Pharmaco of Inflammation - Welsh 4/13/16 Flashcards
inflammation signs and symptoms
SHaRP
- swelling
- heat
- redness
- pain
how?
- vasodilation → increased blood flow to area → red/warm
- increased vessel permeability → plasma moves into interstitial tissues, edema
- pressure on nerves and infl chemicals → pain
infl response
- purpose
- 3 key processes
infl response serves to…
- prevent spread of pathogens
- minimize tissue damage
- promote repair/healing
3 key processes involved:
- vasodilation → increased blood flow
- increased cap permeability → plasma leakage into surrounding area → edema
- migration of neutrophils&leukocytes into area
infl response
cells that come through and what they do
1. neutrophils
- first WBCs to come to the site
- remove damaged tissue by phagocytosis
2. macrophages
- come a little later than neutrophils (after 1-2h on through next few days), and are more long-lived
- phagocytose pathogens and cellular debris
- engulf neutrophils during resolution of inflammation
3. mast cells
- mediate wound healing and defense against pathogens
- release histamine (vasodil), play key role in allergies/eczema/anaphylaxis
kinin cascade
involved in pain reception in inflammation
together, PG and bradykinin → stimulation of pain neurons
kinins cause vasodilation, increase vessel permeability, lower bp, stimulate pain receptors
- prostaglandins produced in massive amounts in infl response potentiate bradykinin action → amplify pain signal
- sometimes pain will continue long after infl (undesirable)
prostaglandins
nomenclature and classification
general features
originally found in prostate glands, but really found all over body
- all derivatives of arachidonic acid
- members of eicosanoid family (eicosa=20 → 20C molecules), which includes:
- prostaglandins (ex. PGE2)
- thromboxanes (ex. TXA2)
- leukotrienes
- *prostaglandins + thromboxanes collectively = prostanoids
general features
- work like hormones BUT work locally (versus systemically)
- same prostaglandin may behave diff in diff tissues of body
function of prostanoids
non inflammatory players
many fx unconnected with infl, such as…
- PGE2, PGF2alpha: promote gastric mucus secretion, prevent gastric acid secretion
[below, 2 molecules with offsetting effects…]
-
PGI2 aka prostacyclin: inhibits platelet aggregation, vasodil
- prevents clots!
- TXA2: promotes platelet aggregation, vasoconst
[implication: need a BALANCE of these two!]
function of prostanoids
inflammatory mediates
main player: PGE2, produced by mast cells and macrophages
- vasodilation
- increased vasc permeability
- pain reception
- increased sensitivity of pain receptors to bradykinin
- pain neuromodulation: enhances sensation of pain in dorsal horn of spinal cord
- pyresis (fever)
biosynthesis of PGE2
PGE2 major inflammatory prostanoid
synthesized from arachidonic acid in mast cells and macrophages at site of injury
key step: upregulation of cyclo-oxygenase 2 [COX2]
- induced by inflammation in mast cells/macrophages
compare/contrast COX2 with…COX1
- expressed constitutively in most cells of body
- produces PGs involved in housekeeping fx, maintaining homeostasis
prostaglandin synthesis: big picture
membrane PL → arachidonic acid [phospholipase] → cyclic endoperoxides [COX1 or COX2] → prostaglandins [prostaglandin synthases]
NSAIDs
effects
examples
Non-Steroidal Anti-Inflammatory Drugs
mechanism: inhibition of COX2
effects:
-
analgesic (pain-killing)
- reduction in swelling/edema (counters dull pain)
- reduction in bradykinin-induced pain
- reduction in allodynia (hyper-tenderness)
- antipyretic (fever-reducing)
- in high doses, anti-inflammatory effects
- reduce production of PGE2
- analgesic effects occur faster than anti-infl effects
- anti-aggregates (inhibit platelet production)
ex. aspirin, ibuprofen, indomethacin, naproxen, diclofenac
NSAID side effects:
- how do they occur
- common side effect
- contraindications
COX1 and COX2 are isozymes: v similar structures
-
drugs targeting COX2 often bind and cross-react with COX1
ie. while NSAIDs can drop inflammatory PGE2 levels → anti-infl effect…
NSAIDs can also affect COX1-mediated non-infl housekeeping effects of prostaglandins
- ex. reduction in PGE2/PGF2alpha that promote gastric mucus secretion to protect stomach → GI upset
contraindicated in: pt with peptic ulcer, hypersensitivity to aspirin, coag defects, severe heart failure, etc
aspirin-induced asthma
mechanism
aspirin is an NSAID : blocks COX2 mediated rxn by which arachidonic acid → PGE2
- now you have a backlog of arachidonic acid, which is shunted into alt pathway: 5-lipoxygenase pathway
arachidonic acid → 5HPETE → leukotrienes [5-lipoxygenase]
- LTC4, LTD4, LTE4 are major players in pathways associated with inflammatory and immune response (allergic rxn, anaphylactic shock)
aspirin as NSAID
- modern use and why
- unique mech
among oldest, but now less popular due to GI symptoms and Reye’s syndrome
today: more popular as anti-platelet drug for CAD patients at risk for thrombosis
- inhibits TXA2 production in platelets → reduces ability to coagulate with fibrin
- lower doses can be used to avoid GI upset
unique mechanism (among NSAIDS): irreversible covalent binding to active site of platelet COX1 and COX2 → long lasting effect!
- since platelets are anuclear (no nucleus, no transc/transl to make new proteins…), only way around it is to make NEW proteins!
COX2-selective inhibitors
why?
why not?
if you could selectively inhibit COX2, you could…
- downreg inflamatory PGE2 → get analgesic, anti-infl effects
AND
- NOT affect COX1-derived housekeeping PGE2, PGF2alpha in gut → not get GI side effects
didn’t work out too well…
- Vioxx and other COX2-selective drugs led to increased risk of CV events → too great a shift in PGI2/TXA2 balance towards vasoconst/aggregation
low dose aspirin and CHD
beneficial for preventing CHD
- inhibits both COX1 and COX2 → blocks synthesis of TXA2, but not really of PGI2
- net result: reduced platelet aggregation
summary of major effects of:
non-selective NSAIDs
COX2-selective NSAIDs
baby aspirin
- inflammation, GI tract, CV effect
