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Adrenocorticosteroids
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Glucocorticoids.
Mineralocorticoids.
Androgens.
Objectives
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Recognize the mechanism of action.
Kinetics
Pharmacological effects.
Uses.
Adrenocorticosteroid antagonists.
Glucocorticoids
Cortisol (hydrocortisone):
Kinetics:
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Well absorbed orally.
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Bound to transcortin (plasma α-globulin) and albumin.
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Distributed allover the body & passes the BBB.
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In the liver, cortisol is reversibly converted to cortisone & conjugated with glucuronic &
sulfuric acid.
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Excreted in urine as 17-hydroxy corticosteroids.
Dynamics:
Mechanism of action:
• Corticosteroids passively pass to the cytoplasm where it binds to mobile cytoplasmic
receptors.
• The mobile cytoplasmic receptors entering the nucleus, bind nuclear response element,
• Increasing or decreasing mRNA which in turn control the protein synthesis giving rise to the cell
response.
Action of glucocorticoids:
• Increase blood sugar (increase glycolysis & gluconeogenesis).
• Increase protein catabolism (breakdown) resulting in growth retardation in children and
osteoporosis in adults.
• Increase deposition of fat in shoulders (bufflo hump) and face (moon face).
• Sodium and water retention resulting in hypertension and increased body weight.
• Increase RBC & thrombocytes.
• Decrease lymphocytes & eosinophils.
• Hypercoagulability of the blood.
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Immunosuppresive: decrease antibody production, T-lymphocytes, eosinophils, monocytes,
macrophages & neutrophils.
• Antiinflammatory: corticosteroids inhibit prostaglandins, leukotrienes, interleukins and PAF
synthesis, inhibit migration of leukocytes to inflammation area, and stabilization of the
lisosomes.
• Antiallergic (decrease the response to antigen/ antibody reactions).
• Increase acidity of the stomach and enhance peptic ulcer diseases.
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Increase uric acid excretion.
Increase urinary calcium excretion which may lead to, renal stone, osteoporosis and
osteomalacia.
• Euphoria, psychosis or depression.
Uses of glucocorticoids:
• Replacement therapy in acute adrenal insufficiency and in Addison’s disease.
• Rheumatoid arthritis (not respond to other drugs).
• Bronchial asthma (not respond to other drugs)
• Acute lymphatic leukemia
• Acute hemolytic anemia.
• Thrombocytopenic purpura.
• Ulcerative colitis.
• Systemic lupus erythematosis (SLE) and other collagen diseases.
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Locally applied in skin and eye allergic disorders.
Shock.
Along with antituberculus in tuberculosis of meninges and joints to prevent hydrocephalus,
blindness and stiffness of joints.
In severe infections (typhoid or milliary tuberculosis) to help in averting shock and sustaining
the patient while chemotherapeutic agents are taking effect.
Adverse reactions of glucocorticoids:
• Diabetes mellitus.
• Peptic ulcer. Perforation of peptic ulcer may take place without its characteristic symptoms.
• Sodium and water retention, hypertension, edema & hypokalemia.
• Iatrogenic Cushing’s syndrome.
• Addisonian crisis on sudden withdrawal (corticosteroids should be withdrawn gradually).
• Hypercoagulability of the blood.
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Immunosuppression.
Masking manifestation of inflammation, spread of infection and delay tissue healing.
Osteoporosis.
Growth retardation.
Euphoria, psychosis or depression may occur. These reactions disappear once the drug is
withdrawn.
Teratogenicity.
Cataract, glaucoma and muscle weakness.
Drug interactions
• Estrogens may decrease prednisone clearance (metabolism).
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Phenobarbital, phenytoin, and rifampicin may increase metabolism of glucocorticoids
(consider increasing maintenance dose).
May cause digitalis toxicity secondary to hypokalemia.
Monitor for hypokalemia with co-administration of diuretics
Preparations:
for clinical purposes synthetic glucocorticoids are used due to:
– Their high affinity to the receptors.
– Slowly inactivated.
– Little salt & water retention.
Examples:
– Prednisone & prednisolone,
– Betamethasone & dexamethasone (no salt retaining action)
– Beclomethasone inhalation for bronchial asthma.
– Triamcinolone in severe asthma and locally (intra-articular)
Mineralocorticoids
(Aldosterone, Desoxycorticosterone & Fludrocortisone)
Aldosterone
• Aldosterone is a very powerful mineralocorticoid, but it has a week glucocorticoid activity.
• Its release from the adrenal cortex is controlled by the renin-angiotensin system.
• It acts on collecting tubules causing reabsorption of sodium, bicarbonate & water. Potassium &
H + are lost in the urine.
• Aldosterone is rapidly inactivated in the liver after oral administration.
• Aldosterone has a short t1/2 (20 min.)
• Used i.m in acute adrenal insufficiency, but it has no place in routine therapeutics.
Desoxycorticosterone (DOC)
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DOC is the naturally occurring precursor of aldosterone.
It has a pure mineralocorticoid activity.
Desoxycorticosterone acetate (DOCA) i.m, s.l, or subcutaneous pellet implantation is used
with cortisol for replacement therapy in Addison's disease.
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.
Adrenocorticosteroid Antagonists
Receptor antagonists:
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Spironolactone: it is a competitive antagonist of aldosterone at its receptor (see diuretics).
Mifepristone: it is a blocker for glucocorticoids and progesterone receptors. it is used in
treatment of Cushing's syndrome.
Synthesis inhibitors
(Metyrapone, Aminoglutethimide & Ketoconazole)
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These drugs inhibit steroid synthesis in the adrenals.
They are used in Cushing's syndrome and adrenal cancer when surgery is contraindicated.
Metyrapone: inhibits beta hydroxylase enzyme & inhibits glucocorticoid synthesis >
aldosterone
Aminoglutethimide is used in advanced cancer breast to suppress adrenal secretion of
estrogenic steroids.
Formestane: it prevent conversion of androgen to estrogen. It is used in relapsed breast cancer
on tamoxifen therapy.
Ketoconazole:
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it is an antifungal blocks ergosterol synthesis in fungi.
It also blocks steroid synthesis in gonads and adrenal cortex.
It is used in Cushing's syndrome & prostatic cancer.
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