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ENDOCRINOLOGYDr. Ashfaq Ahmad

ADRENOCORTICAL HORMONE

ADRENOCORTICOSTEROIDS

CORTICOSTEROIDS

Dr. Ashfaq Ahmad

DERIVATIVES OF CHOLESTEROLCarbon atomsParent HydrocarbonBiologically imp. compoundC18OestraneOestrogenC19AndrostaneAndrogenC21PregnaneProgesteroneAdrenal hormones

Cyclo Pentano Perhydro Phenanthrine Ring

Steroid Nucleus

CholesterolPregnenoloneProgesterone17-hydroxy pregnenolone17-hydroxy progesteroneDeoxy CortocosteronDehydroEpiandrosterone11-DeoxycortisolCorticosteroneAndrostenedioneALDOSTERONECORTISOLETESTOSTERONE

CortisoneESTRADIOL

C21 SteroidsSELYS TERMINOLOGYGlucocorticoids ( Cortisole )Energy metabolismCarbohydrate, Protein,FatMineralocorticoids ( Aldosterone )ElectrolytesNa, K, Fluid balanceSyntheticPrednisoloneDexamethasone9-a-Flourocortisole

Adrenocortical HormonesZ. FasicuZ. GlomeruZ. ReticulataGlucocorticoidsAldosteroneAndrogen (Hydrocorisone)(Renin-Angiotensinsystem.) ( Salt Retaining )- DHEA, DHEAS, ( DEHYDROEPIANDROSTERONE )-AndrostenedioleSource of ESTROGEN- IN Or AFTER MenopauseNet effect- Defective/Absent OvaryAntagonism of Insulin

CVS FUNCTIONSGROWTHimmunity

Steroid PreparationsAn ideal Glucocorticoid should not have Mineralocorticoid Activity

By structural changes (many compounds)

With minimal Mineralocorticoid ActivityGreater PotencyLonger duration of actionStability Plasma Half lifeRate of Elimination

Injectable

Betamethasone, Dexamethasone MethylprednisolonePrednisolone, Hydrocortsone, TriamacinoloneOral

Betamethasone, Dexamethasone Methylprednisolone, Prednisolone,Prednisone. Fludricortisone

Topical

ClobetasolFlucinolonMometasoneBetamethasone

Inhalational

BeclomethasoneBudesonideFlunisolide

Mechanism of ActionSpecific ReceptorsGRsMRsTwo Genes Control the formation of these receptors

Alternative splicing of human GR Pre-mRNA generate two isoforms -- hGR alpha in human, Classic form of GRs ( transcriptionly active )--h GR beta - Not transcriptionaly active- Inhibit the effects of hormone-activated hGR alpha effects (Physiological Endogenous relevant inhibitor)Two hGR alternative transcripts have 8 translation initiation sites 16 GR alpha & GR beta Isoforms 256 homodiamers & heterodiamers

Glucocorticoid Receptor800 Aminoacids3 Functional DomainsGlucocorticoid binding domainAt carboxyl terminal of the moleculeDNA binding domainLocated in the middle, 9 cysteine Residues, Two finger structure Stabilized by Zinc ions connected with cysteine. Form two terahedronesTranscription activating domainAmino terminal ( Transactivation of receptor & Increase specificity)

Ligand binding conformational change (hsp90)DiamerizationEntry in nucleusIn the Responsive Gene promoter have receptor Element (GRE) attachment with GRE at specific site

Ligand bound receptor form complexes with other Transcription Factors (AP1, NF-KB) non GRE containing PromotersContribute to - Regulation of Transcription of responsive Genes- Regulation of Growth factors, proinflammotory cytokines, Antigrowth, Anti-inflammatory, Immunosuppressive effects of glucocortciods

Coregulators

Proteins (several families) are

Involved in

Interaction of ligand bound GR with GREs & other Transcription factors

Facilitate (co activators)Inhibit (co repressors)

Effects 0f GlucocorticoidsDirect EffectsGluconeogenesis (Net effect mimic Diabetes) Homeostatic ResponseIn Response ofInsulin, GlucagonPermissive Effects (Normal / Physiological)Sensitization to Catacholamine ActionsVascular SMsBronchial SMsFat CellsSensitization toACTH effectsGH effects

Fetal Lung Maturation

CVSSteroid receptors on SMs of vesselsDirect effects on VMSBy sensitazation to catecholaminesBy increasin circulating volumeDirect effects on Heart & Vessel toneB.P. Regulation

Therapeutic Effects/usesDiagnostic dexamethasone suppression TestTreatmentDefficiency( HRT ( Hormone Replacement Therapy )Anti-inflammatory (all steps of inflammation are blocked ( basis of use )Rh. Arthritis- HIV related disordersBr. Asthma- ShockHypersensitivity ReactionNephrotic Synd- LeukemiaSLE- Cronns DiseaseBells Palsy

Effects on Events of InflammationDramatically reduce inflammationsuppress cytokines, chemokines, Affect leukocytes (conc. Dist. Function)

Infiltration of leukocytesWhite cell adhesion moleculesIn the BloodNeutrophils Mono, Baso, EosinoLympho ( T, B )

ImmunosuppressionAntigen Presenting ( Grafted Cells )Delay VascularizationInterfere with sensitizationCytotoxic T-Lymphocytes ( Decrease )Antibody Forming Cells ( Decrease )

Dexamethasone Suppression TestFor Diagnosis of Cushing Syndrome& Depressive Psychatric IllnessFirst Screening test1mg at 11 PM . Plasma sample in morningIf more than 5mcg ( normal 3mcg)Then Suppression With Large Doses0.5 mg oral 6hrly for 2 days . Urine assay8mg at11PM . Plasma cortisol in the morning

Therapeutic Uses of Corticosteroids

COMPLICATIONSSide effects / ToxicityGITPeptic UlcerFatty LiverPancreatitisNausea, Vomiting OcularIncreased IOPPost. Sub. Cap. CataractSkinThinning, AchneHirsutismStriae PupuraCNSInsomniaDepressionPsychosisNervousnessFluid & ElectrolytesNa Retension, K lossHypertensionGeneralMetabolicHyperglycemiaMusculoskeletalMyopathy, Growth FailureOsteopenia

Mineralocorticoid

MinrelocorticoidsNatural

Aldosterone ( zona glomeruloza )Deoxycoticosterone ( DOC ) Not used

Synthetic

Fludrocortisone

Aldosterone

Zona glomeruloza

Relese is through ACTH .. 50% feed back controle on release as compared to cortisole

Angiotensin Maintain & regulate secretion

Physiological & PharmacologicalEffects of AldosteroneReabsorption Na from DCT, which is loosely coupled to excretion of K & H ions

Receptors in cytoplasm of target cellsDrug receptor complex MOA As GC This receptors has same affinity for GC Metebolism is same as GCDOC (Deoxy corticosterone ) is precursor as Aldosterone

Fludrocortisone Potent SteroidBoth Mineralocorticoid & Glucocorticoid activity

Oral 0.1mg, two to seven times weekly( potent salt retaining activity )Used in INSUFFICIENCY

Dose is too small to have anti inflamatory, or antigrowth activity

Adrenal AndrogensDHEA (Alternate source of Estrogen in menopausal age )AndrostendioneTestosterone

Do not stimulate or support major androgen puberty changes

Synthesis inhibitors & Glucocorticoid Antagonist

Aminoglutethemide ( Block conversion ofcholesterol to pregnenolone )Ketoconazole ( antifungal.. Also block synthesis)Metyrapone ( block cortisole & corticosterone synthesisTrilostane ( inhibit adrenal & Gonadal hormones)Abiraterone ( Synthesis Inhibitors )

Mifepristone ( RU486 )(GC receptor Blocker)

Mitotane ( Cytotoxic,DDT group, less toxic for human, ORAL, toxic effect may reduce dose, Withdrawn in USA, Available on compassionate

Mineralocorticoid AntagonistSpironolactone ( K sparing Diuretic )Eplerenone ( more selective than spironolactone, ( HTN 50-100mg/day)Drospirenone ( also progestin in OCP)

THANKS