NSAIDs

Question 1

Describe the main effects of NSAIDs. Explain how NSAIDs have these effects.

Answer 1

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

All of these actions are due to NSAIDs’ ability to inhibit prostaglandin biosynthesis by direct action on cyclo-oxygenase enzymes.

Question 2

Describe the general mechanism(s) behind NSAIDs’ inhibition of cyclo-oxygenases (COX) .

Answer 2

1) An irreversible, time-dependent inhibition of the enzyme

2) A rapid, reversible competitive inhibition of the enzyme (majority of them)

Question 3

Identify two NSAIDs, which respectively undertake one of the two general mechanisms for inhibition of cyclo-oxygenases (COX). Explain their specific mechanism.

Answer 3

1) An irreversible, time-dependent inhibition of the enzyme
• 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

2) A rapid, reversible competitive inhibition of the enzyme
• e.g. IBUPROFEN
– binds reversibly to the enzyme
– competes with natural substrate, Arachidonic Acid

Question 4

Why were prostaglandins called that ?

Answer 4

Because it was believed that they originated from the prostate gland (actually found in almost every tissue)

Question 5

Briefly explain how prostaglandins are generated ?

Answer 5

Generated in tissues from a precursor (arachidonic acid) by cyclo-oxygenase enzymes
– Thromboxanes, prostaglandins & leukotrienes all products of arachidonic acid metabolism

Question 6

What is the prostaglandins’ main physiological function ?

Answer 6

Maintaining GI integrity

Question 7

Distinguish between the two groups of cyco-oxygenase enzymes.

Answer 7

COX-1
– Constitutive
– Important in maintaining GIT integrity (expressed in GI)
– Membrane bound

COX-2
– Inducible (e.g. when need for anti-inflammatory response)
– Involved in inflammatory response
– Implicated in cancer development

Identical features
– Membrane bound
– Structurally similar except COX-2 has side pocket
– Function is generating prostaglandins, thromboxanes, and leukotrienes from arachidonic acid

Question 8

Describe the affinity of NSAIDs to COX-1, or COX-2, giving examples.

Answer 8

– Most of NSAIDs have mixed affinity for either COX 1 or COX 2
E.g.
-Aspirin slightly more selective for COX 1
-Ibuprofen in the middle
-Flurbiprofen more selective for COX-1
-Celecoxib more selective for COX-2

Question 9

Explain whether inhibition of COX-1 or COX-2 is most useful, giving reasons.

Answer 9

Inhibition of COX-1 less useful because COX-1 is normally expressed whereas COX-2 is the ‘bad guy’ causing anti-inflammatory responses

Question 10

Briefly describe Prostaglandin biosynthetic pathway, explaining where NSAIDs interfere.

Answer 10

Phospholipid –> Arachidonate –> (catalyzed by COOX) TXA2 (thromboxane), PGD2, PGE2, PGF2, PGI2 (prostaglandins)
NSAIDs inhibit COOX

Question 11

Since biosynthesis of Prostaglandins does not directly involve leukotrienes (since they are not produced by catalyzed cleavage of arachidonate), why do NSAIDs still have effects on leukotrienes.

Answer 11

If inhibit COX, preventing production of thromboxane and prostaglandins, which means there is shift in which substrate is used by these enzymes.
As a result, increased production of leukotrienes, leading to asthma symptoms

Question 12

Describe the role of prostaglandins in inflammation.

Answer 12

• Inflammation always accompanied by release of prostaglandins
– Predominantly PGE2 but also PGI2, and also PGD2 from mast cells

• Actions
– Act as potent vasodilators (result in oedema) (less effect on cellular accumulation or migration)
– Synergise with other inflammatory mediators (e.g. histamine and bradykinin)
– Potentiate histamine and bradykinin actions on postcapillary venule permeability and pain sensory nerves

Question 13

Describe the aspects of inflammation that NSAIDs affects.

Answer 13

• 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 14

Describe the molecular basis of fever in inflammation.

Answer 14

• Body temperature is regulated by the hypothalamus
– 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 15

Explain the anti-pyretic effects of NSAIDs.

Answer 15

• NSAIDs act by preventing the formation of prostaglandins and prevent the rise in temperature
– No effect on normal body temperature (if take aspirin or paracetamol without increase in body temperature, NSAIDs will not decrease it )

Question 16

Describe the molecular basis of pain in inflammation.

Answer 16

• 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 17

Explain the analgesic effects of NSAIDs.

Answer 17

• By preventing prostaglandin (and mediators in general) production NSAIDs prevent sensitization to pain-producing compounds (do not stop them from firing)

Question 18

List the main NSAIDs.

Answer 18

• Salicylates (Aspirin)
• Propionic acids (ibuprofen, naproxen) and fenamates (mefenamic acid)
• Paracetamol (=acetaminophen)
• Diclofenac
• Selective COX-2 inhibitors (Dicoflenac to a certain extent, Coxibs, such as Celecoxib)

Question 19

Identify a salicylate, and describe its main features.

Answer 19

ASPIRIN (acetylsalicylic acid)
– pro-drug, can directly acetylate COX enzyme
– also metabolised to active compound (salicylic acid) by plasma and tissue esterases

Question 20

What is the onset time and peak concentration time for salicylates ?

Answer 20

Salicylates found in plasma within 30 mins (onset)

peak plasma concentrations within 1-2 hr (Tmax)

Question 21

List the main unwanted effects of salicylates, explaining why each one arises.

Answer 21

STOMACH
– bleeding, ulcers (destroying integirty of GI due to inhibition of COX 1)

SYSTEMIC
–tinnitus (at high concentrations), dizziness, impaired hearing, nausea, vomiting, hypersensitivity

METABOLIC CHANGES
– acid/base balance affected

HAEMOSTASIS
– blood coagulation affected through and action on platelets (Because of effect on thromboxanes and platelet aggregation)

CNS EFFECTS
– stimulation initially, ultimately coma and respiratory depression

RENAL
– insufficiency in susceptible patients and with chronic use and overdose

Question 22

Identify propionic acids, and describe its main features.

Answer 22

– e.g. Ibuprofen, Naproxen
– not prodrugs
– well absorbed
– last for 4-6 hours.

Question 23

Identify Fenamates, and describe its main features.

Answer 23

Mefenamic acid

Question 24

Describe the main features of Paracetamol.

Answer 24

– 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 25

How is paracetamol administered ? Identify its Tmax and half life in plasma for therapeutic doses.

Answer 25

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

Question 26

Describe the main side effects of paracetamol.

Answer 26

• Fewer side effects than other NSAIDs (perhaps due to its selectivity for COX enzymes)
•
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 27

Identify a selective COX-2 inhibitor and describe its main features.

Answer 27

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 28

Describe the clinical uses of NSAIDs, identifying the specific NSAIDs prescribed for each use.

Answer 28

1. Analgesia
   (e. g. headache, dysmennorhea, backache, bony metastases of cancers, postoperative pain)

• For short term analgesia: aspirin, paracetamol, ibuprofen
• For chronic pain – naproxen, diclofenac (longer lasting)

2. Anti-inflammatory actions
   – Both chronic or acute inflammatory conditions

– For chronic inflammatory disorders, dosage is high and low incidence of side effects is important: Ibuprofen (mainly), Coxibs (sometimes used for osteoarthritis and rheumatoid arthritis)

3. Anti-pyretic actions (to lower temperature)
   - Paracetamol preferred because it lacks GIT side effects