NSAIDs & Non-Opioid Analgesics (Exam V) Flashcards
What is the cause of chronic inflammation?
WBC infiltration of the tissue in response to acute inflammation.
What inflammatory mediators, released by WBCs, are involved in a chronic inflammatory response?
- Interleukins
- GM
- TNF
what is GM
What is the most important autocoid involved in acute inflammation?
Prostaglandin
What is the main pathway target when using NSAIDs?
What is the secondary pathway?
- COX pathway
- LOX pathway
Differentiate COX-1 & COX-2.
COX1 - Constitutive “always on”
COX2 - Stimulus dependent, inflammatory response.
How does COX inhibition lead to gastric irritation?
COX1 inhibition = less constitutive PG synthesis = less gastric mucus production.
What portion of the aspirin molecule binds to COX-1?
Where does it bind to?
Is this reversible?
- Acetyl group
- Serine group of COX1 molecule
- The binding is irreversible.
How metabolized in aspirin?
Very metabolized
- Phase I by CYP450s
- Phase II by UGTs
How do NSAIDs treat headaches?
- Decrease sensitivity of brain vessels to bradykinin & histamine = CNS vasoconstriction.
Which NSAID irreversibly blocks COX-1, thus preventing platelet aggregation?
How long will this platelet inhibition last?
- Aspirin
- 8-10 days (the lifespan of the platelet)
Which NSAID is COX-1 selective?
Which NSAID is COX-2 selective?
- Aspirin
- Celecoxib
Which NSAIDs block COX-1 & COX-2 with equal efficacy?
- Ibuprofen
- Toradol
- Meclofenamate
Which NSAIDs are both COX & LOX inhibitors?
- Indomethacin
- Diclofenac
What are the three areas of toxicity/irritation seen with NSAID use?
- Gastric irritation (variable)
- Nephrotoxicity
- Hepatotoxicity
How was aspirin extracted prior to modern medicine?
- Willow Bark extraction
How does aspirin treat fevers?
- Direct peripheral vasodilation
What is the primary use of aspirin?
- Clot prevention (81-325mg day)
What cancer has aspirin recently been show to decrease incidence of?
- Colon cancer
What is the primary adverse effect of aspirin?
Why does this occur?
- GI upset
- Weak acid so it upsets stomach, & inhibition of PG mucus production.
What is the benefit of enteric coated aspirin?
How would this affect PG inhibition?
- Skips weak acid effects upsetting stomach.
- PG still inhibited.
What can occur with chronic use of COX-2 selective agents?
- Thrombosis from ↑ PLT aggregation
How can prostaglandin inhibition affect pregnancy (specifically labor) ?
- PG’s needed for labor (NSAIDs bad for pregnancy)
Why is aspirin not given to children (especially after a viral illness)?
- Reye Syndrome (hepatic injury & encephalopathy)
What things are given for aspirin toxicity?
- Activated Charcoal
- Bicarb & IV fluids
- Dialysis
What symptom are hallmarks of moderate salicylate poisoning?
- Tinnitus & fever
What are the uses of Celecoxib?
What allergy would preclude the use of celecoxib?
How expensive is celecoxib?
- Rheumatoid/Osteo arthritis & ulcer reduction
- Sulfonamide allergy
- Very expensive
Adverse cardiovascular events are related to all NSAIDs except ________.
aspirin
What black box warning exists for celecoxib?
- Cardiovascular events due to PGI₂ inhibition (PGI₂ decreases plt aggregation)
What drug can be given with Diclofenac to decrease its adverse GI effect profile?
Why is this?
- Misoprostol (Cytotec)
- Misoprostol is a synthetic PG
What rare adverse effects can occur from chronic, high doses of ibuprofen?
- Agranulocytosis
- Aplastic Anemia
What are Indomethacin’s uses?
- Patent Ductus Arteriosus (PDA)
- Rheumatism
- Gout
What might indomethacin inhibit in addition to COX?
What would be the result of this?
- Phospholipase A & C
- ↓ WBC
What is PDA (Patent Ductus Arteriosus)?
What drug could be used for his prior to surgery?
Why?
- Shunt between Aorta & pulmonary veins in fetu.
- Indomethacin
- PG keep the shunt open; PG inhibition should close it.
What NSAID is a potent pain reliever used in a lot of sports medicine programs?
Can this NSAID help lower opioid usage?
- Toradol (Ketorolac)
- Yes, 25-50% reduction in opioid usage.
What is Acetaminophen’s mechanism of action?
Does acetaminophen have antiinflammatory properties?
- COX-2 inhibition (primarily CNS) pain signaling.
- No anti-inflammatory effects.
Fatal doses of acetaminophen are associated with failure of what organs?
- Liver (hepatotoxicity)
- Kidney (acute renal tubular necrosis)
What is the primary path of metabolism of acetaminophen?
How is it metabolized with higher doses?
- Phase II primarily
- Switches to Phase I with higher doses.
When would the selection of COX-2 selective drug make the most sense?
- When the patient is at high risk for GI bleeds.
What is the primary short-term use of glucocorticoid?
- Suppression of Inflammation
What are the adverse effects of chronic glucocorticoid usage?
- Immunosuppression
- DM, obesity, muscle wasting
- Depression
- HTN
What is the general mechanism of action of glucocorticoids in regards to blocking the immune response?
- Inhibition of immune response by blocking transcription/translation.
Glucocorticoids upregulate Annexin-1; what does Annexin-1 do?
- Phospholipase A2 suppression (↓ AA)
- ↓ WBCs
What three molecules increase due to translation when glucocorticoids are administered?
- Annexin-1
- Secretory Leukoprotease Inhibitors
- IL-10 (immunosuppressant)
What inflammatory cytokine is inhibited by glucocorticoids?
NFkappaB
What two primary indications for glucocorticoids were discussed in lecture?
- Inflammation suppression
- Fetal Lung Maturation (↑ surfactant production)
What are immune complexes?
What disease do these occur in? Explain the sequence for immune complex formation.
Where do these immune complexes end up at?
- Chains of antibodies strung together
- Rheumatoid Arthritis. Rheumatoid antibodies are created & bind to “good” antibodies creating immune complexes.
- Joints (WBCs follow)
What lab tests measure Rheumatoid Arthritis?
- Sed rate
- C-Reactive Protein
- Rheumatoid Factor (measures immune complexes)
Non-biologic DMARDs (disease-modifying anti-rheumatic drugs) are useful for what?
Name the three mentioned in lecture.
- Immunosuppression (non-specific)
1. Methotrexate (anticancer, ↓ dose for RA)
2. Cyclophosphamide
3. Cyclosporine
Biologic DMARDs (disease-modifying anti-rheumatic drugs) are different from non-biologics how?
- Very specific (block specific things in inflammation response)
