2.1 Pharm Exam3: Corticosteroids

Front 1

Hypothalamic-Pituitary-Adrenal Axis:

Hypothalamus releases ______ to the Anterior pituitary

Anterior Pituitary release ______ to the Adrenal cortex

Adrenal cortex release _______ into circulation

Back 1

Hypothalamus releases CRH (corticotropin-releasing hormone)

Anterior Pituitary release ACTH (adrenocorticotropic hormone)

Adrenal Cortex releases Cortisol

Front 2

________ has negative feedback effect on BOTH ACTH & CRH release

What may override this negative feedback?

Back 2

Cortisol

stress (hypoglycemia, trauma, cold, etc)

Front 3

Cortisol release follows what?

Back 3

circadian rhythm

*peaks early morning & after meals

(2/3 dose in morning, 1/3 later in day to follow natural cycle)

Front 4

___________ is synthesized & released from the zona fasciulata of the adrenal cortex, in response to the HPA axis.

What does this hormone do?

Back 4

glucocorticoids - CORTISOL

Impacts regulation and function of the following:
- Metabolism
- Stress Response
- CNS functions
- Immunity

Front 5

________ is synthesized & released from the zona glomerulosa of the adrenal cortex, in response to the renin-angiotensin system (angiotensin II receptors).

What does this hormone do?

Back 5

Mineralocorticoids - ALDOSTERONE

Impacts regulation of:
- Na+ and K+ concentrations in extracellular fluids (↓K+, ↑Na+) (electrolyte regulation)

Front 6

Most of circulating cortisol is (active/inactive)

Why?

Back 6

Inactive

Most circulating cortisol is bound to corticosteroid-binding globulin (CBG), making it inactive

(cortisol is hydrophobic, thus must be bound)

(synthetics such as dexamethesone mostly bound to albumin)

Front 7

11-keto formulation (Hydroxyl at carbon 11 converted to ketone) confers a ____________ state on glucocorticoids

What enzyme converts the ketone back to a hydroxyl?

Back 7

less active state

11-beta-hydroxysteroid dehydrogenase

(converts prodrug prednisone--> active prednisolone)

Front 8

3-keto formulation (carbon 3 ketone) & 4, 5 double bonds (carbons 4 & 5) are required for __________

Back 8

glucocorticoid, mineralcorticoid, & androgen activity

Front 9

Where is cortisol metabolized?

Back 9

LIVER, via

- reduction of double bonds between C4,5

- conversion of ketone at C3 to a hydroxyl

- conjugation with sulfate glucuronate,

*excretion by kidneys.

Front 10

T/F

Cortisone & Prednisone are used topically

Back 10

FALSE

these require activation via 11-beta-hydroxysteroid dehydrogenase, which is in the liver

Front 11

What determines the potency of topical GCs?

Back 11

1. intrinsic activity

2. concentration

3. vehicle

Front 12

Physiological Effects 
of Corticosteroids: Metabolism

Back 12

(sometimes referred to as the anti-insulin)
- Incr. Hepatic Gluconeogenesis (AA & glycerol--> glucose)
- Incr. Hepatic Formation of glycogen
- Incr. Protein breakdown--> amino acids
(~ may lead to skeletal muscle weakness and wasting)
- Decr. Glucose utilization
----= incr. blood glucose

incr. lipolysis - incr. free fatty acids
- increase deposition of fat in back of neck and face (moonface)
- decrease deposition of fat in extremities

= Redistribution of body fat

(extremities/lateral--> central/medial region)

Front 13

Physiological Effects 
of Corticosteroids: Electrolyte and water balance

Back 13

- distal tubules and collecting ducts of kidney to enhance reabsorption of Na+
-- Urinary retention of Na+ & inc. extracellular fluid volume
-- Urinary excretion of K+ & H+
(^ less of an effect than MCs, regulated by RA)

Front 14

Physiological Effects 
of Corticosteroids: Cardiovascular

Back 14

(effects are secondary to MC changes in renal Na+ excretion)
- Excess of CS = hypertension, arteriosclerosis, cardiomyopathy, & enhanced vascular responsiveness to vasoconstrictors such as norepinephrine and angiotensin
- Deficiency in CS = hypotension, unresponsiveness to vasoconstrictors

Front 15

Physiological Effects 
of Corticosteroids: CNS

Back 15

altered mood
- Excess CS– mood elevation, euphoria, insomnia, motor activity
- Deficiency in CS– apathy, depression, irritability, psychosis

Front 16

Physiological Effects 
of Corticosteroids: Bone

What should you give along side chronic corticosteroids to prevent neg. bone effects?

Back 16

- Decr. osteoblast bone formation
- Incr. osteoclast bone resorption
-- Alters Ca++ & Vit D homeostasis

= Osteoporosis

* give bisphosphonates (prevent bone loss)

Front 17

Physiological Effects 
of Corticosteroids: Immune System

*primary therapeutic effects*

Back 17

Anti-inflammatory & immunosuppressive effects

(primarily GC, not MC)
-Dec. pro-inflammatory: IL-2, GM-CSF, & TNFα
- Incr. anti-inflammatory: IL-10, IκBα
(Decr PGs & LTs)

= impair proliferation, activation, & chemotaxis of leukocytes

Front 18

where are GC receptors (GCR) & MC receptors (MCR) located?

Back 18

GCR: Widely distributed throughout the body

MCR: kidney (distal tubule, collecting ducts), colon, sweat glands

(Cortisol has equal affinity for GCR & MCR. Actions of Cortisol on MCR-expressing tissues minimized by 11β-hydroxylase – converts cortisol--> inactive cortisone)

Front 19

Direct, Type I MOA: GC

Back 19

- GC enters cellular membrane via passive diffusion (d/t lipophilic cholesterol-like backbone)
- GC binds to GCR in cytoplasm
- GC then dissociates from chaperone complex of heat shock proteins (HSPs) (normally bound)
- GC/Receptor complex crosses nuclear membrane, entering nucleus
- Complex forms homodimer & binds directly to DNA at Glucocorticoid Response Element (GRE) region
- Homodimer binding alters transcription rates of DNA into mRNA
-- Alters mRNA translation into protein
-- Alters levels of inflammatory mediators

Front 20

Indirect, Type II MOA: GC

Back 20

-GC/Receptor complex binds to HAT (histone acetyl transferase)
-HAT is inactivated (activated HAT opens DNA & allows transcription of pro-inflammatory genes)

-Complex recruits HDAC2 (histone deacetylase 2)

--> causes gene supression of pro-inflammatory genes

Front 21

GCs cause (decrease/increase) in NF-kB

what does this lead to?

Back 21

Decrease NF-κB =

-> Decr COX-2 --> *Decr PGs
-> Decr PLA2--> *Decr arachidonic acid--> decr COX--> dec PG & LT

-> Decr NOS

-> Decr IL-5

-> Decr eosinophil

-> Dec GM-CSF*

-> Dec leukocytes

-> TNFalpha activity*

Front 22

GCs decrease signal transduction of TNFalpha via impaired NF-kB. What does this lead to?

Back 22

(TNFα signaling impaired since NF-κB is an intracellular 2nd messenger for TNF)

*Decr Chemotaxis of all leukocytes

-- dec macrophage activation, acute phase protein release, Selectin & CAM expression, CCL3 & CXCL8-IL8 expression, & dec integrins

Front 23

GC also cause a decrease in transcription of....

Back 23

*IL-1 (--> dec macrophage, CAM, CCL3, CXCL8-IL8, integrin, & chemotaxis*)
*IL-2 (--> dec T cell*& B cell* activity, also monocyte & NK)

*IL-6 (--> dec acute phase proteins, B cell & neutrophil)

*GM-CSF (--> dec leukocytes)

*AP-1

(also IL-3 & IFNgamma dec)

Front 24

GC decrease in AP-1 activity leads to?

Back 24

Decrease AP-1 transcription of Collagenase & IL-2 genes

(AP-1 = c-Jun + c-Fos--> binds to RNA polymerase II to cause gene transcription)

Front 25

GCs increase the transcription of what?

Back 25

*IL-10--> suppresses helper T cells

*IkBalpha--> inhibits NF-kB

Front 26

Glucocorticoids: Adverse Effects of Cushing Syndrome/Hypercortisolism

Back 26

- Weight gain (↑ appetite, inc gluconeogenesis)
- Muscle weakness
- Excess hair growth*
- Hair loss*
- Fat redistribution
- High blood pressure*
- Osteoporosis
- Gonadal Dysfunction*

Front 27

Hypocortisolism is due to?

Back 27

-primary adrenal insufficiency/Addisons = no cortisol production

-secondary adrenal insufficiency (defective HPA axis or ant pit.)= not enough cortisol

-exogenous administration of glucocorticoids (atrophy of ant pit & hypo.)= not enough cortisol

Front 28

Glucocorticoids: Adverse Effects of Addison's / Hypocortisolism (adrenal insufficiency)

Back 28

*life-threatening (if acute adrenal insufficiency)

-GI symptoms (nausea/vommiting)

-dehydration

-hyponatriemia

-hyperkalemia

-weakness

-hypotension

Front 29

Why should you NEVER withdraw corticoisteroids abruptly after prolonged therapy?

Back 29

*may result in acute adrenal insufficiency (LIFE-THREATENING, d/t offset HPA axis)

- Recovery of full adrenal function may take 2-18 months

Longer the duration = slower the withdraw*

Front 30

T/F

you should always use the lowest dose, the shortest time, & as local of administration possible when using corticosteroids

Back 30

TRUE!

limits neg side effects

Front 31

What GC is used for the diagnosis of Cushing Syndrome?

Back 31

Dexamethasone

administered at night-

-if hypercortisol due to over production of hypothalamic or pituitary hormone the cortisol levels are decrease in morning (=HPA response)
-if due to a cortisol-secreting tumor (Cushings), circulating cortisol levels will be unchanged

Front 32

GC Therapeutic Uses:

Back 32

*Primary Addisons, secondary or tertiary adrenocortical insufficiency

*Inflammatory bowel disease (IBD)

*Asthma

*Eczema

*Psoriasis

*Inflammation

*Immunosuppresion

*Allergies

*Stimulation of Lung maturation in fetus

Front 33

Primary (Addisons), Secondary, Tertiary adrenocortical insufficiency: DOC

Back 33

hydrocortisone

*2/3 dose in morning, 1/3 dose later in day

Front 34

Addison's disease tx may also requires

Back 34

Fludrocortisone (a mineralcorticoid)

(ONLY in Addisons)

Front 35

IBD, severe asthma (systemic/oral tx of inflammation): DOC

Back 35

Prednisolone

Front 36

Asthma (inhalation therapy): DOCs

Back 36

- Beclomethasone & budesonide

Front 37

Allergic rhinitis: DOC

Back 37

Fluticason

Front 38

Immunosuppression (graft vs. host): DOC

Back 38

methylprednisone or dexamethasone

Front 39

Severe psoriasis: DOC

Back 39

Triamcinolone acetonide

Front 40

Topical therapy (Eczema, distal UC, Crohn/s): DOC

Back 40

hydrocortisone

Front 41

Lung maturation in developing Fetus:

Back 41

Beclomethasone

- Glucocorticoid administration to mother when delivery is expected prematurely (before 34 weeks) decreases the incidence of respiratory distress syndrome
- Treated with beclomethasone 48 hours prior to birth and then 24 hours prior to birth

Front 42

Which GC drugs have poor bioavailability & are rapidly metabolized?

What are they used for?

Back 42

Beclomethasone dipropionate

Budesonide

Flutocasone

anti-inflammation (allergy, asthma), either inhaled or topical

Front 43

What are the oral glucocorticoids?

Which one's have the greatest systemic effects?

Back 43

short-acting (8-12 hrs): hydrocortisone (cortisol)

intermediate-acting (18-36): triamcinolone, beclomethasone, prednisolone, methylprednisone

long-acting (36-54): dexamethasone

*greatest systemic (HPA) effects (longer they last)

(also have less salt-retaining effects)