Anti-inflammation Pharm Flashcards
2 main actions of corticosteroids
- prevent conversion of membrane phospholipids to arachidonic acid
- prevent induction of COX2 synthesize to result in pain, inflammation and fever
describe GI effects of COX inhibitors
PGE2 and PGI2 are produced in gut epithelia by COX1
act through G-protein coupled receptors -> limits activity of proton pump in the gut
COX1 inhibition –> proton pump uninhibited –> high acidity in the stomach –> dyspepsia
describe platelet effects of COX inhibitors
COX1 mediates production of thromboxane A2 to initiate clotting reaction. Inhibit COX1 --> limit clotting and promote bleeding Aspirin permanently (irreversibly) inactive platelets
describe renal effects of COX inhibition
COX1 controls renal hemodynamics and GFR
COX2 effects salt and water excretion (blocks it in dehydration)
inhibit COX –> decreased PGE2 –> sodium retention, increased BP, increased weight
inhibit COX –> decreased PGI2 –> hyperkalemia and acute renal failure
describe NSAID mech of preventing inflammation
leukocytes produce PGE2 –> vasodilation and pain –> redness & warmth, increased fluid transudation across leaky capillary beds, swelling
NSAIDS block PGE2 production
describe NSAID mech of preventing pain
PGE2 (synth by COX-1 constitutively) causes pain in acute inflammation
in acute inflammation, COX-2 expression increases –> increase in PGE2 production
describe NSAID mech of preventing fever
Prostaglandin @ hypothalamus mediates fever (mech unknown)
NSAIDs in 3rd trimester of pregnancy
prostaglandins maintain ductus arteriosus in open state
avoid prolonged use of NSAIDs in 3rd trimester –> avoid premature ductus closure
indomethacin: approved to close patent ductus
factors leading to CV risk in COX2 inhibitors
COX2 –> prostacyclin
Prostacyclin action: 1. vasodilation, 2. blocks production of adhesion molecules for platelet clumping
Platelets only have COX1, so COX2 inhibitors DO NOT block thrombosis
–> platelets can still initiate thrombosis + aggregate in constricted vasculature
what cells are involved in chronic inflammation?
neutrophil polymorphs
what cells are involved in chronic inflammation?
mixed inflammatory cell infiltrate - macrophages, lymphocytes, plasma cells
(minor components are neutrophils and eosinophils)
can get lymphoid cells and follicles
what is the key step in initiation of chronic inflammation?
migration of cells to the site of inflammation. involves leukotriene-mediated chemotaxis.
describe the 4 steps of chronic
- migration of cells to site of inflammation
- macrophages accumulate at site of inflammation at 24 hrs
- macrophage activation –> production of mediators ( IL1, TNFalpha, PGDF, FGF, CSF)
- T-lymphocytes and B-cells migrate to the site after macrophages
3 strategies to combat chronic inflammation
- chemo ablation of immune modulatory cells: DMARDs
- suppress cytokine and immune cell activity: corticosteroids
- disruption of cytokine activity: anti-TNFalpha biologics
methotrexate
inhibits folate metabolism –> decreased DNA synth
onset of action 3-6 weeks
leflunomide
inhibits dihydroorotate dehydrogenase –> blocks pyrimidine biosynthesis
prevents histamine release and COX-2 expression
prodrug
hepatic toxicity more common than methotrexate
sulfasalazine
mesalamine: COX2 inhibition + inhibits leuktriene synth
sulfapyridine: free oxygen radical scavenger –> reduces tissue damage and blocks immune signaling
prodrug metabolized by colonic bacteria (less GI SEs)
More toxicity than methotrexate and leflunomide
important biologic activity of TNFalpha
increased expression and release of extracellular proteases that mediate tissue destruction and remodeling –> high degree of long-term suffering and debilitation in RA pts
infliximab
“humanized” mouse monoclonal antibody directed against TNF alpha
adalimumab
recombinant human anti-TNF-alpha antibody
enbrel
recombinant fusion protein consisting of two TNF-receptor moieties linked to Fc portion of human IgG
