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


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


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


Cyclooxygenase (COX)Pathway


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


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


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


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


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


Metabolism Of The Salicylates


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


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


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


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.


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


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.


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


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.


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


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


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


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


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.


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


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.


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


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


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


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


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)


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


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.


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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non steroidal anti-inflammatory drugs(nsaid)

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