NSAIDs

  • Created by: LBCW0502
  • Created on: 20-10-18 12:59
NSAIDs target which receptors in the nociceptive pathway?
Mediator release - BK, 5HT, PGs (prevent inflammation)
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What are NSAIDs used for?
Treatment of minor pain and the management oedema and tissue damage resulting from inflammatory joint disease (arthritis). NSAIDs have antipyretic activity and analgesic activity
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Give examples of primary indications of NSAIDs
Rheumatoid arthritis, oesteoarthritis, ankylosing spondylitis, tissue damage resulting from inflammatory joint disease (arthritis)
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Describe features of prostaglanlins
Biosynthesised from arachidonic acid (found esterified on cell membrane phospholipid). Concentration of arachidonic acid is very low. Biosynthesis of eicosanoids depends on the release from cellular stores by acyl hydrolyses or phospholipase
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Outline the reaction to form prostaglanlins H2
Arachidonic acid to prostaglanlin-G2 using O2 and COX. Prostaglanlin-G2 to prostaglanlin-H2 using peroxidase
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What is the major mechanism by which NSAIDs elect their therapeutic effects?
Inhibition of prostaglandin synthesis (antipyretic, analgesic, anti-inflammatory activation) - NSAIDs competitively inhibit COX enzymes (which catalyse synthesis of cyclic endoperoxide from of arachidonic acid to form prostaglandins)
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Describe features of COX 1 and COX 2 - clinical classification
COX found in ER (3 isoforms). COX-1 (constitutive) - acts in physiological conditions. COX2 - (inducible) - induced by inflammatory cells by pathological stimulus, COX2 found in the brain
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The metabolic pathway resulting in inflammation involves with COX enzyme?
COX -2 (COX-1 involved in metabolic pathway for - intestine, platelets, stomach, kidneys). COX 2 specific inhibitors reduce pain/fever/inflammation without causing GI or renal injury
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What is the difference between COX 1 and COX 2?
COX 1 uses arachidonic acid and isoleucine at the active. COX 2 uses arachidonic acid and di-homo-y-linolenate as substrate. COX1 uses Ile (skinny molecule), COX 2 uses Val (fat molecule) - differ by methyl group (relates to specificity)
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Describe features of the selectively ratio
SR = COX2 IC50/COX1 IC50 (low value for COX 2 - tight binders, high value for COX1 - weak binders). COX2 selective drugs will have a selectivity ratio value less than 1
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Give examples of COX-2 selective drugs
Diclofenac, celecoxib, refecoxib
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Give examples of NSAIDs
Salicylates, propanoic acids (profens), aryl/heteroarylacetic acids, anthranilates (Fenametes), oxicams (enol acids), phenylpyrazolones, analides (general structure - acid moiety attached to planar aromatic)
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Describe features of salicylates
Potent inflammatory activity, mild analgesic/antipyretic activities, COX-1 selective, GIT irritation. Aspirin modifies COX enzymes, steric block
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What is Benorylate?
A prodrug (inactive). Breaks down in the body via ester hydrolysis to form aspirin and paracetamol (active substances)
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Describe features of Diflunisal
Analgesic and antipyretic. Treatment of pain associated with RA, OA and muscle pain. Less GIT ulceration than aspirin
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Describe features of Profens
Phenyl propanoic acids, strong acids (pKa 3-5), a-methyl to increase COX inhibitory activity, S isomer more potent to COX inhibitor. Racemates - inactive R converted to active S in vivo (except Naproxen) - see mechanism
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Why is the S isomer of naproxen marketed?
R-naproxen causes liver toxicity (S-naproxen is COX2 selective)
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Give examples of profens
Ibuprofen, fenoprofen, ketoprofen, fluroprofen - COX1 selective, RA/OA, less GIT effect than salicylate
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Describe features of nabumetone
Prodrug, metabolised by naphthylacetic acid, long half life of 24h, COX2 selective, RA/OA, less GIT effects
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Describe features of aryl acetic acids
COX1 selective, RA/OA, CNS toxicity from headaches to delusions to psychoses. Prodrug (sulphide) 500 time more active, anti-inflammatory, COX 1 selective, RA/OA
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Describe features of anthranilates
Steric effects in structures, diclofenac for RA/OA and post op pain (other examples - menfenamic acid, meclofenamate)
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Describe features of COX-2 preferential inhibitors
4-hydroxy with enolate anion stabilised by intramolecular H bonding with amide group, pKa of 6.3 (less acidic than COOH NSAIDs), COX2 selective than other NSAIDs, RA/OA, slowly absorbed after oral administration, half life of 20-50h (1 OD dosing)
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Describe features of paracetamol
Doesn't posses COOH functionality, possess little inhibitory activity against COX. Scavengers of hydroperoxide radicals. No anti-inflammatory activity. Analgesic/antipyretic. Can cause liver damage in overdose (binding of toxic metabolite to liver)
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How can paracetamol toxicity be prevented?
IV administration of sulfhydryl donors such as N-acetylcysteine if treatment is administered quickly (mechanism for paracetamol with GSH - conjugate addition)
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Describe features of selective COX-2 inhibitors
>50 fold COX2 selectivity, Celecoxib, Refecoxib, inhibit COX-2 in sites of inflammation. Doesn't block of COX1, antipyretic, anti-inflammatory, analgesic. GIT protective compared to non-selective NSAIDs
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Describe features of COX-2 Coxibs
Selective COX-2 inhibitors. Anti-inflammatory, analgesic, antipyretic, low ulceration potential, cause infertility and cardiovascular risk, Celecoxib (RA/OA), Etoricoxib (2nd generation - more selective COX-2, OA/RA), Refecoxib withdrawn due MIs
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Other cards in this set

Card 2

Front

What are NSAIDs used for?

Back

Treatment of minor pain and the management oedema and tissue damage resulting from inflammatory joint disease (arthritis). NSAIDs have antipyretic activity and analgesic activity

Card 3

Front

Give examples of primary indications of NSAIDs

Back

Preview of the front of card 3

Card 4

Front

Describe features of prostaglanlins

Back

Preview of the front of card 4

Card 5

Front

Outline the reaction to form prostaglanlins H2

Back

Preview of the front of card 5
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