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Dr.U.P.Rathnakar
MD.DIH.PGDHM
1
ARACHIDONIC ACID
Cyclooxygenase-1
[Constitutive-Good???]
Cyclooxygenase-2
[Induced-Bad???]
ADEs
NSAIDs
Uses
PGs
-Gastro protective -Platelet function -Renal function -Uterine contractions -Inflammation -Fever -Pain 2
Classification-NSAIDs
Nonselective Irreversible inhibitors of COX Aspirin Nonselective reversible inhibitors of COX Ibuprofen, Diclofenac, Indomethacin, Piroxicam Weak inhibitors of COX1 Nimesulide Preferential inhibitors of COX-2[>10times] Meloxicam,Nabumetone, Etodolac Selective reversible inhibitors of COX-2[>50 times] Rofecoxib, Celecoxib, Valdecoxib, Etoricoxib, Parecoxib Inhibitors of COX-3[?] or hypothalaamic COX-1 inhibitors Paracetamol, Analgin NSAIDs Not inhibitors of COX 3 Nefopam, Diacerein
Paracetamol [Acetaminophen]
[COX3 inhibitor???]
Analgesicantipyretic agent Anti-inflammatory effects are much weaker. WHY? Indicated in osteoarthritis Not suitable in rheumatoid arthritis. WHY? low incidence of GI side effects. WHY? OTC drug Hepatotoxic drug. WHY?
Paracetamol
[Pharmacological actions-MOA]
Weak anti-inflammatory effects Poor inhibition COX in the presence of high concentrations of peroxides, as are found at sites of inflammation. COX3 inhibition in brain?? No effect on the cardiovascular and respiratory systems, on platelets, or on coagulation. Acidbase changes and uricosuric effects do not occur, NO gastric irritation, erosion, or bleeding
Paracetamol
[PK & Metabolism]
Excellent oral bioavailability Metabolism-Conjugation & N-hydroxylation N-acetyl-p-benzoquinoneimine (NAPQI), a highly toxic intermediate removed by GSH conjugation[saturable]
Paracetamol [Uses]
Suitable substitute for aspirin for analgesic or antipyretic uses [Not antiinflammatory] When aspirin is contraindicated (e.g., those with peptic ulcer, aspirin hypersensitivity, children with a febrile illness). OA-not in Rh.arthritis [Not antiinflammatory] Not more than 4000mg/day[8 tab]2000mg in alcoholics
Paracetamol [ADEs]
Usually is well tolerated Hypersensitivity reactions[No cross sensitivity] Most serious acute adverse effect hepatic necrosis. Due to accumulation of NAPQI [GSH depletion] Others-Renal damage, neutropenia
Paracetamol[acetaminophen] toxicity
Ac.Hepatotoxicity
[Glutathione donor]
13
Management of Acetaminophen
Medical emergency Gastric lavage-activated charcoal N-acetylcysteine (NAC) Oral loading dose 140 mg/kg -70 mg/kg every 4 hours for 17 doses
i.v. 150 mg/kg by infusion in 200 mL of 5% dextrose over 60 minutes followed by 50 mg/kg by intravenous infusion in 500 mL of 5% dextrose over 4 hours, then 100 mg/kg by intravenous infusion in 500 mL of 5% dextrose over 16 hours
Indomethacin Pharmacological properties Anti-inflammatory and analgesic antipyretic properties More potent inhibitor of COX than is aspirin Intolerance limits its use to short-term dosing.
Indomethacin is 20 times more potent than aspirin ADEs are more and common-GIT, CNS When tolerated, indomethacin more effective than aspirin [OA.ankylosing spondylitis]. Intolerance limits the long-term use as analgesic Not commonly used as an antipyretic unless the fever has been refractory to other agents (e.g., Hodgkin's disease).
Diclofenac [Uses]
Rheumatoid arthritis, OA, ankylosing spondylitis, pain, primary dysmenorrhea, and acute migraine Available in combination with misoprostol, a PGE1 analog Ophthalmic solution -treatment of postoperative inflammation following eye surgery
Ketorolac
Potent analgesic -moderately effective anti-inflammatory Acute pain[Post op] -administered i.m, i.v, or orally Aspirin sensitivity is a contraindication Inflammation of eye
Ibuprofen MOA, ADEs, Uses same as other NSAIDs Tablets, capsules, caplets, and gelcaps, oral drops; and as an oral suspension Preparations-200mg-OTC in USA Better tolerated than Aspirin or indomethacin May interfere with action of low dose aspirin
Naproxen
Less serious adverse effects May offer cardioprotection CNS side effects -drowsiness, headache, dizziness, and sweating,fatigue, depression, and ototoxicity Safer NSAID like ibuprofen
Piroxicam
Oral-absorbed completely Enterohepatic circulation-long half life Slow onset of action and delayed attainment of steady state-Not for acute conditions Rheumatoid arthritis and osteoarthritis Once a day More GI and serious skin reactions than other nonselective NSAIDs
COX-2Selective NSAIDs
[Celecoxib, Parecoxib,Etoricoxib]
Higher affinity for COX-2 than COX-1 Analgesic, antipyretic, antinflammatory Less GI adverse effects No efficacy advantage over other NSAIDs May carry cardiovascular risk Rofecoxib and Valdecoxib-withdrawn due to CV risk Not to be used in IHD and stroke pts. Carefully used in high CV risk pts Lowest effective dose for shortest possible time!
They were found increase risk of MI COXIBS selectively inhibit PGI2 in vascular endothelium without affecting TXA2. This increases the risk of thromboembolism In addition-Inhibition of PG production in the kidneyhypertension and edemaoccur
Nimesulide
Weak and preferntial[COX2] inhibitor Hepatotoxic Can be used in aspirin sensitivity
Atypical NSAIDs
[Do not inhibit PG synthesis]
Nefopam
MOA-not known
Diacerein
Inhibits IL-1
Topical NSAIDs
Many are available as gel NSAIDs are not counter irritants Any benefit from such a preparation is obtained from the other contents [Methyl salicylate] Negligible amounts may enter circulation Some quantity may reach synovial fluid.
Choice of NSAID
Paracetamol for non inflammatory pain Ibuprofen or Naproxen as antiinflammatory Other NSAIDs only when no relief with the above GIT risk and CVS risk should be considered. NSAIDs can be combined with PPIs of misoprostol to reduce GIT effects Specific purpose: low dose aspirin for secondary prevention or indomethacin in PDA Is the pt. on low dose aspirin?
Low aspirin Paracetamol Ibuprofen Diclo Indomethacin Piroxicam COX2 inhibitors Nimesulde
IHD Fever Antiinflammatory Antiinflammatory PDA Long acting Less GIT effects Aspirin sensitivity
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NSAIDs
Source Synthetic
OPIOIDS
Natural alkaoids/ semisynthetic/ synthetic derivatives Acts on opioid receptors (, , , , ) Depress CNS Also alters pain perception No such action
Inhibition of PG synthesis Does not depress CNS Raises pain threshold Most are antiinflammatory and antipyretic GIT and others No dependence & tolerance
ADEs
Availability