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Pharmacology Year 2 > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

What are the three major uses of NSAIDs?

A

Anti-pyretic (reduce fever)
Anti-inflammatory
Analgesic (mild/moderate pain relief)

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2
Q

Broadly speaking, how do NSAIDs act?

A

They inhibit the production of prostanoids via inhibition COX enzymes

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3
Q

What are the main prostanoids? Where are they found?

A

Prostaglandins (D2, E2 and F2) Prostacyclin (PGI2) Thromboxane A2

Prostanoids are ubiquitous compounds, found in most tissues. They cannot be stored, but are released immediately they have been synthesised.

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4
Q

1) Where does arachidonic acid come from? 2) What does COX convert arachidonic acid to? Describe this reaction.
3) How are the prostanoids subsequently formed?

A

1) Arachidonic acid is freed from a phospholipid molecule by the enzyme phospholipase A2.

2) PGH2
1. Oxygenation reaction converts arachidonic acid to PGG2.
2. Peroxidation reaction, catalysed by a different part of the enzyme, converts PGG2 to PGH2.

3) PGH2 is then converted by specific synthases (named after the prostanoid) to:
- Thromboxane A2
- Prostacyclin (PGI2)
- Prostaglandin D2, E2, F2

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5
Q

Describe the difference between COX-1 and COX-2 iso-forms

A

COX-1 is a constitutively expressed enzyme with a “house-keeping” role in regulating many normal physiological processes
COX-2 is an enzyme facultatively expressed in inflammation (called upon by tissue injury and other stimuli such as lipopolysaccharide (LPS), interleukin-1, and tumor necrosis factor alpha (TNFα))

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6
Q

How are prostanoid receptors named?

A

Prostanoid receptors aren’t very specific - they are named based on which prostanoid they have the highest affinity for (e.g. DP1 has the highest affinity for PGD2)

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7
Q

List all the prostanoid receptors.

A 
DP1, DP2
EP1, EP2, EP3, EP4
FP
IP1, IP2
TP
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8
Q

What type of receptor are all the prostanoid receptors?

A

G protein coupled receptors (though not all their actions are G protein mediated)

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9
Q

Explain why the EP receptor system is complex.

A
  • There are four different EP receptors

- cAMP-dependent and independent downstream mechanisms

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10
Q

State some unwanted actions of PGE2.

A
  • Increased pain perception (prostaglandins sensitise nociceptors)
  • Increased body temperature
  • Acute inflammatory response
  • Immune responses
  • Tumorigenesis
  • Inhibition of apoptosis
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11
Q

How does PGE2 increase pain perception/lower the pain threshold (hyperalgesia)?

A

There is involvement of EP4 receptors and endocannabinoids

The mechanism is unclear

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12
Q

How does PGE2 affect body temperature?

A

PGE2 stimulates hypothalamic neurones initiating a rise in body temperature
NOTE: there is a bit of a lag between PGE2 rising and temperature rising

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13
Q

State some desirable actions of PGE2 and other prostanoids.

A

GASTROPROTECTION
Regulation of renal blood flow
Bronchodilation
Vasoregulation (dilation and constriction)

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14
Q

Describe the gastroprotective action of PGE2.

A

PGE2 downregulates stomach acid production
PGE2 stimulates mucus production
PGE2 stimulates bicarbonate production

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15
Q

What side-effect do NSAIDs have on the GI tract?

A

Increased risk of GI ulceration

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16
Q

What main effects does PGE2 have on the kidneys?

A

Increase renal blood flow

17
Q

What effect do NSAIDs have on the kidneys?

A

Constriction of the afferent arteriole
Reduction in renal artery flow
Reduced GFR

18
Q

Why should NSAIDs not be given to asthma patients?

A

Most prostaglandins are bronchodilators, so a reduction in prostaglandin production due to COX inhibition could exacerbate asthma
Inhibition of COX favours the production of leukotrienes, which are bronchoconstrictors (note that leukotrienes are products of the lipooxygenase pathway derived from arachidonic acid)

19
Q

Prostanoids are vasoregulators, so what are the consequences of NSAIDs on the cardiovascular system?

A

Increased risk of MI and stroke because chronic use of NSAIDs cause:

  • Small rise in blood pressure
  • Sodium retention
  • Vasoconstriction
  • Reduced effectiveness of anti-hypertensives
20
Q

What is the difference in terms of risk of side effects when using NSAIDs for analgesic use compared to anti-inflammatory use?

A 
Analgesic use (only occasionally used) 
- low risk of side effects

Anti-inflammatory use (often sustained use with higher doses)
- higher risk of side effects

21
Q

Name two non-selective COX inhibitors.

A

Ibuprofen

Indomethacin

22
Q

Name a COX-2 selective inhibitor.

A

Celecoxib

23
Q

What is the major problem with COX-2 selective NSAIDs?

A

They have a significantly increased risk of cardiovascular disease than conventional NSAIDs

24
Q

Describe the relative GI and CVS risks of COX-1 selective and COX-2 selective NSAIDs when compared to non-selective NSAIDs.

A

COX-1 selective:

  • Same CVS risk as non-selective NSAIDs
  • Increased GI risk

COX-2 selective:

  • Decreased GI risk
  • Increased CVS risk
25
Q

What are the potential reasons for increased risk of cardiovascular disease with non-selective and COX-2 selective NSAIDs?

A

Non-selective NSAIDs and COX-2 selective NSAIDs both increase cardiac work
Also, all NSAIDs produce oxygen free radicals, which can contribute to cardiovascular disease

26
Q

State some strategies for avoiding/limiting the GI side effects of NSAIDs.

A
  • Topical application
  • Minimise NSAID use in patients with a history of GI ulceration
  • Treat H. pylori if present
  • If NSAID is essential, administer omeprazole or another proton pump inhibitor
  • Minimise NSAID use in patients with other risk factors and reduce risk factors where possible e.g. alcohol consumption, anticoagulant use
27
Q

Describe the action of aspirin. Selectivity? What are the consequences of this relative to that of NSAID administration?

A

It irreversibly binds to cox enzymes (binds covalently)
It is selective for COX-1

The consequences of this are that its actions are much longer-lasting than those of other NSAIDs and can only be reversed by de novo synthesis of new enzyme.

28
Q

Explain how aspirin reduces platelet aggregation.

A

Aspirin irreversibly inhibits COX-1 in platelets meaning that they can’t produce thromboxane A2, which enhances platelet activation and aggregation
Furthermore, aspirin preserves the production of prostacyclin (since it is derived from the endothelium), which decreases platelet action

29
Q

Why is it important to use a low dose of aspirin?

A

A low dose will allow the endothelial cells to resynthesise COX-1, which can then continue to produce prostacyclin
A high dose would mean that the COX-1 in the endothelial cells would be inhibited as it is being produced, thus decreasing prostacyclin production as well as thromboxane production

30
Q

What are the major side effects of therapeutic doses of aspirin?

A

Gastric irritation and ulceration
Bronchospasm in sensitive asthmatics
Prolonged bleeding times
Nephrotoxicity

31
Q

Why is paracetamol NOT an NSAID?

A

Has minimal anti-inflammatory effect

32
Q

Explain how paracetamol overdose can cause liver failure.

A

Paracetamol is metabolised to produce a toxic metabolite (N-acetyl-p-benzochinon imine (NAPQI))
This is normally mopped up rapidly by glutathione
In overdose, the glutathione stores are depleted and the free toxic metabolite binds indiscriminately to any –SH groups
The –SH groups tend to be on key hepatic enzymes and this interference leads to cell death

33
Q

What is the antidote for paracetamol poisoning?

A

IV Acetyl cysteine or Oral Methionine
This has a lot of –SH groups
If this is given too late, the liver damage could be permanent

34
Q

What legislation was brought in to try and reduce paracetamol related deaths?

A

No more than 2 packs per transaction

Illegal to sell more than 100 paracetamol in 1 transaction

Pharmacology Year 2 (32 decks)

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