NSAIDs and Paracetamol

Question 1

Define eicosanoid. (2)

Answer 1

Prostanoids and leukotrienes.

Question 2

Describe the dietary source of arachidonic acid. (3)

Answer 2

Can be produced in the liver from phospholipids or linoleic acid (vegetable oils).

Question 3

Describe the rate limiting step in eicosanoid production. (3)

Answer 3

Releasing arachidonic acid from phospholipids through Phospholipase A2 action.

Question 4

Describe the five main prostanoids and at least three functions for each.

Answer 4

PGE2 - Good for stomach - pain, pyrexia and inflammation.
PGF2 alpha - pain, pyrexia and inflammation.
PGD2 - pain, pyrexia and inflammation.
PGI2 - inhibition of platelet aggregation, vasodilator, cytoprotective in the CVS.
TXA2 - generally bad for CVS, platelet aggregator, vasoconstrictor.

Question 5

Describe prostanoids (3)

Answer 5

Prostaglandins + prostacyclin (PGI2) + thromboxane.

Question 6

Describe the function of cyclooxygenase enzymes. (4)

Answer 6

Converting arachidonic acid to prostanoids via PGG2 and PGH2.

Question 7

Describe the isoforms of cyclooxygenase enzymes. (4)

Answer 7

COX-1 - constitutively active across most tissues.

COX-2 - inductively, active only in inflamed tissues - larger, more flexible.

Question 8

Describe the homeostatic functions of COX-1. (4)

Answer 8

GI protection (acid and mucus release)
Platelet aggregation
Vascular resistance
Renal blood flow.

Question 9

Describe the homeostatic functions of COX-2. (4)

Answer 9

Renal homeostasis
Tissue repair and healing
Uterine contractions
Inhibition of platelet aggregation.

Question 10

Describe the pathological functions of COX-1. (3)

Answer 10

Chronic inflammation
Chronic pain
Hypertension

Question 11

Describe the pathological functions of COX-2. (5)

Answer 11

Chronic inflammation 
Chronic pain
Fever
Increased blood vessel permeability
Tumour cell growth.

Question 12

Describe how prostanoids work. (4)

Answer 12

Act locally at GPCRs, and so their specific action depends on the location and the type of receptor. Often their action is enhanced locally by autocoids, including bradykinin and histamine.

Question 13

Explain why TXA2 and PGI2 need to be in careful balance. (5)

Answer 13

Thromboxane (promotes platelet aggregation and vasoconstricts) and prostacyclin (inhibits platelet aggregation and vasodilates) have opposite effects, so they need to be carefully balanced so stroke / MI does not occur.

Question 14

Describe the relationship between fish oils and CVD. (3)

Answer 14

With a diet rich in fish oils, more prostacyclin is produced, and because it’s cytoprotective in the CVS, incidence of CVD goes down.

Question 15

Describe the mechanism of action of most NSAIDs. (4)

Answer 15

Inhibition of CO leading to reduced prostaglandins, reduced prostacyclin and reduced thromboxane, having various analgesic, antipyretic and anti-inflammatory effects.

Question 16

Define NSAID. (1)

Answer 16

Non-steroidal anti-inflammatory drug.

Question 17

Describe how aspirin is not a common NSAID. (8)

Answer 17

At low doses it is an anticoagulent - irreversible COX-1 inhibition which inhibits TXA2 formation, so inhibits platelet aggregation.
At higher doses it is an anti-inflammatory - COX-1 and COX-2 inhibition, which blocks prostaglandin and prostacyclin production, so analgesic and antipyretic effects.

Question 18

Describe the MoA of the analgesic effects of an NSAID. (5)

Answer 18

In two parts:
Local peripheral action at site of pain - higher efficacy in inflammation.
Central component associated with decreased PGE2 (prostaglandin) synthesis in the dorsal horn leading to reduced neurotransmitter release, leading to decreased excitability of neurones in the pain relay.

Question 19

Describe the MoA of the anti-inflammatory effects of an NSAID. (4)

Answer 19

Decrease in production of prostaglandins released during injury (esp PGE2 and PGD2). This stops their normally vasodilatory and swelling effects, which reduces swelling.

Question 20

Describe the MoA of the antipyretic effects of an NSAID. (2)

Answer 20

Inhibition of hypothalamic COX-1 to reduce the cytokines-induced prostaglandin release which is causing the fever.

Question 21

Describe why the selectivity of COX enzyme inhibitors is important. (3)

Answer 21

Many of the ADRs of NSAIDs are related to the inhibition of the homeostatic functions of COX-1, which has lead to some mixed COX-1 and COX-2 inhibitors, and some exclusively COX-2 inhibitors.

Question 22

Name 6 NSAIDs. (6)

Put them in order of most selective for COX-1 to most selective for COX-2. (6)

Answer 22

COX-1 —> COX-2

Aspirin, ibuprofen, naproxen, diclofenac, celecoxib, parecoxib.

Question 23

Describe why NSAID use needs to be specially considered in asthmatics. (2)

Answer 23

Because NSAIDs have indirect reduction on leucotrienes through inhibition of PGE2, which is important in asthmatics.

Question 24

Describe the pharmacokinetics of most NSAIDs. (9)

Answer 24

Absorbed in the stomach.
Don’t undergo first pass metabolism.
t1/2 is varied (1-60hours), but they often accumulate where needed (eg in synovial fluid) so can have a prolonged time of action.
Highly protein bound with small Vd - important for displacement of other protein bound drugs.
Heptatically metabolised by CYP450s - important for inducers or inhibitors of these.

Question 25

Describe the GI ADRs of NSAID use. (7)

Answer 25

Most common ADR - dyspepsia, nausea, peptic ulceration, bleeding, perforation.
4x the incidence of GI haemorrhage
NSAIDs decreas the mucus and bicarb secretion and increase acid secretion. Then they decrease mucosal blood flow leading to hypoxia and cytotoxia.

Question 26

Describe the risk factors for incidence of GI ADRs relating to NSAID use. (8)

Answer 26

Age
Prolonged use
Corticosteriod use
Smoking
Anticoagulants
Alcohol
H. Pylori
History of peptic ulceration

Question 27

Describe the renal ADRs of NSAID use. (7)

Answer 27

Reversible decrease in GFR due to inhibition of prostaglandins causing vasoconstriction of afferent arteriole. This increases blood creatinine and decreases medullary blood flow.
Damage is more likely in CKD or with reduced blood flow (CHF, cirrhosis).
Increased salt and water retention leads to hypertension, oedema and hyperkalaemia.

Question 28

Describe the cardiovascular ADRRs of NSAID use. (3)

Answer 28

Increased salt and water retention can exacerbate heart failure and cause hypertension.
NSAIDs (except low dose aspirin) have even seen to be pro-thrombotic.

Question 29

Describe selective COX-2 inhibitors.
Why are they prescribed?
Adverse reactions?
(3)

Answer 29

Reduced ADRs generally because COX-1 left uninhibited, but can be pro-thrombotic, and selectivity for COX-2 only is hard due to COX polymorphisms.

Question 30

Name two COX-2 selective inhibitors. (2)

Give the common feature of the names of these. (1)

Answer 30

Celecoxib, parecoxib

-coxib

Question 31

Describe the common DDIs of NSAIDs. (10)

Answer 31

NSAIDs and low dose aspirin interact as they compete for COX-1, so the cardioprotective effects of aspirin are lost.
NSAIDs also outcompete these drugs for protein binding:
Sulphonureas - hypoglycaemia
Methotrexate - hepatotoxicity with accumulation
DMARDs - RA flare ups
Warfarin - increased bleeding risk.
Aspirin in children can cause rapid onset encephalopathy.

Question 32

Explain the consequences of taking NSAIDs in labour. (4)

Answer 32

Can delay labour, increase blood loss and prompt premature closure or the ductus arteriosus, due to inhibition of prostaglandins.

Question 33

Describe indications for NSAID use. (9)

Answer 33

Inflammatory conditions of the joint or soft tissue 
Osteoarthritis 
Post operative pain 
Cataracts (topical) 
Menorrhagia
Low dose aspirin for cardioprotective 
Opioid use reduced
Close ductus arteriosus 
Cancer reduction - reduces cellular proliferation by up to 50%.

Question 34

Describe paracetamol. (3)

Answer 34

A non-NSAID, non-opioid analgesic with anti-pyretic actions.

Question 35

Describe the ADRs of paracetamol at therapeutic doses. (2)

Answer 35

Few, because prostaglandins are uninhibited.

Question 36

Describe the absorption and metabolism of paracetamol. (4)

Answer 36

Well absorbed in the GI tract, with a t1/2 of 2h.
Phase 1 metabolism of paracetamol produces NAPQI, which at therapeutic doses is rendered harmless by hepatic conjugation with glutathione.

Question 37

Describe the metabolism of paracetamol in overdose. (3)

Define an overdose of paracetamol. (2)

Answer 37

Hepatic glutathione is limited, so NAPQI builds up in overdose. This leads to necrosis and apoptosis due to oxidation of thiol groups on key metabolic groups (due to lack of glutathione).
150mg/kg (normally 10-20 tablets) is enough to cause severe hepatocellular and renal tubular damage.

Question 38

Describe the presentation and treatment of paracetamol overdose. (7)

Answer 38

Overdose often remains asymptomatic initially, then N+V present in the first 24 hours, then with UQ pain on day 2, and maximal liver damage on days 3-4, indicated by prothrombin time.
Treated with acetylcysteine which replenishes hepatic glutathione.