Corticosteroids Pharmacology - drdhriti
Upcoming SlideShare
Loading in...5
×

Like this? Share it with your network

Share

Corticosteroids Pharmacology - drdhriti

  • 4,601 views
Uploaded on

A power point presentation on Corticosteroids suitable for reading by undergraduate medical students.

A power point presentation on Corticosteroids suitable for reading by undergraduate medical students.

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
No Downloads

Views

Total Views
4,601
On Slideshare
4,594
From Embeds
7
Number of Embeds
1

Actions

Shares
Downloads
516
Comments
3
Likes
4

Embeds 7

http://study.myllps.com 7

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide
  • Addison’s disease is named after Dr. Thomas Addison – adrenal insufficiency. It was described by Harvey Cushing in 1932. [2] [3] - also called hyperadrenocorticism or hypercorticism )
  • Bring about a series of reactions to form steroids. Corticoids are 21 carbon compounds having cyclopentanoperhydrophenanthrene nucleus
  • In absence lipolytic hormones hydrocortisone does not cause lipolysis Adrenaline and noradrenaline do not cause lipolysis in absence of glucocorticoids
  • Principal action is to enhance Na+ reabsorption in distal tubule
  • Glucocorticoids have dose related important effects in carbohydrate, protein, fat metabolism but these effects are also responsible for some its serious adverse effects. Because of release of glucose in blood insulin is released in peripheral tissues and inhibit uptake of glucose by muscles
  • An enzyme that inhibits the activity of phospholipase A2. Lipocortins are activated by glucocorticoids.
  • Decrease movement of neutrophils from blood vessels and increased activity of neutrophils and macrophages by altering the gene transcription of CAM and cytokines Decrease movement of neutrophils from blood vessels and increased activity of neutrophils and macrophages by altering the gene transcription of CAM and cytokines
  • DOCA – only mineralocorticoid activity, used occasionally in addison`s disease for replacement therapy Sub lingual route 2.5 to 5 mg)
  • Bell's palsy or idiopathic facial paralysis [1] is a dysfunction of cranial nerve VII (the facial nerve ) that results in inability to control facial muscles on the affected side. Several conditions can cause a facial paralysis , e.g., brain tumor , stroke , and Lyme disease . However, if no

Transcript

  • 1. Corticosteroids Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
  • 2. Steroids Steroids are fast catching up with antibiotics as the most abused class of drugs today High doses of corticosteroids and other immunosuppressive agents may cause AIDS
  • 3. Introduction
    • The adrenal produces various classes of hormones, each of which aid in dealing with the stress faced by animals and people almost daily
    • At least two of these groups –
    • Glucocorticoids and Mineralocorticoids
    • are necessary for life
    • Corticosteroids or corticoids refer to natural
    • gluco- and mineralo-corticoids and their
    • synthetic analogues
  • 4. Contents
    • History and Biosynthesis
    • Mechanism of action
    • Physiological and Pharmacological actions
    • Pharmacokinetics and preparations
    • Uses – therapeutic and diagnostic
    • Dosage schedule and withdrawal
    • Adverse reactions and contraindications
    • Precautions during therapy
    • Contraindications
  • 5. History
    • 1855 – Addison`s disease
    • 1856 – Adrenal glands essential for life
    • 1930 – Cortex > medulla
    • 1932 – Cushing’s syndrome
    • 1952 – Aldosterone
  • 6. Anatomy
    • An inner medulla, is a source of catecholamine – adrenaline and nor-adrenaline
    • Chromaffin cell is the principal cell type
    • Medulla is richly innervated by sympathetic fibres and is considered as extension of sympathetic nervous system
    • Medulla develops from ectoderm (neural crest)
    • An outer cortex, which secretes several classes of steroid hormones including Glucocorticoids and Mineralocorticoids
    • Three different concentric zones of cells that differ in major steroid hormones they secrete
    • Cortex develops from mesoderm
  • 7. 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
    Adrenal cortex also produces sex steroids – Androgens, Dehydroepiandrosterone (DHEA) – z. reticularis Glucose and many other homeostasis Hydrocortisone or cortisol (z. fasciculata) Corticosterone Glucocorticoid Na, K and water homeostasis Aldosterone (z. glomerulosa) Mineralocorticoid Physiological effect Prototype Steroid Class
  • 8. Biosynthesis
    • Synthesized from cholesterol through a series of enzyme-mediated transformations
    • ACTH stimulates adrenal steroid synthesis
    • Aldosterone synthesis is not stimulated by ACTH but by angiotensin II, although ACTH does stimulate synthesis of aldosterone precursors
    • Circulating Potassium exerts a permissive effect on angiotensin II stimulation; high potassium enhances and low potassium diminishes
  • 9. Steroid Biosynthesis - contd.
  • 10. Basal Secretion 15 – 30 mg 0.4 – 0.8 mg Trace DHEA Progesterone Oestradiol Sex Hormones Androgen Progestogen Oestrogen 5 – 150 mcg Trace Aldosterone 11- deoxycorticosterone Mineralocorticoids 5 – 30 mg 2 – 5 mg Cortisol Corticosterone Glucocorticoids Daily Hormone Group
  • 11. Regulation of Synthesis
    • Synthesized and
    • released under
    • influence of ACTH - Ant.
    • Pituitary (HPA axis)
    • • Regulated by CRH
    • from hypothalamus
    • and by feedback
    • levels of blood concentrations
  • 12.
    • Control by circadian rhythm (Diurnal rhythm) – morning rise
    • Stress: hypoglycaemia, physical stress etc.
    Regulation of Synthesis - Others
  • 13. Diurnal variation of Cortisol
  • 14. Glucocorticoids - MOA
    • Not stored:
      • rate of synthesis = rate of release
    • Synthesize rhythmically and controlled by irregular pulses of ACTH, influenced by light and major pulses occur early in the morning and after meals
    • Glucocorticoids act via their receptors located in nucleus (GR)
    • GRs are widely distributed and located almost in all cells of the body
    • They are made up of almost 800 amino acids
  • 15. Glucocorticoids - MOA
    • GR receptors are located in the cytoplasm
    • One GR receptor has a DNA binding domain and a ligand binding domain along with stabilizing proteins (HSP 90 and HSP 70)
    • This receptor is incapable of activating transcription
    • Binding of free steroid molecule to GR forms an unstable compound
    • Therefore HSP and other proteins get dissociated
    • The S+GR complex enters the nucleus and binds to Glucocorticoids response element (GRE) on gene and regulate transcription by RNA polymerase II and others
    • The resulting mRNA is transported to cytoplasm for production of protein and bring about final response
  • 16. Glucocorticoids - MOA
  • 17. Actions
    • Numerous and widespread actions:
    • Carbohydrate, lipid and protein metabolism
    • Fluid and electrolyte balance
    • Normal functioning of CVS, immune system, kidneys, skeletal muscles and nervous system
    • Provides resistance to stress and noxious stimuli and environmental changes
    • Permits and facilitates the actions of other hormones
    • Direct Actions
    • Permissive Actions
        • Lipolytic effects
        • Effect on BP
        • Effect on bronchial muscles
        • (e.g.,sympathomimetic amine)
  • 18. Actions of Corticosteroids - Mineralocorticoid
    • 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 hyponatraemia, hyperkalamia, acidosis, massive loss of Na+ and decreased EFC volume (essential for survival)
    • Hyperaldosterinism: Positive Na+ balance, expansion of ECF, increased plasma Na, hypokalaemia, alkalosis and progressive rise in BP – hypertension, myocardial fibrosis etc.
  • 19. 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
    • 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
      • Mobilization of amino acids – muscles, thinning of bone and skin
  • 20. Actions: Carbohydrate and protein metabolism
    • Gluconeogenesis
      • Peripheral actions (mobilize AA & glucose and glycogen)
      • Hepatic actions
    • Peripheral utilization of glucose
    • Glycogen deposition in liver
        • (activation of hepatic glycogen synthase)
    Negative nitrogen balance & hyperglycaemia
  • 21. 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
  • 22. 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
    • CNS:
      • Euphoria – in pharmacological doses
      • Addison's disease – apathy, depression and psychosis
      • High doses – induce seizure
  • 23. 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 (Basis of Use)
      • Minor effects on haemoglobin and RBCs – protect against haemolysis of RBCs – Increase in number of RBCs
      • Decreases the numbers of circulating lymphocytes, monocytes, eosinophils and basophils but increases Polymorphs
  • 24. Glucocorticoids – anti-inflammatory and immunosuppressive effects
    • Suppress inflammatory response to all noxious stimuli: Pathogens, chemical,physical and immune mediated stimuli, hypersensitivity
    • Underlying cause of disease is not corrected
    • Reduction in cardinal signs of inflammation
    • Anti-inflammatory effects are non—specific and covers all components of inflammation:
      • Effects on concentration, distribution and functions of peripheral leukocytes – increased neutrophils & their activity
      • In macrophages: reduction of arachidonic acid metabolites (mediators) like PG, LT and PAF synthesis that results from activation of phospholipase A2
      • Basis of exogenous use of most clinical uses
  • 25. Glucorticoids - Multiple Mechanisms
    • Recruitment of WBC & monocyte - macrophage into affected area & elaboration of chemotactic substances
    • Lipocortin : decreased production of PG, LT and PAF
    • Negative regulation of COX 2: inducible PG production
    • Negative regulation of genes in cytokines of macrophages, endothelial cells and lymphocytes:
    • production of IL (1, 2, 3, 6), TNF α , GM-CSF etc. – fibroblast proliferation and T-lymphocyte function – interference with chemotaxis
  • 26. Contd.
    • In endothelial cells-Endothelial leucocyte adhesion molecule (ELAM) and other CAM are inhibited – adhesion and localization of leucocytes interfered
    • Release of histamine from basophils is inhibited
    • Decreased production of collagenase – prevention of tissue destruction
    • Decreased functioning of osteoblasts and increased activity of osteoclastic activity - osteoporosis
    • Decreased IgG production
    • Decreased generation of induced nitric oxide
  • 27. Phospholipids Arachidonic acids lipoxygenase Cycylooxygenase Leukotriene Prostaglandins, Thromboxane Prostacyclins Phospholipase A2 Lipocortin Corticosteroids PAF by lipocortin
  • 28. Immunosuppressive & anti-allergic actions
    • Suppresses all types of hypersensitivity & allergic phenomenon
    • At High dose: Interfere with all steps of immunological response
    • Causes greater suppression of CMI (graft rejection & delayed hypersensitivity)
    • Transplant rejection: antigen expression from grafted tissues, delay revascularization, sensitisation of T lymphocytes etc.
  • 29. Glucocorticoids – Anti-inflammatory and Immunosuppressive effects
  • 30. Glucocorticoids - Pharmacokinetics
    • Therapeutically given by various routes – orally, IM, IV, topically
    • Hydrocortisone undergoes high first pass metabolism
    • Oral bioavailability of synthetic corticoids is high
    • Both, endogenous and therapeutically administered GC are bound to Corticosteroid Binding Globulin (CBG)
    • Synthetic steroids have to undergo reduction in liver to active compounds
    • Metabolized in liver and excreted in urine
    • Exogenously administered hydrocortisone has t1/2 of 1.5 Hrs
  • 31. Steroid Preparations
    • An ideal GC should have no mineralocorticoid activity
    • Structural changes to the basic cortisol molecule resulted in a number of compounds with
      • Minimal mineralocorticoid activity
      • Greater potency
      • Longer duration of action
  • 32. Important agents
    • Injectable:
      • Betamethasone Dexamethasone
      • Prednisolone Methylprednisolone
      • Hydrocortisone Triamcinolone
    • Oral:
      • Betamethasone Fludricortisone
      • Prednisolone Prednisone
      • Methylprednisolone
    • Topical:
      • Betamethasone Clobetasol
      • Flucinolone Mometasone
    • Inhalation:
      • Beclomethasone Budesonide
      • Flunisolode
  • 33. Chemical Structures Pharmaceutical steroids are usually obtained from “ cholic acid” (obtained from cattle) or sapogenins found in plants of Liliacaceae
  • 34. Cyclopentanoperhydrophenanthrene skeleton Rings are labeled as A, B, C and D. Natural steroids have two methyls Numbering of each position essentially follows a uniform pattern except for the methyls.
  • 35. Relative Activity 2.5 (S. lingual) 100 0 MC Desoxycortisone acetate (DOCA) NU 500 - 3000 0.3 MC Aldosterone 0.75 0 25 LA Betmethasone 0.75 0 25 LA Dexamethasone 4 0 5 IA Triamcinolone 4 0.5 5 IA Methyl Prednisolone 5 0.8 4 IA Prednisolone 20 1 1 SA Hydrocortisone Equivalent dose (mg) MC GC Duration Compound
  • 36. Corticosteroids - Clinical Pharmacology
  • 37. Therapeutic uses
    • A number of diverse disease states respond to GCs
    • Physiologic doses of Corticosteroids are used for replacement therapy in primary and secondary adrenal insufficiency such as Addison`s disease
    • Supraphysiologic doses are used for their anti-inflammatory effects in arthritis, asthma and inflammatory bowel disease
    • In organ transplant patients and those with autoimmune disorders corticosteroids are used for their immunosuppressive effects
  • 38. Replacement Therapy
    • Adrenal insufficiency – acute/chronic
      • Abrupt withdrawal of steroid therapy
      • Chronic infections – Tuberculosis
      • Autoimmune adrenal disease
      • Surgery, Hemorrhage and AIDS
    • Congenital adrenal hyperplasia
      • Congenital disorder due to deficiency of 21-hydroxylse enzyme – no cortisol but ACTH – increased androgen production
    CAH
  • 39. Replacement Therapy
    • Acute adrenal insufficiency
      • IV replacement of sodium chloride and fluid
      • IV hydrocortisone 100 mg stat followed by100 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
  • 40. Anti-inflammatory Uses
    • For suppression of inflammatory components in –
      • Rheumatoid arthritis – as adjuvant with NSAIDs in severe cases
      • Osteoarthritis – NSAIDs, intra-articular injection
      • Rheumatic fever – severe cases with carditis and CHF
      • Gout – NSAID failed cases and colchicine failed cases – intra-articular injection
      • Vasculitic disorders: Polyarteritis nodosa
  • 41. Intra-articular Steroids
    • Can be used in inflammatory
    • Non-inflammatory diseases
    • Knee joint
    • Shoulder joint
    • Tennis elbow
    • Carpal tunnel syndrome
  • 42. Autoimmune diseases
    • Autoimmune haemolytic anaemia
    • Idiopathic thrombocytopenic purpura
    • Active chronic hepatitis, alcoholic hepatitis
    • (Prednisolone 1-2 mg/kg/day given till remission followed by gradual withdrawal or low dose maintenance)
    ITP
  • 43. Renal diseases
    • Nephrotic syndrome in children
    • Renal disease secondary to SLE
    • Renal sarcoidosis
    • Glomerulonephritis – membranous type
    • (Life saving importance – usually given in large doses followed by tapering to maintenance dose)
    SLE
  • 44. Organ Transplant
    • Combined with other immunosuppressants – cyclosporin, azathioprine
    • For prolonged use:
    • Prednisolone or methylprednisolone are used
      • Intermediate duration of action
      • Can be easily tapered
      • Can be converted to an alternate regime
  • 45. Allergic Disorders
    • Exhibit a delayed response in allergies (1-2 hrs even in IV injection)
    • In anaphylaxis, angioneurotic oedema and serum sickness etc. – adrenaline is the choice
    • Seasonal allergies, bee sting, drug allergies –
      • Allergic reactions can be suppressed by corticosteroids as supplements
    • Intranasal administration in allergic rhinitis - budesonide and flunisolide
  • 46. 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
      • IV hydrocortisone Methylprednisolone
      • Oral prednisolone
    • Acute attacks:
    • *Inhaled beclmethasone, budesonide, flunisolide
    • alone or combined with beta-2 agonists/ipratropium
    • *Oral steroids
  • 47. Infectious Diseases
    • Indicated only in severe infective diseases to tide over crisis or prebent complictions
      • AIDS and pneumocystis carinii pneumonia
      • In haemophilus influenza meningitis to reduce neurological complications
      • Tubercular meningitis
      • Lepra reaction
      • Scepticaemia
    Lepra reaction
  • 48. Ocular Diseases
    • Important drug therapy for suppressing inflammation in eye and preservation of sight
    • Topical instillations are used for conditions of the anterior chamber – allergic conjunctivitis, iritis, iridocyclitis and keratitis etc.
    • Systemic steroids for the posterior chamber
    • Dexamethasone topical 0.1%
    • Prednisolone oral
    • Contraindicated in viral, fulminant bacterial infections, fungal infections and injuries
  • 49. Skin Diseases
    • The largest application of steroid therapy
    • Topical forms are widely used in many eczematous skin diseases
    • Systemic therapy are also required and may be life saving in
      • Pemphigus vulgaris
      • Exfoliative dermatitis
      • Stevens-Johnson syndrome
    Pemphigus vulgaris
  • 50. GIT
    • Inflammatory conditions of intestine like
      • Ulcerative colitis
      • Crohn`s disease
      • Coeliac disease
      • (oral therapy or retention enema with hydrocortisone)
    • May mask the major complications like perforation and peritonitis
  • 51. Malignancy
    • Essential for combined chemotherapy of
      • Acute lymphatic leukemia
      • Hodgkin's and other lymphomas
      • Hormone responsive breast carcinoma
    • Symptomatic relief in other advance malignancies by improving appetite and controlling secondary hypercalcaemia
    Hodgkin`s lymphoma
  • 52. Cerebral Oedema
    • Cerebral oedema due to tumors (neoplasms)
    • Traumatic and poststroke oedema (?)
    • (Dexamethasone or betamethasone is preferred because no Na+ retaining activity)
    • Other CNS conditions - spinal chord injury, Bell`s palsy and neurocysticercosis
    • (Oral Prednisolone is the preferred drug)
  • 53. Other Uses
    • Antiemetic – with ondansetron
    • Acute mountain sickness
    • Aspiration pneumonia, pulmonary oedema from drowning
    • Hyperthyroidism – thyroid storm
  • 54. Adverse Effects
    • Two types:
      • From abrupt withdrawal
      • Chronic therapeutic use of high dose
    • Withdrawal
      • Flare up of underlying disease
      • Suppression of HPA axis and acute adrenal insufficiency
      • Increased ICT and papilloedema
  • 55. Adverse Effects Cushing`s habitus
  • 56. Other Important Adverse Effects
    • Fluid and Electrolyte Disturbance – Na and water retention
    • Precipitation of Diabetes mellitus – hyperglycemia
    • Increased susceptibility to infections – immune response suppression
    • Peptic ulceration – bleeding & perforation
    • Osteoporosis – flat spongy bones
    • Osteonecrosis – avascular necrosis of head of femur, humorous etc.
    • Myopathy – weakness of muscles
    • Cataract – posterior sub capsular
    • Glaucoma – prolonged topical therapy
    • Growth retardation – in children
  • 57. Contraindications
    • Say no to any drug formulation combined with steroids
    • Remember that STEROIDS are life saving drugs
    • Note the following conditions where u have to be extremely cautious:
      • Peptic ulcer
      • Hypertension and Diabetes mellitus
      • Viral and fungal infections
      • Tuberculosis and other diseases
      • Osteoporosis
      • Epilepsy and psychosis
      • CHF and renal failure
  • 58. Choosing a Steroid
    • Benefit/risk ratio is a major consideration
    • Drugs with primary glucocorticoid activity are used
    • Minimal dose to achieve the desired effects is chosen
    • Topical or local therapy is preferred whenever possible
  • 59. Choosing a Steroid – contd.
    • Once daily dosing is usually
    • preferred for oral glucocorticoids
    • Large steroid doses are
    • administered in divided doses to
    • reduce local GIT effects
    • In order to mimic the normal diurnal
    • cycle and reduce the risk of
    • adrenal suppression, GCs should
    • be given in the morning between
    • 6-10 AM
    • Alternate day therapy allows the
    • HPA axis to recover on off days
    Single dose Steroid
  • 60. Withdrawal of Steroid Therapy
    • Taper the dose to reduce GC dose by 2.5-5 mg of prednisolone equivalent daily
    • Once the GC dose is reduced to 5 mg of prednisolone equivalent, the patient may be switched to a shorter acting agent for further tapering
    • Intermediate acting corticosteroids allow for more flexible dosing schedule
      • Have potent glucocorticoid effects
      • Causes lesser suppression of HPA axis
      • Causes less GIT irritation
      • Preferred for oral therapy
      • Prednisolone, methylprednisolone and triacinolone have a half life of 12-36 Hrs, are available in a number of dosage forms
  • 61. Adrenocorticosteroid Inhibitors
    • Metyrapone: 11 beta-hydroxylase enzyme inhibitor – used in Cushing`s syndrome and test of pituitary efficiency
    • Aminoglutethemide: Stops conversion of cholesterol to pregnelone (Medical adrenalectomy) – Breast cancers
    • Mifepristone: Progesterone antagonist
    • Spironolactone: Aldosterone antagonist
    • Ketoconazole: Inhibits synthesis of all hormones in testes and adrenal cortex – used in Cushing`s syndrome and also in hirsutism in female
  • 62. Must Know!
    • Biosynthesis and Regulation of Corticosteroids
    • Mechanism of action of Corticosteroids
    • Name of commonly used Glucocorticoids
    • Anti-inflammatory and immunosuppressive actions of Glucocorticoids
    • Important Adverse effects of Corticosteroids
    • Therapeutic uses of Corticosteroids
  • 63. Thank You