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Drugs affecting endocrine system Weiwei Hu [email protected] 88208226 Dept. Pharmacology, Medical School, Zhejiang University Drugs related to adrenocortical hormones Thyroid hormones and antithyroid drugs Insulin and oral hypoglycemic drugs Cortex:adrenocorticoid Glucocorticoids (Glucocorticosteroids) Mineralocorticoids Sex hormones Medulla:epinephrine norepinepherine Adrenocorticoid Glucocorticoids : hydrocortisone, cortisone Mineralocorticoids: aldosterone,desoxycortone Sex hormones 黄山药 穿地龙 薯蓣属植物(黄山药、穿地龙) 提取薯蓣皂苷元合成皮质激素 Basic structure of adrenocorticoid drugs 甾核结构 Cortisone (可的松) aldosterone (醛固酮) Hydrocortisone (氢化可的松) Structure and Activity Relationship (1) 1位和2位碳之间改成不饱和的双键: cortisone prednisone hydrocortisone prednisolone 基本结构 Cortisone (可的松) Hydrocortisone (氢化可的松, Cortisol) Prednisone (泼尼松) Prednisolone (泼尼松龙) Structure and Activity Relationship (2) 9引入氟原子: fludrocortosone (氟氢可的松). 基本结构 (3)引入甲基: 6-methylprednisolone,dexamethasone (6甲泼尼龙, 地塞米松). (4) 16引入羟基: triamcinolone(曲安西龙). Fludrocortisone (氟氢可的松) (地塞米松) Triamcinolone (曲安西龙) Non-gene modulation Gene modulation (GCS, TH) Mechanisms of glucocorticoid actions binding to glucocorticoid receptor (GR) nuclear translocation binding to GRE or nGRE regulating related gene transcription biological effects (usually slow) Action mode of glucocorticoid drugs CBG: corticosteroid binding globulin S: glucocorticoid steroids GR: glucocorticoid receptor HSP: heat shock protein IP: immunophilin GRE: glucocorticoidresponse element Nuclear translocation of glucocorticoid receptors (GR) Dexamethasone was used GR was labeled with green fluorescent protein 1. Pharmacological effects Mechanisms of glucocorticoid actions (1) Effects on metabolisms (2) Permissive action (3) Anti-inflammatory effects (4) Effects on immune and allergy (5) Anti-shock (6) Other effects antipyretic effects effects on blood and blood-forming organs skeletal system CNS effects Glucocorticoid drugs (1) Effects on metabolisms a) Carbohydrate: blood glucose ↑: gluconeogenesis ↑, glycolysis↓, glucose utilization↓ b) Protein: synthesis ↓, degradation ↑ c) Lipid: long term use: plasma cholesterol ↑, fat redistribution (central obesity: moon face, buffalo hump) d) Water and electrolytic: Na+ excretion ↓, K+ excretion ↑, Ca2+ excretion↑and absorption↓ Glucocorticoid drugs (2) Permissive action Potentiating the effects of catecholamines and glucagon (3) Anti-inflammatory effects Acute: inhibiting microvascular leakage leukocyte infiltration Chronic: inhibiting fibroblast proliferation deposition of collagen cicatrization (瘢痕形成) Glucocorticoid drugs a) Inhibiting inflammation related proteins or enzymes inducing lipocortin, inhibiting phospholipase A2 activity, decreasing mediators: PGs, LTs, PAF inhibiting the expression of PLA2, COX-2, inducible NOS, etc. inducing ACE, degrade bradykinin. PAF Lipid-derived autocoids and related drugs Glucocorticoid drugs a) Inhibiting inflammation related proteins or enzymes inducing lipocortin, inhibiting phospholipase A2 activity, decreasing mediators: PGs, LTs, PAF inhibiting the expression of COX-2, inducible NOS, etc. inducing ACE, degrade bradykinin. b) Inhibiting cytokines: decreasing the transcription and activities of TNF, IL-1, IL-2, IL-5, IL-6, IL-8, etc. c) Inhibiting adhesion molecules d) Inducing the apoptosis of inflammatory cells Glucocorticoid drugs (4) Effects on immune and allergy Suppressing immunological functions and allergy a) inhibit DNA, RNA and protein synthesis, and induce the DNA degradation of lymphocytes b) inducing apoptosis of lymphocytes c) inhibiting transcription factor nuclear factor B (NFB) and increase expression of I B a d) inhibit the allergic mediator production (4) Effects on immune and allergy Glucocorticoid drugs (4) Effects on immune and allergy Suppressing immuneological functions and allergy a) inhibit DNA, RNA and protein synthesis, and induce the DNA degeneration of lymphocytes b) inducing apoptosis of lymphocytes c) inhibiting transcription factor nuclear factor B (NFB) activity and increase expression of I B d) inhibit the allergic mediator production Examples of glucocorticoid actions: Inhibition of proinflammatory factors (AP-1 and NFB) Glucocorticoid drugs (4) Effects on immune and allergy Suppressing immuneological functions and allergy a) inhibit DNA, RNA and protein synthesis, and induce the DNA degeneration of lymphocytes b) inducing apoptosis of T and B lymphocytes c) inhibiting transcription factor - such as nuclear factor B (NF-B) or activating protein-1 (AP-1) activity d) inhibit the allergic mediator production Glucocorticoid drugs (5) Anti-shock Septic shock a) improving cardiovascular functions b) inhibiting the production of inflammatory factors c) stabilizing lysosome membrane: decreasing the release of myocardial depressant factor (MDF) d) increasing the tolerance to endotoxin from bacteria Glucocorticoid drugs (6) Other effects a) antipyretic effects b) effects on blood and blood-forming organs red blood cells ; lymphocytes ; neutrophils (function ); eosinophils ; platelets c) skeletal system: osteoporosis d) CNS: increasing excitability (elevated mood, euphoria, insomnia, restlessness, increased motor activity) Glucocorticoid drugs 2. ADME and properties of commonly used drugs Binding to corticosteroid-binding globulin (CBG, 皮质激 素运载蛋白) in the plasma Cortisone and prednisone are reduced and transformed to hydrocortisone and prednisolone (active forms) in the liver Metabolism will be increased by hepatic enzyme inductors (phenobarbital, phenytoin, rifampine, etc.) Glucocorticoid drugs Commonly used drugs Short-acting: hydrocortisone (cortisol) cortisone 可的松 氢化可的松 Intermediate-acting: prednisone 泼尼松, 强的松 prednisolone 泼尼松龙, 强的松龙 Long-acting: dexamethasone Topical: fluocinolone 地塞米松 氟轻松 PK – Administration and Absorption Intravenous conjugated with phosphate or hemisuccinate to increase solubility Oral Prednisolone and prednisone are the most common Others include methylprednisolone, dexamethasone Inhalation Increase local effective dose and decrease systemic toxicity Glucocorticoid drugs 3. Clinical uses (1) Immune diseases a) autoimmune disorders: rheumatic fever, rheumatic carditis, rheumatic arthritis, osteoarthritis, systemic lupus erythematosus, polyarteritis nodosa, nephritic syndrome, etc. b) rejection of organ transplantation c) allergic diseases: urticaria, serum sickness, contact dermatitis, drug allergic reactions, chronic severe asthma, status asthmaticus, angioneurotic edema, etc. Glucocorticoid drugs (2) Severe infection and inflammation a) acute severe infections: merely suppressing inflammatory manifestations but at times lifesaving Causion: combination with effective antimicrobial drugs ! Usually not used in viral infections except for those with cerebral edema or severe systemic symptoms b) prevention of sequelae of some types of inflammation, such as in brain, heart, eye, joint, etc. Glucocorticoid drugs (3) Septic shock: larger dose, short-term, combined with antimicrobial drugs (4) Hemological diseases: acute lymphocytic leukemia, lymphomas, aplastic anemia, hemolytic anemia, leukocytopenia, thrombocytopenia, etc. (5) Replacement therapy (6) Topical applications: skin, eye, respiratory tract, joint (local injection) Glucocorticoid drugs 4. Adverse effects (1) Effects resulting from continued used of large doses a) Hypercorticism-like syndrome (医源性肾上腺皮质功能 亢进): central obesity (moon face, buffalo hump, etc.); hypertension; glycosuria, hypokalemia; muscular atrophy, etc. b) Increasing susceptibility to infections: specific antimicrobial drugs should be administered with GCs c) Digestive system: peptic ulcers, etc. Glucocorticoid drugs d) Cardiovascular system: hypertension, arteriosclerosis e) Myopathy and osteoporosis: vertebral compression fractures, spontaneous fractures, especially in postmenopausal women f) CNS: behavioral disturbances, induction of epileptic seizures g) Inhibition or arrest of growth in children h) skin Adverse effects of glucocorticoid drugs Effects resulting from continued used of large doses Glucocorticoid drugs (2) Withdrawal syndrome a) iatrogenic adrenocortical insufficiency: suppression of hypothalamic-pituitary-adrenal axis b) Exacerbation of the underlying diseases (rebound) (3) Contraindications psychiatric disorders; epilepsy; active peptic ulcers; fractures; hypercorticism; severe hypertension; diabetes mellitus; viral or fungal infections, etc. Feedback inhibition of CRH and ACTH by plasma cortisol Circadian rhythm of the secretion of ACTH and cortisol Plasma cortisol Glucocorticoid drugs (2) Withdrawal syndrome a) iatrogenic adrenocortical insufficiency: suppression of hypothalamic-pituitary-adrenal axis b) Exacerbation of the underlying diseases (rebound) (3) Contraindications psychiatric disorders; epilepsy; active peptic ulcers; fractures; hypercorticism; severe hypertension; diabetes mellitus; viral or fungal infections, etc. 糖皮质激素利弊对比 Glucocorticoid drugs Balance the ratio of benefit / risk before the use of GCs !!! Glucocorticoid drugs 5. Applications (1) Low dose-replacement therapy: usually using hydrocortisone, cortisone (2) Prompt intensive treatment: i.v. gtt hydrocortisone, dexamethasone (3) Long-term therapy: oral morning single dose (hydrocortisone, cortisone); alternate-day therapy (prednisone or prednisolone) for less severe and sustained patients; less suppression on hypothalamic-pituitary-adrenal (HPA) axis (4) Topical applications: skin; eye; respiratory tract Case A: Part 1 A 55-year-old male immigrant with no significant past medical history came to the emergency department for evaluation of a 3-day history of dyspnea, nonproductive cough, and fever. Physical examination revealed tachypnea(心悸), diffuse end expiratory wheezes. The patient was started empirically on a cephalosporin(头孢菌素) and a macrolide(大环内酯) for community-acquired pneumonia. Given the diffuse wheezing on exam, he was also treated with intravenous corticosteroids. Case: Part 2 Over subsequent days, the patient deteriorated, developing respiratory failure and requiring transfer to the intensive care unit. Diffuse wheezing persisted. Subsequent chest radiographs and CT scans revealed progressive bilateral diffuse granular opacities. More extensive work-up pursued to evaluate for atypical and fungal pneumonia revealed no culprit organism. Bronchoscopy revealed thick yellow mucus and cultures were sent. Ultimately, bronchial washings demonstrated the larvae of strongyloides stercoralis (粪类圆线虫). What will you do then? What do you learn from this case? The Presented Case Proper therapeutic regimen would have included discontinuing glucocorticoids, and providing appropriate anti-infectives for S. stercoralis: thiabendazole(噻苯咪唑) and ivermectin(伊维菌素) Glucocorticoids Glucocorticoids not helpful in Strongyloides stercoralis Should be considered essentially for acute use, with plans to taper or replace with other medications Exceptions are chronic or prolonged diseases for which there are no more therapeutic options Glucocorticoid drugs Balance the ratio of benefit / risk before the use of GCs !!! Future developments Further separation of their anti-inflammatory effects from the toxicity associated with their metabolic effect, e.g. Deflazacort, a predinisolone derivative with lower lipid solubility, has less activity on bone, carbohydrate and lipid metabolism Concurrent administration of other drugs to diminish the side effects: e.g. Ca++ and vitamin D supplementation; growth hormone treatment to reverse glucocorticoid-induced growth retardation in children. Elucidation of downstream pathways may allow the design of new drugs which mimic corticosteroid action, e.g. screening of small molecules that can interact with co regulator proteins or NF-kB transcription factors may represent a promising approach in this effort. Mineralocorticoid drugs Aldosterone 醛固酮 Na+ excretion , K+ excretion : edema, hypertension, hypokalemia, etc. Effects of Aldosterone Cardiac Myocyte Fibroblast Peripheral Artery Hypertrophy Hyperplasia Vasoconstriction Potassium Loss Norepinephrine Release Collagen Synthesis Endothelial Dysfunction Sodium Retention Fibrosis Hypertrophy Decreased Compliance Kidney Mineralocorticoid drugs Replacement therapy for chronic adrenocortical hypofunction (desoxycortone) Aldosterone antagonists Drugs Without Positive Inotropic Effects Used in Heart Failure Spironolactone and Eplerenone get additional function to decrease morbidity and mortality in patients with severe heart failure who are also receiving ACE inhibitors and other standard therapy. Probability of Survival (%) RALES: Aldosterone Antagonist Reduces All-Cause Mortality in Chronic HF 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 Spironolactone (25 mg) + standard care (n = 822) Placebo + standard care (n = 841) HR = 0.70 (95% CI, 0.60 to 0.82) P<.001 0 0 3 6 9 12 HR = hazard ratio; RR = risk reduction. 15 18 21 24 27 30 33 36 Months *Ejection fraction ≤35% Class III or IV symptoms at some point in prior 2 months. Pitt B et al. N Engl J Med. 1999;341:709-717. Cumulative Incidence (%) EPHESUS Co-Primary Endpoint: Total Mortality 22 20 18 (16.7%) Eplerenone + standard care (n = 3319) (14.4%) Placebo + standard care (n = 3313) 16 14 12 10 8 6 HR = 0.85 (95% CI, 0.75 to 0.96) P = .008 4 2 0 0 3 6 9 12 15 18 21 Months Since Randomization HR = hazard ratio. Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321. 24 27 Adrenocorticotropic hormone and corticosteroid synthetase inhibitors 1. Adrenocorticotropic hormone (ACTH) Used for diagnosis of pituitary-adrenocortical function Used for diagnosis of adrenocortical function after long-term glucocorticoid drug use Use after glucocorticoid withdrawal to prevent adrenocortical insufficiency Case2 part1 A 35-year-old woman with a 6-year history of Hashimoto’s thyroiditis (甲状腺炎) (autoimmune thyroiditis) with hypothyroidism, who had been well and stable on treatment with levothyoxine(左旋甲状腺素) 0.125 mg daily, came to see her physician with complaints of fatigue, lethargy(嗜 睡), and loss of appetite over the preceding 3-4 months. She also complained of intermittent nausea and dizziness on standing up from a recumbent position. Physical examination revealed a lean (瘦弱) and rather frail person with a BP of 115/70 in the supine(仰卧) position and 90/60 when she stoop up. She said that she had not been in the sun for at least a year, yet her skin was tanned and there was increased pigmentation in the creases of her palms and on the gum margins. The thyroid gland was at the upper range of normal size, and she was clinically euthyroid(甲状腺功能正常) on her usual dose of levothyroxine. Addison’s disease Use ACTH for diagnosis of pituitary-adrenocortical function Detect base level of serum ACTH Case 2 part2 Laboratory investigations revealed a mild normochromic normocytic anemia, normal T4 and T3 levels, but elevated serum K+. A random plasma sample showed a cortisol level of 200 nmol/L(normal range 170-660) and an ACTH level of 330 pmol/L(normal<22). A presumptive diagnosis of Addison’s disease was made. The patient was quickly stabilized with intravenous hydrocortisone hemisuccinate and rehydration with intravenous saline. Subsequently , a 3-day infusion of ACTH was given to test adrenal cortical function, but no adrenal response to ACTH was found. She was therefore started on long-term replacement therapy with prednisone 5 mg each morning and 2.5 mg each evening, together with fludrocortisone acetate 0.1 mg twice daily . She has felt well and completely symptom-free on this therapy. Adrenocorticotropic hormone and corticosteroid synthetase inhibitors 2. Corticosteroid synthetase inhibitors Mitotane 米托坦 damaging cells in zones of fasciculate & reticularis in the adrenal cortex Metyrapone 美替拉酮 inhibiting 11-hydroxylation Aminoglutethimide 氨鲁米特 inhibiting production (hydrocortisone and aldosterone) of 20-hydroxyl cholesterol from cholesterol Used for adrenocortical tumors or hypercorticism