COX chemistry

Question 1

what do you consider when treating pain?

Answer 1

–Identify source of pain
–Treat source if possible
–Provide analgesia if necessary
–Start on lowest appropriate part of pain ladder

Question 2

what is inflammation in response to?

Answer 2

injury or disease

Question 3

what is the purpose of inflammation?

Answer 3

–Treatment of inflammation: reduce the source of pain

Question 4

what kind of pain relief does paracetamol provide?

Answer 4

Analgesic and anti-pyretic, but not anti-inflammatory

Question 5

what is paracetamols target?

Answer 5

known to act weakly on
cyclooxygenase (COX) enzymes
– Not convincing evidence for strong analgesia
• Recently discovered paracetamol metabolite
activates TRPA1 (protein on surface of nerve cells)
– Blocks transmission of pain

Question 6

what is the metabolism reactions that occur in paracetamol?

Answer 6

sulfation

glycuronidation

Question 7

what causes paracetamol overdose?

Answer 7

high levels of NAPQI
it is an intermediate
it is toxic and reacts with proteins in the liver and causes damage

Question 8

what can paracetamol be oxadised by?

Answer 8

CYP enzymes, particularly in liver

CYP3A4, CYP2E1, CYP1A2, CYP2D6

Question 9

what does NAPQI stimulate?

Answer 9

TRPA1

Question 10

how does the body detoxify itself in paracetamol overdose?

Answer 10

NAPQI is highly electrophilic, and is
susceptible to attack from N and S
nucleophiles.
• N-Acetylcysteine is more bioavailable than
Cys, making it a better treatment for OD.
• Sometimes methionine is used

Question 11

how do inflamatory disease cause inflamation?

Answer 11

– Release of leukocytes, which produce interleukin-1(IL-1)
• Potent proinflammatory cytokine
– IL-1 stimulates the action of phospholipase A2, which acts
on membrane phospholipids to release arachidonic acid
• Key precursor for the biosynthesis of prostaglandins,
thromboxanes, prostacyclin and leukotrienes
• Arachidonic acid also synthesized from dietary linoleic acid

Question 12

which leukotrines are unstable?

Answer 12

A

Question 13

what is leukotriene A converted to?

Answer 13

• Rapidly converted to other leukotrienes, e.g. Leukotrienes B, C, D, E

Question 14

what are leukotrines C,D ad E? how do they act?

Answer 14

cysteinyl leukotrienes
– Epoxide attacked by cysteine SH
– Act on CysLT1 and CysLT2 receptors
– Cause anaphylaxis: potent hypotensives and bronchoconstrictors
– Antagonists to cysteinyl leukotriene receptors are used as prophylactics
against asthma
– e.g. Montelukast (Singulair) blocks the action of LTD4 on CysLT1

Question 15

what do inhibitors of leukotriene also prove successful vs?

Answer 15

asthma eg- Zileuton (Zyflo) inhibits 5-lipoxygenase (LOX)

Question 16

what does PGE3 cause?

Answer 16

key chemical mediator in 
inflammation
• Causes:
– Pyresis in joints and tissues
– Redness and swelling
– Pain: PGE2 acts directly on peripheral and CNS neurons, causing pain 
signal

Question 17

how is PGE2 formed?

Answer 17

Formed by action of cyclooxygenase (COX) on arachidonic
acid
– Via PGH2

Question 18

what is COX essential in?

Answer 18

essential enzyme in arachidonic acid pathway
– Biosynthesis of inflammatory mediators
– Inhibitors active as anti-inflammatory agents
•  Non-steroidal anti-inflammatory drugs (NSAIDs)

Question 19

how do steroids produce their anti-inflammatory action?

Answer 19

Glucocorticoid steroids, such as dexamethasone, activate lipocortin,
which inhibits phospholipase A2 and prevents the formation of
arachidonic acid

Question 20

what are the classes of NSAIDS

Answer 20

Salicylates, aryl- and heteroaryl-alkanoic acids, oxicams,

anthranilic acids, pyranocarboxylic acids, plus prodrugs

Question 21

what is the only non-reversible COX inhibitor?

Answer 21

aspirin

Question 22

what does sulindac undergo?

Answer 22

redox transformation

reduces it to thioether

Question 23

how is the prodrug of sulindac reactivated?

Answer 23

through an oxidoreductase enzyme

Question 24

what is the pka of piroxicam?

Answer 24

4.6

Question 25

how do NSAIDs work?

Answer 25

all NSAIDs inhibit COX - except aspirin

reduces fomration of pge2

Question 26

what are the result of NSAID?

Answer 26

– anti-inflammatory (reducing source of pain)
– analgesic (block signalling of pain)
– anti-pyretic (reduce temperature rise – pyresis – associated with
inflammation)

Question 27

what is aspirin synthesised from?

Answer 27

willow bark

Question 28

how does aspirin work?

Answer 28

Acetyl salicylate more palatable and less damaging to oral

and GI tissues and acetyl gives potent COX inhibition

Question 29

why is aspirin irreversible?

Answer 29

• Irreversible COX inhibition through acetylation of serine in
active site
– Also suppresses formation of TXA2 by inhibiting COX in platelets
– TXA2 induces platelet aggregation
– Hence aspirin leads to inhibition of platelet aggregation
– Risk of myocardial infarction reduced significantly

Question 30

what is the difference in the two isoforms of COX enzymes?

Answer 30

COX-1 (constitutive)
– Present in most tissues all the time
– Induces platelet aggregation
– Produces PGs that protect gastric mucosa
– Appears linked to normal cellular activity: homeostasis?
• COX-2 (inducible)
– Present in brain and kidney normally (constitutive)
– Induced by cytokines (inflammation) and injury in most tissues
– Produces PGs that inhibit platelet aggregation and cause pain/swelling
– Part of inflammatory response

Question 31

what is produced by cox 2?

Answer 31

Prostacyclin (PGI2)
– Vasodilator
– Produced by endothelial cells
– Inhibits platelet aggregation

Question 32

what is produced by COX 1

Answer 32

• Thromboxane A2
– Vasoconstrictor
– Produced by platelets
– Induces platelet aggregation