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Therapeutics > Exam 1 Corticosteroids > Flashcards

Exam 1 Corticosteroids Flashcards

1
Q

What does the adrenal cortex produce?

A

glucocorticoids, mineralocorticoids, androgens

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2
Q

What does the adrenal medulla produce?

A

epinephrine and norepinephrine

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3
Q

What are glucocorticoids?

A
  1. stress hormones
  2. increase circulating glucose concentrations → when stressed, need sugar
  3. potent anti-inflammatory effects
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4
Q

What are mineralocorticoids?

A
  1. Na+ retention
  2. increase blood volume
  3. increase blood pressure
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5
Q

What is epinephrine?

A
  1. binds to beta adrenergic receptor (GPCR)
  2. initiates signal transduction cascade
  3. induces immediate response
  4. breaks down glycogen and release glucose
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6
Q

What does cortisol (hydrocortisone) do?

A
  1. binds to glucocorticoid receptor (nuclear hormone receptor)
  2. regulates gene transcription and translation and protein production
  3. induces long term, persistent biological response
  4. induces gluconeogenic enzymes to make you stronger
  5. inhibit pro-inflammatory processes → natural painkiller
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7
Q

When is cortisol released?

A

everyday! higher levels in the morning which is why it causes no appetite in the morning since cortisol releases glucose

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8
Q

How is mineralocorticoid synthesis regulated?

A

when the pituitary gland is surgically removed in animals, aldosterone synthesis is not affected significantly → anterior pituitary does not control synthesis of mineralocorticoids (aldosterone)

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9
Q

How is aldosterone synthesized?

A

angiotensinogen → angiotensin I → angiotensin II → adrenal glands → aldosterone

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10
Q

What is the mechanism of action of glucocorticoids?

A

DNA binding domains of activated dimers bind to specific DNA sequences called GRE which is upstream of steroid responsive genes → binding alters rate of transcription → glucocorticoids up regulate enzymes for gluconeogenesis and anti-inflammatory proteins: PEP carboxykinase and lipcortin I

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11
Q

How do glucocorticoids immunosuppress?

A

activated glucocorticoid receptor (GR) binds to NFkB and prevents binding of NFkB to its response element → transcription of cytokine genes are repressed

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12
Q

What are the physiologic effects of glucocorticoids?

A
  1. liver → increase gluconeogenesis and increase glycogen storage
  2. muscle → promote protein degradation, decrease protein synthesis, decrease sensitivity to insulin
  3. adipose tissues → promote lipolysis and decrease sensitivity to insulin
  4. immune system → block the synthesis of cytokine (immunosuppression) and inhibit production of eicosanoids (anti-inflammatory)
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13
Q

What is adrenal insufficiency?

A

hypoadrenalism → decreased secretion of steroid hormones by the adrenal cortex

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14
Q

What are the causes of adrenal insufficiency?

A
  1. destruction of the cortex by tuberculosis or atrophy (primary, Addison’s disease)
  2. decreased secretion of ACTH due to diseases of anterior pituitary (secondary, no hypoaldosteronism)
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15
Q

What are the symptoms of adrenal insufficiency?

A
  1. extreme weakness
  2. anorexia, anemia, nausea, vomiting
  3. low blood pressure (in primary only)
  4. hyperpigmentation of the skin (primary only)
  5. mental depression
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16
Q

Cessation of long term systemic glucocorticoid therapy can lead to what?

A

Addisonian symptoms → no cortisol in the body (can’t stop cold turkey)

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17
Q

What is primary adrenal insufficiency?

A

adrenal defect: CRH increased, ACTH increased, cortisol decreased, aldosterone decreased

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18
Q

What is secondary adrenal insufficiency?

A

pituitary defect: CRH increased, ACTH decreased, cortisol decreased, aldosterone not affected

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19
Q

What is tertiary adrenal insufficiency?

A

hypothalamic defect: CRH decreased, ACTH decreased, cortisol decreased, aldosterone is not affected

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20
Q

What is Cushing’s disease?

A

hyperadrenalism → too much cortisol

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21
Q

What are the causes of Cushing’s?

A
  1. tumors in the adrenal cortex (adrenal)
  2. increased production of ACTH dur to pituitary carcinoma (pituitary)
  3. ectopic production of ACTH due to non-pituitary carcinoma (ectopic)
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22
Q

What are the symptoms of Cushing’s?

A
  1. increased protein catabolism (easy bruising, delayed wound healing, muscle wasting) and increased glucose levels
  2. osteoporosis
  3. opportunistic infections
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23
Q

Long term use of systemic glucocorticoids can lead to what?

A

Cushing’s symptoms

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24
Q

What is adrenal Cushing’s disease?

A

CRH decreased, ACTH decreased, cortisol increased

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25
Q

What is pituitary Cushing’s disease?

A

CRH decreased, ACTH increased, cortisol increased

26
Q

What is ectopic Cushing’s disease?

A

CRH decreased, ACTH decreased, cortisol increased, ectopic ACTH increased (by cancer cells)

27
Q

What are the therapeutic uses of corticosteroids?

A
  1. primary adrenal insufficiency (Addison’s disease)
  2. allergic reactions → insect stings, angiodema
  3. inflammation and autoimmune diseases → bursitis, synovitis, tendonitis, RA, systemic lupus, IBD, chronic hepatitis
  4. asthma
  5. miscellaneous uses → immunosuppressive and anti-cancer
28
Q

What is the difference between cortisol (hydrocortisone) vs cortisone?

A

the oxidation of 11 hydroxyl to ketone inactivates glucocorticoids which is catalyzed by 11beta-hydroxysteroid dehydrogenase in the liver but the reaction is reversible → cortisone is effective as cortisol systemically but cortisone should not be used in patients with impaired liver functions

29
Q

What are examples of short acting systemic corticosteroids?

A

hydrocortisone and cortisone (half life of 8-12 hours)

30
Q

What are examples of intermediate acting corticosteroids?

A

prednisone, prednisolone, methylprednisolone, triamcinolone (half life of 12-36 hours)

31
Q

What are examples of long acting systemic glucocorticoids?

A

dexamethasone and betamethasone (half life of 36-54 hours)

32
Q

How can glucocorticoids have aldosterone like activity?

A

because it can interact with aldosterone receptors

33
Q

Longer acting glucocorticoids have higher or lower GC activity?

A

higher GC activity (shorter lasting have smaller GC activity)

34
Q

What is fludrocortisone?

A
  1. has 9alpha fluorine group
  2. greater glucocorticoid activity
  3. strong mineralocorticoid activity → intense Na+ retention leading to edema
  4. used in mineralocorticoid replacement therapy
35
Q

What is prednisone (oxidized)/prednisolone (reduced)?

A
  1. extra double bond between C1 an C2 → altered ring structure
  2. more potent glucocorticoid activity with stronger binding to glucocorticoid receptor
  3. reduced mineralocorticoid activity
  4. interconvertible by 11 beta hydroxysteroid dehydrogenase
36
Q

What is methylprednisolone?

A
  1. has 6 alpha methyl group
  2. potency similar to prednisolone
  3. reduced mineralocorticoid activity
  4. increased lipophilicity and receptor binding
37
Q

What is triamcinolone?

A
  1. has 9 alpha fluorine and 16 alpha OH
  2. glucocorticoid activity similar to prednisone
  3. reduced mineralocorticoid activity (because of OH group)
  4. increased hydrophilicity
  5. low oral bioavailability because of extra OH group since it is too hydrophobic
38
Q

What is decamethasone?

A
  1. has 16 alpha methyl group
  2. increased lipophilicity → increased receptor binding and significantly stronger effect
  3. increased stability in human plasma
  4. reduced mineralocorticoid activity
39
Q

What is betamethasone?

A
  1. enantiomer of dexamethasone at C16

2. has similar properties as dexamethasone

40
Q

What are C 21 esters?

A
  1. hydroxyl group at C21 can be modified to an ester to control the property of glucocorticoids
  2. prodrugs activated through hydrolysis by esterases
  3. acetate (COCH3) and butyrate (COC3H7) have increased lipophilicity and prolonged action upon IM injection
  4. succinate group makes it more soluble and have slower hydrolysis
  5. phosphate group increases solubility and has rapid hydrolysis by phosphatases (10 minutes) → IM or IV injection for emergencies
41
Q

What is the SAR for glucocorticoids?

A
  1. 1,2 double bond → 5 fold enhancement in GR/MR ratio
  2. 11 beta OH required for full GR/MR activity, more important for GR
  3. 21 OH, F, Cl required for GR/MR activity and the ester prodrug must be hydrolyzed to OH for maximum activity
  4. 17 alpha O required for GR activity → can be acetonide ring or ester
  5. 16 alpha or beta methyl or O substituent → decreases MR activity
  6. 9 alpha F or Cl enhances GR and MR potency
  7. 6 alpha methyl or F enhances GR/MR ratio
42
Q

Are glucocorticoids used to stop an asthma attack while it is happening?

A

NO → glucocorticoids do not directly relax airway smooth muscle and has little effect on acute bronchoconstriction

43
Q

How are glucocorticoids effective in inhibiting airway inflammation?

A
  1. modulation of cytokine and chemokine production
  2. inhibition of eicosanoid synthesis
  3. inhibition of accumulation of immune cells in lung tissue
  4. decreased vascular permeability
44
Q

How do inhaled glucocorticoids control asthma?

A
  1. beneficial effects may be seen within a week and maximal improvement may occur until after several weeks of treatment
  2. compliance is not a concern
45
Q

What are the desired properties of inhaled glucocorticoids?

A

high potency, minimal systemic effects. prolonged action, no long half life

46
Q

What are some solutions to inhaled glucocorticoids?

A
  1. high lipophilicity → tighter binding to receptor, better tissue penetration, prolonged action by forming poorly soluble microcrystals
  2. low oral bioavailability → 70-90% is swallowed
  3. rapid clearance → short half life
47
Q

What is triamcinolone acetonide?

A
  1. inhaled glucocorticoid
  2. Azmacort
  3. acetonide is resistant to hydrolysis
  4. 8 times more potent than prednisolone
  5. more lipophilic
48
Q

What is beclomethasone dipropionate?

A
  1. inhaled glucocorticoid
  2. Vanceril, Qvar
  3. converted rapidly to 17-monopropionate by hydrolysis
  4. 14 times more potent than dexamethasone
49
Q

What is flunisolide?

A
  1. inhaled glucocorticoid
  2. Aerobid
  3. rapid absorption from nasal or lung tissue
  4. rapid metabolism by the liver → extensive first pass metabolism and minimal systemic adverse effect with long term therapy
  5. has acetonide to increase lipophilicity and fluorine increases activity
50
Q

What is budesonide?

A
  1. inhaled glucocorticoid
  2. Pulmicort
  3. 1:1 mixture of epimers at 16,17-butylacetal
  4. faster topical uptake
  5. low oral bioavailability → less systemic side effects
  6. extensive first path metabolism → rapid
51
Q

What is mometasone furoate?

A
  1. inhaled glucocorticoid
  2. Asmanex
  3. highly potent
  4. more rapid onset of action
  5. negligible systemic availability → rapid metabolism and low oral bioavailability
52
Q

What is fluticasone propionate?

A
  1. inhaled glucocorticoid
  2. Flovent
  3. inactivated by hydrolysis of thioester → rapid first path metabolism
  4. highly lipophilic and insoluble → highly potent, poor absorption from GI, rapid topical uptake
  5. has 17 OH group blocked by ester and have 21 sulfur instead
53
Q

What are desired properties of topical glucocorticoids?

A

high lipophilicity, fast absorption, minimal systemic effect, prolonged action

54
Q

What are important properties of topical glucocorticoids?

A
  1. halogenated analogues are usually potent
  2. once absorbed through the skin, topical glucocorticoids are metabolized primarily in the liver and excreted into the urine or bile
  3. glucocorticoids with low potency are safest for chronic application → hydrocortisone cream
  4. glucocorticoids with high potency can have risk of systemic exposure and should only be used for a short time
55
Q

What forms have better potency for topical applications?

A

acetonide or ester forms because of high lipophilicity → triamcinolone acetonide (high potency), fluocinonide (high potency), betamethasone valerate (medium potency)

56
Q

What are 21-chlorocorticoids?

A

the substitution of chlorine for the 21 OH group greatly enhances topical anti-inflammatory activity → clobetasol propionate, halobetasol propionate, halcinonide

57
Q

Why do fluticasone propionate and mometasone furoate have medium potency?

A

high lipophilicity and highest binding affinity but poor solubility since it can make crystals on the surface of airways that slowly dissolve over time so it’s bad as a topical since it won’t penetrate skin and can be washed away → poor dissolution into inflamed tissue

58
Q

What are adverse effects of glucocorticoids?

A
  1. crossover mineralocorticoid activity → Na+ and water retention, development of hypertension, correctable with selective synthetic glucocorticoids
  2. metabolic effects → steroid myopathy (cause wasting muscle for prolonged use), reduced long bone growth in children (cause premature closing of epiphyseal junction and stop growth), osteoporosis (osteoblasts are inhibited but can be prevented by bisphosphate)
  3. Cushing like effects (redistribution of fat) → moon face and buffalo hump
  4. impaired glucose tolerance → hyperglycemia from gluconeogenesis and decreased insulin response (can unmask diabetes)
  5. suppression of immune system → increased susceptibility to infections and impaired wound healing
  6. GI → greater peptic ulcer risk
  7. CNS → linked to glucose metabolism, euphoria, depression
  8. cataracts → protein damage in lens due to diabetes
  9. adrenal insufficiency upon withdrawal (Addisonian crisis)
59
Q

What is Addisonian crisis?

A
  1. due to negative feedback on hypothalamus and pituitary from prolonged pharmacological doses of glucocorticoids
  2. delayed recovery of hypothalamus and pituitary
  3. depressed ACTH release and adrenal response to ACTH
  4. directly related to dose and duration of therapy
  5. symptoms → inability to withstand stress, hypotension, weakness
60
Q

Which side effect of glucocorticoids is least reversible?

A

most are reversible except moon face/ buffalo hump (have to lose weight) and cataracts (can’t reverse the eye damage)

Therapeutics (15 decks)

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