Decreased activity of 11ß-HSD type 2 results in excessive activation of MR mediated by cortisol. - Inhibition of this enzyme will increase activation of MR by cortisol to cause: - 2 substances which embody this concept:

Hypertension - Glycyrrhizin (active ingredient in licorice root extract) – increased activity of cortisol at MR >> increased Na+ and H2O retention >> increased BP - Carbenoxolone (approved in UK to treat esophageal ulcers)

Placental 11ß-HSD type 2 reduces fetal exposure to maternal cortisol. - Inhibition of the placental enzyme leads to: - (Low/high) weight at birth - (Increased/decreased) risk of HTN at adult age

Placental 11ß-HSD type 2 reduces fetal exposure to maternal cortisol. - Inhibition of the placental enzyme leads to elevated levels of cortisol in fetal tissues - Low weight at birth - Increased risk of HTN at adult age

Effects of glucocorticoids on carb metabolism: - Increased phosphoenolpyruvate carboxykinase >> (increase/decrease) gluconeogenesis - Increased glucose-6-phosphatase >> (increase/decrease) glucose output into circulation - Increased glycogen synthase in liver >> (increase/decrease) glycogen synthesis - Decreased expression of GLUT4 >> (increase/decrease) glucose uptake by muscle and adipose tissues

Effects of glucocorticoids on carb metabolism: - Increased gluconeogenesis - Increased glucose output into circulation - Increased glycogen synthesis in liver - Decreased glucose uptake by muscle and adipose tissues

Effects of glucocorticoids on lipid metabolism: - Promote stimulation of hormone-sensitive lipase >> (increase/decrease) lipolysis - (Increase/decrease) mobilization of free fatty acid and glycerol into the gluconeogenic pathway - Increase insulin secretion >> (increase/decrease lipogenesis) - Net (increase/decrease) in fat deposition - What is the effect glucocorticoids in terms of fat distribution?

Effects of glucocorticoids on lipid metabolism: - Increase lipolysis - Increase mobilization of free fatty acid and glycerol into the gluconeogenic pathway - Increase lipogenesis - Net increase in fat deposition - Increased fat accumulation in the upper body (shoulders, neck area, rounded face)... (thinning arms and legs due) ... (adipocyte sensitivity to insulin vs. glucocorticoids varies in differnet areas of the body)

Antagonists of adrenal corticosteroids. - Steroid synthesis inhibitors: (4) - Glucocorticoid antagonist: (1) - Aldosterone antagonists: (2)

Antagonists of adrenal corticosteroids. Steroid synthesis inhibitors - Aminoglutethimide (Cytadren) - Ketoconazole (Nizoral) - Metyrapone (Metopirone) - Mitotane (Lysodren) Glucocorticoid antagonist -Mifepristone (Korlym, Mifeprex) Aldosterone antagonists - Spironolactone (Aldactone) - Eplerenone (Inspra)

Pharm Flashcards by Lauren Gruenebaum

High during pregnancy (increased by estrogen)
Low in liver dz (cirrhosis)
Aka Corticosteroid Binding Globulin (CBG)

Transcortin

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Main target cell type of mineralocorticoids:

2 effect on gene expression those cells:

-Principal cells of distal tubule and collecting duct.

Increase epithelial Na+ channel (ENaC)
Increase Na+/K+ pump

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Mineralocorticoids
Effects on gene expression:
-NADPH reductase >>
-Collagen, TGF-ß >>
-IL-6, cell adhesion molecules >>
-PAI-1 >>

Mineralocorticoids
Effects on gene expression:
-NADPH reductase&raquo_space; oxidative stress
-Collagen, TGF-ß&raquo_space; fibrosis, cell senescence
-IL-6, cell adhesion molecules&raquo_space; inflammation
-PAI-1&raquo_space; inhibition of fibrinolysis, blood clotting

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What is the transactivation mechanism of glucocorticoids?

What is the transrepression mechanism?

Transactivation mechanism of glucocorticoids: GR-ligand complex binds to GRE in gene promoters to activate gene expression

Transrepression: GR-ligand complex binds to other transcriptions factor complexes to suppress their activation of gene transcription

NF-kB, AP-1
Anti-inflammatory, immunosuppressive, anti-growth effects

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Decreased activity of 11ß-HSD type 2 results in excessive activation of MR mediated by cortisol.

Inhibition of this enzyme will increase activation of MR by cortisol to cause:
2 substances which embody this concept:

Hypertension

Glycyrrhizin (active ingredient in licorice root extract) – increased activity of cortisol at MR&raquo_space; increased Na+ and H2O retention&raquo_space; increased BP
Carbenoxolone (approved in UK to treat esophageal ulcers)

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Inactivating mutations in 11ß-HSD type 2 cause AME (apparent mineralocorticoid excess) leading to: (2)

Hypertensive syndromes and edema

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Placental 11ß-HSD type 2 reduces fetal exposure to maternal cortisol.

Inhibition of the placental enzyme leads to:
(Low/high) weight at birth
(Increased/decreased) risk of HTN at adult age

Placental 11ß-HSD type 2 reduces fetal exposure to maternal cortisol.

Inhibition of the placental enzyme leads to elevated levels of cortisol in fetal tissues
Low weight at birth
Increased risk of HTN at adult age

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Effects of glucocorticoids on carb metabolism:

Increased phosphoenolpyruvate carboxykinase&raquo_space; (increase/decrease) gluconeogenesis
Increased glucose-6-phosphatase&raquo_space; (increase/decrease) glucose output into circulation
Increased glycogen synthase in liver&raquo_space; (increase/decrease) glycogen synthesis
Decreased expression of GLUT4&raquo_space; (increase/decrease) glucose uptake by muscle and adipose tissues

Effects of glucocorticoids on carb metabolism:

Increased gluconeogenesis
Increased glucose output into circulation
Increased glycogen synthesis in liver
Decreased glucose uptake by muscle and adipose tissues

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Effects of glucocorticoids on lipid metabolism:

Promote stimulation of hormone-sensitive lipase&raquo_space; (increase/decrease) lipolysis
(Increase/decrease) mobilization of free fatty acid and glycerol into the gluconeogenic pathway
Increase insulin secretion&raquo_space; (increase/decrease lipogenesis)
Net (increase/decrease) in fat deposition
What is the effect glucocorticoids in terms of fat distribution?

Effects of glucocorticoids on lipid metabolism:

Increase lipolysis
Increase mobilization of free fatty acid and glycerol into the gluconeogenic pathway
Increase lipogenesis
Net increase in fat deposition
Increased fat accumulation in the upper body (shoulders, neck area, rounded face)… (thinning arms and legs due) … (adipocyte sensitivity to insulin vs. glucocorticoids varies in differnet areas of the body)

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Effects of glucocorticoids on protein metabolism:
-(Increased/decreased) amino acid uptake into cells
-(Increased/decreased) protein synthesis, negative nitrogen
balance
-Mobilization of amino acids into the ___________ pathway
-Skeletal muscle – suppressed protein synthesis will lead to the development of: (2)

Effects of glucocorticoids on protein metabolism:

Decreased amino acid uptake into cells
Decreased protein synthesis, negative nitrogen balance
Mobilization of amino acids into the gluconeogenic pathway
Skeletal muscle: suppressed protein synthesis will lead to the development of myopathy and muscle wasting

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Effects of glucocorticoids on immune system and inflammation:
Occur due to transrepression of NF-kB and AP-1 effects.
-Decreased phospholipase A2 and COX2&raquo_space; (increased/decreased) production of prostaglandins and leukotrienes
-(Increased/decreased) production and increased apoptosis of immune cell types
-(Increased/decreased) production of cytokines (TNFa, IL-1, IFNg, etc.) and their receptors
-(Increased/decreased) expression of cell adhesion molecules
-(Increased/decreased) transmigration of neuts and macrophages from blood into tissues

Effects of glucocorticoids on immune system and inflammation:
Occur due to transrepression of NF-kB and AP-1 effects.
-Decreased phospholipase A2 and COX2&raquo_space; decreased production of prostaglandins and leukotrienes
-Decreased production and increased apoptosis of immune cell types
-Decreased production of cytokines (TNFα, IL‐1, IFNg ,etc.) and their receptors
-Decreased expression of cell adhesion molecules
-Decreased transmigration of neutrophils and macrophages from blood into tissues

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List a few effects of glucocorticoids on the cardiovascular system.

What are some consequences?

Incr production of Epi and NE
Na+/H2O retention
Decrease in capillary permeability
Incr HR and CO
Incr BP

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List a few effects of glucocorticoids on the GI system.

Decr production of gastro-protective prostglandins
Decr immune response against Helicobacter pylori
Incr in gastric acid and pepsin secretion

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List a few effects of glucocorticoids on the CNS.

Insomnia
Irritability
Euphoria followed by depression
Decr sexual libido in males

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List a few effects of glucocorticoids on bone/growth.

Decr activity of osteoblasts
Incr activity of osteoclasts
Decr intestinal and renal Ca2+ absorption
Growth retardation in children
Osteoporosis, bone fractures

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List a few effects of glucocorticoids on skin.

Decr collagen synthesis
Decr fibroblast proliferation
Decr wound healing, increased bruising
Fragile and thin skin with stretch marks (“striae”)

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What is the replacement therapy for adrenal insufficiency (Addison’s dz)

A combination of hydrocortisone (glucocorticoid) and fludrocortisone (mineralocorticoid).

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What is the diagnostic test for Cushing’s dz?

Dexamethasone suppression test – no dexamethasone suppression of ACTH release

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List a few adverse effects of mineralocorticoids (fludrocortisone)/.

Retention of Na+/H2O, edema
HTN
Incr preload and cardiac enlargement&raquo_space; CHF
K+ loss and alkalosis

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List some adverse effects of glucocorticoids.

Immunosuppression
Hyperglycemia
Striae, easy bruising
Muscle wasting, myopathy
HTN
Steroid-induced glaucoma
Peptic ulcers
Psych disorders
Weight gain
Osteoporosis
Growth retardation in children

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Glucocorticoid used to treat asthma and allergic rhinitis

- Prodrug activated by esterases present in bronchial epithelial cells (local effect only, avoid systemic effects)

Ciclesonide (Alvesco)

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Antagonists of adrenal corticosteroids.

Steroid synthesis inhibitors: (4)
Glucocorticoid antagonist: (1)
Aldosterone antagonists: (2)

Antagonists of adrenal corticosteroids.

Steroid synthesis inhibitors

Aminoglutethimide (Cytadren)
Ketoconazole (Nizoral)
Metyrapone (Metopirone)
Mitotane (Lysodren)

Glucocorticoid antagonist
-Mifepristone (Korlym, Mifeprex)

Aldosterone antagonists

Spironolactone (Aldactone)
Eplerenone (Inspra)

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What protein acts as the main carrier for synthetic corticosteroid drugs?

Albumin

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About 80% of cortisol is metabolized by the liver. What can we then say about the half-life of cortisol in pts with liver dz’s and hypothyroid pts?

Half-life is increased (takes longer to metabolize)

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57yo pt with an advanced liver dz. Will the effects of cortisol be: A. Enhanced in this pt B. Reduced in this pt C. Not changed in this pt

A. Enhanced in this pt | cannot be metabolized, leading to effect lasting longer

The release of which steroid hormone is regulated primarily by angiotensin II? ``` A. Cortisol B. Dehydroepiandrosterone C. Progesterone D. Aldosterone E. Corticosterone ```

D. Aldosterone

Which of the following are effects of glucocorticoids? ``` A. Increased muscle mass B. Hypoglycemia C. Inhibition of leukotriene synthesis D. Improved wound healing E. Increased excretion of salt and water ```

C. Inhibition of leukotriene synthesis

List 2 short-acting (HL = 8-12hr) corticosteroid drugs.

- Cortisol | - Cortisone

List 5 intermediate-acting (HL = 12-36hr) corticosteroid drugs.

- Fludrocortisone - Prednisone - Prednisolone - 6a-methylprednisolone - Triamcinolone

List 2 long-acting (HL = 36-72hr) corticosteroid drugs.

- Betamethasone | - Dexamethasone

Which glucocorticoid receptor subtype may be responsible for glucocorticoid resistance?

GRß - Lacks 35aa at the C-terminal – does not bind ligands and is inactive - Induced by TNFa

11ß-HSD type 2 converts cortisol into cortisone (inactive) at mineralocorticoid receptors in such tissues as renal tubular epithelium, salivary glands, sweat glands, and colon epithelium. What is the effect?

Makes mineralocorticoid tissues responsive to aldosterone, because it is able to get rid of cortisol in the cytosol of those tissues. I.e., This enzyme protects mineralocorticoid target tissues from excessive amount of cortisol. Therefore they're able to respond to aldosterone.

Which of the following is the mechanism of selective activation of mineralocorticoid responsive tissues by aldosterone? A. A mineralocorticoid receptor (MR) can be activated by aldosterone and not by cortisol. B. Cortisol is not transported into the cytosol where MR is located. C. Cortisol is converted in these tissues into a compound that is inactive at MR. D. Cortisol is present in these tissues at concentrations that are too low to activate MR.

C. Cortisol is converted in these tissues into a compound that is inactive at MR. (cortisone)

Glucocorticoids provide anti-insulin actions: - Gluconeogenesis in liver - Decr glucose uptake, decr glycogen synthesis, incr proteolysis in skeletal muscle - Decr glucose uptake, incr lipolysis in adipose tissue All these lead to:

Hyperglycemia

Which 2 drugs interact with ONLY glucocorticoid receptors?

Long-acting synthetic drugs: - Betamethasone - Dexamethasone

Naturally-occurring corticosteroid drugs are (more/less) potent than synthetic drugs?

LESS

Glucocorticoids have proved useful in the treatment of: ``` A. Vomiting induced by chemotherapeutic drugs B. Chronic obstructive pulmonary disease C. Depression D. Parkinson's disease E. Type 2 diabetes ```

B. Chronic obstructive pulmonary disease

Common adverse effects of long-term administration of glucocorticoid include: ``` A. A "lupus-like" syndrome B. Adrenal gland neoplasm C. Hepatotoxicity D. Osteoporosis E. Precocious puberty in children ```

D. Osteoporosis

56yo female pt has been taking Etanercept (Enbrel) for her advanced rheumatoid arthritis. More recently, she had a severe asthma attack, was taken to emergency department, and has been on Prednisone since then. What will be the most likely outcome of this drug combination? A. Hyperglycemia and exacerbation of diabetes B. Sodium, water retention and swelling C. Immunosuppression and opportunistic infection D. Osteoporosis and bone fractures

C. Immunosuppression and opportunistic infections

- Blocks the conversion of cholesterol to pregnenolone | - Causes a reduction in the synthesis of all hormonally active steroids

Aminoglutethimide

Aminoglutethimide is used in conjunction with dexamethasone or hydrocortisone to:

Reduce or eliminate estrogen production in pts with carcinoma of the breast.

High-dose side effects of aminoglutethimide:

- Lethargy | - Rash

Aminoglutethimide can be used in conjunction with metyrapone or ketoconazole to reduce steroid secretion in pts with:

Cushing's syndrome due to adrenocortical cancer

What is the effect of aminoglutethimide on the clearance of some steroids, including dexamethasone?

Enhances the metabolism of dexamethasone (increases the clearance)

- Antifungal imidazole derivative | - Potent nonselective inhibitor of adrenal and gonadal steroid synthesis at high doses

Ketoconazole

How does ketoconazole inhibit steroid hormone synthesis?

Ketoconazole inhibits the cholesterol side-chain cleavage, P450c17, C17,20-lyase, 3ß-hydroxysteroid dehydrogenase, and P450c11 enzymes required for steroid hormone synthesis.

Ketoconazole has been used for the treatment of pts with:

Cushing's syndrome

Main adverse effect of ketoconazole:

Hepatotoxicity | P450 inhibition

Selective inhibitor of steroid 11-hydroxylation, which interferes with cortisol and corticosterone synthesis

Metyrapone

Toxicities of metyrapone:

- Transient dizziness | - GI disturbances

Steroid synthesis inhibitor administered to pregnant women with Cushing's syndrome:

Metyrapone

2 major adverse effects of metyrapone:

- Na+/H2O retention | - Hirsutism

What drug is commonly used in tests of adrenal function?

Metyrapone

- 3ß-17 hydroxysteroid dehydrogenase inhibitor - Interferes with the synthesis of adrenal and gonadal hormones - Comparable to aminoglutethimide

Trilostane

Adverse effect of trilostane:

- Antagonist at the glucocorticoid receptor | - Has strong anti-progestin activity

Mifepristone

High doses exert anti-glucocorticoid activity by blocking the glucocorticoid receptor, causing - Stabilization of the hsp-glucocorticoid receptor complex and inhibition of the dissociation of the receptor from the hsp chaperone proteins - Formation of a transcriptionally inactive complex in the cell nucleus Result: Inhibition of glucocorticoid receptor activation.

Mifepristone

What is the half-life of mifepristone?

20 hours (due to strong binding to plasma proteins, with no affinity to corticosteroid binding globulin – only binds albumin and a1-acid glycoprotein)

Present use of mifepristone:

Inoperable pts with ectopic ACTH secretion or adrenal carcinoma who have failed to respond to other therapies.

- Drug related to DDT class of insecticides | - Nonselective cytotoxic action on the adrenal cortex in dogs and to a lesser extent in humans

Mitotane

Mitotane is indicated for:

Pts with adrenal carcinoma | 1/3 show a reduction in tumor mass

List a few toxic effects of mitotane.

- Nausea, vomiting, diarrhea - Depression - Somnolence - Skin rashes

- Aldosterone (mineralocorticoid) antagonist - Onset is slow, and effects last 2-3 days after drug is discontinued - Reverses many of the manifestations of aldosteronism - Used in the treatment of primary aldosteronism

Spironolactone

- Drug used diagnostically for the detection of aldosteronism in hypokalemic pts with HTN - May reduce the incidence of cardiac arrhythmias - Reduces mortality in heart failure

Spironolactone

Drug sometimes used in the treatment of hirsutism in women: | Both and aldosterone antagonist and androgen antagonist

Spironolactone

List a few adverse effects of spironolactone.

- Hyperkalemia - Cardiac arrhythmia - Menstrual abnormalities - Gynecomastia - Sedation - Headache - GI disturbances - Skin rash

-Aldosterone (mineralocorticoid) receptor antagonist -More selective than spironolactone and has no reported effects on androgen receptors -Approved for treatment of HTN -Like spironolactone, reduces mortality in heart failure -

Eplerenone