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Pharmacology and Therapeutics > 17. NSAIDs > Flashcards

17. NSAIDs Flashcards

1
Q

What properties make NSAIDs so widely used?

A

Analgesic (mild to moderate pain)
• Toothache, headache etc.
• Postoperative pain
• Dysmenorrhea

Antipyretic
• Reduction of fever

Anti-inflammatory
• rheumatoid arthritis
• osteoarthritis
• other musculoskeletal injury
• soft tissue injury
• gout
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2
Q

How do NSAIDs work (generally)?

A
  • Inhibit COX enzymes
  • Synthesis of prostanoids from is inhibited (prostaglandins/thromboxane/prostacyclin)
  • These act is many ways e.g. inflammatory mediators
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3
Q

Are prostanoids stored pre-form?

A

No, they are produced and released straight away

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4
Q

What is the rate limiting step for the production of all prostanoids?

A

COX

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5
Q

What is arachidonic acid produced from?

A

Phospholipid membranes

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6
Q

What does COX convert arachidonic acid into?

A

Prostaglandin H2

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7
Q

Which 5 products does prostaglandin H2 convert to?

A
  • PGI2 (prostacyclin)
  • PGE2
  • PGD2
  • PGF2
  • Thromboxane A2
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8
Q

What do the products of COX action look like?

A

5-membered ring with 2 lipid tails

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9
Q

What are the 10 known prostanoid receptors and what are the names based on?

A
  • DP1
  • DP2
  • EP1
  • EP2
  • EP3
  • EP4
  • FP
  • IP1
  • IP2
  • TP

(name based on agonist potency - but not totally specific e.g. PGE2 can activated EP1, 2, 3 and 4)

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10
Q

Are prostanoid actions G-protein mediated?

A

Both G protein-dependent and independent effects

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11
Q

What 2 different G-protein mechanisms can PGE2 work through?

A

cAMP-dependent and independent downstream

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12
Q

What are the unwanted actions of PGE2?

A
  • Increased pain perception
  • Increased body temperature
  • Acute inflammatory response
  • Immune responses (+ve and -ve)
  • Tumorigenesis
  • Inhibition of apoptosis
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13
Q

What effect do PGE2 analogues have on pain?

A
  • Lower the pain threshold
  • Hyperalgesia
  • Smaller stimulus will produce pain
  • EP1 and EP4 (periphery and spine) involved
  • Endocannabinoids involved (thalamus, spine and periphery)
  • Decreased beta-endorphin (spine)
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14
Q

What happens if you co-inject a COX 2 inhibitor with a NSAID?

A

Reduce the duration of prolonged pain

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15
Q

How is PGE2 pyrogenic?

A
  • PGE2 increases during inflammation
  • Stimulates hypothalamic neurones
  • Homeostatic thermostat is influenced
  • Rise in body temperature initiated
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16
Q

How does PGE2 cause inflammation?

A
  • Keratinocytes are stimulated by external stimuli to produce PGE2
  • EP3 receptors on mast cells are stimulated
  • EP3 works through multiple mechanisms (calcium regulated and G-protein coupled)
  • Cross-talk between cells
  • Calcium release => degranulation => histamine
17
Q

What desirable actions does PGE2 (and other prostanoids) have?

A
  • Bronchodilation (except PGD2)
  • Renal salt and water homeostasis in the kidney (COX 1 and 2 involved in nephron)
  • Gastro-protection
  • Vaso-regulation (dilaiton/constriction depending on receptor)
18
Q

Why do NSAIDs cause worsening symptoms in (10% of) asthma patients?

A
  • COX inhibition decreases its products which favour bronchodilation
  • COX inhibition also favours production of leukotrienes - bronchoconstrictors
19
Q

How an NSAIDs cause renal toxicity?

A
  • Constriction of afferent renal arteriole
  • Reduction in renal artery flow
  • Reduced glomerular filtration rate
20
Q

How is PGE2 involved in gastric cytoprotection?

A
  • Parietal cells normally produce HCl
  • Cells lining the stomach produce a mucous layer and also use bicarbonate secretion to protect from acid
  • PGE2 down-regulates HCl secretion, and stimulates mucus and bicarbonate secretion
  • Both COX 1 dependent
21
Q

How does NSAIDs increase the risk of gastric/duodenal ulceration?

A
  • Inhibition of COX 1 in the stomach decreases PGE2
  • Less protective effects => stomach is more vulnerable to damage from acidity
  • As NSAIDs are taken orally, this further increases the effect
22
Q

Which COX isoform do most NSAIDs inhibit?

A

Most reversibly inhibit both COX 1 and 2

23
Q

Which COX isoform do the Coxib family (NSAID) inhibit and why is this useful?

A
  • Reversibly inhibit COX 2

* Gastroprotective (however there are other negative effects)

24
Q

What unwanted cardiovascular effects do NSAIDs have?

A
  • Vasoconstriction
  • Salt and water retention
  • Reduced effects of antihypertensive drugs

NSAIDs pose a risk of hypertension, MI and stroke

25
Q

What does evidence suggest for the unwanted CVS effects of selective COX-2 inhibitors compared to conventional NSAIDs?

A
  • COX-2 inhibitors pose a higher risk of CVD
  • COX-2 is found in the vascular endothelial and smooth muscle cells, heart and kidney
  • Mechanism is unclear and complex but this could play a role
26
Q

How does the risk of GI bleeds and CVS events change in different types of NSAIDs?

A
  • The most COX-2 binding NSAIDs have a higher CVD risk but lower GI risk
  • As the drug becomes more COX-1 selective and less COX-2 selective, risk for CVD decreases and GI bleed increases

e.g.
• Coxibs (COX-2 selective) - worse for CVS, better for for GI
• Ibuprofen (non-selective) - minimal risks for CVS and GI
• Piroxicam (COX-1 selective) - better for CVS, worse for GI

27
Q

Is it worse to use NSAIDs as an analgesic or anti-inflammatory?

A

Worse as anti-inflammatory
• often sustained (occasional as analgesic)
• higher doses
• tends to be elderly (with impaired kidney function => more side effects)

28
Q

What strategies can be used for limiting GI side effects other than COX-2 (which increase CVS effects)?

A
  • Topical application (however limited systemic dose)
  • Minimise use in patients with GI ulceration history or other risk factors
  • Treat H. pylori if present
  • Administer with omeprazole (PPI)
  • Reduce risk factors e.g. alcohol, anticoagulant/glucocorticoid use
29
Q

How doe aspirin work and what makes it unique?

A
  • COX-1 selective
  • Unique => binds irreversibly (covalent)
  • Acetylation of the active site of both COX enzymes, but particularly COX-1
  • Also reduces platelet aggregation in low doses
30
Q

What effects do the products of PGH2 have on platelet action?

A

• Platelets produce thromboxane A2 => enhanced platelet action
- by COX-1
• Endothelial cells produce prostacyclin => decreased platelet action
- by COX 1 and 2

31
Q

How does low dose aspirin effect platelet aggregation?

A
  • COX-1 of platelets inhibited
  • Platelets have no nucleus so cannot recover to produce thromboxane A2 => decreased platelet action, less clotting
  • Endothelial cells can regenerate COX and continue producing prostacyclin => anti-aggregatory
  • Endothelial cells also have COX-2 which is less affected
32
Q

How does high dose aspirin effect platelet aggregation?

A

• COX-1 of platelets inhibited
=> no thromboxane A2 to cause platelet aggregation
• However, endothelial cell COX is permanently inhibited due to high dose
=> no prostacyclin produced to decrease platelet aggregation
• Effects cancel out - almost no effect

33
Q

What are the major side-effects of aspirin?

A
  • Gastric irritation and ulceration
  • Bronchospasm in sensitive asthmatics
  • Prolonged bleeding
  • Nephortoxicity

Side-effects with aspiring more likely due to covalent inhibition rather than COX-1 selectivity

34
Q

How is paracetamol similar and different to NSAIDs?

A
  • Also analgesic for mild-moderate pain
  • Also anti-pyretic
  • Not anti-inflammatory
  • Probably central, as well as peripheral, effect
  • COX-3? Cannabinoid? Endogenous opioid?
35
Q

What is the maximum dose of paracetamol?

A

4g (8 tablets) / 24 hours

36
Q

What effect can a paracetamol overdose have?

A
  • Paracetamol normally metabolised by CYP450
  • Toxic, highly reactive metabolite produced (NAPQI)
  • Normally this is mopped up by glutathione and inactivated
  • In overdose, glutathione is depleted (saturated with NAPQ1)
  • Excess NAPQI oxidises thiol groups of key hepatic enzymes and causes cell death
  • Hepatotoxicity => slow death
37
Q

What is the antidote for paracetamol poisoning?

A
  • Add compound with -SH groups (IV acetylcysteine, occasionally oral methionine)
  • If not administered early enough, liver failure may be unpreventable
38
Q

How was the sale of paracetamol restricted in 1998?

A

Pack size restricted to 16 x 500mg tablets

39
Q

What do the 2009 guidelines for the sale of paracetamol state?

A
  • No more than 2 packs per transaction
  • Illegal to sell more than 100 paracetamol in one transaction

Since 2009, deaths from overdose have fallen by 43% and registrations for liver transplants have decreased by 60%

Pharmacology and Therapeutics (33 decks)

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