NSAIDs Flashcards
What are the properties of NSAIDs?
- analgesic
- anti-pyretic
- anti-inflammatory
When are NSAIDs used for their analgesic properties?
- toothache
- headache
- backache
- post-operative
- dysmenorrhoea (menstrual pain)
When are NSAIDs used for their anti-pyretic properties?
reducing fever in influenza for example
When are NSAIDs used for their anti-inflammatory properties?
- rheumatoid arthritis
- osteoarthritis
- musculoskeletal inflammation
- soft tissue injuries
- gout
How do NSAIDs work?
They inhibit the production of prostanoids by COX enzymes (COX1, COX2). COX is the rate limiting step for the production of all prostanoids
What are prostonoids?
prostaglandins, thromboxane and prostacyclin
What are some features of prostanoids?
- they are widely distributed
- not stored pre-formed, when made they are released
- act on receptors
What are all prostanoids made from?
From arachidonic acid
Give some examples of prostanoids
PGE2 PGI2 (prostacyclin) PGD2 PGF2 Thromboxane
How many prostanoid receptors are there?
10 - named based on agonist potency
DP1, DP2, EP1, EP2, EP3, EP4, FP, IP1, IP2, TP
Are prostanoid receptors specific?
NO - different prostanoids can act on the same receptor hence the effects of inhibiting prostanoid production can have multiple complex effects
How do prostanoid receptors work?
They have G protein dependent and independent actions
Which receptors does PGE2 activate?
What are the unwanted effects of PGE2?
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
What do PGE2 analogues do?
- 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
How do prostanoids lower the pain threshold?
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
How is PGE2 pyrogenic?
- 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
How is PGE2 involved in inflammation?
- 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
What are some desirable effects of prostanoids?
- Bronchodilation (except PGD2 which does opposite)
- Renal salt and water homeostasis
- Gastro-protection
- Vaso-regulation (dilation and constriction depending on receptor activated)
Why do prostanoids cause bronchodilation?
- Cyclooxygenase inhibition favours production of leukotrienes (bronchoconstrictors
- NSAIDS should not be taken by asthmatic patient
How does PGE2 affect the kidney?
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)
How can NSAIDs cause renal toxicity?
- Constriction of afferent renal arteriole
- Reduction in renal artery flow
- Reduced glomerular filtration rate
What is the role of PGE2 in gastric protection?
Which COX is involved?
- 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
How can NSAIDs have unwanted effects on the stomach and duodenum?
- 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
COX1 and COX2 - are they completely isolated in distribution?
- COX-1 and COX-2 have different (but frequently overlapping) cellular distributions
Give an example of an NSAID that inhibits COX 1+2 and one that inhibits only COX2
- Both: ibuprofen
- COX2: celecoxib
What are COXib drugs?
selectively inhibit COX2: thought to be gastroprotective and even though they were, there were other effect from them
What are some serious unwanted CV effects of NSAIDs?
- Vasoconstriction
- Salt and water retention
- Reduce the effects of antihypertensive drugs
What CV conditions do NSAIDs have a risk of increasing?
- Hypertension
- Myocardial infarction
- Stroke
COX2 inhibitors and CVS effects
- 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
Give an example of an NSAID that is COX-1 selective?
piroxicam
What do all NSAIDs increase the risk of?
Particularly what do COX-2 and COX-1 selective NSAIDs increase the risk of?
- 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
What are the risks and benefits of using NSAIDs for analgesic and anti-inflammatory purposes?
- 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
How can the GI side effects of NSAIDs be avoided? (other than use COX2 selective drugs)
- 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
Why is aspirin a unique NSAID?
Binds IRREVERSIBLY to COX enzymes
What is aspirin selective for/
COX1 particularly but works by acetylation of both enzyme’s active sites
What are the roles of aspirin?
- Has anti-inflammatory, analgesic and anti-pyretic actions
- Reduces platelet aggregatio
Why are the effects of aspirin dose dependent?
- 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
What happens with high and low dose aspirin?
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
Why does aspirin have anti-platelet activity?
- 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
What are the side effects of aspirin?
- 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
What is paracetamol used for? Is it an NSAID and why?
- Is a good analgesic for mild-to-moderate pain
- Has anti-pyretic action
- Does not have any anti-inflammatory effect so not an NSAID
How does paracetamol work?
- 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?
Why does paracetamol overdoes cause liver failure?
- 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
What is the antidote for paracetamol poisoning?
- 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
How have rules been put in place to reduce paracetamol overdoses?
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
Has legislation reduced deaths from paracetamol overdose?
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)
