Corticosteroids

Question 1

Physiological role of cortisol (hydrocortisone)

Answer 1

Metabolic effects

1. Increase gluconeogenesis, decrease peripheral glucose uptake
2. Glycogen deposition
3. Increase lipolysis + increase lipogenesis - net increase in fat deposition
4. Mineralocorticoid activitiy - H20 retention

Catabolic effects

1. Proteins in lymphoid, muscle, skin, bone, connective tissue (broken down/downregulated)
2. Negative nitrogen & calcium balance

Feedback Inhibition
1. Decrease ACTH secretion

Miscellaneous effects

1. Increase number of platelets & RBCs
2. Surfactant production in lung

Question 2

Mechanism of action of steroids & anti-inflammatory actions (3)

Answer 2

1. Dissociate from corticosteroid-binding globulin - lipophilic, passes through plasma membrane and enters cytoplasm
2. Binds with glucocorticoid receptor - homodimer - enters nucleus - affects gene expression - protein - altered cell function - anti-inflammatory actions:

(A) Decreases gene transcription
- cytokines, chemokines, inflammatory enzymes, adhesion molecules, receptors

(B) Increases gene transcription
- annexin-1, β2-adrenoceptor, IL-IR2, neutral endopeptidase, secretory leukoprotease inhibitor, IL-1R antagonist, endonucleases, IkB-α

(C) Cellular anti-inflammatory effects
- decreased T/B cells, monocytes, macrophages, eosino/basophils in circulation, decreased macrophage phagocytosis & cytokine & protease prod, decreased cap perm, decreased delayed hypersensitivity, decreased Ag release from grafted tissue, decreased Ab prod

Question 3

Examples of corticosteroids

Answer 3

1. Cortisone (prodrug)
2. Hydrocortisone (cortisol)
3. Prednisone
4. Prednisolone
5. Methylprednisolone
6. Triamcinolone
7. Dexamethasone
8. Betamethasone

• 1-4 have mineralocorticoid effect, water retention

Question 4

Uses of corticosteroids (8)

Answer 4

1. Allergic reactions (asthma, atopic dermatitis, rhinitis, urticaria, serum sickness, anaphylaxis)
2. Collagen-Vascular disease (SLE, RA)
3. GI disease (UC, CD)
4. Hematologic disorders (leukemia, lymphoma, hemolytic anemia, thrombocytopenia)
5. Renal disorders (nephrotic syndrome)
6. Organ transplants (GvHD, organ rejection)
7. Eye diseases (uveitis, conjunctivitis)
8. Surfactant production - given to premature infants to combat respiratory distress syndrome

Question 5

Toxicity of corticosteroids (8)

Answer 5

1. Endocrine-metabolic effects (hyperglycemia, moon face, buffalo hump, truncal obesity, increased fat dep, muscle wasting, growth retardation, acne, hirsutism, menstrual disturbances, delayed wound healing, skin thinning, Na/fluid retention, edema, HTN, CHF)
2. MSK (osteoporosis, aseptic necrosis of femoral head, myopathy)
3. Immune suppression (infections - TB, herpes, CMV, candida, aspergillus, cryptococcus, toxoplasmosis)
4. Eye (posterior subcapsular lens cataract, glaucoma)
5. GIT (PUD/GI bleeding)
6. Nervous system (euphoria, depression, psychosis)
7. Withdrawal phenomenon (lethargy, headache, fever, joint pain, HPA insufficiency)
8. Glucocorticoid resistance