Medical Pharmacology Chapter 28:  Physiology and Pharmacology: Adrenocorticosteroids / Adrenocortical Antagonists

Glucocorticoids (naturally occurring; cortisol -- hydrocortisone)

• Pharmacokinetics

  • Synthesis

    • Major glucocorticoid: cortisol

    • Precursor: cholesterol

    • Site of adrenal cortisol synthesis:

      1. Zona fasciculata

      2. Zona reticularis

    • Cortisol release modulated by ACTH

  • Characteristics

    • Release rate of cortisol controlled by circadian rhythm affected by ACTH pulses

    • 75% of cortisol bound to plasma proteins

      • Corticosteroid-binding globulin (CBG) --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

        • ↑pregnancy

        • ↑estrogen administration (increased hepatic synthesis)

        • ↑hyperthyroidism

        • ↑hypothyroidism

        • ↑protein deficiency

        • ↑diminished synthetic capability (genetics)

      • Cortisol half-life: about 60-90 minutes

      • Factors that increase cortisol half-life

        1. Stress

        2. Hypothyroidism

        3. Liver disease

        4. Large dosage of hydrocortisone administration

    • Cortisol metabolism:

      • 20% converted to cortisone (by renal/other tissues with mineralocorticoid receptors) -- catalyzed by 11-hydroxysteroid dehydrogenase

      • Cortisol and cortisone inactivated in the liver by conversion (3-hydroxysteroid dehydrogenase catalyzed) to:

        1. Tetrahydrocortisol

        2. Tetrahydrocortisone

      • 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

• Pharmacodynamics

  • Mechanism of Action:

    • Glucocorticoid action through glucocorticoid receptors

    • Receptor Properties

      • Member of receptor superfamily that includes:

        • Steroid receptors

        • Thyroid receptors

        • Other receptors (many with unknown function -- "orphan receptors"

      • Receptors bound to heat shock proteins (Hsp/hsp90)

    • Sequence of activation

      1. Free glucocorticoid hormone enters the cell

      2. Binds to the receptor, inducing a conformational change

      3. Receptor dissociates from heat shock proteins

      4. Hormone-receptor complex associate to form homodimers

      5. Homodimers actively transported to the nucleus

      6. Homodimers bind to glucocorticoid receptor elements (GREs) of target genes

      7. 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)

• Physiological effects of glucocorticoids

  • Major metabolic effects: due to direct cellular action

    • Some effects:secondary to homeostatic insulin and glucagon responses

  • Physiological responses modulated by glucocorticoids ("permissive" effects)

    1. Catecholamine vascular/bronchial smooth muscle response:

       • Diminished in the absence of cortisol

       • Restored by physiological amounts of cortisol

    2. Catecholamine-induced lipolytic adipocytes response:

       • Reduced in the absence of glucocorticoids (unknown mechanism)

• Metabolic Effects

  • Glucocorticoids: stimulate and are required for:

    • Gluconeogenesis (fasted state, diabetes);

    • Increasing hepatic and renal amino acid uptake

    • Increase gluconeogenic enzyme activity

  • Hepatic effects

    • Simulation of glycogen synthase

    • Increase glucose production from protein-- stimulating insulin release

  • Adipocytes

    • Inhibit glucose uptake promoting increased lipolysis

    • Counteracted by enhanced insulin secretion which stimulates lipogenesis

    • Net effect: fat deposition

  • Glucocorticoid effects most prominent in the fasting state, through:

    • Stimulation:  gluconeogenesis

    • Stimulation: amino acid release from muscle (catabolism)

    • Inhibition: peripheral glucose uptake

    • Stimulation: lipolysis

• Catabolic Effects

  • Promotion of catabolism:

    • Lymphoid tissue

    • Connective tissue

    • Muscle

    • Fat

    • Skin

  • High (supraphysiologic) glucocorticoid levels cause decreases in muscle mass and weakness

  • Reduced growth in children (not prevented by growth hormone)

  • Catabolic effects on bone:

    •  Osteoporosis in Cushing's syndrome

    •  Major limitation in long-term use

• Anti-inflammatory/Immunosuppressive Effects

  • Reduction in inflammation

    • 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)

    • Glucocorticoids inhibit:

      • Leukocyte and tissue macrophage function

      • Reduced antigenic and mitogenic responsiveness

      • Macrophage effects:

        • Decreased interferon-gamma, interleukin 1, pyrogen, collagenase, elastase, tumor necrosis factor, plasminogen activator

      • Lymphocyte effects:

        • 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:

      1. Reducing kinin activity

      2. Reducing bacterial endotoxin activity

      3. Reducing basophils histamine release

• Other Effects

  • 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)

1. Goldfien, A.,Adrenocorticosteroids and Adrenocortical Antagonists, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 635-650.

2. 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