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Y2 LCRS Pharm Fwong > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

What are the three major uses of NSAIDs?

A

Anti-pyretic
Anti-inflammatory
Analgesic

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2
Q

What are most deaths due to NSAIDs caused by?

A

GI ulceration

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3
Q

Broadly speaking, how do NSAIDs act?

A

They inhibit the production of prostanoids by COX enzymes

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4
Q

What are the main prostanoids?

A

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

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5
Q

What does COX convert arachidonic acid to?

A 
Prostaglandin H2  
Which is then converted by specific synthases to: 
 Thromboxane A2
 Prostacyclin (PGI2)
 Prostaglandin D2, E2, F2
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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 EFFECTS are GPCR mediated)

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9
Q

Explain why the EP receptor system is complex.

A

There are four different EP receptors and EP2 has two mechanisms of action and five pathways

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10
Q

State some unwanted actions of PGE2.

A 
Increased pain perception  
Thermoregulation  
Acute inflammatory response  
Tumorigenesis  
Inhibition of apoptosis
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11
Q

How does PGE2 increase pain perception?

A

Stimulation of PG receptors in the periphery sensitises nociceptors which cause pain acutely and chronically (lowers pain threshold). Exact mechanism is unclear. One possible mechanism is that PGE2 normally activates PKA pathway which leads to low level activation of P2X3 nociceptors. At times of increased PGE2 (inflammation), an alternative pathway is triggered which leads to greater activation of these nociceptors and hene hyperalgesia

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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

Hence NSAIDS are antipyretic

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13
Q

What is the problem with PGE2 inhibiting apoptosis?

A

Inhibition of apoptosis increases the likelihood of necrosis

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14
Q

State some desirable actions of PGE2 and other prostanoids.

A

GASTROPROTECTION
renal salt and water homeostasis
Bronchodilation
Vasoregulation

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15
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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16
Q

What effect do NSAIDs have on the GI tract?

A

Increased risk of GI ulceration

17
Q

What main effects does PGE2 have on the kidneys?

A

Increase renal blood flow

renal salt and water homeostasis

18
Q

What effect do NSAIDs have on the kidneys?

A

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

19
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
Furthermore, inhibition of COX favours the production of leukotrienes, which are bronchoconstrictors

20
Q

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

A

NSAIDS can have serious CVS effects
 Sodium/water retention
 Vasoconstriction
 Can reduce the effectiveness of anti-hypertensives

21
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 – usually occasionally used and lower doses so low risk of side effects
Anti-inflammatory use – often sustained use with higher doses = higher risk of side effects

22
Q

Name a non-selective COX inhibitors.

A

Ibuprofen

23
Q

Name a COX-2 selective inhibitor.

A

Celecoxib (coxib family)

24
Q

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

A

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

25
Q

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

A

Essentially, the more COX 1 selective it is, the higher the GI risk. The more COX 2 selective, the higher the CVD risk. Hence in the middle (non selective) has the lowest risk for both GI and CVD

26
Q

What effect does ibuprofen have on the action of anti-hypertensive drugs?

A

It reduces the effectiveness of anti-hypertensive drugs It will reduce the drop in blood pressure that has been seen when the anti-hypertensives are used without ibuprofen

27
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

28
Q

State some strategies for avoiding/limiting the GI side effects of NSAIDs other than using COX 2 inhibitors.

A

Use 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

29
Q

Describe the action of aspirin.

A

It irreversibly binds to cox enzymes (binds covalently)

It is selective for COX-1

30
Q

Explain how aspirin reduces platelet aggregation.

A

Aspirin irreversibly inhibits COX-1 in platelets meaning that they can’t produce thromboxane A2. TXA2 production is via COX1 only. TXA2 normally promotes aggregation (by increasing Gp2b/3a on platelets - haemostasis lecture)
Furthermore, aspirin preserves the production of prostacyclin (which is produced by endothelial cells via COX1 and 2). Prostacyclin normally inhibits platelet aggregation (see slides 34-36)

31
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

32
Q

Why don’t you want to inhibit COX-2 too much?

A

Inhibition of prostacyclin synthesis is proportional to inhibition of COX-2
We don’t want to inhibit prostacyclin production too much so we’d like to keep COX-2 inhibition low

33
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

34
Q

Why is paracetamol NOT an NSAID?

A

It does not have (has minimal) anti-inflammatory action

35
Q

Explain how paracetamol overdose can cause liver failure.

A

Paracetamol is metabolised to produce a toxic metabolite NAPQI
This is normally converted to an inactive form by glutathione S transferase
In overdose, the glutathione S transferase stores are depleted and the free toxic metabolite binds indiscriminately to any –SH groups (thio groups)
The –SH groups tend to be on key hepatic enzymes and this interference leads to hepatic cell death

36
Q

What is the antidote for paracetamol poisoning?

A

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

37
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

Y2 LCRS Pharm Fwong (40 decks)

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