Corticosteroids

This ppt discusses pharmacological actions, toxic effects and clinical applications of corticosteroids. It also mentions precations to be taken while using steroids

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)
p
la
s
m
a

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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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.351
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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.
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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.).
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31. Pharmacological Actions
1.Carbohydrate
2.Protein
3.Lipid
4.Electrolyte and H
2
O
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 retainingTopical
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 retainingTopical
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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