Glucocorticoid Actions

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Chapter: Essential pharmacology : Corticosteroids

Glucocorticoids promote glycogen deposition in liver (they are assayed on the basis of this action) by inducing hepatic glycogen synthase and promoting gluconeogenesis.


GLUCOCORTICOID ACTIONS

 

1. Carbohydrate And Protein Metabolism

 

Glucocorticoids promote glycogen deposition in liver (they are assayed on the basis of this action) by inducing hepatic glycogen synthase and promoting gluconeogenesis. They inhibit glucose utilization by peripheral tissues. This along with increased glucose release from liver results in hyperglycaemia, resistance to insulin and a diabeteslike state. They also cause protein breakdown and amino acid mobilization from peripheral tissues—responsible for side effectslike muscle wasting, lympholysis, loss of osteoid from bone and thinning of skin. The amino acids so mobilized funnel into liver used up in gluconeogenesis, excess urea is produced negative nitrogen balance. Glucocorticoids are thus catabolic. Their function appears to be aimed at maintaining blood glucose levels during starvation—so that brain continues to get its nutrient. When food is withheld from an adrenalectomized animal—liver glycogen is rapidly depleted and hypoglycaemia occurs.

 

They also increase uric acid excretion.

 

2. Fat Metabolism

 

The action is primarily permissive in nature: promote lipolysis due to glucagon, growth hormone, Adr and thyroxine. cAMP induced breakdown of triglycerides is enhanced. Fat depots in different areas respond differently—redistribution of body fat occurs. Subcutaneous tissue over extremities loses fat which is deposited over face, neck and shoulder —‘moon face’, ‘fish mouth’, ‘buffalo hump’. Explanation offered is—because peripheral adipocytes are less sensitive to insulin, corticosteroid enhanced lipolytic action of GH and Adr predominates, whereas truncal adipocytes respond mainly to enhanced insulin levels under the influence of glucocorticoids.

 

3. Calcium Metabolism

 

They inhibit intestinal absorption and enhance renal excretion of Ca2+. There is also loss of calcium from bone indirectly due to loss of osteoid (decreased formation and increased resorption), negative calcium balance. Spongy bones (vertebrae, ribs, etc.) are more sensitive.

 

4. Water Excretion


 

Effect on water excretion is independent of action on Na+ transport; hydrocortisone and other glucocorticoids, but not aldosterone, maintain normal g.f.r. In adrenal insufficiency, the capacity to excrete a water load is markedly reduced—such patients are prone to water intoxication from i.v. infusions.

 

Glucocorticoids also enhance secretory activity of renal tubules.

 

5. CVS

 

Glucocorticoids restrict capillary permeability, maintain tone of arterioles and myocardial contractility. Applied topically, they cause cutaneous vasoconstriction. They have a permissive effect on pressor action of Adr and angiotensin. They also play a permissive role in development of hypertension—should be cautiously used in hypertensives.

 

Adrenal insufficiency is attended by low cardiac output, arteriolar dilatation, poor response to Adr (repeated doses of Adr cause destructive changes in blood vessels) and increased permeability of capillaries. These changes along with hypovolemia (due to lack of mineralocorticoid) are responsible for cardiovascular collapse.

 

6. Skeletal Muscles


 

Optimum level of corticosteroids is needed for normal muscular activity. Weakness occurs in both hypo and hypercorticism, but the causes are different.

 

Hypocorticism: diminished work capacity and weakness are primarily due to hypodynamic circulation.

Hypercorticism: excess mineralocorticoid action hypokalaemia weakness;

 

Excess glucocorticoid action muscle wasting and myopathy weakness.

 

7. CNS

 

Mild euphoria is quite common with pharmacological doses of glucocorticoids. This is a direct effect on brain, independent of relief of

disease symptoms; sometimes progresses to cause increased motor activity, insomnia, and hypomania or depression. On the other hand, patients of Addison’s disease suffer from apathy, depression and occasionally psychosis.

 

Glucocorticoids also maintain the level of sensory perception and normal level of excitability of neurones. High doses lower seizure threshold—cautious use in epileptics. This action is independent of electrolyte changes in the brain and is not shared by aldosterone.

 

8. Stomach

 

Secretion of gastric acid and pepsin is increased—may aggravate peptic ulcer.

 

9. Lymphoid Tissue And Blood Cells

 

Glucocorticoids enhance the rate of destruction of lymphoid cells (T cells are more sensitive than B cells); but in man the effect on normal lymphoid tissue is modest. However, a marked lytic response is shown by malignant lymphatic cells; basis of their use in lymphomas.

 

Glucocorticoids increase the number of RBCs, platelets and neutrophils in circulation. They decrease lymphocytes, eosinophils and basophils. This is not due to destruction of these cells but due to their sequestration in tissues. Blood counts come back to normal after 24 hours.

 

10. Inflammatory Responses

 

Irrespective of the type of injury or insult, the attending inflammatory response is suppressed by glucocorticoids. This is the basis of most of their clinical uses. The action is nonspecific and covers all components and stages of inflammation. This includes reduction of—increased capillary permeability, local exudation, cellular infiltration, phagocytic activity and late responses like capillary proliferation, collagen deposition, fibroblastic activity and ultimately scar formation. The action is direct and local—topical use is possible. The cardinal signs of inflammation—redness, heat, swelling and pain are suppressed.

 

Glucocorticoids interfere at several steps in the inflammatory response (see cellular mechanism below), but the most important overall mechanism appears to be limitation of recruitment of inflammatory cells at the local site and production of proinflammatory mediators like PGs, LTs, PAF through inhibition of phospholipase A2.

 

Corticoids are only palliative, do not remove the cause of inflammation; the underlying disease continues to progress while manifestations are dampened. They favour spread of infections because capacity of defensive cells to kill microorganisms is impaired. They also interfere with healing and scar formation: peptic ulcer may perforate asymptomatically. Indiscriminate use of corticoids is hazardous.

 

11. Immunological And Allergic Responses

 

Glucocorticoids impair immunological competence. They suppress all types of hypersensitization and allergic phenomena. At high concentrations and in vitro they have been shown to interfere with practically every step of the immunological response, but at therapeutic doses in vivo there is no impairment of antibody production or complement function. The clinical effect appears to be due to suppression of recruitment of leukocytes at the site of contact with antigen and of inflammatory response to immunological injury.

 

They cause greater suppression of CMI in which T cells are primarily involved, e.g. delayed hypersensitivity and graft rejection—basis of use in autoimmune diseases and organ transplantation (see Ch. No. 63). Factors involved may be inhibition of IL1 release from macrophages; inhibition of IL2 formation and action T cell proliferation is not stimulated; suppression of natural killer cells, etc.

 

The broad action seems to be interruption of communication between cells involved in the immune process by interfering with production of or action of lymphokines.

 


 

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