Term
| What are the available types of drugs in the management of arthritis? |
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Definition
1) Analgesics (acetaminophen, ibuprofen, narcotics)
2) Anti-inflammatory (NSAIDs, corticosteroids
3) Biologic agents (anti-TNF, Anakinra (anti-IL1R), anti B-cell (Rituximab), anti T-cell (abatacept), anti-cytokines)
4) SAARDS or "remitting agents"- gold, penicillamine, anti-malarials, sulfasalazine, MTX, azathioprine, cyclosporine, alkylating agents
5) Combination therapy- SAARDs with anti-inflammatories and analgesics. |
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Term
| What are the functional/structural aspects of CS |
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Definition
"Cortisol" in humans
1) 21C steroids
2) C11-OH, C3-Ketone, C20, unsaturated C4-C5 (required for biological activity) |
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Term
| What is the basic physiology of cortisol (hydrocortisone) synthesis? |
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Definition
1) Made in the adrenal cortex and derived from hydroxylation of cortisone
2) Plasma cortisol maintained at 5-25 ug/ml by HPA axis |
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Term
| How does the HPA axis maintain cortisol levels? |
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Definition
1) Stress leads to CRH synthesis/release by hypothalamus (+) Anterior Pituitary to release ACTH and make corticotrophin
2) ACTH (+) the Adrenal Cortex to make cortisol and (-) to the Hypothalamus
3) Cortisol (-) to both the Anterior Pituitary and Hypothalamus.
90% of cortisol is bound to CBG and albumin, while 10% is biologically active (synthetic analogs are less bound and more diffuse) |
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Term
| What is the basic mechanism of action of CS? |
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Definition
1) Free cortisol (C) crosses cell membrane and binds receptors in cytoplasm
2) Receptor binding displaces HSP and causes confirmation change in receptor-C complex
3) C-receptor complex migrates to nucleus and binds reversibly to DNA sites, increasing certain gene transcription and inhibits others (TNF-a and ILs) |
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Term
| How does CS exert anti-inflammatory effects? |
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Definition
| CS increases lipcortin sythesis, which inhibits PLA-2, prevents cleavage of AA and subsequent Eicosanoid signalling. |
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Term
| How long does it take to detect CS effects? |
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Definition
| Most within 2 hours and some within 10 minutes! |
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Term
| What are the effects of CS on Innate/Acquired Immunity? |
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Definition
Inhibits phagocytosis of Ab-coated cells, causes neutrophilia and lymphopenia (T-cell)
1) CS (-) FcR expression, reducing clearing of Ab-coated cells in reticuloendothelial system (compromising phagocytosis!)
2) CS inhibits vascular permeability by inhibition of up-reguation of adhesion molecules such as ELAM-1 and ICAM-1 (this causes Neutrophilia)
3) CS causes lymphopenia (inhibits T cell activation (IL-2?), but B cells are resistant. |
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Term
| What are the differences between CS dosing regimens? |
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Definition
1) Alternate day is least effective but least toxic
2) Single daily
3) Divided daily (6-8 hours) is effective but toxic (most rapid inflammation control).
4) Pulse therapy- 1 gram methylprednisolone IV per day for 3 consecutive days per month (rapid effect in severe disease complications) |
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Term
| What are the clinical indications for CS use? |
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Definition
DON"T look at disease, look at symptom manifestation
Example, In RA and SLE, steroids are not good usually (low dose can be effective) |
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Term
| What are adverse effects of CS use? |
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Definition
1) affect many cell types
2) Dose- and time-dependent
3) Osteopenia- loss of trabecular bone through cecrased intestinal calcium absorption and increased urinary ecretion- can cause secondary hyperthyroidism.
4) Early/unavoidable (insomnia, irritability, weight gain)
5) Later- Cushingoid changes, HPA suppression, infection, myopathy, impaired wound healing
6)Common- hypertension, hyperglycemia, acne
7) Delayed- Osteoporosis, cataracts, atherosclerosis, growth retardation |
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Term
| How can CS use cause osteopenia? |
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Definition
Loss of trabecular bone
1) Decreased calcium intestinal absorption and increased urinary excretion
2) Leads to secondary hyperthyroidism |
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Term
| How can CS use cause HPA axis suppression? |
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Definition
Caused by daily administration of CS above basal level (18-25 mg cortisol/day)
1) The longer the duration and the higher the dose, the worse the suppression.
2) May need supplemental steroids during stress because of adrenal insufficiency. |
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