S8 L1 NSAIDs Flashcards

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1
Q

What is the principal action of non-steroidal anti-inflammatory drugs and the therapeutic effects?

A

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
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2
Q

What are some examples of prostanoids and how are they produced?

A
  • 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
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3
Q

What are some of the functions of the prostanoids?

A
  • 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

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4
Q

What is the difference between the two main isoforms of COX enzyme?

A

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
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5
Q

Why is it good to have a diet high in fish oils?

A

Contain fatty acids that can be converted into TXA3 and PGI3 which are better prostanoids than the others, can cause lower incidence of CVD

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6
Q

How do NSAIDs have an analgesic effect?

A
  • 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
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7
Q

How do NSAIDs have an anti-inflammatory effect?

A
  • 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

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8
Q

Why is long term NSAID use associated with a reduction in particular cancers?

A
  • NSAIDs can decrease ROS by it’s oxygen scavenging properties independent of its action through COX
  • Therefore reduction in certain cancers
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9
Q

How do NSAIDs (and paracetamol) have an anti-pyretic effect?

A
  • 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
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10
Q

What is the difference in selectivity across the NSAIDs?

A

- COX1 inhibition have more ADRs so a lot of COX2 selective inhibitors (coxibs)

  • Indirect action on leukotrienes through PGE2
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11
Q

What are some GI ADRs associated with the use of NSAIDs and what is the mechanism behind this?

A

- 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
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12
Q

What are some risk factors associated with GI side effects from the use of NSAIDs?

A
  • 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

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13
Q

What are some renal ADRs associated with the use of NSAIDs and what is the mechanism behind this?

A
  • 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
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14
Q

What are some examples of selective COX-2 inhibitors and why are they used?

A

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

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15
Q

What are some highly protein bound drugs affected by NSAIDs and what issues arise when administering both together?

A
  • NSAIDs displace the bound drugs increasing free drug concentration 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

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16
Q

When are some indications for NSAID use?

A
  • Pain like headache, gout, RA
17
Q

When do you need to be cautious with prescribing NSAIDs?

A
  • CVS risk
  • Renal function (age)
  • Previous GI disease
  • DDIs: ACEis/ARBs, diuretics, sulfonylureas, methotrexate, warfarin
  • Level of pain, pyrexia or inflammation
18
Q

What is the mechanism of action of paracetamol and its therapeutic effects?

A

- 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

19
Q

Why does paracetamol not have an antiinflammatory effect?

A

Peroxidases in peripheral inflammation inhibit the action of paracetamol

20
Q

How is paracetamol metabolised?

A

- 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
21
Q

How does a paracetamol OD present and how can we treat it?

A
  • 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
22
Q

Why is I.V N-acetylcysteine used and not glutathione in a paracetamol OD?

A

Glutathione cannot be absorbed into hepatocytes but N-Acetylcysteine can!!!

23
Q

What is the difference in the mechanism of action of aspirin and other NSAIDs?

A

Aspirin irreversibly inhibits COX but other NSAIDs do it reversibly