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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 Androstane Androgen
• C21 Pregnane
–Progesterone
–Adrenal hormones
Cyclo Pentano Perhydro Phenanthrine Ring
Steroid Nucleus
Pharmacology (Corticosteroids Lecture)
Pharmacology (Corticosteroids Lecture)
Cholesterol
Pregnenolone
Progesterone 17-hydroxy pregnenolone
17-hydroxy progesterone
Deoxy Cortocosteron DehydroEpiandrosterone
11-Deoxycortisol
Corticosterone Androstenedione
ALDOSTERONE CORTISOLE TESTOSTERONE
Cortisone ESTRADIOL
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
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
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
Pharmacology (Corticosteroids Lecture)
• Injectable
– Betamethasone,
– Dexamethasone
– Methylprednisolone
– Prednisolone,
– Hydrocortsone,
– Triamacinolone
• Oral
– Betamethasone,
– Dexamethasone
– Methylprednisolone,
– Prednisolone,
– Prednisone.
– Fludricortisone
• Topical
– Clobetasol
– Flucinolon
– Mometasone
– Betamethasone
• Inhalational
– Beclomethasone
– Budesonide
– Flunisolide
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
( 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 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)
Pharmacology (Corticosteroids Lecture)
Pharmacology (Corticosteroids Lecture)
• 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
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 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
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
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 )
• Immunosuppression
– Antigen Presenting ( Grafted Cells )
– Delay Vascularization
– Interfere with sensitization
– Cytotoxic T-Lymphocytes ( Decrease )
– Antibody Forming Cells ( Decrease )
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
Therapeutic Uses of Corticosteroids
Pharmacology (Corticosteroids Lecture)
Pharmacology (Corticosteroids Lecture)
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
Mineralocorticoid
Minrelocorticoids
• Natural
– 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 & 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
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
Adrenal Androgens
• DHEA …(Alternate source of Estrogen in
menopausal age )
• Androstendione
• Testosterone
Do not stimulate or support major
androgen puberty changes
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
Mineralocorticoid Antagonist
• Spironolactone ( K sparing Diuretic )
• Eplerenone ( more selective than
spironolactone, ( HTN 50-100mg/day)
• Drospirenone ( also progestin in “OCP”)
THANKS

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Pharmacology (Corticosteroids Lecture)

  • 3. DERIVATIVES OF CHOLESTEROL Carbon atoms Parent Hydrocarbon Biologically imp. compound • C18 Oestrane Oestrogen • C19 Androstane Androgen • C21 Pregnane –Progesterone –Adrenal hormones
  • 4. Cyclo Pentano Perhydro Phenanthrine Ring Steroid Nucleus
  • 7. Cholesterol Pregnenolone Progesterone 17-hydroxy pregnenolone 17-hydroxy progesterone 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. 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
  • 10. 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
  • 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 Specific Receptors •GRs •MRs Two Genes Control the formation of these receptors
  • 14. • 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
  • 15. 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)
  • 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 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 )
  • 23. • Immunosuppression – Antigen Presenting ( Grafted Cells ) – Delay Vascularization – Interfere with sensitization – Cytotoxic T-Lymphocytes ( Decrease ) – Antibody Forming Cells ( Decrease )
  • 24. 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
  • 25. Therapeutic Uses of Corticosteroids
  • 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
  • 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 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
  • 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 & 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
  • 36. Mineralocorticoid Antagonist • Spironolactone ( K sparing Diuretic ) • Eplerenone ( more selective than spironolactone, ( HTN 50-100mg/day) • Drospirenone ( also progestin in “OCP”)