Corticosteroids - 16,17 Flashcards
Adrenal glands
- the cortex produces ___, ___, and ___
- the medulla produces ___ and ___
- glucocorticoids, mineralcorticoids, and androgens
- epinephrine and norepinephrine
Glucocorticoids
- ___ hormones
- increase circulating ___
- potent ___ effects
- ___ critical for selectivity
- stress
- glucose
- anti-inflammatory
- 17a-OH
Mineralocorticoids
- ___ retention
- ___ blood volume
- ___ blood pressure
- Na+
- increased
- increased
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
- GPCR
- cascade
- immediate
- glycogen, glucose
- short
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
- glucocoricoid, nuclear
- protein
- long
- induces
- inhibits
Regulation of glucocorticoid synthesis
- stress causes hypothalamus to release ___
- this triggers the pituitary gland to release ___
- this triggers adrenal gland to release ___ leading to physiological responses and a negative feedback loop
- Corticotropin releasing hormone (CRH)
- Adrenocorticotropic hormone (ACTH)
- Cortisol
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.
mineralocorticoids
aldosterone
Renin-angiotensin-aldosterone system
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
- dimers, Glucocorticoid Responisve Elements (GRE)
- trascription
- gluconeogenesis, anti-inflammatory
- PEP
- phospholipase A2, eicosanoid
Mechanism of immunosuppression by glucocorticoids
- activated glucocorticoid receptor (GR) binds to ___ and prevents binding of ___ to its response element
- transcription of ___ genes are repressed
- NFkB
- cytokine
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)
- increased
- promote, decreased
- promote, decreased
- cytokines, eicosanoids
Overall: increase blood glucose levels
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 ___)
- decreased
- tuberculorsis, Addison’s
- Adrenocorticotropin (ACTH)
- anterior pituitary, hypoaldosteronism
Adrenal insufficiency
Addison’s disease symptoms
* extreme ___
* ___, nausea, vomiting
* ___ blood pressure - ___ only
* hyperpigmentation of the skin - ___ only
* depression
- weakness
- anorexia
- low, primary
- primary
T or F: Cessation of long-term systemic glucocorticoid therapy can lead to Cushing symptoms.
False; leads to Addisonian symptoms
Types of adrenal insufficiency
Primary - adrenal defect
CRH:
ACTH:
Cortisol:
Aldosterone:
increase
increase
decrease
decrease
CRH and ACTH have no negative feed back
Types of adrenal insufficiency
secondary - pituitary defect
CRH:
ACTH:
Cortisol:
Aldosterone:
- increase
- decrease
- decrease
- not affected
tertiary - hypothalamic defect
CRH:
ACTH:
Cortisol:
Aldosterone:
- decrease
- decrease
- decrease
- not affected
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)
- adrenal cortex
- increased
- non-pituitary
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.
- catabolism, bruising, wasting, increased
- long term
adrenal Cushing’s disease
CRH:
ACTH:
Cortisol:
- decrease
- decrease
- increase
pituitary Cushing’s disease
CRH:
ACTH:
Cortisol:
- decreased
- increased
- increased
ectopic Cushing’s disease
CRH:
ACTH:
Cortisol:
ectopic ACTH:
- decrease
- decrease
- increase
- increase
ectopic ACTH is produced from cancer cells (suppress immune system)
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
- primary, adrenal
- angioedema
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
- 11 hydroxyl
- liver
- reversible
- systemically
- liver
Systemic corticosteroids
short acting
t1/2 = ___
* 2 examples
- 8-12 hours
- hydrocortisone
- cortisone
Systemic corticosteroids
Intermediate-acting
t1/2 = ___
* 4 examples
- 12-36 hours
- prednisone
- prednisolone
- methylprednisolone
- triamcinolone
week long therapy
Systemic corticosteroids
long acting
t1/2 = ___
* 2 examples
36-54 hours
* dexamethasone
* betamethasone
Synthetic glucocorticoids
Fludrocortisone
* 9aF
* greater ____ activity than hydrocortisone
* really strong ___ activity. Used in ___ replacement therapy
* intense Na+ retention leading to ___
- glucocorticoid
- mineralcorticoid, aldosterone
- edema
Synthetic glucocorticoids
Prednisone/prednisolone
* Extra double bond between ___
* more potent ___ activity
* reduced ___ activity
* interconvertable by ___
- C1 and C2
- glucocorticoid
- mineralcorticoid
- 11B-hydroxysteroid dehydrogenase
Synthetic glucocorticoids
Methylprednisolone
* ___a-methyl group
* potency similar to ___
* reduced ___ activity
- 6
- prednisolone
- mineralcorticoid
Synthetic glucocorticoids
Triamcinolone
* 9a-F and ___a-OH
* glucocorticoid activity similar to ___
* reduced ___ activity
* ___ hydrophilcity
* ___ oral bioavailability
- 16
- prednisone
- mineralocorticoid
- reduced
- low
Synthetic glucocorticoids
Dexamethasone
* ___a-methyl group
* ___ lipophilicity
* ___ receptor binding
* significantly stronger effect.
* increased stability in plasma
* reduced ___ activity
- 16
- increased
- increased
- mineralocortioid
Synthetic glucocorticoids
Betamethasone
* ___ of dexamethasone at 16
* has simialr properties as ___
- enantiomer
- dexamethasone
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
- ester
- esterases
- increased, prolonged
- slow (30-45 min)
- increased, rapid, phosphatases
one method of prodrug activation is hydrolyzing its ester
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
- GR/MR
- B-OH
- OH, prodrug, OH
- a-O
- MR
- GR, MR
- GR/MR
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
- dilate, bronchoconstriction
- slow
- inflammation
- cytokine, chemokine
- eicosanoid
- immune
- decreased
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
- prophylactically
- 1 week several
- compliance
Inhaled glucocorticoids
Desired properties
- high potency
- minimal systemic effects
- prolonged action
Inhaled glucocorticoids
Solutions
___ lipophilicity
* tight receptor binding
* better tissue penetration
* ___ action by forming poorly soluble ___
* low ___ bioavailability
* rapid clearance (___ half life)
- High
- prolonged, microcrystals
- oral
- short
Triamcinolone acetonide (Azmacort)
- acetonide is resistant to ___
- 8x more potent than ____
Inhaled glucocorticoids
- hydrolysis
- prednisolone
Beclomethasone dipropionate (Vanceril, Qvar)
- converted rapidly to 17-monopropionate by ___
- 14x more potent than ___
Inhaled glucocorticoids
- hydrolysis
- dexamethasone
Flunisolide (Aerobid)
- ___ absorption from nasal or lung tissue
- rapid metabolism by the ___
- minimal systemic adverse effect with ___ therapy
Inhaled glucocorticoids
- rapid
- liver
- long term
Budesonide (Pulmicort)
- 1:1 mixture of epimers at 16,17 butylacetal
- ___ topical uptale
- low oral ____
- extensive ___ metabolism
Inhaled glucocorticoids
- faster
- bioavailability
- first pass
Mometasone furoate (Asmanex)
- ___ potency
- rapid ___ of action
- negligible ___ availability
- ___ oral bioavailability (1%)
Inhaled glucocorticoids
- high
- onset
- systemic
- low
Fluticasone propionate (Flovent)
- inactivated by hydrolysis of ___
- rapid ___ metabolism
- highly ___ and insoluble
- ___ potency
- ___ absorption of GI
- ___ topical uptake
Inhaled glucocorticoids
- thioester
- first pass
- lipophilic
- high
- poor
- rapid
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.
- high
- minimal
- Halogenated
- liver
T or F: Glucocorticoids with high potency are safest for chronic application.
False; low potency is safest is applied often
high potency
should be used only for a short duration of treatment.
Triamcinolone acetonide
___ potency
Topical glucocorticoid
high
Fluocinonide
___ potency
high
Betamethasone valerate
___ potency
medium
21-chlorocorticoids
Substitution of a ___ atom for the 21-hydroxyl group greatly enhances ___ anti-inflammatory activity.
Chlorine, topical
T or F: Fluticasone propionate and mometasone furoate have only medium potency.
True
Adverse effects of glucocorticoids
Crossover mineralocorticoid activity
* ___ and ___ retention
* development of ___
* Correctable with ___
- Na+ and water
- hypertension
- selective synthetic glucocorticoids
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
- wasting
- long bone, closing
Osteoporosis
* Pharmacological dose of glucocorticoids inhibit ___
* Can be prevented by ___
- osteoblasts
- bisphosphonate
Adverse effects of glucocorticoids
Cushing’s like effects - redistribution of ___
* moon face
* buffalo hump
Impaired glucose tolerance
* hyperglycemia from ___
* decreased ___ response
* may unmask diabetes ___
- faft
- gluconeogenesis
- insulin
- mellitus
Adverse effects of glucocorticoids
___ of immune system
* increased susceptibility to infections (THRUSH)
* ___ wound healing
Gastrointestinal
* greater ___ risk
CNS
* linked to ___ metabolism
* euphoria
* depression
Cataracts
- suppression
- impaired
- peptic ulcer
- glucose
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 ___
- hypothalamus and pituitary
- ACTH
- stress
What is this?
Cortisol
glucocorticoid
What is this?
Aldosterone
mineralocorticoids
What is this?
Cortisone
inactive
What is this?
Fludrocortisone
Used in mineralocorticoids replacement therapy
What is this?
Prednisone
What is this?
Prednisolone
What is this?
Methylprednisolone
What is this?
Triamcinolone
What is this?
Dexamethasone
What is this?
Betamethasone
enantiomer of dexamethasone
What is this?
Triamcinolone acetonide (Azmacort)
inhaled/topical glucocorticoid
What is this?
Beclomethasone dipropionate
inhaled glucocorticoid
What is this?
Flunisolide
inhaled/topical glucocorticoid
What is this?
Budesonide (Pulmicort)
inhaled glucocorticoid
What is this?
Mometasone furoate
Inhaled/topical glucocorticoids
What is this?
Fluticasone propionate
Inhaled/topical glucocorticoid
What is this?
Betamethasone valerate
topical (medium potency)
What is this
Clobetasol propionate
21-cholorocorticoid topical
What is this?
Halobetasol propionate
21-cholorocorticoid topical
What is this
Halcinonide
21-cholorocorticoid topical
