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Y2 - PHARM > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

Give 3 medicinal properties that NSAIDs are useful for

A
  1. Analgaesic
  2. Anti-pyretic
  3. Anti-inflammatory
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2
Q

Outline the prostaglandins synthesis pathway

A
  1. Arachidonic Acid is converted into Prostaglandin H2 by Cyclooxygenase enzymes (COX 1 and COX 2)
  2. Prostaglandin H2 is converted into all the prostanoids by specific synthases, including…
  • Prostacyclin
  • PGI2
  • PGE2
  • PGD2
  • PGF2
  • TXA2
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3
Q

There are 10 different prostanoid receptors, they are DP1, DP2, EP1, EP2, EP3, EP4, FP, IP1, IP2, TP.

What’s receptor mediated action is more potent, action through EP1 or EP2 for example, i.e. what is the naming rule?

A
  • EP2 is more powerful than EP1
  • The higher the potency of the pathway mediated by the receptor, the higher the number at the end
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4
Q

What receptors does PGE2 act on and what mechanism do these receptors work by?

A
  • EP1, EP2, EP3, EP4
  • They are all G-protein linked but some can work by different mechanism e.g. EP2 works by 2 mechanisms
  • Can be both CAMP-dependent and independent G-protein linked
  • Can be PLC / IP3 mediated etc
  • Basically G-protein linked is what I’m trying to say
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5
Q

List some unwanted actions of PGE2

A
  • Increased pain perception
  • Increased body temperature
  • Inflammatory
  • Immune responses
  • Tumorigenesis
  • Inhibition of apoptosis
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6
Q

Describe the role of PGE2 in pain perception and the mechanism of how prostanoids do this

A
  • Lowers the pain threshold
  • Stimulation of PG receptors (e.g. EP1, 2, 3, 4) sensitises nociceptors

Mechanisms are unclear but may be to do with:

  • EP1, 4 receptor mediated (EP4 in periphery and spine)
  • Endocannabinoids (neuromodulators in spine, thalamus and periphery)
  • Increasing beta-endorphin in the spine
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7
Q

Describe the role of PGE2 in body temperature regulation

A
  • PGE2 is pyrogenic
  • PGE2 stimulates hypothalamic neurones to influence the body’s homeostatic thermostat
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8
Q

Describe the role of PGE2 in inflammation

A
  • Keratinocytes are stimulated to synthesise and secrete PGE2
  • PGE2 acts on EP3 receptors on mast cells
  • This is Gi protein linked causing a signalling cascade pathway via PLC / IP3 / DAG ultimately leading to calcium release
  • This stimulates mast cell degranulation and thus histamine release
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9
Q

Briefly just list 4 desirable (or just not undesirable) physiological actions of PGE2 (and other prostanoids)

A
  1. Bronchodilation
  2. Gastroprotection
  3. Renal salt and water homeostasis
  4. Vaso-regulation
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10
Q

Which prostanoid is an exception to the rule that all prostanoids are bronchodilators?

A

PGD2

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11
Q

Outline the mechanism by which prostanoids cause bronchodilation and thus why you should not administer NSAIDs to people with asthma

A
  • It’s not so much a direct effect, it’s more an impact on the synthesis pathway
  • Arachidonic acid can either be converted into PGH2 and begin going down the prostanoid pathway through the action of COX 1 and 2, or it can go down the leukotriene synthesis pathway
  • The leukotrienes are bronchoconstrictors
  • So, prostanoid synthesis takes away the arachidonic acid which could be used to form the bronchoconstrictory leukotrienes, thereby causing bronchodilation
  • Therefore, you must not administer NSAIDs to patients with asthma because they prevent the action of COX enzymes to convert arachidonic acid into PGH2 and enter the prostanoid pathway, thereby promoting the leukotriene pathway and causing bronchoconstriction which is harmful to patients who already struggle to breathe with asthma
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12
Q

Describe the role of PGE2 in the kidneys and thus describe the (usually unwanted) effect that NSAIDs can have here and how they do this

A
  • PGE2 increases renal blood flow
  • N.B COX 1 and 2 also act on multiple parts of the nephron

NSAIDS can therefore cause renal toxicity by counteracting this effect, they act on the kidneys to:

  • Constrict afferent arterioles
  • Decrease blood flow in renal arteries
  • Decrease the glomerular filtration rate (GFR)
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13
Q

Describe the role of PGE2 and prostanoids in the stomach and thus an undesired effect of NSAIDs you must be wary of in terms of the stomach and thus why it is preferred to not have NSAIDS on an empty stomach

A
  • PGE2 is gastroprotective
  • It inhibits the synthesis of gastric acid from parietal cells
  • It promotes the synthesis of gastric mucous and of bicarbonate which act as a protective layer for the epithelial cells lining the stomach surface from the strong gastric acid
  • Therefore, NSAIDs can counteract these effects and thereby result in increased risk of gastric and duodenal ulceration
  • You must not have NSAIDs on an empty stomach, the food helps protect the stomach lining
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14
Q

Name an NSAID which is an unselective COX antagonist (i.e. antagonist against both the COX isoforms, 1 and 2)

A
  • Ibuprofen
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15
Q

Name a family of NSAIDs that selectively inhibit COX-2 and an example drug belonging to it

A
  • Coxib family
  • E.g. celecoxib
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16
Q

Describe the unwanted CVS effects that NSAIDs can have and, in particular which type of NSAID?

A
  • Vasoconstriction
  • Salt and water retention
  • Reduce the effects of anti-hypertensive drugs

This increases the risks from:

  • HTN
  • MI
  • Stroke

Particular risk from selective COX-2 inhibitors

17
Q

Name a COX-1 selective antagonist

A

Piroxicam

18
Q

What is a particular risk with each of these and name an example drug / drug family belonging to each:

1) Selective COX-1 inhibitors
2) Selective COX-2 inhibitors

A

1)

  • GI bleeds
  • Piroxicam

2)

  • CVS events
  • Coxib family
19
Q

What are some strategies for preventing GI side effects of NSAIDs use?

A
  • Give COX-1 selective antagonists rather than COX-2 if appropriate because COX-1 antagonists have the most gastric side effects
  • Topical application rather than oral
  • Minimise NSAID use in patient with history of gastric problems
  • Treat H.Pylori if present
  • Co-administer omeprazole or other proton pump inhibitors
  • Minimise use in patients with other risk factors including alcohol use or anticoagulant or glucocorticoid steroid use
20
Q

What is it about the action of aspirin which makes it unique amongst the NSAIDs?

A
  • Because it irreversibly antagonises COX-1 enzymes
  • Other NSAIDs usually reversibly antagonise the COX enzymes
21
Q

Describe the effects that aspirin has and how its actions are dose dependent, explain the physiology behind all this

A
  • Endothelial cells produce PGI2 using both COX-1 AND COX-2, which inhibits platelet aggregation
  • Platelets produce TXA2 (thromboxane A2) using COX-1, which promotes platelet aggregation
  • At low dose of aspirin, a selective irreversible COX-1 antagonist, you inhibit the platelet’s production of TXA2, thereby impairing platelet aggregation. Also, you are impairing somewhat to a lesser extent the production of PGI2, therefore slightly also increasing it (but not as much as it is reduced). Also, since the endothelial cells have nuclei which can just compensate by increasing COX production while platelets are anuclear and cannot compensate, there is greater impact on TXA2. SO AT LOW DOSE, THERE IS INHIBITION OF PLATELET AGGREGATION
  • At high dose: There is both inhibition of TXA2 production by the platelets and PGI2 production by the endothelial cells, and to a greater extent TXA2 is inhibited. The high dose counteracts the compensatory increase in nuclear synthesis of COX enzymes by the endothelial cells so this doesn’t matter. SO AT HIGH DOSE, THERE IS LITTLE EFFECT ON PLATELET AGGREGATION
22
Q

Why is Paracetamol not considered an NSAID?

A
  • Because, while it is anti-pyretic and a good analgaesic, it does not have anti-inflammatory effects
23
Q

Outline the metabolism of paracetamol and then what would happen in Paracetamol overdose and how this may cause death

A
  • Paracetamol is metabolised by CYP450 enzymes into the toxic metabolite NAPQI, but this is not fatal at therapeutic dose
  • NAPQI is further metabolised as it is mopped up by glutathione donated by N-acetylcysteine, glutathione-s-transferase used to reduce the NAPQI and conjugate on the glutathione. This is the inactive reduced form which is no longer toxic and ready for excretion
  • In overdose, there may be overload of glutathione with NAPQI such that this conversion into the inactive form cannot occur
  • The toxic metabolite NAPQI which builds up can now oxidise thiol groups of key hepatic enzymes and cause cell death
  • Liver toxicity leads to death
24
Q

What is the antidote to Paracetamol overdose?

A
  • I.V Acetylcysteine - donates extra glutathione to mop up the toxic NAPQI metabolite of Paracetamol and convert it into its reduced, inactive form

Y2 - PHARM (27 decks)

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