NSAIDs Flashcards
NSAIDs?
Non-Steroidal Anti-Inflammatory Drugs
Major clinical uses of NSAIDs?
o Analgesic
– toothache/headache, post-op pain (opiate-sparing), menstrual pain
o Anti-pyretic
– influenza
o Anti-inflammatory
– rheumatoid arthritis, osteoarthritis, gout, soft-tissue injuries
Use of NSAIDs in the UK?
Note NSAIDs are widely used and available OTC
Deaths from NSAIDs are on par with road traffic accidents (half due to GI upsets, and half due to CVS issues)
o ~2000 deaths/annum in 2011
What is the MoA of NSAIDs?
NSAIDs INHIBIT prostanoid synthesis by blocking COX
Prostanoids:
• Derived from arachidonic acid
• Examples – prostaglandins, TXA2, prostacyclin
• Widely distributed and not stored pre-formed
• Receptor-mediated
In what forms can COX be found?
Two isoforms of COX
• COX1 & COX2)
• NSAIDs inhibit BOTH to varying degrees (e.g. ibuprofen)
Coxib family – selectively reversibly inhibits COX2 (e.g. celecoxib).
Prostanoid action is ALL receptor-mediated - explain this
Prostanoids (5 known) bind to 10 known receptors:
• DP1-2, EP1-4, FP, IP1-2, TP – named based on potency
- DP1 has the greatest affinity for prostaglandin D2
• All g-protein coupled (have effects independent of coupling however)
• Actions can be
- physiological OR pro-inflammatory
How many prostaglandins are known and receptors?
5 known agonists!
At least 10 different receptors
Inhibition of prostanoid production can have multiple complex consequences - give an example
PGE2:
• Activates 4 receptors – EP1, EP2, EP3, EP4.
• cAMP-dependant (EP2/4) OR Ca2+ mobilisation (EP1/3) OR both (EP3)!
Unwanted actions: Increased pain perception Thermoregulation Acute inflammatory response Other – immune responses, tumorigenesis, inhibition of apoptosis (so more likely necrosis)
Explain the unwanted action of ‘pain sensitisation’ of PGE2
Pain sensitisation – stimulation of PG receptors sensitises the nociceptors which causes pain acutely & chronically
• Co-injection of COX2 inhibitors prevents or reduces duration of prolonged pain (i.e. RAISE pain threshold)
Mechanism – unclear:
• Activation of EP1 and EP4 receptors (in spine & periphery)
• Endocannabinoid involvement (neuromodulators in thalamus, spine & periphery)
- This is not mutually exclusive – i.e. there IS cross-talk between prostanoids and endocannabinoids
Explain the unwanted action of ‘thermoregulation’ of PGE2
Thermoregulation – PGE2 is pyrogenic:
- PGE2 stimulates hypothalamic neurones to initiate a rise in body temperature –> hyper-pyrexia
- NSAIDs have been shown to reduce a raised temperature in influenza
Explain the unwanted action of ‘acute inflammatory response’ of PGE2
o PGE2 –> EP3 signalling.
o The EP3 receptor then signals downstream using two mechanisms – cAMP & Ca2+ mobilisation
Effects on IS is EP4 mediated
Prostanoids do have desirable effects however - briefly state these desirable effects
- GASTRO-PROTECTION
- Regulation of renal blood flow
- Bronchodilation
- Vasoregulation
Explain the desired action of ‘gastro-protection’ of PGE2
Gastro-protection – gastro-cyto-protection:
• Downregulated HCl production in the stomach
• PGE2 stimulates mucus and HCO3- secretion into the gut
• NSAIDs therefore increase the risk of ulceration –> resulting in 1000 deaths/annum.
The ulceration is thought to be due to blocking of COX1…
Fewer deaths when using Celecoxib (COX2-selective inhibitor) rather than normal NSAIDs.
Explain the desired action of ‘increase in renal blood flow’ of PGE2
PGE2 increases renal blood flow so NSAIDs can cause renal toxicity (not for renal failure patients)
Renal toxicity via:
Constriction of afferent renal arteriole.
Reduction in renal artery flow.
Reduced glomerular filtration rate.
Explain the desired action of ‘bronchodilation’ of PGE2
Bronchodilation – hence why asthmatics shouldn’t take NSAIDs
Approx. 10% of asthmatics experience worsening symptoms with NSAIDs
COX inhibition favours production of leucotrienes (as the other pathway for arachidonic acid is inhibited) which are potent Broncho-constrictors.
• Asthmatics should NOT take NSAIDs.
Explain the desired action of ‘vasoregulators’ of PGE2
Vaso-regulation – dilation OR constriction depending on receptors activated
NSAIDs are complex vaso-regulators:
Vasoconstriction.
Salt & water retention.
Reduced effect of anti-hypertensives.
There has been increasing acknowledgment of risk of:
Hypertension, MI and stroke.
NSAIDs therefore increase risk of CVS events –> resulting in 1000 deaths/annum.
CV effects of COX-2 Inhibitors and Total Effects?
COX-2 inhibitors pose a higher risk of CVS disease than conventional NSAIDs – mechanism unclear.
Mechanisms
– raise BP
– endothelial dysfunction (thromboxane rises = risk of thrombosis)
– oxidative injury, etc
COX-1 inhibition
increased GI risk (as PGE2 in stomach generated through COX-1 action)
COX-2 inhibition
increased CVS risk
Ibuprofen & Indomethacin
vs.
Celecoxib
Ibuprofen & Indomethacin
- NON-SELECTIVE NSAIDs (inhibit BOTH COX-1 & COX-2)
- Inhibit COX REVERSIBLY
- Have analgesic, anti-pyretic & anti-inflammatory actions
- Significant SEs
Celecoxib
- SELECTIVELY inhibits COX-2
- Led to a decrease in ulceration incidence
- BUT increasing evidence is posed a HIGHER RISK of CVD
What is an issue with selective COX-2 inhibitors?
Difficult to make as BOTH COX enzymes are structurally very similar
Risk/benefits of NSAID use in analgesic use vs. anti-inflammatory use?
Analgesic use:
• Usually occasionally so relatively low risk of side effects
Anti-inflammatory use:
• Used chronically in higher doses so a relatively high risk of side effects
Strategies other than COX-2 selective NSAIDs for limiting GI side effects?
Topical application
– less systemic access
Limit use in patients with a GI-ulceration history or with other risk factors
– e.g. alcoholics
– e.g. anticoagulant OR glucocorticoid steroid use
Treat H. pylori if present
If NSAID is essential, co-administer omeprazole (or another PPI)
– proton pump inhibitor
Development of newer NSAIDs which may be safer?
Dual COX & LOX inhibitors
– for asthmatic patients
– no safe option on market (liver injury)
NO or H2S releasing NSAIDs
– protective to GI & CVS
Summary of NSAID SEs?
Onenote!!
Give a general overview of Aspirin
SELECTIVE for COX-1
Unique among NSAIDs
– binds IRREVERSIBLY to COX enzymes
Main actions:
– anti-inflammatory
– analgesic
– anti-pyretic
Reduces platelet aggregation
General effects of prostanoids on platelet aggregation?
Platelets:
- reduces TXA2 production via COX1
- no re-production as the platelet has no nucleus
Endothelial cells:
- reduces PGI2 synthesis by COX1/2 (PGI2 decreases platelet action)
- Reproduction possible due to nucleus
How does aspirin use lead to reduced platelet aggregation then?
HENCE:
• LESS TXA2
&
• NORMAL PGI2 (as can replenish COX-1 due to nucleus)
leads to reduced platelet aggregation
What gives rise to the anti-platelet actions of aspirin?
Anti-platelet action due to:
- High degree of COX1 inhibition which supresses TXA2 synthesis in platelets
- Covalent bonding which permanently inhibits platelet COX1
- Relatively low capacity to inhibit COX2
- Need a LOW dose to enable endothelial re-synthesis of COX2 (if high, will keep inhibiting it)
What is the inhibition if prostacyclin (PGI2) proportional to?
Inhibition of PGI2 is
PROPORTIONAL TO
Inhibition of COX-2
• we do NOT want to inhibit PGI2 production SO too much COX-2 inhibition is a bad thing
Main SEs of aspirin seen at therapeutic doses?
• Gastric ulceration • Bronchospasm - in sensitive-asthmatics • Prolonged bleeding time • Nephrotoxicity
Side effects more likely with aspirin over other NSAIDs
• due to permanent inhibition (rather than reversible)
Aspirin and Reye’s syndrome?
Patients <20years
Viral infection & aspirin
Damage to mitochondria
• leads to ammonia production
• results in astrocyte damage = oedema in brain
Action of paracetamol?
NOT an NSAID as NO anti-inflammatory action
Actions:
o Relieve mild –> moderate pain
o Anti-pyretic actions
o NO anti-inflammatory actions
Is paracetamol classed as an NSAID?
NO
as NO anti-inflammatory action
MoA of paracetamol?
NOT understood completely
• but believe probably central
COX-3?
Cannabinoid receptors?
Interactions w. endogenous-opioids?
Interaction w. 5HT/adenosine receptors?
What can paracetamol OD cause?
Irreversible liver failure
Explain what happens when someone ODs on paracetamol
If GLUTATHIONE is depleted (saturated whilst metabolising the other paracetamol molecules)
• the metabolites oxidise the thiol groups (–SH) of key hepatic enzymes = cause apoptosis
Antidote for paracetamol poisoning?
Add a compound with an –SH group.
• IV Acetylcysteine – used in cases of attempted suicide
• If not administered early enough, liver failure may be unpreventable
Occasionally give Oral methionine
• but IV Acetylcysteine usual
Legal issues with OTC of analgesics?
1998 pack size restricted paracetamol to 16x500mg tablets.
2009 guidelines state:
o No more than 2 packs per transaction.
o Illegal to sell more than 100 pills per transaction.
Deaths have fallen by 43% since 2009.
Aspirin is unique amongst NSAIDS because:
A. It has no effect on COX-1 B. It has no effect on COX-2 C. It binds covalently to COX enzymes D. It binds covalently to TP receptors E. It causes gastric ulceration
A. It effectively inhibits COX-1
B. It has some effect on COX-2
C. This is the best answer
D. Untrue
E. True but not unique to aspirin
Inhibition of which enzyme will reduce platelet aggregation with fewest side effects?
A. COX-1 B. COX-2 C. Prostacyclin synthase D. Prostaglandin E synthase E. Thromboxane A2 synthase
A. No - rate limiting for multiple prostanoids
B. No - rate limiting for multiple prostanoids
C. No – prostacyclin reduces platelet aggregation
synthase
D. No – multiple complex effects
E. Yes - Thromboxanes causes platelet aggregation, but not much else
Assertion:
Inhibition of PGI2 synthesis by low dose aspirin decreases the risk of stroke
Because :
Decreased PGI2 reduces platelet aggregation
A. Assertion true, reason true and explains assertion
B. Assertion true, reason true but does not explain assertion
C. Assertion true, reason false
D. Assertion false, reason true
E. Assertion false, reason false
E
Synthesis of PGI2 (prostacyclin) is inhibited by low dose aspirin, but it is not this action which decreases the risk of stroke, because PGI2 actually reduces platelet aggregation.
It’s the inhibition of thromboxane synthesis
