NSAIDs Flashcards
NSAID
-most commonly used analgesic in vet med - anti-inflammatory and analgesics - chemically diverse most are weak acids there are some non- acidic NSAIDs - NSAIDs= COX inhibitors
corticosteroids block
arachadonic acid production bc they are inhibitors of PLA2 (phospholipase A2) which is responsible for hydrolysis of phospholipids -> arachadonic acid which leads to diverse range of adverse effects as well as beneficial anti-inflammatory effects bc arachadnonic acid is precursor for multiple signaling molecules (EETs, LTs, LXs, PGH2)
NSAIDs fx by
mostly by inhibiting cyclooxyrgenase (COX) (not aspirin or grape-rant) - inhibit COX enzymes by competing with arachadonic acid binding
COX
converts arachadonic acid into prostaglandin H2 (PGH2) a precursor for signaling prostaglandins including - prostaglandin E2 (PGE2) - thromboxane A2 (TXA2) - prostacyclin (PGI2)
prostaglandins promote
redness, swelling, pain, hypalgesia (ie inflammation) so NSAIDs are considered antiinflamtory drugs as well as analgesics
acidic NSAIDs
- salicylates (aspirin) - propionates (carprophen) - acetats (indomethacin) - enolates (meloxicam and piroxicam) -pyridinemonocarboxylic acid (flunixin) - robenacoxib (cox2 specific inhibitor)
non acidic nsaids
- mavacoxib= COX2 specific inhibitor
NSAID that is not COX inhibitor
Grapiprant (galliparant); works by inhibiting EP4 prostaglandin receptor by competing with PGE2
How does aspirin work
covalently and irreversibly modifieds COX by acetylation of hydroxyl group of serine residue in arachadonic acid binding pocket - this acetylation inhibits cyclooxygenatse activity of COX-1 and converts COX-2 enzyme activity from cycloxygenase to lipoxygenase
arachadonic acid signaling
- arachadonic acid produced through hydrolysis of phospholipids by phosholipase A2 (PLA2) -> 2. AA catalyzed into 3 classes signaling molecules by COXs: - epoxyeicosatrienoic acids (EETs) - Leukotrienes (LTs)/ Lipoxins (LXs) - PGH2
epoxyeicosatrienoic acids (EETs)
EETs plays important role in - anti-inflammatory -pro-fibrinolytic effects - vasorelaxation
Leukotrienes (LTs)/ Lipoxins (LXs)
LTs, LXs play important role in: - inflammation - bronchoconstrictoin
cyclooxygenases are
-targets of NSAIDs - bifunctional enzymes that catalyze prostanoid (bioactive oxygenated C18-C22 compounds) biosynthesis
heme-dependent COX reaction
converts AA to PGG2 and subsequent peroxidase (POX) reaction reduces 15-hydroperoxide of PGG2 to form PGH2
COX isoforms
- COX-1 and COX-2 -membrane bound and are present on luminal surfaces of ER and inner and outer membranes of nuclear envoelpe
COX-1 vs COX-2
-COX-1 widely distributed and constitutively expressed in most tissues; this enzyme provides prostaglandins (PGs) required for homeostatic fxs including mucosal defense (PGE2), renal perfusion (PGE2 and PGI2) and platelet aggregation (TXA2) - COX-2 expression level dramatically increase upon inflammation or tumorigenesis
contributors to auto regulatory and homeostatic prostanoids
both COX1 and COX2 contribute to this
differences between classical NSAIDs and COX-2 inhibitors arise
in part from slight differences in amino acids surrounding active sites of COX-1 and COX-2
Prostaglandin production
-PGH2 produced by COXs and processed into other prostanoids (PGs and thromboxane A2) by series of specific isomerase and synthase enzymes - 4 principal bioactive prostaglandins generated in vivo= prostaglandin E2 (PGE2), prostaglandin I2 (PGI2; prostacyclin), prostaglandin D2 (PGD2), and prostaglandin F2alpha (PGF2alpha)
Prostaglandins play key role in
generation of inflammatory response; their biosynthesis is increased in inflamed tissue and contribute to development of cardinal signs of acute inflammation
PGs exert their effects by
activating specific G protein-coupled receptors
Prostaglandin E2
- PGE2 - most abundant PGs exhibit versatile biological activities
PGE2 fx
- under physiological conditions important mediator of many biological functions like -regulation of immune responses -blood pressure -GI integrity - fertility - involved in all processes leading ot classical signs of inflamation
redness and edema PGE2
redness and edema result from increased blood flow into inflamed tissue through PGE2 mediated augmentation arterial dilation and increased microvascular permeability
pain PGE2
pain results from PGE2 action on peripheral sensory neurons and on central sites w/ in spinal cord and brain
how does PGE2 get to site of action
PGE2 actively transported through membrane by transporter or diffuses across plasma membrane to act at or near site of secretion
PGI2 function
- potent vasodilator - inhibitor of platelet aggergation - leukocyte adhesion - VSMC proliferation - PGI2 important mediator of edema and pain that accompany acute inflammation
PGD2 synthesized in
CNS and peripheral tissue
PGD2 function
- inflammatory and homeostatic capacity - in brain PGD2 involved in regulation of sleep and other central nervous system activities like pain perception - in peripheral tissues PGD2 mainly produced by mast cells but also by leukocytes like DCs and Th2 cells
PGF2alpha
- derived mainly from COX-1 in female repro system - ovulation, luteolysis, contraction uterine smooth muscle, initiation parturition, renal function, contraction arteries, myocardial dysfunction, brain injury, and pain - administration PGF2alpha leads to acute inflammation NSAIDs inhibit its biosynthesis
Thromboxane A2 (TXA2)
- unstable arachadonic acid metabolite - predominantly derived from platelet COX-1 - TXA2 binds to thromboxane prostaniod TP) receptor and initiates amplification loop -> further platelet activation, aggregation, and TXA2 formation - in vasculature TXA2 induces vasoconstriction and proliferation of vascular smooth muscle cells, TXA2 activates endothelial inflammatory responses
why are NSAIDs effective analgesics for inflammatory pain?
PGs play role in central and peripheral sensitization, reduce PG levels by blocking COXs -> suppression acute and chronic pain
NSAIDs can be used to treat
- preoperative pain - traumatic pain - orthopedic pain - post-surgical pain - anti-inflammatory (facilitating recovery chronic arthritis or tendonitis) - mild to moderate cancer pain
Asprin use in vet med
- rarely used as analgesic but used at low does to prevent thromboembolic complications
how does aspirin prevent thromboembolic complications
asprin inhibits platelet function as TXA2 production blocked for lifetime of platelet (8-11days) via inhibition of COXs via acetylation; platelets can’t produce new COX enzymes bc lack nucleus
Aspirin at high dose
will have anti-thrombotic effect diminished bc production of antithrombotic PGI2 also decreases
antithormbotic
prevents clotting
thromboxane A2 (TXA2) fx in vessels
stimulates vasoconstriction, platlet aggregation and adhesion, inhibit this inhibit clotting (low dose aspirin achieves this)
