Downloaded 507 times
Uploaded byAshfaq Ahmad
Pharmacology (Corticosteroids Lecture)
This document discusses adrenocortical hormones and corticosteroids. It begins by describing how corticosteroids are derived from cholesterol and the different zones of the adrenal cortex that produce glucocorticoids, mineralocorticoids, and androgens. It then covers the mechanisms of action of glucocorticoids like cortisol via glucocorticoid receptors, their therapeutic uses to treat inflammatory and autoimmune disorders, and their potential side effects. The document also discusses mineralocorticoids like aldosterone, their effects on sodium reabsorption, and synthetic alternatives like fludrocortisone. Inhibitors of corticosteroid synthesis and antagonists of mineralocorticoid receptors
More Related Content
Similar to Pharmacology (Corticosteroids Lecture)
Pharmacology (Corticosteroids Lecture)
- 1.
- 2.
- 3. DERIVATIVES OF CHOLESTEROL Carbonatoms Parent Hydrocarbon Biologically imp. compound • C18 Oestrane Oestrogen • C19 Androstane Androgen • C21 Pregnane –Progesterone –Adrenal hormones
- 4. Cyclo Pentano PerhydroPhenanthrine Ring Steroid Nucleus
- 7. Cholesterol Pregnenolone Progesterone 17-hydroxy pregnenolone 17-hydroxyprogesterone Deoxy Cortocosteron DehydroEpiandrosterone 11-Deoxycortisol Corticosterone Androstenedione ALDOSTERONE CORTISOLE TESTOSTERONE Cortisone ESTRADIOL
- 8. C21 Steroids SELY’S TERMINOLOGY Glucocorticoids( Cortisole ) – Energy metabolism • Carbohydrate, Protein,Fat • Mineralocorticoids ( Aldosterone ) – Electrolytes • Na, K, Fluid balance • Synthetic – Prednisolone – Dexamethasone – 9-a-Flourocortisole
- 9. Adrenocortical Hormones Z. FasicuZ. Glomeru Z. Reticulata Glucocorticoids Aldosterone Androgen (Hydrocorisone) (Renin-Angiotensinsystem.) ( Salt Retaining ) - DHEA, DHEAS, ( DEHYDROEPIANDROSTERONE ) -Androstenediole Source of ESTROGEN - IN Or AFTER Menopause Net effect - Defective/Absent Ovary 1. Antagonism of Insulin 2. CVS FUNCTIONS 3. GROWTH 4. immunity
- 10. Steroid Preparations • Anideal Glucocorticoid should not have Mineralocorticoid Activity • By structural changes (many compounds) – With minimal Mineralocorticoid Activity – Greater Potency – Longer duration of action – Stability … Plasma Half life – Rate of Elimination
- 12. • Injectable – Betamethasone, –Dexamethasone – Methylprednisolone – Prednisolone, – Hydrocortsone, – Triamacinolone • Oral – Betamethasone, – Dexamethasone – Methylprednisolone, – Prednisolone, – Prednisone. – Fludricortisone • Topical – Clobetasol – Flucinolon – Mometasone – Betamethasone • Inhalational – Beclomethasone – Budesonide – Flunisolide
- 13. Mechanism of Action SpecificReceptors •GRs •MRs Two Genes Control the formation of these receptors
- 14. • Alternative splicingof 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
- 15. Glucocorticoid Receptor • 800Aminoacids • 3 Functional Domains – Glucocorticoid binding domain • At carboxyl terminal of the molecule – DNA binding domain • Located in the middle, 9 cysteine Residues, Two finger structure Stabilized by Zinc ions … connected with cysteine. Form two terahedrones – Transcription activating domain • Amino terminal ( Transactivation of receptor & Increase specificity)
- 18. • Ligand binding… conformational change … (hsp90) • Diamerization • Entry in nucleus • In 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 Promoters Contribute to - Regulation of Transcription of responsive Genes - Regulation of Growth factors, proinflammotory cytokines, Antigrowth, Anti- inflammatory, Immunosuppressive effects of glucocortciods
- 19. Coregulators Proteins (several families)are Involved in Interaction of ligand bound GR with GREs & other Transcription factors Facilitate … (co activators) Inhibit … (co repressors)
- 20. Effects 0f Glucocorticoids •Direct Effects – Gluconeogenesis (Net effect mimic Diabetes) • Homeostatic Response In Response of – Insulin, Glucagon • Permissive Effects (Normal / Physiological) – Sensitization to Catacholamine Actions • Vascular SMs • Bronchial SMs • Fat Cells – Sensitization to • ACTH effects • GH effects • Fetal Lung Maturation • CVS – Steroid receptors on SMs of vessels – Direct effects on VMS – By sensitazation to catecholamines – By increasin circulating volume – Direct effects on Heart & Vessel tone B.P. Regulation
- 21. Therapeutic Effects/uses • Diagnostic… dexamethasone suppression Test • Treatment – Defficiency • ( HRT ( Hormone Replacement Therapy ) – Anti-inflammatory (all steps of inflammation are blocked ( basis of use ) • Rh. Arthritis - HIV related disorders • Br. Asthma - Shock • Hypersensitivity Reaction • Nephrotic Synd - Leukemia • SLE - Cronn’s Disease • Bell’s Palsy
- 22. Effects on Eventsof Inflammation Dramatically reduce inflammation suppress cytokines, chemokines, Affect leukocytes (conc. Dist. Function) • Infiltration of leukocytes • White cell adhesion molecules In the Blood – Neutrophils – Mono, Baso, Eosino – Lympho ( T, B )
- 23. • Immunosuppression – AntigenPresenting ( Grafted Cells ) – Delay Vascularization – Interfere with sensitization – Cytotoxic T-Lymphocytes ( Decrease ) – Antibody Forming Cells ( Decrease )
- 24. Dexamethasone Suppression Test • ForDiagnosis of Cushing Syndrome & Depressive Psychatric Illness • First Screening test – 1mg at 11 PM …. Plasma sample in morning • If more than 5mcg ( normal 3mcg) • Then Suppression With Large Doses – 0.5 mg oral 6hrly for 2 days …. Urine assay – 8mg at11PM …. Plasma cortisol in the morning
- 25. Therapeutic Uses ofCorticosteroids
- 28. COMPLICATIONS Side effects /Toxicity • GIT – Peptic Ulcer – Fatty Liver – Pancreatitis – Nausea, Vomiting • Ocular – Increased IOP – Post. Sub. Cap. Cataract • Skin – Thinning, – Achne – Hirsutism – Striae Pupura • CNS – Insomnia – Depression – Psychosis – Nervousness • Fluid & Electrolytes – Na Retension, K loss – Hypertension • GeneralMetabolic – Hyperglycemia • Musculoskeletal – Myopathy, Growth Failure – Osteopenia
- 29.
- 30. Minrelocorticoids • Natural – Aldosterone( zona glomeruloza ) – Deoxycoticosterone ( DOC ) … Not used • Synthetic – Fludrocortisone
- 31. Aldosterone • Zona glomeruloza •Relese is through ACTH ….. 50% feed back controle on release as compared to cortisole • Angiotensin Maintain & regulate secretion
- 32. Physiological & Pharmacological Effectsof Aldosterone • Reabsorption Na from DCT, which is loosely coupled to excretion of K & H ions – Receptors in cytoplasm of target cells – Drug receptor complex … MOA … As “ GC ” – This receptors has same affinity for “ GC ” – Metebolism is same as “GC” – DOC (Deoxy corticosterone ) is precursor as Aldosterone
- 33. Fludrocortisone • Potent Steroid •Both 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
- 34. Adrenal Androgens • DHEA…(Alternate source of Estrogen in menopausal age ) • Androstendione • Testosterone Do not stimulate or support major androgen puberty changes
- 35. Synthesis inhibitors & GlucocorticoidAntagonist • Aminoglutethemide ( Block conversion of cholesterol to pregnenolone ) • Ketoconazole ( antifungal.. Also block synthesis) • Metyrapone ( block cortisole & corticosterone synthesis • Trilostane ( inhibit adrenal & Gonadal hormones) • Abiraterone ( Synthesis Inhibitors ) • Mifepristone ( RU–486 )…(“GC” receptor Blocker) • Mitotane ( Cytotoxic,DDT group, less toxic for human, ORAL, toxic effect … may reduce dose, Withdrawn in USA, Available on compassionate
- 36. Mineralocorticoid Antagonist • Spironolactone( K sparing Diuretic ) • Eplerenone ( more selective than spironolactone, ( HTN 50-100mg/day) • Drospirenone ( also progestin in “OCP”)
- 37.