Corticosteroids I and II (B. Law) PDF

Adrenocorticosteroids and Adrenocortical Antagonists Brian Law, Ph.D. Department of Pharmacology and Therapeutics 273-9423 [email protected]  Learning Objectives Become familiar with commonly prescribed corticosteroids and their use...

Adrenocorticosteroids and Adrenocortical Antagonists Brian Law, Ph.D. Department of Pharmacology and Therapeutics 273-9423 [email protected]  Learning Objectives Become familiar with commonly prescribed corticosteroids and their uses Understand the mechanisms by which corticosteroids suppress inflammation and the immune response Be able to manage the toxicities associated with the chronic usage of corticosteroids Distinguish between the actions of mineralocorticoids and corticosteroids  Drugs to Know Hydrocortisone (Cortisol) Prednisone/Prednisolone Dexamethasone Betamethasone Fludrocortisone Fluticasone (Inhaled)  Corticosteroids Steroid hormones produced by the adrenal cortex (glucocorticoids and mineralocorticoids). In humans, the major glucocorticoid is cortisol and the major mineralocorticoid is aldosterone. Physiological Actions of Adrenal Corticosteroids - CRH Hypothalamus + - ACTH Anterior Pituitary + + Adrenal Cortisol Aldosterone Androgens Cortex Adrenal Disorders Addison’s Disease — Hyposecretion Cushing’s Syndrome — Hypersecretion  Physiological Actions of Adrenal Corticosteroids 12th Edition, Goodman and Gillman Mechanism of Action of Glucocorticoids  Glucocorticoids – Mechanism of Action Glucocorticoids bind to glucocorticoid receptors (GR) The ligand-bound receptor complex binds to DNA elements called glucocorticoid receptor elements (GREs) to regulate the transcription of numerous genes. The ligand-bound receptor can also bind to other transcription factors, which act on non-GRE containing promoters, to regulate gene transcription. *Note: Glucocorticoids (cortisol) can bind to mineralocorticoid receptors (MR). A mineralocorticoid effect is avoided in some tissues by expression of 11b- hydroxysteroid dehydrogenase type 2, which converts cortisol to cortisone (cortisone has minimal affinity for aldosterone receptors).  Physiological Effects of Glucocorticoids Mediates the stress response Regulates glucose, lipid, and protein metabolism. Catabolic and anti-anabolic effects on bone, lymphoid and connective tissue, peripheral fat, and skin. Anti-inflammatory and immunosuppressive effects Fetal lung development Maintenance of normal blood pressure Regulation of GFR Modulation of perception and emotional functioning Many of the effects of glucocorticoids are dose-related and become amplified when large amounts are given therapeutically.  Effects of Corticosteroids on Immune Cells 1) Inhibition of migration from vascular space to site of injury ( endothelial intercellular adhesion molecules for leukocyte localization) 2) Inhibition of Phospholipase A2 and Cyclooxygenase-2 Arachidonic Acid Prostaglandins/Leukotrienes Cortisol Lipocortin PGs COX2 PLA2 membrane AA phospholipids Leukotrienes  Effects on Immune Cells Continued... 3) Mast cells and basophils Histamine release 4) Monocytes/Macrophages Production of proinflammatory cytokines (IL-1, IL-6, TNF-a) Chemotaxis response Differentiation into macrophages 5) Lymphocytes T cell response to antigens, mitogens Proliferation (IL-1 and 2) Proinflammatory Cytokine Gene Expression (ILs-1, 2, 3, 6, TNF-a, INF-g) Little direct effect on antibody formation Net Effect Immunosuppression Anti-inflammatory (frequently palliative, rather than curative) Pain Tissue destruction  Corticosteroid Drugs Short acting – t1/2 less than 12 hrs Intermediate acting – t1/2 12-36 hrs Long acting – t1/2 36-72 hrs Well-absorbed, inexpensive Alterations in the steroid molecule affect its affinity for the glucocorticoid and mineralocorticoid receptors, protein-binding affinity, side chain stability, rate of elimination and metabolic products. Prodrugs exist in some cases – for example, prednisone is rapidly converted to the active product prednisolone in the liver (Note: prednisone may be poorly activated in patients with severe liver disease).  Many routes of administration IV Oral Nasal sprays Topical Ophthalmic forms (drops) IM  Equivalent Anti-inflam- Mineralo- Oral Dose Agent matory corticoid Forms Available (mg) Short-acting corticosteroids (8-12 hours) Hydrocortisone (cortisol) 1 1 20 Oral, injectable, topical Cortisone 0.8 0.8 25 Oral Intermediate-acting corticosteroids (12-36 hours) Prednisone 4 0.8 5 Oral Prednisolone 4 0.8 5 Oral, injectable Methylprednisolone 5 0 4 Oral, injectable Triamcinolone 5 0.5 4 Oral, injectable, topical Long-acting corticosteroids (36-72 hours) Betamethasone 30 0 0.6 Oral, injectable, topical Dexamethasone 30 0 0.75 Oral, injectable, topical Mineralocorticoids Fludrocortisone 10 250 2 Oral Other (Inhaled/Nasal) Beclomethasone Fluticasone  Oral/Systemic Administration of Corticosteroid Drugs Oral Administration: Relative Doses: Replacement: Physiologic Cortisol 20 mg/day Prednisone 5 mg/day Dexamethasone 0.8 mg/day Anti-inflammatory: Therapeutic Prednisone: Initial 60-80 mg/day Chronic 20 mg/day Pharmacologic Action: Inhibits inflammatory process Little effect on underlying disease process. Palliative – relieves symptoms Physiological vs. Pharmacological Doses of Glucocorticoids Replacement Therapy Pharmacological Doses Primary adrenal insufficiency Supraphysiological doses (Addison’s disease) Numerous applications (see Secondary adrenal later slides) insufficiency (Iatrogenic suppression of HPA axis) Acute adrenal insufficiency Congenital adrenal hyperplasia After removal of adrenal glands or pituitary adenoma (Cushing’s syndrome)  Replacement Therapy Primary adrenal insufficiency (Addison’s disease) – Insufficient cortisol and aldosterone production. Treat with hydrocortisone and fludrocortisone. Secondary adrenal insufficiency – Affects only cortisol production. Treat with hydrocortisone. Acute adrenal insufficiency – Glucose, electrolyte replacement, IV hydrocortisone, eventual maintenance with hydrocortisone and fludrocortisone.  Replacement Therapy, cont. Congenital adrenal hyperplasia – Treat with hydrocortisone and fludrocortisone (if necessary). In utero administration of dexamethasone to the mother suppresses excessive androgen production and prevents female virilization. (Usually, key enzymes in cortisol synthesis are lacking, resulting in low negative feedback on CRH and ACTH production, causing high androgen production; see last slide) Cushing’s syndrome – if adrenal gland or pituitary adenoma is removed, the patient is given high IV doses of hydrocortisone on the day of surgery, followed by reduction to normal replacement levels. If adrenalectomy is performed, long-term maintenance is similar to that for adrenal insufficiency.  Therapeutic Indications for the Use of Glucocorticoids in Nonadrenal Disorders Not to be memorized for the exam Disorder Examples Allergic reactions Angioneurotic edema, asthma, bee stings, contact dermatitis, drug reactions, allergic rhinitis, serum sickness, urticaria Collagen-vascular disorders Giant cell arteritis, lupus erythematosus, mixed connective tissue syndromes, polymyositis, polymyalgia rheumatica, rheumatoid arthritis, temporal arteritis Eye diseases Acute uveitis, allergic conjunctivitis, choroiditis, optic neuritis Gastrointestinal diseases Inflammatory bowel disease, nontropical sprue, subacute hepatic necrosis Hematologic disorders Acquired hemolytic anemia, acute allergic purpura, leukemia, lymphoma, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, multiple myeloma Systemic inflammation Acute respiratory distress syndrome (sustained therapy with moderate dosage accelerates recovery and decreases mortality) Infections Acute respiratory distress syndrome, sepsis Inflammatory conditions of Arthritis, bursitis, tenosynovitis bones and joints Neurologic disorders Cerebral edema (large doses of dexamethasone are given to patients following brain surgery to minimize cerebral edema in the postoperative period), multiple sclerosis Organ transplants Prevention and treatment of rejection (immunosuppression) Pulmonary diseases Aspiration pneumonia, bronchial asthma, prevention of infant respiratory distress syndrome, sarcoidosis Renal disorders Nephrotic syndrome Skin diseases Atopic dermatitis, dermatoses, lichen simplex chronicus (localized neurodermatitis), mycosis fungoides, pemphigus, seborrheic dermatitis, xerosis Thyroid diseases Malignant exophthalmos, subacute thyroiditis Miscellaneous Hypercalcemia, mountain sickness Basic & Clinical Pharmacology, 12e > Chapter 39. Adrenocorticosteroids & Adrenocortical Antagonists  Glucocorticoids (GCs) for the Treatment of Nonendocrine Diseases (examples not to be memorized for the exam) Rheumatoid Disorders, such as SLE, RA, etc. – GCs are used to suppress the immune system and for pain relief. Used for short term relief of flare ups. Can be injected directly into joints, if needed. Renal Disease – GCs are used to treat nephrotic syndrome secondary to minimal change disease.  Glucocorticoids for the Treatment of Nonendocrine Diseases (Examples), cont. Allergic Disease – Allergic diseases with limited duration (hay fever, contact dermatitis, drug reactions, bee stings, etc.) can be treated with adequate doses of GCs. Intranasal sprays are available for allergic rhinitis. GCs provide a delayed response, so anaphylaxis requires immediate therapy with epinephrine.  Glucocorticoids for the Treatment of Nonendocrine Diseases (Examples), cont. Bronchial Asthma – GCs are used to decrease inflammation and edema. Inhaled GCs (e.g. fluticasone, beclomethasone, triamcinolone) can reduce the use of oral GCs. Oral or injected GCs are used for asthma unresponsive to inhaled steroids or other treatments.  Glucocorticoids for the Treatment of Nonendocrine Diseases (Examples), cont. Ocular Diseases – used to suppress inflammation in the eye. Skin Diseases – used for the treatment of inflammatory dermatoses. GI Diseases – used for inflammatory bowel disease. Cerebral Edema – used to reduce or prevent cerebral edema associated with parasites. Malignancies – used to treat acute lymphocytic leukemia and lymphomas because of their anti- lymphocytic effects.  Glucocorticoid Toxicity – Two categories 1. Toxicity due to withdrawal of steroid therapy. 2. Toxicity due to continued use of supraphysiological doses. The side effects from both categories are potentially life threatening. Toxicity due to withdrawal of steroid therapy STRESS Potential flare-up of the underlying disease. Potential iatrogenic acute adrenal insufficiency due to - PITUITARY suppression of the HPA axis. X ACTH May take weeks to months ADRENAL for HPA axis to return to normal. X cortisol  Reducing Toxicity 1. Tapering Dose after a therapeutic response is achieved gradual reduction in dose over weeks or 2-3 months prevents flare of inflammatory process erratic dosing hazardous 2. Alternate Day Therapy reduces side effects in patients receiving long-term therapy (metabolism/infection/growth) can prevent adrenal-pituitary suppression — allows recovery of ACTH release 3. Localized Delivery When possible, nonsystemic GC therapy should be used to deliver higher local concentrations while minimizing systemic exposure.  Toxicity due to continued use of supraphysiological doses Hyperglycemia Increased susceptibility to infection, including latent TB Psychosis Cataracts/Glaucoma Osteoporosis Growth retardation Peptic Ulcers Weight Gain Edema Hypertension Impaired wound healing Myopathy  Inhibitors of Steroid Synthesis Agents that inhibit steroidogenesis include ketoconazole, metyrapone, aminoglutethimide, trilostane, and etomidate. These drugs are rarely used to treat Cushing’s syndrome due to toxicity. Ketoconazole – an antifungal drug that is a nonselective inhibitor of adrenal and gonadal steroid synthesis. Hepatoxicity is associated with this drug. Ketoconazole inhibits CYP3A4 and P-glycoprotein, so drug interactions are possible.  Mineralocorticoids Fludrocortisone – a potent steroid with both glucocorticoid and mineralocorticoid activity. Used for the treatment of adrenocortical insufficiency associated with mineralocorticoid deficiency. Low enough doses are given to maintain potent salt-retaining activity without having anti- inflammatory or antigrowth effects.  Mineralocorticoid Antagonists Spironolactone – used to treat primary hyperaldosteronism (Conn’s syndrome) and secondary hyperaldosteronism. Binds to mineralocorticoid receptors in the cortical collecting ducts to decrease sodium and water reabsorption and decrease the secretion of potassium. Restores potassium levels to normal and reduces the risk of cardiac arrhythmias. Also used as a potassium-sparing diuretic and to treat hirsutism in women (due to anti-androgenic effects). Other mineralocorticoid antagonists include eplerenone (does not have anti-androgenic effects).  Interesting facts about corticosteroids 90% of plasma cortisol associated with Corticosteroid Binding Globulin (CBG) with the remainder free or bound to albumin. In contrast, synthetic steroids are mostly bound to albumin. 10-20% of all genes are regulated by glucocorticoids GR and MR bind cortisol with equal affinity. Cortisol mineralocorticoid effects are avoided through conversion to cortisone by 11ß-hydroxysteroid dehydrogenase Loss of ACTH only decreases aldosterone levels by about 50% (angiotensin, K+) Permissive effects of corticosteroids: Corticosteroids enhance tissue responsiveness to a number of ligands (e.g. catecholamines) by increasing the expression of their receptors From Wikipedia