7. GIT 8. Lymphoid tissue & blood cells 9. Inflammatory response 10.Immunological & allergic response
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  EFFECT ON BLOODCELLS AND IMMUNITY • Decrease production of eoisinophils and lymphocytes • Suppresses lymphoid tissue systemically therefore decrease in T cell & antibody production there by decreasing immunity • Decrease immunity could be fatal in diseases such as tuberculosis • Decrease immunity effect of cortisol is useful during transplant operations in reducing organ rejection. 39
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  40 Anti-inflammatory action • reducesphagocytic action of WBCs • reduces fever • suppresses allergic reactions • wide spread therapeutic use
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  ANTI-INFLAMMATORY EFFECTS OFCORTISOL 41
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  42 OTHER CORTICOIDS 1. Hydrocortisone(cortisol) 2. Prednisolone 3. Methylprednisolone 4. Triamcinolone 5. Dexamethasone 6. Betamethasone 7. Deflazacort 8. Desoxycorticosterone acetate (DOCA) it has only mineralocorticoid activity. used occasionally for replacement therapy in Addison’s disease. 9. Fludrocortisone
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  43 Systemic corticosteroids • Naturalcorticosteroids • Hydrocortisone/ Cortisol (short acting) • Cortisone • Synthetic corticosteroids • Prednisone • Methylprednisolone • Triamcinolone • Deflazacort • Dexamethasone • Betamethasone • Salt retaining activity • Fludrocortisone Intermediate acting Long acting
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  44 USES I. Replacement therapy •Acute adrenal insufficiency • Chronic adrenal insufficiency (Addison’s disease) • Congenital adrenal hyperplasia (Adrenogenital syndrome)
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  45 II. Pharmacotherapy (fornonendocrine diseases) Use in nonendocrine diseases is empirical and palliative, but may be life saving. Guidelines for use of corticosteroids • A single dose (even excessive) is not harmful • Short courses (even high dose) are not likely to be harmful in the absence of contraindications • Long-term use is potentially hazardous • Initial dose depends on severity of the disease • No abrupt withdrawal after a corticoid has been given for > 2 to 3 weeks: may precipitate adrenal insufficiency. • Infection, severe trauma, surgery or any stress during corticoid therapy—increase the dose. • Use local therapy (cutaneous, inhaled, intranasal, etc) wherever possible.
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  46 • Arthritis • Rheumatoidarthritis • Osteoarthritis • Rheumatic fever • Gout • Collagen diseases • Severe allergic reactions • Autoimmune diseases • Bronchial asthma • Status asthmaticus • Acute asthma • Severe chronic asthma • Other lung diseases Pharmacotherapeutic uses
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  47 • Infective diseases •Eye diseases • Skin diseases • Intestinal diseases • Cerebral edema • Malignancies • Organ transplantation and skin allograft • Septic shock • Thyroid storm • To test pituitary-adrenal axis function
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  48 ADVERSE EFFECTS 1. Cushing’shabitus 2. Fragile skin, purple striae—typically on thighs & lower abdomen, easy bruising, telangiectasis, hirsutism. Cutaneous atrophy localized to the site occurs with topical application as well. 3. Hyperglycaemia: may be glycosuria, precipitation of diabetes. 4. Muscular weakness: proximal (shoulder, arm, pelvis, thigh) muscles are primarily affected. Myopathy occurs 5. Susceptibility to infection: nonspecific for all types of pathogenic organisms. 6. Delayed healing: of wounds and surgical incisions. 7. Peptic ulceration: risk is doubled; bleeding and silent perforation of ulcers may occur 8. Osteoporosis: vertebrae & other flat spongy bones. Calcium supplements + vit D, Estrogen/raloxifene or androgen replacement therapy in females & males respectively. However, bisphosphonates are the most effective drugs in this regard. Avascular necrosis of head of femur, humerous, or knee joint
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  49 9. Posterior subcapsularcataract: may develop after several years of use, especially in children. 10.Glaucoma: may develop in susceptible individuals after prolonged topical therapy. 11.Growth retardation: Recombinant GH given concurrently 12. Foetal abnormalities: Intrauterine growth retardation can occur after prolonged therapy, and neurological/ behavioural disturbances in the offspring are feared. Prednisolone : safer than dexa/ beta methasone, as it is metabolized by placenta, reducing foetal exposure. 13.Psychiatric disturbances: High dose: Mild euphoria ---- manic psychosis. Nervousness, decreased sleep & mood changes. Depressive : after long-term use. 14. Suppression of hypothalamo-pituitary-adrenal (HPA) axis: malaise, fever, anorexia, nausea, postural hypotension, electrolyte imbalance, weakness, pain in muscles & joints
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  51 1. Peptic ulcer 2.Diabetes mellitus 3. Hypertension 4. Viral and fungal infections 5. Tuberculosis and other infections 6. Osteoporosis 7. Herpes simplex keratitis 8. Psychosis 9. Epilepsy 10. CHF 11. Renal failure CONTRAINDICATIONS
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  Adrenal Cortex Dysfunctions HYPOADRENALISM– Addison’s Disease • Adrenal cortex produces inadequate amounts of hormones • Caused by autoimmunity against cortices 80% • Also caused by tuberculosis, drugs, cancer •Plasma sodium decreases & may lead to circulatory collapse • Melanin Pigmentation: uneven distribution of melanin deposition in thin skin •eg. Mucous membranes, lips, thin skin of the nipples. • Treatment: • Total destruction, if untreated, could lead to death within a few days. • Treatment – small quantities of mineralocorticoids & glucocorticoids daily 52
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  HYPERADRENALISM – Cushing’sSyndrome • Caused by exogenous glucocorticoids & by tumours (adrenal or pituitary) • Zona glomerulosa tumour increases aldosterone -increased sodium, blood pressure -80% suffer from hypertension • Zona reticularis tumour increases cortisol - excess protein catabolism, redistribution of fat • Features : Buffalo torso • Redistribution of fat from lower parts of the body to the thoracic & upper abdominal areas • Moon Face • Oedematous appearance of face • Acne & hirsutism (excess growth of facial hair) 53
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  WHAT WOULD THEFEEDBACK LOOP LOOK LIKE FOR CUSHING’S SYNDROME? 54
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  CARBOHYDRATE METABOLISM “Adrenal diabetes” •Hypersecretion of cortisol results in increase blood glucose levels, up to 2 x normal (200mg/dl) • Prolonged over-secretion of insulin “burns out” the beta cells of the pancreas resulting in life long diabetes mellitus PROTEIN METABOLISM • Decrease protein content in most parts of the body resulting in muscle weakness • In lymphoid tissue – decrease protein synthesis results in suppression of immune system • Lack of protein deposition in bones can result in osteoporosis • Collagen fibers in subcutaneous tissue tear forming striae 55
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  56 • Combination ofany other drug with corticosteroids in fixed dose formulation for internal use is banned. • Metyrapone Inhibits 11-β hydroxylase in adrenal cortex and prevents synthesis of hydrocortisone so that its blood level falls → increased ACTH release → increased synthesis, release and excretion of 11- desoxycortisol in urine. Thus, it is used to test the responsiveness of pituitary and its ACTH producing capacity. • Aminoglutethimide, trilostane & high doses of the antifungal drug Ketoconazole: Inhibit steroidogenic enzymes. Ketoconazole reduces gonadal steroid synthesis as well. Use: Cushing’s disease when surgery / other measures are not an option. • Glucocorticoid antagonist / Antiprogestin: Mifepristone : In Cushing’s syndrome --- suppress the manifestations of corticosteroid excess, but blockade of feedback ACTH inhibition leads to over- secretion of ACTH → more hydrocortisone is produced, which tends to annul the GR blocking action of mifepristone. Use: Only in an inoperable cases of adrenal carcinoma & in patients with ectopic ACTH secretion. SOME IMPORTANT POINTS
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  MINERALOCORTICOIDS 57
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  • Produced inthe Zonaglomerulosa • Primary mineralocorticoid :Aldosterone • Aldosterone is secreted in response to • high extracellular potassium levels • low extracellular sodium levels • low fluid levels & blood volume. 58
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  ALDOSTERONE • Steroid hormone •Essential for life (acute) • Responsible for regulating Na+ reabsorption in the distal tubule and the cortical collecting duct • Target cells are called “principal (P) cell” - Stimulates synthesis of more Na/K-ATPase pumps 59
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  REGULATION OF ALDOSTERONERELEASE • Direct stimulators of release - increased extracellular K+ - decreased osmolarity - ACTH • Indirect stimulators of release - decreased blood pressure - decreased macula densa blood flow 61
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  EFFECTS OF ALDOSTERONE •Renal & circulatory effects (ECF volume regulation, sodium & potassium ECF concentrations) • Promotes reabsorption of sodium from the ducts of sweat & salivary glands during excessive sweat/saliva loss. • Enhances absorption of sodium from the intestine especially colon: absence leads to diarrhea. 62
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  ALDOSTERONE EFFECT ONMETABOLISM IN 3 WAYS: 1) Increases urinary excretion of potassium ions 2) Increases interstitial levels of sodium ions 3) Increases water retention & blood volume 63
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  Renin Angiotensin System 64
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  Renin-angiotensin system (RAS)or the renin-angiotensin-aldosterone system (RAAS) : a hormone system regulating blood pressure & water (fluid) balance. Low blood volume----- renin secretion by juxtaglomerular cells in the kidneys 65 Renin stimulates production of Angiotensin I Angiotensin I Angiotensin II constriction of blood vessels Aldosterone secretion increased blood pressure Reabsorption of sodium & water into the blood
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  MINERALOCORTICOID DEFICIENCY Symptoms • Waterloss : decreased ECF volume • Hyperkalemia • Hyponatremia • Mild acidosis • Increase RBC concentration • Low blood pressure: increased cardiac output 66 Kalium is the Latin word for Potassium Hypokalemia : low potassium levels in the blood & hyperkalemia : high potassium levels. Natrium is the Latin word for Sodium Hyponatremia : low levels of sodium & hypernatremia : high levels of sodium Causes • Hypo-aldosternism • Angiotensin inhibitors • Heparin therapy • Primary adrenal insufficiency • NSAIDs
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  MINERALOCORTICOID EXCESS 67 symptoms • Hypokalemia •Hypernatremia • Muscle cramp • Weakness • Excessive thirst • Micturation • High blood pressure: decreased cardiac output Causes • Tumour • Blockage of renal artery • Chronic liver disease • Heart failure • Diuretucs
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  THANKYOU 68