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MHD2/Pharm - Endocrine > Pharm - Adrenocorticosteroids and antagonists > Flashcards

Pharm - Adrenocorticosteroids and antagonists Flashcards

1
Q

What are the 3 major hormones secreted from the adrenal cortex and which layer is each produced in?

A

Aldosterone: zona glomerulosa
Cortisol: zona fasciculata
Androgens: zona reticularis

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2
Q

What are the functions of cortisol during stress?

A

Protecting glucose dependent tissues
Lipid metabolism: increased catabolism and glycerol/FFA release
Carbohydrate metabolism: Increased gluconeogenesis and decreased peripheral glucose use
Protein metabolism: Increased catabolism, increased AA release

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3
Q

What tissues are glucose dependent?

A

Brain, kidney and heart

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4
Q

What is the physiological effect of aldosterone?

A

Causes Na/H2O resorption and K+/H+ excretion by the kidney

This is important for electrolyte balance, hydration/dehydration, and acid-base control

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5
Q

What are the effects of aldosterone excess?

A

Hypertension due to increased Na reabsorption, increased extracellular fluid volume

Alkalosis due to excretion of K+ and H+

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6
Q

What are the effects of aldosterone deficiency?

A

Hypotension due to Na wasting and decreased extracellular fluid volume.

Acidosis due to decreased excretion of K+ and H+

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7
Q

Describe the hormonal control of adrenal hormones

A

CRH is released from the hypothalamus in response to stress and circadian rhythms

Triggers release of ACTH from the anterior pituitary

ACTH causes production of aldosterone, cortisol and androgens in the adrenal cortex

Cortisol feeds back to downregulate release of CRH and ACTH

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8
Q

What is the cause of skin pigmentation in the setting of excess ACTH?

A

The gene that produces ACTH (POMC gene) also produces alpha MSH, which stimulates melanocytes to produce pigment

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9
Q

What effect do exogenous glucocorticoids have on the HPA axis?

A

Exogenous glucocorticoids like dexamethasone shut down the HPA axis by negative feedback. They cause loss of endogenous cortisol production, which is dangerous when stopping the treatment.

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10
Q

Describe the production of cortisol and aldosterone throughout the day

A

Cortisol is controlled by circadian rhythm. It peaks first thing in the morning (6-8am) and reaches its trough around 11pm-12am.

Aldosterone levels are constant throughout the day

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11
Q

What is the mechanism of action of corticosteroids?

A

Bind to cytoplasmic glucocorticoid receptors (GR)
GRs dimerize and move to nucleus
Act on GRE to modify gene expression

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12
Q

What is the role of 11beta hydroxysteroid dehydrogenase?

A

Because cortisol has mineralocorticoid activity, 11b-HSD2 is expressed in aldosterone sensitive tissues (kidney, colon). 11b-HSD2 inactivates cortisol to cortisone.

11b-HSD1 reactivates cortisone to cortisol in adipose tissue and brain

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13
Q

What is the activity of fludrocortisone?

A

A potent mineralocorticoid

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14
Q

What is the activity of dexamethasone?

A

A potent glucocorticoid with no mineralocorticoid activity.

NOT a substrate for 11bHSD2

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15
Q

What is required for effective topical glucocorticoids?

A

They must be prepared in the active form

Skin and joints do not express 11b-HSD1, so cortisone cannot be activated in these sites

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16
Q

What glucocorticoid is used for treating fetal problems?

A

Dexamethasone crosses the placenta without being inactivated by 11b-HSD2

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17
Q

What are the clinical uses for corticosteroids?

A

HRT: physiologic doses are used to treat adrenal insufficiency and CAH

Higher doses are used to treat autoimmune diseases, anti-inflammation, asthma, cancer and cerebral edema

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18
Q

What are the major causes of primary adrenal insufficiency?

A

Autoimmune destruction of the adrenal cortex (70%)
Tuberculosis (20%)
Fungal infection/hemorrhage/cancer

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19
Q

What is the difference between primary and secondary adrenal insufficiency?

A 
Primary = destruction of adrenal cortex
Secondary = suppression of HPA axis, defective ACTH/CRH
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20
Q

Why does adrenal atrophy occur in secondary adrenal insufficiency?

A

The HPA axis is shut down (exogenous glucocorticoids), so ACTH is decreased. ACTH is a trophic factor on the zona fasciculata and reticularis. The absence of ACTH causes adrenal atrophy

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21
Q

Which cortical hormone is still produced in secondary adrenal insufficiency?

A

Aldosterone because the zona glomerulosa is unaffected by the lack of ACTH

22
Q

What symptoms are seen in primary adrenal insufficiency but not secondary adrenal insufficiency?

A

The zona glomerulosa is affected in primary leading to hyponatremia, dehydration, and hyperkalemia (cardiac arrhythmia, muscle weakness and malaise)

23
Q

What is the treatment for adrenal insufficiency?

A

Cortisol replacement with hydrocortisone (multiple daily doses), prednisone or dexamethasone (1 dose/day)

Aldosterone replacement with fludrocortisone in primary adrenal insufficiency (unnecessary in secondary insufficiency)

24
Q

What is the presentation of acute adrenal insufficiency?

A

Hypovolemic circulatory shock with nausea, vomiting, weakness, fatigue, fever, hyponatremia and hyperkalemia

25
Q

What is the initial treatment for acute adrenal insufficiency?

A

IV electrolyte replacement plus IV hydrocortisone or dexamethasone. Once they are stabilized, they are switched to oral hydrocortisone plus fludrocortisone

26
Q

What happens when a patient with adrenal insufficiency get a minor illness, surgery or become pregnant?

A

Cortisol levels do not appropriately rise, and could cause an adrenal crisis. Treatment dose must be raised to keep cortisol levels safely high.

27
Q

Describe the pathogenesis of congenital adrenal hyperplasia

A

Genetic deficiency of steroid 21-hydroxylase leads to impaired cortisol and aldosterone production. Cortisol no longer feeds back to inhibit ACTH, so ACTH levels are high.

The steroid precursors are all shunted to form androgens leading to androgen excess.

28
Q

How do the symptoms of CAH differ between males and females?

A

In males, sex organs appear normal, not much effect

Females are hypervirilized and have ambiguous genetalia due to excessive androgens

29
Q

What is the treatment for CAH?

A

Hydrocortisone and fludrocortisone are used to avoid adrenal crisis and suppress ACTH in order to prevent androgen overproduction

30
Q

How is prenatal screening done for CAH?

A

Amniotic fluid can be tested for high levels of 17 hydroxypregnenolone

fetal DNA can also be examined for CYP21 mutations

31
Q

If a CYP21 mutation is identified in a female in utero, what treatment is advised?

A

In utero treatment with dexamethasone before the 9th week until delivery

32
Q

What are the effects of glucocorticoids on the inflammatory response?

A

Induce IkB expression (inhibits NF-kB)
Inhibits binding of AP1 to target site
Directly inhibits expression of pro-inflammatory genes

33
Q

What glucocorticoid is used to treat rheumatoid disorders like RA, SLE and vasculitides?

A

Prednisone is the drug of choice to treat joint inflammation and symptomatic pain relief during flare ups. Only given for short period of time, and then tapered off.

34
Q

What is the mechanism of action for glucocorticoid therapy for atopic reactions like asthma, allergic rhinitis, contact dermatitis and insect bites?

A

Decreased inflammatory cytokine production
Decreased number of mast cells, eosinophils and dendritic cells
Decreased mucus secretion

35
Q

Do inhaled glucocorticoids cause HPA suppression?

A

No. There is a significant first pass effect and very low oral bioavalibility. The drug is administered straight to the lungs, so there is a low risk for adverse effects, HPA suppression.

36
Q

Is it safe to switch from systemic oral glucocorticoids to inhaled glucocorticoids?

A

Abrupt switch between oral and inhaled can cause adrenal crisis. The dose of inhaled glucocorticoids is much lower than the oral and has little/no effect on systemic cortisol levels

37
Q

How are glucocorticoids used to treat neonatal respiratory distress syndrome (NRDS)?

A

Dexamethasone administration promotes fetal lung maturation in order to increase surfactant production and prevent alveolar collapse

38
Q

How does dexamethasone treat cerebral edema?

A

Decreases intracranial pressure by decreasing inflammation, stabilizing the BBB, decreasing endothelial permeability, decreasing CSF production and increasing CSF clearance

39
Q

What are the two major causes of adverse effects of glucocorticoid therapy?

A

Abrupt withdrawal: adrenal crisis

Chronic supraphysiological signaling: Cushingoid symptoms

40
Q

How does glucocorticoid use increase risk of diabetes?

A

Causes hyperglycemia and peripheral insulin resistance

41
Q

What is Cushing’s syndrome?

A

Excess glucocorticoid activity causes moon facies, buffalo hump, central obesity, abdominal striae

42
Q

Describe a low dose dexamethasone suppression test

A

Dexamethasone normally suppresses the HPA axis. In the presence of a pituitary adenoma, ACTH secreting tumor, or cortisol secreting adrenal tumor, dexamethasone will not decrease cortisol levels

43
Q

Describe a high dose dexamethasone suppression test.

A

Cortisol is partially suppressed in the presence of a pituitary adenoma, but not suppressed at all when the origin is an ACTH secreting tumor or adrenal tumor

44
Q

What are the treatment options for Cushin’s disease?

A

Surgical removal of tumor, tumor irradiation

Pharmaceutical inhibition of cortisol production

45
Q

What drugs inhibit adrenocorticoid synthesis?

A

Ketoconazole (antifungal)
Etomidate (IV anesthetic/sedative)
Metyrapone

46
Q

What are the major differences between ketoconazole, etomidate and metyrapone for treatment of Cushing’s syndrome?

A

Ketaconozole and etomidate inhibit CYP11A1 and 11B1
Metyrapone inhibits CYP11B2 and 11B1
Metyrapone is the only one safe for pregnancy

47
Q

What is mitotane?

A

Adrenocorticolytic drug
Ablates cortisol production by causing mitochondrial destruction and necrosis of adrenocortical cells.
Spares the zona glomerulosa

48
Q

What are the contraindications for mitotane treatment?

A

Pregnancy: can cause permanent fetal adrenal damage

49
Q

What is mifepristone?

A

At high doses it is an antagonist of glucocorticoid receptors. This prevents excessive activation in Cushing’s

50
Q

What are the adverse effects of mifepristone?

A

Adrenal insufficiency

Contraindicated in pregnant women (abortion drug)

MHD2/Pharm - Endocrine (7 decks)

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