Drugs affecting endocrine system Weiwei Hu huww@zju.edu.cn 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) Hydrocortisone (氢化可的松) aldosterone (醛固酮)

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 Prednisone (泼尼松) 基本结构 Cortisone (可的松) Hydrocortisone (氢化可的松, Cortisol) Prednisolone (泼尼松龙)

Structure and Activity Relationship (2) 9引入氟原子: fludrocortosone (氟氢可的松). (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). 基本结构 (地塞米松) Fludrocortisone (氟氢可的松) Triamcinolone (曲安西龙)

Gene modulation (GCS, TH) 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: glucocorticoid-response 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.

Lipid-derived autocoids and related drugs 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 (NF-B) 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 (NF-B) activity and increase expression of I B a d) inhibit the allergic mediator production

Examples of glucocorticoid actions: Inhibition of proinflammatory factors (AP-1 and NFB)

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) 氢化可的松 cortisone 可的松 Intermediate-acting: prednisone 泼尼松, 强的松 prednisolone 泼尼松龙, 强的松龙 Long-acting: dexamethasone 地塞米松 Topical: fluocinolone 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

Balance the ratio of benefit / risk before the use of GCs !!! 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, non-productive 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

Balance the ratio of benefit / risk before the use of GCs !!! 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 Kidney Hypertrophy Slide 9 Activation of the renin-angiotensin-aldosterone system plays a key role in the pathophysiology of heart failure. Hypoperfusion of the kidney stimulates the release of renin which catalyzes the synthesis of angiotensin I from angiotensinogen. The angiotensin converting enzyme (ACE) converts angiotensin I into angiotensin II. Angiotensin II exerts a wide range of biologic actions which contribute to disease progression in heart failure. Angiotensin II is a potent vasoconstrictor contributing to increased systemic vascular resistance. Angiotensin II results in cardiac and vascular cellular hypertrophy as well as myocardial fibrosis. Angiotensin II plays a fundamental role in progressive left ventricular remodeling that occurs in heart failure and following myocardial infarction. Increased oxidative stress and endothelial dysfunction also result. Since the renin-angiotensin-aldosterone system plays such a key role in the pathophysiology of heart failure, medications that block this system would be expected to beneficial in heart failure patient management. (Francis GS. Pathophysiology of the heart failure clinical syndrome. In: Topol EJ, ed. Textbook of Cardiovascular Medicine. Philadelphia: Lippincott-Raven; 1998;2179-2203.) Hyperplasia Vasoconstriction Potassium Loss Endothelial Dysfunction Norepinephrine Release Collagen Synthesis Sodium Retention Hypertrophy Fibrosis Decreased Compliance

Mineralocorticoid drugs Replacement therapy for chronic adrenocortical hypofunction (desoxycortone)

Aldosterone antagonists 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. Drugs Without Positive Inotropic Effects Used in Heart Failure

Probability of Survival (%) RALES: Aldosterone Antagonist Reduces All-Cause Mortality in Chronic HF Added (25 mg) to top key, per Dr Conti Added RR arrow, per Dr Fonarow 1.00 Spironolactone (25 mg) + standard care (n = 822) 0.95 Placebo + standard care (n = 841) 0.90 0.85 0.80 Added asterisk footnote for title, per Dr Conti HR = 0.70 (95% CI, 0.60 to 0.82) 0.75 Probability of Survival (%) 0.70 0.65 The Randomized Aldactone Evaluation Study (RALES) was designed to test the hypothesis that the aldosterone-receptor blocker spironolactone would reduce the risk of death in patients with severe HF from left ventricular systolic dysfunction. Pitt et al enrolled 1663 patients with severe HF and an LVEF of ≤35% who were being treated with an ACE inhibitor (if tolerated) and a loop diuretic. Digoxin and vasodilators were allowed, but potassium-sparing diuretics were not. A total of 833 patients were randomized to spironolactone 25 mg qd plus standard care and 841 patients to placebo plus standard care. The primary endpoint was death from all causes. The trial was terminated early, after a mean follow-up of 24 months, because an interim analysis revealed that the effect of spironolactone on the primary endpoint exceeded the prespecified critical z value. The placebo group experienced 386 deaths (46%), and the spironolactone group experienced 284 deaths (35%). The relative risk of death was 0.70 (95% CI, 0.60 to 0.82, P<.001). The 30% risk reduction in the spironolactone group was attributed to a lower risk of death from progressive HF as well as a lower risk of sudden death from cardiac causes. The incidence of serious hyperkalemia was 1% in the placebo group and 2% in the spironolactone group. However, the incidence of gynecomastia or breast pain in men was 1% in the placebo group and 10% in the spironolactone group (P<.001). Reference Pitt B, Zannad F, Remme W, et al, for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709-717. Figure reprinted with permission. ©1999 Massachusetts Medical Society. All rights reserved. 0.60 0.55 P<.001 0.50 0.45 3 6 9 12 15 18 21 24 27 30 33 36 Months HR = hazard ratio; RR = risk reduction. *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.

EPHESUS Co-Primary Endpoint: Total Mortality Added % values, per Dr Conti Cumulative Incidence (%) 22 20 18 16 14 12 10 8 6 4 2 3 9 15 21 24 27 Months Since Randomization HR = 0.85 (95% CI, 0.75 to 0.96) P = .008 Eplerenone + standard care (n = 3319) (16.7%) Added RR arrow, per Dr Fonarow (14.4%) Placebo + standard care (n = 3313) over the duration of the study, 478 patients in the eplerenone group (14.4%) and 554 patients in the placebo group (16.7%) died. The relative risk of death from any cause for patients receiving eplerenone versus placebo was 0.85 (P = .008), for a relative risk reduction of 15%. The Kaplan-Meier mortality estimate at 1 year was 11.8% in the eplerenone group and 13.6% in patients receiving placebo. Eplerenone maintained a survival benefit throughout the follow-up period. Patients were followed for a mean of 16 months. Improved CV survival was primarily driven by reductions in sudden death, acute MI, and HF. There were 478 deaths (14.4%) in the eplerenone group and 554 deaths (16.7%) in the placebo group. It is important to note that the 15% reduction in total mortality achieved in the eplerenone group was above and beyond that achieved by optimal standard therapy. Reference Pitt B, Remme W, Zannad F, et al, for the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321. Figure adapted with permission. ©2003 Massachusetts Medical Society. All rights reserved. HR = hazard ratio. Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321.

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 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