Anti- inflammartories I Flashcards
3 examples of anti-inflammatory and immunosuppressant drugs?
1) NSAIDs (inc. coxibs)
2) Antirheumatic drugs
3) Biologicals (biopharmaceuticals)
What are NSAIDs?
Examples?
Non-steroidal anti-inflammatory drugs
Including:
- Aspirin
- Paracetamol
- Ibuprofen
What is special about the bark of the willow tree?
Fever lowing (antipyretic) and pain lowering (analgesic)
What is the precursor of aspirin and isolated it discovered it and when?
Salicylic acid
Isolated by Henry Leroux in 1828
What did Felix Hoffmann do?
Added an ester group to salicylic acid - making acetyl salicylic acid
- Gave the drug to his grandfather
Which was more tolerated, salicylic acid or acetyl salicylic acid?
Acetyl salicylic acid
What do NSAIDs provide? (3)
- Pain relief
- Lower fever
- Some reduce swelling
What is the action of NSAIDs?
They inhibit the production of certain inflammatory meditators by inhibiting the CYLCOOXYGENASE enzymes which lead to the production of PROSTANOIDS
This inhibits the production of PROSTAGLANDINS and THROMBOXANES
What are inflammatory mediators an example of?
Paracrine mediators
What are paracrine mediators?
Produced by one cell and interact with other cells
Can interact with:
- The same type of cell
- Different types of cell
What are prostanoids?
Prostanoids are a subclass of molecules consisting of:
1) Prostaglandins
2) Thromboxanes
3) Prostacyclins
What are prostaglandins mediators of?
Inflammatory and anaphylatic reactions
What are thromboxanes mediators of?
Vasoconstriction and clot formation
What are prostacyclins and what are they mediators of?
They are a PROSTAGLANDIN member
Mediators of:
- Inhibition of platelet aggregation
- Vasodilation
What is the process for formation of inflammatory mediators?
1) Phospholipase A2 enzyme in the plasma membrane creates an intermediates from phospholipids - ARACHIDONATE
2) Aracadonate is the substrate of CYCLOOXYGENASE
3) Leads to the production of prostaglandins, prostacyclins and thromboxanes (PROSTANOIDS)
What determines what mediators are made?
Which ENZYMES are expressed in a particular tissue
What is COX?
Cyclo-oxygenase
What prostaglandins are made as a result of the COX pathway?
What are their functions?
PGD2 - Vasodilator and inhibitor of platelet aggregation
PGE2 - Vasodilator and hyperalgesic (increase pain signalling) and HYPERPYRETIC
What prostacyclins are made as a result of the COX pathway?
What is its function?
PGI2
- Vasodilator
- Inhibit platelet aggregation
- Hyperalgesic (increase pain sensitivity)
What thromboxanes are made as a result of the COX pathway?
What is its function?
TXA2
- Thrombotic (cause clot formation)
- Vasoconstrictor
What happens if cyclo-oxygenase is inhibited by NAIDs?
Inhibit the functions of the prostanoids (prostaglandins, prostanoids, thromboxanes):
1) Anti-inflammatory
2) Analgesic
3) Antipyretic
What does algesic relate to?
Sensitivity of pain
What does pyretic relate to?
Fever (temperature)
How are NSAIDs anti-inflammatory?
- Inhibit prostanoids (PGI2, PGE2)
- Inhibit VASODILATION and ODEMA (swelling an bruising)
What are NSAIDs ineffective against?
Why?
Mediators that contribute to tissue damage associated with CHRONIC INFLAMMATION
These mediators AREN’T prostanoids (NSAIDs are only affective with prostanoids)
How do NSAIDs reduce pain sensitivity?
Inhibit prostanoids (PGI2 and PGE2)
How does PGI2 (prostacyclin) usually cause pain sensitivity?
1) Released in area of tissue damage
2) Feeds onto nerve endings - activating GPCR
3) Sensitises nociceptive receptors to inflamaory mediators such as bradykinins and 5-HT
How doe NSAIDs reduce temperature/fever?
Prevent production of IL-1 which causes the release of PGE2 which activates the thermostat in the hypothalamus and increases the temperature of the body
How are headaches controlled?
Why?
Anti-inflammatory mechanisms!!
Caused by vasodilation of the blood vessels of the brain
What is the structure of COX (cyclo-oxygenase)?
- 2 identical subunits, each with a catalytic active site
- Forms a CHANNEL where arachidonate goes through
What is the substrate of COX?
What happens to this as is passes through the COX enzyme?
Arachindonate (precursor of prostanoid)
As passes through enzyme - undergoes 2 catalytic reactions which lead to prostaglandin synthesis
Where are COX enzymes situated?
In the endoplasmic reticulum membrane (INTRACELLULAR)
What are the different isoforms of COX?
COX1
COX2
COX3 (a spliced variant of COX1)
What is the differences between COX1 and COX2?
COX1:
- Expressed all the time in a vast majority of cells (constitutive expression)
- ISOLEUCINE amino acid
COX2:
- Inducible - expression is tightly regulated by certain triggers
- VALINE amino acid (has a smaller side chain than isoleucine)
- Therefore pore in COX2 is larger than in COX1
- Quick acting and switched off quickly too
Which COX isoform is expressed in the kidney and colon?
COX1
What is the function of COX1?
House-keeping:
- Involved in homeostasis
- Produces prostaglandins involved in platelet aggregation and mucus secretion (to protect the stomach and GI tract)
What can taking chronic aspirin cause and why?
How can this be overcome?
Ulceration of the stomach and GI tract as it prevents COX1 from functioning (which makes prostaglandins involved in making mucus)
Can be overcome by developing drugs which are selective to COX2
What is COX2 expression triggered by?
Inflammation, cytokines and growth factors
What do NSAIDs inhibit?
BOTH COX1 and COX2
What are examples of where COX2 is expressed?
Kidney and CNS
What is COX3 and where is it expressed?
What exerts its action here
A spliced variant of COX1
Expressed largely in the brain
Where PARACETAMOL exerts its action
Which drugs are more selective to COX2?
Examples?
COXIBS:
Celecoxib
Etoricoxib
Rofecoxib
What is more selective to COX1, aspirin or ibuprofen?
Aspirin
What type of drugs are coxibs?
Non-steroidal anti-inflmmatories
COX2 selective inhbitors
How can drugs be more selective to COX2 than COX1?
- Pore in COX2 is larger due to the isoleucine –> valine amino acid switch
- Therefore drugs can be too big to fit in COX1 but small enough to fit in COX2
What are the side effects of NSAIDs in the gut?
Why?
- Dyspepsia (indegestion)
- Diarrhoea
- Nausea
- Vomiting
- Gastric bleeding
- Ulceration
Due to preventing prostanoids which protect the gut with mucus and PREVENT ACID SECRETION
What is normally prescribed with high doses of NSAIDs to prevent ulceration?
Analogue of prostaglandins (misoprostol)
What are some side effect of NSAIDs?
1) Renal faliure
2) Problems in the gut
3) Bronchospasms
4) Skin rashes
5) Liver damage
6) Bleeding disorder
Why can NSAIDs cause renal faliure?
Prostanoids are involved in maintaining renal blood flow
Which NSAID can cause liver damage and how?
High doses of paracetamol
- Forms a toxic intermediate after phase 1 reaction, which normally undergoes glucuronidation to prevent it
- However, in large doses - GLUCAONIDASE enzyme is overloaded, so the phase 2 reaction cannot occur
- High conc of toxic intermediate
Why can NSAIDs cause a bleeding disorder?
When is this prevalent?
NSAIDs prevent thromboxaines, which usually work at the level of platelets to cause clots
Prevalent in patients taking Warfarin (already reduces blood clotting)
What are the advantages of COX1 selective NSAIDs?
Favoured because of its actions on platelets - good for people at risk of thrombosis
What are the advantages of COX2 selective NSAIDs?
- Less side effects
- Reduces pain associated with inflammation
What are the limitations of using COX1 selective NSAIDs?
Have to asses the overall health of the patients (ulcers etc)
What are the limitations of using COX2 selective NSAIDs?
COX2 is important in the kidneys
In some people, what can COX2 inhibition cause?
Cardiac complictations
Why is aspirin a ‘suicide inhibitor’? (process of inhibition)
1) Converts back to salicylic acid in the body
2) Interacts with SERINE residues in the COX enzymes to form a COVALENT bond
3) COX enzyme becomes PERMANENTLY inactive
4) Have to synthesise a NEW enzyme to overcome the effects of the aspirin
What is the time taken for aspirin to wear off proportional to?
The time taken for the body to re-synthesise new COX enzymes, which have been permanently inactivated by salicylic acid interacting with the serine residues in the enzyme
What does paracetamol target?
COX3 enzymes in the brain
Describe the absorption of aspirin
Rapid and efficient in the ileum
What does the use of aspirin reduce?
Colonic and rectal cancer
Alzhemier’s
Thrombosis (has anti-platelet action)
What are the actions of paracetamol? Why?
Analegesic and antipyretic
Due to its actions in the CNS
What is paracetamol not good at?
Reducing inflammation
With long term use, which has fewer side-effects; aspirin or paracetamal?
Paracetamol
How is aspirin made?
Bark of willow tree –> salycilic acid –> add ester group –> acetyl salycilic acid (aspirin)
