Adrenocorticoid drugs. §Adrenocortical hormones § Mineralocorticoids § Glucocorticoids § (Glucocorticosteroids) § Sex hormones

Adrenocorticoid drugAdrenocorticoid drugss

Adrenocorticoid drugsAdrenocorticoid drugs

Adrenocortical hormonesAdrenocortical hormones

MineralocorticoidsMineralocorticoids

Glucocorticoids Glucocorticoids (Glucocorticosteroids)(Glucocorticosteroids)

Sex hormonesSex hormones

Adrenal cortex:Adrenal cortex:

origin of adrenocortical hormonesorigin of adrenocortical hormones

球状带球状带

束状带束状带

网状带网状带

Endogenous GEndogenous GCS (cortisol) bCS (cortisol) biosynthesisiosynthesis

Feedback inhibition of CFeedback inhibition of CRH and ACTH by plasmRH and ACTH by plasma cortisola cortisol

Circadian rhythm of the secretion Circadian rhythm of the secretion of ACTH and cortisolof ACTH and cortisol

1. 1. Pharmacological effectsPharmacological effects

Mechanisms of glucocorticoid actionsMechanisms of glucocorticoid actions (1) Effects on metabolisms (1) Effects on metabolisms (2) Permissive action(2) Permissive action (3) Anti-inflammatory effects(3) Anti-inflammatory effects (4) Effects on immune and allergy (4) Effects on immune and allergy (5) Anti-shock(5) Anti-shock (6) Other effects(6) Other effects antipyretic effectsantipyretic effects effects on blood and blood-forming organseffects on blood and blood-forming organs skeletal systemskeletal system CNS effectsCNS effects

A.A. Glucocorticoid drugs Glucocorticoid drugs

Mechanisms of glucocorticoid actionsMechanisms of glucocorticoid actions

binding to glucocorticoid receptor (GR) binding to glucocorticoid receptor (GR)

nuclear translocationnuclear translocation

binding to GR element binding to GR element

regulating related gene transcriptionregulating related gene transcription

biological effects (usually slow) biological effects (usually slow)


CBG: CBG: corticosteroid binding globulin;corticosteroid binding globulin; S: S: glucocorticoid steroids; glucocorticoid steroids; R: R: glucocorticoid glucocorticoid receptor; receptor; GRE: GRE: glucocorticoid response element; glucocorticoid response element; HSP90: HSP90: heat shock protein 90heat shock protein 90

Interaction between glucocorticoid receptor (GR) and Interaction between glucocorticoid receptor (GR) and DNA (glucocorticoid-response element)DNA (glucocorticoid-response element)

Molecular basis of GR-DNA (HRE) interactionMolecular basis of GR-DNA (HRE) interaction

Nuclear translocatNuclear translocation of glucocorticoion of glucocorticoid receptors (GR)id receptors (GR)

DexamethasoneDexamethasone was u was usedsed

GRGR was labeled with was labeled with green fluorescent progreen fluorescent proteintein

Examples of glucocorticoid actions:Examples of glucocorticoid actions:

Inhibition of proinflammatory gene transcription (AP-1 and NF-Inhibition of proinflammatory gene transcription (AP-1 and NF-BB))

(1) Effects on metabolisms(1) Effects on metabolisms

a) Carbohydrate:a) Carbohydrate: blood glucose blood glucose ↑↑:: gluconeogenesis gluconeogenesis ↑↑, ,

glucose utilization↓glucose utilization↓

b) Protein:b) Protein: synthesis ↓, degradation ↑synthesis ↓, degradation ↑

c) Lipid:c) Lipid: plasma cholesterol ↑, fat redistribution (central plasma cholesterol ↑, fat redistribution (central obesity: moon face, buffalo hump)obesity: moon face, buffalo hump)

d) Water and electrolytic:d) Water and electrolytic: NaNa++ excretion ↓, excretion ↓,

KK+ + excretion ↑, Caexcretion ↑, Ca2+2+ excretion↑and absorption↓ excretion↑and absorption↓


(2) Permissive action(2) Permissive actionPotentiating the effects of catecholamines and glucagPotentiating the effects of catecholamines and glucag

onon (3) Anti-inflammatory effects(3) Anti-inflammatory effectsAcute: Acute: inhibiting microvascular leakageinhibiting microvascular leakage & leukocyte infiltration& leukocyte infiltrationChronic:Chronic: inhibiting fibroblast proliferation, inhibiting fibroblast proliferation, deposition of collagen,deposition of collagen, & cicatrization (& cicatrization ( 瘢痕形成瘢痕形成 ))


Inhibition of leukocyte infiInhibition of leukocyte infiltration and plasma leakagltration and plasma leakage by glucocorticoid drugse by glucocorticoid drugs

a) Inhibiting inflammation related proteins or enzya) Inhibiting inflammation related proteins or enzymesmes

inducing lipocortin,inducing lipocortin, inhibiting phospholipase A inhibiting phospholipase A22 activity, de activity, de

creasing mediators: PGs, LTs, PAFcreasing mediators: PGs, LTs, PAF inducing vasocortin,inducing vasocortin, decreasing microvascular permeability decreasing microvascular permeability inhibiting the expression of PLAinhibiting the expression of PLA22, COX-2, inducible NOS,, COX-2, inducible NOS, etet

c.c.

b) Inhibiting cytokinins:b) Inhibiting cytokinins: decreasing the transcription andecreasing the transcription and activities of TNFd activities of TNF, IL-1, IL-2, IL-5, IL-6, IL-8, , IL-1, IL-2, IL-5, IL-6, IL-8, etc.etc.

c) Inhibiting adhesion moleculesc) Inhibiting adhesion molecules

d) Inducing the apoptosis of inflammatory cellsd) Inducing the apoptosis of inflammatory cells


(4) Effects on immune and allergy(4) Effects on immune and allergy

Suppressing immuneological functions and allergySuppressing immuneological functions and allergy

a) inducing apoptosis of T and B lymphocytesa) inducing apoptosis of T and B lymphocytes

b) inhibiting transcription factor b) inhibiting transcription factor －－ such assuch as nuclear nuclear factor factor B (NF-B (NF-B) B) oror activating protein-1 (AP-1) activating protein-1 (AP-1) actiactivityvity


One of glucocorticoid’s actions:One of glucocorticoid’s actions:

Inhibition of gene transcription (AP-1 and NFInhibition of gene transcription (AP-1 and NFBB))


(5) Anti-shock(5) Anti-shock Septic shockSeptic shock

a) improving cardiovascular functionsa) improving cardiovascular functions

b) inhibiting the production of inflammatory factb) inhibiting the production of inflammatory factorsors

c) stabilizing lysosome membrane: c) stabilizing lysosome membrane: decreasing the decreasing the release of myocardial depressant factor (MDF)release of myocardial depressant factor (MDF)

d) increasing the tolerance to endotoxin from bacd) increasing the tolerance to endotoxin from bacteriateria


(6) Other effects(6) Other effects

a) antipyretic effectsa) antipyretic effects

b) effects on blood and blood-forming organsb) effects on blood and blood-forming organs red blood cells red blood cells ; lymphocytes ; lymphocytes ; neutrophils ; neutrophils (function (function

); eosinophils ); eosinophils ; platelets; platelets

c) skeletal system: c) skeletal system: osteoporosisosteoporosis

d) CNS: d) CNS: increasing excitability (elevated mood, euphoria, increasing excitability (elevated mood, euphoria, insomnia, restlessness, increased motor activity)insomnia, restlessness, increased motor activity)


2. 2. ADME and properties of commonly used druADME and properties of commonly used drugsgs

Binding to corticosteroid-binding globulin (CBG) in Binding to corticosteroid-binding globulin (CBG) in the plasmathe plasma

CortisoneCortisone and and prednisoneprednisone are reduced and transform are reduced and transformed to ed to hydrocortisonehydrocortisone and and prednisoloneprednisolone (active forms) i(active forms) in the livern the liver

Metabolism will be increased by hepatic enzyme indMetabolism will be increased by hepatic enzyme inductors (uctors (phenobarbital, phenytoin, rifampine, phenobarbital, phenytoin, rifampine, etc.etc.))


Commonly used drugsCommonly used drugs

Short-acting:Short-acting: hydrocortisone (cortisol) hydrocortisone (cortisol) 氢化可的松氢化可的松 cortisone cortisone 可的松可的松

Intermediate-acting:Intermediate-acting: prednisone prednisone 泼尼松泼尼松 , , 强的松强的松 prednisolone prednisolone 泼尼松龙泼尼松龙 , , 强的松龙强的松龙

Long-acting:Long-acting: dexamethasone dexamethasone 地塞米松地塞米松

Topical:Topical: fluocinolone fluocinolone 氟轻松氟轻松


C=O

CH2OH

HO OH

O

1

1711

9

6

16

Hydrocortisone (cortisol)Hydrocortisone (cortisol)

2

1-2:1-2: double bonddouble bond ~ prednisone, prednisolone ~ prednisone, prednisolone

1616:: -OH-OH ~ triamcinolon ~ triamcinolon

66/16/16 :: -CH-CH33 ~ methylprednisone/dexamethasone ~ methylprednisone/dexamethasone

99 (6 (6):): -F-F ~ dexamethasone, triamcinolon ~ dexamethasone, triamcinolon

O

11

cortisone cortisone prednisoneprednisone

CortisoneCortisone

可的松可的松HydrocortisoneHydrocortisone

氢化可的松氢化可的松

CortisolCortisol

PrednisonePrednisone

泼尼松泼尼松PrednisolonePrednisolone

泼尼松龙泼尼松龙

FluocinoloneFluocinolone

氟轻松氟轻松地塞米松地塞米松

HH

3. 3. Clinical usesClinical uses

(1) Immune diseases(1) Immune diseases

a) autoimmune disorders:a) autoimmune disorders: reumatic fever, reumatic cardireumatic fever, reumatic carditis, rhumatic arthritis, rheumatoid arthritis, osteoarthritis, sytis, rhumatic arthritis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, polyarthritis nodosa, nephritic sstemic lupus erythematosus, polyarthritis nodosa, nephritic syndrome, yndrome, etc.etc.

b) rejection of organ transplantationb) rejection of organ transplantation

c) allergic diseases:c) allergic diseases: urticaria, serum sicknss, contact dermurticaria, serum sicknss, contact dermatitis, drug allergic reactions, chronic severe asthma, status aatitis, drug allergic reactions, chronic severe asthma, status asthmaticus, angioneurotic edema, sthmaticus, angioneurotic edema, etcetc. .


(2) Severe infection and inflammation(2) Severe infection and inflammation

a) acute severe infections:a) acute severe infections: merely suppressing inflammatmerely suppressing inflammatory manifestations but at times lifesavingory manifestations but at times lifesaving

Causion:Causion: combination with effective antimicrobial dcombination with effective antimicrobial drugs !rugs !

Usually be not used in viral and fungal infections exceUsually be not used in viral and fungal infections except for those with cerebral edema or severe systemic sypt for those with cerebral edema or severe systemic symptomsmptoms

b) prevention of sequelae of some types of inflammatb) prevention of sequelae of some types of inflammationion, , such as in brain, heart, eye, joint,such as in brain, heart, eye, joint, etc etc..


(3) Septic shock: (3) Septic shock: larger dose, short-term, combined with alarger dose, short-term, combined with antimicrobial drugsntimicrobial drugs

(4) Hemological diseases: (4) Hemological diseases: acute lymphocytic leukemia, lyacute lymphocytic leukemia, lymphomas, aplastic anemia, hemolytic anemia, leukocytopenia,mphomas, aplastic anemia, hemolytic anemia, leukocytopenia, thrombocytopenia, thrombocytopenia, etetc.c.

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

t (local injection)t (local injection)

(6) Some types of tumors:(6) Some types of tumors: acute lymphocytic leukemia, bacute lymphocytic leukemia, breast and prostatic cancers, reast and prostatic cancers, etcetc. .

(7) Replacement therapy(7) Replacement therapy


4. 4. Adverse effectsAdverse effects

(1) Effects resulting from continued used of large do(1) Effects resulting from continued used of large dosesses

a) Hypercorticism-like syndrome:a) Hypercorticism-like syndrome: central obesity (moocentral obesity (moon face, buffalo hump, etc.); hypertension; glycosuria, hypokaln face, buffalo hump, etc.); hypertension; glycosuria, hypokalemia; emia; etcetc..

b) Increasing susceptibility to infections:b) Increasing susceptibility to infections: specific antispecific antimicrobial drugs should be administered with GCsmicrobial drugs should be administered with GCs

c) Digestive system:c) Digestive system: peptic ulcers, peptic ulcers, etcetc..


d) Cardiovascular system:d) Cardiovascular system: hypertension, arteriosclhypertension, arteriosclerosiserosis

e) Myopathy and osteoporosis:e) Myopathy and osteoporosis: vertebral compresvertebral compression fractures, spontaneous fractures, especially in postsion fractures, spontaneous fractures, especially in postmenopausal womenmenopausal women

f) CNS:f) CNS: behavioral disturbances, induction of epileptibehavioral disturbances, induction of epileptic seizuresc seizures

g) Inhibition or arrest of growth in childreng) Inhibition or arrest of growth in children

h) Glucocorticoid-induced glaucomah) Glucocorticoid-induced glaucoma


Adverse effects of gluAdverse effects of glucocorticoid drugs:cocorticoid drugs:

Effects resulting from coEffects resulting from continued used of large dontinued used of large dosesses

(2) Withdrawal syndrome(2) Withdrawal syndrome

a) Suppression of hypothalamic-pituitary-adrenal axa) Suppression of hypothalamic-pituitary-adrenal axisis

b) Exacerbation of the underlying diseases (rebounb) Exacerbation of the underlying diseases (rebound)d)

(3) Contraindications(3) Contraindications

psychiatric disorders; epilepsy; active peptic ulcers; psychiatric disorders; epilepsy; active peptic ulcers; fractures; hypercorticism; severe hypertension; diabfractures; hypercorticism; severe hypertension; diabetes mellitus; viral or fungal infections, etes mellitus; viral or fungal infections, etc.etc.


Negative feedback on hypothalNegative feedback on hypothalamic-pituitary-adrenal axis afteamic-pituitary-adrenal axis after long-term use of glucocorticoir long-term use of glucocorticoidsds

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


5. 5. ApplicationsApplications

(1) Replacement therapy:(1) Replacement therapy: usually using hydrocortisoneusually using hydrocortisone

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

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

morning single dose; alternate-day therapymorning single dose; alternate-day therapy for less severe and less sustained patients; for less severe and less sustained patients; less suppression on hypothalamic-pituitary-adrenal (HPA) axisless suppression on hypothalamic-pituitary-adrenal (HPA) axis

(4) Topical applications:(4) Topical applications: skin; eye; respiratory tractskin; eye; respiratory tract


Morning single dose: Morning single dose: based on thebased on the circadian rhythm of the secretion circadian rhythm of the secretion of ACTH and cortisolof ACTH and cortisol

Aldosterone Aldosterone 醛固酮醛固酮

NaNa++ excretion excretion , K, K+ + excretion excretion : : edemaedema hypertensionhypertension hypokalemia, hypokalemia, etc.etc. used for used for adrenocorticaladrenocortical dysfunction with dysfunction with imbalance of water imbalance of water and electrolytesand electrolytes

B.B. Mineralocorticoid drugs Mineralocorticoid drugs

Action of aldosterone on mineralocorticoid receptoAction of aldosterone on mineralocorticoid receptorr

1. 1. Adrenocorticotropic hormoneAdrenocorticotropic hormone (ACTH)(ACTH)

Used for Used for diagnosis of adrenocortical functiondiagnosis of adrenocortical function inhibition of secretion of adrenocortical hinhibition of secretion of adrenocortical h

ormones after long-term glucocorticoid drug useormones after long-term glucocorticoid drug use

Easily inducing allergy to ACTHEasily inducing allergy to ACTH

C.C. Adrenocorticotropic hormone and c Adrenocorticotropic hormone and corticosteroid synthetase inhibitorsorticosteroid synthetase inhibitors

2. 2. Corticosteroid synthetase inhibitorsCorticosteroid synthetase inhibitors

MitotaneMitotane 米托坦米托坦 damaging cells in zones of fasciculate & reticdamaging cells in zones of fasciculate & reticularis in the adrenal cortexularis in the adrenal cortex

Metyrapone Metyrapone 美替拉酮美替拉酮 inhibiting 11inhibiting 11-hydroxylation-hydroxylation

Aminoglutethimide Aminoglutethimide 氨鲁米特氨鲁米特 inhibiting production of 20inhibiting production of 20--hydroxyl cholesterol from cholesterolhydroxyl cholesterol from cholesterol

Used for adrenocortical tumors or hypercorticismUsed for adrenocortical tumors or hypercorticism

C.C. Adrenocorticotropic hormone and c Adrenocorticotropic hormone and corticosteroid synthetase inhibitorsorticosteroid synthetase inhibitors

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Adrenocorticoid drugs. §Adrenocortical hormones § Mineralocorticoids § Glucocorticoids § (Glucocorticosteroids) § Sex hormones