NSAIDS

Question 1

How do NSAIDS work

Answer 1

Inhibition of prostaglandin and thromboxane synthesis
Lipid mediators derived from arachidonic acid
Cyclo-oxygenase enzymes
Widely distributed
Not stored pre-formed
Receptor-mediated

Question 2

Describe the arachidonic acid pathway

Answer 2

1. Membrane phospholipid converted to arachidonic acid via phospholipase A2
2. Conversion to prostaglandin H2 or leukotrienes (bronchoconstrictor)

Question 3

What enzyme is used to convert arachidonic acid to prostaglandin H2 and what can be produced from this

Answer 3

COX 1 and 2

PGE2, PGI2 (prostacyclin), Thromboxane A2
PGF2A, PGD2

Question 4

What enzyme is used to convert arachidonic acid to leukrotrienes

Answer 4

Lipooxygenase

Question 5

What are the unwanted actions of PGE2

Answer 5

Lowers the pain threshold 
Increases body temperature (fever)
Causes inflammation
Activates T-helper cells involved in certain hypersensitive conditions
Tumorigenesis
Inhibition of apoptosis

Question 6

What receptors can PGE2 activate and what is the order of affinity for them

Answer 6

EP1-4
EP1 has the greatest affinity and EP4 has the least affinity
cAMP-depednent and independent downstream mechanisms

Question 7

How does PGE2 cause fever and inflammation

Answer 7

PGE2 stimulates the neurones in the hypothalamus involved in temperature control leading to an increase in temperature (fever!)
PGE2 leads to mast cell degranulation leading to inflammation

Question 8

How does PGE2 lower pain threshold

Answer 8

Increases pain sensation by sensitising the nociceptors

Question 9

What are the desirable effects of PGE2

Answer 9

Is cytoprotective in the stomach
Causes bronchodilation a long with other prostaglandins
Increases GFR -> renal salt and water homeostasis
Vasoregulation (dilation and constriction depending on receptor activated)

Question 10

Explain how PGE2 is gastroprotective

Answer 10

stimulates bicarbonate and mucous secretion in the stomach

Downregulates HCl secretion

Question 11

Explain how PGE2 causes an increased GFR

Answer 11

Increases renal blood flow by acting as a vasodilator on the afferent arteriole to the glomerulus

Question 12

Why may NSAIDS cause renal toxicity

Answer 12

Constriction of afferent renal arteriole
Reduction in renal artery flow
Reduced glomerular filtration rate

Question 13

Why may NSAIDS cause worsening symptoms in asthmatics

Answer 13

Cyclooxygenase inhibition favours production of leukotrienes, which are bronchoconstrictors

Question 14

What are the unwanted effects of NSAIDS

Answer 14

Vasoconstriction
Salt and water retention 
Reduced effect of antihypertensives 
Hypertension 
Myocardial infarction 
Stroke

Question 15

Compare COX-1 and COX-2 and their inhibitors

Answer 15

Different (but overlapping) cellular distributions
Most NSAIDs reversibly inhibit both isoforms (example: ibuprofen)
Coxib family: selectively reversibly inhibit COX-2 (example: celecoxib)

Question 16

What class of drug is ibuprofen

Answer 16

Non-selective reversible COX inhibitor

Question 17

Describe the pharmacodynamics of ibuprofen

Answer 17

Inhibits COX, which stops PGE2 production leading to analgesia, reduced inflammation and reduced fever

Question 18

What are the side effects of ibuprofen

Answer 18

Gastric irritation and ulceration
Bronchospasm
Prolonged bleeding
Nephrotoxicity

Question 19

What is the advantage of COX-1 specific inhibitors over COX-2 specific inhibitors

Answer 19

COX-2 inhibitors increase the risk of CVD compared to COX-1 specific inhibitors
May be due to imbalance between anti-thrombolytic prostacyclin and pro-thrombotic thromboxane A2

Question 20

Compare the roles of COX-1 with COX-2

Answer 20

COX-1 - more involved in gastric cytoprotection and platelet haemostasis

COX-2 - Expressed in inflammatory cells, involved in pain and inflammation

Question 21

What is the advantage of COX-2 specific inhibitors over COX-1 specific inhibitors

Answer 21

Cause fewer GI effects because there is a smaller decrease in PGE2 in the stomach.

Question 22

What class of drug is Celecoxib

Answer 22

Selective reversible COX2 inhibitor

Question 23

Describe the pharmacodynamics of celecoxib

Answer 23

Has similar effects to ibuprofen but you get more PGE2 formed in the stomach (because PGE2 is formed from COX1 in the stomach) so there is less risk of ulceration

Question 24

What are the side effects of celecoxib

Answer 24

Less severe GI and nephrotic side effects compared to aspirin and ibuprofen
Greater risk of CVD

Question 25

Describe paracetamol metabolism and why it is important in overdose

Answer 25

Produces a toxic metabolite that is usually inactivated by glutathione.
If this metabolite is produced in excess (e.g. in paracetamol overdose), then the metabolite starts binding to hepatic enzymes with –SH groups on them.
This leads to liver failure

Question 26

What drug is used for a paracetamol overdose and why

Answer 26

Acetylcysteine

Contains an –SH group, and so mops up the toxic metabolite during paracetamol overdose

Question 27

Why is aspirin the only NSAID used to manage thrombotic disease

Answer 27

Aspirin irreversibly binds to COX1
Platelets lack a nucleus and so cannot resynthesise COX1
Irreversibly inhibiting COX1 will permanently prevent TXA2 production from the targeted platelets, but endothelial cells will be able to replenish their COX1 and continue to produce prostacyclin, which is anti-thrombitic