NSAIDs-III

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

NSAIDs-Common benefits and ADEs
Beneficial effects • Analgesic • Anti-inflammatory • Antipyretic • Antithrombotic • Closure of D.A.-new born Toxicities • Gastric ulcer • GI bleed • Nephropathy • Delay in labour • Hypersensitivity • Premature closure of D.A.

4

Aspirin [Irreversible inhibitor]
• Ph.actions• Uncoupling of oxidative phosphorylation • Metabolic, • Resp, • Acid-base, • CVS, • GIT, • Blood

• ADEs • Uses Low Medium High

Paracetamol [Acetaminophen]
[COX3 inhibitor???]

• Analgesic–antipyretic 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. Acid–base 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

Management of Acetaminophen Overdose
• Single dose of 10-15g[20-30 tab] toxic • Less dose in chronic alcoholics
[enzyme induction]

• Fasting or malnutrtion [GSH
defeciency]

• Rarely in therapeutic doses

Management of Acetaminophen Overdose-Symptoms & signs
• Initial two days-gastric distress • Raised transaminases, hepatomegaly, jaundice, coagulopathy • Hepatic encephalopathy • Biopsy-centrilobular necrosis • May be reversible if survives

Paracetamol[acetaminophen] toxicity

P.Mol Toxic doses N-Hydroxylation]

Large amounts of NAPQI N-Acetylcysteine [NAC]
[GSH]

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

ACETIC ACID DERIVATIVES
SULINDAC, AND ETODOLAC, INDOMETHACIN,

• •
• •

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).

INDOMETHACIN Therapeutic uses

INDOMETHACIN Therapeutic uses
• Persistent PDA in premature infants • i.v. administration of 0.1-0.25 mg/kg every 12 hours for three doses • Successful closure can be expected in >70% • Used to decrease the incidence and severity of intraventricular hemorrhage in low-birth-weight neonates

Diclofenac [Reversible non-selective]
• Most commonly used NSAIDs in ’EU’ • Analgesic, antipyretic, and antiinflammatory activities. • Has selectivity for COX-2 [CV risk??] • Accumulates in synovial fluid -duration of therapeutic effect is considerably longer than its plasma t1/2

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

Good for humans. Bad for avians!

Indian white-rumped vulture
A critically endangered species that has lost 99.9 percent of its population due to DICLOFENAC POISONING

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

Propionic acid derivative
[Ibuprofen,Naproxen, Fenoprofen, Ketoprofen, Flurbiprofen]

• •
• • •

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-2–Selective 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!

Why some COX2 inhibitors [Rofecoxib] withdrawn from the market?

• 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 kidney—hypertension and edema—occur

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

www.manipal.edu

Differences between NSAIDS & Opioids

NSAIDs
Source Synthetic

OPIOIDS
Natural alkaoids/ semisynthetic/ synthetic derivatives Acts on opioid receptors (μ, κ, δ, ε, ζ) Depress CNS Also alters pain perception No such action

MOA CNS Effect on pain Other actions

Inhibition of PG synthesis Does not depress CNS Raises pain threshold Most are antiinflammatory and antipyretic GIT and others No dependence & tolerance

ADEs

Dependence & tolerance most important

Availability

Many are OTC drugs

Very strictly controlled 32

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