17. NSAIDs Flashcards by Yash Kapoor

What properties make NSAIDs so widely used?

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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How do NSAIDs work (generally)?

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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Are prostanoids stored pre-form?

No, they are produced and released straight away

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

COX

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What is arachidonic acid produced from?

Phospholipid membranes

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What does COX convert arachidonic acid into?

Prostaglandin H2

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Which 5 products does prostaglandin H2 convert to?

PGI2 (prostacyclin)
PGE2
PGD2
PGF2
Thromboxane A2

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What do the products of COX action look like?

5-membered ring with 2 lipid tails

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

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

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Are prostanoid actions G-protein mediated?

Both G protein-dependent and independent effects

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

cAMP-dependent and independent downstream

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What are the unwanted actions of PGE2?

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

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What effect do PGE2 analogues have on pain?

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

Reduce the duration of prolonged pain

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How is PGE2 pyrogenic?

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

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How does PGE2 cause inflammation?

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

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

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)

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

COX inhibition decreases its products which favour bronchodilation
COX inhibition also favours production of leukotrienes - bronchoconstrictors

How an NSAIDs cause renal toxicity?

Constriction of afferent renal arteriole
Reduction in renal artery flow
Reduced glomerular filtration rate

How is PGE2 involved in gastric cytoprotection?

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

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

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

Which COX isoform do most NSAIDs inhibit?

Most reversibly inhibit both COX 1 and 2

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

Reversibly inhibit COX 2

* Gastroprotective (however there are other negative effects)

What unwanted cardiovascular effects do NSAIDs have?

Vasoconstriction
Salt and water retention
Reduced effects of antihypertensive drugs

NSAIDs pose a risk of hypertension, MI and stroke

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

* 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

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

* 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

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

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

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

* 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

How doe aspirin work and what makes it unique?

* 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

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

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

How does low dose aspirin effect platelet aggregation?

* 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

How does high dose aspirin effect platelet aggregation?

• 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

What are the major side-effects of aspirin?

* 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

How is paracetamol similar and different to NSAIDs?

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

What is the maximum dose of paracetamol?

4g (8 tablets) / 24 hours

What effect can a paracetamol overdose have?

* 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

What is the antidote for paracetamol poisoning?

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

How was the sale of paracetamol restricted in 1998?

Pack size restricted to 16 x 500mg tablets

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

* 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%