Download - Non steroidal anti-inflammatory drugs(nsaid)
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 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
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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
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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 biliaryexcretion 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
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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
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Cyclooxygenase (COX)Pathway
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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
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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 evenaplastic 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
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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
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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
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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
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Metabolism Of The Salicylates
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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
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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
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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 occurat antithrombotic doses.
• Contraindicates its use by patients with hemophilia
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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
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.
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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
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Clinical Use: Ibuprofen
• effective in closing patent ductusarteriosus 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.
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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), andfluid retention have been reported
• Concomitant administration of ibuprofenand aspirin – Antagonistic effect
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Celecoxib
• selective COX-2 inhibitor—about 10–20 timesmore 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 usualdoses.
• It interacts occasionally with warfarin
• Adverse effects are the common toxicities listed above.
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Diclofenac
• Phenylacetic acid derivative that is relatively non-selective as a COX inhibitor.
• Its available as diclofenacsodium salt.
• Gastrointestinal ulceration may occur less frequently than with some other NSAIDs.
• Antiplatelet action is short lasting.
• T1/2 : 2 hrs• Good tissue penetrability
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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
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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
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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
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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 opioidrequirement by 25–50%.
– ophthalmic preparation is available for ocular inflammatory conditions.
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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
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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.
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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
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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
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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, butnegligible anti-inflammatory action
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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
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Clinical Use
• One of the most commonly OTC drug for analgesic: headache, migraine, musculoskeletal pain, dysmenorrhea
• But is relatively ineffective when inlflamationis prominent.
• First choice analgesic for osteoarthritis by many professional bodies
• Drug of choice: as antipyretic, especially inchildren (no risk of Reye's syndrome)
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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
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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.
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References
• Basic & Clinical Pharmacology Bertram G. Katzung Twelfth Edition
• Essential of medical pharmacology - K.D. Tripathi6th edition
• Lippincott - Modern Pharmacology With Clinical Applications 6E
• Color Atlas Of Pharmacology, 2Nd Ed (Lüllmann, Thieme 2000)
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