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

•   Glucocorticoid Toxicity

  • Metabolic Effects

    •  Iatrogenic Cushing's syndrome

      1.  Moon facies

      2.  Fat redistribution; e.g. truncal obesity

      3.  Acne

      4.  Hirsuitism

      5.  Insomnia, increased appetite

      6.  Weight gain

      7.  Muscle wasting

      8.  Skin thinning, bruising

      9.  Hyperglycemia

      10.  Osteoporosis, diabetes, aseptic hip necrosis

      11.  Wound healing

  •  Other Effects:

    • Peptic ulcer development

    • Myopathy (triamcinolone)

    • Nausea, dizziness, weight loss (triamcinolone, methylprednisolone)

    • Psychosis (large dose corticosteroids)

    • Subcapsular cataracts

    • Increased intraocular pressure/glaucoma

    • Benign intracranial hypertension

    • Growth retardation and children

    • Cortisone/hydrocortisone in greater than physiologic amounts: mineralocorticoid effects:

      1. Sodium/fluid retention

      2. Potassium loss-- hypokalemia

      3. Hypochloremic alkalosis

      4. Hypertension

  •   Adrenal Suppression

    • Significant adrenal suppression observed with extended treatment

    • Patient should receive supplemental steroid in cases of accidental trauma/surgery

    • The presence of adrenal suppression requires slow tapering of adrenocorticoid dosage

  •  Precautions

    • Patient should be observed to detect development of:

      • Hyperglycemia

      • Glycosuria

      • Na retention with edema

      • Hypertension

      • Hypokalemia

      • Peptic ulcer

      • Osteoporosis

      • Hidden infections

  • Contraindications:

    • Peptic ulcer disease

    • Heart disease/hypertension with congestive heart failure

    • Psychoses

    • Diabetes

    • Osteoporosis

    • Glaucoma

    • Herpes simplex infection

• ACTH use

  • Probably not appropriate as a therapeutic agent unless androgen increase is desired

•  Corticosteroid dosage forms

  • Ophthalmic -- eye disease

  • Intra-articular -- joint disease

  • Hydrocortisone enemas-- ulcertive colitis

  • Aerosols (e.g.beclomethasone) -- asthma

  • Nasal spray (beclomethasone, triamcinolone, flunisolide) -- allergic rhinitis

  • Ointments, creams -- dermatological applications

• Mineralocorticoids (Aldosterone, Desoxycorticosterone, Fludrocortisone)

  • Most important mineralocorticoid: aldosterone

    • Secondarily: desoxycorticosterone (DOC)

  • Most commonly prescribed salt-retaining hormone: fludrocortisone

  • Aldosterone:

    • Synthesized in zona glomerulosa of the adrenal cortex

      • Regulation -- ACTH, angiotensin

    • Promotes sodium reabsorption by distal renal tubule (loosely coupled to potassium and hydrogen on and secretion)

    • Excessive aldosterone-- (secondary to tumor/overdosage):

      • Hypernatremia

      • Hypokalemia

      • Metabolic alkalosis

      • Hypertension

      • Increased plasma volume

    • Mechanism of Action:

      1. Mmineralocorticoid binding to cytoplasmic receptor (e.g.renal collecting tubule principal cells)

      2. Subsequent steps similar to those described for glucocorticoids

  • Desoxycorticosterone (DOC)

    • Precursor to aldosterone

    • Secretion of DOC controlled by ACTH

    • DOC secretion enhanced in abnormal conditions e.g.:

      • Adrenal carcinoma

      • Congenital adrenal hyperplasia (with reduced P450c11or P450c17)

  • Fludrocortisone (Florinef)

    • Most widely used mineralocorticoid

    • Glucocorticoid and mineralocorticoid activity

    • Used in management of adrenocortical insufficiency

• Adrenal Androgens

  • Large amounts of dehydroepiandrosterone (DHEA) secreted; smaller amounts of androstenedione and testosterone secreted

  • Probably contribute to normal maturation processes

   

• Antagonists of Adrenocortical Agents

  • Synthesis Inhibitors and Glucocorticoid Antagonists

    • Metyrapone:

      • Delective inhibitor of steroid synthesis (inhibiting 11-hydroxylation which interferes with cortisol and corticosterone synthesis)

      • Produces dizziness and gastrointestinal disturbance

      • Not widely used for Cushing's syndrome

      • Reduces cortisol production to normal in some patients with:

        • Adrenal tumor

        • Ectopic ACTH syndromes

        • Hyperplasia

      • May be useful in management of severe effects of cortisol excess on a temporary basis

      • Major adverse effects:

        1. Salt and water retention

        2. Hirsuitism

      • Most commonly used in adrenal function tests

    • Aminoglutethimide:

      • Blocks cholesterol to pregnenolone conversion

      • Reduces synthesis of all hormonally active steroids

      • Used together with dexamethasone (Decadron) or hydrocortisone (Cortef, Solu-Cortef) to eliminate estrogen and androgen production in patients with breast carcinoma

      • Used with ketoconazole (Nizoral) to reduce steroid secretion impatience with Cushing's syndrome (due to adrenocortical cancer -- not responding to mitotane)

    • Ketoconazole: (Nizoral)

      • Antifungal imidazole derivative: potent, nonselective adrenal and gonadal steroid synthesis inhibitor

      • Inhibition of P450 enzymes induces a compensatory increase in ACTH production and increases in progesterone, aldosterone and suppression of plasma renin activity

      • Occasionally causes gynecomastia by increasing estradiol/testosterone plasma ratio

      • Use for treating patients with Cushing's disease

    • Mifepristone (RU-486)

      • Synthetic, partial agonist steroid

      • Binds to glucocorticoid and progesterone receptors

      • Treatment of Cushing's syndrome (experimental)

    •  Mitotane:  toxicities resulted in drug withdrawal from U.S. market

      • Interferes with biosynthetic pathways in human adrenal cortex

    • Trilostane:  similar to aminoglutethimide;3ß-17 hydroxysteroid dehydrogenase inhibitor

  • Mineralocorticoid Antagonists

    • Spironolactone: (Aldactone)

      • Used in treating primary aldosteronism

      • Diagnostic use

      • Management of symptoms while patient awaits adenoma surgical removal

      • Treating hirsuitism in women

      •  Adverse effects:

        • Hyperkalemia

        • Menstrual abnormalities

        • Gynecomastia

        • Sedation

        • Headache

        • Gastrointestinal disturbances

        • Skin rashes

    • Drospirenone:  progestin; antagonizes aldosterone effects

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