Steroidal Anti-Inflammatory Drugs (complete)

Question 1

Describe the regulation of glucocorticoid secretion by the hypothalamic-pituitary-adrenal gland axis

Answer 1

hypothalamus —» secretes CRF —» anterior pituatary + ADH —» secretes ACTH —» adrenal cortex—» secretes glucocorticoids and mineralocorticoids

ACTH: (-)ve fdbk to hypothalamus

Glucocorticoids: (-)ve fdbk to ant. pituatary, hypothalamus (also exogenous glucocorticoids)

Question 2

Describe how the mechanism of glucocorticoid drug-induced suppression of adrenal gland function regulates the hypothalamic-pituitary-adrenal gland axis

Answer 2

When exogenous glucocorticoids are ingested, there’s a (-)ve feedback to the ant. pituitary

Leads to adrenal gland suppression (then it’ll stop doing it’s job!)

Question 3

What are the metabolic effects associated with glucocorticoids?

Answer 3

• Carbohydrate
• Protein
• Fat

Question 4

Describe the carbohydrate metabolic effect associated with glucocorticoids

Answer 4

^ gluconeogenesis —» ^ blood glucose (^ insulin)

Causes diabetes-like state

Question 5

Describe the protein metabolic effect associated with glucocorticoids

Answer 5

Decrease protein synthesis —» ^ AA conversion to glucose

Causes: muscle wasting, skin-CT atrophy

Question 6

Describe the fat metabolic effect associated with glucocorticoids

Answer 6

^ lipolysis (peripherally) —» ^ free fatty acids

Causes:

• net effect is lipogenesis due to ^ insulin release
• centripetal obesity (buffalo hump, ab fat)

Question 7

Describe the mineralocorticoid effects (aldosterone) associated with glucocorticoids

Answer 7

• ^ Na+ reabsorption at kidney —»> ^ blood volume and BP
• Also ^ K+ and H+ secretion

Causes: fluid retention, hypertension, hypokalemia, metabolic alkalosis

Question 8

Describe the mechanism of anti-inflammatory and immunosuppressive actions

Answer 8

Vascular effects: reduced vasodilation, decreased fluid exudation

Cellular effects:

• overall decrease in accumulation/activation of inflammatory and immune cells
• Decreased synthesis of inflammatory and immune mediators

PROS: suppress chronic inflammation and autoimmune rxns

CONS: decrease healing and diminish immunoprotection

Question 9

Describe the metabolic pathways (activating/inactivating)

Answer 9

Liver inactivation:
- reduce double bonds —» conjugation from cortisol to glucoronide

Kidney inactivation: 11B-HSD II converts cortisol to cortisone

Liver activation: 11B-HSD I converts cortisone back to coritsol

Question 10

Describe glucocorticoid metabolism in pregnant women

Answer 10

• Placental 11B-HSD II is active, but not 11B-HSD I
• Can treat mom w/ GCs w/o effect on fetus
• Placental enzyme converts active drug back to prodrug

To treat fetus:
- use agent that is poor substrate for 11B-HSDII

Question 11

The activity of a glucocorticoid is determined by the 11-carbon on the general structure. Which group is the active form? Which group is the inactive form?

Answer 11

Active: -OH (hydroxyl group)

Inactive: =O (keto group)

The inactive form is used as a prodrug. Must bypass the liver to be activated

Question 12

What are the clinical considerations for the use of cortisol?

Answer 12

AKA: hydrocortisone

• Physiologic doses for replacement therapy and emergencies
• GC and MC actions! [1:1]
• Administered orally and parenterally

Question 13

What are the clinical considerations for the use of prednisone?

Answer 13

• in the keto form (a prodrug) — activated to prednisolone in liver
• Most commonly used oral agent when burst therapy is desired
• GC and MC actions! [13:1]
• NO TOPICAL ACTIVITY — not activated until first pass hepatic metabolism

Question 14

What are the clinical considerations for the use of methylprednisolone?

Answer 14

• Used if parenteral administration desired for steroid burst
• Not better than oral prednisolone in acute asthma exacerbations
• MINIMAL MC action
• Oral and parenteral forms

Question 15

What are the clinical considerations for the use of dexamethasone?

Answer 15

• Most potent anti-inflammatory agent
• Used in cerebral edema or chemo induced vomiting
• NO MC action
• Greatest suppression of ACTH secretion in pituitary

Question 16

What are the clinical considerations for the use of Triamcinolone?

Answer 16

• Potent systemic agent
• Excellent topical activity
• NO MC action

Question 17

Explain the rationale for alternate day therapy for chronic GC use

Answer 17

• Minimalize adrenal suppression

- Overall — you want anti-inflammatory actions to outlast HPA suppression

Question 18

Explain the rationale for the necessity for taper withdrawal following chronic GC use

Answer 18

• Minimizes disease rebound
• Gives adrenal gland opportunity to get going again!
• Minimizes symptoms for adrenal insufficiency (adrenal crisis)

Question 19

What are the routes of administration

Answer 19

1) Oral
2) Topical
3) Ophthalmic
4) Intra-articular
5) Enemas
6) Inhalants
7) Nasal spray

Question 20

Describe oral administration

Answer 20

• Most common

- Systemic actions (also given IV and IM)

Question 21

Describe topical administration

Answer 21

• Relatively insoluble
• HOWEVER Systemic effects possible if potent steroids are applied for long periods
• or occlusive dressings used
• or applied over large areas

Question 22

What are some considerations you should take into account when dosing?

Answer 22

• MC side effects vary w/ agent
• Dosage = trial and error
• Reduce dosage once therapy objectives are achieved
• Alternate days
• Taper once therapy is complete

OVERALL: Use large doses for a short amount of a time!!