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LCRS Pharmacology and Therapeutics > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

What are the major clinical uses of NSAIDs?

A 
Relief of mild pain (analgesic):
- Toothache, headache and backache
-Post-op pain
-Dysmenorrhoea
Reduction of fever (antipyretic)
Reduction of inflammation (anti-inflammatory):
-Rheumatoid arthritis 
-Osteoarthritis
-Soft tissue injuries
-Gout
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2
Q

How do NSAIDs work?

A

They inhibit the production of prostanoids by COX enzymes

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3
Q

What are prostanoids derived from?

A

Arachidonic acid

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4
Q

Name three main prostanoids?

A

Prostaglandins
Thromboxane
Prostacyclin

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5
Q

What are prostanoid actions mediated by?

A

They are all receptor mediated: DP1 DP2 EP1 EP2 EP3 EP4 FP IP1 IP2 TP

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6
Q

What are prostanoid receptors named based on?

A

Their potency/highest affinity- DP1 has the greatest affinity for prostaglandin D2

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7
Q

What sort of receptors are all prostanoid receptors?

A

G protein coupled but not all their actions are G protein mediated

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8
Q

How many prostaglandins do we have?

A

5

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9
Q

Which receptors can PGE2 activate and how many pathways does it work through?

A

4 receptors: EP1, EP2, EP3 and EP4

5 pathways

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10
Q

What is neuroplasticity?

A

A desirable feature- ability of one neurone to take over the job of another neurone if it were to become damaged

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11
Q

What are the unwanted actions of PGE2?

A 
Increased pain perception
Thermoregulation
Acute inflammatory response
Immune responses
Tumorigenesis
Inhibition of apoptosis- more likely to get necrosis
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12
Q

What effect do PGE2 analogues have on pain threshold?

A

Lower the pain threshold and increases pain sensitivity

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13
Q

What is believed to be involved in the mechanism by which COX inhibitors raise the pain threshold?

A 
EP4 receptors (in periphery and spine)
Endocannabinoids (neuromodulators in thalamus, spine and periphery)- cross talk between the two so there is neuromodulation
They block the production of PGE2
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14
Q

What effect does PGE2 have on body temperature?

A

It is pyrogenic- it stimulates hypothalamic neurones initiating a rise in body temperature

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15
Q

What mediates the effect of PGE2 on the immune system?

A

EP4

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16
Q

What inflammatory conditions are treated with NSAIDs?

A

Contact dermatitis
Multiple sclerosis
Rheumatoid arthritis
PGE2 is important in acute and chronic inflammation

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17
Q

Why are the anti-apoptic effects of prostaglandins undesirable?

A

You are more likely to get necrosis- will contribute to inflammation

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18
Q

What desirable actions do PGE2 and other prostanoids have?

A

Gastroprotection
Regulation of renal blood flow
Bronchodilation
Vasoregulation

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19
Q

How does PGE2 have a role in gastroprotection?

A

Downregulates HCl secretion in the stomach

Stimulates production of mucus (physical barrier) and bicarbonate (neutralises stomach acid)

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20
Q

What effect does NSAID use have on the gastric system?

A

Reduces PGE2 so causes increase in risk of ulceration

21
Q

What effect do NSAIDs have on renal blood flow?

A

Can cause renal toxicity:
Constriction of afferent arteriole
Reduction in renal artery flow
Reduced glomerular filtration rate

22
Q

In terms of the lungs what do most COX products cause?

A

Bronchodilation

23
Q

What do asthma patients experience with use of NSAIDs?

A

Exacerbation of symptoms- Inhibition of COX favours production of leukotrienes which are bronchoconstrictors

24
Q

What effect do NSAIDs have on cardiovascular system?

A

Serious unwanted effects- increase incidence in MI and stroke:
Small rise in blood pressure
Sodium retention
Vasoconstriction

25
Q

What is the risk vs benefit of NSAID use like for analgesic use and anti-inflammatory use?

A 
Analgesic:
Usually occasional
Low risk of side effects
Anti inflammatory:
Often sustained
Higher doses
High risk of side effects
26
Q

Do NSAIDs vary in affinity for COX-1 and COX-2?

A

Yes

27
Q

What is the selectivity for ibuprofen and indomethacin like?

A

Typically non-selective NSAIDs and inhibit both COX1 and 2 - irreversibly

28
Q

What effects do ibuprofen and indomethacin have?

A

Analgesic
Anti-pyretic
Anti-inflammatory

29
Q

Why are selective COX-2 inhibitors used more to avoid side effects?

A

It’s very difficult to make a selective COX-2 inhibitor because both COX enzymes are structurally very simiilar

30
Q

What does celecoxib do?

A

Selectively inhibits COX2- less effect on COX-1 mediated process than conventional NSAIDs such as ibuprofen- led to decrease in ulceration

31
Q

What do COX-2 selective inhibitors pose a greater risk of than conventional NSAIDs?

A

Cardiovascular disease even though mechanism is unclear

32
Q

What is the difference between COX-1 selective NSAIDs and conventional NSAIDs?

A

Cardiovascular risk is unchanged but GI risk is increased- PGE2 in stomach is generated through COx-1

33
Q

How are COX-2 inhibitors tolerated in asthmatics?

A

Well but not recommended

34
Q

What happens when a patient on antihypertensives takes ibuprofen?

A

Blood pressure will rise

35
Q

How do non-selective and COX 2 selective drugs increase cardiovascular disease?

A

They cause an increase in work
COX2 selective probably exert effects via interfering with balance between prostacyclin and thromboxane- increase in thromboxane will cause increased risk of thrombosis
All NSAIDs increase production of oxygen free radicals and they affect multiple different pathways that contribute to CVD

36
Q

What other strategies are there to limit GI side effects of NSAIDS apart from COX2 selective?

A

Topical application
Minimise NSAID use in patients with history of GI ulceration
Treat H pylori if present
Administer with omeprazole or other proton pump inhibitor
Minimise NSAID use in patients with other risk factors and reduce risk factors where possible

37
Q

What does aspirin do?

A

Selective for COX1 and binds irreversibly
Has analgesic, anti-inflammatory and anti-pyretic actions
It is unique among NSAIDs

38
Q

What is the effect of aspirin on platelets?

A 
Inhibit thromboxane (which enhances platelet action) production by platelets
In high doses, reduces prostacyclin (which decreases platelet action) production by endothelial cells
39
Q

Why are platelets not able to resynthesises COX after aspirin binds?

A

Platelets lack a nucleus so once aspirin irreversibly inhibits the COX enzymes in a platelet, it will not be able to resynthesise COX and hence will not regain its ability to produce thromboxane
(Endothelial cells can replenish so maintain prostacyclin)

40
Q

What is responsible for anti platelet actions of aspirin?

A

Very high degree of COX-1 inhibition by covalent binding which irreversibly suppresses thromboxane A2 production

41
Q

Why do you need to give a low dose of aspirin?

A

To allow endothelial cells to resynthesises COX otherwise you will keep inhibiting endothelial COX as fast as it’s being made so won’t get beneficial effects- the inhibition of prostacyclin is proportional to the inhibition of thromboxane

42
Q

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

A 
Gastric irritation and ulceration
Bronchospasm in asthmatics
Prolonged bleeding times
Nephrotoxicity
Side effects more likely with aspirin than other NSAIDs because it inhibits covalently
43
Q

What does paracetamol do?

A

It is a good analgesic for moderate pain and has anti-pyretic action

44
Q

Why is paracetamol not a NSAID?

A

It is not anti-inflammatory

45
Q

What is thought to be involved in the mechanism of paracetamol’s action?

A

COX-3
Via cannabinoid receptors
Interaction with endogenous opioids
Interaction with 5HT and adenosine receptors

46
Q

What can overdose of paracetamol cause?

A

Liver failure

47
Q

What normally happens in paracetamol metabolism?

A

Toxic metabolite is formed (toxic= generates free radicals) and is normally mopped up by glutathione and is rendered safe

48
Q

How does paracetamol overdose cause liver failure?

A

Too much toxic metabolite is being generated leading to depletion of glutathione which means the toxic metabolite will indiscriminately bind to any -SH group that it can find- most of which are attached to key hepatic enzymes and you get inevitable cell death

LCRS Pharmacology and Therapeutics (33 decks)

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