NSAIDS NSAIDS ComparisonComparison

Which One To Be Prescribed?Which One To Be Prescribed?

Dr. Saleem Akhtar Rana, Dr. Saleem Akhtar Rana,

Dr. Arshad Javaid Sheikh, Dr. Arshad Javaid Sheikh,

Dr. Mahboob AshrafDr. Mahboob Ashraf

Agenda For todayAgenda For today Assessment of our shortcomingsAssessment of our shortcomings Assessment of Practice in USAAssessment of Practice in USA Does any specific NSAID good for everyone?Does any specific NSAID good for everyone? Factors to select any particular NSAIDsFactors to select any particular NSAIDs How these NSAIDS work?How these NSAIDS work? Differences between non selective NSAIDs and Differences between non selective NSAIDs and

Cox-2 inhibitors.Cox-2 inhibitors. Indications for NSAIDsIndications for NSAIDs Side effects of NSAIDSSide effects of NSAIDS Questions marks on Cox-2 inhibitorsQuestions marks on Cox-2 inhibitors Some specific drugs; Celecoxib, Meloxicam, Some specific drugs; Celecoxib, Meloxicam,

Aceclofenac, Diclofenac.Aceclofenac, Diclofenac.

Agenda for todayAgenda for today

What are our deficiencies? What are our deficiencies? ShortcomingsShortcomings

ShortcomingsShortcomings

OveruseOveruse Proper indication; proper NSAIDProper indication; proper NSAID Co-morbid conditionsCo-morbid conditions Contra-indicationsContra-indications Side effectsSide effects DosageDosage InteractionsInteractions ChildrenChildren PregnancyPregnancy

Prescription Practices of NSAIDs In Prescription Practices of NSAIDs In USAUSA

NSAID-associated upper gastrointestinal adverse NSAID-associated upper gastrointestinal adverse events are estimated to result in events are estimated to result in

103,000 hospitalizations per year103,000 hospitalizations per year 16,500 deaths per year in the United States, and 16,500 deaths per year in the United States, and represent 43% of drug-related emergency visits. represent 43% of drug-related emergency visits. a review of physician visits and prescriptions a review of physician visits and prescriptions

estimated that unnecessary prescriptions for estimated that unnecessary prescriptions for NSAIDs were written in 42% of visits.NSAIDs were written in 42% of visits.[[

An estimated 10-20% of NSAID patients experience An estimated 10-20% of NSAID patients experience dyspepsiadyspepsia, and Many of these events are , and Many of these events are

avoidable; avoidable;

One for all?One for all?

Will any specific NSAID will work in all Will any specific NSAID will work in all individuals similarly?individuals similarly?

After how many days any specific After how many days any specific NSAID should be changed?NSAID should be changed?

Which One?Which One?

What factors should be considered What factors should be considered before we select any specific NSAID?before we select any specific NSAID?

Basis of Choice Of Any Basis of Choice Of Any Specific NSAIDSpecific NSAID

Their potency, Difference is there!Their potency, Difference is there! Duration of action, Duration of action, Mode Of eliminated from the body,Mode Of eliminated from the body, Condition to be treated = Prostaglandin associated: Condition to be treated = Prostaglandin associated:

Diagnosis, Degree of SeverityDiagnosis, Degree of Severity AgeAge Co morbid conditions like Hypertension, Heart Co morbid conditions like Hypertension, Heart

disease, bleeding tendencies where Cox-2 inhibitors disease, bleeding tendencies where Cox-2 inhibitors (Coxibs) are contraindicated(Coxibs) are contraindicated

Drug interactions = Mechanism of actionDrug interactions = Mechanism of action Side effects = Cox 1 & 2 inhibitionSide effects = Cox 1 & 2 inhibition Effects on cartilageEffects on cartilage History of dyspepsia where Cox-2 inhibitors may be History of dyspepsia where Cox-2 inhibitors may be

preferred.preferred.

Basis of Choice Of Any Basis of Choice Of Any Specific NSAIDSpecific NSAID

Their ability to cause ulcers and promote Their ability to cause ulcers and promote bleeding. bleeding.

Their ability to raise blood pressure, Their ability to raise blood pressure, increase fluid retention and cause increase fluid retention and cause renal failure and CCFrenal failure and CCF

Please Remember: Please Remember: The more an NSAID blocks Cox-1, the The more an NSAID blocks Cox-1, the greater is its tendency to cause greater is its tendency to cause ulcers and promote bleeding.ulcers and promote bleeding.

PhPharmacokineticsarmacokinetics

Most NSAIDs are metabolised in the Most NSAIDs are metabolised in the liverliver by by oxidation and conjugation to inactive oxidation and conjugation to inactive metabolites which are typically excreted in metabolites which are typically excreted in the the urineurine, although some drugs are partially , although some drugs are partially excreted in excreted in bilebile. Metabolism may be abnormal . Metabolism may be abnormal in certain disease states, and accumulation in certain disease states, and accumulation may occur even with normal dosage.may occur even with normal dosage.

Ibuprofen and diclofenac have short half-lives Ibuprofen and diclofenac have short half-lives (2–3 hours). Some NSAIDs (typically oxicams) (2–3 hours). Some NSAIDs (typically oxicams) have very long half-lives (e.g. 20–60 hours).have very long half-lives (e.g. 20–60 hours).

Which NSAID???Which NSAID???

Before we select one of the non-Before we select one of the non-selective NSAIDs or Cox-2 inhibitors selective NSAIDs or Cox-2 inhibitors we must know what are the important we must know what are the important differences?differences?

Only then we can select an Only then we can select an appropriate molecule.appropriate molecule.

John VaneJohn Vane (1927-2004), who later (1927-2004), who later received a received a Nobel PrizeNobel Prize for his work for his work

Different Pathways Of inflammationDifferent Pathways Of inflammation

Inflammation is induced by following 4 Inflammation is induced by following 4 chemical mediators .chemical mediators .

Amines: Histamine & 5-OH TryptamineAmines: Histamine & 5-OH Tryptamine ProstaglandinsProstaglandins Small peptides; BradykininSmall peptides; Bradykinin Larger peptides; Interleukin-1Larger peptides; Interleukin-1

NSAIDs can benefit only where NSAIDs can benefit only where prostaglandins are the chemical prostaglandins are the chemical

mediators.mediators.

Mechanism of action of NSAIDsMechanism of action of NSAIDs

How these drugs act?How these drugs act?

Very fundamental molecuesVery fundamental molecues

Arachidonic Acid Arachidonic Acid (present in all cells)(present in all cells)

Many isoenzymes of CyclooxegenaseMany isoenzymes of Cyclooxegenase Prostaglandins + Thromboxanes+ Prostaglandins + Thromboxanes+

ProstacyclinProstacyclin

Different types of isoenzymes produce Different types of isoenzymes produce specific types of prostaglandins so specific types of prostaglandins so differences in actions.differences in actions.

Different isoenzymes present in different Different isoenzymes present in different tissues so differences in actionstissues so differences in actions

Cox-1 & Cox-2Cox-1 & Cox-2

Prostaglandins, Thromboxane-A, Prostaglandins, Thromboxane-A, ProstacyclineProstacycline

These are chemical mediatorsThese are chemical mediators

These perfom certain good day-to-day jobs in the These perfom certain good day-to-day jobs in the body like house-keeper.body like house-keeper.

These mediate in inflammation and produce pain, These mediate in inflammation and produce pain, fever and inflammation.fever and inflammation.

If these are inhibited then pain and fever may If these are inhibited then pain and fever may subside but the good jobs done also suffer and subside but the good jobs done also suffer and this factor is the focus of all serious side effects.this factor is the focus of all serious side effects.

NSAIDS & Cox-2 InhibitorsNSAIDS & Cox-2 Inhibitors(No therapeutic Cox-1 inhibitor)(No therapeutic Cox-1 inhibitor)

NSAIDS Inhibits all isoenzymes,

including Cox-1, so all kinds of prostaglandins, good and bad.

Active in baseline conditions

Acts almost in all tissues of body

So when good prostaglandins will be inhibited there are going to undesirable side effects even if pain and other symptoms are controlled.

Cox-1 is present in platelets, I tract,CNS,Kidneys.

Cox-1 inhibition takes away protective mechanisms from GIT, kidneys, blood vessels and blood clotting.

Cox-2 inhibitorsCox-2 inhibitors Inhibits only Cox-2 produced

prostaglandins, mainly required to control pain fever and inflammation

Is induced, i.e., becomes active only when inflammation is there.

Acts only where cox-2 isoenzyme is present.

When good prostaglandins are not inhibited, less side effects should be there.

Also present in kidneys and produces prostacyclin. Affects hemodynamics of kidneys probably in negative ways and increases thrombotic tendencies

Supposed to protect GIT against the ill effects of NSAIDs. Does so but does not bring the risk to zero.

Some studies suggest this increases atherogenesis tendencies also.

Cox-1 & Cox-2, & Cox-Cox-1 & Cox-2, & Cox-3, Cox-4,3, Cox-4,

Different Isoenzymes of CyclooxygenaseDifferent Isoenzymes of Cyclooxygenase

Produce different PGDs, F,D,E etcProduce different PGDs, F,D,E etc

A generalization A generalization ? Correct? Correct

Cox-1 InhibitionResponsible for all side effects of

NSAIDs

Cox-2 InhibitionResponsible for all therapeutic

benefits of NSAIDS

Non-selective NSAIDsNon-selective NSAIDs

Non selective NSAIDs Non selective NSAIDs are are accused accused of of what side effects?what side effects?

Which one goes away with Cox-2 Which one goes away with Cox-2 inhibitor?inhibitor?

Side effects of Non-selective NSAIDSSide effects of Non-selective NSAIDS GI side effects, GI side effects, raising blood pressure,raising blood pressure, Nephrotoxicity,Nephrotoxicity, Cardiotoxicity, Cardiotoxicity, Chondropathy,Chondropathy, Allergies, photoxicitiesAllergies, photoxicities CNS symptomsCNS symptoms

Fever Fever

How do NSAIDS work as anti-How do NSAIDS work as anti-pyretics?pyretics?

One Example Of NDAIDS One Example Of NDAIDS InhibitionInhibition

Fever is produced byFever is produced by PG E2, acting on thermostat in hypothalamus,PG E2, acting on thermostat in hypothalamus,

Resetting the thermostat on higher level.Resetting the thermostat on higher level.

PGE2 is produced by pyrogens from PGE2 is produced by pyrogens from arachidonic acid by inducing cox enzymes.arachidonic acid by inducing cox enzymes.

NSAIDS block this chemical reaction and thus NSAIDS block this chemical reaction and thus act as antipyretics. Both non-selective and act as antipyretics. Both non-selective and Cox-2 inhibitors are better antipyretics than Cox-2 inhibitors are better antipyretics than paracetamol.paracetamol.

NSAIDS & CartilageNSAIDS & Cartilage Strength flexibility and capacity to bear weight depends upon the Strength flexibility and capacity to bear weight depends upon the

amount of Protoglycans and Hyaloronic Acid in the matrix of amount of Protoglycans and Hyaloronic Acid in the matrix of cartilage.cartilage.

This differential effect of NSAIDs on cartilage metabolism is most This differential effect of NSAIDs on cartilage metabolism is most relevant to clinical practice since any drug, that suppresses relevant to clinical practice since any drug, that suppresses proteoglycan synthesis and impairs the chondrocyte to repair its proteoglycan synthesis and impairs the chondrocyte to repair its damaged extracellular matrix, could potentially accelerate the damaged extracellular matrix, could potentially accelerate the breakdown of the cartilage tissue. breakdown of the cartilage tissue.

Some NSAIDs inhibit the synthesis of cartilage proteoglycans Some NSAIDs inhibit the synthesis of cartilage proteoglycans whereas other do not ; ability of the chondrocyte to repair its whereas other do not ; ability of the chondrocyte to repair its damaged extracellular matrix may be impaired. damaged extracellular matrix may be impaired.

In cartilage with MOA and SOA, the metabolic balance of In cartilage with MOA and SOA, the metabolic balance of proteoglycan and HA was unaffected by diclofenac.proteoglycan and HA was unaffected by diclofenac.

Aceclofenac and Meloxicam did not hamper biochemical Aceclofenac and Meloxicam did not hamper biochemical properties of cartilage and so may delay the process in OA. properties of cartilage and so may delay the process in OA.

How NSAIDs bring relief?How NSAIDs bring relief? In the periphery NSAIDs work by decreasing the In the periphery NSAIDs work by decreasing the

sensitivity of the pain receptors to painful stimuli sensitivity of the pain receptors to painful stimuli induced by heat, trauma, or inflammation.induced by heat, trauma, or inflammation.

In the central nervous system, they are thought In the central nervous system, they are thought to function as antihyperalgesics and block the to function as antihyperalgesics and block the increased transmission of repetitive incoming increased transmission of repetitive incoming signals to higher centers.signals to higher centers.

In effect, they modulate perception of pain In effect, they modulate perception of pain caused by repetitive stimulation from the caused by repetitive stimulation from the periphery. Since they function by modulation of periphery. Since they function by modulation of the perception of pain, they may be useful when the perception of pain, they may be useful when given in the preoperative period and may reduce given in the preoperative period and may reduce the need for postoperative analgesiathe need for postoperative analgesia..

Is classification beneficial?Is classification beneficial? NSAIDs within a group will tend to have NSAIDs within a group will tend to have

similar characteristics and tolerability. similar characteristics and tolerability. There is little difference in clinical efficacy There is little difference in clinical efficacy

among the NSAIDs when used at among the NSAIDs when used at equivalent doses. equivalent doses.

Rather, differences among compounds Rather, differences among compounds tend to be with regards to tend to be with regards to

• Dosing regimens (related to the compound's Dosing regimens (related to the compound's elimination half-lifeelimination half-life), ), • Route of administration, and Route of administration, and

• Tolerability profile.Tolerability profile.

ClassificationClassification

Fenamic acid derivatives•Mefenamic acid•Meclofenamic acid•Flufenamic acid•Tolfenamic acid

Selective COX-2 inhibitors (Coxibs)•Celecoxib •Rofecoxib (withdrawn from market•Valdecoxib (withdrawn from market•Parecoxib FDA withdrawn•Lumiracoxib TGA cancelled registration•Etoricoxib FDA withdrawn

Propionic] acid derivatives derivativesNaproxenIbuprofenKetoprofenFlurbiprofenOxaprozin Acetic acid derivatives derivatives•Indomethacin•Sulindac•Etodolac•Diclofenac (Safety alert by FDA (Safety alert by FDAEnolic acid ( (Oxicam) derivatives) derivatives•Piroxicam•Meloxicam•Tenoxicam•Droxicam•Lornoxicam•Isoxicam

NSAIDs IndicationsNSAIDs Indications

•Rheumatoid arthritis•Osteoarthritis•Inflammatory arthropathies Inflammatory arthropathies (e.g. (e.g. ankylosing spondylitis, , psoriatic arthritis, , Reiter's syndrome))•Acute Acute gout•Dysmenorrhoea ( (menstrual pain) pain)•Metastatic bone pain bone pain•Headache and and migraine•Postoperative painPostoperative pain•Mild-to-moderate pain dueMild-to-moderate pain due to inflammation and to inflammation andtissue injurytissue injury•Pyrexia ( (fever))

•Ileus•Renal colic•They are also given to neonate infants They are also given to neonate infants whose whose ductus arteriosus is not closed within 24 hours of birth is not closed within 24 hours of birth•Research continues into their Research continues into their potential for prevention of potential for prevention of colorectal cancer, , and treatment of and treatment of other conditions, other conditions, such as cancer such as cancer and and cardiovascular disease..

Drug InteractionsDrug Interactions NSAIDs, like all drugs, may interact with other NSAIDs, like all drugs, may interact with other

medications. For example, concurrent use of NSAIDs medications. For example, concurrent use of NSAIDs and and quinolonesquinolones may increase the risk of quinolones' may increase the risk of quinolones' adverse adverse central nervous systemcentral nervous system effects, including effects, including seizure.seizure.

Combinational riskCombinational risk If a COX-2 inhibitor is taken, one should not use a If a COX-2 inhibitor is taken, one should not use a

traditional NSAID (prescription or over-the-counter) traditional NSAID (prescription or over-the-counter) concomitantly. In addition, patients on daily aspirin concomitantly. In addition, patients on daily aspirin therapy (e.g. for reducing cardiovascular risk) need therapy (e.g. for reducing cardiovascular risk) need to be careful if they also use other NSAIDs, as the to be careful if they also use other NSAIDs, as the latter may block the cardioprotective effects of latter may block the cardioprotective effects of aspirin.aspirin.

Possible Side EffectsPossible Side Effects NSAIDS are toxic drugs. Be alert and always keep warning NSAIDS are toxic drugs. Be alert and always keep warning

patients to keep looking for expected side effects.patients to keep looking for expected side effects. These effects are dose dependent. Use minimum dose for These effects are dose dependent. Use minimum dose for

minimum duration.minimum duration. Do not hesitate to stop these immediately if problem arises.Do not hesitate to stop these immediately if problem arises. The frequency of side effects varies between the The frequency of side effects varies between the

drugs.drugs. There are also some differences in the propensity of There are also some differences in the propensity of

individual agents to cause gastrointestinal adverse individual agents to cause gastrointestinal adverse drug reactions (ADRs). drug reactions (ADRs).

Indomethacin, ketoprofen and piroxicam appear to Indomethacin, ketoprofen and piroxicam appear to have the highest prevalence of gastric ADRs, while have the highest prevalence of gastric ADRs, while ibuprofen (lower doses) and diclofenac appear to ibuprofen (lower doses) and diclofenac appear to have lower rates. have lower rates.

A meta-analysis of 11 case-control studies and one A meta-analysis of 11 case-control studies and one cohort study found that ibuprofen was significantly cohort study found that ibuprofen was significantly less toxic than other NSAID.less toxic than other NSAID.

Side Effects: Side Effects: CardiovascularCardiovascular

80% increase in the risk of myocardial infarction 80% increase in the risk of myocardial infarction with both newer COX-2 antagonists and high dose with both newer COX-2 antagonists and high dose

traditional anti-inflammatories compared with traditional anti-inflammatories compared with placebo.placebo.

Doubled risk of symptomatic heart failure in Doubled risk of symptomatic heart failure in patients without a history of cardiac disease. patients without a history of cardiac disease.

In patients with such a history, however, use of In patients with such a history, however, use of NSAIDs (aside from low-dose aspirin) was NSAIDs (aside from low-dose aspirin) was associated with more than 10-fold increase in associated with more than 10-fold increase in heart failure. If this link is found to be causal, heart failure. If this link is found to be causal,

NSAIDs are estimated to be responsible for up to NSAIDs are estimated to be responsible for up to 20 percent of hospital admissions for congestive 20 percent of hospital admissions for congestive heart failure.heart failure.

Side Effects: Heart, Blood Side Effects: Heart, Blood Pressure, KidneysPressure, Kidneys

NSAIDs reduce the blood flow to the kidneys NSAIDs reduce the blood flow to the kidneys leading to salt & fluid retention.leading to salt & fluid retention.

This can lead to edema and hypertension.This can lead to edema and hypertension. If high doses are used for longer periods of times If high doses are used for longer periods of times

as in chronic conditions, can lead to renal failure.as in chronic conditions, can lead to renal failure. Combination with nephrotoxic agents increase Combination with nephrotoxic agents increase

the risk of renal failure.the risk of renal failure. Renal failure is especially a risk if the patient is Renal failure is especially a risk if the patient is

also concomitantly taking an ACE inhibitor and a also concomitantly taking an ACE inhibitor and a diuretic. diuretic. NSAIDs are excreted by kidneys.NSAIDs are excreted by kidneys.

NSAIDS & GITNSAIDS & GIT

NSAIDs cause a dual insult on the GIT:NSAIDs cause a dual insult on the GIT: The acidic molecules directly irritate the gastric The acidic molecules directly irritate the gastric mucosamucosa, , Inhibition of COX-1 reduces the levels of protective Inhibition of COX-1 reduces the levels of protective prostaglandinsprostaglandins. .

Inhibition of prostaglandin synthesis in the GI tract causesInhibition of prostaglandin synthesis in the GI tract causes

Increased gastric acid secretion, Increased gastric acid secretion, Diminished bicarbonate secretion, Diminished bicarbonate secretion, Diminished mucous secretion and Diminished mucous secretion and Diminished trophic effects on epithelial mucosa.Diminished trophic effects on epithelial mucosa.

Risk of ulceration increases with duration of therapy, and with Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimise GI ADRs, it is prudent to higher doses. In attempting to minimise GI ADRs, it is prudent to use the lowest effective dose for the shortest period of time, a use the lowest effective dose for the shortest period of time, a practice which studies show is not often followed. practice which studies show is not often followed.

Recent studies show that over 50% of patients taking NSAIDs have Recent studies show that over 50% of patients taking NSAIDs have sustained damage to their small intestine.sustained damage to their small intestine.

Side Effects: GastrointestinalSide Effects: Gastrointestinal

Nausea, Nausea, Dyspepsia, Dyspepsia, Vomiting, Vomiting, Diarrhea Diarrhea A burning, bloated feeling in the pit of A burning, bloated feeling in the pit of

the stomach, the stomach, Gastric ulceration/bleeding. Gastric ulceration/bleeding. To help protect the stomach, NSAIDs To help protect the stomach, NSAIDs

should always be taken with food or should always be taken with food or directly after a meal.directly after a meal.

Differences in NSAIDS & GIT Differences in NSAIDS & GIT side effectsside effects

IndomethacinIndomethacin, , ketoprofenketoprofen and and piroxicampiroxicam appear to have appear to have the highest prevalence of gastric ADRs, while the highest prevalence of gastric ADRs, while ibuprofenibuprofen (lower doses) and (lower doses) and DiclofenacDiclofenac appear to have lower rates. appear to have lower rates.

Certain NSAIDs, such as aspirin, have been marketed in Certain NSAIDs, such as aspirin, have been marketed in enteric-coatedenteric-coated formulations which are claimed to reduce formulations which are claimed to reduce the incidence of gastrointestinal ADRs. However, in the incidence of gastrointestinal ADRs. However, in consideration of the mechanism of such ADRs and indeed in consideration of the mechanism of such ADRs and indeed in clinical practice, these formulations have not been shown to clinical practice, these formulations have not been shown to have a reduced risk of GI ulceration.have a reduced risk of GI ulceration.

Commonly, gastrointestinal adverse effects can be reduced Commonly, gastrointestinal adverse effects can be reduced through suppressing acid production, by concomitant use of through suppressing acid production, by concomitant use of a a proton pump inhibitorproton pump inhibitor, e.g. , e.g. omeprazoleomeprazole, , esomeprazoleesomeprazole; or ; or the prostaglandin analogue the prostaglandin analogue misoprostolmisoprostol. Misoprostol is itself . Misoprostol is itself associated with a high incidence of gastrointestinal ADRs associated with a high incidence of gastrointestinal ADRs (diarrhea). (diarrhea).

Side Effects: Allergic Side Effects: Allergic ReactionsReactions

NSAIDs can also cause extreme allergic reactions. NSAIDs can also cause extreme allergic reactions. People with asthma are at a higher risk for People with asthma are at a higher risk for

experiencing serious allergic reaction to NSAIDs. experiencing serious allergic reaction to NSAIDs. Patients with asthma, sinusitis and nasal polyps Patients with asthma, sinusitis and nasal polyps

should stay away from NSAIDS.should stay away from NSAIDS. Allergy with one NSAIDS predisposes to allergy to Allergy with one NSAIDS predisposes to allergy to

others also.others also. Use of aspirin in children and teenagers with Use of aspirin in children and teenagers with

chicken pox or influenza has been associated with chicken pox or influenza has been associated with the development of Reyes's syndrome. Please the development of Reyes's syndrome. Please stop using brufen syrups.stop using brufen syrups.

Side Effects: RSide Effects: Renal adverse enal adverse drug reactionsdrug reactions

The mechanism of these renal ADRs is due to changes in The mechanism of these renal ADRs is due to changes in renal haemodynamics (blood flow), ordinarily mediated by renal haemodynamics (blood flow), ordinarily mediated by prostaglandins, which are affected by NSAIDs. prostaglandins, which are affected by NSAIDs.

Prostaglandins normally cause vasodilation of the Prostaglandins normally cause vasodilation of the afferent arteriolesafferent arterioles of the of the glomeruliglomeruli. This helps maintain . This helps maintain normal glomerular perfusion and normal glomerular perfusion and glomerular filtration rateglomerular filtration rate (GFR), an indicator of (GFR), an indicator of renal functionrenal function..

This is particularly important in renal failure where the This is particularly important in renal failure where the kidney is trying to maintain renal perfusion pressure by kidney is trying to maintain renal perfusion pressure by elevated angiotensin II levels. At these elevated levels, elevated angiotensin II levels. At these elevated levels, angiotensin II also constricts the afferent ateriole into the angiotensin II also constricts the afferent ateriole into the glomerulus in addition to the efferent arteriole one it glomerulus in addition to the efferent arteriole one it normally constricts. Prostaglandins serve to dilate the normally constricts. Prostaglandins serve to dilate the afferent arteriole; by blocking this prostaglandin-mediated afferent arteriole; by blocking this prostaglandin-mediated effect, particularly in renal failure, NSAIDs cause unopposed effect, particularly in renal failure, NSAIDs cause unopposed constriction of the afferent arteriole and decreased renal constriction of the afferent arteriole and decreased renal perfusion pressure. perfusion pressure.

Common ADRs associated with Common ADRs associated with altered renal function include:altered renal function include:

Salt and fluid retentionSalt and fluid retention HypertensionHypertension (high blood pressure) (high blood pressure) These agents may also cause renal impairment, especially These agents may also cause renal impairment, especially

in combination with other nephrotoxic agents. Renal failure in combination with other nephrotoxic agents. Renal failure is especially a risk if the patient is also concomitantly taking is especially a risk if the patient is also concomitantly taking an an ACE inhibitorACE inhibitor and a and a diureticdiuretic - the so-called "triple - the so-called "triple whammy" effect.whammy" effect.

In rarer instances NSAIDs may also cause more severe In rarer instances NSAIDs may also cause more severe renal conditions:renal conditions:

Interstitial nephritisInterstitial nephritis Nephrotic syndromeNephrotic syndrome Acute renal failureAcute renal failure Acute tubular necrosisAcute tubular necrosis

NSAIDs in combination with excessive use of NSAIDs in combination with excessive use of phenacetinphenacetin and/or and/or paracetamolparacetamol may lead to may lead to analgesic nephropathyanalgesic nephropathy..

Side Effects: Side Effects: PhotosensitivityPhotosensitivity

PhotosensitivityPhotosensitivity is a commonly overlooked is a commonly overlooked adverse effect of many of the NSAIDs. It is adverse effect of many of the NSAIDs. It is somewhat ironic that these anti-inflammatory somewhat ironic that these anti-inflammatory agents may themselves produce inflammation in agents may themselves produce inflammation in combination with exposure to sunlight. The 2-combination with exposure to sunlight. The 2-arylpropionic acids have proven to be the most arylpropionic acids have proven to be the most likely to produce photosensitivity reactions, but likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including other NSAIDs have also been implicated including piroxicampiroxicam, , diclofenacdiclofenac and and benzydaminebenzydamine..

While While ibuprofenibuprofen is somewhat of an exception, is somewhat of an exception, having weak absorption, it has been reported to having weak absorption, it has been reported to be a weak photosensitising agent.be a weak photosensitising agent.

NSAIDS & PregnancyNSAIDS & Pregnancy NSAIDs are not recommended during pregnancy, particularly NSAIDs are not recommended during pregnancy, particularly

during the during the third trimesterthird trimester. .

While NSAIDs as a class are not direct While NSAIDs as a class are not direct teratogensteratogens, they may cause , they may cause premature closure of the fetal premature closure of the fetal ductus arteriosusductus arteriosus

and renal ADRs in the fetus.and renal ADRs in the fetus. premature birthpremature birth..

Aspirin, however, is used together with Aspirin, however, is used together with heparinheparin in pregnant in pregnant women with women with antiphospholipid antibodiesantiphospholipid antibodies..

In contrast, In contrast, paracetamolparacetamol (acetaminophen) is regarded as being (acetaminophen) is regarded as being safe and well-tolerated during pregnancy. Doses should be taken safe and well-tolerated during pregnancy. Doses should be taken as prescribed, due to risk of as prescribed, due to risk of hepatotoxicityhepatotoxicity with overdoses. with overdoses.

Side Effects: othersSide Effects: others Raised liver enzymes,Raised liver enzymes, Headache, Headache, Dizziness.Dizziness.

Uncommon ADRs include:Uncommon ADRs include: Hyperkalaemia, Hyperkalaemia, Confusion, Confusion, BronchospasmBronchospasm Rash.Rash. Rapid and severe swelling of the face and/or body. Rapid and severe swelling of the face and/or body. Ibuprofen may also rarely cause Ibuprofen may also rarely cause irritable bowel syndromeirritable bowel syndrome

symptoms.symptoms. In very rare cases, ibuprofen can cause aseptic meningitis.In very rare cases, ibuprofen can cause aseptic meningitis. Inflammatory bowel disease: Inflammatory bowel disease: NSAIDs are never to be used in NSAIDs are never to be used in

individuals with individuals with Inflammatory Bowel DiseaseInflammatory Bowel Disease (e.g., (e.g., Crohn's DiseaseCrohn's Disease or or Ulcerative ColitisUlcerative Colitis) due to their tendency to cause gastric ) due to their tendency to cause gastric bleeding and form ulceration in the gastric lining. Pain relievers bleeding and form ulceration in the gastric lining. Pain relievers such as such as paracetamolparacetamol or drugs containing or drugs containing codeinecodeine (which slows (which slows down bowel activity) are safer medications for pain relief in IBD.down bowel activity) are safer medications for pain relief in IBD.

NSAIDs: NSAIDs: Precautions & Precautions & ContraindicationsContraindications

NSAIDs cannot be used (are NSAIDs cannot be used (are contraindicated) in the following casescontraindicated) in the following cases

Allergy to aspirin or any NSAIDAllergy to aspirin or any NSAID Aspirin should not be used under the age of 16 Aspirin should not be used under the age of 16

yearsyears Chronic liver and kidney diseasesChronic liver and kidney diseases During pregnancyDuring pregnancy During breast feedingDuring breast feeding On blood thinning agents (anticoagulants)On blood thinning agents (anticoagulants) Suffering from coagulation disorder.Suffering from coagulation disorder. Active peptic ulcerActive peptic ulcer

Drug InteractionsDrug Interactions

Combination with quinolones may increase the risk for convultions Combination with quinolones may increase the risk for convultions and other CNS affacts.and other CNS affacts.

NSAIDs may rarely cause hypo or hyperglycemia.NSAIDs may rarely cause hypo or hyperglycemia. ACE Inhibitors (eg. Benazepril Hydrochloride)ModerateMay ACE Inhibitors (eg. Benazepril Hydrochloride)ModerateMay

decrease antihypertensive and natriuretic effectsMonitor blood decrease antihypertensive and natriuretic effectsMonitor blood pressure and cardiovascular functionpressure and cardiovascular function

ProbenecidModerateMay result in reversal of the uricosuric effects ProbenecidModerateMay result in reversal of the uricosuric effects of the other drugAvoid concurrent use of high-dose aspirin with of the other drugAvoid concurrent use of high-dose aspirin with probenecidprobenecid

LithiumModerateMay increase lithium plasma levels and decrease LithiumModerateMay increase lithium plasma levels and decrease its clearance renallyMonitor for lithium toxicityits clearance renallyMonitor for lithium toxicity

WarfarinModerateMay result in an increased risk of bleedingMonitor WarfarinModerateMay result in an increased risk of bleedingMonitor PT (prothrombin time) and INR (international normalized ratio)PT (prothrombin time) and INR (international normalized ratio)

MethotrexateSevereMay result in increased risk of methotrexate MethotrexateSevereMay result in increased risk of methotrexate toxicityDO NOT administer NSAIDs within 10 days of high dose toxicityDO NOT administer NSAIDs within 10 days of high dose methotrexatemethotrexate

Question Marks on Cox-2 InhibitorsQuestion Marks on Cox-2 Inhibitors

While it was hoped that this COX-2 While it was hoped that this COX-2 selectivity would reduce selectivity would reduce gastrointestinal adverse drug gastrointestinal adverse drug reactions (ADRs), there is little reactions (ADRs), there is little conclusive evidence that this is true. conclusive evidence that this is true.

Risk of adverse gastrointestinal outcomes in patients taking Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-

inflammatory drugs: population based nested case-control inflammatory drugs: population based nested case-control analysisanalysis

Julia Hippisley-CoxJulia Hippisley-Cox, , professor of clinical epidemiology and general practiceprofessor of clinical epidemiology and general practice1, 1, Carol CouplandCarol Coupland, , senior senior

lecturer in medical statisticslecturer in medical statistics1, 1, Richard LoganRichard Logan, , professor of clinical epidemiologyprofessor of clinical epidemiology22 BMJ  2005;330 (11 June), doi:10.1136/bmj.330.7504.0-cBMJ  2005;330 (11 June), doi:10.1136/bmj.330.7504.0-c ConclusionConclusion No consistent evidence was No consistent evidence was

found of enhanced safety against found of enhanced safety against gastrointestinal events with any of the new gastrointestinal events with any of the new cyclo-oxygenase-2 inhibitors compared with cyclo-oxygenase-2 inhibitors compared with non-selective non-steroidal anti-non-selective non-steroidal anti-inflammatory drugs. The use of ulcer inflammatory drugs. The use of ulcer healing drugs reduced the increased risk of healing drugs reduced the increased risk of adverse gastrointestinal outcomes with all adverse gastrointestinal outcomes with all groups of non-steroidal anti-inflammatory groups of non-steroidal anti-inflammatory drugs, but for diclofenac the increased risk drugs, but for diclofenac the increased risk remained significant.remained significant.

Where is the ulcer?Where is the ulcer?

Do selective cyclo-oxygenase-2 inhibitors and Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs traditional non-steroidal anti-inflammatory drugs

increase the risk of atherothrombosis? Meta-analysis increase the risk of atherothrombosis? Meta-analysis of randomised trialsof randomised trials

Patricia M KearneyPatricia M Kearney, , clinical research fellowclinical research fellow1, 1, Colin BaigentColin Baigent, , reader in clinical epidemiologyreader in clinical epidemiology1, 1, Jon GodwinJon Godwin, , research research fellowfellow1, 1, Heather HallsHeather Halls, , research assistantresearch assistant1, 1, Jonathan R EmbersonJonathan R Emberson, , senior statisticiansenior statistician1, 1, Carlo PatronoCarlo Patrono, , professor of professor of

pharmacologypharmacology22 What this study addsWhat this study adds Selective COX 2 inhibitors are associated with a moderately Selective COX 2 inhibitors are associated with a moderately

increased risk of vascular events, largely attributable to a increased risk of vascular events, largely attributable to a twofold increased risk of myocardial infarction twofold increased risk of myocardial infarction

High dose regimens of some traditional NSAIDs, such as High dose regimens of some traditional NSAIDs, such as diclofenac and ibuprofen, but not high dose naproxen, are diclofenac and ibuprofen, but not high dose naproxen, are associated with a similar excess risk of vascular events associated with a similar excess risk of vascular events

The choice between different anti-inflammatory regimens The choice between different anti-inflammatory regimens requires assessment of the individual expected absolute requires assessment of the individual expected absolute attributable risks of cardiovascular and serious attributable risks of cardiovascular and serious gastrointestinal events gastrointestinal events

Use NSAIDs for renal colic Use NSAIDs for renal colic In patients with acute renal colic, non-In patients with acute renal colic, non-

steroidal anti-inflammatory drugs (steroidal anti-inflammatory drugs (NSAIDsNSAIDs) ) should be the drug treatment of choice. should be the drug treatment of choice. Reviewing 20 trials including 1613 patients Reviewing 20 trials including 1613 patients with renal colic, Holdgate and Pollock (with renal colic, Holdgate and Pollock (p 1401p 1401) found that patients taking non-steroidal ) found that patients taking non-steroidal anti-inflammatory drugs had slightly less pain anti-inflammatory drugs had slightly less pain and were less likely to need additional and were less likely to need additional analgesia than those taking opioids. Those analgesia than those taking opioids. Those taking opioids were more likely to have taking opioids were more likely to have vomiting or other adverse events. vomiting or other adverse events.

Table 2: Conversion Dosing Guide for Chronic NSAID Therapy* Table 2: Conversion Dosing Guide for Chronic NSAID Therapy* NSAID Agent NSAID Agent

Low Dose Medium Dose High or Max Dose Low Dose Medium Dose High or Max Dose Salsalate 500-Salsalate 500-750mg bid 750mg tid 1000mg tid Fenoprofen 200-300mg qid 750mg bid 750mg tid 1000mg tid Fenoprofen 200-300mg qid 600mg tid-qid 800mg qid Flubriprofen 50mg bid 50mg tid-qid 600mg tid-qid 800mg qid Flubriprofen 50mg bid 50mg tid-qid 100mg tid Ibuprofen 400mg tid 600mg tid-qid 800mg qid** 100mg tid Ibuprofen 400mg tid 600mg tid-qid 800mg qid** Ketoprofen 25-50mg tid 75mg tid IR =300mg/day (divide), SR Ketoprofen 25-50mg tid 75mg tid IR =300mg/day (divide), SR =200mg/day Naproxen 250mg tid 500mg bid 1250mg/day =200mg/day Naproxen 250mg tid 500mg bid 1250mg/day (divided) Naproxen sodium 275mg tid 550mg bid 1375mg/day (divided) Naproxen sodium 275mg tid 550mg bid 1375mg/day (divided) Oxaprozin 600mg qd 1200mg qd 1200mg qd (divided) Oxaprozin 600mg qd 1200mg qd 1200mg qd Diclofenac potassium 50mg bid 50mg tid 50mg qid (in OA/RA Diclofenac potassium 50mg bid 50mg tid 50mg qid (in OA/RA only) Diclofenac sodium 50mg bid 75mg bid 50mg qid or only) Diclofenac sodium 50mg bid 75mg bid 50mg qid or 100mg SR bid (in RA only) Etodolac 200mg tid 400mg bid 100mg SR bid (in RA only) Etodolac 200mg tid 400mg bid 1200mg max (IR or SR divided doses) Sulindac 150mg bid 1200mg max (IR or SR divided doses) Sulindac 150mg bid 200mg bid 200g bid Piroxicam 10mg qd 20mg qd 40mg per day 200mg bid 200g bid Piroxicam 10mg qd 20mg qd 40mg per day (not indicated for OA or RA) Nabumetone 1000mg qd 1000mg (not indicated for OA or RA) Nabumetone 1000mg qd 1000mg bid 2000mg/day (qd or divided bid) Meloxicam/Mobic# 7.5mg bid 2000mg/day (qd or divided bid) Meloxicam/Mobic# 7.5mg qd 7.5mg qd 15mg qd Celecoxib/Celebrex# 200mg qd 200mg qd 7.5mg qd 15mg qd Celecoxib/Celebrex# 200mg qd 200mg bid 200mg bid Rofecoxib/Vioxx# 12.5mg qd 25mg qd 50mg qd bid 200mg bid Rofecoxib/Vioxx# 12.5mg qd 25mg qd 50mg qd for max of 5 days (acute pain) Valdecoxib/Bextra# 10mg qd for max of 5 days (acute pain) Valdecoxib/Bextra# 10mg qd 10mg qd 20mg bid (primary dysmenorrhea only) 10mg qd 20mg bid (primary dysmenorrhea only)

DrugDrug Low doseLow dose Med DoseMed Dose Max doseMax doseFenoproen 200-300 mg qid 750 mg tid 1000 mg tid

Flubriprofen 50 mg bid 50 mg tid or qid 100 mg tid

Ibuprofen 400 mg tid 600 mg tid or qid

800 mg qid

Naproxen 250 mg tid 500 mg bid 1250 mg/day

Oxaprozin 600 mg qd 1200 mg qd 1200 mg qd

Diclofenac Na 50 mg bid 75 mg bid 50 mg qid or 100 mg bid

Diclofenac K 50 mg bid 50 mg tid 50 mg qid or 100 mg bid

Etodlac 200 mg tid 400 mg tid 1200 mg/day

Sulindac 150 mg bid 200 mg bid 200 mg bid

Piroxicam 10 mg qd 20 mg qd 40 mg qd

Meloxicam 7.5 mg qd 7.5 mg qd 15 mg qd

Aceclofenac 100 mg bid 100 mg bid

Celecoxib 200 mg qd 200 mg bid 200 mg bid

Sodium Or Potassium Sodium Or Potassium DiclofenacDiclofenac

The selection of a specific formulation of The selection of a specific formulation of diclofenac is important because only one of diclofenac is important because only one of the available formulations (sodium or the available formulations (sodium or potassium salts ) of diclofenac provides potassium salts ) of diclofenac provides prompt relief (potassium formulation), a prompt relief (potassium formulation), a characteristic essential in the management characteristic essential in the management of acute pain. of acute pain.

Efficacy has been demonstrated with Efficacy has been demonstrated with postoperative pain including gynecologic, postoperative pain including gynecologic, oral, and orthopedic surgery models, as well oral, and orthopedic surgery models, as well as dysmenorrhea.as dysmenorrhea.

What is the most powerful analgesic?What is the most powerful analgesic?

Most powerful NSAIDsMost powerful NSAIDs The major NSAIDs of potency comparable to opioids The major NSAIDs of potency comparable to opioids

are diclofenac and ketorolac (Inj TORADOL). are diclofenac and ketorolac (Inj TORADOL). Moderate postoperative pain, for example, may be Moderate postoperative pain, for example, may be managed using these agents.managed using these agents.

Ketorolac (Torodol) is a very potent NSAID and is Ketorolac (Torodol) is a very potent NSAID and is used for moderately severe pain that usually used for moderately severe pain that usually requires narcotics. The overall analgesic effect of 30 requires narcotics. The overall analgesic effect of 30 mg of ketorolac is equivalent to that of 6 to 12 mg of mg of ketorolac is equivalent to that of 6 to 12 mg of morphine. Efficacy has been demonstrated for morphine. Efficacy has been demonstrated for postsurgical pain including oral, orthopedic, postsurgical pain including oral, orthopedic, gynecologic, and abdominal procedures. Efficacy for gynecologic, and abdominal procedures. Efficacy for acute musculoskeletal pain has also been shown. Its acute musculoskeletal pain has also been shown. Its antipyretic activity is significant. antipyretic activity is significant.

Anti-inflammatory activity is achieved only at doses Anti-inflammatory activity is achieved only at doses higher than those needed for analgesia. Ketorolac higher than those needed for analgesia. Ketorolac causes ulcers more frequently than any other NSAID causes ulcers more frequently than any other NSAID and is, therefore, not used for more than five days.and is, therefore, not used for more than five days.

AspirinAspirin is a unique NSAID, not only is a unique NSAID, not only because of its many uses, but because it because of its many uses, but because it is the only NSAID that is able to inhibit is the only NSAID that is able to inhibit the clotting of blood the clotting of blood for a prolonged for a prolonged period (4 to 7 days)period (4 to 7 days). This prolonged . This prolonged effect of aspirin makes it an ideal drug effect of aspirin makes it an ideal drug for preventing the blood clots that cause for preventing the blood clots that cause heart attacks and strokes. heart attacks and strokes. Most other Most other NSAIDs inhibit the clotting of blood NSAIDs inhibit the clotting of blood for only a few hours.for only a few hours.

CelecoxibCelecoxib

AceclofenacAceclofenac Aceclofenac has been shown to have potent analgesic Aceclofenac has been shown to have potent analgesic

and anti-inflammatory activities, similar to and anti-inflammatory activities, similar to indomethacin and diclofenac and due to its preferential indomethacin and diclofenac and due to its preferential cox-2 blockade it has better safety than conventional cox-2 blockade it has better safety than conventional NSAIDs with respect to adverse effects on NSAIDs with respect to adverse effects on gastrointestinal and cardiovascular systemgastrointestinal and cardiovascular system. .

Aceclofenac is well tolerated, with most adverse events being Aceclofenac is well tolerated, with most adverse events being minor and reversible and affecting mainly the GI system. Most minor and reversible and affecting mainly the GI system. Most common events include dyspepsia (7.5%), abdominal pain common events include dyspepsia (7.5%), abdominal pain (6.2%), nausea (1.5%), diarrhea (1.5%), flatulence (0.8%), (6.2%), nausea (1.5%), diarrhea (1.5%), flatulence (0.8%), gastritis (0.6%), constipation (0.5%), vomiting (0.5%), gastritis (0.6%), constipation (0.5%), vomiting (0.5%), ulcerative stomatitis (0.1%), pancreatitis (0.1%). ulcerative stomatitis (0.1%), pancreatitis (0.1%).

Other adverse effect, which is not common such as dizziness Other adverse effect, which is not common such as dizziness (1%), vertigo (0.3%), and rare cases: par aesthesia and (1%), vertigo (0.3%), and rare cases: par aesthesia and tremor. tremor.

It is probably best,even better than meloxicam, as a cartilage It is probably best,even better than meloxicam, as a cartilage protector, delaying cartilage damage in Osteo-arthritis.protector, delaying cartilage damage in Osteo-arthritis.

MeloxicamMeloxicam It is an NSAID which has mixed qualities, in between non-selective It is an NSAID which has mixed qualities, in between non-selective

and Cox-2 inhibitors.and Cox-2 inhibitors. It does not inhibit Cox-1 as strongly as other non-selective NSAIDs It does not inhibit Cox-1 as strongly as other non-selective NSAIDs

so it has few GIT side effects. Still it canso it has few GIT side effects. Still it canMeloxicam use can result Meloxicam use can result in gastrointestinal toxicity and bleeding, in gastrointestinal toxicity and bleeding, tinnitustinnitus, blinding , blinding headaches, rash, very dark or black stool (sign of intestinal headaches, rash, very dark or black stool (sign of intestinal bleeding). bleeding).

It is as good as other NSAIDs for pain reduction.It is as good as other NSAIDs for pain reduction. Meloxicam may also have a cardio protective role: in patients with Meloxicam may also have a cardio protective role: in patients with

acute coronary syndrome without ST-segment elevation, a lower acute coronary syndrome without ST-segment elevation, a lower incidence of cardiovascular events was observed in those who incidence of cardiovascular events was observed in those who received meloxicam plus aspirin and heparin versus aspirin and received meloxicam plus aspirin and heparin versus aspirin and heparin alone, both during coronary care stay and at 90-day heparin alone, both during coronary care stay and at 90-day follow-up.follow-up.

It has protective role in Osteoarthritis, for delaying cartilage It has protective role in Osteoarthritis, for delaying cartilage damage. damage.

Although meloxicam does inhibit Although meloxicam does inhibit thromboxanethromboxane A, it does not A, it does not appear to do so at levels that would interfere with appear to do so at levels that would interfere with plateletplatelet function.function.

NimesulideNimesulide NimesulideNimesulide is a relatively is a relatively COX-2 selectiveCOX-2 selective, ,

non-steroidal anti-inflammatory drugnon-steroidal anti-inflammatory drug (NSAID) with (NSAID) with analgesicanalgesic and and antipyreticantipyretic properties. properties.

Its approved indications are the Its approved indications are the treatmenttreatment of of acute pain, the acute pain, the symptomaticsymptomatic treatment of treatment of osteoarthritisosteoarthritis and primary and primary dysmenorrhoeadysmenorrhoea in in adolescentsadolescents and adults above 12 years old. Due and adults above 12 years old. Due to concerns about the risk of to concerns about the risk of hepatotoxicityhepatotoxicity, , nimesulide has been withdrawn from market in nimesulide has been withdrawn from market in many countries.many countries.

The drug has certain side effects, that can affect The drug has certain side effects, that can affect individuals in different ways. The following are individuals in different ways. The following are some of the side effects, that are often associated some of the side effects, that are often associated with the drug:Diarrhoea, Vomiting, Skin rash, with the drug:Diarrhoea, Vomiting, Skin rash, Pruritis, Dizziness, Headache Pruritis, Dizziness, Headache

DiclofenacDiclofenac Most powerful NSAIDsMost powerful NSAIDs Diclofenac may also be a unique member of the Diclofenac may also be a unique member of the NSAIDsNSAIDs. There is . There is

some evidence that diclofenac inhibits the some evidence that diclofenac inhibits the lipoxygenaselipoxygenase pathways,[ pathways,[citationcitation needed needed] thus reducing formation of the leukotrienes (also ] thus reducing formation of the leukotrienes (also pro-inflammatory autacoids). There is also speculation[pro-inflammatory autacoids). There is also speculation[by whom?by whom?] ] that diclofenac may inhibit phospholipase A2 as part of its that diclofenac may inhibit phospholipase A2 as part of its mechanism of action.[mechanism of action.[citation neededcitation needed] These additional actions may ] These additional actions may explain the high potency of diclofenac – it is the most potent NSAID explain the high potency of diclofenac – it is the most potent NSAID on a broad basis.[on a broad basis.[citation neededcitation needed] ]

Diclofenac has a low to moderate preference to block the COX2-Diclofenac has a low to moderate preference to block the COX2-isoenzyme (approximately 10-fold) and is said to have therefore a isoenzyme (approximately 10-fold) and is said to have therefore a somewhat lower incidence of gastrointestinal complaints than noted somewhat lower incidence of gastrointestinal complaints than noted with with indomethacinindomethacin and and aspirinaspirin. .

Causes less gastric irritation than Piroxicam, Naproxin, Indomethacin, Causes less gastric irritation than Piroxicam, Naproxin, Indomethacin, but more than ibuprofenbut more than ibuprofen

Available as OTC in many counteriesAvailable as OTC in many counteries Is neutral for cartilageIs neutral for cartilage Can be given by all routesCan be given by all routes Diclofenac potassium is estabished as fast reliever of pain; within Diclofenac potassium is estabished as fast reliever of pain; within

minutesminutes

Diclofenac has been found to be effective against all strains of multi drug Diclofenac has been found to be effective against all strains of multi drug resistant E. coli, with a MIC of 25 micrograms/mL. Therefore, it may be resistant E. coli, with a MIC of 25 micrograms/mL. Therefore, it may be suggested that diclofenac has the capacity to treat uncomplicated urinary suggested that diclofenac has the capacity to treat uncomplicated urinary tract infections (UTI) caused by tract infections (UTI) caused by E. coliE. coli.[6] It has also been shown to be .[6] It has also been shown to be effective in treating Salmonella infections in mice[7] and is under effective in treating Salmonella infections in mice[7] and is under investigation for the treatment of tuberculosis.[8] investigation for the treatment of tuberculosis.[8]

Diclofenac is an antiuricosuric Diclofenac is an antiuricosuric Diclofenac may prevent the development of Alzheimer's disease if given Diclofenac may prevent the development of Alzheimer's disease if given

daily in small doses during many years.daily in small doses during many years. ver due to malignant lymphogranulomatosis (Hodgkin's lymphoma) often ver due to malignant lymphogranulomatosis (Hodgkin's lymphoma) often

responds to diclofenac. responds to diclofenac. In many countries[In many countries[where?where?] eye-drops are sold to treat acute and chronic ] eye-drops are sold to treat acute and chronic

non-bacterial inflammations of the anterior part of the eyes (e.g. non-bacterial inflammations of the anterior part of the eyes (e.g. postoperative states).[postoperative states).[citation neededcitation needed] A common brand name is Voltaren-] A common brand name is Voltaren-ophta. ophta.

An external, gel-based formulation containing 3% of diclofenac (Solaraze) An external, gel-based formulation containing 3% of diclofenac (Solaraze) is available for the treatment of facial actinic keratosis which is caused by is available for the treatment of facial actinic keratosis which is caused by over-exposure to sunlight. Some countries have also approved the external over-exposure to sunlight. Some countries have also approved the external use of diclofenac 1% gel to treat musculoskeletal conditions use of diclofenac 1% gel to treat musculoskeletal conditions