Riley Pharmacology II - Exam #3

Glucocorticoids mimic the actions of the adrenal endocrine hormone __________

Glucocorticoids mimic the actions of the adrenal endocrine hormone __________

cortisol

In the adrenal gland, the fasciculata layer secretes __________ that regulates metabolism, response to stress, immune function, etc.

cortisol

In the adrenal gland, the glomerulosa layer secretes __________ that regulates salt and water balance, blood volume, blood pressure, etc.

aldosterone

In the adrenal gland, the reticularis layer secretes __________

androgens

Within the cells of the adrenal cortex, __________ is the starting material for steroid hormone synthesis

cholesterol

During glucocorticoid biosynthesis, cholesterol is first transported to the ______________ by sterol carrier proteins

mitochondria

Cholesterol is delivered from the outer to the inner mitochondrial membrane by the _______ protein, which catalyzes the rate limiting step for the production of all steroid hormones

StAR (steroidogenic acute regulatory protein)

The conversion from cortisol to pregnenalone occurs in the mitochondria, but synthesis from pregnenalone to 11-dexoycortisol occurs in the...

endoplasmic reticulum

True or False. After cholesterol is converted into 11-dexoycortisol, the compound then goes back to the mitochondria to be synthesized into cortisol.

True

True or False. Different adrenal zones contain different CYP enzymes which is how different steroids are synthesized within the adrenal gland.

True

The hypothalamus produces _______, which stimulates cells in the pituitary gland which then causes _______ release which travels in the blood to the adrenal cortex and stimulates the synthesis of adrenocorticoids.

CRH (corticotropin-releasing hormone); ACTH (adrenocorticotropic hormone)

Cortisol acts as a feedback __________ on the hypothalamus and pituitary to _______ CRH and ACTH production

inhibitor; limit

Synthetic ACTH, called cosyntropin, is often used clinically for...

diagnosis of primary adrenocortical failure (an increase in plasma cortisol rules out adrenal insufficiency)

True or False. Protein-bound cortisol is what is regulated by homeostasis compared to free hormone.

False

The kidney possesses the enzyme ___________________________ to _______ cortisol

11-beta-hydroxysteroid dehdrogenase type 2; inactivate

The liver possesses the enzyme ___________________________ to _______ cortisol

11-beta-hydroxysteroid dehdrogenase type 1; activate

Some glucocorticoid drugs including __________ and __________ are inactive and must be metabolized by liver 11-beta-HSD type 1 which is why these drugs cannot be used topically in most cases.

cortisone; prednisone

True or False. The placenta has 11-beta-HSD type 2 which is why mothers can be given prednisone without fetal side effects.

True

Glucocorticoid mechanism of action

activate or inactivate gene expression

Glucocorticoid trans-activation

binding to a gene and activating gene transcription (dimers)

Glucocorticoid cis-repression

binding to a gene and repressing gene transcription (dimers)

Glucocorticoid trans-repression

binding to a protein and repressing its activity (monomers)

The glucocorticoid gene regulation type(s) that are associated with decreased inflammation

1. Trans-repression
2. Trans-activation

The glucocorticoid gene regulation type(s) that are associated with some adverse effects

Cis-repression

True or False. The glucocorticoid (GR) receptor or type II receptor is expressed by most human cell types.

True

__________ CpG methylation has been positively associated with cortisol response and psychosocial stress.

Increased

True or False. There are glucocorticoid drugs available that exclusively act via non-genomic effects.

False

The pro-inflammatory actions of eicosanoids are inhibited by glucocorticoid drugs through multiple mechanisms: (3)

1. Limit the production of arachidonic acid
2. Limit the production of prostaglandins and thromboxanes from arachidonic acid
3. Block actions of leukotrienes

This disease is characterized by primary adrenal insufficiency where the adrenal cortex is selectively destroyed with deficits of both cortisol and aldosterone.

Addison's Disease

Recovery from hypothalamic-pituitary axis suppression or HPA (prolonged administration of glucocorticoids) may take...

a year

This syndrome is characterized by excessive cortisol production which has multiple causes.

Cushing's Syndrome

Duration of action for cortisol and glucocorticoid analogues are determined by four factors:

1. Fraction of drug bound to plasma proteins (higher binding = longer duration)

2. Affinity for 11-beta-HSD type 2 (lower affinity = longer duration)

3. Lipophilicity (increased lipophilicity = longer duration)

4. Affinity for glucocorticoid receptor (higher affinity = longer duraiton)

True or False. Dexamethasone or betamethasone can be given during pregnancy to promote fetal lung maturation as these drugs are poor substrates for placental 11-beta-HSD type 2.

True

Replacement therapy for primary adrenal insufficiency (2)

1. Typically daily oral hydrocortisone at dosing that replaces cortisol
2. In many cases, mineralocorticoid treatment is also required

Replacement therapy for secondary adrenal insufficiency (2)

1. Typically daily oral hydrocortisone at dosing that replaces cortisol
2. Mineralocorticoid treatment is usually NOT required

Glucocorticoid mechanisms of immune suppression (4)

1. Inhibition of COX-2 and phospholipase A2
2. Inhibition of cytokine production and release
3. Reduced expression of ELAM-1 and ICAM-1 adhesion molecules
4. Inhibit histamine and leukotriene C4 release

True or False. It is possible to inhibit a single type of corticosteroid.

False

Mitotane function and clinical use(s)

Selectively kills adrenocorticoid cells, used to treat Cushing's syndrome from inoperable adrenocortical carcinoma

Aminoglutethimide function and clinical use(s)

Primarily inhibits CYP11A1, used to treat Cushing's syndrome and hormonally responsive tumors

Ketoconazole function and clinical use(s)

Inhibits CYP17, most effective drug for Cushing's disease

Metyrapone function and clinical use(s)

Selective inhibitor of CYP11B1, most commonly used to diagnosis HPA axis disorders

Mifepristone function and clinical use(s)

Glucocorticoid receptor antagonist at higher concentrations, treatment of life-threatening glucocorticoid levels in ectopic ACTH syndrome, and emergency contraceptive

Aldosterone actions (4)

1. Enhanced Na+ reabsorption
2. Enhanced K+ excretion
3. Enhanced H+ excretion
4. Retain fluid and increase blood and ECF volume

The mineralocorticoid receptor agonist used for replacement therapy with minimal first pass metabolism

Fludrocortisone

Aspirin is the only _____________ inhibitor of COX-1

irreversible

Aspirin inhibits...

COX-1 and COX-2

Epi-lipoxins are non-classical eicosinoids that are formed via the acetylation of _______ in the presence of acetylsalicylic acid (Aspirin)

COX-2

Unlike Aspirin, other NSAIDs are competitive inhibitors of COX-1 and the _____________ effects end when the drug is gone

antiplatelet

For age 45-74 years old, the risk for significant GI bleeding with NSAIDs increases about...

4-fold

For age >75 years old, the risk for significant GI bleeding with NSAIDs increases about...

20-fold

True or False. Other NSAIDs used with low dose aspirin can prevent cardiovascular benefits.

True

At low doses, Aspirin elimination follows ______-order kinetics

first

At high doses, Aspirin elimination follows ______-order kinetics

zero

Acetaminophen mechanism of action

a selective COX-2 inhibitor that has reduced effectiveness at sites of peripheral inflammation

True or False. Toxic doses of acetaminophen are only 2-3 times the maximum therapeutic dose.

True

Therapeutic use(s) for gold salts

secondary line of therapy for rheumatoid arthritis

Therapeutic use(s) for Omalizumab

functions as an anti-IgE monoclonal antibody for allergies and asthma

Therapeutic use(s) for Zileuton

used for long-term control of asthma by inhibiting the production of LTB4, LTC4, LTD4, and LTE4

List the agents that neutralize acid in the GI system (4)

1. Aluminum hydroxide
2. Magnesium hydroxide
3. Sodium bicarbonate
4. Calcium bicarbonate

List the agents that reduce acid secretion via H2 receptor antagonism on parietal cells (4)

1. Cimetidine
2. Ranitidine
3. Famotidine
4. Nizatidine

What class of drugs block acid secretion via irreversible inhibition of the H+/K+ ATPase?

Proton Pump Inhibitors (PPIs)

What is the prostaglandin analogue used specifically for treatment of NSAID-induced ulcers?

Misopristol

What is the agent that treats mucosal inflammatory/ulceration by forming a viscous gel that "coat"s epithelial cells and ulcer craters?

Sucralfate

Which agents are used for the treatment of inflammatory bowel diseases that contain an azo bond that is cleaved by resident bacteria in the colon?

Sulfasalzine, balsalazide, and olsalazine

Which agent, for the treatment of Inflammatory Bowel Diseases, utilizes Mesalamine-based, time-released microgranules that spread throughout the small intestine?

Pentasa

Which agent, for the treatment of Inflammatory Bowel Diseases, utilizes Mesalamine-based, pH-sensitive resin that dissolves in the distal ileum and proximal colon?

Asacol

What is the name of the mesalamine-based enema that delivers high concentrations to the rectum and sigmoid colon?

Rowasa

What is the name of the mesalamine-based suppositories that deliver high concentrations to the rectum and sigmoid colon?

Canasa

What is the name of the biological agent used as an anti-tumor necrosis factor therapy in Crohn’s Disease?

Infliximab

What is the name of the biological agent used to target alpha-4 integrin subunit in patients with severe Crohn's Disease?

Natalizumab

For patients with Irritable Bowel Syndrome who mainly have symptoms of diarrhea, what type of therapy is recommended?

Anti-kinetic, 5-HT3 antagonists (i.e. Alosetron)

For patients with Irritable Bowel Syndrome who mainly have symptoms of constipation, what type of therapy is recommended?

Pro-kinetic, 5-HT4 agonists (i.e. Tegaserod)

Colchicine (Colcyrs®) mechanism of action and clinical use(s)

-Binds to tubulin and prevents microtubule polymerization
-Prophylaxis and treatment of gout flares

List the three discussed drugs that increase colchicine levels (3)

1. Cyclosporine
2. Tacrolimus
3. Verapamil

List the Xanthine Oxidase Inhibitors (XOI) that decrease the formation of urate (2)

1. Allopurinol (Zyloprim®)
2. Febuxostat (Uloric®)

True or False. Febuxostat (Uloric®) is a non-purine Xanthine Oxidase Inhibitor.

True

List the discussed uricosuric agent that blocks uric acid reabsorption via the URAT1 transporter

Probenecid (Probalan®)

List the discussed recombinant uricase agent used for the treatment of patients with refractory gout

Pegloticase (Krystexxa®)

List the discussed recombinant uricase agent used for the treatment of patients with tumor lysis syndrome

Rasburicase (Elitek®)

True or False. It is appropriate to recommend recombinant uricase agents for patients that are G6PD deficient.

False

______ generation antihistamines tend to be more lipid soluble and enter the CNS

First

______ generation antihistamines tend to be substrates for P-glycoprotein transporter in the blood-brain barrier

Second

True or False. Tolerance may occur with first generation antihistamines.

True

H1 antihistamine peak blood concentrations occur in ______ hours after oral administration

1-3 hours