PHARM: Glucocorticoids and Mineralocorticoids

Glucocorticoid Mechanism of Action

Same as other steroids

1. Passive diffusion into target cells through CBG

2. Binding to Hsp90 chaperone proteins

3. Binding of specific cytoplasmic GC receptors

4. Dimerization and activation of receptor allows to enter nucleus

5. Alteration of transcription and translation

Hydrocortisone/Cortisol

• Physiological effect

• Pharmacokinetics

• Clinical effects

• Physiological effect:

  • Endocrine/feedback: Rapid suppression of ACTH.

  • Metabolism: ↑ Gluconeogenesis, ↑ glycogen storage, ↓ glucose uptake → hyperglycemia/diabetes.

  • Protein/bone: Protein catabolism → ↓ muscle mass; ↓ vitamin D action → osteoporosis.

  • Fat: Redistribution to face/abdomen (Cushingoid habitus).

  • Immune/inflammation: Strong anti-inflammatory & immunosuppressive (↓ PLA₂, ↓ prostaglandins/leukotrienes, ↓ COX-2, ↓ leukocyte activity).

  • Vascular: ↑ Vasoconstriction; ↓ histamine release.

  • GI: ↑ Gastric acid/pepsin → peptic ulcers.

  • Lungs (fetus): ↑ Surfactant production

• Pharmacokinetics:

  • Good oral bioavailability and topically absorbed

  • HL: 60-90 min

  • Metabolized by liver and kidney

• Clinical effects:

  • Diagnosis and tx of disturbed adrenal function

  • Management of inflammatory and immunologic disorders

  • Tx of allergic rxns

Synthetic Glucocorticoids

• Physiological effect

• Pharmacokinetics

• Clinical effects

• Physiological effect: same as natural

• Pharmacokinetics:

  • Rapid and complete oral absorption

  • Prolonged HL

  • Decreased mineralocorticoid activity

• Types:

  • Short-medium acting:

    • Cortisone, Prednisone, Prednisolone, Methylprednisolone

      • Have mineralocorticoid activity!

  • Intermediate: Triamcinolone

    • No mineralocorticoid activity!

    • Enhanced anti-inflammatory activity, topical and duration

  • Long-acting: most potent in the market, no mineralocorticoid activity, enhanced topical activity

    • Dexamethasone: used in differential diagnoses of Addison’s disease:

      • 50% reduction of Cortisol: pituitary adenoma

      • No effect in cortisol:

        • Reduced ACTH: adrenal tumor

        • Increased ACTH: ectopic ACTH-producing tumor in another site, likely lungs

    • Betamethasone: stimulates fetal surfactant bc it has less plasma binding proteins and is able to cross thru the placenta

  • Locally acting: Beclomethasone, Budesonide, Ciclesonide, Fluticasone, Flunisolide, Mometasone

    • Absorbed rapidly and avoid systemic effects/side effects

    • Used in management of allergic rhinitis, asthma (+beta agonist for bronchodilation) and other inflammatory conditions

    • Budesonide is used for Crohn’s disease and ulcerative colitis

    • Fluticasone/Vilanterol is used for COPD and emphysema

• Clinical use:

  • Tx of inflammatory, autoimmune, allergic and hematologic disorders

  • Organ transplant rejection

  • Infections -but must be accompanied by antibiotics

  • Stimulation of fetal lung maturation

  • Replacement therapy for Cushing’s or adrenalectomy

  • Addison’s Disease:

    • 1^o: hydrocortisone + fludrocortisone (mineralocorticoid)

    • 2^o: hydrocortisone and + fludrocortisone if angiotensin II isn’t enough to manage mineralocorticoid secretion

  • Congenital adrenal hyperplasia (CAH): reduced cortisol synthesis makes adrenal glands grow to make up for deficiency

    • In females, testosterone cannot convert to estradiol therefore there might be genital ambiguity

    • Tx with GC and MC combo

  • Rheumatoid arthritis, lupus, arteritis, multiple sclerosis

  • Chemotherapy vomiting

  • hematological cancers

• Adverse effects: Therapy should be tapered down slowly if not u might get cushing’s

  • Don’t use in heart disease or other conditions that will be worsened by the side effects

Mineralocorticoids/Aldosterone

• Physiological effect

• Analogs

• Clinical use

• Physiological effect: synthesized in zona glomerulosa of adrenal cortex and regulated by ACTH and Angiotensin II

  • Same mechanism of action as other steroids

  • Promotes reabsorption of sodium and excretion of potassium and H+ ions→ overall water retention

• Analogs: none

  • Fludrocortisone: synthetic oral corticosteroid that has both glucocorticoid and mineralocorticoid activity; Most prescribed

    • Used for Addison’s disease, congenital adrenal hyperplasia, and adrenalectomy

• Adverse Effects:

  • Hypernatremia, Hypokalemia, metabolic alkalosis (due to H+ loss)

  • Edema and Hypertension

Corticosteroid Antagonists

• Physiological effect

• Types

• Clinical use

• Physiological effect: inhibit corticosteroid/mineralocorticoid activity

  • Adverse effects: hyponatremia, Hyperkalemia, hypotension, menstrual abnormalities

• Types:

  • Spironolactone - mineralocorticoid antagonist

    • Inhibits renal tubule sodium reabsorption and potassium excretion → Diuretic

    • Tx of edema and ascites due to hepatic cirrhosis, primary hyperaldosteronism (Conn’s Syndrome)

  • Eplerenone: selective mineralocorticoid receptor antagonist

    • Diuretic, inhibits Na reabsorption and K excretion

    • Tx of hypertension, Heart failure

  • Mifepristone: both glucocorticoid and progesterone receptor antagonist

    • Tx of hyperglycemia, abortion inducer