Thyroid hormones and antithyroid drugs Dept of Pharmacology Shi-Hong Zhang ( 张张张 ) [email protected]
Dec 23, 2015
Thyroid hormones and antithyroid drugs
Dept of Pharmacology
Shi-Hong Zhang ( 张世红 )
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