COX chemistry Flashcards
what do you consider when treating pain?
–Identify source of pain
–Treat source if possible
–Provide analgesia if necessary
–Start on lowest appropriate part of pain ladder
what is inflammation in response to?
injury or disease
what is the purpose of inflammation?
–Treatment of inflammation: reduce the source of pain
what kind of pain relief does paracetamol provide?
Analgesic and anti-pyretic, but not anti-inflammatory
what is paracetamols target?
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
what is the metabolism reactions that occur in paracetamol?
sulfation
glycuronidation
what causes paracetamol overdose?
high levels of NAPQI
it is an intermediate
it is toxic and reacts with proteins in the liver and causes damage
what can paracetamol be oxadised by?
CYP enzymes, particularly in liver
CYP3A4, CYP2E1, CYP1A2, CYP2D6
what does NAPQI stimulate?
TRPA1
how does the body detoxify itself in paracetamol overdose?
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
how do inflamatory disease cause inflamation?
– 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
which leukotrines are unstable?
A
what is leukotriene A converted to?
• Rapidly converted to other leukotrienes, e.g. Leukotrienes B, C, D, E
what are leukotrines C,D ad E? how do they act?
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
what do inhibitors of leukotriene also prove successful vs?
asthma eg- Zileuton (Zyflo) inhibits 5-lipoxygenase (LOX)
what does PGE3 cause?
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
how is PGE2 formed?
Formed by action of cyclooxygenase (COX) on arachidonic
acid
– Via PGH2
what is COX essential in?
essential enzyme in arachidonic acid pathway
– Biosynthesis of inflammatory mediators
– Inhibitors active as anti-inflammatory agents
• Non-steroidal anti-inflammatory drugs (NSAIDs)
how do steroids produce their anti-inflammatory action?
Glucocorticoid steroids, such as dexamethasone, activate lipocortin,
which inhibits phospholipase A2 and prevents the formation of
arachidonic acid
what are the classes of NSAIDS
Salicylates, aryl- and heteroaryl-alkanoic acids, oxicams,
anthranilic acids, pyranocarboxylic acids, plus prodrugs
what is the only non-reversible COX inhibitor?
aspirin
what does sulindac undergo?
redox transformation
reduces it to thioether
how is the prodrug of sulindac reactivated?
through an oxidoreductase enzyme
what is the pka of piroxicam?
4.6
how do NSAIDs work?
all NSAIDs inhibit COX - except aspirin
reduces fomration of pge2
what are the result of NSAID?
– anti-inflammatory (reducing source of pain)
– analgesic (block signalling of pain)
– anti-pyretic (reduce temperature rise – pyresis – associated with
inflammation)
what is aspirin synthesised from?
willow bark
how does aspirin work?
Acetyl salicylate more palatable and less damaging to oral
and GI tissues and acetyl gives potent COX inhibition
why is aspirin irreversible?
• 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
what is the difference in the two isoforms of COX enzymes?
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
what is produced by cox 2?
Prostacyclin (PGI2)
– Vasodilator
– Produced by endothelial cells
– Inhibits platelet aggregation
what is produced by COX 1
• Thromboxane A2
– Vasoconstrictor
– Produced by platelets
– Induces platelet aggregation
