Corticosteroids

Question 1

What are the 2 types of corticosteroids?

Answer 1

1. Glucocorticoids (cortisol)
2. Mineralocorticoids (aldosterone)

Question 2

Name all the commonly used corticosteroids.

Answer 2

1. Cortisol (prodrug: cortisone)
2. Prednisolone (prodrug: prednisone)
3. Methylprednisolone
4. Triamcinolone
5. Dexamethasone
6. Betamethasone

(In order of increasing DOA, GC action & decreasing MC n dose)

Question 3

List the metabolic effects of Cortisol.

Answer 3

1. Increases glucose in circulation: via gluconeogenesis & decreased peripheral glucose uptake
2. Increased glycogen deposition
3. increased NET fat deposition: via increased lipolysis & increased lipogenesis
   => results in buffalo hump, lipid redistribution
4. Mineralocorticoid activity (water retention)

Question 4

List the catabolic effects of Cortisol.

Answer 4

1. Negative Nitrogen & Calcium balance
   - increases nitrogen excretion in urine, from protein breakdown (lose muscle mass)
   - reduces calcium reabsorption & increases calcium excretion (leads to osteoporosis)
2. Breaks down protein in lymphoid, muscle, skin, bone & connective tissues

Question 5

Feedback inhibition of Hydrocortisone/Cortisol:

Answer 5

• increased cortisol => decreases ACTH secretion
• cuz ACTH triggers adrenal gland to produce cortisol mah
• reduce endogenous cortisol pdn

Question 6

Structure of the steroid receptor:

Answer 6

• nuclear receptor that also functions like a transcription factor

1. Nuclear receptor
2. Gene-active receptor

Question 7

Mechanism of action of Steroids:

Answer 7

1. Highly lipophilic, cross cell membrane => bind to intracellular nuclear receptor
2. Receptor forms homodimer & enters nucleus => regulate gene expression => regulate protein level

Question 8

What are the ‘forms’ of Steroid receptors?

Answer 8

Nuclear receptor (gene-active receptor)
- GRα-form: active form of glucocorticoid receptor
- GRβ-form: dominant -ve form => inhibits signalling of alpha

Question 9

What is the pro-drug of Cortisol?

Answer 9

Cortisone

Question 10

What is the pro-drug of Prednisolone?

Answer 10

Prednisone

Question 11

Name the 2 corticosteroid pro-drugs.

Answer 11

Prednisone & Cortisone

Question 12

Side effects of Corticosteroids on the Musculoskeletal system.

Answer 12

1. Osteoporosis (trabecular bone)
   - due negative calcium balance
   - decreased Ca reabsorption & increased Ca excretion
2. Aseptic necrosis of femoral head
   - rarely happens but still documented
   - bilateral, occurs on both sides of femoral head
3. Myopathy (dexamethasone/triamcinolone)
   - muscle weakness, dysfunction of muscle fiber

Question 13

Side effects of Corticosteroids on the Immune system.

Answer 13

Opportunistic infections (we often prescribe steroids post-op to suppress immune system, good to prescribe antibiotics tgt to prevent infection)
Can be:
Bacterial (TB), Viral (Herpes & CMV), Fungal (candidal, asperigilles & crytococcal), Parasitic (toxoplasmosis)

Question 14

Side effects of Corticosteroids on the GIT system.

Answer 14

Peptic ulcers, GI bleeding (esp when combined w NSAIDs)

Question 15

What is the withdrawal phenomena w corticosteroids?

Answer 15

Cuz adrenal cortex has been suppressed from producing endogenous cortisol due to negative feedback

Thus,
no abrupt withdrawal of steroids!, otherwise: lethargy, headache, fever, joint pain, HPA insufficiency (hypothalamic-pituitary-adrenal axis)
must taper dose gradually

Question 16

Side effects of Corticosteroids on the Nervous system.

Answer 16

• usually occurs in medical settings at higher doses
• euphoria, depression, psychosis

Question 17

Side effects of Corticosteroids on the Endocrine-Metabolic system.

Answer 17

1. Hyperglycemia (more glucose in circulation)
2. Moon face, ‘buffalo hump’ & truncal obesity (increased fat deposition & redistribution)
3. Muscle wasting (-ve nitrogen + protein breakdown)
4. Growth retardation (pediatric patients)
5. Acne, hirsutism (abnormal hair growth) & menstrual disturbances (cuz steroid is a male hormone)
6. Delayed wound healing (suppressed immune system)
7. Skin thinning (protein breakdown)
8. Na/fluid retention, oedema, hypertension, chronic heart failure (mineralcorticoid effects)

Question 18

Anti-inflammatory actions of corticosteroids:

Answer 18

First line immunosuppressant in solid organ and hematopoietic stem cell transplantation.

1. decreases T cells, B cells, monocytes, eosinophils & basophils but increases circulating neutrophils
   - immune cells downregulated thru increased apoptosis
   - increases neutrophils in circulation via increased pdn & reduced extravasation
   - reduced extravasation: neutrophils constrained within circulation, cannot reach tissues => reduces excessive tissue damage
2. Decreases size & lymphoid content of lymph nodes
   - due to catabolic effect (break down) on proteins in lymph nodes
3. Has more effects on cellular immunity than on humoral immunity
   - aka more effect on t cells than on b cells & pdn of immunoglobulins
4. Increases macrophage efferocytosis & promotion of resolution of inflammation
   - more cleaning up & eating of dead cells
5. Decreased type-IV delayed hypersensitivity reaction (e.g. transplantation rejection)

Question 19

How can corticosteroid drugs be administered?

Answer 19

Systemic: oral, IV, IM
Local: (decreased systemic adverse effects)
- topical (mouthwash, ointments)
- ophthalmic forms
- inhalation for asthma
- nasal sprays for allergic rhinitis
- intra-articular injection for joint disease
- enemas for ulcerative colitis

Question 20

Clinical uses of corticosteroids:

Answer 20

1. Allergic rxns: asthma, atopic dermatitis, rhinitis
2. Collagen-vascular disorders:** Lupus erythematosus** (autoimmune, attack of own tissues, widespread inflammation), rheumatoid arthritis
3. GI diseases: Crohn’s disease, ulcerative colitis (both are types of inflammatory bowel)
4. Haematologic disorders: leukemia (blood cancer), lymphoma (lymph cancer), Hemolytic anemia, thrombocytopenia
5. Organ transplants: tranplantation rejection
6. Dental conditions: gingivitis, oral lichen planus (chronic inflammatory condition that affects mucus membranes in mouth), surgical swelling
7. Eye diseases: Uveitis, Conjunctivitis

• most of these diseases involve inflammation, except leukemia & lymphoma (emphasis on these on reduction of blood cells & break down of lymph nodes)

Question 21

Effects of aldosterone. + what happens in excess?

Answer 21

Mineralocorticoid. Binds to mineralocorticoid receptor to upregulate Na+/K+ ATPase gene expression at distal renal tubule
- Na+ reabsorption
- K+ & H+ excretion

In excess: hypernatremia, hypokalemia, metabolic alkalosis(due to loss of H+), edema

Question 22

Name the glucocorticoid drugs that do not have water-retention side effects.

Answer 22

1. Methylprednisolone
2. Triamcinolone
3. Betamethasone
4. Dexamethasone

Question 23

Which glucocorticoids still have water-retention side effects?

Answer 23

Cortisol/cortisone
Prednisolone/prednisone (less water retention than cortisol)

Question 24

Steroids are not ________, only ________ inflammation.

Answer 24

Steroids are not curative, only suppress inflammation.

Question 25

What are the gene targets **decreased** by steroids?

Answer 25

1. **Cytokines**: TNF-α, IL-1β,IL-6 2. **Chemokines**: RANTES 3. **Inflammatory enzymes**: COX-2, 5-LOX, phospholipase A2 4. **Adhesion molecules**: ICAM-1, VCAM-1 (prevent cell infiltration into inflammatory sites) 5. **Receptors**: IL-2 receptor, T-cell receptor (decreased expression of pro-inflammatory genes) -> general effect: less inflammation

Question 26

What are the gene targets **increased** by corticosteroids?

Answer 26

1. **Annexin-A1** (phospholipase A2 inhibitor) 2. **β-adrenoreceptor** (related to asthma) 3. **IKB-α** (inhibitor of NF-KB) (NF-KB: pro-inflammatory TF)

Question 27

Side effects of corticosteroids on the eye.

Answer 27

- cataracts - glaucoma