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Pharmacology > Adrenal Corticosteroids > Flashcards

Adrenal Corticosteroids Flashcards

1
Q

What are the 3 modes of regulation by Hypothalamic-Pituitary-Adrenal HPA axis?

A
  1. Diurnal rhythm (release CRH in response to sleep-wake cycle–> ACTH release–> cortisol release)
  2. Neg. feedback reg. by circulating corticoseroids at hypothalamus and pituitary DECREASE ACTH release and steroidogensis (endogenoous and exogenous agents)
  3. Stress (injury, hemorrhage, severe infection, surgery, hypoglycemia, cold pain, fear) override neg. feedback and produce marked INCREASED steroiodgenesis
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2
Q

Pituitary adrenocorticotropic hormone (ACTH) release is controlled by ___ from the hypothalamus. Synthesis and secretion of glucocorticoids and androgens is controlled by actions of ___ at the adrenal cortex. NOTE: The ___ is the primary regulator of mineralocorticoid (aldosterone) synthesis and release.

A

corticotropin-releasing factor (CRF)

ACTH

renin-angiotensin system

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3
Q

Long-term administration of large doses of prednisone is likely to cause reductions in the synthesis of all of the following hormones EXCEPT:
A.  Cortisol
B.  Corticotropin (ACTH)
C.  Corticotropin-releasing hormone (CRF)
D.  Aldosterone
E.  Growth hormone

A

D.  Aldosterone

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4
Q 
A child with severe asthma is being treated with high doses of inhaled corticosteroids. Which of the following adverse
effects is of particular concern? 
A.  Hyperglycemia 
B.  Oral candidiasis 
C.  Growth suppression 
D.  Cushing syndrome 
E.  Cataract formation
A

B.  Oral candidiasis

C.  Growth suppression**

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5
Q

Glucocorticoid pathway is a substrate-limited system with synthetic enzymes in excess that provides for rapid responsiveness. Rate-limiting step is ____. ___ stimulates this step and at several levels in zona FASICULATA and in the zona RETICULARIS (androgens). Synthesis is inhibited by ____

A

conversion of cholesterol to pregnenolone

ACTH

metyrapone and mitotane (also inhibited by ketoconazole)

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6
Q

Mineralocorticoid pathway in zona GLOMERULOSA has 18-OH-steroid dehydrogenase enzyme that converts corticosterone to ___. Renin-angiotensin system (via angiotensin II) stimulates conversion of cholesterol to pregnenolone and corticosterone to aldosterone (independent of ACTH).

A

aldosterone

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7
Q

Describe the PK of cortisol in terms of pattern of release, and half life

A
  1. secretion of cortisol circadian rhythm via ACTH pulses– 20 mg daily peak ealry in AM and evenin
  2. only free cortisol is active
  3. t1/2= 60-90 min.
    - increased in stress, hypothyroidism, liver dz
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8
Q

Describe the pharmacologic glucocorticoid metabolic effects of cortisol

A
  1. Carbs: increase gluconeogensis= increase blood glucose and insulin
  2. Protein: decrease protein synthesis–> increase AA into glucose
  3. Fat: increase lipolysis (peripherally) –> increased FFA
    - but net effect is increased lipogenesis due to increased insulin release

**Net result: maintenance of glucose supply to brain

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9
Q

Describe the pharmacologic glucocorticoid metabolic effects of cortisol when in EXCESS

A
  1. Carbs: diabetes-like state, hyperglycemia
  2. Protein: muscle wasting, skin CT atrophy
  3. Fat: increase lipogenesis (centrally via insulin action)–> centripetal obesity (moon facies, buffalo hump)

**Iatrogenic Cushings Disease

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10
Q

Permissive effects of glucocorticoids (Responses occur only in presence of glucocorticoids, but not further stimulated with increased amounts of GCs )

A
  1. Vasoconstrictor: bronchdilator response to Epi
  2. Fat cell lipolytic response to Epi, ACTH, GH
  3. required for normal cardiac output
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11
Q

Describe the pharmacologic mineralocorticoid effects of aldosterone when in EXCESS

A
  1. sodium-fluid retention,
  2. HTN**
  3. hypokalemia
  4. metabolic alkalosis
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12
Q

Describe the pharmacologic mineralocorticoid effects of aldosterone

A

increase Na reabsorption at kidney–> increase BV and BP (loosely coupled to K+ and H+ secretion)

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13
Q 
All of the following adverse effects are associated with glucocorticoid therapy EXCEPT: 
A.  Glaucoma 
B.  Increased risk of infection 
C.  Hyperglycemia 
D.  Hypotension 
E.  Emotional disturbances 
F.   Peripheral edema
A

D.  Hypotension

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14
Q

Side effects of glucocorticoids

A
  1. Euphoria
  2. Hyperglycemia
  3. skin atrophy/muscle wasting
  4. Obesity (buffalo hump, increased central obesity)
  5. Moon facies
  6. Cataracts
  7. Easy bruising
  8. poor wound healing
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15
Q
  • When using glucocorticoid agents in physiologic replacement regimens (e.g., Addison’s disease), it is necessary to use ____
  • When using glucocorticoid agents in pharmacologic doses for their anti-inflammatory or immunosuppressive actions, it is desirable to use ____
A

an agent with both glucocorticoid and mineralocorticoid activity such as cortisol.

an agent with minimal or no mineralocorticoid activity (e.g., dexamethasone).

*It is not possible to avoid glucocorticoid metabolic side effects with the anti-inflammatory glucocorticoids currently available.

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16
Q

What are the upsides and downsides to GCs

A

upside: suppress chronic inflammation and autoimmune rxns
downside: decrease healing and diminish immunoprotection

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17
Q

A 50-year-old woman, an asthmatic for the past 30 years, presented to the ED with a 2-day history of worsening breathlessness and cough. Chest auscultation revealed bilateral polyphonic inspiratory and expiratory wheeze. Supplemental oxygen, nebulized albuterol and ipratropium, as well as IV methylprednisolone were administered. Which of the following is a pharmacologic effect of exogenous glucocorticoids?
A.  Increased muscle mass
B.  Hypoglycemia
C.  Inhibition of leukotriene synthesis
D.  Improved wound healing
E.  Increased excretion of salt and water

A

C.  Inhibition of leukotriene synthesis

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18
Q 
A patient with Addison’s disease is being treated with hydrocortisone (cortisol) but is still having problems with dehydration and hyponatremia. Which of the following drugs would be best to add to the patient’s therapy? 
A.  Dexamethasone 
B.  Prednisone 
C.  Aldosterone 
D.  Fludrocortisone 
E.  Triamcinolone
  • Prior to receiving the new drug, what would be the status of the patient’s blood potassium levels?
A

D.  Fludrocortisone

*hyperkalemia

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19
Q

Structural Modification of cortisol affect

A
  1. receptor specificity (GC vs MC)
  2. Potency
  3. Membrane permeability
  4. Absorption
  5. Protein-binding
  6. Rates of Metabolism-excretion
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20
Q

Glucocorticoids-Structure activity relationships:

11-OH for GC activity

A

Cortisol

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21
Q

Glucocorticoids-Structure activity relationships:

C6 methyl for increased A-I activity

A

Methyprednisolone

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22
Q

Glucocorticoids-Structure activity relationships:

C16 methyl to eliminate MC activity

A

Dexamethasone

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23
Q

Glucocorticoids-Structure activity relationships:

C1-C2 double bond for increased A-I activity

A

Prednisolone

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24
Q

Glucocorticoids-Structure activity relationships:

Increased MC vs GC activity

A

Fludrocortisone

25
Q

___ glucocorticoids that are physiologically active:

___ glucocorticoids are prodrugs that must be activated by 11β hydroxysteroid dehydrogenase I (11β-HSD I)

A
  • 11- hydroxy
  • Cortisol, prednisolone, Dexamethasone, Fludrocortisone
  • *11-keto
  • Prednisone
  • Cortisone
26
Q

11-keto glucocorticoids are prodrugs that must be activated by ___

A

11β hydroxysteroid dehydrogenase I (11β-HSD I)

27
Q

The level of activity of endogenous cortisol (as well as glucocorticoid drugs) in various tissues can be determined by which type of 11β-hydroxysteroid dehydrogenase (11βHSD) is expressed. Describe what is expressed in the liver, kidney, and fetus and its effects

A

Liver: 11B-HSD1
-Activating: Converts cortisone–> cortisol

Kidney: 11B-HSD2
-Inactivating: converts Cortisol–> cortisone (less GC and MC activity)

Fetus: 11B-HSD2 active but 11BHSD1 is not active as fetal liver is not functional
**Can tx mom w/ GCs w/o effect on fetus bc placental enzymes can convert active drug back to prodrug (prednisolone–> prednisone)

28
Q

How can you tx the fetus w/ GCs (ie. lung development prior to premature delivery)

A

use agent that is poor substrate for 11B-HSD2 (ie. Betamethasone)

29
Q

Adverse effects of pharmacologic doses that are unlikely to be seen with dexamethasone but possible with prednisone include:
A.  Secondary adrenal insufficiency resulting from block of pituitary ACTH release
B.  Hyperglycemia
C.  Fluid retention
D.  Osteoporosis with extended duration of use
E.  Hypokalemia
F.   Centripetal obesity
G.  Muscle wasting

A

C.  Fluid retention – MC

E.  Hypokalemia –MC

30
Q

For cortisol (Hydrocortisone) describe the

  1. Use-
  2. GC: MC actions-
  3. Form
A
  1. Use:physiologic dose–> replacement therapy and emergencies
  2. GC: MC actions- 1:1
  3. Forms: oral and parenterally
31
Q

For Prednisone describe the

  1. Use-
  2. GC: MC actions-
  3. Form
A
  1. Use: most commonly used oral agent for steroid burst therapy
  2. GC: MC actions- 5:1
  3. Form: oral
    * *activated to prednisolone in liver (NO topical activity)
32
Q

For Methylprednisolone describe the

  1. Use-
  2. GC: MC actions-
  3. Form
A
  1. Use- steroid burst (no better than oral)
  2. GC: MC actions- minimal mineralcorticoid action
  3. Form: oral and parental
33
Q

For Dexamethasone (Decadron) describe the

  1. Use-
  2. GC: MC actions-
A
  1. Use- most potent anti-inflammatory agent, cerebral edema, chemotherapy-induced vomiting
  2. GC: MC actions- minimal mineralcorticoid actions

*greastest suppression of ACTH secretion at pituitary

34
Q

For Triamcinolone (Kenalong) describe the

  1. Use-
  2. GC: MC actions-
  3. Form
A
  1. Use- potent systemic agent w/ excellent topical activity
  2. GC: MC actions- no mineralcorticoid action
  3. Form: oral and topical
35
Q 
Corticosteroids are useful in the treatment of all of the following disorders EXCEPT: 
A.  Addison’s disease 
B.  Adrenal gland crisis 
C.  Allergic rhinitis 
D.  Asthma 
E.  COPD 
F.   Cushing’s syndrome
A

F.   Cushing’s syndrome— not for hypercortisolism

*more useful in asthma than COPD

36
Q

Describe the hormone problem in:

  1. Addison’s Disease
  2. Cushing’s syndrome
A
  1. Addisons: adrenocortical insufficiency (low cortisol)

2. Cushings Syndrome (high cortisol)

37
Q

Describe the treatment of Chronic AI (Addison’s disease)

A
  1. Oral Hydrocortisone 2-3x/day OR
    - long acting agents (dexamthesone-prednisone

*increase dose by 3x w/ illness or surgery (periods of acute stress)

  1. +/- Fludrocortisone if additonal salt-retaining activity is needed (ie. pt. is hypotensive)
  2. +/- DHEA in women for mood and well-being
38
Q

Describe the treatment of acute AI (adrenal crisis)

A
  1. Large amounts of IV cortisol until stable
  2. Correct fluid/electrolyte abnormalities (NS)
  3. +/- hydrocortisone for MC action ONLY if hyperkalemia present (K>6)
39
Q

Describe the treatment of Cushing’s Syndrome

A
  1. Surgery is tx of choice
  2. Pharmacotherapy: generally reserved for adjunctive therapy in refractory or inoperable cases, can include:
    - GC synthesis inhibitors (early-Ketoconazole, late-Metyrapone)
    - GC receptor antagonists (Mifepristone (RU-486))
40
Q

Glucocorticoid synthesis inhibitors: Divided into agents affecting early (broad effects) or later (more specific effects) steps in steroid biosynthesis.
Early: ___
Late: ___

A

early:
Ketoconazole– inhibits cholesterol to pregnenolone step (+ androgen synthesis)

late:
Metyrapone– inhibits 11B-hyroxylase–> 11-deoxycortisol to cortisol step

41
Q

Approved in 2012 to control hyperglycemia secondary to Cushing’s syndrome

A

Mifepristone

*can increase cortisol secretion via block of neg. feedback at pituitary

42
Q

Mifepristone is contraindcated in who

A

Pregnancy

*women of child bearing age should use contraception

43
Q

What are the uses of Ketoconazole

A
  1. used for Cushing’s syndrome and prevents aldosterone (inhibits cholesterol–> pregnenolone step) and DHEA (17, 20)
    * **HD than antifungal use
  2. decrease testosterone synthesis (DHEA)
44
Q

What are possible adverse reactions of Ketoconazole

A
  1. HA
  2. N/V
  3. gynecomastia-impotence
  4. reversible hepatotoxicity
45
Q

Describe the hormone problem in CAH (congenital adrenal hyperplasia)

A

***Adrenocortical Hyperfunction

Cortisol synthesis is diminished (due to enzyme defects in pathway) resulting in increased ACTH (loss of cortisol to suppress ACTH secretion), which results in overstimulation of adrenal gland and adrenal hyperplasia

*can be accompanied by excess or deficiency of adrenal mineralocorticoids or androgens

46
Q

Goal of therapy in CAH is

A
  1. replace-normalized deficient steroids (GC +/- MC)
  2. Minimized excess androgen production (GC suppresses ACTH)
  3. Avoid GC excess via overtreatment
47
Q

Types of enzyme deficiency in CAH

A
  1. 21-hydroxylase deficiency
  2. 17-a-hydroxylase deficiency
  3. 11-B hydroxylase deficiency
48
Q

What does 21-hydroxylase deficiency result in

A
  1. No cortisol synthesis–> increase ACTH–> allow excess androgens= VIRILIZING
  2. No desoxycorticosterone OR aldsterone synthesis–> decrease MC activity–> HYPOTENSION
49
Q

What does 17-a-hydroxylase deficiency result in

A
  1. No cortisol synthesis–> increase ACTH–> increase desoxycorticosteroine–> increase MC activity–> HYPERTENSION
  2. No adrenal androgen synthesis–> NON-VIRILIZING
50
Q

What does 11-B hydroxylase deficiency result in

A
  1. No cortisol synthesis–> increase ACTH–> allow excess androgens= VIRILIZING
  2. No cortisol synthesis–> increase ACTH–> increase desoxycorticosteroine–> increase MC activity–> HYPERTENSION
    * 17-21-11
51
Q

Describe the enzymes in the synthetic pathways for adrenal steroid synthesis for

  1. DHEA
  2. Cortisol
  3. Aldosterone
A

17–>20–> DHEA

3–> 17–> 21–> 11 –> Cortisol

3–> 21–> 11–> aldosterone

52
Q

The diagnosis of congenital adrenal hyperplasia (symptoms of virilizing hypotension) is confirmed in a child. This condition can be effectively treated by:
A.  Administration of an androgen antagonist
B.  Surgical removal of the adrenal gland
C.  Administration of ketoconazole to decrease cortisol synthesis
D.  Administration of a glucocorticoid receptor agonist
E.  Administration of a glucocorticoid receptor antagonist
F.   Administration of ACTH

A

Virilzing hypotension (21 def.)

D.  Administration of a glucocorticoid receptor agonist

53
Q

A newborn girl exhibited ambiguous genitalia, hyponatremia, hyperkalemia, and hypotension as a result of 21α hydroxylase activity. Treatment consisted of fluid and salt replacement and hydrocortisone administration. In this
type of adrenal hyperplasia in which there is excess production of cortisol precursors, which of the following describes the primary therapeutic effect of glucocorticoid administration?
A.  Increased adrenal estrogen synthesis
B.  Inhibition of aldosterone synthesis
C.  Prevention of hypoglycemia
D.  Recovery of normal immune function
E.  Suppression of ACTH secretion

A

E.  Suppression of ACTH secretion

54
Q

What is the hormone problem in PCC

A

**Adrenomedullary hyperfunction

  1. excess catecholamine secretion
55
Q

Describe the treatment of PCC

A
  1. Surgery is tx of choice
  2. Pharmacologic preparations for surgery: alpha-adrenergic receptor blockade to avoid hypertensive crisis and volume expansion during surgery
56
Q

What medications are used for PCC pre-surgery

A
  1. Phenoxybenzamine- irreversible A1 and A1 antagonist
  2. Beta-blockers (metoprolol, B1, Labetaolol, A1, B1, B2 blocker)
  3. +/- CCB (Nicardipine)
  4. +/- Metyrosine (catecholamine synthesis inhibitor used if inoperable or metastatic )
57
Q

Describe the use of beta-blockers for PCC

A
  1. Metoprolol (B1) given AFTER adequate alpha-adrenergic receptor blockade to control tachycardia and arrhythmias OR
  2. Labetalol (A1-B1-B2 blocker)
58
Q

Block of beta-2 receptors (i.e., block of beta-2 mediated vasodilation) with non-selective beta blockers (e.g., propranolol [β1-β2] or labetalol [α1-β1-β2]) prior to alpha-1 block may result in ___ due to ____

A

severe hypertension due to effects of epinephrine on alpha-1 receptors mediating unopposed vasoconstriction.

59
Q

Describe the use of CCBs for PCC

A

Nicardipine–> if BP control is inadequate

Pharmacology (31 decks)

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