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Pharm Exam 3 > Corticosteroids > Flashcards

Corticosteroids Flashcards

1
Q

Steroid molecules are derived from ____________.

A

Cholesterol

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2
Q

Where do steroid molecules bind to their receptors?

A

Intracellularly - alter gene expression

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3
Q

Where are corticosteroids synthesized and released?

A

Adrenal cortex

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4
Q

What are the different clinical uses of corticosteroids?

A

1) Diagnosis of adrenal function
2) Treatment of adrenal function disorders
3) treatment of inflammatory and immunological disorders

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5
Q

What molecule determines how much or how little corticosteroids are formed?

A

ACTH

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6
Q

Intermediary metabolism, catabolism, immune responses, inflammation, Ex: Cortisol

A

Glucocorticoids

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7
Q

Regulation of sodium and potassium reabsorption in the collecting tubules of the kidney, Ex: Aldosterone

A

Mineralcorticoid

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8
Q

Where are glucocorticoid receptors present what are the effects due to their placement?

A

They are in virtually every cell type and therefor e have diverse effects and subsequent side effects.

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9
Q

Cortisol release is modulated by ACTH pulses under the control of what? When are the highest and lowest levels?

A

Circadian clock - Peak levels are in the morning and lowest levels are at night

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10
Q

95% of cortisol is bounds to plasma proteins. What are these proteins?

A

1) Coricosteroid-binding globulin (CBG) - an Alpha 2 globulin
2) Serum albumin

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11
Q

Free cortisol plasma concentrations (rise/fall) rapidly if CBG binding capacity is exceeded

A

Rise

Free cortisol plasma concentrations RISE rapidly if CBG binding capacity is exceeded

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12
Q

What are some factors that change the plasma CBG concentration?

A

Pregnancy, estrogen administration, hyperthyroidism, hypothyroidism

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13
Q

What is the cortisol half life and what effect does the liver have on it?

A

Half life is 60-90 minutes and this half life increases if there is hepatic dysfunction because it can’t clear it as fast since the cells aren’t working properly

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14
Q

What are some factors that increase cortisol half life?

A

Stress, hypothyroidism, liver disease, and a large dosage of hydrocortisone administration.

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15
Q

How is cortisol metabolized and what are the products produced?

A

20% of cortisone is converted to cortisol (by 11-hydroxysteroid dehydrogenase in other tissues with mineralocorticoid receptors (renal for ex))

Cortisol and cortisone and inactivated by the liver to Tetrahydrocortisol and tetrahydrocortisone (by 3-hydroxysteroid dehydrogenase)

Other metabolites are cortol and cortisone

Some metabolites undergo hepatic conjugation to form glucuronic acid or sulfate derivatives.

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16
Q

How does cortisol diffuse across the skin?

A

It diffuses poorly across the skin. However, it is readily absorbed across inflamed skin/mucous membranes.

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17
Q

How do glucocorticoids reach its receptor? Give the mechanism of action.

A

Glucocorticoids readily cross the plasma membrane and binds to it intracellular receptor. The receptor dissociates from heat shock proteins and combine to form homodimers. These homodimers are actively transported to the nucleus and binds to glucocorticoid receptor elements (GREs) of target genes to activate transcription. These “genomic effects” results in the synthesis of new proteins.

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18
Q

What is the effect of glucocorticoids on metabolism?

A

They stimulate gluconeogenesis (production of glucose). This causes and increase in blood glucose, muscle catabolism, and stimulates insulin secretion. It also increases lipolysis and lipogenesis in specific areas. The fat is redistributed from the extremities to the face (moon facies) and shoulder and back (buffalo hump).

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19
Q

What are the catabolic effects of glucocorticoids (breakdown promotion of what)?

A

Promotion of catabolism in lymphoid tissue, connective tissue, muscle, fat, and skin.

High (suprophysiologic glucocorticoid) levels cause: Decreased muscle mass and weakness, reduced growth in children (which can not be prevented by GH), and development of osteoporosis (limitation of longterm use).

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20
Q

How do glucocorticoids aid in anti-inflammatory actions?

A

Reduce inflammation - reduces pain, heat, redness and swelling.

Inhibits phospholipase A2 which produces arachidonic acids. These arachidonic acids can be broken down by cyclooxygenase 2 in inflammatory cells to make prostaglandin and thromboxanes. These products are known as Eicosanoids which cause inflammation.

Therefore, glucocorticoids block aracidonic acid production (block phospholipase A2) and therefore block the production of prostaglandins and thromboxanes (block COX2) which help to reduce inflammation

It also reduces the levels of lymphocytes, monocytes, eosinophils, and basophils

Decreases the release of histamine (inflammation causer).

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21
Q

What are the immunosuppressive effects of glucocorticoids?

A

It inhibits cell mediated immunologic functions dependent on lymphocytes. Glucocorticoids are lymphotoxic making it useful in the treatment of hematologic cancers. They therefore help to delay organ rejection reactions in transplants.

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22
Q

What are some other effects of glucocorticoids?

A

Suppression of pituitary ACTH release (makes since because when there is Cortisol being made and used, it will tell the brain that it has enough and down regulates ACTH)

Inhibits action of Vitamin D on calcium absorption (studies show that it might actually decrease Vit D receptor)

Developing fetus - Requird for the production of surfactant (essential for breathing air)

Stimulates gastric acid secretion (could lead to ulcer formation)

Renal function - important for the normal excretion of water loads (excess levels of glucocorticoids have a salt retaining effect).

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23
Q

What are synthetic glucocorticoids synthesized from?

A 
Cholic acid (cattle source) 
Steroid sapogenins (plants)
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24
Q

Do synthetic glucocorticoids act the same way as natural glucocorticoids?

A

YES - they have the same mechanism of action.

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25
Q

How much is absorbed when glucocorticoids are given orally?

A

Complete absorption

Metabolized similar to endogenous steroids but there are some differences.

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26
Q

What are some differences between synthetic and natural glucocorticoids?

A

Some of the synthetic glucocorticoids might have molecular alterations that cause differences in:

1) Affinity for mineralcorticoid or glucocorticoid receptors
2) Extent of protein binding
3) Stability (half-life and duration of action)

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27
Q

What are locally-acting glucocorticoids used for?

A

The management of asthma and allergic rhinitis. They readily penetrate airway mucosa and are rapidly metabolized following absorption by plasma esterases. The systemic toxicity is greatly reduced.

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28
Q

What agents are common for first line therapy to treat moderate to severe asthma?

A 
Beclomethasone 
Budesonide
Ciclesonide
Flunisolide
Fluticasone
Mometasone (Nasonex)
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29
Q

What is another name for primary adrenocortical insufficiency?

A

Addison’s disease

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30
Q

What is Addison’s disease?

A

A rare disease that may occur at any age and affects both sexes with equal frequency. It is caused by progressive destruction of the adrenals (>90% must be destroyed before symptoms of adrenal insufficiency appear).

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31
Q

What is Addison’s disease identified by?

A

Lack of response to ACTH

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32
Q

What is the treatment of Addison’s disease?

A

It requires the correction of both glucocorticoid and mineralcorticoid deficiency.

Special considerations to be made include increasing the dose of hydrocortisone during illness or before surgery and increasing fludrocortisone plus salt upon strenuous exercise or gastrointestinal upsets.

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33
Q

What are some treatment complications of hydrocortisone?

A

Rare - except for gastritis

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34
Q

What does fludrocortisone do and what are the complications involved?

A

It helps to control the amount of sodium and fluids in the body. Since there is no aldosterone being made by the diseased kidneys, there is no reabsorption of sodium, so this drug helps to reabsorb sodium (and water).

Adequacy of this treatment is assessed by serum electrolyte and blood pressure measurements

Complications include: Hypokalemia, hypertension, cardiac enlargement, congestive heart failure (secondary to sodium retention).

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35
Q

What are some of the causes of acute adrenocortical insufficiency?

A

Rapid intensification of chronic adrenal insufficiency precipitated by sepsis or surgical stress.

Acute hemorrhagic adrenal gland destruction in a previous healthy individual.

Rapid withdrawal of steroids from patients who have adrenal atrophy following prolonged chronic steroid administration (most frequent cause of acute adrenal insufficiency)

Patients with congenital adrenal hyperplasia or with decreased adrenocortical reserve

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36
Q

What are a couple ways for acute hemorrhagic adrenal gland destruction in a previously healthy individual can occur?

A

1) In children: Pseudomonas asepticemia or meningiococcemia

2) In adults: Anticoagulant treatment/coagulation disorder

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37
Q

What is the most frequent cause of acute adrenal insufficiency?

A

Rapid withdrawal of steroids from patients who have adrenal atrophy following prolonged chronic steroid administration.

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38
Q

What are some ways which patients with congenital adrenal hyperplasia or with decreased adrenocortical reserve might cause acute adrenal insufficiency?

A

If they are given drugs that inhibit steroid synthesis

  • Mitotane (Lysodren)
  • Ketoconazole (Nizoral)

If they are given drugs that increase steroid metabolism

  • Phenytoin (Dilantin)
  • Rifampin (Rimactane)

*Any drug that can reduce the amount of steroids - inhibit its synthesis or increase the rate at which it is metabolized.

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39
Q

What drugs inhibit steroid synthesis?

A
  • Mitotane

- Ketoconazole

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40
Q

What drugs increase steroid metabolism?

A
  • Phenytoin

- Rifampin

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41
Q

What is the treatment for acute adrenal insufficiency?

A

Treatment is based on replacing glucocorticoids and sodium/water deficits.

  • Initiated with IV bolus of 100 mg of hydrocortisone, followed by continuous hydrocortisone infusion (10 mg/hr)
  • Intravenous 5% Glucose infusion (in normal saline)
  • Management of hypotension requires glucocorticoid replacement and correction of sodium and water deficit
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42
Q

What is congenital adrenal hyperplasia (CAH)?

A

This disease is due to an enzyme defect in cortisol production, often as a result of autosomal recessive mutations.

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43
Q

What is the most common adrenal disorder of childhood and infancy?

A

Congenital adrenal hyperplasia (CAH)

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44
Q

What fetal therapeutics can be administered in order to avoid genital abnormalities in a fetal patient with congenital adrenal hyperplasia?

A

Dexamethasone is given to the mother

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45
Q

What is the most common deficiency in someone with congenital adrenal hyperplasia (CAH) and how does it affect steroid levels?

A

Decrease or lack of cytochrome P450c21 (21-Beta hydroxyls activity) (95% frequency), which results i cortisol synthesis reduction and compensatory increase of ACTH release and increased synthesis of cortisol precursors

Increased compensatory ACTH can result in normal levels of cortisol if sufficient P450c21 activity is present; however the gland will become hyper plastic and produce excessive precursors such as 17-hydroxyprogesterone which is then diverted to androgen pathways leading to virilization.

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46
Q

When virilization occurs in children with CAH what happens to each sex?

A

Females - ambiguous external genitalia (pseudohermaphraditism)

Males - enlarged genitalia

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47
Q

How are infants with congenital adrenal hyperplasia treated ?

A

Acute crisis: IV hydrocortisone, fludrocortisone to bring mieralocorticoid activity to normal and electrolyte solutions.

After stabilization, oral hydrocortisone is adjusted as required:

  • Alternative: Prednisone (Deltasone) - this achieves greater ACTH suppression without increasing growth inhibition (hydrocortisone causes growth inhibition)
  • Mineralcorticoids may be required (fludrocortisone) to maintain normal BP, plasma renin activity, and electrolytes
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48
Q

What is Cushing’s syndrome?

A

Disease characterized by prolonged exposure to inappropriate high levels of cortisol.

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49
Q

What is the primary cause of Cushing’s syndrome?

A

Iatrogenic administration of steroids (prolonged use of glucocorticoids taken for another medical condition)

50
Q

What are the primary non-iatrogenic causes of Cushing’s syndrome?

A
  • Adrenal hyperplasia due to pituitary adenoma (basophilic tumor) - Excess secretion of ACTH
  • Adrenal neoplasm (20-25% of the time)
  • ACTH hyper section by other tumors
51
Q

What are the manifestations seen in patients with Cushing’s syndrome?

A
  • Abnormal fat deposition - truncal obesity (moon facies and buffalo hump)
  • Hirsuitism
  • Effects of protein loss: muscle wasting, skin thinning, striae (stretch marks), poor wound healing, bruising, osteoporosis
  • Mental disorders: Irritability/emotional lability, severe depression, confusion, and psychosis
  • Diabetes (frequency <20%)
  • Impaired glucose tolerance: increased hepatic gluconeogenesis, insulin resistance, and hypertension (common)
52
Q

What is the short-term treatment for Cushing’s syndrome caused by iatrogenic administration of steroids?

A

Gradually discontinue the use of glucocorticoids to allow the pituitary and adrenal glands to resume normal function. For conditions requiring prolonged glucocorticoid therapy, and alternate plan for managing the symptoms of Cushing’s syndrome is necessary.

53
Q

What is the short-term treatment for Cushing’s syndrome caused by pituitary tumor/adenomas?

A

-Surgical pituitary tumor removal

  • Irradiation/removal of pituitary adenomas (ACTH producing). When doing this you need to have patient management (surgical intevention):
    1) before surgery give large doses of cortisol
    2) During and immediately after surgery give large doses of cortisol
    3) Tapered cortisol to normal replacement doses (long-term maintenance)
  • Slow reduction in dose to prevent cortiso withdrawal (fevers and joint pain)
    4) Fludrocortisone administered to regulate salt and water metabolism
54
Q

What test is used for diagnosis of underlying cause of Cushing’s and depressive psychiatric states?

A

Dexamthasone suppression testing

55
Q

What test is used to see if theres a pituitary adenoma (Cushing’s syndrome)?

A

Initial screening:
1 mg oral dexamthasone 11 pm, serum plasma concentration measured the following morning.
Normal = < 3 mcg/dL
Cushings = > 5 mcg/dL

56
Q

What is a combined dexamethasone test used for?

A

Used to distinguish between elevated cortisol due to anxiety, depression, alcoholism, and bona fide Cushing’s.

Dexamethasone 0.5 mg given orally every 6 hours for 2 days, followed by corticotrophin-releasing hormone (CRH) test (bolus IV CRH 2 hrs after last dose of dexamethasone)

57
Q

What tests are used to distinguish Cushing’s from steroid producing tumors?

A
  • Suppression with large dose of dexamethasone
  • Dexamethasone 0.5 mg given orally every 6 hours for 2 days; then 2 mg orally every 6 hours for 2 days, urine assayed for cortisol and its metabolites.
  • 8 mg oral dexamethasone 11 pm, serum plasma concentration measured the following morning
58
Q

What are the results from the tests used to distinguish Cushing’s from steroid producing tumors?

A
  • Cushing’s disease (pituitary adenoma) = 50% reduction in hormone levels
  • Cortisol producing adrenal tumor = No suppression, low ACTH
  • Ectopic ACTH producing tumor = No suppression, high ACTH
59
Q

What is fetal lung maturation dependent on?

A

Cortisol

60
Q

If a delivery is expected before 34 weeks gestation, maternal glucocorticoid supplementation reduces likelihood of respiratory distress syndrome. What should be given?

A

An intramuscular injection of Betamethasone (Celestone) preferred due to reduced protein binding, which makes it more available for placental transfer to the fetal circulation. There is also less placental metabolism of this agent compared to cortisol.

61
Q

What are some non-adrenal disorders that adrenocorticosteroids are used to treat?

A

Asthma and allergic rhinitis
Contact dermatitis
Lupus erythematosus & Rheumatoid arthritis
Allergic conjunctivitis & optic neuritis
IBD, Crohn’s disease and ulcerative colitis
Leukemia, lymphoma, multiple myeloma
Gram negative septicemia
Osteoarthritis, bursitis, arthritis
Cerebral edema, multiple sclerosis
Prevention/treatment of rejection (immunosuppression)
Bronchial asthma, prevention of infant respiratory distress
Atopic dermatitis, mycoses fungoides, seborrheic dermatitis

62
Q

What is the absorption of all glucocorticoids?

A

Excellent oral bioavailability, some given IV, IM or as aerosols

90% of absorbed glucocorticoids are bound to CBG

63
Q

What is the metabolism of all glucocorticoids?

A

Oxidized by hepatic microsomal enzymes

Metabolites are glucuronidated and excreted in urine (reduced dose for hepatic dysfunction)

64
Q

What are the Metabolic effects if theres a toxicity with glucocorticoids?

A

Iatrogenic Cushing’s syndrome (100 mcg hydrocortisone > 2 weeks)

  • Moon facies
  • Fat redistribution; truncal obesity
  • Acne
  • Hirsuitism
  • Insomnia
  • Increased appetite & weight gain
  • Muscle wasting
  • Skin thinning, bruising
  • Hyperglycemia
  • Osteoporosis, diabetes, aseptic hip necrosis
  • Wound healing impaired and increased risk of infection
65
Q

What are some other effects of toxic amounts of glucocorticoids?

A
  • Peptic ulcer development
  • Myopathy (Triamcinolone)
  • Nausea, dizziness, weight loss (Triamcinolone, Methylpredisolone)
  • Psychosis (large doses of corticosteroids)
  • Subcapsular cataracts
  • Increased intraocular pressure/glaucoma
  • Benign intracranial hypertension
  • Growth retardation and children (long acting synthetics -Betamethasone and Dexamethasone)
  • Cortisone/Hydrocortisone in greater than physiologic amounts have mineralocorticoid effects
66
Q

What are the effects of excess cortisone/hydrocortisone?

A

Mineralocorticoid effects:

1) Sodium/fluid retention
2) Potassium loss - hypokalemia
3) Hypochloremic alkalosis
4) Hypertension

Minimize effects by using non-salt-retaining steroids, sodium reconstruction and potassium supplementation.

67
Q

Patients should be observed to detect if there is a development in what thing when taking glucocorticoids?

A 
Hyperglycemia
Glycosuria
Na+ retention with edema
Hypertension
Hypokalemia
Peptic Ulcer
Osteoporosis
Hidden Infections
68
Q

What are some approaches for reducing the adverse effects associated with glucocorticoids?

A
  • Local or topical application (aerosols for asthma and allergic rhinitis)
  • Alternate-day therapy (to decrease ACTH suppression)
  • Reducing dose following therapeutic response
69
Q

How should one stop taking glucocorticoids (suddenly/over a period of time for ex)?

A

Significant adrenal suppression observed with extended treatment

The presence of adrenal suppression requires slow tapering of adrenocorticoid dosage in order to permit recovery of normal adrenal function.
-Instant withdrawal may induce a lethal, acute adrenal insufficiency syndrome

70
Q

What are some of the contraindication of taking glucocorticoids?

A
  • Peptic ulcer disease
  • Heart disease/hypertension with congestive heart failure
  • Varicella/Tuberculosis
  • Psychoses
  • Diabetes
  • Osteoporosis
  • Glaucoma
71
Q

ACTH use is not appropriate as a therapeutic agent unless ____________ increase is desired.

A

Androgen

ACTH use is not appropriate as a therapeutic agent unless ANDROGEN increase is desired.

72
Q

What are the different corticosteroid dosage forms and what are they used for?

A

Opthalmic - eye disease

Intra-articular - joint disease

Hydrocortisone enemas - ulcertive colitis

Aerosols (beclomethasome) - asthma

Nasal Strays (beclomethasone, triamcinolone, flunisolide) - allergic rhinitis

Ointments/creams - dermalogical applications

73
Q

What are mineralocorticoids used for?

A

Important in the regulation of blood volume and blood pressure.

These include: Aldosterone, Deoxycorticosterone (DOC) and Fludrocortisone

74
Q

Aldosterone is the major natural mineralocorticoid in humans and is synthesized from cholesterol in the zona __________ of the adrenal cortex.

A

Zona Glomerulosa

75
Q

What regulates aldosterone secretion?

A

1) ACTH
2) Angiotensin system (Angiotensin II)
3) Most strongly - by Potassium

76
Q

What are the principal effects of aldosterone?

A

Salt Retaining activity

Promotes reabsorption of sodium, bicarbonate, and water via the distal renal tubules

Decreases reabsorption of potassium and hydrogen ions - helps to regulate electrolyte concentrations, water (load) volume and blood pressure

77
Q

What is the mechanism of action of mineralcorticoids?

A

Mineralcorticoid binding to the cyoplasmic mineralcorticoid receptor (MR) in the renal collecting tubule principal cells. This binding causes an increase in gene expression of Na+/K+-ATPase and the epithelial sodium channel (ENaC). Receptor has the same affinity for cortisol, but the presence of 11Beta-hydroxysteroid dehydrogenase in the kidney converts the cortisol to cortisone (which has a low affinity for the MR).

78
Q

What are the effects of excessive aldosterone?

A 
Hypernatremia
Hypokalemia
Metabolic Alkalosis
Hypertension
Increased plasma volume
79
Q

What is the plasma half life of aldosterone?

A

Short half life (15-20 minutes) and minimal glucocorticoid activity

80
Q

What is deoxycorticosterone (DOC)?

A

It is a precursor to aldosterone.

Unlike aldosterone, the primary regulator of DOC secretion is ACTH.

81
Q

How is DOC secretion greatly enhanced?

A

DOC secretion is greatly enhanced in abnormal conditions such as adrenal carcinoma and congenital adrenal hyperplasia (with reduced P450c11 or P450c17 activity).

82
Q

What is the most widely used mineralocorticoid?

A

Fludrocortisone (Florinef)

It is almost exclusively given for replacement therapy in combination with a glucocorticoid.

83
Q

FLudrocortisone has a glucocorticoid and mineralcorticoid activity. What is the result?

A

Potent salt retaining activity

84
Q

What is fludrocortisone used for?

A

Management of adrenocortical insufficiency:

  • Addison’s disease
  • Congenital adrenal hyperplasia (CAH)
  • Replacement following adrenalectomy

Doses are usually too low to have anti-inflammatory or antigrowth effects

85
Q

What is primary aldosteronism?

A

Results from an adrenal adenoma associated with excessive aldosterone production.

Twice more common in women than in men and presents between 30-50 years of age.

It can also result from hyper plastic adrenal glands or a malignant tumor.

Clinical presentation: Diastolic hypertension (due to increased sodium reabsorption and volume expansion), headaches, polyuria, weakness, tetany and hypokalemia.

86
Q

What is the treatment for primary aldosteronism?

A

Adenomas: Surgical removal, restriction of sodium intake, aldosterone antagonist -> Spironolactone (Aldactone)

87
Q

What is secondary aldosteronism?

A

Characterized by an inappropriate increase in aldosterone production due to renin-angiotensin system activation (can occur in response to pregnancy or chronic high blood pressure).

Physiologically characterized: Increased plasma renin activity, moderate/marked increases in aldosterone levels and hypokalemic alkalosis.

88
Q

What are some of the synthesis inhibitors and glucocorticoid antagonists?

A
  • Aminoglutethimide
  • Metyrapone
  • Ketoconazole
  • Mifepristone

Also listed earlier in packet: Mitotane

89
Q

What does aminoglutethimide do?

A

It blocks the conversion of cholesterol to pregnenolone and thus reduces synthesis of all hormonally active steroids.

90
Q

Historically aminoglutethimide was used with _______________ or _____________ to eliminate estrogen and androgen production in patients with breast carcinoma.

A

Historically aminoglutethimide was used with DEXAMETHASONE or HYDROCORTISONE to eliminate estrogen and androgen production in patients with breast carcinoma.

91
Q

What has replaced aminoglutethimide?

A

Tamoxifen and aromatase inhibitors

92
Q

Aminoglutethimide is used with __________ to reduce steroid secretions in patients with Cushing’s syndrome (due to adrenocortical cancer - not responding to other drugs).

A

Ketoconazole (Nizoral)

93
Q

T/F - Aminoglutethimide enhances the clearance of other steroids.

A

True - Aminoglutethimide enhances the clearance of other steroids.

For example: It reduces dexamethasone half-life from 5 hours to 2 hours.

94
Q

What is metyrapone?

A

It is a selective inhibitor of steroid synthesis (inhibiting 11-hydroxylation which interferes with cortisol and corticosterone synthesis).

95
Q

What drug is most commonly used in adrenal function test to check for compensatory increase in pituitary ACTH secretion?

A

Metyrapone

96
Q

What are the indications and adverse effects of metyraphone?

A

Indications: not widely used for Cushing’s syndrome, may be useful in management of severe cortisol excess on a temporary basis

Produces dizziness and gastrointestinal disturbances

Major adverse effects: salt and water retention, hirsutism, more DOC and androgen synthesis

97
Q

What is Ketoconazole?

A

It is an anti fungal imidazole derivative. It inhibits both fungal and mammalian CYP450 enzymes thereby blocking ALL steroid synthesis.

98
Q

What are the indications and toxicity of ketoconazole?

A

Indications: Cushing’s disease, Adrenal carcinoma, prostate cancer

Toxicity: Hepatotoxicity, many drug-drug Cyp450 interactions

99
Q

What is Mifepristone (RU-486, Mifeprex)?

A

It is a synthetic, glucocorticoid and progesterone receptor antagonist. It binds to the receptor but rapid dissociation induces faulty nuclear translocation.

100
Q

What is the half life of mifepristone?

A

20 hours - strong binding to plasma proteins

101
Q

What are the indications and toxicities of mifeprestone?

A

Indications: Treatment of Cushing’s Syndrome (experimental) -> reverses hypercortisolism phenotype, medical abortion

Toxicities: vaginal bleeding in females, abdominal pain, gastrointestinal upset, diarrhea, headache

102
Q

What are some mineralocorticoid antagonists?

A 
Spironolactone
Eplerenone (Inspra)
Drospirenone
103
Q

What is Spironolactone (Aldactone)?

A

It is a synthetic steroid.

It is a competitive aldosterone antagonist binding to cytoplasmic mineralocorticoid receptors - preventing receptor complex translocation to the nucleus

It is also a weak antagonist of androgen receptors.

In addition, it also inhibits formation of an active metabolite of aldosterone by inhibiting 5-alpha reductase activity

104
Q

What is the duration of action of spironolactone?

A

Duration of action: 24-36 hours

Hepatic inactivation

Slow onset of action

105
Q

What are the indication and adverse effects of spironolactone?

A

Indications: Aldosteronism (due to any cause), hypokalemia due to other diuretics, post-myocardial infarction, hirsuitism in women

Adverse effects: Hyperkalemia, gynecomastia, menstrual abnormalities, sedation, headache, gastrointestinal disturbances, and skin rashes

106
Q

What is Eplerenone (Inspra)?

A

Same MOA as spironolactone but more selective MR antagonist (no androgen receptor effects), both spironolactone and eplerenone have been shown to reduce mortality rate in heart failure.

107
Q

What is Drospirenone?

A

A progestin component of many oral contraceptives (Yasmin, Yasminelle, Yaz, Beyaz, Ocella, Zarah, and Angelique) and is mown to have antagonistic effects on aldosterone. These drugs are contraindicated in worn with renal insufficiency because of the risk of hyperkalemia.

108
Q

Why is aldosterone elevated in patients with congestive heart failure?

A

The reduction in cardiac output associated with heart failure decreases the effective arterial blood volume and renal blood flow. Decreased pressure in renal arterioles and increased sympathetic neural activity both stimulate renin release, which increases production of angiotensin II. Angiotensin II is a powerful stimulus of aldosterone secretion.

109
Q

How does the increase in aldosterone contribute to the signs and symptoms of heart failure?

A

Acting through nuclear receptors in the epithelial cells that line renal collecting tubules, aldosterone promotes renal uptake of salt and water. This retention of salt and water exacerbates the peripheral and pulmonary edema associated with congestive heart failure and further overloads the weakened heart. In addition to these renal effects, aldosterone is also implicated in myocardial and vascular fibrosis and baroreceptor dysfunction.

110
Q

What happens to serum potassium concentrations in patients who are treated with aldosterone antagonists?

A

The aldosterone antagonists are also known as “potassium-sparing diuretics” because, unlike other diuretics, they do not promote renal excretion of potassium. Because the excretion of potassium in the renal tubule is linked to the reuptake of sodium, the reduction in sodium uptake caused by spironolactone and eplerenone results in potassium retention and an increase in serum potassium.

111
Q

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

Glucocorticoids inhibit the production of both leukotrienes and prostaglandins. This is a key component of their anti- inflammatory action

112
Q 
A 34-year-old woman with ulcerative colitis has required long-term treatment with pharmacologic doses of a glucocorticoid agonist. Which of the following is a toxic effect associated with long-term glucocorticoid treatment?
(A) A “lupus-like” syndrome 
(B) Adrenal gland neoplasm 
(C) Hepatotoxicity
(D) Osteoporosis
(E) Precocious puberty in children
A

(D) Osteoporosis

One of the adverse metabolic effects of long-term glucocorti- coid therapy is a net loss of bone, which can result in osteo- porosis.

113
Q 
A 46-year-old male patient has Cushing’s syndrome that is due to the presence of an adrenal tumor. Which of the following drugs would be expected to reduce the signs and symptoms of this man’s disease?
(A) Betamethasone 
(B) Cortisol
(C) Fludrocortisone 
(D) Ketoconazole 
(E) Triamcinolone
A

(D) Ketoconazole

Ketoconazole inhibits many types of cytochrome P450 enzymes. It can be used to reduce the unregulated overproduc- tion of corticosteroids by adrenal tumors.

114
Q

A newborn girl exhibited ambiguous genitalia, hyponatremia, hyperkalemia, and hypotension as a result of genetic deficiency of 21β-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 adrenal aldosterone synthesis
(C) Prevention of hypoglycemia
(D) Recovery of normal immune function
(E) Suppression of ACTH secretion

A

(E) Suppression of ACTH secretion

A 21β-hydroxylase deficiency prevents normal synthesis of cortisol and aldosterone, and causes accumulation of corti- sol precursors (Figure 39–2). The hypothalamic-pituitary system responds to the abnormally low levels of cortisol by increasing ACTH release. High levels of ACTH induce adrenal hyperplasia and excess production of adrenal andro- gens, which can cause virilization of females and prepubertal males. Glucocorticoid is administered to replace the missing mineralocorticoid and glucocorticoid activity and to suppress ACTH release, which removes the stimulus for excess adrenal androgen production.

115
Q

Which of the following best describes a glucocorticoid response element?
(A) A protein regulator that controls the interaction between
an activated steroid receptor and DNA
(B) A short DNA sequence that binds tightly to RNA
polymerase
(C) A small protein that binds to an unoccupied steroid receptor protein and prevents it from becoming denatured
(D) A specific nucleotide sequence that is recognized by a
steroid hormone receptor-hormone complex
(E) The portion of the steroid receptor that binds to DNA

A

(D) A specific nucleotide sequence that is recognized by a
steroid hormone receptor-hormone complex

Activated steroid hormone receptors mediate their effects on gene expression by binding to hormone response elements, which are short sequences of DNA located near steroid- regulated genes.

116
Q 
Glucocorticoids have proved useful in the treatment of which of the following medical conditions?
(A) Chemotherapy-induced vomiting
(B) Essential hypertension
(C) Hyperprolactinemia 
(D) Parkinson’s disease 
(E) Type II diabetes
A

(A) Chemotherapy-induced vomiting

Glucocorticoids are used in combination with other anti-emetics to prevent chemotherapy-induced nausea and vomiting, which are commonly associated with anti-cancer drugs.

117
Q

A 56-year-old woman with systemic lupus erythematosus had been maintained on a moderate daily dose of prednisone for 9 mo. Her disease has finally gone into remission and she now wishes to gradually taper and then discontinue the prednisone. Gradual tapering of a glucocorticoid is required for recovery of which of the following?
(A) Depressed release of insulin from pancreatic B cells
(B) Hematopoiesis in the bone marrow
(C) Normal osteoblast function
(D) The control by vasopressin of water excretion
(E) The hypothalamic-pituitary-adrenal system

A

(E) The hypothalamic-pituitary-adrenal system

Exogenous glucocorticoids act at the hypothalamus and pituitary to suppress the production of CRF and ACTH.
As a result, adrenal production of endogenous corticoste- roids is suppressed. On discontinuance, the recovery of normal hypothalamic-pituitary-adrenal function occurs slowly. Glucocorticoid doses must be tapered slowly, over several months, to prevent adrenal insufficiency.

118
Q

A 54-year-old man with advanced tuberculosis
has developed signs of severe acute adrenal insufficiency.

Which of the following signs or symptoms is this patient most likely to exhibit?
(A) A moon face
(B) Dehydration
(C) Hyperglycemia 
(D) Hypertension 
(E) Hyperthermia
A

(B) Dehydration

In acute adrenal insufficiency, there is loss of salt and water that is primarily due to reduced production of aldosterone. The loss of salt and water can lead to dehydration.

119
Q

A 54-year-old man with advanced tuberculosis
has developed signs of severe acute adrenal insufficiency.

The patient should be treated immediately. Which of the following combinations is most rational?
(A) Aldosterone and fludrocortisone
(B) Cortisol and fludrocortisone
(C) Dexamethasone and metyrapone 
(D) Fludrocortisone and metyrapone 
(E) Triamcinolone and dexamethasone
A

(B) Cortisol and fludrocortisone

A rational combination of drugs should include agents with complementary effects (ie, a glucocorticoid and a mineralo- corticoid). The combination with these characteristics is cortisol and fludrocortisone. (Note that although fludrocortisone may have sufficient glucocorticoid activity for a patient with mild disease, a patient in severe acute adrenal insufficiency needs a full glucocorticoid such as cortisol.)

120
Q 
Which of the following is a drug that, in high doses, blocks the glucocorticoid receptor?
(A) Aminoglutethimide
(B) Beclomethasone
(C) Ketoconazole 
(D) Mifepristone 
(E) Spironolactone
A

(D) Mifepristone

Mifepristone is a competitive antagonist of glucocorticoid and progesterone receptors. Ketoconazole and aminoglutethimide also antagonize corticosteroids; however, they act by inhibiting steroid hormone synthesis.

Pharm Exam 3 (4 decks)

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