Transcript A. Glucocorticoid drugs

Drugs affecting
endocrine system
Huifang Tang
Department of pharmacology
Email: [email protected]
Hypothalamus-pituitary gland:
The regulatory center of endocrine system
Membrane receptor
Nuclear receptor (GCS, TH)
Part1 Adrenocorticoid drugs
Part2 Insulin and oral hypoglycemic drugs
Part3 Thyroid hormones and antithyroid drugs
Part1 Adrenocorticoid drugs
Adrenocortical hormones





Mineralocorticoids
Glucocorticoids
(Glucocorticosteroids)
Sex hormones
History(1)


In 1849, Addison first appreciated the importance of the
adrenal glands
Addison T. On the Constitutional and Local Effects of Disease of the Supra-renal Capsules.
London, UK: Samuel Highley; 1855.
Zona
Faseciculata
Zona
Reticularis
Androgens
Adrenaline
Structure and function of adrenal cortex.
History(2)

As early as 1912, Cushing described
patients with hypercorticism, and
later recongized that pituitary
basophilism represented the cause
of the adrenal overactivity.
History(3)


In 1948, the role of hypothalamus
in pituitary control was
established by Harris.
In 1949, Hench and colleagues
demonstrated the dramatic effect
of glucocorticoids and ACTH in the
treatment of rheumatoid arthritis.
Contents

A. Glucocorticoid drugs

B. Mineralocorticoid drugs

C. ACTH and corticosteroid synthetase inhibitors
A. Glucocorticoid drugs
Basic structure of glucocorticoid drugs:
甾
H
A
C
B
D
甾体结构
A. Glucocorticoid drugs
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.
(2)16引入羟基:
triamcinolone(曲安西龙).
(3)6引入甲基:
基本结构
6-methylprednisone
(6甲基泼尼松).
(4)9引入氟原子:
H
D
C
fludrocortosone
A
B
(氟氢可的松).
19
1213 18
14
2 1
10 9 8
3
5
4
6 7
16
15
A. Glucocorticoid drugs
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
A. Glucocorticoid drugs
One of glucocorticoid’s anti-inflammatory actions:
Inhibition of proinflammatory gene transcription (AP-1 and
NFB)
Non-genomic mechanisms of action of
glucocorticoids.
C. Boardman et al. / Pulmonary Pharmacology & Therapeutics 29 (2014) 129e143
A. Glucocorticoid drugs
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
A. Glucocorticoid drugs
(1) Effects on metabolisms
①Glucose metabolism:
gluconeogenesis, glucose
utilization
 blood glucose.
②Protein metabolism:
synthesis, degradation.
③Lipid metabolism:
plasma cholesterol, fat
redistribution (central obesity:
moon face, buffalo hump, etc.).
④Water and electrolytic metabolism:
water excretion, Na+ excretion,
K+ excretion, Ca2+ excretion and
absorption.
Weaker action of glucocorticoid drugs
(cortisol) on mineralocorticoid receptor
A. 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. Glucocorticoid drugs
a) Increasing inflammation related proteins or
enzymes
inducing lipocortin(脂皮素), inhibiting phospholipase A2
activity, decreasing mediators: PGs, LTs, PAF
inducing angiotension-convertion enzyme,ACE)
inducing vasocortin(血管皮素), decreasing microvascular
permeability
inhibiting the expression of PLA2, COX-2, inducible NOS, etc.
b) Inhibiting cytokinins: decreasing the transcription and
activities of TNFα, IL-1, IL-2, IL-5, IL-6, IL-8, etc.
c) I nhibiting adhesion molecules :
decreasing the
transcription and activities ofICAM-1, E-selectin etc.
d) Inducing the apoptosis of inflammatory cells
A. Glucocorticoid drugs
(4) Effects on immune and allergy
Suppressing immunological functions and allergy
a) inducing apoptosis of T and B lymphocytes
b) inhibiting transcription factor activity(eg. AP1, NFB):
A. 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
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
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
Cortisone
Hydrocortisone
可的松
氢化可的松
Cortisol
Prednisone
泼尼松
H
Prednisolone
泼尼松龙
Fluocinolone
氟轻松
地塞米松
A. Glucocorticoid drugs
3. Clinical uses
(1) Immune diseases
a) autoimmune disorders: reumatic fever, reumatic
carditis, rhumatic arthritis, rheumatoid arthritis,
osteoarthritis,
systemic
lupus
erythematosus,
polyarthritis nodosa, nephritic syndrome, etc.
b) rejection of organ transplantation
c) allergic diseases: urticaria, serum sickenss, contact
dermatitis, drug allergic reactions, chronic severe
asthma, status asthmaticus, angioneurotic edema, etc.
A. Glucocorticoid drugs
(2) Severe infection and inflammation
a) acute severe infections: merely suppressing
inflammatory manifestations but at times lifesaving
Causion: ①combination with effective anti-microbial
drugs; ②Large dose; ③short term administration !
Usually be not used in viral and fungal infections
except for those with cerebral edema or severe
systemic symptoms
b) prevention of sequelae (后遗症) of some types of
inflammation, such as in brain, heart, eye, joint, etc.
A. Glucocorticoid drugs
(3) Septic shock:
Causion: larger dose, short-term, and combined with
antimicrobial drugs.
(4) Hemological diseases: acute lymphocytic leukemia,
lymphomas, aplastic anemia (再生障碍性贫血),, hemolytic
anemia, leukocytopenia, thrombocytopenia, etc.
(5) Topical applications: skin, eye, respiratory tract,
joint (local injection)
(6) Some types of tumors: breast and prostatic
cancers, acute lymphocytic leukemia, etc.
A. Glucocorticoid drugs
4、Adverse effects of
glucocorticoid drugs:
Effects resulting from
continued used of large
doses
A. Glucocorticoid drugs
4. Adverse effects
(1) Effects resulting from continued used of large
doses
a) Hypercorticism-like syndrome: central obesity
(moon face, buffalo hump, etc.); hypertension;
glycosuria, hypokalemia; etc.
b) Increasing susceptibility to infections:
Causion: specfic antimicrobial drugs should be
administered with GCs
c) Ingestive system: peptic ulcers, etc.
A. 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) cartarcts(白内障): well established complication of
glucocorticoid therapy. Children appear to be
particularly at risk. slit-lamp examination
h) Inhibition or arrest of growth in children
‒
ACTH
Suppression of
hypothalamicpituitary-adrenal
axis
and glucocorticoid drugs
A. Glucocorticoid drugs
(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;
fractures;
hypercorticism;
severe
hypertension; diabetes mellitus; viral or fungal
infections, etc.
A. Glucocorticoid drugs
Balance the ratio of benefit /
risk before the use of GCs !!!
A. Glucocorticoid drugs
5. Applications
(1) Replacement therapy: usually using hydrocortisone
(2) Prompt intensive treatment: i.v. gtt hydrocortisone,
dexamethasone
(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-adrenal (HPA)
axis
(4) Tipical applications: skin; eye; respiratory tract
B. Mineralocorticoid drugs


Aldosterone 醛固酮
Na+ excretion , K+ excretion : edema
hypertension
hypokalemia, etc.
used for
adrenocortical
dysfunction with
imbalance of water
and electrolytes
Action of aldosterone on mineralocorticoid
receptor
AIP
Mineralocorticoid receptor signal transduction.
 MR: mineralocorticoid receptor;
 HRE: hormone responsive element.
 AIP: Aldosterone induced protein
C. Adrenocorticotropic hormone and
corticosteroid synthetase inhibitors
C. Adrenocorticotropic hormone and
corticosteroid synthetase inhibitors

1. Adrenocorticotropic hormone (ACTH)

Used for diagnosis of adrenocortical function


inhibition of secretion of adrenocortical
hoemones after long-term glucocorticoid drug use
Easily inducing allergy to ACTH
C. Adrenocorticotropic hormone and
corticosteroid synthetase inhibitors
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

Extraadrenal effects of Adrenocorticotropic
hormone (ACTH)
In larger doses, ACTH cause a number of metabolic
changes in adrenalectomized animals, including
ketosis,lipolysis,hypoglycemia( immediately after
treatment) , and resistance to insulin(later after
treatment)
Hyperpigmentation: ACTH activated the MSH
receptor on melanocytes.
Diagnosis of H-P-A Axis status:
Adrenocortical function test
Cosyntropin

synthetic ACTH used as adrenal cortical stimulant
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Normal response:
plasma cortisol levels are elevated
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Abnormal response:
plasma cortisol level are unchanged
C. Adrenocorticotropic hormone and
corticosteroid synthetase inhibitors
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2. Inhibitor of the biosythesis
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Mitotane 米托坦--o,p'-DDD, an adrenocorticolytic agent

Corticosteroid synthetase inhibitors
inhibit cytochrome P450 enzymes involved in adrenocorticosteroid biosynthesis
Metyrapone 美替拉酮
Aminoglutethimide 氨鲁米特
Ketoconazole 酮康唑
target: different steroid hydrolases

Used for adrenocortical tumors or hypercorticism
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Common rsik: precipitating acute adrenal insufficiency
C. Adrenocorticotropic hormone and
corticosteroid synthetase inhibitors
3、Antiglucocorticoids （抗糖皮质激素药）
mifepristone (RU-486) 米非司酮

Antiprogestagen, can terminate early pregnacy.
At higher doses, it also inhibits the
glucocorticoid receptor, blocking the feedback
regulation of HPA axis and secondarily
increasing endogenous ACTH and cortisol levels
 Potential clinicla use: hypercorticism

Cortisol Suppression Tests
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􀂄 Principle

􀂄 Based on the ability of exogenous cortisol to exert (-)

feedback on hypothalamus-pituitary release of ACTH

􀂄 Can’t measure with cortisol itself (exogenous would just

replace endogenous)

􀂄 Must use a more potent glucocorticoid derivative

􀂄 usually dexamethasone
Diagnosis of H-P-A Axis status:
H-P suppression test
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Dexamethasone:

􀂄 used to evaluate the basis for elevated cortisol
levels in individuals with suspected pituitary adenoma (Cushing’s
disease)

􀂄 Normal response in Cushing’s disease:
plasma ACTH and cortisol, urine 17-OH corticosteroid levels are reduced

􀂄 Abnormal response in cortisol-producing adrenal tumor
(low ACTH) or ectopic ACTH-producing tumors (high
ACTH):

􀂄 plasma ACTH and cortisol, urine 17-OH corticosteroid
levels are unchanged