Steroids .pdf

Steroids Overview ○ Adrenal glands are located above the kidneys ○ Two major parts: Adrenal cortex Adrenal medulla ○ Produce hormones that help regulate metabolism, immune system, BP, response to stress and othe...

Steroids Overview ○ Adrenal glands are located above the kidneys ○ Two major parts: Adrenal cortex Adrenal medulla ○ Produce hormones that help regulate metabolism, immune system, BP, response to stress and other essential functions Steroid synthesis ○ Adrenal cortex accounts for 90% of adrenal gland ○ Three major layers, produces 3 major steroid hormones Mineralocorticoids Glucocorticoids Adrenal androgens Endogenous steroids ○ Aldosterone is major Mineralocorticoid ○ Cortisol is major glucocorticoid ○ DHE is major adrenal androgen Other effects of glucocorticoids ○ Induce enzymes involved in gluconeogenesis and have anti-insulin effect ○ Insufficiency can lead to hypoglycemia during stress ○ Activates enzymes involved in protein catabolism which increases supply of AAs needed for gluconeogenesis ○ Stimulate lipolysis and inhibit uptake of glucose by adipose tissue Drugs ○ Many semi-synthetic glucocorticoid drugs Used to attain anti-inflammatory effects supraphysiologic doses Used as replacement therapy in treatment of adrenal insufficiency and treatment of adrenogenital syndrome ○ Mineralocorticoids used as a replacement therapy in adrenal insufficiency Mineralocorticoids ○ Aldosterone is not suitable for clinical use, causes electrolyte disturbances ○ Fludrocortisone is used as replacement therapy in patient with primary adrenal insufficiency (Addison’s disease) Glucocorticoids ○ Many glucocorticoids available for PO, parenteral, inhalation, and topical administration ○ Used to treat inflammatory, allergic, autoimmune and other disorders ○ Topical and inhalation preferred, well tolerated and avoids most systemic side effects Classification ○ Glucocorticoids classified by potency and duration of action ○ When given systemically, duration of action is determined by potency at glucocorticoid receptors, not half life. ○ Highly potent drugs evoke longer-lasting stimulation ○ Low potency, short acting  ○ Medium potency, intermediate acting ○ High potency, long acting Low-potency, short acting ○ Hydrocortisone is pharmaceutical version is cortisol ○ Duration of action is 8-12 hours ○ Equal glucocorticoid and mineralocorticoid effects ○ Preferred for replacement therapy in patient with adrenal insufficiency ○ Anti-inflammatory properties by more potent drugs usually used instead Medium-potency, intermediate-acting ○ Prednisone ○ Prednisolone ○ Methylprednisolone (medrol) ○ Triamcinolone ○ Glucocorticoids most often used for systemic treatment ○ Prednisone rapidly converted in body to prednisolone ○ Duration of action 12-36 hours ○ Used to treat cancer, inflammation, allergies, and autoimmune disorders High-potency, long acting ○ Betamethasone ○ Dexamethasone Related drugs, stereo-isomers Betamethasone can be systemically, topical preps used to treat psoriasis, seborrheic or atopic dermatitis Dexamethasone used in dexamethasone suppression tests and treatment of neoplastic, infectious, and other inflammatory conditions Budesonide is a long-acting inhaled glucocorticoid Anti-inflammatory effects ○ Suppress activation of T lymphocytes ○ Suppress production of cytokines by activated T helper cells ○ Decrease release of chemical mediators of inflammation (histamine, prostaglandins, leukotrienes) ○ Stabilize lysosomal membranes of neutrophils, prevent release of catabolic enzymes ○ Cause vasoconstriction and decrease capillary permeability ○ Decrease activation of macrophages Indications ○ Inflammation, allergies, autoimmune disorders ○ Cancer ○ Respiratory distress syndrome ○ Adrenal insufficiency ○ Congenital adrenal hyperplasia ○ Cushing syndrome ○ Dermatologic conditions  Indications: Inflammation ○ Used to suppress inflammation and immune dysfunction ○ Counteracts inflammation caused by trauma, extreme, noxious chemicals, radiation damage and microbial pathogens ○ Also suppress inflammation caused by allergic and autoimmune reactions ○ Beclomethasone and mometasone available for nasal insufflation, oral inhalation to treat Ar and asthma ○ Ciclesonide is a newer agen, used for hay fever and AR ○ Many preparations available to treat corneal inflammation and keratitis Tobramycin/loteprednol (zylet) Difluprednate (Durezol) ○ Other combinations with antibiotics used to treat superficial bacterial infections of external auditory canal (swimmers ear) Neomycin/polymyxin B/ hydrocortisone (Cortisporin) Ciprofloxacin/dexamethasone (ciprodex) Indications: Cancer ○ Glucocorticoids have lymphotoxic effects ○ Used in treatment of lymphocytic leukemias and lymphomas ○ Dexamethasone is long-acting, used in combo with other drugs to prevent emesis during chemo Indications: RDS ○ Betamethasone used to prevent respiratory distress syndrome in premature infants ○ Acts by promoting fetal lung maturation similar to endogenous cortisol ○ Readily enters placental circulation Indications: dermatologic conditions ○ High potency steroids Desoximetasone fluocinonide ○ Very high potency steroids Betatheasone dipropionate clobetasol Indications: other disorders ○ Glucocorticoids used to treat hypercalcemia ○ Drug of choice for managing sarcoidosis ○ Also used as immunosuppressant to prevent organ graft rejection Systemic administration ○ Highly lipid soluble, well absorbed from gut after PO administration ○ Administered orally to treat allergic reactions, autoimmune disorders, neoplastic diseases, and other conditions ○ Administered parenterally for acute adrenal crisis, acute allergic reactions Adverse effects ○ Supraphysiologic doses given >2 weeks produce tissue and metabolic changes similar to cushing syndrome Moon face Fat deposits in supraclavicular and dorsocervical regions (“buffalo hump”) Hirsutism, weight gain, muscle wasting, weakness  Acne, bruising, thinning of skin Metyrapone ○ Inhibits synthesis of glucocorticoids by blocking an enzyme that catalyzes final step in synthesis ○ Steroid biosynthesis is shifted to production of adrenal androgens ○ Occasionally used to treatment Cushing syndrome refractory to other treatment and not candidates for surgery ○ Also sometimes used to test adrenal function Ketoconazole and fluconazole ○ Antifungal drugs that inhibit several cytochrome P450 enzymes involved in steroid biosynthesis ○ Can be used to treat cushing syndrome ○ Also inhibit androgen synthesis and may cause gynecomastia in males Corticosteroid receptor antagonists ○ Spironolactone Mifepristone Spironolactone ○ Synthetic steroid that competes with aldosterone for mineralocorticoid receptor in renal tubules ○ Used as K-sparing diuretic and an agent to treat hyperaldosterone ○ Drug of choice for primary hyperaldosteronism caused by adrenal hyperplasia Surgery treatment of choice for hyperaldosterone secondary aldosterone-producing adenoma