Lecture 7 (Anti-inflammatories)

Question 1

What do NSAIDs do?

Answer 1

They reduce the production of prostaglandins and thromboxane

Question 2

What do anti-inflammatory NSAIDs do? (2)

Answer 2

(modify inflammatory reaction)
-Decrease vasodilation, and in turn oedema
-Ineffective against mediators that contribute to tissue damage associated with chronic inflammatory conditions

Question 3

What do analgesic NSAIDs do? (2)

Answer 3

(reduce certain sorts of pain)
-Decrease production of PGs (prostaglandins) in damaged and inflamed tissue which sensitises nociceptors to inflammatory mediators eg. bradykinin, 5-HT

Question 4

What do antipyretic NSAIDs do? (2)

Answer 4

(lower raised temperature)
-Thermostat in hypothalamus activated via IL-1 induced COX2 production of PGE (Prostaglandin E1)

Question 5

How many subunits is COX made up from?

Answer 5

two identical subunits, each with two catalytic sites

Question 6

Where are these expressed? (3) :
COX1
COX2
COX3

Answer 6

-COX1 is expressed in many tissues and has homeostatic function

-COX2 is not expressed by cells and is inducible enzyme, induced made in cells in response to injury and inflammation for protective function

-COX3 its expression is limited and found in brain and kidneys – paracetamol exerts its action through COX3 (why its for headaches)

Question 7

What do COX 1 and 2 inhibitor do?

Answer 7

COX1 and COX2 inhibitors inhibit Cyclooxygenation reaction of Arachidonic Acid to prevent production of PGE2

Question 8

What is COX3 a variant of?

Answer 8

COX1

Question 9

How does the structure of COX1 and COX2 differ?

Answer 9

Pore is slightly different between COX 1 and 2
In kink there is isoleucine for COX 1 and valine for COX2 (smaller amino acid)
so allows bigger drugs to get in compared to COX1

Question 10

What do prostaglandins do? (3)

Answer 10

Affect several bodily functions, including inflammation, pain and uterine contractions.

Question 11

What does aspirin bind to covalenty?

Answer 11

Aspirin binds covalently to a Ser residue in COX preventing arachadonic acid from reaching the cyclooxygenase site

Question 12

What are desired effect mediated by (which COX)? (2)
and which COX mediates unwanted side effects? (2)

Answer 12

Most Desired effects (anti-inflammatory) mediated by COX2
Unwanted side effects eg. on gastrointestinal tract, mediated by COX-1

Question 13

What type of inhibitor are most NSAIDs?

Answer 13

Suicide inhibitors (irreversible)

Question 14

What side effects are associated with NSAIDs? (5)

Answer 14

-Dyspepsia, diarrhoea, nausea, vomiting, gastric bleeding, ulceration
-Renal failure
-Liver Damage
-Bronchospasm asthma attacks
-Skin Rashes

Question 15

What should drugs target to avoid targets of NSAIDs?

Answer 15

COX2 / COX3

Question 16

What are the NSAID effects of COX1?
Undesirable (1)
Desirable (1)

Answer 16

Undesirable : Gastrotoxicity
Desirable : Antithrombotic (reduces formation of clots)

Question 17

What are the NSAID effects of COX2?
Undesirable (3)
Desirable (2)

Answer 17

Undesirable : Increases blood pressure, salt retention, prothrombotic
Desirable : Anti-inflammatory, Analgesic

Question 18

What is the clinical use of antithrombotic drugs?

Answer 18

e.g. Aspirin for patients at high risk of arterial thrombosis

Question 19

What are the clinical uses of analgesic drugs? (3)

Answer 19

-Short term aspirin, paracetamol, ibuprofen
-Chronic pain longer lasting more potent drug eg. Naproxen (+codeine)
-Reduce requirement for narcotic analgesics

Question 20

What is and example of an anti-inflammatory drug and an antipyretic drug? (2)

Answer 20

-Ibuprofen
-Paracetamol

Question 21

What does Thromboxane do?

Answer 21

Thromboxane’s lead to blood clotting and also involve vasoconstriction

Question 22

What is COX?

Answer 22

Cyclooxygenase (COX) is an enzyme that helps create the chemicals prostaglandin and thromboxane

Question 23

What COX should you avoid targeting to avoid most side effects?

Answer 23

COX1

Question 24

What do COX1 and COX2 do?

Answer 24

COX1 – has homeostatic function in maintaining body health
COX2 – induced enzyme in response to inflammation

Question 25

What does Aspirin do? (3)
What does Ibuprofen do? (1)

Answer 25

-Anti-platelet action
-Weak acid, rapid and efficient absorption in the ileum
-Suicide inhibitor (irreversible) - Irreversibly inhibits COX1 and 2 (inhibits 1 more than 2)

Reduced risk of colonic and rectal cancer
Reduced risk of Alzheimer’s

-Same as Aspirin but competitive inhibitor

Question 26

What does paracetamol do? (4)

Answer 26

-Analgesic-antipyretic (group of drugs) due to CNS effects
-Weak anti-inflammatory
-Cox3/1 selective
-N-acetyl-p-benzoquinone imine is hepatotoxic in unconjugated form competitive Inhibitor

Well absorbed, metabolized in liver
Less side-effects than aspirin with long term use, but large doses may increase kidney damage