Nursing Pharmacology Chapter 28: Physiology and Pharmacology: Adrenocorticosteroids / Adrenocortical Antagonists
Major glucocorticoid: cortisol
Cortisol precursor is cholesterol.
Site of adrenal cortisol synthesis
Cortisol release modulated by ACTH
Release rate of cortisol controlled by circadian rhythm affected by ACTH pulses
75% of cortisol bound to plasma proteins
Corticosteroid-binding globulin (CBG) is α2 globulin.
Cortisol also bound to serum albumin.
Free cortisol plasma concentrations rise rapidly if CBG binding capacity is exceeded.
Factors that change plasma CBG concentration
↑estrogen administration (increased hepatic synthesis)
↑diminished synthetic capability (genetics)
Cortisol half-life is about about 60-90 minutes.
Factors that increase cortisol half-life
Large dosage of hydrocortisone administration
20% converted to cortisone by renal/other tissues with mineralocorticoid receptors.
This reaction is catalyzed by the enzyme 11-hydroxysteroid dehydrogenase.
Cortisol and cortisone are inactivated in the liver by enzymatic conversion, catalyzed by 3-hydroxysteroid dehydrogenase to:
Other metabolites: cortol, cortolone
Some metabolites ultimately excreted in the urine as 11-oxy, 17-ketosteroids
Some metabolites undergo hepatic conjugation to form glucuronic acid or sulfate derivatives
Glucocorticoid action through glucocorticoid receptors.
Member of receptor superfamily that includes:
Other receptors less well-defined
Receptors bound to heat shock proteins (Hsp/hsp90)
Free glucocorticoid hormone enters the cell
Binds to the receptor, inducing a conformational change
Receptor dissociates from heat shock proteins
Hormone-receptor complex associate to form homodimers
Homodimers actively transported to the nucleus
Homodimers bind to glucocorticoid receptor elements (GREs) of target genes
Genomic effects: protein synthesized; Indirect mediation of some genomic effects by paracrine influences of hormone-regulated cytokines on nearby cells
Some physiological effects occur to rapidly to be accounted for by gene transcription/ protein synthesis:
Feedback suppression of pituitary ACTH (unknown mechanism)
Major metabolic effects are due to direct cellular action.
Some effects occur secondary to homeostatic insulin and glucagon responses.
Physiological responses modulated by glucocorticoids ("permissive" effects)
Catecholamine vascular/bronchial smooth muscle response:
Diminished in the absence of cortisol
Restored by physiological amounts of cortisol
Catecholamine-induced lipolytic adipocytes response:
Reduced in the absence of glucocorticoids (unknown mechanism)
Gluconeogenesis (fasted state, diabetes);
Increasing hepatic and renal amino acid uptake
Increase gluconeogenic enzyme activity
Simulation of glycogen synthase
Increase glucose production from protein-- stimulating insulin release
Inhibit glucose uptake promoting increased lipolysis
Counteracted by enhanced insulin secretion which stimulates lipogenesis
Net effect: fat deposition
Stimulation: amino acid release from muscle (catabolism)
Inhibition: peripheral glucose uptake
Promotion of catabolism:
High ("supraphysiologic") glucocorticoid levels cause:
Decreased muscle mass and weakness
Reduced growth in children (not prevented by growth hormone)
Catabolic effects on bone:
Osteoporosis in Cushing's syndrome which represents a major limitation associated with long-term use.
Leukocyte-mediated; reduced leukocyte infiltration
Glucocorticoid inhibition of interactions involving cell adhesion molecules (especially on endothelial cells)
Following glucocorticoid administration:
Neutrophils levels are increased, but a decrease is noted in lymphocytes (T and B cells, monocytes, eosinophils, basophils-- movement from vasculature to lymphoid tissue)
Leukocyte and tissue macrophage function
Reduced antigenic and mitogenic responsiveness
Decreased interferon-gamma, interleukin 1, pyrogen, collagenase, elastase, tumor necrosis factor, plasminogen activator
Decreased interleukin 2
Reduction of prostaglandin and leukotriene synthesis (resulting from phospholipase A2 activation)
Reduction of cyclooxygenase in inflammatory cells (reducing prostaglandin synthesis)
Of the two isoforms of cyclooxygenase (COX1 and COX-II), glucocorticoids inhibit COX-II gene expression.
Glucocorticoids decrease capillary permeability by:
Reducing kinin activity
Reducing bacterial endotoxin activity
Reducing basophils histamine release
Adrenal-insufficiency: EEG changes (slowing of alpha rhythms)
Increased levels: behavioral changes;
Decreased pituitary release of ACTH and beta-lipotropin
Decreased TSH and FSH secretion
Increased excess acid/pepsin production (large doses)
Increased fat absorption
In addition: effective vitamin D on calcium absorption
Increased platelet production, erythrocyte production
Without adequate cortisol: renal function -- impaired
Glucocorticoids important in tissue development (structure/functional changes in the lung)
Goldfien, A.,Adrenocorticosteroids and Adrenocortical Antagonists, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 635-650.
Williams, G. H and Dluhy, R. G. , Diseases of the Adrenal Cortex, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2035-2056