Term
| How do you treat an elderly patient with prior hx of bleeding GI ulcers caused by NSAIDs? (1, 2a/b) |
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Definition
1. Let the ulcer heal
2a. Diclofenac/misoprostol alone OR misoprostol + NSAID
2b. If the patient can't tolerate the misoprostol + NSAID because of misoprostol's S/E then:
-NSAID + proton-pump inhibitor (suppressed acid secretion risks C. diff diarrhea/recurrent infections)
-NSAID + H2-histamine-R antagonist (increased stomach pH predisposes to C. diff diarrhea)
-Celecoxib (can still cause GI ulceration) |
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Term
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Definition
| Biologic disease-modifying anti-rheumatic drugs, meaning monoclonal Ab for the treatment of RA |
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Term
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Definition
abatacept
anakinra
etanercept
infliximab |
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Term
| DMARDs that are TNF antagonists (2) |
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Definition
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Term
| DMARD that's a T-cell co-stimulatory blocker |
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Definition
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Term
| DMARD that's an IL1-R antagonist |
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Definition
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Term
| Where does TNF come from in RA and what does it do? |
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Definition
TNF is produced by synovial macrophages/lymphocytes
TNF mediates the destruction of cartilage and bone |
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Term
| TNF antagonist (etanercept, infliximab) physiological effects (3) |
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Definition
Decrease symptoms of RA
Improve quality of life
Slow radiographic damage |
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Term
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Definition
Recombinant protein that links the human gene for TNF-R with the one for IgG-Fc
Etanercept binds TNF and thereby clears it from the system
There is decreased function of macrophages and T-cells |
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Term
| Etanercept, infliximab: S/E (2) |
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Definition
Increased risk of infection
Reactivation of latent TB
Etanercept only: transient neutropenia |
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Term
| Infliximab: indications other than RA (3) |
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Definition
Psoriatic arthritis
Ankylosing spondylitis
Crohn's disease |
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Term
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Definition
Binds to APC CD80/86
Prevents the co-stimulation of T-cell CD28
The T-cell can't activate |
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Term
| Why would you give a patient abatacept versus the other DMARDs? |
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Definition
| Give abatacept to treat RA when everything else has failed |
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Term
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Definition
| Increased risk of infection |
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Term
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Definition
Anakinra is an altered IL1 that has no intrinsic activity
Anakinra binds to the IL1-R and thereby prevents the binding of endogenous IL1 |
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Term
| Gout therapy is aimed at... (3) |
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Definition
Suppression of leukocyte activation (colchicine, indomethacin)
Increasing renal excretion of urate (aspirin, probenecid)
Decreasing urate production (allopurinol, febuxostat) |
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Term
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Definition
allopurinol
colchicine
febuxostat
indomethacin
probenecid |
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Term
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Definition
Colchicine binds to intracellular tubulin
Prevents microtubule polymerization
Leukocytes can't migrate or phagocytize |
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Term
| Colchicine: indications (2) |
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Definition
Acute attacks of gout
Prophylaxis for recurrent gout when uricosuric drug + allopurinol treatment has failed |
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Term
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Definition
Diarrhea, ab pain, myopathy
Alopecia, bone marrow suppression |
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Term
| Why would you use indomethacin for acute attacks of gout instead of colchicine? |
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Definition
Indomethacin has fewer S/E (namely no diarrhea)
Indomethacin is also analgesic, anti-inflamm |
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Term
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Definition
Indomethacin inhibits the synthesis of PG and other inflammatory mediators
Macrophages, synoviocytes can't phagocytize the urate crystals |
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Term
| Indomethacin: indications (2) |
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Definition
Initial therapy for acute gout
Alternative to colchicine for acute gout |
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Term
| Describe how uric acid moves through the nephron |
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Definition
Freely filtered
Completely reabsorbed
Secreted by acid transport in PT
-This isn't affected by renal failure unless GFR < 15ml/min |
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Term
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Definition
Decrease net reabsorption of uric acid thereby increasing the renal clearance of urate
Even though plasma urate may not fall, the urate pool is depleted |
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Term
| Uricosuric drugs, allopurinol, febuxostat: physiological effects |
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Definition
Reabsorb tophaceous urate deposits
Joint inflammation remits and bone re-mineralizes
Allopurinol, febuxostat only: decreases plasma urate without increasing renal excretion of uric acid |
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Term
| Uricosuric drugs: indications (3) |
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Definition
After several acute attacks (start therapy 2-3 weeks later)
If tophi appear
If plasma urate is greatly elevated |
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Term
| Allopurinol, febuxostat: MOA |
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Definition
Inhibit xanthine oxidase
Hypoxanthine/xanthine are not converted to uric acid
Plasma urate decreases and the urate pool is depleted, but hypoxanthine/xanthine concentrations increase |
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Term
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Definition
Renal stones may form as urinary urate concentration increases
-Can be avoided by alkalinizing urine with Na-bicarb, Na/K-citrate, acetazolamide |
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Term
| Allopurinol, febuxostat: indications (4) |
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Definition
Patients with poor renal function
Grossly-elevated plasma uric acid
Chronic tophaceous gout, recurrent urate stones |
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Term
| Allopurinol, febuxostat: S/E |
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Definition
May have acute attacks soon after therapy is begun
-Avoided with uricosuric drug or colchicine
Decrease clearance of theophylline |
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Term
| Why would you use febuxostat over allopurinol? (3) |
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Definition
Febuxostat is more effective
-Some patients who didn't respond to allopurinol actually responded to febuxostat
Long-term treatment with febuxostat decreased gout flares, size/number of tophi
But it costs way more than allopurinol! |
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Term
| For acute attacks of gout you would use... (2) |
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Definition
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Term
| For chronic gout prophylaxis you would use... (2) |
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Definition
| Uricosuric drugs and/or xanthine oxidase inhibitors |
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Term
| Misoprostol is a stable analog of ___ |
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Definition
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Term
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Definition
Inhibit prostaglandin synthetase/COX
This prevents the synthesis of all PG but doesn't affect the synthesis of LT |
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Term
| What's different about aspirin wrt the other NSAIDs? |
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Definition
Aspirin (ASA) is an irreversible inhibitor of COX
-But most of this is actually converted to the reversible inhibitor salicylate during first-pass metab
All of the other NSAIDs are reversible inhibitors of COX |
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Term
Small doses of NSAIDs block ___.
Large doses of NSAIDs are needed to ___. |
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Definition
Block COX (small doses)
Anti-inflamm effect (large doses) |
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Term
| NSAIDs: physiological effects (6) |
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Definition
Anti-inflamm
Antipyretic
Anti-platelet
Analgesic
Chondro-protective
Equally efficacious in tx of OA |
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Term
| NSAID anti-inflammatory effects: physiology (6) |
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Definition
Decrease synthesis of PG
Inhibit granulocyte adherence to damaged vessels
Inhibit migration of PMNLs and macro
Inhibit phagocytosis of urate crystals by synoviocytes and maco
Indirectly interfere with kinin synthesis
Stabilize lysosomes |
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Term
| NSAID chondro-protective effects: physiology |
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Definition
Inflammatory mediators stimulate increased production of stromelysin/collagenase by chondrocytes in arthritis
NSAIDs prevent this increased production
This protects cartilage from breakdown |
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Term
| Large daily doses of aspirin exhibit... |
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Definition
| Non-linear kinetics = increased t1/2 |
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Term
| Non-salicylate NSAIDs (3) |
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Definition
Diclofenac
Indomethacin
Oxaprozin |
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Term
| Diclofenac: properties (2) |
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Definition
Relatively selective for COX2
Some ability to inhibit lipoxygenase |
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Term
| Indomethacin: properties (2), S/E (1) |
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Definition
Some ability to inhibit lipoxygenase
Pharm properties unrelated to the inhibition of PG synthesis
High incidence of CNS issues, especially in elderly |
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Term
| Celecoxib: MOA, physiological effects (2), indications (2) |
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Definition
COX2 inhibitor
No effect on platelet aggregation/BT
Doesn't interfere with aspirin's antiplatelet effect
Treat OA, RA, primary dysmenorrhea, post-op pain
Prevent colorectal cancer and Alzheimer's? |
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Term
| Celecoxib: pharmacokinetics |
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Definition
Little/no first pass metabolism = good F
Highly bound to plasma albumin = small Vd
Low hepatic clearance (mostly cleared by kidneys)
Concentration in synovial fluid is 60% of plasma concentration (transfer from blood to synovium is slow, though) |
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Term
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Definition
Short: diclofenac, indomethacin, salicylate
Intermediate: celecoxib
Long: oxaprozin, salicylate |
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Term
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Definition
Antipyresis
Analgesia (peripheral inhibition of PG synthesis in inflamed tissue)
OA, RA, ankylosing spondylitis (diclofenac, indomethacin only)
Decrease number of colorectal polyps in patients with familial adenomatous polyps
Aspirin only: reduce risk of colorectal cancer by 40-50% |
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Term
| Aspirin hypersensitivity: pathophysiology, associations |
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Definition
Increase LT synthesis causes anaphylactic-like reaction
Within 3 hours of ingestion
-Rhinoconjunctivitis
-Angioedema
-Urticaria
-Asthma with laryngeal stridor (severe cases)
Will show the same adverse reaction when treated with any NSAID (except tylenol, selective COX2 inhibitors)
Associated with nasal polyps, adult onset asthma |
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Term
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Definition
Aspirin hypersensitivity
Increased BP
Decreased renal function
Renal interstitial nephritis
GI ulceration and bleeding
CNS reactions |
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Term
| NSAIDs increased BP effect: pathophysiology |
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Definition
Sympathetic fibers terminating on arterioles release NE, which stimulates vascular adventitial a1R to activate PLA2
PLA2 makes PG, which normally acts
-prejunctionally to inhibit the release of NE
-postjunctionally as VD to counteract NE VC
Inhibition of PG by aspirin allows the full expression of NE's VC properties
This VC also affects renal arterioles, which decreases GFR and RBF
PGs are also responsible for inhibiting ADH-stimulated adenyl cyclase in the CD
Inhibition of PG synthesis allows the ADH to fully express itself
Salt, water retention occur
Can lead to hyponatremia especially if concurrently treated with HCTZ
NSAIDs also interfere with anti-HTN effects of B-blockers, thiazides, ACEI (but this isn't a contraindication for the use of NSAIDs in patients with arthritis) |
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Term
| NSAIDs decreased renal function effect: pathophysiology |
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Definition
This happens in patients who depend on renally-synthesized PG to maintain RBF
Predisposed:
-CHF, CV disease treated with diuretics
-Chronic renal failure (S-Cr >2 mg/dl)
-Hypovolemia
->60yo |
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Term
| NSAIDs renal interstitial nephritis: symptoms (3) |
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Definition
flank pain
hematuria
proteinuria |
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Term
| NSAIDs GI ulceration and bleeding: pathophysiology |
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Definition
Stomach PG normally
-inhibits acid secretion
-stimulates mucus secretion
-stimulates bicarb production
-stimulates cell growth, repair
-increases mucosal blood flow
Predisposed:
-prior hx of peptic ulcer, NSAID intolerance
-EtOH abuse
-corticosteroids
-cigarette smoking
->60yo |
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Term
| Incidence of gastric ulceration with bleeding during treatment with non-selective NSAIDs |
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Definition
2-4% over the course of a year
But risk increase 10x if the patient has a prior hx of GI bleeding |
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Term
| Do nausea, dyspepsia, ab pain indicate GI ulceration during therapy with NSAIDs? |
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Definition
No, because people can have these symptoms but only a fraction have actual ulceration
And some older patients have bleeding but no symptoms! |
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Term
| NSAIDs CNS effects: symptoms (3) |
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Definition
Headache
Dizziness
Tinnitus |
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