The best agent of corticosteroids

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 hormone
adrenocorticotrophic 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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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 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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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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