Presentation on theme: "Hormones Are chemical released by a cell or a gland in one part of the body that send out messages that affect cells in other parts of the organism. Only."— Presentation transcript:
1 HormonesAre chemical released by a cell or a gland in one part of the body that send out messages that affect cells in other parts of the organism. Only a small amount of hormones is required to alter cell metabolism.In essence, they are chemical messenger that transport a signal from one cell to another.
2 Chemical characteristics of hormones Amines (from tyrosine)hydroxylation - catecholaminesiodination - thyroid hormonesPeptides/proteinsSteroids (from cholesterol)adrenocorticoidssex hormonesactive metabolites of vitamin DEcosanoidProstaglandins
11 Eicosanoid Produced from 20-carbon fatty acid, arachidonic acid Produced in all cells except RBCsAct as 2nd messengerProstaglandins and leukotrienes are among these hormonesPlay a major role in inflammation process
12 HUMAN ORGANS OF THE ENDOCRINE SYSTEM pinealSteroid hormones are synthesisedprimarily in:Adrenal Cortex - AdrenocorticoidsOvaries , testes - Sex steroidshypothalmuspituitaryparathyroidthyroidthymusstomachadrenalSteroid secretion is generallycontrolled by peptides secretedfrom the Hypothalmus and pituitarypancreaskidneyduodenumovaryuterustestes
13 Steroidal hormones These hormones are classified as: 1.Sex hormones produced by genital glands: estrogens, progestins & androgens.2.Adrenocortical hormones:Mineralocorticoids: control salts & waterGlucocorticoids: indicated in the treatment of collagen diseases (rheumatoid arthritis), asthma, hey fever, serum sickness & various skin & eye disorders.
14 MAJOR NATURAL GLUCOCORTICOIDS Cortisol (hydrocortisone)CyclopentaperhydrophenanthreneCorticosteroneCortisone
15 MAJOR NATURAL MINERALOCORTICOIDS Aldosteronedesoxycorticosterone
16 Biosynthesis OF Mineralocorticoids and Glucocortecoids c,defg
17 ANTIINFLAMMATORY EFFECTS OF GLUCOCORTICOIDS April, Gram cortisone isolated by KendallSeptember 21, 1948 Hench administers 100mg of cortisone by intra-muscular injection to patient Mrs. G. suffering chronic Rheumatoid ArthritisSeptember 28, 1948 Mrs. G. first time in years walks downtown to go shopping.Represented a new approach to therapy with natural hormonesby utilizing a dose much higher than that naturally produced by the bodyie. pharmacological rather than physiological dose.
18 MODE OF ACTION of GLUCOCORTICOIDS IN PREVENTING INFLAMMATION Intracellular membranephospholipidsSteroid + receptorPhospholipase A2Arachidonic acidSynthesis lipocortinor annexin 1prostaglandinRepressesinducibleCOX2inhibitsRelease into cytosolor from cellINFLAMMATION
19 THERAPEUTIC APPLICATION ADRENOCORTICOIDS Glucocorticoids (GR)Agonists - adrenal insufficiency- rheumatoid disease and allergic manifestations(eg. severe asthma, rheumatoid arthritis, rheumatic fever)Palliative therapy only not curativeAntagonists - Cushings Syndrome (hyperadrenocorticism or hypercorticism).Mineralocorticoids (MR)Agonists - adrenal insufficiency, generally glucocorticoids used in thisapplicationAntagonists - Cushings syndrome- test functioning of hypothalamico-pituitary axis
20 CORTISONE PREPARATIONS Cortisone is primarily used as its 21-acetatebecause of increased stability and longerduration of actionOther 21-ester derivatives availableinclude:Oral or intramuscular dose usually25 mg 4 times dailyTopically 1 to 2.5% lotionHydrocortisone cypionate R =Hydrocortamate sodium succinateR = Na+ -OOCCH2CH2CO- (water soluble)Intraveinous emergency treatment
21 RELATIVE POTENCIES OF CORTICOSTEROIDS Compound Na+ Hepatic Antiinflammatoryretention glycogen effectdepositionCortisolCortisoneCorticosterone11-desoxycortico-steroneAldosterone ?Most natural or synthetic compounds have some activity at both GRand MR receptors
22 STRUCTURE-ACTIVITY Of GLUCOCORTICOIDS Intensive efforts for compounds with reduced mineralocorticoid activityStructure-activity for glucocorticoid activityRequired for activity3-keto group4,5-double bond11- oxygen (keto or alcohol)17-b ketol sidechain
23 SARThe steroid is a mineralocorticoid if it contains no oxygen-function at C11.Oxygen at C11 is essential for glucocorticoids and alcoholic is superior than ketonic one.Introduction of 17-α-OH increases glucocorticoid activity.Introduction of 6-α-F or 9-α-F increases both glucocorticoid & mineralocorticoid activity.Double bond at C1 increases antiinflammatory activity & decreases minerlacorticoid effects.
25 Synthetic Corticosteroids Diprofose: (R = 16-β-CH3) Betamethasone.Decadron: (R = 16-α-CH3) Dexamethasone.Kenacort: ( R = 16-α-OH) Triamcinolone.Triamcinolone acetonide is the acetone ketal with Both (OH) at C-16 & C-17.
26 Synthetic Corticosteroids 9a-bromo analogue1/3 activity of cortisone acetateGlucocorticoid activity inverselyProportional to size of 9a-halogen11 times activity of cortisone acetateFludrocortisone
27 SYNTHETIC GLUCOCORTICOIDS Prednisolone(GR 4 MR unchanged)Methylprednisolone(GR 5 MR unchanged)Rheumatoid arthritis 2-4 mg /dayGreater activity allows smaller dosesto be used reducing side effectsPrednisone and Prednisolone can be usedinterchangeablyPrednisone(GR 4 MR unchanged)
28 SYNTHETIC GLUCOCORTICOIDS betamethasone GR 35 foldFludrocortisone (GR activity 11)Rheumatic and dermatologic disordersShort period use onlyMR activity foldMR activitytriamcinolone acetonidetriamcinolone GR 5 fold20% more effective than prednisoloneUnusual toxic side effectsUsed topically for treatment ofpsoriasis and other skin conditions
29 TOXICITY OF ADRENOCORTICAL STEROIDS Prolonged usePrimarily results in fluid and electrolyte disturbanceseg. hypertension, hyperglycemia, glycosuriaIncreased susceptibility to infection including tuberculosisPeptic ulcers, osteoporosis, myopathy, central obesity, behavioraldisturbancesWithdrawal effectsProlonged adrenocorticoid use results in pituitary- adrenal suppresionThis system may take as long as 1 to 2 years to recoverPatients may need supplemental corticosteroids during this period
30 THERAPEUTIC USE OF CORTICOSTEROIDS 1. Appropriate dose in each case is determined by trial and error2. Single dose of corticosteroid is virtually without harmful effect3. A few days of usage is unlikely to produce harmful effects exceptat extreme doses.4. Prolongation of treatment increases the incidence of disabling orlife threatening effects5. Corticosteroids are neither specific or curative treatment6. Abrupt cessation of prolonged high dose treatment may induceadrenal insufficiency serious enough to be life threatening.
32 INHIBITORS OF BIOSYNTHESIS OF CORTICOSTEROIDS Metyraponeinhibits 11b-hydroxylationreactionUsed for diagnosis hypothalmus-pituitary malfunctionKetoconazoleblocks cholesterol sidechaincleavage in the adrenal(Cushings Syndrome)Trilostaneinhibits 3b-hydroxysteroid dehydrogenase(Cushings Syndrome - currently not recommended)
33 Summary1. Glucocorticoids modulate carbohydrate metabolism ie cortisol, cortisone2. Mineralocorticoids modulate water balance and Na+/K+ transportie aldosterone and desoxycorticosterone3. Biosynthesis of corticosteroids starts with cholesterol the pregnenolonethen progesterone and then final hormone4. Antiinflammatory effects of glucocorticoids mediated by inhibition ofphospholipase A2, inducible COX2 and annexin Iesterification facilitates administration6. All corticosteroids contain both glucocorticoid and mineralocorticoidactivity7. SAR for glucocorticoid activity: 3-keto, 4,5-double bond, 11-oxy, 17-b ketolall essential for activity
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