L11 - Anti-inflammatories - NSAIDs

Question 1

Aspirin discovery - 1828

Answer 1

White powder called salicin isolated and converted to salicylic acid

Question 2

Aspirin discovery - 1897

Answer 2

Felix Hoffmann derivatized hydroxyl groups in salicylic acid with an acetyl group

• Reduced the negative effect of salicylic acid
• First patented on March 6, 1899

Question 3

NSAIDs are prescribed for

Answer 3

Rheumatic musculoskeletal pains
Aches
Pains
Swelling

Question 4

Arachidonic acid is produced by?

Answer 4

Produced from membrane phospholipids by Phospholipase A2

Question 5

Arachidonic acid role

Answer 5

Acts as a second messenger and substrate for lipoxygenases and cyclooxygenase

• Leads to generation of lipid-soluble mediators
• Lipoxygenase and cyclooxygenase pathway

Question 6

Lipoxygenase pathway

Answer 6

Production of leukotrienes



Question 7

Cyclooxygenase pathway

Answer 7

Production of prostaglandins and thromboxanes

- E.g. prostaglandin E2

Question 8

Prostaglandins

Answer 8

Unlike most hormones, they are created by cells and then act only in the surrounding area

Question 9

Prostaglandins control

Answer 9

Constriction of muscle cells around blood vessels
Aggregation of platelets
Constriction of the uterus
Delivering and strengthening pain signals
Inducing inflammation

Question 10

Properties of NSAIDs

Answer 10

Anti-inflammatory
Analgesic
Antipyretic
Effectiveness against headaches

Question 11

Properties of NSAIDs - anti-inflammatory

Answer 11

Modify inflammatory reaction decreasing vasodilation and oedema
Ineffective against mediators that contribute to tissue damage associated with chronic inflammatory conditions

Question 12

Properties of NSAIDs - analgesic

Answer 12

Decrease production of prostaglandins in damaged and inflamed tissue
Sensitises nociceptors to inflammatory mediators

Question 13

Properties of NSAIDs - antipyretic

Answer 13

Lower raised temperature

Thermostat in hypothalamus activated via IL-1 induced COX2 production of prostaglandin

Question 14

Properties of NSAIDs - headaches

Answer 14

Reduce vasodilator effect of prostaglandins on cerebral vasculature

Question 15

COX1/COX2 selective NSAIDS

Answer 15

COX2-selective NSAIDs/inhibitors reduce effect of gastrointestinal toxicity (antiarthritic and analgesic)
- Concerns regarding cardiovascular safety

Question 16

Most NSAIDs show little selectivity

Answer 16

Main differences are in toxicity, duration of action, and patient tolerance

Question 17

NSAID effects from COX1 inhibition

Answer 17

Undesirable – gastrotoxicity

Desirable – antithrombotic

Question 18

NSAID effects from COX2 inhibition

Answer 18

Undesirable – increased blood pressure, salt retention, prothrombotic
Desirable – anti-inflammatory, analgesic

Question 19

COX1 and COX2 inhibitors inhibit

Answer 19

Cyclooxygenation reaction of Arachidonic Acid to prevent production of PGE2

Question 20

COX2 structure

Answer 20

Wider at the bend because it has a smaller amino acid (valine)
Cox1 has an isoleucine
- This gives rise to a gap which can act as a filter for drug

Question 21

Side effects of NSAIDs - gut

Answer 21

Prostaglandins normally inhibit acid secretion and protect mucosa
Leads to dyspepsia, diarrhoea, nausea, vomiting, gastric bleeding, ulceration
Co-administration of prostaglandin analogue may be protective

Question 22

Side effects of NSAIDs - liver

Answer 22

Leads to liver damage

Paracetamol creates toxic, reactive intermediate

Question 23

Side effects of NSAIDs - renal

Answer 23

Prostaglandins normally maintain renal blood flow

Leads to renal failure

Question 24

Side effects of NSAIDs - lung

Answer 24

Bronchospasm asthma attacks

More common with aspirin

Question 25

Side effects of NSAIDs - bleeding disorders

Answer 25

Thromboxane is involved in platelet aggregation | Too many drugs can reduce thromboxane

Question 26

Side effects of NSAIDs - GI complications

Answer 26

34-45% users will sustain some form of GI damage | Small percentage lead to serious effects and hospitalisation

Question 27

Aspirin binds to?

Answer 27

Aspirin binds covalently to a ser residue in COX | Prevents arachidonic acid from reaching the cyclooxygenase site

Question 28

What is a suicide inhibitor?

Answer 28

Useful cardiovascular drug due to inhibition of platelet aggregation Acts on both cox1 and cox2 Aspirin and warfarin increase risk of bleeding

Question 29

Aspirin blocks?

Answer 29

The cyclooxygenase active site Aspirin has two parts - an acetyl group attached to salicylic acid When it attacks cyclooxygenase, it connects its acetyl group to a serine amino acid, permanently inactivating the enzyme

Question 30

Aspiring overview

Answer 30

Anti-platelet action Reduced risk of colonic and rectal cancer Reduces risk of Alzheimer’s Weak acid, rapid and efficient absorption in the ileum Suicide inhibitor

Question 31

Paracetamol overview

Answer 31

Analgesic-antipyretic due to CNS effects Weak anti-inflammatory Well absorbed and metabolised in the liver Less side effects than aspirin with long term use Large doses may increase kidney damage Competitive inhibitor

Question 32

Ibuprofen overview

Answer 32

Like aspirin except it is a competitive inhibitor

Question 33

Clinical uses of NSAIDs

Answer 33

Antithrombotic Analgesia Anti-inflammatory Antipyretic

Question 34

Clinical uses of NSAIDs - antithrombotic

Answer 34

Aspirin for patients at high risk of arterial thrombosis

Question 35

Clinical uses of NSAIDs - analgesia

Answer 35

Short term - aspirin, paracetamol, ibuprofen | Chronic pain - longer lasting more potent drug

Question 36

Clinical uses of NSAIDs - anti-inflammatory

Answer 36

Ibuprofen | Naproxen

Question 37

Clinical uses of NSAIDs- antipyretic

Answer 37

Paracetamol

Question 38

COX subunits

Answer 38

Two identical subunits, each with two catalytic sides A cyclooxygenase site that binds to the endoplasmic reticulum A endoperorixase site

Question 39

COX1

Answer 39

Found in most cells and is constitutively active, so a NSAID binding to COX1 may have many adverse side effects

Question 40

COX2

Answer 40

Found in most cells and is active only when induced, so a NSAID binding to COX2 will have few, selective side effects

Question 41

COX3

Answer 41

Found mostly on cells within the CNS and paracetamol binds to it