NSAIDs Flashcards

1
Q

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

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Describe the 2 general mechanisms behind NSAIDs’ inhibition of cyclo-oxygenases (COX) .

A

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

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

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

A

1) An irreversible, time-dependent inhibition of the enzyme
* e.g. ASPIRIN
– inactivates the enzyme
– aspirin acetylates the alpha-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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Why were prostaglandins called that ?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Briefly explain how prostaglandins are generated ?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is the prostaglandins’ main physiological function ?

A

Maintaining GI integrity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Distinguish between the two groups of cyco-oxygenase enzymes.

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

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

A

– 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

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

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Briefly describe Prostaglandin biosynthetic pathway, explaining where NSAIDs interfere.

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

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.

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Describe the role of prostaglandins in inflammation.

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Describe the aspects of inflammation that NSAIDs affects.

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Describe the molecular basis of fever in inflammation.

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Explain the anti-pyretic effects of NSAIDs.

A
  • 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 )
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Describe the molecular basis of pain in inflammation.

A
17
Q

Explain the analgesic effects of NSAIDs.

A
  • By preventing prostaglandin (and mediators in general) production, NSAIDs prevent sensitization to pain-producing compounds (do not stop them from firing)
18
Q

List the main NSAIDs.

A
  • 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)
19
Q

Identify a salicylate, and describe its main features.

A

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

20
Q

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

A

Salicylates found in plasma within 30 mins (onset)

peak plasma concentrations within 1-2 hr (Tmax)

21
Q

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

A

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

22
Q

Identify propionic acids, and describe its main features.

A
23
Q

Identify Fenamates, and describe its main features.

A

Mefenamic acid

24
Q

Describe the main features of Paracetamol.

A

– 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)

25
Q

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

A

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

26
Q

Describe the main side effects of paracetamol.

A
  • 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 glucoronide
    and sulphate conjugation
    – When these enzymes saturated, toxic metabolites are formed
    – Result can be hepatic necrosis
27
Q

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

A

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

28
Q

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

A
  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)
  1. 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)

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