thyroid hormones and antithyroid drugs dept of pharmacology shi-hong zhang ( 张世红 )...

Thyroid hormones and antithyroid drugs

Dept of Pharmacology

Shi-Hong Zhang ( 张世红 )

shzhang713@zju.edu.cn

Front view

Thyroid gland

Thyroid hormones

1. Uptake of iodide

2. Oxidation of iodide (peroxidase) and iodination and coupling of tyrosine

3. Formation of thyroxine (T4) and triiodothyronine (T3) from iodotyrosine

4. Secretion of thyroid hormones (proteolytic enzymes)

5. Regulation by thyroid stimulating hormone (TSH), T4, T3

HyperthyroidismHyperthyroidism

颤抖

腱反射亢进

心慌，心脏肥大

甲状腺肿大，突眼，情绪激动 多食、腹泻、消瘦

HypothyroidismHypothyroidism

cretinism ( 呆小症 )

瘿

simple goiter( 单纯性甲状腺肿 )

• Hyperthyroidism:– antithyroid drugs: thiourea derivatives 硫脲类

iodine and iodides 碘和碘化物 receptor antagonists

Radioiodines 放射性碘 : 131I

• Hypothyroidism: – thyroid hormones – iodine and iodides

Therapeutic drugs on thyroid dysfunction

丙硫氧嘧啶

卡比马唑

甲巯咪唑Thiourea derivatives

Antithyroid drugs

Thiourea derivatives

1. Pharmacological effects

(1) Inhibiting the formation of thyroid hormones by interfer

ing with iodination: inhibiting peroxidation, then the iodi

nation and coupling

Symptom relieving: 2-3 weeks

Basic metabolic rate returning: 1-2 months

(2) Inhibiting peripheral deiodination of T4: T4 T3 (propy

lthiouracil 丙硫氧嘧啶 )

Antithyroid drugs

Thiourea derivatives1. Pharmacological effects(3) Inhibiting glucose metabolism by down-

regulating βreceptor

(4) Immunosuppression: TSI↓

Antithyroid drugs

Mechanism of inhibition of thyroid hormone synthesis by thioureas: Thioureas are oxidized by oxidized thyroid peroxidase (TPO)

2. Clinical uses

(1) Non-operative therapy of hyperthyroidism: latent period

(2) Preoperative therapy of hyperthyroidism: combined with iodid

e

(3) Thyrotoxic crisis: combined with larger dose of iodide, propylt

hiouracil

 3. Adverse effects

(1) Agranulocytosis (0.2%)

(2) Hypersensitivity

(3) GI reactions

(5) Goitrogenic action (goiter): TSH↑

Thiourea derivatives

Iodine and iodides

1. Pharmacological effects

(1) Small doses: simple goiter

(2) Larger doses: inhibiting the release of thyroid hormones (proteolysis ) and synthesis

After iodide use, the thyroid vascularity is reduced, and the gland becomes much firmer, the cells become smaller.

Antithyroid drugs

Mechanism of iodidesMechanism of iodides

2. Clinical uses(1) Simple goiter

(2) Preoperative therapy of hyperthyroidism: combined with thiourea derivatives

(2) Thyrotoxic crisis: combined with thioure

a derivatives (propylthiouracil) Lugol’s solution 卢戈氏液 : 5% iodine and 10

% potassium iodide

Antithyroid drugs

3. Adverse effects

(1) Acute effects: hypersensitivity, angioedema, swelling of the larynx

(2) Chronic intoxication (iodism)

(3) Thyroid dysfunction: exacerbation of hyperthyroidism, goiter

Antithyroid drugs

Radioiodines

• 131I, 125I, 123I

• Destroying thyroid tissue: βray

• Careful use for hyperthyroidism and differentiated thyroid carcinoma

• Radioactive iodine uptake test

Antithyroid drugs

receptor antagonists

1. Pharmacological effects(1) Heart: 1 block

(2) CNS: relieving anxiety

(3) Presynaptic 2 receptor: NE release

2. Clinical usesAdjuvant therapeutic drug

Antithyroid drugs

Pancreatic hormones & antidia

betic drugs

胰高血糖素胰岛素生长抑素

Overview of Glucose Regulation by insulin

Amended from Dinneen SF. Diabetes Med. 1997;14(suppl 3):S19-24.

Insulin secretion

Glucose disposal

Persistent Hepatic Glucose

Output

Glucose absorption

lipogenesis

lipolysis

Glycogenesis

Different forms of diabetes mellitus

“Beta-cell failure”prediabetic metabolic syndrome

Complications of diabetes mellitus

• Acute complications– Diabetic ketoacidosis ( 酮症酸中毒 )

– Hyperosmotic nonketotic coma( 高渗性非酮症性昏迷）

• Chronic complications– Cardiovascular diseases– Renal damage– Retinal damage– Nerve degeneration– Infection – Myopathy – etc.

Pharmacological therapy

Insulin Oral hypoglycemic drugs

Insulin secretagogues ( 促胰岛素分泌药 ):Sulfonylureas 磺酰脲类Meglitinides (Non-SU) 格列奈类GLP-1 agonists and DPP-4 inhibitors

Insulin sensitizers 胰岛素增敏剂 :Thiazolidinediones (TDs ，噻唑烷二酮类 )Biguanides 双胍类

α-glucosidase inhibitors α- 葡萄糖苷酶抑制剂 Amylin analogue 胰淀粉样多肽类似物 Aldose reductase inhibitor 醛糖还原酶

A.A. Insulin Insulin

Frederick Sanger (1918- )

A. Insulin

1. Pharmacological effects

(1) Carbohydrate metabolism: reducing blood glucose levels by

glycogenolysis , glycogen synthesis , gluconeogenesis (ket

one bodies ), glucose transport .(2) lipid metabolism: fat synthesis , lipolysis , plasma free fatt

y acids (3) Protein metabolism: active transport of amino acids , incor

poration of amino acids into protein , protein catabolism (4) Mechanism of insulin actions

Interacting with insulin receptor

2. Clinical uses(1) Insulin-dependent patients with diabetes mellitu

s (type 1 diabetes mellitus)

(2) Insulin-independent patients: failure to other drugs

(3) Diabetic complications: diabetic ketoacidosis ( 酮症酸中毒 ), hyperosmotic nonketotic coma （高渗性非酮症性昏迷） (4) Critical situations of diabetic patients: fever, sever

e infection, pregnancy, trauma, operation

(5) Others: promotion of K+ uptake into the cells

A. Insulin

3. Preparations

Fast-acting insulin

Regular insulin 正规胰岛素Monocomponent insulin 单组分胰岛素

• Start working 0.5-1h after injection, reach peak 2-4h, an

d last 5-7h.

A. Insulin

3. Preparations

Intermediate-acting insulin

Neurtral protamine hagedorn (NPH) 中性精蛋白锌胰岛素Isophane insulin 低精蛋白锌胰岛素Globin zinc insulin 珠蛋白锌胰岛素

• Start working 1-1.5h after injection, reach peak 8-12h, a

nd last 24h.

A. Insulin

3. Preparations

Long-acting insulin

Protamine zinc insulin(PZI) 鱼精蛋白锌胰岛素

• Start working 4-8h after injection, reach peak 14-20h, a

nd last 24-36h.

A. Insulin

3. Preparations

Mixed insulin

Human insulin isophane 低精蛋白锌胰岛素 +

Human insulin 人胰岛素

• Start working 0.5h after injection, reach peak 2-12h, an

d last 16-24h.

A. Insulin

3. Preparations

Fast-acting insulin analogs

Insulin aspart 门冬胰岛素Insulin lispro 赖脯胰岛素

• Start working 5-15 minutes after injection, reach peak a

t 1h, and last ~4 hours.

A. Insulin

3. Preparations

Super-long acting insulin analogs

Insulin glargine 甘精胰岛素• Onsets 1-2 h after injection and continues to work for a

s long as 24 hours.

• Used to treat type 1 or type 2 diabetes mellitus.

• Less soluble than native human insulin at physiological

pH, and precipitates in skin following subcutaneous inje

ction, resulting in delayed absorption.

A. Insulin

• For patients who eat meals out, may consider use of an insulin pen.

• Most insulins now available as pen

Insulin Pump and Glucose Monitoring

Insulin Pump – “Open Loop”Patient sets basal infusion rate and superimposedboluses

Continuous Glucose Monitor

“Closed Loop” insulin pump system is ultimate goal: infusion rate adjusted based on input from continuous glucose monitor.

4. Adverse effects(1) Hypersensitivity: treated with H1 receptor antagonist,

glucocorticoids

(2) Hypoglycemia: adrenaline secretion (sweating, hunge

r, weakness, tachycardia, blurred vision, headache, etc.), tre

ated with 50% glucose

(3) Insulin resistance: acute, chronic

(4) Lipoatrophy and lipohypertrophy

(5) Weight gain

(6) Refractive errors

(7) Edema

A. Insulin

B. Oral hypoglycemic drugs Insulin secretagogues （促胰岛素分泌药） :

Sulfonylureas 磺酰脲类Meglitinides (Non-SU) 格列奈类 ( 苯丙胺酸衍生物 )GLP-1 agonists and DPP-4 inhibitors

Insulin sensitizers 胰岛素增敏剂 :Thiazolidinediones (TDs ，噻唑烷二酮类 )Biguanides 双胍类

α-glucosidase inhibitors α- 葡萄糖苷酶抑制剂 Amylin analogue 胰淀粉样多肽类似物 Aldose reductase inhibitor 醛糖还原酶

Sulfonylureas （磺酰脲类）

Tolbutamide (D860) 甲苯磺丁脲Chlorpropamide 氯磺丙脲Glibenclamide 格列本脲 ( 优降糖 )

Glipizide 格列吡嗪（美吡达）Gliclazide 格列齐特 ( 达美康 )

B. Oral hypoglycemic drugs

1. Pharmacological effects 1) Increase insulin release: blocking ATP sensitive

K+ channel, Ca2+ inflow

Sulfonylureas

1. Pharmacological effects 2) Increase receptor affinity to insulin (long-ter

m use)

3) Promote glucose uses

4) Increase sensitivity of cells to glucose

5) Anti-uretic effect (Chlorpropamide 氯磺丙脲 )

6) Anti-platelet effect (Gliclazide 格列齐特 )

Sulfonylureas

2. Clinical uses

(1) Insulin-independent diabetic patients (t

ype 2): alone or combined with insulin

(2) Diabetes insipidus ( 尿崩症 ): Chlorpropamide ( 氯磺丙脲 ): anti-uretic hormone

(ADH)

Sulfonylureas

3. Adverse effects

(1) GI reactions

(2) CNS reactions

(3) Hypoglycemia: especially in elderly, hepatic or renal insufficiencies

(4) Others: leukopenia ( 白细胞减少 ), cholestatic jaundice ( 胆汁郁积性黄疸 ), hepatic damage

Sulfonylureas

4. Drug interactions(1) Potentiation of hypoglycemic effects

replacement in plasma protein binding: salicylic acid,

sulfates, indomethacin, penicillin, warfarin, etc.

inhibition of hepatic microsomal enzymes:

chloramphenicol, warfarin

(2) Attenuation of hypoglycemic effects

induction of hepatic microsomal enzymes: phenytoin,

phenobarbital, etc.

interactions in pharmacodynamics: glucagon,

thiazides, etc.

Sulfonylureas

• Act by binding to SUR1 on beta cells to promote insulin secr

etion. • Repaglinide ( 瑞格列奈 ) and Nateglinide ( 那格列奈 ) are c

urrent agents in class. • Major advantage is rapid onset and offset

– Can dose just prior to meals with better post-prandial con

trol– Fewer overnight lows– Ability to skip the dose if skip the meal.

• Efficacy for repaglinide appears to be similar to SU’s

Non-SU Insulin Secretagogues

• Hepatic metabolism permits use in patients with impaire

d renal function.• Major side effect is hypoglycemia.

• Many drug interactions. Most concerning is gemfibrozil

( 吉非罗齐 ) which increases repaglinide ( 瑞格列奈 ) co

ncentration and may result in prolonged effect.

• Cost may be an issue (1 or 2 mg tabs: $122.09/month a

t drugstore.com)

Non-SU Insulin Secretagogues

• Exenatide ( 依可那肽 ): only available as injection

• Sitagliptin ( 西他列汀 )

GLP-1 agonists and DPP-4 inhibitors

Insulin sensitizersThiazolidinediones (TZDs) 噻唑烷酮类化合物 Rosiglitazone 罗格列酮 Pioglitazone 吡格列酮Biguanides （双胍类） Metformin 二甲双胍

B. Oral hypoglycemic drugs

1. Pharmacological effects Selective agonists for nuclear peroxisome prolif

erator activated receptor- (PPAR , 过氧化物酶增殖体激活受体 ), increasing glucose transport into mus

cle and adipose tissue.

(1) Lowering insulin resistance

(2) Lipid metabolism regulation: TG, free fatty acid

(3) Preventive effects on diabetic complications

(4) Improve cell function

Thiazolidinediones

2. Clinical uses Used for treatment of insulin-resistant diabetic

patients or type 2 patients;

Delayed onset of action – takes 8-12 weeks to achieve

maximal effect;

Absence of hypoglycemia when used as monotherapy;

No reliance on renal excretion

Thiazolidinediones

3. Adverse effects Edema: at higher doses and used with insulin, in older pat

ients, patients with multiple medical problems, patients with u

nderlying CAD or CHF

Headache

Myalgia ( 肌痛 )

GI reactions

Hepatic damage (troglitazone).

Contraindicated with Class III or IV heart failure or significant

liver disease.

Thiazolidinediones

1. Pharmacological effects Increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles Decreasing glucose absorption in gut and glucagon release

 2. Clinical uses Mild insulin-independent patients with obesity

Major advantages: Lack of weight gain; Absence of hypoglycemia; Low cost with generic prep.

3. Adverse effects Severe lactic acidosis, malabsorption of vitamin B12 and foli

c acid 

Biguanides

Alpha-Glucosidase inhibitors Acarbose-Precose 阿卡波糖 Miglitol-Glyset 米格列醇 Voglibose 伏格列波糖

B. Oral hypoglycemic drugs

Alpha-Glucosidase inhibitors

• Acarbose is an oligosaccharide, whereas miglitol

resembles a monosaccharide. • Miglitol is fairly well-absorbed by the body, as opposed to

acarbose. • Reducing intestinal absorption of starch ( 淀粉 ), dextrin

( 糊精 ), and disaccharides ( 二糖 ) by inhibiting the action

of intestinal brush border -glucosidase.• Acarbose also blocks pancreatic alpha-amylase ( 淀粉酶 ).• Used for diabetes mellitus type 2, particularly with regard

to postprandial hyperglycemia.

• Must be taken at the start of main meals to have maximal e

ffect. • Efficacy will depend on the amount of complex carbohydrat

es in the meal.• Absence of hypoglycemia when used as monotherapy. • Side effects: gastrointestinal side effects such as flatulence

and diarrhea; voglibose, in contrast to acarbose, has less of

GI side effects and more economical.

Alpha-Glucosidase inhibitors

Amylin analogues• Mechanism of action:

– Inhibits postprandial glucagon secretion, thereby reducing hepatic gl

ucose production– Slows gastric emptying– Promotes satiety reduces caloric intake

• Pramlintide (Symlin 普兰林肽 ) is the only amylin analog on t

he market• As adjunct therapy for patients with type 1 or 2 diabetes to c

ontrol postprandial glucose• Increases the risk of severe hypoglycemia • Main side effect is nausea.

Riddle and Drucker. Diabetes Care 2006; 29:435-49.

B. Oral hypoglycemic drugs

Alsose reductase– Aldose reductase activity increases in those tissu

es that are not insulin sensitive, including lenses,

peripheral nerves and glomerulus.– Epalrestat ( 依帕司他 ) inhibits aldose reductase.– Delay the progression of diabetic neuropathy an

d ameliorate the associated symptoms of the dis

ease.

B. Oral hypoglycemic drugs

Mechanism of Action Class of Agent Indications for Use

Stimulators of insulin secretion SulfonylureasGlinides

Primary

Insulin sensitizers Thiazolidinediones (PPAR agonists)

Primary or Secondary

Suppressors of hepatic glucose production

Biguanides Primary or Secondary

Reduces postprandial glucose excursion

Alpha-glucosidase Inhibitors

Glinides

Secondary

Enhance incretin/GLP1 action GLP1 analogs

DPPIV inhibitors

Secondary

B. Oral hypoglycemic drugs

Type II Diabetic Medications

Medication Site of Action/Mechanism

Side-Effects

Sulfonylurea (eg. glyburide)

Augments insulin secretion, binds SUR

Hypoglycemia, caution renal insufficiency, elderly

Thiazolidinediones (eg. rosiglitazone)

PPARg receptor/increased insulin sensitivity

Liver, LE edema, congestive heart failure, MI

Biguanide (metformin) Reduced hepatic gluconeogenesis

GI upset, Lactic acidosis (very rare), only use if creatinine<1.5 mg/dl

Glinides (repaglinide) Bind SUR, short action Hypoglycemia, caution in renal insufficiency

Alpha-glucosidase inhibitors (acarbose)

Inhibits brush border enzyme/Reduce glucose absorption

Flatulence, diarrhea

Incretins/GLP-1 (exenatide)

Stimulates insulin, delays gastric emptying, satiety

Nausea, vomiting (given by injection)

DPP4 Inhibitors (vildagliptin)

Inhibits GLP1 breakdown GI side effects

Adrenocorticoids & adrenocort

ical antagonists

Adrenocortical hormones– Glucocorticoids

(Glucocorticosteroids)

– Mineralocorticoids

– Sex hormones

Structure and function of adrenal cortex

ZonaReticularis

Adrenaline

ZonaFaseciculata

AndrogensAndrogens

ACTH

Regulation of glucocorticoi

ds

‒‒

Basic structure of glucocorticoid drugs

AA BB

CC DD

甾体结构

HH

A. Glucocorticoid drugs

12

34

56

7

89

10

1213

14 15

16

18

19

Structure(1) 1 位和 2 位碳之间改成不饱和的双键 : cortisone prednisone; hydrocortisone prednisolone.(2) 16 引入羟基 : triamcinolone( 曲安西龙 ).(3) 6 引入甲基 : 6-methylprednisone (6 甲基泼尼松 ).(4) 9 引入氟原子 : fludrocortosone ( 氟氢可的松 ).

1 2

3 4

56 7

810 9

121314 15

16 18

19

A B

C D

基本结构基本结构

H

A. Glucocorticoid drugs

H

Cortisone( 可的松 )

Prednisone( 泼尼松 )

( 地塞米松 )

Hydrocortisone( 氢化可的松 ,

Cortisol)

Prednisolone( 泼尼松龙 )

Fluocinolone( 氟轻松 )

2. ADME and properties of commonly used drugs

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.)

A. 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

A. Glucocorticoid drugs

binding to glucocorticoid receptor (GR)

nuclear translocation

binding to GRE or nGRE

regulating related gene transcription

biological effects (usually slow)

A. Glucocorticoid drugs

Mechanisms of glucocorticoid actions

Genetic action mode of glucocorticoid drugs

CBG: corticosteroid binding globulinS: glucocorticoid steroidsGR: glucocorticoid receptorHSP: heat shock proteinIP: immunophilinGRE: glucocorticoid-response element

Nuclear translocation of glucocorticoid receptors (GR)

Dexamethasone

Examples of glucocorticoid actions:

Inhibition of proinflammatory gene transcription (AP-1 and NFB)

1. Pharmacological effects(1) Effects on metabolism

(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

A. Glucocorticoid drugs

(1) Effects on metabolism

①Glucose metabolism:

gluconeogenesis, glucose oxidation and utilization blood glucose. ②Protein metabolism:

synthesis, degradation. ③Lipid metabolism:

plasma cholesterol, fat redistribution (central

obesity: moon face, buffalo hump, etc.).

④Water and electrolytic metabolism:

Na+ excretion, K+ excretion, Ca2+ excretion and

absorption.

A. Glucocorticoid drugs

Weaker action of glucocorticoid drugs (cortisol氢化可的松 ) on mineralocorticoid receptor

 (2) Anti-inflammatory effects1) Acute

a) Increasing anti-inflammatory proteins and enzymes

inducing lipocortin ( 脂皮素 ), inhibiting phospholipase A2 activity, dec

reasing mediators: PGs, LTs, PAF

inducing vasocortin ( 血管内皮素 ), decreasing microvascular permeab

ility

inhibiting the expression of COX-2, inducible NOS, etc.

b) Inhibiting cytokines: decreasing the transcription and activities

of TNFα, IL-1, IL-2, IL-5, IL-6, IL-8, etc.

c) Inhibiting adhesion molecules

d) Inducing apoptosis of inflammatory cells

A. Glucocorticoid drugs

 (2) Anti-inflammatory effects

Chronic: inhibiting fibroblast proliferation

deposition of collagen

cicatrization ( 瘢痕形成 )

A. Glucocorticoid drugs

Inhibition of proinflammatory gene transcription (AP-1 and NFB)

(3) Suppressive effects on immune and allergy

a) inducing apoptosis of T and B lymphocytes

b) inducing DNA degradation of T and B lymphocytes

c) Inhibiting DNA and protein synthesis of T and B lymph

ocytes

d) inhibiting transcription factor activity (eg. AP-1, NF-B

e) Inhibiting mast cells (anti-allergic)

(4) Permissive action

Potentiating the effects of catecholamines and glucago

n

A. Glucocorticoid drugs

(5) anti-shock

a) improving cardiovascular functions

b) inhibiting the production of inflammatory fa

ctors

c) stabilizing lysosome membrane: decreasing

the release of myocardial depressant factor

(MDF)

d) increasing the tolerance to endotoxin from

bacteria

A. Glucocorticoid drugs

(6) Other effects

a) antipyretic effects

b) effects on blood and blood-forming organs

red cell ; lymphocytes ; neutrophils (function ); eosinophils ; platelets

c) skeletal system: osteoporosis

d) CNS: increasing excitability (elevated mood, euphoria,

insomnia, restlessness, increased motor activity)

A. Glucocorticoid drugs

3. Clinical uses

(1) Immune diseases

a) autoimmune disorders: rheumatic fever, rheumatic

carditis, rheumatic arthritis, rheumatoid arthritis, o

steoarthritis, systemic lupus erythematosus, polyar

thritis nodosa, nephritic syndrome, etc.

b) rejection of organ transplantation

c) allergic diseases: urticaria ( 风疹 ), serum sickness,

contact dermatitis, drug allergic reactions, chronic

severe asthma, status asthmaticus, angioneurotic e

dema, etc.

A. Glucocorticoid drugs

3. Clinical uses

(2) Severe infection and inflammation

a) acute severe infections: merely suppressing inflammato

ry manifestations but at times lifesaving

Caution: combination with effective anti-microbial drugs;① Large dose; short term administration !② ③

Usually be not used in viral and fungal infections except fo

r those with cerebral edema or severe systemic sympto

ms

b) prevention of sequelae ( 后遗症 ) of some types of inflam

mation, such as in brain, heart, eye, joint, etc.

A. Glucocorticoid drugs

3. Clinical uses

(3) Septic shock:

Caution: larger dose, short-term, and combined wit

h antimicrobial drugs.

 (4) Hemological diseases: acute lymphocytic leukemia,

lymphomas, aplastic anemia ( 再生障碍性贫血 ), hemol

ytic anemia, leukocytopenia, thrombocytopenia, etc.

(5) Topical applications: skin, eye, respiratory tract, join

t (local injection)

(6) Some types of tumors: breast and prostatic cancers,

acute lymphocytic leukemia, etc.

A. Glucocorticoid drugs

4. Adverse effects(1) Effects resulting from continued used of large

doses

a) Hypercorticism-like syndrome: central obesity (m

oon face, buffalo hump, etc.); hypertension; glycosuria,

hypokalemia; etc.

b) Increasing susceptibility to infections: Caution: specific antimicrobial drugs should be admini

stered with GCs

c) Ingestive system: peptic ulcers, etc.

A. Glucocorticoid drugs

4. Adverse effects

d) Cardiovascular system: hypertension, arterios

clerosis

e) Myopathy and osteoporosis: vertebral compre

ssion fractures, spontaneous fractures, especially i

n postmenopausal women

f) CNS: behavioral disturbances, induction of epilepti

c seizures

g) Inhibition or arrest of growth in children

A. Glucocorticoid drugs

Suppression of hypothalamic-pituitary-adrenal axis

and glucocorticoid drugs

‒‒

ACTH

4. Adverse effects

(2) Withdrawal syndrome

a) Suppression of hypothalamic-pituitary-adrenal axis

b) Exacerbation of the underlying diseases (rebound)

 (3) Contraindications

psychiatric disorders; epilepsy; active peptic ulcers; fr

actures; hypercorticism; severe hypertension; diabete

s mellitus; viral or fungal infections, etc.

A. Glucocorticoid drugs

Balance the ratio of benefit/risk before the use of GCs !

5. Applications

(1) Replacement therapy: usually using hydrocortisone

(2) Prompt intensive treatment: i.v. gtt hydrocortisone, de

xamethasone

(3) Long-term therapy: oral prednisone or prednisolone

morning single dose

alternate-day therapy

Notes: for less severe and less sustained patients;

less suppression on hypothalamic-pituitary-adr

enal (HPA) axis

(4) Typical applications: skin; eye; respiratory tract

A. Glucocorticoid drugs

Some indications for the use of glucocorticoids

Aldosterone 醛固酮

• Roles:

Na+ excretion , K+ excretion edema

hypertension

hypokalemia, etc.• Used for adrenocortical dysfunction with imb

alance of water and electrolytes

B. Mineralocorticoid drugs

Action of aldosterone on mineralocorticoid receptor

Mineralocorticoid receptor signal transduction. • MR: mineralocorticoid receptor;• HRE: hormone responsive element.• AIP: Aldosterone induced protein

AIP

Adrenocorticotropic hormone (ACTH)1. Used for diagnosis of adrenocortical function

2. inhibition of secretion of adrenocortical hormones after long-term glucocorticoid drug use

3. Easily inducing allergy to ACTH

C. Adrenocorticotropic hormone and corticosteroid synthetase inhibitors

2. Corticosteroid synthetase inhibitors

Mitotane 米托坦 Metyrapone 美替拉酮 Aminoglutethimide 氨鲁米特 Used for adrenocortical tumors or

hypercorticism

C. Adrenocorticotropic hormone and corticosteroid synthetase inhibitors