NSAIDs (I & II) Flashcards
Pain is..
The unpleasant sensory and emotional experience associated w actual or potential TISSUE DAMAGE.
NSAIDs inhibit..
COX enzymes, thus inhibiting prostaglandin pdn (thus, less potent than steroids)
Steroids inhibit phospholipase A2 (more potent)
Isomerases of Prostanoids:
- Prostacyclin (PGI2)
- Prostaglandins (PGE2)
- Thromboxanes (TXA2)
Steroids inhibit..
Phospholipase A2
- inhibits process higher up
- thus, inhibiting formation of all eicosanoids
- in long term, it will suppress immune response
Uses of Aspirin
- Anti-inflammatory
- Analgesic (pain)
- Anti-pyretic (fever)
- Anti-platelet
Explain why there is an ‘analgesic ceiling’.
Tissue injury-> 1. Bradykinins 2. Leukotrienes 3. Prostaglandins
NSAIDs reduces sensitization by inhibiting prostaglandins pdn. In severe pain however, there will still be high levels of 1. & 2. that still sensitize the nociceptors to pain.
Some typical NSAIDs are..
- Naproxen
- Indomethacin
- Diclofenac
Aspirin is linked to (what syndrome)
Reye’s Syndrome
Reye’s syndrome occurs in ..
Occurs most commonly in children. Increased risk if aspirin is taken by children with viral infections.
- chickenpox patient(child or young adult) who takes aspirin ends up w Reye’s syndrome (cuz liver gets affected by both the VZV n aspirin => buildup of ammonia in body)
What is Reye’s syndrome?
- very rare but life-threatening condition mostly IN CHILDREN
- swelling of brain & liver
- increased risk if aspirin is taken by children w viral infections (e.g. chicken pox or flu)
- symptoms: vomiting, personality changes, listlessness etc etc
Caused by Aspirin in children
(thats why aspirin is no longer avail in paediatric doses)
COX 1 typically produces:
TXA2 (thromboxane)
COX 2 typically produces:
PGI2 (prostacyclins) & PGE2 (classical prostaglandins)
TXA2 (thromboxanes) effects on CVS:
Vasoconstriction
Platelet aggregation
PGI2 (prostacyclin) effect on CVS
Vasodilation
Inhibits platelet aggregation
How is Aspirin anti-pyretic?
Physiologic rxn - COX induces hypothalamus to release PGE2 (prostaglandins)=> induces fever=> body is trying to kill virus/bacteria by increasing temp
- NSAIDs block PGE2 production => reduce fever if too high
How is Aspirin Anti-inflammatory?
- blocks pdn of PGI2 n PGE2 (prostacyclin & prostaglandin)
Thus, - block vasodilation (PGI2) (less heating, redness n swelling)
- blocks increased vascular permeability (PGE2) (less swelling)
- blocks pain associated w inflammation (PGE2)
Effect of PGE2 (mostly)
Vascular permeability
Pain
How is Aspirin analgesic?
Physiologic - prostaglandins sensitize the nociceptive fibres to stimulation by other inflammatory mediators
- NSAIDs block pdn of prostaglandins (PGE2)
- it only blocks sensitization, not direct nociceptive activation (therefore there is an analgesic ceiling, aka insufficient for severe pain)
- typical NSAIDs also have additional analgesic actions in the CNS
How is Aspirin Anti-platelet (stop blood from clotting)?
- TXA2
- pdn of TXA2 via COX BY PLATELETS =>promotes platelet aggregation
- but COX is inhibited in the platelets = no TXA2 formation
- pdn of TXA2 can only be restored by formation of new platelets (1-2 weeks) - PGI2
- pdn of PGI2 by endothelial cells=> inhibits platelet aggregation
- but COX inhibited in the endothelial cells = no PGI2 pdn
- BUT PGI2 CAN be restored by synthesis of new COX enzyme (takes a few hours)
TRICKY BUT IMPT PART:
PGI2 is restored in a few hours but TXA2 is gone. Aka inhibition of platelet aggregation»»» platelet aggregation
MUST KNOW: THAT ASPIRIN IS SUPER ANTIPLATELET!!!
Facts about Naproxen:
- more effective in _______
- long half life of ______
- often used for __________
- more effective in women
- long half life 12-14h
- often used for dysmenorrhea (menstrual cramps)
- issa typical NSAID
Facts about Indomethacin:
- additional steroid-like _________________ inhibition => strongly ___________
- BUT adverse CNS effects: __________________________________
- additional steroid-life phospholipase A2 inhibition => strongly anti-inflammatory
- BUT adverse CNS effects: confusion, depression, psychosis, hallucinations
- issa typical NSAID
Facts about Diclofenac:
- short ______ half life (<2h) => _______ risk
- longer half life in ______________=> useful for ___________
- __________ administration
- short plasma half life (<2h) => low GI risk
- longer half life in synovial fluid => useful in inflammatory joint disease
- topical/oral administration
Other than for pain, inflammation & fever, Aspirin is also prescribed for….
- prescribed at low doses as a ‘blood thinner’ for those at risk of cardiovascular disease
Paracetamol has taken over _______ as a ________due to adverse effects.
Paracetamol has taken over Aspirin as a ‘pain killer’
The dose-dependent effects of Aspirin can be classified into 2 categories, _______ & ________. Name some notable effects.
- COX inhibition (low dose therapeutic effects)
- analgesic
- anti-pyretic
- anti-inflammatory
- anti-platelet
- gastric intolerance (-ve) - Salicylate toxicity (high does toxic effects)
- tinnitus
- renal & respiratory failure
- metabolic n respiratory acidosis
Physiologic effect of Prostaglandins on the GIT:
- Reduce gastric acid secretions
- Increase mucosal blood flow /in mucosa
- Increase secretion of mucus
- Increase secretion of bicarbonate
Basically, protect the stomach
- COX 1 (constitutive) produces PGE2
Secretions, Blood flow, Mucus, Bicarbonate
If PGE2 pdn is inhibited, what happens? (-ve effects)
- dyspepsia (symptoms are acid reflux, heartburn), nausea, vomiting
- ulcer formation & potential haemorrhage risk in chronic users
Basically, protective mech is gone, excess acid happens, stomach attacked
Adverse effects of NSAIDs on RENAL system:
- inhibition of COX= inhibition of both PGE2 n PGI2 pdn
Inhibition of PGE2 results in :
1. Sodium retention
2. Water retention
3. Peripheral oedema
4. Hypertension
Clinical implications:
- must check if patient alr has hypertension, udw to worsen their existing hypertension
Inhibition of PGI2 results in :
1. Suppression of renin n aldosterone reaction (less sodium retention)
2. Hyperkalemia
3. Acute renal failure
^ might seem contradictory that 1. Suppression of renin n aldosterone may recover 2. Sodium retention
- but nope, the processes happen at diff parts of the renal tubule
- inhibition of Na+ occurs at ascending limb (PGE2) (25% resorbed)
- aldosterone/renin suppression occurs at CD (PGI2) (1-2% decreased reabsorption)
- overall effect: NSAID causes Na+ retention (water retention)
Renal adverse effects due to inhibition of PGI2 (prostacyclin):
No more prostacyclin means:
1. Suppression of renin & aldosterone secretion
- effects occur in CD
- only 1-2% reduction in reabsorption of Na+
2. Hyperkalemia
3. Acute renal failure
Think ‘cyclin’ the more complex sounding one to ‘glandin’ aka all the effects more secondary.
Renal adverse effects due to inhibition of PGE2 (prostaglandin):
No more PGE2 (prostaglandin) means:
1. Sodium retention
- occurs in thick ascending limb (TAL)
- 25% increase in reabsorption of Na+ back into blood
2. Water retention
3. Peripheral oedema
4. Hypertension
Urm, think ‘glandin’ -> gland -> gland of sodium water oedema hypertension shit
- more primary factor
Name some OTHER adverse effects of typical NSAIDs:
- Pseudo-allergic reaction (skin rashes, swelling, itching)
- Asthma (can trigger bronchospasms in susceptible asthmatics)
- Bleeding (failure of haemostasis, bruising)
Note: effects elicited by Aspirin might be stronger than other NSAIDs cuz it is an IRREVERSIBLE COX inhibitor
Why is Aspirin a unique NSAID?
Irreversible COX inhibitor
Why do NSAIDs elicit an unwanted Asthma & Pseudo-allergic reaction in some ppl:
- inhibition of COX=> more arachidonic acid gets converted to leukotrienes by LOX
- excess leukotrienes => bronchospasms in asthmatics & allergic reaction-like symptoms
All NSAIDs are _______ inhibitors!
All NSAIDs are COX-2 inhibitors!
- just different in what they are selective for
NSAIDs are contraindicated in __________ of pregnancy.
Strongly contraindicated in third trimester of pregnancy.
- it causes premature closure of ductus arteriosus (fetal lung bypass) in late pregnancy
- can
COX 2 effects on ovulation:
- causes delayed follicular rupture
- makes it harder to become pregnant, though not impossible
Aspirin is far more ___________ than other selective COX1 COX2 inhibitor NSAIDs cuz of its ___________.
Aspirin is far more anti-platelet than other selective COX1 COX2 inhibitor NSAIDs cuz of its irreversible binding
COX2 inhibitors _________ wound healing, may _________ ulcers. So how?
COX2 inhibitors impair wound healing, may exacerbate ulcers.
Clinical implications:
- patients w existing ulcers
- post-surgical painkillers/analgesia
Patients who were on 1st gen NSAIDs n developed ulcers did not improve aft switching to coxibs(2nd gen cox2 inhibitors)
- need to stop all NSAIDs-> let patient recover, then can start coxibs
Why does selective COX2 inhibition increase risk of thrombosis?
- relative increase in TXA2 => favours platelet aggregation => thrombosis
- due to inhibition of COX2 => PGI2 downregulated
Advantages of Paracetamol:
Paracetamol - CNS selective COX inhibitor
- Good analgesic
- Potent antipyretic
- Spares GIT
- Few & uncommon side effects
- Few drug-drug interactions
Disadvantages of Paracetamol:
Paracetamol - CNS selective COX inhibitor
- Weak anti-inflammatory => does not block COX in periphery involved in inflammatory response
- Allergic skin rxns
- Toxic doses => nausea, vomiting, liver damage
- hepatotoxicity exacerbated by overdose/chronic alcohol use
- alcohol induces CYP2E1 & deplete glutathione => accumulate toxic metabolite
- can replenish glutathione by NAC (N-acetyl-cysteine)
