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ENDOCRINOLOGY
Dr. Ashfaq Ahmad
ADRENOCORTICAL HORMONE
ADRENOCORTICOSTEROIDS
CORTICOSTEROIDS
Dr. Ashfaq Ahmad
DERIVATIVES OF CHOLESTEROL
Carbon atoms Parent Hydrocarbon Biologically imp. compound
• C18 Oestrane Oestrogen
• C19 Andro...
Cyclo Pentano Perhydro Phenanthrine Ring
Steroid Nucleus
Cholesterol
Pregnenolone
Progesterone 17-hydroxy pregnenolone
17-hydroxy progesterone
Deoxy Cortocosteron DehydroEpiandros...
C21 Steroids
SELY’S TERMINOLOGY
Glucocorticoids ( Cortisole )
– Energy metabolism
• Carbohydrate, Protein,Fat
• Mineraloco...
Adrenocortical Hormones
Z. Fasicu Z. Glomeru Z. Reticulata
Glucocorticoids Aldosterone Androgen
(Hydrocorisone) (Renin-Ang...
Steroid Preparations
• An ideal Glucocorticoid should not have
Mineralocorticoid Activity
• By structural changes (many co...
• Injectable
– Betamethasone,
– Dexamethasone
– Methylprednisolone
– Prednisolone,
– Hydrocortsone,
– Triamacinolone
• Ora...
Mechanism of Action
Specific Receptors
•GRs
•MRs
Two 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
( transcripti...
Glucocorticoid Receptor
• 800 Aminoacids
• 3 Functional Domains
– Glucocorticoid binding domain
• At carboxyl terminal of ...
• Ligand binding … conformational change … (hsp90)
• Diamerization
• Entry in nucleus
• In the Responsive Gene … promoter ...
Coregulators
Proteins (several families) are
Involved in
Interaction of ligand bound GR with GREs &
other Transcription fa...
Effects 0f Glucocorticoids
• Direct Effects
– Gluconeogenesis (Net
effect mimic Diabetes)
• Homeostatic Response
In Respon...
Therapeutic Effects/uses
• Diagnostic … dexamethasone suppression Test
• Treatment
– Defficiency
• ( HRT ( Hormone Replace...
Effects on Events of Inflammation
Dramatically reduce inflammation
suppress cytokines, chemokines,
Affect leukocytes (conc...
• Immunosuppression
– Antigen Presenting ( Grafted Cells )
– Delay Vascularization
– Interfere with sensitization
– Cytoto...
Dexamethasone Suppression
Test
• For Diagnosis of Cushing Syndrome
& Depressive Psychatric Illness
• First Screening test
...
Therapeutic Uses of Corticosteroids
COMPLICATIONS
Side effects / Toxicity
• GIT
– Peptic Ulcer
– Fatty Liver
– Pancreatitis
– Nausea, Vomiting
• Ocular
– Incr...
Mineralocorticoid
Minrelocorticoids
• Natural
– Aldosterone ( zona glomeruloza )
– Deoxycoticosterone ( DOC ) … Not used
• Synthetic
– Fludr...
Aldosterone
• Zona glomeruloza
• Relese is through ACTH ….. 50% feed
back controle on release as compared to
cortisole
• A...
Physiological & Pharmacological
Effects of Aldosterone
• Reabsorption Na from DCT, which is
loosely coupled to excretion o...
Fludrocortisone
• Potent Steroid
• Both Mineralocorticoid & Glucocorticoid activity
Oral 0.1mg, two to seven times weekly
...
Adrenal Androgens
• DHEA …(Alternate source of Estrogen in
menopausal age )
• Androstendione
• Testosterone
Do not stimula...
Synthesis inhibitors &
Glucocorticoid Antagonist
• Aminoglutethemide ( Block conversion of
cholesterol to pregnenolone )
•...
Mineralocorticoid Antagonist
• Spironolactone ( K sparing Diuretic )
• Eplerenone ( more selective than
spironolactone, ( ...
THANKS
Pharmacology (Corticosteroids Lecture)
Pharmacology (Corticosteroids Lecture)
Pharmacology (Corticosteroids Lecture)
Pharmacology (Corticosteroids Lecture)
Pharmacology (Corticosteroids Lecture)
Pharmacology (Corticosteroids Lecture)
Pharmacology (Corticosteroids Lecture)
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Pharmacology (Corticosteroids Lecture)

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Transcript of "Pharmacology (Corticosteroids Lecture)"

  1. 1. ENDOCRINOLOGY Dr. Ashfaq Ahmad
  2. 2. ADRENOCORTICAL HORMONE ADRENOCORTICOSTEROIDS CORTICOSTEROIDS Dr. Ashfaq Ahmad
  3. 3. DERIVATIVES OF CHOLESTEROL Carbon atoms Parent Hydrocarbon Biologically imp. compound • C18 Oestrane Oestrogen • C19 Androstane Androgen • C21 Pregnane –Progesterone –Adrenal hormones
  4. 4. Cyclo Pentano Perhydro Phenanthrine Ring Steroid Nucleus
  5. 5. Cholesterol Pregnenolone Progesterone 17-hydroxy pregnenolone 17-hydroxy progesterone Deoxy Cortocosteron DehydroEpiandrosterone 11-Deoxycortisol Corticosterone Androstenedione ALDOSTERONE CORTISOLE TESTOSTERONE Cortisone ESTRADIOL
  6. 6. 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
  7. 7. Adrenocortical Hormones Z. Fasicu Z. 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
  8. 8. Steroid Preparations • An ideal 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
  9. 9. • Injectable – Betamethasone, – Dexamethasone – Methylprednisolone – Prednisolone, – Hydrocortsone, – Triamacinolone • Oral – Betamethasone, – Dexamethasone – Methylprednisolone, – Prednisolone, – Prednisone. – Fludricortisone • Topical – Clobetasol – Flucinolon – Mometasone – Betamethasone • Inhalational – Beclomethasone – Budesonide – Flunisolide
  10. 10. Mechanism of Action Specific Receptors •GRs •MRs Two Genes Control the formation of these receptors
  11. 11. • 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
  12. 12. Glucocorticoid Receptor • 800 Aminoacids • 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)
  13. 13. • 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
  14. 14. Coregulators Proteins (several families) are Involved in Interaction of ligand bound GR with GREs & other Transcription factors Facilitate … (co activators) Inhibit … (co repressors)
  15. 15. 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
  16. 16. 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
  17. 17. Effects on Events of 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 )
  18. 18. • Immunosuppression – Antigen Presenting ( Grafted Cells ) – Delay Vascularization – Interfere with sensitization – Cytotoxic T-Lymphocytes ( Decrease ) – Antibody Forming Cells ( Decrease )
  19. 19. Dexamethasone Suppression Test • For Diagnosis 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
  20. 20. Therapeutic Uses of Corticosteroids
  21. 21. 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
  22. 22. Mineralocorticoid
  23. 23. Minrelocorticoids • Natural – Aldosterone ( zona glomeruloza ) – Deoxycoticosterone ( DOC ) … Not used • Synthetic – Fludrocortisone
  24. 24. Aldosterone • Zona glomeruloza • Relese is through ACTH ….. 50% feed back controle on release as compared to cortisole • Angiotensin Maintain & regulate secretion
  25. 25. Physiological & Pharmacological Effects of 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
  26. 26. 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
  27. 27. Adrenal Androgens • DHEA …(Alternate source of Estrogen in menopausal age ) • Androstendione • Testosterone Do not stimulate or support major androgen puberty changes
  28. 28. Synthesis inhibitors & Glucocorticoid Antagonist • 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
  29. 29. Mineralocorticoid Antagonist • Spironolactone ( K sparing Diuretic ) • Eplerenone ( more selective than spironolactone, ( HTN 50-100mg/day) • Drospirenone ( also progestin in “OCP”)
  30. 30. THANKS
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