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PHRM 825 > Corticosteroids - 16,17 > Flashcards

Corticosteroids - 16,17 Flashcards

1
Q

Adrenal glands

  • the cortex produces ___, ___, and ___
  • the medulla produces ___ and ___
A
  • glucocorticoids, mineralcorticoids, and androgens
  • epinephrine and norepinephrine
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2
Q

Glucocorticoids

  • ___ hormones
  • increase circulating ___
  • potent ___ effects
  • ___ critical for selectivity
A
  • stress
  • glucose
  • anti-inflammatory
  • 17a-OH
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3
Q

Mineralocorticoids

  • ___ retention
  • ___ blood volume
  • ___ blood pressure
A
  • Na+
  • increased
  • increased
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4
Q

Contrasting modes of action of stress hormones - epinephrine

  • binds to B adrenergic receptor ___
  • initiated signal transduction ___
  • ___ response
  • breaks down ___ and release ___
  • fight or flight - ___ term
A
  • GPCR
  • cascade
  • immediate
  • glycogen, glucose
  • short
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5
Q

Contrasting modes of action of stress hormones - cortisol

  • binds to ___ receptor (a ___ hormone receptor)
  • regulates gene transcription, translation, and ___ production
  • induced ___ term response
  • ___ gluconeogenic enzymes
  • ___ pro-inflammatory processes
A
  • glucocoricoid, nuclear
  • protein
  • long
  • induces
  • inhibits
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6
Q

Regulation of glucocorticoid synthesis

  1. stress causes hypothalamus to release ___
  2. this triggers the pituitary gland to release ___
  3. this triggers adrenal gland to release ___ leading to physiological responses and a negative feedback loop
A
  • Corticotropin releasing hormone (CRH)
  • Adrenocorticotropic hormone (ACTH)
  • Cortisol
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7
Q

Regulation of mineralocorticoid synthesis

The anterior pituitary does not control the synthesis of ___
* When the pituitary gland is surgically removed in animals, ___ synthesis is not affected significantly.

A

mineralocorticoids
aldosterone

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8
Q

Renin-angiotensin-aldosterone system

A
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9
Q

Hormone response elements

  • DNA-binding domains of activated ___ bind to specific DNA sequences
    called ___, upstream of steroid responsive genes.
  • Binding alters rate of ___.
  • Glucocorticoids up-regulate enzymes for ___ and ___ proteins.
  • ___ carboxykinase - catalyzes the rate limiting step of gluconeogenesis
  • lipocortin 1 - suppresses ___ which has a critial role in ___ synthesis
A
  • dimers, Glucocorticoid Responisve Elements (GRE)
  • trascription
  • gluconeogenesis, anti-inflammatory
  • PEP
  • phospholipase A2, eicosanoid
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10
Q

Mechanism of immunosuppression by glucocorticoids

  • activated glucocorticoid receptor (GR) binds to ___ and prevents binding of ___ to its response element
  • transcription of ___ genes are repressed
A
  • NFkB
  • cytokine
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11
Q

Physiologic effects

  • Liver: ___ gluconeogenesis and glycogen storage
  • Muscle: ___ protein degradation, ___ protein synthesis and sensitivity to insulin
  • Adipose tissues: ___ lipolysis, ___ sensitivity to insulin
  • Immune system: block synthesis of ___ (immunosuppression), inhbit production of ___ (anti-inflammation)
A
  • increased
  • promote, decreased
  • promote, decreased
  • cytokines, eicosanoids

Overall: increase blood glucose levels

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12
Q

Adrenal insufficiency

  • hypoadrenalism
  • ___ secretion of steroid hormones by the adrenal cortex
  • caused by destruction of cortex by ___ or atrophy (primary; ___’s disease)
  • decreased secretion of ___ due to diseases of ___ (secondary; no ___)
A
  • decreased
  • tuberculorsis, Addison’s
  • Adrenocorticotropin (ACTH)
  • anterior pituitary, hypoaldosteronism
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13
Q

Adrenal insufficiency

Addison’s disease symptoms
* extreme ___
* ___, nausea, vomiting
* ___ blood pressure - ___ only
* hyperpigmentation of the skin - ___ only
* depression

A
  • weakness
  • anorexia
  • low, primary
  • primary
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14
Q

T or F: Cessation of long-term systemic glucocorticoid therapy can lead to Cushing symptoms.

A

False; leads to Addisonian symptoms

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15
Q

Types of adrenal insufficiency

Primary - adrenal defect
CRH:
ACTH:
Cortisol:
Aldosterone:

A

increase
increase
decrease
decrease

CRH and ACTH have no negative feed back

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16
Q

Types of adrenal insufficiency

secondary - pituitary defect
CRH:
ACTH:
Cortisol:
Aldosterone:

A
  • increase
  • decrease
  • decrease
  • not affected
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17
Q

tertiary - hypothalamic defect
CRH:
ACTH:
Cortisol:
Aldosterone:

A
  • decrease
  • decrease
  • decrease
  • not affected
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18
Q

Cushing’s disease

  • hyperadrenalism
    causes:
  • Tumors in the ___ (adrenal Cushing’s disease)
  • ___ production of ACTH due to pituitary carcinoma (pituitary Cushing’s disease)
  • Ectopic production of ACTH due to ___ carcinoma (ectopic Cushing’s disease)
A
  • adrenal cortex
  • increased
  • non-pituitary
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19
Q

Symptoms
* increased protein ___ (easy ___, delayed wound healing, muscle ___) and ___ glucose levels
* osteoporosis
* opportunistic infections
* ___ therapeutic use of systemic glucocorticoids can lead to Cushing’s
symptoms.

A
  • catabolism, bruising, wasting, increased
  • long term
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20
Q

adrenal Cushing’s disease
CRH:
ACTH:
Cortisol:

A
  • decrease
  • decrease
  • increase
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21
Q

pituitary Cushing’s disease
CRH:
ACTH:
Cortisol:

A
  • decreased
  • increased
  • increased
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22
Q

ectopic Cushing’s disease
CRH:
ACTH:
Cortisol:
ectopic ACTH:

A
  • decrease
  • decrease
  • increase
  • increase

ectopic ACTH is produced from cancer cells (suppress immune system)

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23
Q

Therapeutic uses of corticosteroids

  • ___ adrenal insufficiency - ___ disease
  • allergic reactions: insect stings and ___
  • ___ and autoimmune diseases: rheumatoid arthhritis, lupus, IBD, chronic hepatic
  • **asthma **
  • immunosuppressive
  • anti-cancer
A
  • primary, adrenal
  • angioedema
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24
Q

Cortisol versus cortisone

  • oxidation of ___ to ketone inactivates glucocorticoids
  • catalyzed by 11B-hydroxysteroid dehydrogenase in the ___
  • ___ reaction
  • cortisone is as effective as cortisol when used ___
  • cortisone should not be used in patients with imparied ___ function
A
  • 11 hydroxyl
  • liver
  • reversible
  • systemically
  • liver
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25
Q

Systemic corticosteroids

short acting
t1/2 = ___
* 2 examples

A
  • 8-12 hours
  • hydrocortisone
  • cortisone
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26
Q

Systemic corticosteroids

Intermediate-acting
t1/2 = ___
* 4 examples

A
  • 12-36 hours
  • prednisone
  • prednisolone
  • methylprednisolone
  • triamcinolone

week long therapy

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27
Q

Systemic corticosteroids

long acting
t1/2 = ___
* 2 examples

A

36-54 hours
* dexamethasone
* betamethasone

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28
Q

Synthetic glucocorticoids

Fludrocortisone
* 9aF
* greater ____ activity than hydrocortisone
* really strong ___ activity. Used in ___ replacement therapy
* intense Na+ retention leading to ___

A
  • glucocorticoid
  • mineralcorticoid, aldosterone
  • edema
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29
Q

Synthetic glucocorticoids

Prednisone/prednisolone
* Extra double bond between ___
* more potent ___ activity
* reduced ___ activity
* interconvertable by ___

A
  • C1 and C2
  • glucocorticoid
  • mineralcorticoid
  • 11B-hydroxysteroid dehydrogenase
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29
Q

Synthetic glucocorticoids

Methylprednisolone
* ___a-methyl group
* potency similar to ___
* reduced ___ activity

A
  • 6
  • prednisolone
  • mineralcorticoid
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30
Q

Synthetic glucocorticoids

Triamcinolone
* 9a-F and ___a-OH
* glucocorticoid activity similar to ___
* reduced ___ activity
* ___ hydrophilcity
* ___ oral bioavailability

A
  • 16
  • prednisone
  • mineralocorticoid
  • reduced
  • low
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31
Q

Synthetic glucocorticoids

Dexamethasone
* ___a-methyl group
* ___ lipophilicity
* ___ receptor binding
* significantly stronger effect.
* increased stability in plasma
* reduced ___ activity

A
  • 16
  • increased
  • increased
  • mineralocortioid
32
Q

Synthetic glucocorticoids

Betamethasone
* ___ of dexamethasone at 16
* has simialr properties as ___

A
  • enantiomer
  • dexamethasone
33
Q

21-esters

  • The hydroxyl group at 21 can be modified to an ___ to control the property of glucocorticoids.
  • Prodrugs activated through hydrolysis by ___
  • acetate and butyrate: ___ lipophilicity and ___ action for injection
  • succinate: soluble, ___ hydrolysis
  • phosphate: ___ solubility, ___ hydrolysis by ___ (10 minutes), IV or IM for emergency conditions
A
  • ester
  • esterases
  • increased, prolonged
  • slow (30-45 min)
  • increased, rapid, phosphatases

one method of prodrug activation is hydrolyzing its ester

34
Q

Structure-activity relationship summary

  • 1,2 double bond lead to a 5 fold ratio enhancement of ___ activity
  • 11___ required for full GR/MR activity
  • 21___, F, or Cl required for GR/MR activity; ester ___ must be hydrolyzed to ___ for max activity
  • 17___ required for GR acrivity
  • 16a or B-CH3 or O substituent decreases ___ activity
  • 9a-F or Cl enhances ___ and ___ potency.
  • 6a-CH3 or F enhances ___ ratio
A
  • GR/MR
  • B-OH
  • OH, prodrug, OH
  • a-O
  • MR
  • GR, MR
  • GR/MR
35
Q

Mechanism of glucocorticoid action in asthma

  • Glucocorticoids do not directly __ airway smooth muscle; little effect on acute ___
  • Glucocorticoids will not stop an asthma attack while it is happening because they are too ___.
  • effective in inhibiting airway ___
  • modulation of ___ and ___ production
  • inhibition of ___ synthesis
  • Inhibition of accumulation of ___ cells in lung tissue
  • ___ vascular permeanility
A
  • dilate, bronchoconstriction
  • slow
  • inflammation
  • cytokine, chemokine
  • eicosanoid
  • immune
  • decreased
36
Q

Mechanism of glucocorticoid action in asthma

Inhaled glucocorticoids are used ___ to control asthma.
* effects may be seen within ___; max improvement in may not occur until after ___ weeks of treatment.
* ___ is a concern

A
  • prophylactically
  • 1 week several
  • compliance
37
Q

Inhaled glucocorticoids

Desired properties

A
  • high potency
  • minimal systemic effects
  • prolonged action
38
Q

Inhaled glucocorticoids

Solutions
___ lipophilicity
* tight receptor binding
* better tissue penetration
* ___ action by forming poorly soluble ___
* low ___ bioavailability
* rapid clearance (___ half life)

A
  • High
  • prolonged, microcrystals
  • oral
  • short
39
Q

Triamcinolone acetonide (Azmacort)

  • acetonide is resistant to ___
  • 8x more potent than ____

Inhaled glucocorticoids

A
  • hydrolysis
  • prednisolone
40
Q

Beclomethasone dipropionate (Vanceril, Qvar)

  • converted rapidly to 17-monopropionate by ___
  • 14x more potent than ___

Inhaled glucocorticoids

A
  • hydrolysis
  • dexamethasone
41
Q

Flunisolide (Aerobid)

  • ___ absorption from nasal or lung tissue
  • rapid metabolism by the ___
  • minimal systemic adverse effect with ___ therapy

Inhaled glucocorticoids

A
  • rapid
  • liver
  • long term
42
Q

Budesonide (Pulmicort)

  • 1:1 mixture of epimers at 16,17 butylacetal
  • ___ topical uptale
  • low oral ____
  • extensive ___ metabolism

Inhaled glucocorticoids

A
  • faster
  • bioavailability
  • first pass
43
Q

Mometasone furoate (Asmanex)

  • ___ potency
  • rapid ___ of action
  • negligible ___ availability
  • ___ oral bioavailability (1%)

Inhaled glucocorticoids

A
  • high
  • onset
  • systemic
  • low
44
Q

Fluticasone propionate (Flovent)

  • inactivated by hydrolysis of ___
  • rapid ___ metabolism
  • highly ___ and insoluble
  • ___ potency
  • ___ absorption of GI
  • ___ topical uptake

Inhaled glucocorticoids

A
  • thioester
  • first pass
  • lipophilic
  • high
  • poor
  • rapid
45
Q

Topical glucocorticoids

Desired properties
* ___ lipophilicity for fast absorption
* ___ systemic effect
* prolonged action
* ___ analogues are usually potent topical glucocorticoids
* Once absorbed through the skin, topical glucocorticoids are metabolized primarily in the ___ and excreted into the urine or in the bile.

A
  • high
  • minimal
  • Halogenated
  • liver
46
Q

T or F: Glucocorticoids with high potency are safest for chronic application.

A

False; low potency is safest is applied often

high potency
should be used only for a short duration of treatment.

47
Q

Triamcinolone acetonide

___ potency

Topical glucocorticoid

A

high

48
Q

Fluocinonide

___ potency

A

high

49
Q

Betamethasone valerate

___ potency

A

medium

50
Q

21-chlorocorticoids

Substitution of a ___ atom for the 21-hydroxyl group greatly enhances ___ anti-inflammatory activity.

A

Chlorine, topical

51
Q

T or F: Fluticasone propionate and mometasone furoate have only medium potency.

A

True

52
Q

Adverse effects of glucocorticoids

Crossover mineralocorticoid activity
* ___ and ___ retention
* development of ___
* Correctable with ___

A
  • Na+ and water
  • hypertension
  • selective synthetic glucocorticoids
53
Q

Adverse effects of glucocorticoids

Metabolic effects (increased glucose production)
* steroid myopathy - high doses over a period of time cause proximal muscle ___
* Reduced ___ growth in children. Premature ___ of epiphyseal junction

A
  • wasting
  • long bone, closing
54
Q

Osteoporosis
* Pharmacological dose of glucocorticoids inhibit ___
* Can be prevented by ___

A
  • osteoblasts
  • bisphosphonate
55
Q

Adverse effects of glucocorticoids

Cushing’s like effects - redistribution of ___
* moon face
* buffalo hump

Impaired glucose tolerance
* hyperglycemia from ___
* decreased ___ response
* may unmask diabetes ___

A
  • faft
  • gluconeogenesis
  • insulin
  • mellitus
56
Q

Adverse effects of glucocorticoids

___ of immune system
* increased susceptibility to infections (THRUSH)
* ___ wound healing

Gastrointestinal
* greater ___ risk

CNS
* linked to ___ metabolism
* euphoria
* depression

Cataracts

A
  • suppression
  • impaired
  • peptic ulcer
  • glucose
57
Q

Adverse effects of glucocorticoids

Adrenal insufficiency upon withdrawal (Addisonian crisis)
* due to negative feedback on the ___ and ___ from prolonged glucocorticoid use
* decreases in ___ release
* hypotension, weakness, inability to withstand ___

A
  • hypothalamus and pituitary
  • ACTH
  • stress
58
Q

What is this?

A

Cortisol

glucocorticoid

59
Q

What is this?

A

Aldosterone

mineralocorticoids

60
Q

What is this?

A

Cortisone

inactive

61
Q

What is this?

A

Fludrocortisone

Used in mineralocorticoids replacement therapy

62
Q

What is this?

A

Prednisone

63
Q

What is this?

A

Prednisolone

64
Q

What is this?

A

Methylprednisolone

65
Q

What is this?

A

Triamcinolone

66
Q

What is this?

A

Dexamethasone

67
Q

What is this?

A

Betamethasone

enantiomer of dexamethasone

68
Q

What is this?

A

Triamcinolone acetonide (Azmacort)

inhaled/topical glucocorticoid

69
Q

What is this?

A

Beclomethasone dipropionate

inhaled glucocorticoid

70
Q

What is this?

A

Flunisolide

inhaled/topical glucocorticoid

71
Q

What is this?

A

Budesonide (Pulmicort)

inhaled glucocorticoid

72
Q

What is this?

A

Mometasone furoate

Inhaled/topical glucocorticoids

73
Q

What is this?

A

Fluticasone propionate

Inhaled/topical glucocorticoid

74
Q

What is this?

A

Betamethasone valerate

topical (medium potency)

75
Q

What is this

A

Clobetasol propionate

21-cholorocorticoid topical

76
Q

What is this?

A

Halobetasol propionate

21-cholorocorticoid topical

77
Q

What is this

A

Halcinonide

21-cholorocorticoid topical

PHRM 825 (49 decks)

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