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Non-steroidal Anti-
Inflammatory Drugs(NSAID)
Dr. Deepak K. Gupta
Introduction
• Inflammation is the immediate response of our
body in response of harmful stimulus.
• The treatment of pati...
NSAID
• Aspirin, the original NSAID, has a number of adverse
effects.
• Many other NSAIDs have been developed in attempts
...
Pharmacokinetics
• NSAID metabolism proceeds, in large part, by way
of the CYP3A or CYP2C families of P450 enzymes
in the ...
Pharmacodynamics
• Mediated chiefly through inhibition of prostaglandin
biosynthesis
• Various NSAIDs have additional poss...
Cyclooxygenase (COX)Pathway
www.facebook.com/notesdental
Prefferential/selective COX-2
inhibitors
• Do not affect platelet function at their usual
doses.
• Efficacy of COX-2-selec...
Adverse Effect
• Central nervous system: Headaches, tinnitus, and dizziness.
• Cardiovascular: Fluid retention, hypertensi...
Classification
• Non-selective COX inhibitors
– Salisylates Aspirin
– Propionic Acid derivatives: ibuprofen naproxen ketop...
Aspirin
• Rarely used as an anti-
inflammatory
medication
• But it has proved to be
beneficial for CVS
patient in terms of...
Pharmacology
• Salicylates are rapidly absorbed from the stomach and
upper small intestine
• Peak plasma level within 1–2 ...
Metabolism Of The Salicylates
www.facebook.com/notesdental
Clinical Uses
• Cardiovascular effect: decreases the incidence of
– transient ischemic attacks,
– Unstable angina,
– coron...
Other uses of Salicylates
• Salicylates are used to treat:
– rheumatoid arthritis
– juvenile arthritis
– osteoarthritis
– ...
Adverse Effect
• Common side effects listed earlier
• Adverse effects at antithrombotic doses are
gastric upset (intoleran...
Adverse effects
• The use of aspirin and
other salicylates to
control fever during viral
infections in children and
adoles...
PROPIONIC ACID DERIVATIVES -
Ibuprofen
• Better tolerated alternative to aspirin
• All have similar pharmacodynamic proper...
Clinical Use: Ibuprofen
• Available as an 'over-the-counter’ OTC drug as
200 mg, 400 mg, 600 mg
• Used as a simple analges...
Clinical Use: Ibuprofen
• effective in closing patent ductus
arteriosus in preterm infants
• oral and intravenous routes a...
Adverse Effect
• Common adverse effects are already listed
• Contraindicated in individuals with nasal polyps,
angioedema,...
Celecoxib
• selective COX-2 inhibitor—about 10–20 times
more selective for COX-2 than for COX-1
• associated with fewer en...
Diclofenac
• Phenylacetic acid derivative
that is relatively non-
selective as a COX inhibitor.
• Its available as diclofe...
Diclofenac – Clinical Use
• Most extensively used NSAID
• Combination of diclofenac and omeprazole: effective
with respect...
Diclofenac – Clinical Use
• Can be used after intraocular lens implantation
and strabismus surgery.
• Topical gel containi...
KETOROLAC
• Novel NSAID with potent
analgesic and moderate
anti-inflammatory effect.
• In post operative pain it
has equiv...
KETOROLAC
• Rapidly absorbed after oral and i.m. administration.
• T1/2 5-7 hrs, highly plasma bound and 60% excreted
unch...
KETOROLAC – Clinical Use
• renal colic and pain due to bony metastasis
• Orally it is used in a dose of 10-20mg
• Rated su...
Nimesulide
• Newer NSAID is a relatively weak inhibitor of PG
synthesis
• There is some evidence to indicate relative COX-...
Nimesulide
• Almost completely absorbed orally,
• T1/2 2-5 hrs, 99% plasma protein
bound,
• Extensively metabolized and ex...
Nimesulide – Adverse Effect
• Common
– Gastrointestinal: epigastralgia, heart burn, nausea, loose
motions
– Dermatological...
Paracetamol
• Acetaminophen: de-ethylated active
metabolite of phenacetin
• Central analgesic action of paracetamol is lik...
Pharmacology
• Analgesic action of aspirin and paracetamol is
additive.
• Well tolerated orally, but only about 1/4th is
p...
Clinical Use
• One of the most commonly OTC drug for
analgesic: headache, migraine,
musculoskeletal pain, dysmenorrhea
• B...
Clinical Use
• Equally efficacious as aspirin for non-
inflammatory conditions, without its side
effect
– Insignificant ga...
www.facebook.com/notesdental
Adverse Effect
• Safe and well tolerated
• Nausea and rashes occur occasionally and other side
effects are similar to othe...
References
• Basic & Clinical Pharmacology Bertram G.
Katzung Twelfth Edition
• Essential of medical pharmacology - K.D. T...
THANKS……
Like, share and comment on
https://www.facebook.com/notesdental
http://www.slideshare.net/DeepakKumarGupta2
www.f...
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Non steroidal anti-inflammatory drugs(nsaid)

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Non steroidal anti-inflammatory drugs(nsaid)

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Non steroidal anti-inflammatory drugs(nsaid)

  1. 1. Non-steroidal Anti- Inflammatory Drugs(NSAID) Dr. Deepak K. Gupta
  2. 2. Introduction • Inflammation is the immediate response of our body in response of harmful stimulus. • The treatment of patients with inflammation involves two primary goals – Relief of symptoms and the maintenance of function: usually the major continuing complaints of the patient; – Slowing or arrest of the tissue-damaging process. • Reduction of inflammation with NSAIDs often results in relief of pain for significant periods www.facebook.com/notesdental
  3. 3. NSAID • Aspirin, the original NSAID, has a number of adverse effects. • Many other NSAIDs have been developed in attempts to improve upon aspirin’s efficacy and decrease its toxicity. • Although there are many differences in the kinetics of NSAIDs, they have some general properties in common • Most are well absorbed, and food does not substantially change their bioavailability. • Most are highly metabolized, some by – Phase I followed by phase II mechanisms – others by direct glucuronidation (phase II) alone www.facebook.com/notesdental
  4. 4. Pharmacokinetics • NSAID metabolism proceeds, in large part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver. • While renal excretion is the most important route for final elimination • Nearly all undergo varying degrees of biliary excretion and re-absorption • Most of the NSAIDs are highly protein-bound (∼ 98%), usually to albumin • All NSAIDs can be found in synovial fluid after repeated dosing www.facebook.com/notesdental
  5. 5. Pharmacodynamics • Mediated chiefly through inhibition of prostaglandin biosynthesis • Various NSAIDs have additional possible mechanisms of action – inhibition of chemotaxis, – down-regulation of interleukin-1 production, – decreased production of free radicals and superoxide – interference with calcium-mediated intracellular events • NSAID’s may be either non-selective COX inhibitor or preferentially/selective COX-2 inhibitor www.facebook.com/notesdental
  6. 6. Cyclooxygenase (COX)Pathway www.facebook.com/notesdental
  7. 7. Prefferential/selective COX-2 inhibitors • Do not affect platelet function at their usual doses. • Efficacy of COX-2-selective drugs equals that of the older NSAIDs, while GI safety may be improved. • Selective COX-2 inhibitors may increase the incidence of edema and hypertension. – Only celecoxib has FDA approval www.facebook.com/notesdental
  8. 8. Adverse Effect • Central nervous system: Headaches, tinnitus, and dizziness. • Cardiovascular: Fluid retention, hypertension, edema, and rarely, myocardial infarction, and congestive heart failure. • Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, and rarely, ulcers or bleeding. – all NSAID are gastric irritants and can be associated with GI ulcers to some extent • Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia. • Hepatic: Abnormal liver function tests and rare liver failure. • Pulmonary: Asthma. • Skin: Rashes, all types, pruritus. • Renal: Renal insufficiency, renal failure, hyperkalemia, and proteinuria www.facebook.com/notesdental
  9. 9. Classification • Non-selective COX inhibitors – Salisylates Aspirin – Propionic Acid derivatives: ibuprofen naproxen ketoprefen flurbiprofen – Anthranilc acid derivative: mephanamic acid – Aryl-acetic acid derivative: Diclofenac aceclofenac – Oxicam: piroxicam tenoxicam – Pyrolo-pyrolle derivative: ketorolac – Indole derivative: indomethacin – Pyrozolone derivative: phenylbutazone oxyphenbutazone • Preferentical COX-2 inhibitors Nimesulide, meloxicam, nabumetone • Selective COX-2 inhibitors: Celecoxib Etoricoxib parecoxib • Analgesic-antipyretics – Paraminophenol: Paracetamol – Pyrozolone derivative: metamizol, propiphenazone www.facebook.com/notesdental
  10. 10. Aspirin • Rarely used as an anti- inflammatory medication • But it has proved to be beneficial for CVS patient in terms of its anti-platelet effects • Salicylic acid is a simple organic acid www.facebook.com/notesdental
  11. 11. Pharmacology • Salicylates are rapidly absorbed from the stomach and upper small intestine • Peak plasma level within 1–2 hours. • It is rapidly hydrolyzed also (serum half life 15 minutes) to acetic acid and salicylate by esterases in tissue and blood • Alkalinization of the urine increases the rate of excretion of free salicylate and its water-soluble conjugates – salicylate poisoning • Mechanism of action: irreversibly inhibits platelet COX so that aspirin’s anti-platelet effect lasts 8–10 days www.facebook.com/notesdental
  12. 12. Metabolism Of The Salicylates www.facebook.com/notesdental
  13. 13. Clinical Uses • Cardiovascular effect: decreases the incidence of – transient ischemic attacks, – Unstable angina, – coronary artery thrombosis with myocardial infarction – Thrombosis after coronary artery bypass grafting • long-term use low dosage is associated with a lower incidence of colon cancer - possibly related to its COX- inhibiting effects • Previously not recommended during pregnancy, – But recently it has proved valuable in treating preeclampsia-eclampsia www.facebook.com/notesdental
  14. 14. Other uses of Salicylates • Salicylates are used to treat: – rheumatoid arthritis – juvenile arthritis – osteoarthritis – other inflammatory disorders • 5-Amino salicylates (mesalamine, sulfasalazine): Crohn's disease. • Salicylic acid is used topically to treat: – plantar warts – fungal infections – Corns www.facebook.com/notesdental
  15. 15. Adverse Effect • Common side effects listed earlier • Adverse effects at antithrombotic doses are gastric upset (intolerance) and gastric and duodenal ulcers • Hepatotoxicity, asthma, rashes, GI bleeding, and renal toxicity rarely if ever occur at antithrombotic doses. • Contraindicates its use by patients with hemophilia www.facebook.com/notesdental
  16. 16. Adverse effects • The use of aspirin and other salicylates to control fever during viral infections in children and adolescents is totally contraindicated • Is associated with an increased incidence of Reye's syndrome, characterized by – vomiting, – hepatic disturbances, – Encephalopathy that has a 35% mortality rate.www.facebook.com/notesdental
  17. 17. PROPIONIC ACID DERIVATIVES - Ibuprofen • Better tolerated alternative to aspirin • All have similar pharmacodynamic properties • But differ considerably in potency and to some extent in duration of action. • The analgesic, antipyretic and anti-inflammatory efficacy is rated somewhat lower than high dose of aspirin • All inhibit PG synthesis: Naproxen being the most potent • Inhibition of platelet aggregation is short-lasting with ibuprofen, but longer lasting with naproxen. www.facebook.com/notesdental
  18. 18. Clinical Use: Ibuprofen • Available as an 'over-the-counter’ OTC drug as 200 mg, 400 mg, 600 mg • Used as a simple analgesic and antipyretic • Effective in dysmenorrhoea • Ibuprofen and its congeners are widely used in rheumatoid arthritis, osteoarthritis and other mucoskeletal disorder • indicated in soft tissue injuries, fracture, vasectomy, tooth extraction and to relieve post- partum pain www.facebook.com/notesdental
  19. 19. Clinical Use: Ibuprofen • effective in closing patent ductus arteriosus in preterm infants • oral and intravenous routes are equally effective • Topical cream preparation appears to be absorbed into fascia and muscle; – Relieve joint pain in osteoarthritis • A liquid gel preparation 400 mg, provides prompt relief and good overall efficacy in postsurgical dental pain. www.facebook.com/notesdental
  20. 20. Adverse Effect • Common adverse effects are already listed • Contraindicated in individuals with nasal polyps, angioedema, and bronchospastic reactivity to aspirin • Aseptic meningitis (particularly in patients with systemic lupus erythematosus), and fluid retention have been reported • Concomitant administration of ibuprofen and aspirin – Antagonistic effect www.facebook.com/notesdental
  21. 21. Celecoxib • selective COX-2 inhibitor—about 10–20 times more selective for COX-2 than for COX-1 • associated with fewer endoscopic ulcers than most other NSAIDs • Probably because it is a sulfonamide, celecoxib may cause rashes • does not affect platelet aggregation at usual doses. • It interacts occasionally with warfarin • Adverse effects are the common toxicities listed above. www.facebook.com/notesdental
  22. 22. Diclofenac • Phenylacetic acid derivative that is relatively non- selective as a COX inhibitor. • Its available as diclofenac sodium salt. • Gastrointestinal ulceration may occur less frequently than with some other NSAIDs. • Antiplatelet action is short lasting. • T1/2 : 2 hrs • Good tissue penetrability www.facebook.com/notesdental
  23. 23. Diclofenac – Clinical Use • Most extensively used NSAID • Combination of diclofenac and omeprazole: effective with respect to the prevention of recurrent bleeding – but renal adverse effects were common in high-risk patients. – Dosage above 150 mg/d: impair renal blood flow and glomerular filtration rate • Other combination includes ibuprofen+diclofenac: excellent pain management as OTC drug. • 0.1% ophthalmic preparation: prevention of postoperative ophthalmic inflammation www.facebook.com/notesdental
  24. 24. Diclofenac – Clinical Use • Can be used after intraocular lens implantation and strabismus surgery. • Topical gel containing 3% diclofenac is effective for solar keratoses. • Rectal suppository form can be considered for preemptive analgesia and postoperative nausea • Also available as an oral mouthwash and for intramuscular administration • osteoarthritis, bursitis, ankylosing spondylitis, toothache, dysmenorrhoea - quick relief of pain www.facebook.com/notesdental
  25. 25. KETOROLAC • Novel NSAID with potent analgesic and moderate anti-inflammatory effect. • In post operative pain it has equivalent efficacy of morhphine – But it does not interact with opoid receptors and is free of opioid side effect www.facebook.com/notesdental
  26. 26. KETOROLAC • Rapidly absorbed after oral and i.m. administration. • T1/2 5-7 hrs, highly plasma bound and 60% excreted unchanged. • Metabolic pathway is glucuronidation conjugation • Clinical use – frequently used in postoperative pain management: dental and acute musculoskeletal pain – When used with an opioid, it may decrease the opioid requirement by 25–50%. – ophthalmic preparation is available for ocular inflammatory conditions. www.facebook.com/notesdental
  27. 27. KETOROLAC – Clinical Use • renal colic and pain due to bony metastasis • Orally it is used in a dose of 10-20mg • Rated superior to aspirin, paracetamol (600 mg) and equivalent to ibuprofen (400 mg) • Continuous use for more than 5 day is not recommended - renal toxicity www.facebook.com/notesdental
  28. 28. Nimesulide • Newer NSAID is a relatively weak inhibitor of PG synthesis • There is some evidence to indicate relative COX-2 selectivity • Mode of action – Reduced generation of superoxide by neutrophils, – inhibition of PAF synthesis and TNFa release, – free radical scavanging, – inhibition of metalloproteinase activity in cartilage. • Analgesic, antipyretic and anti-inflammatory activity has been rated comparable to other NSAIDs. www.facebook.com/notesdental
  29. 29. Nimesulide • Almost completely absorbed orally, • T1/2 2-5 hrs, 99% plasma protein bound, • Extensively metabolized and excreted mainly in urine. • Dose: 100 mg BD • Clinical Use: primarily for short-lasting painful inflammatory conditions – sports injuries, – Sinusitis and other ear-nose-throat disorders, – Dental surgery, – bursitis, low backache, – dysmenorrhoea, – postoperative pain, – osteoarthritis and for fever www.facebook.com/notesdental
  30. 30. Nimesulide – Adverse Effect • Common – Gastrointestinal: epigastralgia, heart burn, nausea, loose motions – Dermatological: rash, pruritus – Central: somnolence, dizziness • Hematuria is reported in few children • Instances of fulminant hepatic failure have been associated with nimesulide • Banned in almost all developed countries • But extremely useful for asthmatics and those who develop bronchospasm or intolerance to aspirin and other NSAIDs • So it should be limited to use in such person only www.facebook.com/notesdental
  31. 31. Paracetamol • Acetaminophen: de-ethylated active metabolite of phenacetin • Central analgesic action of paracetamol is like aspirin, i.e. it raises pain threshold • It is a poor inhibitor of PG synthesis in peripheral tissues, but more active on COX in the brain. • Its a good and promptly acting antipyretic, but negligible anti-inflammatory action www.facebook.com/notesdental
  32. 32. Pharmacology • Analgesic action of aspirin and paracetamol is additive. • Well tolerated orally, but only about 1/4th is protein bound • It is uniformly distributed in the body • Metabolism occurs mainly by conjugation of glucuronic acid and sulfate • Plasma t1/2 2-3 hrs, effects after an oral dose last for 3-5 hours www.facebook.com/notesdental
  33. 33. Clinical Use • One of the most commonly OTC drug for analgesic: headache, migraine, musculoskeletal pain, dysmenorrhea • But is relatively ineffective when inlflamation is prominent. • First choice analgesic for osteoarthritis by many professional bodies • Drug of choice: as antipyretic, especially in children (no risk of Reye's syndrome) www.facebook.com/notesdental
  34. 34. Clinical Use • Equally efficacious as aspirin for non- inflammatory conditions, without its side effect – Insignificant gastric irritation, mucosal erosion and bleeding – Occurs rarely in overdose. – does not affect platelet function, clotting factors www.facebook.com/notesdental
  35. 35. www.facebook.com/notesdental
  36. 36. Adverse Effect • Safe and well tolerated • Nausea and rashes occur occasionally and other side effects are similar to other NSAID • Analgesic nephropathy: after years of heavy use – Personality defect. – Pathological lesions like necrosis, tubular atrophy followed by renal fibrosis • Acute paracetamol poisoning: especially in small children who have low hepatic glucuronide conjugating ability. • If a large dose > 150 mg/kg or > 10 g in an adult: serious toxicities • Fatality is common > 250 mg/kg. www.facebook.com/notesdental
  37. 37. References • Basic & Clinical Pharmacology Bertram G. Katzung Twelfth Edition • Essential of medical pharmacology - K.D. Tripathi 6th edition • Lippincott - Modern Pharmacology With Clinical Applications 6E • Color Atlas Of Pharmacology, 2Nd Ed (Lüllmann, Thieme 2000) www.facebook.com/notesdental
  38. 38. THANKS…… Like, share and comment on https://www.facebook.com/notesdental http://www.slideshare.net/DeepakKumarGupta2 www.facebook.com/notesdental

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