Pharm-RA-Corticosteroids Flashcards
What are the 4 Corticosteroids (CS’s) used in the Rx of RA?
- Dexamethasone
- Hydrocortisone
- Prednisone
- Triamcinolone
Characteristic ending of names of CS’s?
“-ONE”
If biologic therapies have proven to be so effective for Rx of RA, why do we not use just biologics? (2)
- Too EXPENSIVE currently
- They’re most justified/cost-effective/best in poor prognostic settings, but it is hard to tell early in RA is prognosis is good or bad
In what two general ways do glucocorticoids (GCs) help in the Rx of RA?
a. They suppress/relieve signs and symptoms rapidly
b. **THEY ALSO HAVE DISEASE-MODIFYING EFFECTS (at least early in RA, and possibly in later well-established disease)
What is the disease-modifying activity of GCs? Is it full or partial?
Inhibition of Erosion Progression (Joint-Sparing Effect on erosions with less impact on width), aka the slowing of joint damage.
However, the erosion inhibitory effect is ONLY PARTIAL; you have to combine with DMARD for control of radiographic joint damage.
(T/F) A pt who has discontinued GC therapy could continue to benefit from the GC disease-modifying effect?
TRUE: The disease modifying effect of GCs probably PERSISTS AFTER DISCONTINUATION of therapy!!! (radiographic joint damage does not show an accelerated rate of progression once GC Rx ends) THIS HAS NOT BEEN SHOWN W/ OTHER DMARD THERAPIES.
GC therapy has a place, even in tight control and treat to target strategy w/ MTX. Why? (3)
Pt’s receiving MTX+Prednisone showed significantly:
a. better clinical response
b. reduced joint pain
c. reduced need for additional biologic therapy
The risk of adverse effects of low-dose GC’s is often __________? Why?
Overestimated; Bias by indication→pt’s w/ severe ds are more likely to take GCs, and negative effects arising from RA/comorbidities may be attributed mistakenly to low-dose GC’s.
What additional effect makes GCs appropriate for the Rx of RA?
RA pt’s have insufficient endogenous cortisol production to counter the effects of pro-inflammatory cytokines, so low dose GC (prednisone) acts as CORTISOL REPLACEMENT THERAPY to redress this imbalance.
When and how are GCs administered most effectively for RA? Why is this?
A modified release formulation at BEDTIME b/c this adds a little GC to the natural CIRCADIAN cortisol secretion at NIGHT-TIME (it’s in accordance w/ physiological circadian rhythms). This prevents and may even reduce the HPA-axis suppression seen when GCs are taken conventionally in the morning.
How are the majority of GCs’ anti-inflammatory effects mediated?
The majority of anti-inflammatory effects occur via cytosolic GC receptors (cGCRs).
What do cGCRs do when activated by binding to GCs? (2)
- Upregulate (transactivation) or downregulate protein synthesis by binding to specific DNA-binding sites called GC-response elements (GRE).
- Negatively interfere with the function of transcription factors (TFs), such as NFkB, activator protein-1 (AP-1), and nuclear factor for activated T cells (NFAT) (TRANSREPRESSION), pathways that are essentially involved in the pathogenesis of RA.
What are the effects of transrepression of NFkB, AP-1, and NFAT pathways by GCs? (2)
- Reduced synthesis of pro-inflammatory cytokines→TNF-a, IL-1, IL-6
- Therefore, reduced production of receptor activator of NFkB ligand (RANKL), which finally supports the generation of osteoclasts, responsible for bone resorption and erosions in RA.
What additional type of effects do GCs have?
VERY RAPID/IMMEDIATE non-genomic immunosuppressive/anti-inflammatory actions:
They exert effects via rapid/immediate NON-genomic mechanisms, including action on Src and intercalation into plasma and mitochondrial membranes.
The pattern of GC ADEs is dependent on what?
dependent upon both cumulative and daily dose
T/F: The ADE profile differs b/t high dose and low dose?
True
Co-administration of GC with __________ increases the risk of ADEs?
DMARDs
T/F: Pt’s on low, medium, or high dose GC therapy should be monitored for ADEs?
False, not low dose. Only medium and high dose need to be monitored (intensely) due to increased risk of ADEs.
ADE for GCs? (4)
PICO!!!
- Peptic Ulcers
- Increased risk of Infections
- CV adverse effects→CAD, cerebral artery ds, sudden death
- Osteoporosis
T/F: Osteoporosis is an absolute CI for GCs?
False
How do you prevent osteoporosis (maintain bone density) in pt’s taking GCs?
Concurrent use BISPHOSPHONATE drugs (better at maintaining bone density/preventing vertebral fractures than Ca2+ or Vit. D supplements) together with adequate monitoring.
Concurrent use of NSAIDs with GCs increases the risk of what? How is this risk reduced? (3)
PUD; this risk can be reduced by:
a. Proton pump inhibitor (PPI; esomeprazole) or a PG analog (misoprostol) used concurrently w/ the NSAID
b. Use of the COX-2 specific inhibitor Celecoxib, is lower risk than non-specific NSAIDs
Why do GCs increase the risk of CV adverse effects? (2)`How do GCs increase this risk even further? (4)
a. RA pt’s are already at increased risk of CV events compared to general pop arising from a combination inflammatory process and dyslipidemia of RA itself with accelerated Atherosclerosis and ADEs of GCs, such as dyslipidemia and HTN.
b. Medium/high GCs cause lipid/endocrine problems that increase CV risk even further→adversely affect lipid profiles, blood glucose regulation, insulin production/resistance, and increase obesity
Before administering GCs, what 4 things need to be screened?
- Osteoporosis
- Fasting Blood Glc levels
- Presence of ankle edema
- Risk factors for glaucoma
