Drugs affecting endocrine system

Drugs affecting endocrine system

Weiwei [email protected]. Pharmacology, Medical School, Zhejiang University

mailto:[email protected]

Drugs related to adrenocortical hormonesThyroid hormones and antithyroid drugsInsulin and oral hypoglycemic drugs

Cortex:adrenocorticoid Glucocorticoids (Glucocorticosteroids) Mineralocorticoids Sex hormones

Medulla:epinephrine norepinepherine

Adrenocorticoid

Glucocorticoids :

hydrocortisone, cortisone Mineralocorticoids ： aldosterone ， desoxycortoneSex hormones

黄山药

薯蓣属植物（黄山药、穿地龙）提取薯蓣皂苷元合成皮质激素

穿地龙

Basic structure of adrenocorticoid drugs

Cortisone( 可的松 )

Hydrocortisone( 氢化可的松 )

甾核结构

aldosterone( 醛固酮 )

http://imgsrc.baidu.com/baike/pic/item/8cf0d51318bd3330dc540159.jpg

http://imgsrc.baidu.com/baike/pic/item/8cf0d51318bd3330dc540159.jpg

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 )

Prednisone( 泼尼松 )

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

Triamcinolone( 曲安西龙 )( 地塞米

松 )

Fludrocortisone( 氟氢可的松 )

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

(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 )


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

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


(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



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 NFB)


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


(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


(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)


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.)


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

http://en.wikipedia.org/wiki/File:Oralcandi.JPG

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.


(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.


(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)


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.


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

(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

Plasm

a cortisol

(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 !!!


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 1A 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 2Over 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 !!!


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.

Aldosterone 醛固酮

Na+ excretion , K+ excretion :

edema, hypertension,

hypokalemia, etc.

Mineralocorticoid drugs

Cardiac Myocyte Fibroblast Peripheral Artery Kidney

Hypertrophy

Norepinephrine Release Collagen Synthesis

Hyperplasia

Decreased ComplianceFibrosis

Vasoconstriction

Hypertrophy

Endothelial Dysfunction

Potassium Loss

Sodium Retention

Effects of Aldosterone

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

RALES: Aldosterone Antagonist Reduces All-Cause Mortality in Chronic HF

*Ejection fraction ≤35% Class III or IV symptoms at some point in prior 2 months.

Spironolactone (25 mg) + standard care (n = 822)Placebo + standard care (n = 841)

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HR = 0.70 (95% CI, 0.60 to 0.82)

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Pitt B et al. N Engl J Med. 1999;341:709-717.

HR = hazard ratio; RR = risk reduction.

EPHESUS Co-Primary Endpoint:Total Mortality

Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321.

Eplerenone + standard care (n = 3319)

Placebo + standard care (n = 3313)

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Months Since Randomization

HR = 0.85 (95% CI, 0.75 to 0.96)P = .008

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(14.4%)

HR = hazard ratio.

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

Adrenocorticotropic hormone and corticosteroid synthetase inhibitors

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.

Case2 part1

Addison’s disease

Use ACTH for diagnosis of pituitary-adrenocortical functionDetect 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.

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

Adrenocorticotropic hormone and corticosteroid synthetase inhibitors

Drugs affecting endocrine system

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