Non-steroidal anti-inflammatory drugs Flashcards
Main risk of NSAIDS
Increased risk of GI and CVS deaths
Main use of NSAIDS + examples
Relief of mild-to-moderate pain (analgesic)
- toothache, headache, backache
- opioid sparing posteroperative pain
- dysmenorrhea
Reduction of fever (antipyretic)
-influenza
Reduction of inflammation (anti-inflammatory)
- Rheumatoid arthritis/osteoarthritis
- Osteoarthritis
- MSK inflammation
- Strains and sprains (soft tissue injury)
- Gout
How do NSAIDS work
What are the products of COX enzymes. What is their distribution and how are they released
Inhibition of prostaglandin and thromboxane synthesis
Lipid mediators derived from arachidonic acid
Cyclo-oxygenase enzymes
Widely distributed
Not stored or pre-formed
Receptor-mediated
Outline arichidonic acid metabolism
AA–> prostglandin H2(BY COX1&2)
–> prostacyclin, prostaglandin E2, prostaglandin D2, prostaglandin F2a, TXA2 (by specific synthases)
What are prostanoid receptors
What are they named on the basis of
How do they achieve their effect
10 known prostanoid receptors
DP1, DP2, EP1, EP2, EP3, EP4, FP, IP1,IP2, TP
Naming based on agonist potency but they are NOT completely specific
Prostanoids have both G protein-dependent and -independent effects
What are the actions of prostanoid receptors
Physiological and pro-inflammatory
How any receptors can PGE2 act on, and to what effect
PGE2 can activate 4 Receptors
cAMP-dependent and independent downstream mechanisms:
EP1 and EP3 can increase Ca2+ mobilisation
EP2& EP4 will increase cAMP activtion
EP3 downregulates cAMP, as can EP2 (can up or downregulate)
What can EP2 do
Increased pain perception Increased body temperature Acute inflammatory response Immune responses Tumorigenesis Inhibition of apoptosis
What effect does PGE2 have on pain threshold and how
PG receptors in the periphery sensitizes the nociceptors which cause pain both acutely and chronically.
HYPERALGESIA
Specific mechanism of action for reduction in pain threshold due to PGE2
- cAMP mediated…. activates P2X3 nociceptors due to PKA (this pathway occurs anyway but can increase with more PGE2 and Epac pathway can be activated too)
- EP1 receptors and/or EP4 receptors (in periphery and spine)
- Could downregulate endocannabinoids (neuromodulators in thalamus, spine and periphery)
- increasing beta-endorphin in spine
SO NSAIDS WOULD REVERSE THESE THINGS
Why do NSAIDS reduce fever
PGE2 is pyrogenic…. stimulates hypothalamic neurones initiating a rise in body temperature
(in the experiment a pyrogenic was injected, and PGE2 rose before temperature did)
What is another important role of PGE2
COMPLEX ROLE IN INFLAMMATION
What is the desirable effects of PGE2
Gastroprotection
Bronchodilation (although there is evidence that PGE2 can desensitise β2adrenoceptors)
Renal salt and water homeostasis
Vasoregulation (dilation and constriction depending on receptor activated)
Why are NSAIDS not used in asthmatics
MANY COX PRODUCTS CAUSE BRONCHODILATION, BUT (e.g. PGE2 is normally protective)
~10% asthma patients experience worsening symptoms with NSAIDS
Cyclooxygenase inhibition favours production of leukotrienes - bronchoconstrictors
But only in some asthmatics… depends on penotypes
(mouse knockouts for PGE2 had aspirin induced asthma, suggesting PGE2 is protective)
What is PGE2 production mediated by
COX1&2
How does PGE2 affect renal blood flow
How can NSAIDS cause renal toxicity
Where are COX enzymes found within the nephron
What location of COX enzymes accounts for the effect of PGE2 on renal blood flow
PGE2 increases renal blood flow
NSAIDs can cause renal toxicity:
Constriction of afferent renal arteriole –> Reduction in renal artery flow –> Reduced glomerular filtration rate
COX1 in the DCT/ collecting duct, COX2 in ALH and macula densa
COX1&2 in the glomerulus
COX-1 and COX-2 enzymes in the glomerulus causes PGE2 production which is affecting this renal blood flow
What is the role of PGE2 in gastric cytoprotection.
Which COX enzyme is this dependent on
PGE2 downregulates HCl secretion
PGE2 stimulates
mucus and bicarbonate secretion
(so increased neutralisation and increased physical barrier)
DEPENDENT ON COX 1 (howeer PGE2 is produced by COX 1 and COX 2 remember)
What is the effect of NSAIDS on the GI system
NSAIDS increase the risk of ulceration
Differentiate the COX 1 and 2
Different (but overlapping) cellular distributions
NOT the case that COX1 inhibition is phsiological and COX2 inhibition is pathological
Most NSAIDs reversibly inhibit both isoforms (example: ibuprofen)
What is the Coxib family of NSAIDS.
What is their benefit?
Coxib family: selectively reversibly inhibit COX-2 (example: celecoxib)
(hypothesised to be gastroprotective, and were, but still CVS effects)
What are the unwanted effects of NSAIDS on CVS
Vasoconstriction (as was seen in the case of renal toxicity of NSAIDS, causing vasoconstriction, it the same here but generalised)
Salt and water retention
Reduced effect of antihypertensives
Risk of HTN, MI and stroke
so even though the coxib (selective COX2 inhibitor) reduced the GI problems there was higher risk of CVS disease
Why is COX 2 not a silver bullet, despite reducing GI effects
Increasing evidence that selective COX-2 inhibitors pose higher risk of cardiovascular disease than conventional NSAIDS even though mechanism is unclear
How do NSAIDS have their effect on the CVS
By vasoconstriction/vasodilation
OR
platelet aggreation
How do the prostanoids affect the CVS:
PGF2a
PGE2
PGI2
PGD2
PGF2a: CONTRACTS smooth muscle (also relevant in the RESP tutorial)
TXA2: Vasoconstricts and INCREASES platelet aggregation
PGI2: Vasodilates and reduces platelet aggregation
PGE2: Vasodilates (or vasoconstricts) + inflammatory mediator
these are all actually important
What can the BLOCKING prostanoids do to CVS risk
No PGI2 (leads to unrestricted platelet activation –> atherothrombosis, and reduced NO –> endothelial dysfunction and HF risk)
Reduced PGI2 and PGE2 (decreased protection against arrhythmias and oxidative injury –? increased HF risl)
Reduced PGI2 adn reduced PGE2 can also have renal effects increasing CV risk
look at diagram… basically:
VASCULAR ENDOTHELIUM/VSMC, CARDIOMYOCYTES AND RENAL EFFECTS WHEN PROSTANOIDS ARE BLOCKED
Outline the bad effects of COX 1 nad COX 2 selective inhibitrs
COX1… increased GI bleed
COX2…. increased CVS risk.
The ones sold in shops do a little bit of each
Outline when the risk of side effects from NSAIDS is high and low
Analgesic use (occasional) low risk of side effects
Anti-inflammatory use (often sustained, higher dose)… high risk of side effects
How can NSAIDS side effects for GI bleeding be limited (other than using COX 2)
In which patients should use of NSAIDS be minimised (in addition to asthmatics, who should not take it at all)
Topical application
Minimise NSAID use in patients with history of GI ulceration
Treat H pylori if present
If NSAID 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
What drugs are being developed that may be safer
Nitric oxide or Hydrogen sulphide releasing NSAIDS
Dual LOX/COX inhibitors (to reduce leukotriene production)
What is the selectivity of aspirin
COX-1
How is aspirin unique to other NSAIDS
Binds IRREVERSIBLY to COX enzymes
(acetylation) to overcome, must produce new COX enzymes
other NSAIDS bind reversibly
What actions do aspirin have
Has anti-inflammatory, analgesic and anti-pyretic actions
Reduces platelet aggregation
Outline the effects of prostaglandins on platelet aggreation
Thromboxane A2 increases aggreation (produced by platelets)
Prostacyclin (PGI2)… will reduce platelet aggreation (endothelial cells)
How does aspirin work on platelet aggreation
TXA2 made by
COX-1
PGI2 synthesis by
COX-1 and COX-2
so aspirin reduces all TXA2 and some PGI2
Covalent binding which permanently inhibits platelet COX-1
so it will have bigger effect on TXA2 as platelets have nonucleus so they cannot produce TXA2 again. But the endothelial cells can produce new prostacylcin
Major side effects of aspirin at therapeutic dose
+
why do the side effect of aspirin occur
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 does paracetemol do?
What class of drug is it
effective analgesic for mild-to-moderate pain which is available over the counter
Has anti-pyretic action
Has minimal anti-inflammatory effect
Therefore it is not a NSAID
What is the mechanism of paracetmol action
Not understood, probably central and peripheral
? COX- 3
? Via Cannabinoid receptors
? Interaction with endogenous opioids
?interaction with 5HT and adenosine receptors
3 OACS
What is the usual metabolism of paracetemol
Firstly, toxic metabolite (called NAPQI) formed through phase I. (has a double bond)
Then, this toxic metabolite is conjugated to the vast supply of glutathione (this reduces the toxic molecule, no double bond now)
INACTIVE REDUCED FORM
What is the consequence of paracetemol overdose
You can use up all the glutathione, in which case the metabolite will oxidise thiol groups of KEY HEPATIC ENZYMES, causing cell death
What is the antidote for paracetemol poisoning
Add compound with –SH groups
Usually intravenous Acetylcysteine
Occasionally oral methionine could be added but increased cost (methionine is like the glutathione which would directly reduce it)
When is acetyl cysteine used
Acetyl cysteine used in cases of attempted suicide and accidental poisoning from paracetemol
T/F liver failure can always be prevented with acetylcysteine
F….If not administered early enough, liver failure may be unpreventable
T/F restriction of paracetemol pack size has reduced number of paracetmol overdose death
T
T/F the action of prostanoids produced in the body can result from a stored form
F… prostanoids are not stored, they work as they are produced, and act on receptors
What is the usual action of COX1&2
Convert AA –> PGH2
The rate limiting step in the production of all prostanoids
What is PGH2 converted into and how
Into Prostacyclin/PGI2, PGE2, PGD2, PGF3, and TXA2 by SPECIFIC SYNTHASES
What is the structure of the AA vs the prostanoid product
Arachidonic acid has a very open structure
All the products have a closed structure, with a 5-membered ring and 2 lipid tails
What are prostanoids
Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes (mediators of vasoconstriction), and the prostacyclins (active in the resolution phase of inflammation.)
Give an example of a drug which proves increased CVS risk, one that increases GI risk and one that provides some level of both risk
Ibuprofen- low level of both risk (non selective)
Coxibs high level of CVS risk (COX 2 SELECTIVE)
Naproxen high level of GI risk e.g. bleed/ulcer (COX 1 SELECTIVE )
T/F aspirin binds irreversibly and acetylates both COX1 and COX2 enzymes
T… but more selective for COX1
How is aspirin dose dependetnt
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 RE-SYNTHESIS of COX-1 in platelets à OVERALL REDUCED AGGREGATION OF PLATELETS.
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 (therefore no production of PGI2 :(
What is the antiplatelet action of aspitrin
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 is the max dose of paracetemol
8 tablets over 24hrs, which is 4mg
