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Disease and Defense > Anti-Inflammatory Corticosteroids > Flashcards

Anti-Inflammatory Corticosteroids Flashcards

1
Q

Which class of corticosteroids has anti-inflammatory activity?

A

glucocorticoids

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2
Q

What do glucocorticoids regulate?

A

protein and carbohydrate metabolism, anti-inflammation, immunosuppression

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3
Q

What do mineralocorticoids regulate?

A

Sodium and water retention (acts on kidneys)

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4
Q

What is the main endogenous mineralocorticoid?

A

aldosterone

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5
Q

What is the main endogenous glucocorticoid?

A

cortisol (cortisol also possesses equal mineralocorticoid activity)

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6
Q

Which corticosteroid triggers the release of androgens from the adrenal gland?

A

Cortisol (adrenal androgens; dihydroandrostenedione and androstenedione)

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7
Q

How is corticosteroid production stimulated (HPA axis)?

A

CRF from hypothalamus triggers the release of ACTH from anterior pituitary, which stimulates production of corticosteroids from the adrenal gland

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8
Q

How is the HPA axis regulated (3 modes)?

A
  1. Circadian (diurnal) rhythm of CRF synthesis, regulated by higher brain areas. (CRF production levels naturally change during the day; peak in AM and after meals)
  2. Negative feedback of circulating glucocorticoids stops production of both CRF (at the level of the hypothalamus) and ACTH (at the level of the AP)
  3. Stress overrides negative feedback. (= increased steroidogenesis)
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9
Q

What is the exact mechanism of ACTH for steroidogenesis of glucocorticoid?

A

ACTH catalyzes the rate-limiting conversion of cholesterol to pregnenolone

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10
Q

What directly stimulates steroidogenesis of mineralocorticoids?

A

Renin-angiotensin system. Angiotensin II stimulates conversion of cholesterol to pregnenolone and conversion of corticosterone to aldosterone

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11
Q

What are the two general mechanisms of glucocorticoid action?

A
  1. Interaction with membrane receptors (fast)

2. Gene transcription, protein synthesis (slow)

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12
Q

What is the half-life of cortisol?

A

60-90 minutes; can be increased by stress, hypothyroidism, or liver disease (metabolised in liver)

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13
Q

How do glucocorticoids affect carbohydrate metabolism?

A

stimulates gluconeogenesis and glycogen synthesis –> increased blood glucose, increased glycogen deposition

Note: increased blood glucose also leads to increased blood insulin

CHRONIC: Diabetes-like state

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14
Q

How do glucocorticoids affect protein metabolism?

A

Increase uptake of AA into liver and kidney for conversion into glucose –> decreased protein synthesis (net movement of protein from muscle –> liver)

CHRONIC: Muscle wasting

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15
Q

How do glucocorticoids affect lipid metabolism?

A

Decrease glucose uptake by fat cells –> lipolysis
Increased blood insulin –> lipogenesis

In central tissues, lipogenesis > lipolysis

CHRONIC: Centripetal obesity (buffalo hump, abdominal fat)

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16
Q

What is the ultimate physiological goal of glucocorticoids?

A

To maintain glucose supply to the brain

17
Q

What is a permissive effect, and what are examples?

A

A permissive effect is an effect that is observed in the presence of glucocorticoids but not increased by increased glucocorticoids.

Ex) Vasoconstriction and bronchodilation, lipolysis, cardiac output

18
Q

What is the mechanism of mineralocorticoid action?

A

Transcription and synthesis of proteins (channels) that increase reabsorption of Na from renal distal tubules.

This reabsorption is loosely coupled to increased H and K excretion.

19
Q

What is the pharmacological use of glucocorticoids?

A

Suppressing inflammatory and immune responses

20
Q

What are the mechanisms for the anti-inflammatory effects of glucocorticoids?

A
  1. Decreased production and action of cytokines
  2. Inhibition of inducible COX-2 and phospholipase A2 (via annexins), which results in decreased production of prostaglandins and leukotrienes
21
Q

What are the mechanisms for the immunosuppressive effects of glucocorticoids?

A
  1. Decreased T cell activation
  2. Decreased cytokine production (also anti-inflammatory)
  3. Prevention of mast cells and eosinophils from releasing chemical mediators of inflammation (histamine, leukotrienes, prostaglandins)

Ultimately: less vasodilation (and less fluid exudate) and less accumulation/activation of cells

Side effects: slower healing, less protection

22
Q

Drugs that are either glucocorticoid or mineralocorticoid with little/no overlap are ideal. What else would be ideal, but isn’t possible?

A

An anti-inflammatory steroid with no glucocorticoid activity.

Since its not, glucocorticoid side effects must always be monitored in PTs:

blood glucose
muscle wasting
obesity

23
Q

What makes glucocorticoids physiologically active?

A

A hydroxyl group on the 11th carbon (11-hydroxy)

24
Q

What activates glucocorticoids that do not have an 11-hydroxy group (11 keto glucocorticoids)?

A

11beta hydroxysteroid dehydrogenase I (11beta HSDI); in liver

cortisone –> cortisol/hydrocortisone

25
Q

What inactivates cortisol and where does this take place?

A

11beta hydroxysteroid dehydrogenase II (11beta HSDII); in the kidney (to protect kidney from mineralocorticoid activity of cortisol)

cortisol –> cortisone

26
Q

Which hydroxysteroid dehydrogenase is active in fetuses?

A

11beta HSDII

Implications: Can treat mother with glucocorticoids with no effect on fetus

Challenges: to administer glucocorticoid to fetus (like to help lung growth), must use one that is poor 11beta HSDII substrate (betamethasone).

27
Q

What is cortisol/hydrocortisone used for?

A

replacement therapy and emergencies

28
Q

What is prednisone used for?

A

steroid burst therapy (activated to prednisolone)

NO topical activity; needs first pass liver metabolism, some mineralocorticoid activity

29
Q

What is methylprednisolone used for?

A

parenteral administration for steroid burst

No first pass metabolism needed, zero mineralocorticoid activity

30
Q

What is dexamethasone used for?

A

Most potent anti-inflammatory agent, used in cerebral edema, chemotherapy-induced vomiting

No first pass metabolism needed, zero mineralocorticoid activity

31
Q

What is triamcinolone used for?

A

Potent systemic agent with excellent topical activity

No first pass metabolism needed, zero mineralocorticoid activity

32
Q

What are some common examples of inflammatory disorders that glucocorticoids can treat?

A

allergic reactions, asthma, IBD, cerebral edema, hemolytic anemia, dermatitis, rheumatoid arthritis (plus NSAIDS and DMARDs) etc.

33
Q

What are possible side effects of an acute, large dose of mineralocorticoid?

A

(increased Na and water retention) = Increased BP, hypokalemia

34
Q

What are possible side effects of an acute, large dose of glucocorticoid?

A

glucose intolerance, insomnia, GI upset, mood changes

35
Q

What are possible side effects of long term, high dose glucocorticoid therapy?

A

Iatrogenic Cushing’s syndrome, HPA suppression –> insufficient stress response, mood disturbance, impaired wound healing, increased susceptibility to infection

36
Q

Large, cumulative doses of glucocorticoids can lead to:

A

osteoporosis, posterior capsular cataracts (esp. in children being treated for asthma), skin atrophy, growth retardation (children), peptic ulceration

37
Q

Why do you taper use of glucocorticoid therapy instead of stopping them outright?

A

to minimize chance of adrenal insufficiency

Disease and Defense (3 decks)

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