13 - NSAIDs Flashcards
What is the principal action of non-steroidal anti-inflammatory drugs and the therapeutic effects?
Principle action – work on key enzyme COX and compete with arachidonic acid for the COX site to stop prostanoid production. Inhibits down stream products of arachidonic acid
- Analgesia
- Anti-Inflammatory
- Antipyretic
- Short half lifes to allow fine control
What are some examples of prostanoids and how are they produced?
- Prostaglandins, Prostacyclin, Thromboxane A2
- Made from arachidonic acid (comes from dietary linoleic acid (vegetable oils) which is converted hepatically into arachidonic acid and then incorporated into phospholipids cell membrane)
- COX enzymes convert arachidonic acid to prostanoids
- Arachidonic acid found all over the brain expecially in muscle, brain and liver
What are some of the functions of the prostanoids?
- Act on tissues through GPCRs and their function is enhanced by autocoids like bradykinin and histamine
- PGE2: Vasodilation, Hyperalgesia, Fever, Immunomodulation
- PGI<u><strong>2:</strong></u> Vasodilator so cardioprotecitve but TXA2 can damage CVS. Imbalance between the two has role in hypertension, MI and stroke
What is the difference between the two main isoforms of COX enzyme?
COX-1: constituitively active across most tissues (protective in nature)
COX-2: inducible, most in chronic inflammation. constituitively in bone, brain and kidney (induce pyrexia and inflammation)
- Platelets only contain COX-1
- COX2 has a larger more flexible substrate channel than COX1
Why is it good to have a diet high in fish oils?
Contain fatty acids that can be converted into TXA3 and PGI3 which are better prostanoids than the others, can cause lower incidence of CVD
How do NSAIDs have an analgesic effect?
- Greater efficacy if tissue is inflammed
- Lack of PGE2 reduces peripheral pain fibre sensitivity as less PGE2 in the dorsal horn so less neurotransmitter release and less excitability of neurones in pain relay pathway
- Efficacious after first dose but full analgesia after several days dosing
How do NSAIDs have an anti-inflammatory effect?
- Lack of prostaglandin synthesis and release in tissue injury when given NSAIDs so less vasodilation and oedema in post capillary venules stopping swelling
- Symptomatic relief but doesn’t treat underlying chronic condition
Why is long term NSAID use associated with a reduction in particular cancers?
- NSAIDs can decrease ROS by it’s oxygen scavenging properties independent of its action through COX
- Therefore reduction in certain cancers
How do NSAIDs (and paracetamol) have an anti-pyretic effect?
- PGE2 normally acts in preoptic area of the hypothalamus (thermoregulatory centre) to increase the set point of temperature, along with pyrogens like cytokines
- NSAIDs stop production of PGE2 so only pyrogens so set point cannot be increased
What is the difference in selectivity across the NSAIDs?
- COX1 inhibition have more ADRs so a lot of COX2 selective inhibitors (coxibs)
- Indirect action on leukotrienes through PGE2
What are some GI ADRs associated with the use of NSAIDs and what is the mechanism behind this?
- Dyspepsia, nausea, peptic ulceration, bleeding, perforation
- Always give PPI with long term NSAID
- NSAIDS decrease mucus and bicarb secretion but increases acid secretion
- Decreased mucosal blood flow* so enhanced cytotoxicity and hypoxia
- Can exacerbate IBS
What are some risk factors associated with GI side effects from the use of NSAIDs?
- Elderly
- Prolonged use (should be smallest dose for smallest time)
- Glucocorticoid steroid use
- Anticoagulant use
- Alcohol and smoking
- History of peptic ulceration
- H Pylori
GIVE A PPI WITH AN NSAID
What are some renal ADRs associated with the use of NSAIDs and what is the mechanism behind this?
- Produce reversible drop in GFR and renal blood flow
- Also prostaglandins inhibit Na absorption in collecting duct but NSAIDs inhibit this so increased water absorption increasing B.P so dont use in hypertension
- Don’t use in CKD and heart failure as the kidneys have greater reliance on prostaglandins for vasodilation and renal perfusion
What are some examples of selective COX-2 inhibitors and why are they used?
Celecoxib and Etoricoxib
- Less GI ADRs as less COX1 inhibition so good in severe OA and RA when needed long term
- Renal ADRs are the same
- Impair PGI2 but not antiplatelet so unopposed aggregatory effects so maybe prothrombotic
- Less analgesic effects
What are some highly protein bound drugs affected by NSAIDs and what issues arise when administering both together?
- NSAIDs displace the bound drugs increasing free drug conc so need to think about lowering dose of other drug. (especially aspirin due to the salicylate)
- Methotrexate: hepatotoxicity, leukopenia, RA
- Warfarin: increased risk of bleeding
- Sulfonylurea: hypoglycaemia
When are some indications for NSAID use?
- Pain like headache, gout, RA
When do you need to be cautious with prescribing NSAIDs?
- CVS risk
- Renal function (age)
- Previous GI disease
- DDIs: ACEis/ARBs, diuretics, sulfonylureas, methotrexate, warfarin
- Level of pain, pyrexia or inflammation
What is the mechanism of action of paracetamol and its therapeutic effects?
- Analgesic and antipyretic but NOT antiinflammatory.
- Not an opiate or NSAID
- Fewer ADRs and no effect on platelets
- MOA not known but COX-2 selective inhibition in CNS so less pain signals to the brain
- Well absorbed by GI with a half life of 2h and inactivated by conjugation in the liver
Why does paracetamol not have an antiinflammatory effect?
Peroxidases in peripheral inflammation inhibit the action of paracetamol
How is paracetamol metabolised?
- Normal levels: conjugation with glutathione hepatically so harmless
- High levels: Phase 2 is overwhelmed so NAPQI build up which causes cell death by oxidising key metabolic enzymes
- 150mg/kg (10 tablets) enough to cause irreversible damage
How does a paracetamol OD present and how can we treat it?
- Asymptomatic for hours then nausea, vomiting and abdominal pain in the first 24 hours with maximal liver damage after 3-4 days
- Give IV N-Acetylcysteine to replace glutathione
- Can give activated charcoal if taken recently and not staggered
- Take blood after 4 hours to work out extent of damage
Why is I.V N-acetylcysteine used and not glutathione in a paracetamol OD?
Glutathione cannot be absorbed into hepatocytes but N-Acetylcysteine can!!!
