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Pharmacology > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

What are the properties of NSAIDs?

A
  • analgesic
  • anti-pyretic
  • anti-inflammatory
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2
Q

When are NSAIDs used for their analgesic properties?

A
  • toothache
  • headache
  • backache
  • post-operative
  • dysmenorrhoea (menstrual pain)
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3
Q

When are NSAIDs used for their anti-pyretic properties?

A

reducing fever in influenza for example

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4
Q

When are NSAIDs used for their anti-inflammatory properties?

A
  • rheumatoid arthritis
  • osteoarthritis
  • musculoskeletal inflammation
  • soft tissue injuries
  • gout
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5
Q

How do NSAIDs work?

A

They inhibit the production of prostanoids by COX enzymes (COX1, COX2). COX is the rate limiting step for the production of all prostanoids

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6
Q

What are prostonoids?

A

prostaglandins, thromboxane and prostacyclin

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7
Q

What are some features of prostanoids?

A
  • they are widely distributed
  • not stored pre-formed, when made they are released
  • act on receptors
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8
Q

What are all prostanoids made from?

A

From arachidonic acid

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9
Q

Give some examples of prostanoids

A 
PGE2 
PGI2 (prostacyclin)
PGD2
PGF2
Thromboxane
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10
Q

How many prostanoid receptors are there?

A

10 - named based on agonist potency

DP1, DP2, EP1, EP2, EP3, EP4, FP, IP1, IP2, TP

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11
Q

Are prostanoid receptors specific?

A

NO - different prostanoids can act on the same receptor hence the effects of inhibiting prostanoid production can have multiple complex effects

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12
Q

How do prostanoid receptors work?

A

They have G protein dependent and independent actions

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13
Q

Which receptors does PGE2 activate?

What are the unwanted effects of PGE2?

A

PGE2 can activate 4 different receptors (EP1, EP2, EP3 and EP4)

Unwanted effects of PGE2:

  • Increased pain perception
  • Increased body temperature
  • Acute inflammatory response
  • Immune responses
  • Tumorigenesis
  • Inhibition of apoptosis
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14
Q

What do PGE2 analogues do?

A
  • They lower the pain threshold (nociceptors cause pain, both acutely and chronically)
  • Stimulation of PG receptors in the periphery sensitises nociceptors -> lowers pain threshold
  • Co-injection of a COX 2 inhibitor prevents or reduces the duration of prolonged pain
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15
Q

How do prostanoids lower the pain threshold?

A

Mechanisms are unclear

  • EP1 receptors and EP4 receptors (EP4 in periphery and spine)
  • Endocannabinoids (neuromodulators in thalamus, spine and periphery)
  • Increasing beta-endorphin in spine
  • Not mutually exclusive
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16
Q

How is PGE2 pyrogenic?

A
  • It stimulates hypothalamic neurones initiating a rise in body temperature
  • Animals were treated with lipopolysaccharide (found on gram –ve bacteria, highly pro-inflammatory)
  • Once injected, the levels of PGE2 raised dramatically, followed by dramatic increase in temperature
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17
Q

How is PGE2 involved in inflammation?

A
  • The role of PGE2-EP3 signalling in acute inflammation EP3 works through multiple mechanisms - calcium regulated and through G protein coupled receptors.
  • There is cross-talk between cells
  • Keratinocytes are stimulated by external stimuli to produce PGE2
  • EP3 receptors on mast cells are in turn stimulated
  • This produces calcium release -> degranulation -> histamine
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18
Q

What are some desirable effects of prostanoids?

A
  • Bronchodilation (except PGD2 which does opposite)
  • Renal salt and water homeostasis
  • Gastro-protection
  • Vaso-regulation (dilation and constriction depending on receptor activated)
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19
Q

Why do prostanoids cause bronchodilation?

A
  • Cyclooxygenase inhibition favours production of leukotrienes (bronchoconstrictors
  • NSAIDS should not be taken by asthmatic patient
20
Q

How does PGE2 affect the kidney?

A

Both COX isoforms (COX 1 and 2) are involved at multiple points in the nephron. PGE2 has a role in renal blood flow (increases flow)

21
Q

How can NSAIDs cause renal toxicity?

A
  • Constriction of afferent renal arteriole
  • Reduction in renal artery flow
  • Reduced glomerular filtration rate
22
Q

What is the role of PGE2 in gastric protection?

Which COX is involved?

A
  • Parietal cells normally produce HCl, secreting it into the stomach hence cells lining stomach must be protected
  • They produce a mucous layer and also protect themselves by bicarbonate secretion
  • PGE2 normally down-regulates HCl secretion and stimulates mucus and bicarbonate secretion
  • THESE ARE BOTH COX 1 DEPENDENT ACTIONS
23
Q

How can NSAIDs have unwanted effects on the stomach and duodenum?

A
  • NSAIDs increase risk of gastric and duodenal ulceration (around 1000 deaths annually in England)
  • NSAIDs are taken orally, so there is a high load in the stomach
24
Q

COX1 and COX2 - are they completely isolated in distribution?

A
  • COX-1 and COX-2 have different (but frequently overlapping) cellular distributions
25
Q

Give an example of an NSAID that inhibits COX 1+2 and one that inhibits only COX2

A
  • Both: ibuprofen

- COX2: celecoxib

26
Q

What are COXib drugs?

A

selectively inhibit COX2: thought to be gastroprotective and even though they were, there were other effect from them

27
Q

What are some serious unwanted CV effects of NSAIDs?

A
  • Vasoconstriction
  • Salt and water retention
  • Reduce the effects of antihypertensive drugs
28
Q

What CV conditions do NSAIDs have a risk of increasing?

A
  • Hypertension
  • Myocardial infarction
  • Stroke
29
Q

COX2 inhibitors and CVS effects

A
  • There is increasing evidence that selective COX-2 inhibitors pose higher risk of cardiovascular disease than conventional NSAIDS even though mechanism is unclear
  • All the prostanoids have some actions on vasoconstriction or vasodilation – so they all affect the vasculature or platelet aggregation
  • If we look specifically at COX-2 (found in the vascular endothelial and smooth muscle cells, the heart and the kidney), there are complex effects. When these are blocked, many unwanted CVS actions may result
30
Q

Give an example of an NSAID that is COX-1 selective?

A

piroxicam

31
Q

What do all NSAIDs increase the risk of?

Particularly what do COX-2 and COX-1 selective NSAIDs increase the risk of?

A
  • All NSAIDS increase risk of GI bleeds and CVS events
  • The more selective the drugs are for COX-1, the more likely you are to get a GI bleed
  • The more selective the drugs for COX-2, the more likely you are to have a cardiovascular event
32
Q

What are the risks and benefits of using NSAIDs for analgesic and anti-inflammatory purposes?

A
  • Analgesic use: Usually occasional and relatively low risk of side effects
  • Anti-inflammatory use: Often sustained, higher doses and relatively high risk of side effects
33
Q

How can the GI side effects of NSAIDs be avoided? (other than use COX2 selective drugs)

A
  • Topical application
  • Minimise NSAID use in patients with history of GI ulceration
  • Treat H pylori if present
  • If NSAID is essential, administer with omeprazole or other proton pump inhibitor
  • Minimise NSAID use in patients with other risk factors and reduce risk factors where possible e.g.
    alcohol consumption, anticoagulant or glucocorticoid steroid use
34
Q

Why is aspirin a unique NSAID?

A

Binds IRREVERSIBLY to COX enzymes

35
Q

What is aspirin selective for/

A

COX1 particularly but works by acetylation of both enzyme’s active sites

36
Q

What are the roles of aspirin?

A
  • Has anti-inflammatory, analgesic and anti-pyretic actions

- Reduces platelet aggregatio

37
Q

Why are the effects of aspirin dose dependent?

A
  • Platelets produce thromboxane, which enhances platelet action (pro-aggregatory)
  • Endothelial cells produce prostacyclin (PGI2), which decreases platelet action (anti-aggregatory)
  • Thromboxane A2 is made by COX-1 in the platelet
  • In the endothelial cell is both COX-1 and COX-2 – so PGI2 is reduced, but not totally
  • Giving aspirin at a high dose will inhibit thromboxane production
  • But it will also reduce prostacyclin production
38
Q

What happens with high and low dose aspirin?

A

LOW DOSE ASPIRIN: The nucleus in the endothelial cell simply replenishes COX enzymes. However, platelets do not have a nucleus. Therefore they cannot recover to produce more thromboxane after aspirin. This leads to no resynthesis of COX-1 in platelets -> overall reduced platelet aggregation

HIGH DOSE ASPIRIN: There is barely any action on platelet aggregation – this is because endothelial cell COX enzymes will be in a permanent state of inhibition

39
Q

Why does aspirin have anti-platelet activity?

A
  • Very high degree of COX-1 inhibition which effectively suppresses TxA2 production by platelets
  • Covalent binding which permanently inhibits platelet COX-1
  • Relatively low capacity to inhibit COX-2
  • Use low dose to allow endothelial re-synthesis of COX-2
40
Q

What are the side effects of aspirin?

A
  • Gastric irritation and ulceration
  • Bronchospasm in sensitive asthmatics
  • Prolonged bleeding times
  • Nephrotoxicity
  • Side effects likely with aspirin because it inhibits COX covalently, not because it is selective for COX-1
41
Q

What is paracetamol used for? Is it an NSAID and why?

A
  • Is a good analgesic for mild-to-moderate pain
  • Has anti-pyretic action
  • Does not have any anti-inflammatory effect so not an NSAID
42
Q

How does paracetamol work?

A
  • The mechanism of action for paracetamol is not well understood
  • Probably central and peripheral mechanism
  • Cannabinoid receptors? Endogenous opioids interaction? 5HT and adenosine receptor interaction?
43
Q

Why does paracetamol overdoes cause liver failure?

A
  • Paracetamol is normally metabolised by the cytochrome P450 complex
  • A toxic metabolite is produced (NAPQI), which is highly reactive
  • At a therapeutic dose, NAPQI is produced is very small amounts and will be mopped up by glutathione (Glutathion-s-transferase)
  • If glutathione is depleted the metabolite oxidises thiol groups of key hepatic enzymes and causes cell death
44
Q

What is the antidote for paracetamol poisoning?

A
  • Add compound with –SH groups (usually intravenous acetylcysteine, occasionally oral methionine)
  • Acetyl cysteine used in cases of attempted suicide and accidental poisoning
  • If not administered early enough, liver failure may be unpreventable
45
Q

How have rules been put in place to reduce paracetamol overdoses?

A

1998 pack size of paracetamol restricted to 16 x 500 mg tablets per pack

2009 guidelines:

  • No more than 2 packs per transaction
  • Illegal to sell more than 100 paracetamol in one transaction
46
Q

Has legislation reduced deaths from paracetamol overdose?

A

Since 2009, deaths from paracetamol overdose have fallen by 43% (~70 people a year) and about 60% fewer registrations for liver transplants (~40 people a year)

Pharmacology (26 decks)

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