CorticoSteroids CorticoSteroids

Mukesh gupta

• Corticostroids hormones- Corticostroids hormones- Includs two hormones-

• MineralocorticoidsMineralocorticoids : : effects on carbohydrate, protein and fat metabolismsrone-

• Glucocorticoids Glucocorticoids (Glucocorticosteroids)(Glucocorticosteroids): cortisol: cortisol- - effects Na+ and K+ and fluid balance.

•

• Use of corticosteroids

•Corticosteroids are used: to reduce inflammation (asthma, arthritis) and

swelling (cerebral oedema) to suppress the immune response (systemic lupus

erythematosis) to reduce nausea and vomiting (as in cancer

chemotherapy) to reduce terminal pain (associated with cancer) as replacement therapy (in Addison's disease)

• Example of -

• hydrocortisone , prednisolone, dexamethasone, beclomethasone , budesonide , fluticasone

Structure and function of adrenal Structure and function of adrenal cortex.cortex.

ZonaZonaReticularisReticularis

AdrenalineAdrenaline

ZonaZonaFaseciculataFaseciculata

AndrogensAndrogens

Basic structure of glucocorticoid Basic structure of glucocorticoid drugs:drugs:

AA BBCC DD

HH

A.A. Glucocorticoid drugs Glucocorticoid drugs

HH

Cortisone

Prednisone

HydrocortisoneCortisol)

Prednisolone

Fluocinolone

HH

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

nuclear translocationnuclear translocation

binding to GRE or nGREbinding to GRE or nGRE

regulating related gene transcriptionregulating related gene transcription

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

Mechanisms of glucocorticoid actionsMechanisms of glucocorticoid actions

1. Pharmacological effectsMechanisms 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

(2) Permissive actionPotentiating the effects of catecholamines and

glucagon  (3) Anti-inflammatory effectsAcute: inhibiting microvascular leakage leukocyte infiltrationChronic: inhibiting fibroblast proliferation deposition of collagen

Anti-shock Septic shocka) 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 effectsa) antipyretic effects

b) effects on blood and blood-forming organsred cell ; lymphocytes ; neutrophils (function ); eosinophils ;

platelets

c) skeletal system: osteoporosis

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

2. ADME 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.)

Commonly used drugsShort-acting: hydrocortisone (cortisol),

fludrocorisone, cortisoneIntermediate- acting: prednisone, prednisolonLong-acting: dexamethasoneTopical: fluocinolone, betamethasone,

dexamethasone

A.A. Glucocorticoid drugs Glucocorticoid drugs

Drug features • Hydrocortisone : Also called cortisol . It is primary

glucocorticoids, and mineralocorticoids as well. Used replacment therapy for shock, asthamaticus, adrenal insufficiency ,ulcerative etc. Dose- 20-30 mg/day

• Prednisolone: 4 times more potent then cortisol. It si more selective to glucocorticoids, have inermediate duration of action. Used in allergic, inflammation, autoimmune disease. Dose – 10-60 mg/ day

• Betamethasone: very potent, selective glucocorticoids, similar to dexamethasone. Used in allergic, shock, edema etc. Dose-0.5-5mg

(1) Immune diseasesa) autoimmune disorders: reumatic fever,

reumatic carditis, rhumatic arthritis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, polyarthritis nodosa, nephritic syndrome, etc.

b) rejection of organ transplantationc) allergic diseases: urticaria, serum sickenss,

contact dermatitis, drug allergic reactions, chronic severe asthma, status asthmaticus, angioneurotic edema, etc.

Clinical uses

(2) Severe infection and inflammation

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

Caution: 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 some types of inflammation, such as in brain, heart, eye, joint, etc.

(3) Septic shock: (3) Septic shock: Causion:Causion: larger dose, short-term, and combined larger dose, short-term, and combined

with antimicrobial drugs.with antimicrobial drugs.  

(4) Hemological diseases: (4) Hemological diseases: acute lymphocytic acute lymphocytic leukemia, lymphomas, aplastic anemia leukemia, lymphomas, aplastic anemia (( 再生障碍性贫再生障碍性贫血血 ),),, hemolytic anemia, leukocytopenia, , hemolytic anemia, leukocytopenia, thrombocytopenia, thrombocytopenia, etetc.c.

(5) Topical applications: (5) Topical applications: skin, eye, respiratory skin, eye, respiratory tract, joint (local injection)tract, joint (local injection)

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

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.

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

Withdrawal syndromea) Suppression of hypothalamic-pituitary-adrenal

axisb) Exacerbation of the underlying diseases

(rebound)  Contraindications

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

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

(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

Applications

• Aldosterone 醛固酮

• Na+ excretion , K+ excretion : edema hypertension hypokalemia, etc. used for adrenocortical dysfunction with imbalance of

water and electrolytes

B.B. Mineralocorticoid drugsMineralocorticoid drugs

• 2. Corticosteroid synthetase inhibitors

• Mitotane• Metyrapone • Aminoglutethimide

• Used for adrenocortical tumors or hypercorticism

C. Adrenocorticotropic hormone and corticosteroid synthetase

inhibitors