Adrenal glands the cortex produces ___, ___, and ___ the medulla produces ___ and ___

glucocorticoids, mineralcorticoids, and androgens epinephrine and norepinephrine

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 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

Corticotropin releasing hormone (CRH) Adrenocorticotropic hormone (ACTH) Cortisol

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

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

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

Corticosteroids - 16,17 Flashcards by Reagan Smith

Adrenal glands

the cortex produces ___, ___, and ___
the medulla produces ___ and ___

glucocorticoids, mineralcorticoids, and androgens
epinephrine and norepinephrine

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Glucocorticoids

___ hormones
increase circulating ___
potent ___ effects
___ critical for selectivity

stress
glucose
anti-inflammatory
17a-OH

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Mineralocorticoids

___ retention
___ blood volume
___ blood pressure

Na+
increased
increased

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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

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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

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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

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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

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Renin-angiotensin-aldosterone system

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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

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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

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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

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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

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Adrenal insufficiency

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

weakness
anorexia
low, primary
primary

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

False; leads to Addisonian symptoms

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Types of adrenal insufficiency

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

increase
increase
decrease
decrease

CRH and ACTH have no negative feed back

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Types of adrenal insufficiency

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

increase
decrease
decrease
not affected

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

decrease
decrease
decrease
not affected

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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

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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

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adrenal Cushing’s disease
CRH:
ACTH:
Cortisol:

decrease
decrease
increase

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pituitary Cushing’s disease
CRH:
ACTH:
Cortisol:

decreased
increased
increased

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

decrease
decrease
increase
increase

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

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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

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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

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# 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

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