The document discusses corticosteroids, detailing their production from the adrenal cortex and medulla, and their physiological regulation via the hypothalamus-pituitary-adrenal axis. It covers various physiological and pharmacological effects, therapeutic uses, side effects, and contraindications associated with corticosteroids, along with their classification into natural and synthetic forms. The document also highlights their application in treating conditions like Addison's disease, Cushing's syndrome, and various inflammatory and autoimmune disorders.

1. Corticosteroids
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2. The hormones produced from three zones of adrenal cortex
Adrenal medulla : Epinephrine (adrenaline)
Zona glomerulosa (outer) : Mineralocorticoids
Zona fasciculata (middle) : Glucocorticoids
Zona reticularis (inner) : Adrenal androgens
Acute stress
Chronic stress
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3. Acute stress
Chronic stress
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4. 4
Hypothalamus
+ CRH
Anterior pituitary
+ ACTH
Adrenal cortex
Hydrocortisone secretion
__
__
__ CRH: corticotropin releasing
hormone; ACTH:ACTH:
adrenocorticotrophic hormoneadrenocorticotrophic hormone
●Physiological regulation mechanism of glucocorticoids secretion
(Hypothalamus-pituitary-adrenal gland axis)
plasma

5. DIAGNOSTIC USES (ACTH)
1. Adrenal insufficiency
Primary insufficiency
No increase in cortisol level
Secondary insufficiency
Increase in cortisol level
2. Cushing syndrome
ACTH injected
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6. THERAPEUTIC USES
Replacement therapy: Tumour in anterior pituitary
To stimulate the adrenal gland inactivated by steroid
therapy
Both uses are expensive & inconvenient
similar to that of steroids.
Being a foreign protein, ACTH may produce anaphylactic
reactions.
Side effects and contraindications
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7. Corticosteroids
History
Synthesis
Pharmacological
Actions
Pharmacokinetics
Preparations
Therapeutic principles
Dosage schedule &
Steroid withdrawal
Uses:
– Therapeutic
– Diagnostic
Adverse reactions
Contraindications
Precautions during
therapy
Glucocorticoid
antagonists
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8. History
1855 – Addison's disease
1856 – Adrenal glands essential for life
1930 – Cortex > medulla
1932 – Cushing’s syndrome
1949 – Hench et al (Steroids in rheumatoid arthritis)
1952 – Aldosterone
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9. CORTICOSTEROIDS
• Adrenal cortex essential for survival
• Adapt for changing environment
• Organ of par excellence -homeostasis
• Zona glomerulosa-aldosterone
• Zona fasciculata- glucocorticoids
• Zona reticulata- sex steroids
• Regulatory control from the hypothalamus
and pituitary.
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10. 04/30/19 10PATKI

11. 04/30/19 11PATKI

12. Basal secretions
Group Hormone Daily
secretions
Glucocorticoids • Cortisol
• Corticosterone
5 – 30 mg
2 – 5 mg
Mineralocorticoids • Aldosterone
• 11- deoxycorticosterone
5 – 150 μg
Trace
Sex Hormones
•Androgen
•Progestogen
•Oestrogen
• DHEA
• Progesterone
• Oestradiol
15 – 30 mg
0.4 – 0.8 mg
Trace
From Essential of Pharmacotherapeutics, ed. FSK Barar. P.35104/30/19 12PATKI

13. Cholesterol
Pregnenolone
Progesterone
Corticosterone
11-Desoxy-
corticosterone
18-Hydroxy-
corticosterone
ALDOSTERONE
17-α- Hydroxy
pregnenolone
11- Desoxy-
cortisol
17- Hydroxy
progesterone
21,β hydroxylase
CORTISOL
11,β hydroxylase
Dehydro-epi
androsterone
Andro-
stenedione
Oestrone
Oestriol
TESTOSTERONE OESTRADIOL
ACTH
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14.
CLASSIFICATION OF ADRENOCORTICOSTEROIDS
Natural
Synthetic
Glucocorticoids
Hydrocortisone (cortisol)
Cortisone
Prednisone, Prednisolone
Methyl-prednisolone
Triamcinolone
Betamethasone, Dexamethasone
Mineralocorticoids
Aldosterone
Desoxycorticosterone (DOC)
Fludrocortisone
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15. Classification
• Natural- mineralocorticoid & glucocorticoid
aldosterone hydrocortisone
• Synthetic :
1.Short acting: hydrocortisone (8-12hrs.) Cortisone
2. Intermediate acting: prednisolone, (12-36hrs.)
triamcinolone
3. long acting (36-72hrs)
dexamethasone, betamethasone
4. Inhalation: fluticasone, budesonide , beclamethasone
5. Topical: clobetasol, mometasone desonide
6. Mineralocorticoid: fludrocortisone
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16. Steroid (free form)
Cytoplasmic protein
receptor
Steroid receptor
complex
Modulation of Gene
Protein synthesis
Response
Response
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17. Mechanism of actions
• Steroid receptor- 70 amino acid domain –Zinc
finger (steroid responsive elements)
• Genomic & non-genomic effects
• Regulate the expressions of responsive genes
• Changes the level of array of proteins
• Action manifest after several hours
• Membrane receptor related effect immediate
• Aldosterone increase membrane protein level
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18. Dynamics
• Numerous actions & wide ranging effect
• Endows capacity to resist noxious stimuli.
• Synthesized and released as needed
• Act at multiple sites
• Permissive role- presence normal functions
• Physiologic actions
• Pharmacological effects
• Life saving
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19. Actions
• Metabolic;
• Catabolic
• Mineralocorticoid
• Anti-inflammatory
• Anti-immune
• Anti-allergic
• Anti-growth
• Anti-stress
• Gastric acid secretion
• Preservation of CVS
• Skeletal muscle
• Anti-vitamin-D
• Renal system
• CNS- neurosteroids
• Delays wound healing
• On blood
• Uricosuric
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20. Metabolic actions
• Carbohydrate: profound effects
• Protect glucose dependent tissues, brain & heart from
starvation
• Anti-insulin effects
• Increase gluconeogenesis
• Reduce glucose uptake & utilization
• Steroid induces diabetes mellitus
• Lipid: Cushingoid habitus increase lipolysis
• Protein: catabolic action- negative nitrogen balance
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21. Electrolyte & water excretion
• Act on distal tube & collecting tubule
• Retains sodium & promote K+ & H+ excretion
• Reduce Ca++ level- increase excretion, reduce
absorption –Anti-vitamin-D action
• Fludrocortisone - synthetic potent
mineralocorticoid
uses: adrenocortical insufficiency
severe orthostatic hypotension
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22. CVS function
• Hyperaldosterinism: Increase BP,
athersclerosis, cerebral hemorrhage, stroke,
hypertensive cardiomyopathy
• Enhance vascular reactivity to vasoactive
substances, increase cardiac fibrosis
• Increase expression of adrenergic receptor in
vascular wall
• Hypoaldosteronism: decrease BP vascular
collapse
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23. Action on lymphocytes
• Increase apoptosis
• IL-1,2,3,6 TNF-alpha, Gm-CSF inhibited
• Inhibit phospholipase-A2 & COX-2
• Cytokines production & release blocked
• Hodgkin's lymphoma
• Inextricably linked to suppression of
inflammation
• Multiple mechanisms
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24. Steroidal anti-inflammatory
• Inextricably linked to immunosuppressive
effect
• Multiple mechanisms are involved
• Decreased release of vasoactive and
chemoattractive factors
• Reduce extravasations of leukocytes
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25. Anti-inflammatory &
immunosuppressive effect
• Suppress both early & late phases
• Affect pro-inflammatory cytokines generation
• Synthesis –lipocortin & macrocortin
• Inhibits Phospholipase- A2- C20 acid release
• PGs, IL-1, Il-6, TNF- alpha , Gm-CSF
• Reduce vasoactive chemoattractant release
• Inhibits fibroblast proliferation-reduce fibrosis
• Reduce collagenase enzymatic activity
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27. On skeletal muscle & blood
• Muscle function – permissive concentration
• Steroid myopathy- high doses
• Enhance lymphocyte apoptosis
• Stimulate erythropoietin secretion
• Diminish destruction of erythrocytes in
autoimmune hemolytic anemia
• Causes polycythemia in Cushing's syndrome
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28. Corticosteroids are Gene-Active
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29. Pharmacological Actions
• For most clinical purposes, synthetic
glucocorticoids are used because they have a
higher affinity for the receptor, are less
activated and have little or no salt-retaining
properties.
• Hydrocortisone used for: orally for
replacement therapy, i.v. for shock and
asthma, topically for eczema (ointment) and
enemas (ulcerative colitis).
• Prednisolone the most widely used drug given
orally in inflammation and allergic diseases.04/30/19 29PATKI

30. Pharmacological Actions
• Betamethasone and dexamethasone: very
potent, w/o salt-retaining properties; thus,
very useful for high-dose therapies (e.g.,
cerebral edemas).
• Beclometasone, diproprionate, budesonide:
pass membranes poorly; more active when
applied topically (severe eczema for local anti-
inflammatory effects) than orally; used in
asthma, (aerosol).
• Triamcinolone: used for severe asthma and
for local joint inflammation (intra-articular
inj.).04/30/19 30PATKI

31. Pharmacological Actions
1. Carbohydrate
2. Protein
3. Lipid
4. Electrolyte and H2O
5. CVS
6. Skeletal Muscle
7. CNS
8. Stomach
9. Blood
10. Anti-inflammatory
11. Immunosuppressant
12. Respiratory system
13. Growth and Cell Division
14. Calcium metabolism
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32. Stress and The Adrenal Glands
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33. Actions: Carbohydrate and protein metabolism
• Gluconeogenesis
– Peripheral actions (mobilize aas and glucose and glycogen)
– Hepatic actions
• Peripheral utilization of glucose
• Glycogen deposition in liver
(activation of hepatic glycogen synthase)
Negative nitrogen balance and hyperglycemia
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34. • Redistribution of Fat
• Buffalo hump
• Moon face
• Promote adipokinetic agents activity
(glucagon, growth hormone, adrenaline, thyroxine)
Actions: Lipid metabolism
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35. Actions: Electrolyte and water balance
• Aldosterone is more important
• Act on DT and CD of kidney
– Na+
reabsorption
– Urinary excretion of K+
and H+
• Addison’s disease ??
• Na+ loss
• Shrinkage of ECF
• Cellular hydration
• Hypodynamic state of CVS
• Circulatory collapse,
renal failure, death
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36. • Restrict capillary permeability
• Maintain tone of arterioles
• Myocardial contractility
Actions: Cardiovascular system
Mineralocorticoid induced hypertension ??
Na+
sensitize blood vessels to the action of
catecholamines & angiotensin
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37. Addison's disease: weakness and fatigue is due to
Prolonged use:
Actions: Skeletal Muscles
Needed for maintaining the normal function of Skeletal
muscle
inadequacy of circulatory system
Steroid myopathy
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38. • Direct:
– Mood
– Behaviour
– Brain excitability
• Indirect:
– maintain glucose, circulation and electrolyte
balance
Actions: CNS
ICP (pseudotumor cerebri) - Rare
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39. Immunosuppressive and anti-allergic actions
• Suppresses all types of hypersensitivity and
allergic phenomenon
• At High dose: Interfere with all steps of
immunological response
• Causes greater suppression of Cell-mediated
immunity (graft rejection and delayed
hypersensitivity)
• Transplant rejection: antigen expression from
grafted tissues, delay revascularization,
sensitisation of T lymphocytes etc.
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41. • Inhibit cell division or synthesis of DNA
• Delay the process of healing
• Retard the growth of children
Actions: Growth and Cell division
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42. • Intestinal absorption
• Renal excretion
• Excessive loss of calcium from spongy bones
(e.g., vertebrae, ribs, etc)
Actions: Calcium metabolism
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43. • Not bronchodilators
• Most potent and most effective anti-inflammatory
• Effects not seen immediately (delay 6 or more hrs)
• Inhaled corticosteroids are used for long term control
Actions: Respiratory system
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44. Preparations
Drug Anti-inflam. Salt retaining Topical
Cortisol 1 1.0 1
Cortisone 0.8 0.8 0
Prednisone 4 0.8 0
Prednisolone 5 0.3 4
Methylpredni-
solone
5 0 5
Intermediate acting
Triamcinolone 5 0 5
Paramethasone 10 0 -
Fluprednisolone 15 0 7
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45. Preparations
Drug Anti-inflam. Salt retaining Topical
Long acting
Betamethasone 25-40 0 10
Dexamethasone 30 0 10
Mineralocorticoids
Fludrocortisone 10 250 10
DOCA 0 20 0
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46. Kinetics
• PO, PR, i.v., im. topical, intra-articular,
inhalation, instillation, epidural, intranasal,
intra-lesional
• Binds to transcortin 90% synthetic congeners
have low affinity
• Sulfate & glucuronide conjugation
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47. Guidelines for steroid therapy
• Largely empirical neither specific nor curative except
replacement therapy
• Dose to be determined by trial & error method and
reevaluate periodically
• Careful patient assessment is mandatory
• A single large dose is virtually without harmful effects &
be reserved for life threatening conditions
• A short course therapy is unlikely to be harmful
• Abrupt withdrawal may be fatal
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48. Therapeutic uses
• Diagnostic: Dexamethasone suppressant test
• Replacement therapy- Addison’s disease
• Life saving indications: acute Addisonian
crisis, anaphylactic shock, SLE, pemphigus
vulgaris, status asthmatics
• Rheumatic diseases
• Renal disorders
• Allergy, skin, git, hepatic, ocular, malignancy
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50. Steroids for Rheumatic diseases
• Serious inflammatory disorders
• SLE
• Polyarteritis nodosa
• Wegener's granulomatosis- granulomatosis
• Churg Strauss syndrome- allergic angitis
• Giant cell arteritis
• Arthritis
• Osteoarthritis
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51. Steroids in Renal Ocular & Skin
diseases
• Nephrotic syndrome
• Membranous glomerulonephritis
• Ocular indications
• topical as anti inflammatory effect not more
than 2 weeks
• Skin diseases
• Pemphigus vulgaris
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52. Prednisolone for malignancy
• Acute lymphocytic leukemia & lymphoma
• Rationale
• Anti –inflammatory
• Immunosuppressant
• Stimulate erythropoietin release
• Reduce hematological toxicity of co-
administered cytotoxic drugs
• Mild euphoria
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53. Therapeutic uses contd…
• Transplantation surgery
• Auto immune hemolytic anemia
• Sarcoidosis
• Thrombocytopenia
• Spinal cord injury
• Shock?
• Cerebral edema?
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54. Therapeutic uses .. cont.
• Chronic ulcerative colitis
• Crohn's disease
• Auto immune hepatitis
• Cerebral edema
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57. Adverse reactions
• Two types:1) due to sudden withdrawal
2) due to supra physiological doses
• Steroid withdrawal acute adrenal insufficiency
• Malaise, fever, arthralgia, myalgia.
• Pseudotumor cerebri - increased intracranial
pressure with papilledema
• Steroid replacement
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58. Steroid toxicity
• Cushing’s syndrome
• Hypertension, Electrolyte abnormalities
• Hyperglycemia, glycosuria
• Supra-infection, prone for infection
• Osteoporosis, avascular/aseptic osteo-
necrosis, spontaneous fracture
• Myopathy
• Psychoses
• Glaucoma, cataract
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60. Adverse reactions….contd
• Peptic ulcer
• Growth arrest
• Acne, hirsutism
• Topical –loss of skin collagen
• Inhalation: hoarseness of voice
• Teratogenicity: cleft palate, altered neuronal
development
• Reactivation of TB
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61. Antagonists of Adrenocortical Agents
A. Synthetic inhibitors and glucocorticoid antagonists
1. Metyrapone – inhibits 11-hydroxylation, interfering
with cortisol and corticosterone synthesis (0.25g
BID to 1g QID)
- used in tests of adrenal function (300-500mg q
4hrs. X 6doses, fed by urine collection
- treat hypercorticotism: 4 g/day
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62. 2. Aminoglutethimide – blocks the conversion of
cholesterol to pregnanelolone and causes a
reduction in the synthesis of all hormonally
active steroids; breast Ca and Cushing’s
syndrome due to adrenocortical Ca: 250 mg
every 6hrs.
- enhances metabolism of dexamethasone
3. Trilostane - inhibits 3beta hydroxysteroid
dehydrogenase
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63. 3. Ketoconazole – an antifungal imidazole
derivative; potent, non-selective inhibitor of
adrenal and gonadal steroid synthesis; tx of
Cushing’s syndrome (200-1200mg/d)
4. Mifepristone (RU 486) –
11β-aminophenyl-substituted 19-norsteroid;
has strong anti-progestin activity; blocks
glucocorticoid receptor
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64. B. Mineralocorticoid Antagonists
1. Spirinolactone – diagnosis of aldosteronism
(400-500mg/day fro 4-8 days); preparing for
surgery (300-40mg/day x 2 wks to reduce the
incidence of arrhythmias); hirsutism in women
(androgen antagonist 50-200mg/d x 2-6 mos);
diuretic
2. Eplerenone
3. Drospirenone – progestin in a new oral
contraceptive, antagonizes the effect of
aldosterone
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65. PATKI
Drug interactions
• Estrogens may decrease prednisone metabolism.
• Phenobarbital, phenytoin, and rifampicin may
increase metabolism of glucocorticoids
• May cause digitalis toxicity secondary to
hypokalemia.
• Monitor for hypokalemia with co-administration of
diuretics
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66. PATKI
Fludrocortisone
• It is the only mineralocorticoid given orally.
• It has a very great mineralocorticoid plus a significant
glucocorticoid activities.
• It has a long duration of action
Fludrocortisone is preferred in:
- Replacement therapy in Addison's disease.
- to preserve sodium and treat hypotension as in cases
of interstitial nephritis and autonomic neuropathy.
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