↑ Na+ reabsorption in DCT & ↑ excretion. in K+ and H+
In mineralocorticoid deficiency :
Na+ is lost but not water dilutional hyponatremia , & excess water enters cells cellular hydration, decrease blood volume and raised hematocrit. Hyperkalemia and acidosis occur.
These distortions in fluid and electrolytes lead to circulatory collapse .
In excessive mineralocorticoid activity :
Fluid retention, hypertension,
hypokalemia and alkalosis occur .
CARBOHYDRATE metabolism :
Promote glycogen deposition in liver & gluconeogenesis.
↑ glucose release from liver and inhibit glucose utilisation-
produce hyperglycemia , resistance to insulin and/or diabetic like state.
PROTEIN metabolism :
Break down of protein & mobilization of Amino Acid from peripheral tissues muscle wasting, loss of osteoid from bone and thinning of skin .
These Amino Acid used up for neoglucogenesis , excess urea, negative nitrogen balance. They are thus catabolic .
Promote lipolysis (stimulate lipase) due to other hormone like glucagon, GH, adrenaline, thyroxine.
Promote cAMP induced breakdown of triglycerides.
Redistribution of fat occurs ( from periphery to neck, face and supraclavicular area producing moon face, fish mouth and buffalo hump).
Calcium metabolism :
Inhibition of Ca++absorption from intestine ( vit.D antagonism ) & ↑ its renal excretion.
Loss of Ca++ from bone ↑ resorption ( reduced function of osteoblast & ↑ function of osteoclast), & negative Ca++ balance.
Inhibit linear growth in children
Skeletal muscles :
Weakness occurs in both hypo and hypercorticism .
In hypocorticism : decrease work capacity & weakness are due to hypodynamic circulation.
In hypercorticism : weakness is due to hypokalemia (excess of mineralocorticoid), & muscle wasting and myopathy (excess of glucocorticoids).
Catabolic and antianabolic effects :
Stimulate protein and RNA synthesis in liver, but have catabolic and antianabolic effect on lymphoid tissue, connective tissue, muscle, fat and skin dec. muscle mass, thinning of skin and osteoporosis. In children- retardation of growth .
Brain- euphoria, inc. motor activity, insomnia, anxiety or depression.
In Addison's disease- apathy, depression and psychosis .
High doses lower seizure threshold .
Increased secretion of gastric acid and pepsin may aggravate peptic ulcer .
RBCs and other blood cells:
Inc. in no. of RBCs and neutrophils and dec. in lymphocytes, eosinophils & basophils.
Involved in Fetal lung development : :---
Destruction of lymphoid cells (T cells more than B cells) used in lymphomas. Hyperplasia of lymphoid tissue is seen in Addison’s disease.
Immunological & allergic responses:
suppress all types of hypersensitization and allergic phenomena.
Produce greater suppression of CMI in which T cells are involved - as in delayed hypersensitivity, graft rejection- autoimmune disease.
Nonspecific suppression of all components, stages and cardinal signs of inflammation .
Produce vasoconstriction, reduce capillary permeability, local exudation, cellular infiltration, phagocytic activity& late responses like capillary proliferation, collagen deposition, fibroblastic activity, & scar formation- action is direct and local .
Action on inflammatory cells.
Decrease migration & reduced activity of neutrophils & macrophages .
Decrease action of T helper cells ,
Action on inflammatory mediators :-----
Induction of annexin I ( lipocortin) which inhibits phospholipase A2 inhibiting production of eicosanoids & PAF;
Dec. expression of COX2- dec. production of prostanoids .
Dec. production of cytokines -IL1 , IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF γ and cell adhesion factors- through inhibition of transcription of the relevant genes.
Dec. in conc. of complement components in plasma.
Dec. generation of induced NO
Dec. release of histamine from basophils.
Dec. IgG production.
Relative potencies and equivalent doses of corticosteroids __________________________________________________________________________________________________________________________ RELATIVE ANTI- RELATIVE APPROXIMATE INFLAMMATORY Na+- DURATION OF EQUIVALENT COMPOUND POTENCY RETAINING ACTION* DOSE † POTENCY (mg) __________________________________________________________________________________________________________________________ Cortisol (Hydrocortisone) 1 1 S 20 Tetrahydrocortisol 0 0 - - Prednisone (∆ 1 -Cortisone) 4 0.8 I 5 Prednisolone (∆ 1 -Cortisol) 4 0.8 I 5 6 -Methylprednisolone 5 0.5 I 4 Fludrocortisone (9 -Fluorocortisol) 10 125 S - 11-Desoxycortisol) 0 0 - - Cortisone (11-Dehydrocortisol) 0.8 0.8 S 25 Corticosterone 0.35 15 S - Triamcinolone (9 -Fluoro-16 -hydroxyprednisolone) 5 0 I 4 Paramethasone (6 -Fluoro-16 -methylprednisolone) 10 0 L 2 Betamethasone (9 -Fluro-16 -methylprednisolone) 25 0 L 0.75 Dexamethasone (9 -Fluoro-16 -methylprednisolone) 25 0 L 0.75 _________________________________________________________________________________________________________________________ *S=Short, or 8 to 12 hour biological half-life; I=intermediate, or 12 to 36 hour biological half-life; L=long, or 36 to 72 hour biological half-life. † These dose relationships apply only to oral or intravenous administration; relative potencies may differ greatly when injected intramuscularly or into joint spaces.
To control inflammatory and immunological diseases
Probable actions –
a) Stabilization of lysosomal membrane
b) Retardation of macrophage movement
c) Prevention of Kinin release
d) Inhibition of lymphocytes and neutrophil function
e) Inhibition of prostaglandin synthesis
f) Decrease of antibody production
Naturally occurring Glucocorticoids.
Glucocorticoids have important dose-related effects on Carbohydrate,Protein & Fat metabolism.
They have Anti-inflammatory & Immunosuppresive Effects
Large doses of Glucocorticoids have been associated with the development of peptic ulcer,possibly by suppressing the local immune response against H.pylori.
Adverse Effects : Prolong use may cause glaucoma, cataract exacerbation of acute infection, osteoporosis in Cushing’s syndrome.
ADVERSE EFFECTS of prolonged use of glucocorticoids
1) Metabolic Effects : —Weight gain, hyperglycemia, aseptic necrosis of the hip bone.
2) Other Complications :—Peptic ulcer, depression, hypomania or acute psychosis, hypertension, heart failure.
3) Adrenal suppression
CONTRAINDICATIONS of Corticosteroids
They must be used with great cautions in patients with---
1) Peptic ulcer
2) Heart disease or hypertension with heart failure
3) Infections like varicella & Tuberculosis
5) Diabetes , osteoporosis or glaucoma
Epidermal and dermal atrophy
(thinning of the skin, striae, telangiectases ,superficial fissures and purpura)
Allergic contact dermatitis (uncommon)
Masking or aggravation of dermatophytoses, impetigo or scabies
Adverse skin reactions to topical glucocorticoids
Drug interactions of glucocorticoids Glucocorticoid dosage is decreased: Antibiotics (erythromycin, trioleandomycin), cyclosporin, isoniazid and ketoconazole reduce the metabolic clearance of glucocorticoids. Estrogens increase the levels of corticosteroid binding protein and thus reduce the free fraction; they also reduce the clearance. Cholestyramine decreases the intestinal absorption. Antiepileptic drugs(barbiturates, phenytoin, carbamazemine), rifampicin,, aminoglutethimide increase the metabolism by inducing hepatic microsomal enzymes. Antianxiety and antipsychotic drugs: Recurrent or poor control of CNS symptoms due to inherent glucocorticoid effects. Glucocorticoid dosage is increased: Glucocorticoid dosage needs adjustment: Anticholinesterases: May precipitate myasthenic crisis Anticoagulants: Effectiveness of anticoagulants decreases Antihypertensives: Their effectiveness decreases Oral hypoglycemics: Their effectiveness decreases Sympathomimetics: Their effectiveness increases Salicylates: Their clearance is increased
THERAPEUTIC USES of glucocoricoids
1.SUBSTITUTION THERAPY —
A) Chronic adrenal insufficiency
B) Acute adrenal insufficiency
C) Septic shock
USES ( Contd .)
2) PHARMACOLOGICAL THERAPY —
A) Pulse therapy : –in acute rejection of renal graft.
B) Intensive short term therapy :–in status asthmaticus.
Principles of treatment of acute adrenal insufficiency
Precautions during glucocorticoid therapy Before starting therapy Enquire about and check for: peptic ulcer, diabetes mellitus, tuberculosis, any other infection (especially one not amenable to chemotherapy). During therapy Prescribe the drug with food Diet low in calories and sodium, and high in potassium
Check periodically for: weight gain, edema, hyperglycemia, hypertension, infection, GI bleeding, hypokalemia, ocular changes
Monitor growth in children
Instruct the patient not to stop the drug abruptly (severe infection, major surgery)
Prescribe oral calcium and vitamin D supplements; alendronate; antacids; H 2 receptor blockers
3) Fludrocortisone (Synthetic )
Pharmacological action- --They promote the reabsorption of sodium from the distal convoluted and cortical collecting renal tubules.
Therapeutic Uses of Mineralocortcoids
1) Addison’s disease
2) Salt losing congenital adrenal hyperplasia
3) Hyporeninemic hypoaldosteronism
ADVERSE EFFECTS of Mineralocorticoids-------------