Regulation, Mode of action, pharmacokinetics, therapeutic agents, replacements therapy of glucocorticoids & mineralocorticoids.

1. Molecular & Cellular Pharmacology &
Mechanism of Action of Corticosteroids
By
Samiksha Tukaram Hamane.
M Pharm (Sem II)

2. Content
 Introduction
 Anatomy
 Biosynthesis of adrenal hormone
 Basal secretion
 Regulation & synthesis
 Glucocorticoids – MOA
 Action of mineralocorticoids
 Pharmacokinetics of glucocorticoids
 Therapeutic agent
 Replacement therapy
 Adverse effect
 Contraindication

3. Introduction
Corticosteroids are hormone produced in cortex of adrenal gland.
At least two of these groups – Glucocorticoids and Mineralocorticoids are necessary for life .
Corticosteroids or corticoids refer to natural glucocorticoids and mineralo-corticoids and their
synthetic analogues.
Corticoids are 21 carbon compound chain with steroid nucleus.

4. Anatomy
An inner medulla, is a source is a source of catecholamine
– adrenaline and nor-adrenaline
develops from ectoderm (neural crest)
An outer cortex, which secretes several classes of steroid
hormones including steroid hormones including
Glucocorticoids and Mineralocorticoids
Three different concentric zones of cells that differ in
major steroid hormones they secrete.
1. Zona glomerulosa – mineralocorticoids
2. Zona fasciculata – glucocorticoids
3. Zona reticularis – androgen precursors
Cortex develops from mesoderm

5. Adrenal Cortex
The adrenal cortex is a factory of steroid hormones 10-30 different steroids are synthesized from
this tissue, but two classes are of importance
Mineralocorticoids – aldosterone (z. glomerulosa) – sodium, potassium and water homeostasis
Glucocorticoids – hydrocortisone or cortisol and corticosteroids – glucose and many other
homeostasis.

6. Biosynthesis of Adrenal Hormone

7. Basal secretion
Group Hormone Daily
Glucocorticoids Cortisol 5-30mg
Corticosterone 2-5mg
Mineralocorticoids Aldosterone 5-150mcg
11- deoxycorticosterone trace

8. Regulation & Synthesis
Synthesized and released under influence of
ACTH and Pituitary.
Regulated by CRH from hypothalamus and by
feedback levels of blood concentrations

9. Glucocorticoids MOA
They are nuclear receptors but present in
inactivate form & found in cytoplasm.
There are 3 domain binding sites
1. Glucocorticoid binding domain
2. DNA binding domain
3. Transcription binding domain

10. Action of Mineralocorticoids
Aldosterone is the prototype of mineralocorticoid effects
Acts on the distal tubule to enhance absorption of Na+
Increase excretion of K+ and H
Similar effects occur in colon, sweat gland and salivary gland
Deficiency of mineralocorticoid action leads to –
 Dilutional hyponatremia
 Hyperkalemia
 Acidosis
 Massive loss of Na+ and decreased EFC volume (essential for survival)

11. Hyperaldosteronism:
Positive Na+ balance
expansion of ECF
increased plasma Na
Hypokalaemia
Alkalosis
progressive rise in BP – hypertension
myocardial fibrosis

12. Glucocorticoid Actions - Carbohydrate &
protein metabolism
Profound effect on carbohydrate and protein metabolism aimed at protecting glucose dependent
tissues (brain and heart)
Promotes glycogen deposition in liver and stimulate it to form glucose from amino acids –
gluconeogenesis
In peripheral tissues decreases utilization of glucose, increase protein breakdown and activate
lipolysis - form amino acids and glycerol for gluconeogenesis A
All these results in –
Diabetes like stat resistant to insulin - increased glucose release from liver + decreased peripheral
glucose utilization
Negative Nitrogen balance (catabolic effect) - amino acid used up in gluconeogenesis - increased
urea production

13. Fat metabolism
Redistribution of fats in different areas of the body
Due to permissive facilitation of effects of other agents - GH, glucagons, ADR, thyroxine and
insulin
Deposition of fats in face, neck and shoulder - moon face/buffalo hump
Glucocorticoids facilitated hormone sensitive lipolysis action of GH and ADR + Glucocorticoids
mediated increased insulin = net result is insulin mediated lipogenesis and fat deposition
Peripheral adipocytes are less sensitive to insulin, but in face and neck predominant action - fat
deposition

14. Actions of Glucocorticoids
Water excretion: Glucocorticoids play important role in maintaining normal GFR - in adrenal
insufficiency capacity to excrete water is lost - water intoxication
Calcium Balance: Decrease absorption of Ca++ in GIT and increased excretion - calcium
depletion – osteoporosis
Skeletal muscle: Normal muscular activity needs Glucocorticoids at its optimum level.
Excess level leads to muscular weakness and wasting
Muscular weakness occurs in both Hypocorticism (due to hypodynamic circulation) and
hypercorticism - due to hypokalaemia

15. Actions of Glucocorticoids
CVS: Permissive role on pressor effect with ADR and angiotensin
• Maintain tone of arterioles and myocardial contractility
• Adrenal insufficiency leads to low cardiac output and arteriolar dilatation and poor response to
adrenaline
• Cardiovascular collapse - along with mineralocorticoids
Blood and lymphoid tissues:
• Destruction of lymphoid tissue - modest in normal persons
• In presence of malignancy of lymphatic cells - lytic actions are significant (apoptosis) - used in
lymphomas
• Minor effects on hemoglobin and RBCs - protect against hemolysis of RBCs - Increase in number of
RBCs
• Decreases the numbers of circulating lymphocytes, monocytes, eosinophils and basophils but increase
polymorphs

16. Actions of Glucocorticoids
Central Nervous System : Mild euphoria, increased motor activity
• Insomnia, hypomania or depression
• Apathy, depression and psychosis in Addison's disease.
• Maintenance of perceptions and excitability of neurons
• Lowers seizure threshold

17. Glucocorticoids - anti-inflammatory and
immunosuppressive effects
o Suppress inflammatory response to all noxious stimuli: Pathogens, chemical, physical and
immune mediated stimuli, hypersensitivity
o Underlying cause of disease is not corrected
o Reduction in cardinal signs of inflammation
o Anti-inflammatory effects are non-specific and covers all components of inflammation:
o Effects on concentration, distribution and functions of peripheral leukocytes - increased
neutrophils & their activity
o In macrophages: reduction of arachidonic acid metabolites (mediators) like PG, LT and PAF
synthesis that results from activation of phospholipase A2
o Basis of exogenous use of most clinical uses

18. Immunosuppressive & anti-allergic
actions
o Suppresses all types of hypersensitivity & allergic phenomenon
o At High dose: Interfere with all steps of immunological response
o Causes greater suppression of CMI (graft rejection & delayed hypersensitivity)
o Transplant rejection: antigen expression from grafted tissues, delay revascularization,
o ↓sensitisation of T lymphocytes etc.

19. Glucocorticoids – Pharmacokinetics
o Therapeutically given by various routes - orally, IM, IV, topically
o Hydrocortisone undergoes high first pass metabolism
o Oral bioavailability of synthetic corticoids is high
o Both, endogenous and therapeutically administered GC are bound to Corticosteroid Binding
Globulin (CBG)
o Synthetic steroids have to undergo reduction in liver to active compounds
o Metabolized in liver and excreted in urine
o Exogenously administered hydrocortisone has t1/2 of 1.5 hrs

20. Important agents
Injectable:
o Dexamethasone
o Methylprednisolone
o Betamethasone
o Prednisolone
o Hydrocortisone
o Triamcinolone
Oral:
o Betamethasone
o Fludricortisone
o Prednisolone
o Prednisone
o Methylprednisolone

21. Important agents
Topical:
o Betamethasone
o Flucinolone
o Clobetasol
o Mometasone
Inhalation:
o Beclomethasone
o Flunisolode
o Budesonide

22. Corticosteroids
Glucocorticoids
Short acting
Hydrocortisone
Intermediate acting
Prednisolone
Methyl prednisolone
Deflazacort
Long acting
Dexamethasone
Betamethasone
Mineralocorticoids
Deoxycorticosterone acetate
(DOCA)
Fludrocortisone
Aldosterone

23. HYDROCORTISONE
o Rapid but short acting with significant Mineralocorticoid activity
o Used for replacement therapy, shock
o Status asthmaticus and adrenal insufficiency
o Topically and as enema for ulcerative colitis

24. PREDNISOLONE
o More potent than hydrocortisone, more GC activity
o Intermediate duration of action
o Less HPA axis suppression
o Used for allergic, inflammation
o Autoimmune diseases, malignancy

25. METHYLPREDNISOLONE
o More potent and more selective
o Retention enema in ulcerative colitis
o Pulse therapy in non responsive RA
o Renal transplant, pemphigus
o Minimal suppression of HPA axis.

26. FLUDROCORTISONE
o Potent mineralocorticoid having some GC activity
o Replacement therapy in Addison's disease
o Congenital adrenal hyperplasia
o Idiopathic hypotension

27. Therapeutic Uses
o Physiologic doses of corticosteroids are used for replacement therapy
o Supraphysiologic doses are used for their anti- inflammatory effects
o Immunosuppressive effects in organ transplant patients and those with autoimmune disorders

28. Replacement Therapy
Adrenal insufficiency - acute/chronic
Abrupt withdrawal of steroid therapy
Chronic infections – Tuberculosis
Autoimmune adrenal disease
Surgery, Haemorrhage and AIDS
Cortisol Congenital adrenal hyperplasia
Congenital disorder due to deficiency of 21- hydroxylse enzyme - no cortisol but ACTH –
increased androgen production

29. Acute adrenal insufficiency
IV replacement of sodium chloride and fluid
IV hydrocortisone 100 mg stat followed by 100 mg every 8 Hrs - maximal daily rate of
secretion(alternatively, dexamethasone can be used)
Chronic adrenal insufficiency
Hydrocortisone
Prednisolone or dexamethasone long acting
Fludrocortisone for mineralocorticoid effects
Congenital adrenal hyperplasia
Hydrocortisone 0.6 mg/kg in divided doses - to maintain feedback suppression

30. Anti-inflammatory Uses
o For suppression of inflammatory components in Rheumatoid arthritis as adjuvant with NSAIDs
in severe cases
o Osteoarthritis - NSAIDs, intra-articular injection
o Rheumatic fever - severe cases with carditis and CHF
o Gout - NSAID failed cases and colchicine failed cases intra-articular injection
o Vasculitis disorders: Polyarteritis nodosa

31. Intra-articular steroids
o Can be used in inflammatory & non inflammatory diseases
o Knee joint
o Shoulder joint
o Tennis

32. Autoimmune disease
o Autoimmune haemolytic anaemia
o Idiopathic thrombocytopenic purpura
o Active chronic hepatitis, alcoholic hepatitis
(prednisolone 1-2 mg/kg/day given till remission followed by gradual withdrawal or low dose
maintenance)

33. Renal diseases
o Nephrotic syndrome in children
o Renal disease secondary to SLE
o Renal sarcoidosis
o Glomerulonephritis - membranous type
(Life saving importance - usually given in large doses followed by tapering to maintenance dose)

34. Organ Transplant
o Combined with other immunosuppressants - cyclosporin, azathioprine
o For prolonged use:
Prednisolone or methylprednisolone are used - Intermediate duration of action
- Can be easily tapered
- Can be converted to an alternate regime

35. Allergic Disorders
o Exhibit a delayed response in allergies (1-2 hrs even in IV injection)
o In anaphylaxis, angioneurotic oedema and serum sickness etc. - adrenaline is the choice
o Seasonal allergies, bee sting, drug allergies - Allergic reactions can be suppressed by
corticosteroids as supplements
o Intranasal administration in allergic rhinitis - budesonide and flunisolide

36. Infectious Diseases
Indicated only in severe infective diseases to tide over crisis or present complications
o AIDS and pneumocystis carinii pneumonia
o In haemophilus influenza meningitis to reduce neurological complications
o Tubercular meningitis
o Lepra reaction
o Septicaemia

37. Skin disease
o The largest application of steroid therapy
o Topical forms are widely used in many eczematous skin diseases
o Systemic therapy are also required and may be life saving in - Pemphigus vulgaris
- Exfoliative dermatitis
- Stevens-Johnson syndrome

38. Bronchial Asthma
The increased recognition of the immunological and inflammatory nature of Bronchial asthma
has led to the use of corticosteroids
In severe asthma attacks
o IV hydrocortisone
o Methylprednisolone
o Oral prednisolone
Acute attacks:
Inhaled beclmethasone, budesonide, flunisolide alone or combined with beta-2
agonists/ipratropium
Oral steroids

39. GIT
o Inflammatory conditions of intestine like
o Ulcerative colitis
o Crohn's disease
o Coeliac disease
(oral therapy or retention enema with hydrocortisone)May mask the major complications like
perforation and peritonitis

40. Other uses
o Antiemetic - with ondansetron
o Acute mountain sickness
o Aspiration pneumonia, pulmonary oedema from drowning
o Hyperthyroidism - thyroid storm

41. Adverse effect
Mineralocorticoids
o Sodium and water retention
o Edema
o Hypokalemic alkalosis
o Progressive rise in bp

42. Glucocorticoids
o Cushing’s habitus
o Fragile skin, purple striae
o Hyperglycemia
o Muscular weakness
o Delayed healing
o Susceptibility
o Peptic ulceration
o Glaucoma
o Posterior sub capsular cataract
o Growth retardation
o Foetal abnormality
o Psychiatric disturbance
o HPA axis suppression

43. Contraindication
o Peptic ulcer
o Diabetes mellitus
o Hypertension
o Viral & fungal infections
o Tuberculosis
o Osteoporosis
o Herpes simple keratitis
o Psychosis
o Epilepsy
o Congestive heart failure
o Renal failure

44. Thank You.