NSAIDs

Question 1

NSAID

Answer 1

-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

Question 2

corticosteroids block

Answer 2

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)

Question 3

NSAIDs fx by

Answer 3

mostly by inhibiting cyclooxyrgenase (COX) (not aspirin or grape-rant) - inhibit COX enzymes by competing with arachadonic acid binding

Question 4

COX

Answer 4

converts arachadonic acid into prostaglandin H2 (PGH2) a precursor for signaling prostaglandins including - prostaglandin E2 (PGE2) - thromboxane A2 (TXA2) - prostacyclin (PGI2)

Question 5

prostaglandins promote

Answer 5

redness, swelling, pain, hypalgesia (ie inflammation) so NSAIDs are considered antiinflamtory drugs as well as analgesics

Question 6

acidic NSAIDs

Answer 6

• salicylates (aspirin) - propionates (carprophen) - acetats (indomethacin) - enolates (meloxicam and piroxicam) -pyridinemonocarboxylic acid (flunixin) - robenacoxib (cox2 specific inhibitor)

Question 7

non acidic nsaids

Answer 7

• mavacoxib= COX2 specific inhibitor

Question 8

NSAID that is not COX inhibitor

Answer 8

Grapiprant (galliparant); works by inhibiting EP4 prostaglandin receptor by competing with PGE2

Question 9

How does aspirin work

Answer 9

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

Question 10

arachadonic acid signaling

Answer 10

1. 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

Question 11

epoxyeicosatrienoic acids (EETs)

Answer 11

EETs plays important role in - anti-inflammatory -pro-fibrinolytic effects - vasorelaxation

Question 12

Leukotrienes (LTs)/ Lipoxins (LXs)

Answer 12

LTs, LXs play important role in: - inflammation - bronchoconstrictoin

Question 13

cyclooxygenases are

Answer 13

-targets of NSAIDs - bifunctional enzymes that catalyze prostanoid (bioactive oxygenated C18-C22 compounds) biosynthesis

Question 14

heme-dependent COX reaction

Answer 14

converts AA to PGG2 and subsequent peroxidase (POX) reaction reduces 15-hydroperoxide of PGG2 to form PGH2

Question 15

COX isoforms

Answer 15

• COX-1 and COX-2 -membrane bound and are present on luminal surfaces of ER and inner and outer membranes of nuclear envoelpe

Question 16

COX-1 vs COX-2

Answer 16

-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

Question 17

contributors to auto regulatory and homeostatic prostanoids

Answer 17

both COX1 and COX2 contribute to this

Question 18

differences between classical NSAIDs and COX-2 inhibitors arise

Answer 18

in part from slight differences in amino acids surrounding active sites of COX-1 and COX-2

Question 19

Prostaglandin production

Answer 19

-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)

Question 20

Prostaglandins play key role in

Answer 20

generation of inflammatory response; their biosynthesis is increased in inflamed tissue and contribute to development of cardinal signs of acute inflammation

Question 21

PGs exert their effects by

Answer 21

activating specific G protein-coupled receptors

Question 22

Prostaglandin E2

Answer 22

• PGE2 - most abundant PGs exhibit versatile biological activities

Question 23

PGE2 fx

Answer 23

• 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

Question 24

redness and edema PGE2

Answer 24

redness and edema result from increased blood flow into inflamed tissue through PGE2 mediated augmentation arterial dilation and increased microvascular permeability

Question 25

pain PGE2

Answer 25

pain results from PGE2 action on peripheral sensory neurons and on central sites w/ in spinal cord and brain

Question 26

how does PGE2 get to site of action

Answer 26

PGE2 actively transported through membrane by transporter or diffuses across plasma membrane to act at or near site of secretion

Question 27

PGI2 function

Answer 27

• potent vasodilator - inhibitor of platelet aggergation - leukocyte adhesion - VSMC proliferation - PGI2 important mediator of edema and pain that accompany acute inflammation

Question 28

PGD2 synthesized in

Answer 28

CNS and peripheral tissue

Question 29

PGD2 function

Answer 29

• 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

Question 30

PGF2alpha

Answer 30

• 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

Question 31

Thromboxane A2 (TXA2)

Answer 31

• 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

Question 32

why are NSAIDs effective analgesics for inflammatory pain?

Answer 32

PGs play role in central and peripheral sensitization, reduce PG levels by blocking COXs -> suppression acute and chronic pain

Question 33

NSAIDs can be used to treat

Answer 33

• preoperative pain - traumatic pain - orthopedic pain - post-surgical pain - anti-inflammatory (facilitating recovery chronic arthritis or tendonitis) - mild to moderate cancer pain

Question 34

Asprin use in vet med

Answer 34

• rarely used as analgesic but used at low does to prevent thromboembolic complications

Question 35

how does aspirin prevent thromboembolic complications

Answer 35

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

Question 36

Aspirin at high dose

Answer 36

will have anti-thrombotic effect diminished bc production of antithrombotic PGI2 also decreases

Question 37

antithormbotic

Answer 37

prevents clotting

Question 38

thromboxane A2 (TXA2) fx in vessels

Answer 38

stimulates vasoconstriction, platlet aggregation and adhesion, inhibit this inhibit clotting (low dose aspirin achieves this)