NSAIDs

Question 1

What does NSAIDs stand for?

Answer 1

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Question 2

What are the main actions of NSAIDs?

Answer 2

1) Anti-inflammatory
2) Analgesic
3) Anti-pyretic

Question 3

What is the primary physiological action of NSAIDs?

Answer 3

Inhibit prostaglandin biosynthesis by direct action on cyclo-oxygenase enzymes

Question 4

What are the mechanisms of action of NSAIDs?

Answer 4

All inhibit cyclo-oxygenase (COX) but do so by two main mechanisms:

1) An irreversible, time-dependent inhibition of the enzyme
2) A rapid, reversible competitive inhibition of the enzyme

Question 5

Describe the irreversible, time-dependent inhibition of the enzyme mechanism of action of NSAIDs

Answer 5

• e.g. aspirin
– inactivates the enzyme
– aspirin acetylates the a-amino group of the terminal serine of the enzyme forming a covalent bond
– further synthesis of prostaglandins requires synthesis of new enzyme

Question 6

Describe the rapid, reversible competitive inhibition of the enzyme mechanism of action of NSAIDs

Answer 6

• e.g. ibuprofen
– binds reversibly to the enzyme
– competes with natural substrate, Arachidonic Acid

Question 7

What are prostaglandins?

Answer 7

A family of compounds generated in tissues from a precursor (arachidonic acid) by cyclo-oxygenase enzymes

Question 8

What are some prostaglandins?

Answer 8

– PGE2 and PGF2a were the first ones isolated and structures determined

– Thromboxanes, prostaglandins & leukotrienes all products of arachidonic acid metabolism

Question 9

What are cyclo-oxygense enzymes?

Answer 9

A group of enzymes consisting of two main enzymes

Question 10

What are the two main cyclo-oxygenase enzymes?

Answer 10

COX-1

COX-2

Question 11

Describe COX-1

Answer 11

– Constitutive
– Important in maintain
GIT integrity

Question 12

Describe COX-2

Answer 12

– Inducible
– Involved in
inflammatory response
– Implicated in cancer development

Question 13

What is the role of prostaglandins in inflammation?

Answer 13

Inflammation always accompanied by release of prostaglandins

Question 14

What are the prostaglandins released in inflammation?

Answer 14

– Predominantly PGE2 but also PGI2

– PGD2 from mast cells

Question 15

What do the prostaglandins released in inflammation do?

Answer 15

PGE2, PGI2 and PGD2
– Act as potent vasodilators
– Also synergise with other inflammatory mediators (e.g. histamine and bradykinin)
– Potentiate histamine and bradykinin actions on postcapillary venule permeability and pain sensory nerves

Question 16

Describe the anti inflammatory action of prostaglandins

Answer 16

Prostaglandins are important mediators of inflammation

– Particularly vasodilation and resultant oedema – Less effect on cellular accumulation or migration

Question 17

What is the impact of the role of prostaglandins in inflammation on the use of NSAIDs?

Answer 17

NSAIDs only effect aspects of inflammation in which prostaglandins play a significant part. NSAIDs can reduce many of the local signs and symptoms of inflammation:
– i.e. redness, heat, swelling, pain

Question 18

What is body temperature regulated by?

Answer 18

The hypothalamus

Question 19

How is a fever caused?

Answer 19

– Fever occurs when the hypothalamic thermostat “set point”
is raised
– Bacterial endotoxins cause release of factors (e.g.
interleukin 1) from macrophages
– Interleukin 1 causes generation of prostaglandins in the
hypothalamus (PGEs)
– Prostaglandins ↑ the thermostat “set point”

Question 20

How do NSAIDs have an anti-pyretic effect?

Answer 20

NSAIDs act by preventing the formation of prostaglandins and prevent the rise in temperature
– No effect on normal body temperature

Question 21

What causes pain in inflamed regions?

Answer 21

Inflamed regions painful due to histamine and bradykinin release
– activate nocioceptive afferent nerve terminals
– register a painful stimulus
Prostaglandins sensitise nocioceptive nerves to these compounds

Question 22

How do NSAIDs have an analgesic effect?

Answer 22

By preventing prostaglandin production NSAIDs prevent sensitisation to pain-producing compounds

Question 23

What is a famous example of salicylates

Answer 23

Also known as the aspirin family

Therefore: aspirin

Question 24

Describe aspirin physiologically

Answer 24

– pro-drug (acetylsalicylic acid)
—-• can directly acetylate COX enzyme
– also metabolised to active compound (salicylic acid) by plasma and tissue esterases
– salicylates found in plasma within 30 mins
– peak plasma concentrations within 1-2 hr

Question 25

What are the unwanted effects of salicylates?

Answer 25

Stomach – bleeding, ulcers Systemic – tinnitus, dizziness, impaired hearing, nausea, vomiting, hypersensitivity Metabolic changes – acid/base balance affected Haemostasis – blood coagulation affected through and action on platelets CNS effects – stimulation initially, ultimately coma and respiratory depression Renal – insufficiency insusceptible patients and with chronic use and overdose

Question 26

What are propionic acids?

Answer 26

– e.g. ibuprofen, naproxen – not prodrugs – well absorbed – last for 4-6 hours

Question 27

What are fenamates?

Answer 27

– e.g. mefenamic acid

Question 28

Describe the physiological effects of paracetamol

Answer 28

Good analgesic and antipyretic activity Poor anti-inflammatory Well tolerated in GIT Weak COX inhibitor – May be selective inhibitor of CNS-specific COX, COX-3

Question 29

How is paracetamol given?

Answer 29

Given orally, well absorbed – Peak plasma conc in 30-60 mins – Half life in plasma 2-4 hr for therapeutic doses

Question 30

What is another name for paracetamol?

Answer 30

acetaminophen

Question 31

What is a benefit of paracetamol?

Answer 31

Fewer side effects than other NSAIDs (perhaps due to its selectivity for COX enzymes)

Question 32

What is a major issue with paracetamol?

Answer 32

Major issue is hepatotoxicity due to overdose – Normally inactivated in the liver by glucoronate and sulphate conjugation – When these enzymes saturated, toxic metabolites are formed – Result can be hepatic necrosis

Question 33

What are selective COX-2 inhibitors?

Answer 33

Coxibs – e.g. celecoxib – used for osteoarthritis and rheumatoid arthritis – restricted for when traditional NSAIDs produce too severe GIT side effects – cardiovascular risk needs to be assessed

Question 34

What are the clinical uses of the analgesic properties of NSAIDs?

Answer 34

``` – headache – dysmennorhea – backache – bony metastases of cancers – postoperative pain ```

Question 35

What NSAIDs should be used for short term analgesia?

Answer 35

– aspirin, paracetamol, ibuprofen

Question 36

What NSAIDs should be used for longer lasting analgesia for chronic pain?

Answer 36

– naproxen, diclofenac

Question 37

What are the clinical uses of the anti-inflammatory properties of NSAIDs?

Answer 37

– Both chronic or acute inflammatory conditions – Dosage for chronic inflammatory disorders is high – Therefore low incidence of side effects is important ----• e.g.ibuprofen – Coxibs sometimes used for osteoarthritis and rheumatoid arthritis

Question 38

What are the clinical uses of the anti-pyretic properties of NSAIDs?

Answer 38

– To lower temperature | – Paracetamol preferred because it lacks GIT side effects