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35 Cards in this Set
- Front
- Back
Acute inflammation
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The topic of this lecture
Precedes immune response and is mediated by release of autocoids (histamine, serotonin, bradykinin, PGs, LTs) |
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Quickly review chart on slide 2
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adf
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Formation of PGs and Thromboxanes
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Membrane phospholipids to arachidonic acid via phospholipase A2. Then AAcid can go to LTs via lipoxygenase or PGs and thromboxanes via Cox-1 and Cox-2
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Cox-1 effects
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PGE2, I2 and thromboxane A2
GI protection, platelet function, regulation of blood flow, kidney function. |
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Cox-2 effects
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PGE2, I2 and thromboxane A2
Inflammation, pain and fever. Potently expressed and comes up really high very quickly in response to things. |
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PGG2
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This is a precursor prostaglandin that is then turned into PGH2 which is then turned into J2, I2 or thromboxanes.
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COX and GI protection
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Dyspepsia occurs because PGE2 and I2 normally inhibits proton pumps in the gut.
Mainly COX-1 inhibition leads to GI toxicity. Avoid these effects with PPIs. |
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COX and platelet effects
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Only COX-1 is present in platelets. No COX-2.
COX-1 makes thromboxane A2 which initiates clotting. Note that aspiriin irrev blocks platelets because it forms a covalent bond with COX1. So using a COX-2 selective NSAID won't effect platelets. |
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COX and renal effects
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COX1 - renal hemodynamics and GFR effects
COX2 - salt and water excretion (inflamm response) Less E2 leads to sodium retention, HTN, water retention (high weight) and CHF. Less I2 leads to hyperkalemia and acute renal failure. |
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Inflammation process
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Leukocytes makes PGE2 which causes pain and vasodilation (redness, warmth, swelling)
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Pain process
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E2 does this.
E2 is constit synth by COX-1 and during acute inflamm COX-2 makes it as well. |
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Fever process
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PG E2 and I2 - that's all we really know.
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COX continuum
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On the physiology side is COX-1 (ubiquitously expressed)
COX-2 is more inflammation and acute. |
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Common themes for NSAIDs
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Time-dependent and reversible (other than aspirin) of the active site of COX.
Comp inhibit arachidonic acid from binding COX. Most do not inhibit LT synthesis and can cause a type of anaphylaxis where more products are shunted to make leukotrienes. (this is different from actual NSAID allergy). |
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Main difference between the NSAID agents
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The COX-1:2 selectivity ratio.
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Ketorolac
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NSAID for IV and IM
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Indomethacin
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For injection close to ductus arteriosus in neonates. (will close it).
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4 major uses of NSAIDs
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antipyretic (less PGE2 and IL-1)
Anti-inflammatory (COX inhibition and salicylates scavenge ROS) Antithrombotic (inhib COX in platelets and endothelium) Analgesic (less PGE2) |
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Pharmacokin
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Well abs
Metab vy CYP3A or 2C amt of biliary excretion and reabs correlates with degree of lower GI irritation. Renal excretion. |
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Toxicity
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safe for the most part.
GI toxicity, inc bleeding, CNS toxicity... CONTRAINDICATED IN THIRD TRIMESTER OF PREG (inhibiting PGE2 and I2 will close DA) - but this is really just a guideline. |
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Diff with acetominophen in indications?
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yes
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Drug interactions
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Reduces effectiveness of diuretics and antiHTN drugs.
Cimetidine makes them be metabolized quicker. (so use famotidine H2 blockers instead) Steroids - has tons of interactions in general. Just know that NSAIDs induce CYP3A and 2C |
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COX-2 selectives
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May be good for cancer chemo (stops the stromal inflammation which is carcinogenic)
They don't block platelets and they do block prostacyclin (so it is thrombogenic) Prostacyclin relaxes BVs and prevents sites of platelet clumping from forming. Same amt of renal complications compared to non-selectives. |
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Acetominophen and COX
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doesn't inhiibit it
Not very good for stopping inflammation. Depletes glutathione which is hepatotoxic (so don't have this with alcohol) |
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Ethanol and smoking on gut
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irritates it and enhances NSAID GI toxicity.
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When to use indomethacin (indol and indende acetic acid)
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Accel closure of patent DA
Tx of rheumatoid and osteoarthritis. Oral, rectal or IV. |
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When to use ibuprofen (arylproprionic acid)
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RA, OA and dysmenorrhea.
Half-life prolonged in pts with cirrhosis. |
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Diclofenac (heteroaryl acetic acid)
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rapid release (pain and dysmen) or delayed release (RA, OA or ankylosing spond)
Ophthalmic activity. but does not affect intraocular pressure. ***dikes go both ways |
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Salicylic acid deriv (aspirin)
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irrev cox inhib.
reduces risk of CV events adn colorectal cancer. |
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para-aminophenol deriv (acetaminophen)
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fewer GI and renal side effects than NSAIDs.
used during preg and breast feeding if benefit to mother outweight risks to fetus/infant. |
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anthranilic acids (meclofenamate)
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contraind in pts with gi or renal issues.
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enolic acids (piroxicam)
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long half life.
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Alkanones (nabumetone)
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prodrug
cox-2 selective at low doses. long half-life **picture mbNABb a PROfessional throwing down the cox-2 pathway |
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cox-2 selective (celecoxib)
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less gastropathy and risk of GI bleeding.
adjuvant in pts with familial adenomatous polyposis. |
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combo preparations
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combine opioid with aspirin or acetaminophen.
caffeine can enhance the analgesic actions of NSAIDs or aceteminophen. |