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Applied Pharmacology > NSAIDS > Flashcards

NSAIDS Flashcards

0
Q

What are the mediators that are released in an inflammatory response?

A 
Granular mediators (histamine, seratonin)
Eicosanoids (PGs and LTs)
Platelet Activating Factor
Plasma-derived inhibitors (bradykinin)
Cytokines (ILs)
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1
Q

What are the adverse effects of the inflammatory response?

A

pain, hyperalgesia, allodynea, release of mediators can induce a cycle that will result in chronic inflammation ( self-perpetuating)

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2
Q

Hoe is pyrexia initiated?

A

IL-1 released from macrophages elevates the hypothalamic set point and stops the correction processes

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3
Q

What happens in endotoxic shock and what do NSAIDS do?

A

The LPS (endotoxins) damage the WBCs and vascular endothelium and release vasoactive mediators, NSAIDS prevent the generation of these mediators during endotoxaemia.

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4
Q

What is important about NSAIDS pharmacokinetics?

A

They are very species variable, so dosing rate in one species cannot be used for another species.

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5
Q

How are NSAIDS absorbed?

A

They are administered orally or parenterally. They are weak acids so are absorbed rapidly in the stomach, food may interfere with absorption e.g. PBZ needs to be given without food whereas mavacoxib needs to be given with food.

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6
Q

How are NSAIDS distributed?

A

They are 99% PPB (careful of small change=toxicity due to inc free drug).
Small apparent Vd of <0.2 (ECF) and they accumulate at the site of inflammation (brought there on the proteins)
Short t1/2, long duration of effect (bind COX)

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7
Q

How are NSAIDS metabolised?

A

Hepatic metabolism and some excretion of unaltered drug in the urine. They have some active metabolites e.g. Salicylate (aspirin).
Metabolism and excretion are slow in young animals.
Some display 0 order kinetics. (salicylate in cat and PBZ in dog)

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8
Q

How do NSAIDS cause GI ulceration?

A

Related to inhibition of COX.
GIT ulceration due to dec synth of GI PG (PGE2)-PGs stimulate mucous secretion and the decreased inhibition of HCl from parietal cells (Gastrin and Histamine promote HCl)
Horses get this in the LI due to PBZ binding to food.

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9
Q

How do NSAIDS cause nephrotoxicity?

A

During hypovolaemia or hypotension in the kidney PGs cause dilation of the efferent arteriole and constriction of the afferent arteriole by activating RAAS. NSAIDS stop PGs from being secreted = hypoxia and hyperosmolarity in medullary interstitial cells.

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10
Q

What is the relationship between NSAIDS and Hepatotoxicity?

A

All have the potential to do this, some cases are idosyncratic and with aspirin and paracetamol it is dose dependant. Labradors and carprofen!!

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11
Q

What do NSAIDS do to the coagulation mechanisms?

A

They have an anti-thrombotic effect.

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12
Q

What would be the advantage of a COX-2 NSAID?

A

It would reduce the COX-1 side effects that are seen a sit would not effect the PGs synthesised for normal cell function and only target those with inflammatory action.

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13
Q

What are the uses of NSAIDS?

A

Anaphylaxis, arthritis/synovitis, endotoxaemia, asthma and anti- thrombotics.

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14
Q

What is the definition of an NSAID?

A

Agents which inhibit the formation of eicosanoids from arachidonic acid. (PGs, thromboxanes and LTs).

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15
Q

What is the mechanism of action of an NSAID?

A

It blocks the enzyme cyclo-oxygenase (COX), there are two forms of the enzyme, COX-1 and COX-2. COX-1 produces cells critical for normal cell function whereas COX-2 produces inflammatory cells. But the NSAIDS are non-selective for COX-1 and COX-2.

16
Q

What are the central effects of NSAIDS?

A

Analgesic and antipyretic.

17
Q

What are the peripheral effects of NSAIDS?

A

Anti-inflammatory, Anti-thrombotic, Anti-endotoxic and cartilage effects.

18
Q

What are the analgesic properties of NSAIDS?

A

They can act on acute pain (insult), persistent pain (insult remains) and chronic pain (insult has gone=hyperalgesia( sensitised pain receptors) and allodynea).
They are good for post-op pain management as they stop the production of cells associated with pain (PGs). We will still have to act against Bradykinnin and cytokines (TNF a and IL-1=macrophages).

19
Q

What are the 3 ways that multiple NSAIDs can interat?

A

1) 2 cyclo-oxygenase inhibitors so there will be added efficacy and toxicity.
2) There is slower clearance when combined NSAIDs are used
3) They are highly protein bound drugs- displacement of the drug with lower binding= toxicity.

20
Q

What are the characteristics of aspirin and what are its side effects?

A

It is hydrolysed to the active salicylate and irreversibly binds cyclo-oxygenase. Its side effects include GI erosions, haemorrhage and emesis.

21
Q

How is aspirin metabolised?

A

It is oxidised and some is conjugated to glucuronide or sulphate.
There are extreme variations in half life.

22
Q

What is the effect of aspirin on thrombus formation?

A 
It is an effective antithrombotic agent at low doses.
Thromboxane A2 (platelets) is inhibited at low doses whereas the PGI2 (endothelium) which promotes vasodilation and disaggregation of platelets is only inhibited at high doses.
23
Q

How is paracetamol metabolised?

A

1) glucuronidation 2) sulphate conjugation 3) N-hydroxylation
The pathway yields NABQ which binds to glutathione, if this becomes saturated it will bind to hepatic proteins and cause necrosis.
This is treated with N-acetylcysteine which a precursor of glutathione that provides a substrate for N-hydroxylation.

24
Q

How does paracetamol differ from NSAIDs?

A

It acts a step lower down on the cyclic endoperoxidases, it is a good anti-pyretic, analgesic but has an inferior inflammatory effect.

25
Q

What are the characteristics of phenylbutazone?

A

It is a more potent anti-inflammatory than an analgesic.
Its associated with cyclo-oxygenase inhibition.
It concentrates in inflammatory exudate as it is brought to the site by albumin.
It can cause protein losing enteropathies in ponies.

26
Q

What are the pharmacokinetics of phenylbutazone?

A

Absorption is reduced by food and there is a large species variation.
An active metabolite, oxyphenbutazone which is an active NSAID.
It has zero order kinetics as the half life varies with dose. (t 1/2 is difficult to predict).

27
Q

What are the characteristics of carprofen?

A

It is a poor cyclo-oxygenase inhibitor but a potent anti-inflammatory.
It is a racemic mix (s and r).
It is COX-1 sparing so is well tolerated and has a good safety profile.

28
Q

What is Carprofen used for?

A

It can be used as a perioperative analgesic with reduced risk of nephropathy.

29
Q

What are the characteristics and benefits of Robenacoxib?

A

It was developed to increase GI safety and only needs to be administered once daily. It has a similar safety profile to carprofen.
It is metabolised in the liver and excreted via the gall bladder.

30
Q

What are the characteristics Mavacoxib and what are the advantages of it?

A

It is a preferential COX-2 inhibitor. It is given orally and food increases it bioavailability. It is highly protein plasma bound and has first order kinetics.
(biliary excretion)

31
Q

What is an example of a drug that is structurally similar to proteoglycans?

A

Hyaluronan- ubiquitous, naturally occurring, chondroprotective agent. (joints)

32
Q

How is hyaluronan used?

A

Intra-articular and IV admin of exogenous hyaluronan. It is used in dogs and horses. It is only licensed in horses.

33
Q

What are the 5 things that hyaluronan does?

A

1) increases proteoglycan synthesis
2) free radical scavenger
3) decreased PGE2 synthesis
4) decreased IL-1 induced proteoglycan release
5) decreased leucocyte and macrophage activity

34
Q

What are the characteristics of heparinoids?

A

Similar structure to heparin so they may inhibit clotting.
Intra-articular and IM use in horses
Stimulates matrix production by chondrocytes and may reduce activity of MMP.
Excreted in the kidney.

35
Q

What are Matrix Metalloproteinsases?

A

Proteolytic enzyme that degrade the matrix. They play a role in joint disease and are a target for new NSAIDs.
They are inhibited by TIMPs.

36
Q

What are Nutraceuticals?

A

e.g. green lipped mussel etc. They have no stringent manufacturing process or undergo any testing for efficacy.

Applied Pharmacology (5 decks)

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