Corticosteroids Flashcards
Binds to Beta-adrenergic receptor (GPCR)
Initiates signal transduction cascade
Induces immediate response
Breaks down glycogen and release glucose
Epinephrine
Binds to glucocorticoid receptor
Regulates gene transcription and thus translation and protein production
Induces long term, persistent biological response
Induces gluconeogenic enzymes
Inhibit pro-inflammatory processes
Cortisol (hydrocortison)
Which part of the kidneys make glucocorticoids, mineralocorticoids, and androgens?
Cortex of the adrenal gland
Which part of the kidneys make epinephrine and norepinephrine?
Medulla of adrenal gland
Stress hormones
Increase circulating glucose concentration
Potent anti-inflammatory effects
Glucocorticoids
Adrenocorticoid that leads to Na+ retention and increased blood volume and pressure
Mineralocorticoids
Regulation of glucocorticoid synthesis
Stress -> Hypothalamus -> CRH -> ACTH -> Cortisol -> physiological responses
DNA-binding domains of activated dimers that bind to specific DNA sequences, upstream of steroid responsive genes
Glucocorticoid Responsive Elements (GRE)
Catalyzes the rate-limiting step in gluconeogenesis
PEP carboxykinase
Suppresses phospholipase A2, which has a critical role in eicosanoid synthesis
lipocortin I
Destruction of the cortex by tuberculosis or atrophy
Addison’s disease (primary)
What happens to CRH, ACTH, Cortisol and Aldosterone in Primary adrenal insufficiency?
Adrenal defect: Increased CRH and ACTH, decreased Cortisol and Aldosterone
What happens to CRH, ACTH, Cortisol and Aldosterone in Secondary adrenal insufficiency?
Pituitary defect: increased CRH and decreased ACTH, Cortisol, and not affected aldosterone
What happens to CRH, ACTH, Cortisol and Aldosterone in Tertiary adrenal insufficiency?
Hypothalamic defect: decreased CRH, ACTH, and Cortisol. Aldosterone not affected.
This condition has a few causes:
Tumors in the adrenal cortex
Increased production of ACTH due to pituitary carcinoma
Ectopic production of ACTH due to non-pituitary carcinoma
Cushing disease
What happens to CRH, ACTH and Cortisol in Adrenal affected Cushing disease?
Decreased CRH and ACTH, increased Cortisol
What happens to CRH, ACTH and Cortisol in Pituitary affected Cushing disease?
Decreased CRH and increased ACTH and Cortisol
What happens to CRH, ACTH and Cortisol in Ectopic affected Cushing disease?
Decreased CRH, ACTH and increased Cortisol and Ectopic ACTH
What is this glucocorticoid?
Cortisone
How is cortisol inactivated?
Oxidation of 11 hydroxyl to ketone
How is Cortisone activated?
Catalyzed by 11Beta-hydroxysteroid dehydrogenase in the liver
What are the short-acting systemic corticosteroids (2)
(-sone): Hydrocortisone and cortisone
What are the intermediate-acting corticosteroids? (4)
(-olone) Prednisone, Prednisolone, Methylprednisolone, and Triamcinolone
What are the long-acting corticosteroids? (2)
(-methasone) Dexamethasone and Betamethasone
Where is the Florine positioned at?
Greater glucocorticoid activity, strong mineralocorticoid activity (intense Na retention leading to edema)
Used in mineralocorticoid replacement therapy
Fludrocortisone: 9alpha-F
Where is the altered ring structure?
More potent glucocorticoid activity, stronger binding to the glucocorticoid receptor
Reduced mineralocorticoid activity
Interconvertible by 11Beta-hydroxysteroid dehydrogenase
Prednisone/prednisolone
Double bond between C1 and C2
Where is the methyl group located?
Potency similar to that for prednisolone
Reduced mineralocorticoid activity
Methylprednisolone: 6alpha-methyl group
Where is the F and OH located at?
Glucocorticoid activity similar to prednisone
Reduced mineralocorticoid activity
Increased hydrophilicity
Low oral bioavailability
Triamcinolone: 9alpha-F and 16alpha-OH
Where is the methyl group located?
Increased lipophilicity (increased receptor binding, significantly stronger effect)
Increased stability in human plasma
Reduced mineralocorticoid activity
Dexamethasone: 16alpha-methyl group
Enantiomer of dexamethasone at what location?
Has similar properties as dexamethasone
Betamethasone: 16Beta instead of 16alpha (Dexamethasone)
Which modifications of 21-esters increase lipophilicity and prolonged action upon IM or intra-articular injection
Acetate and butyrate
Which modification of 21-esters is soluble and has slow hydrolysis (peak 30-40min)?
Succinate
Which modification of 21-esters increases solubility, has rapid hydrolysis by phosphatases, and IV or IM injection for emergency use?
phosphate
T/F: Glucocorticoids are are method of stopping an asthma attack while its happening?
FALSE
Which type of glucocorticoid?
where acetonide is resistant to hydrolysis
8x more potent than prednisolone
Triamcinolone acetonide (Azmacort)
Inhaled
Which type of glucocorticoid?
Converted rapidly to 17-monopropionate by hydrolysis
14x more potent than dexamethasone
Beclomethasone dipropionate
Inhaled
Which type of glucocorticoid?
Rapid absorption from nasal or lung tissue
Rapid metabolism by the liver: extensive first-path metabolism, minimal systemic adverse effect with long-term therapy
Flunisolide (Aerobid)
Which type of glucocorticoid?
1:1 mixture of epimers at 16, 17-butylacetal
Faster topical uptake
Low oral bioavailability
Extensive first-path metabolism
Budesonide (Pulmicort)
Inhaled
Which type of glucocorticoid?
Highly potent, more rapid onset of action, negligible systemic availability (Rapid metabolism, low oral bioavailability)
Mometasone furoate (Asmanex)
Inhaled
Which type of glucocorticoid?
Inactivate by hydrolysis of thioester (Rapid first-path metabolism)
Highly lipophilic and insoluble (highly potent, poor absorption from GI, rapid topical uptake)
Fluticasone propionate
Inhaled
What are the three high potency topical glucocorticoids?
Triamcinolone acetonide, Fluocinonide, and Halcinonide
What are two very high potency topical chlorocorticoids?
Clobetasol propionate and halobetasol propionate
What are three medium potency topical glucocorticoids?
Betamethasone valerate, fluticasone propionate and mometasone furoate
High lipophilicity
Minimal systemic effect
Prolonged action
Are desired properties of what?
Topical glucocorticoids
High potency
Minimal systemic effects
Prolonged action
Are desired properties of what?
Inhaled glucocorticoids
