NSAIDs Flashcards

1
Q

What are the major uses of NSAIDs?

A

Relief of mild to moderate pain (analgesic)

Reduction of fever (antipyretic)

Reduction of inflammation (anti-inflammatory)

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2
Q

What is the mechanism of action of NSAIDs?

A

They inhibit the production of Prostanoids by COX enzymes

They inhibit Cyclo-oxygenases (COX 1 & 2)

Prevent production of Prostaglandin H2 from Arachidonic acid

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3
Q

How do prostanoids exert their effects?

A

All receptor-mediated (G-protein coupled)

Action can be physiological or pro-inflammatory

The receptors may act through different pathways (e.g. EP2 receptor acts through 5 pathways - leading to beneficial and detrimental effects)

(We have 5 prostaglandins, but at least 10 different receptors)

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4
Q

What are the main actions of PGE2?

A

Increased Pain perception

Thermoregulation

Acute Inflammatory response

Immune responses

Tumorigenesis

Inhibition of Apoptosis - leading to necrosis

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5
Q

How does PGE2 lower the pain threshold?

A

Stimulation of PG receptors sensitises the nociceptors, meaning pain sensitivity increases

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6
Q

How do COX inhibitors raise the pain threshold?

A

We’re not really sure…

EP4 receptors (in spine and periphery)
Endocannabinoid involvement (Neuromodulation)

Both sensitise Nociception

COX inhibitors reduce levels of PGE2 which stimulate these - raising the threshold

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7
Q

How does PGE2 act as a Pyrogenic?

How do COX inhibitors reduce this effect?

A

PGE2 stimulates Hypothalamic neurones to initiate a rise in body temperature - hyperpyrexia

Reducing levels of PGE2 reduces this effect, and has been shown to have anti-pyretic effects in influenza

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8
Q

What is the role of PGE2 in acute inflammation?

A

PGE2 binds to EP3 receptors (Mast cells)

Has multiple pathways that lead to the secretion of Ca2+, Histamine degranulation and Interleukin release (Leukocyte recruitment)

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9
Q

Why are NSAIDs useful in treating Contact dematitis, MS and rheumatoid arthritis?

A

EP4 mediated PGE2 effects activated many complicated immune pathways that cause the maturation of Naive T-cells

This sustains chronic inflammation
Therefore COX inhibition and reduced levels of PGE2 reduce this effect

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10
Q

Apart from direct acute and chronic inflammatory effects, how else may PGE2 contribute to inflammation?

A

They have anti-apoptotic effects

If you don’t have managed and programmed cell death, you are more likely to get Necrosis which will contribute to inflammation

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11
Q

What are the main Desirable effects of Prostanoids?

A

Gastroprotection

Regulation of renal blood flow

Bronchodilation

Vasoregulation

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12
Q

What is the role of PGE2 in Gastric Cytoprotection?

What is the significance of this?

A

PGE2 downregulates HCL production

It also stimulates the production of mucus and bicarbonate - boots the physical barrier between the acidic lumen and the cell surface

Therefore reducing PGE2 levels increases the risk of ulceration due

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13
Q

How do NSAIDs cause renal toxicity?

A

Reducing PGE2 causes:
Constriction of the afferent arterioles
Reduction in renal artery flow
Reduced glomerular filtration rate

This not that good really…

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14
Q

Why should Asthmatics probably not take NSAIDs?

A

Prostanoids cause bronchodilation

Inhibition of COX favours the production of leukotrienes which are bronchoconstrictors

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15
Q

What are the unwanted effects of NSAIDs on the CVS?

What has this been shown to increase the incidence of?

A

NSAIDs cause:

Small rise in BP
Sodium retention
Vasoconstriction
May reduce the effects fo anti-hypertensives

Significant rise in incidence of MI and Strokes in chronic NSAID users

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16
Q

Why are Ibuprofen and Indomethacin simmilar?

A

They are both non-selective, reversible COX inhibitors

17
Q

Why did we try to make COX-2 selective inhibitors?

What was the problem with them?

A

It was believed they would lessen the GI side-effects - they did

They proved to produce a higher risk of Cardiovascular disease than conventional NSAIDs

(they could also be tolerated by asthmatic patients)

18
Q

What strategies for limiting GI side-effects of NSAIDs other than COX-2 selection are there?

A

Topical application

Minimise use in patients with risk factors:
History of ulceration
High alcohol consumption
Anticoag or Glucocorticoid steroid use

Coadminister PPIs in use is essential

19
Q

Why is Aspirin special and unique??

A

It is selective for COX-1

It Irreversibly binds to COX-1

20
Q

How does Aspirin reduce platelet aggregation?

A

It reduces the production of Thromboxane A2 made by COX-1 in platelets
Reduces production of PGI2 (Prostacyclin) by COX-1&2 in endothelial cells

This leads to reduced Platelet aggregation

21
Q

What is the difference between the effects of Aspirin on Platelets and endothelial cells in terms of levels of TXA2 and PGI2?

A

Once (high dose) aspirin is given existing Platelets will irreversible be unable to produce TXA2 as they won’t be able to replenish supply of COX-1 as they don’t have a nucleus

Endothelial cells will replenish their COX-1 and therefore begin to produce PGI2 again

22
Q

What are the major side effects seen with Therapeutic doses of Aspirin?

A

Gastric irritation and ulceration

Bronchospasm in sensitive asthmatics

Prolonged bleeding times

Nephrotoxicity

Side effects are more likely with aspirin than other NSAIDs because it inhibits

COX covalently, rather than just because it is selective for COX-1

23
Q

Why is Paracetamol not an NSAID?

A

It does not have any anti-inflammatory effect

24
Q

How does Paracetamol work?

A

Not understood. Probably central

COX-3 and Cannabinoid receptors?

25
Q

What happens in a Paracetamol overdose?

A

Normal Paracetamol metabolism produces a toxic intermediary metabolite which is reduced by Glutathione

In an overdose, the Glutathione may be depleted

The toxic metabolite will indiscriminately bind to any -SH (thiol) group it can find

These groups are often attached to key hepatic enzymes which will lead to apoptosis of hepatocytes and Liver Failure

26
Q

What is the antidote for Paracetamol poisoning?

A

Compounds with -SH groups

Usually IV Acetylcysteine
(Occasionally Oral methionine)