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INVITED ARTICLE

NON -STEROIDAL ANTI-INFLAMMATORY DRUGS - USES AND COMPLICATIONS SCNg

ABSTRACT Non -Steroidal Anti-inflammatory Drugs (NSAIDs) are important in the management of any inflammatory arthritis. However, all NSAIDs have side effects - NSA ID related gastropathy (the most common serious side -effect), reversible NSAID nephropathy, dermal complications, hematologic complications, hepatic complications, central nervous system complications, pulmonary complications etc. Patients who have more severe forms of rheumatic disease, take higher doses of NSA IDs with steroids and suffer concomitant medical illness are at higher risk for these toxicities. In all cases, the benefits from the use of NSA IDs must outweigh the risk. When managing a high risk patient, consider alternate therapy and if an NSAID must be used, always monitor the patient carefully.

Keywords : Non -steroidal anti-inflammatory drugs, uses, complications

SINGAPORE MED J 1992; Vol 33: 510-513

INTRODUCTION Enolic acid Non -steroidal anti-inflammatory drugs (NSAIDs) as the name Pyrazolidinediones - phenylhutazone, oxyphenylbutazone suggests, are drugs which suppress inflammation. Patients of- - , ten call them pain -killers, but they do more than stop the pain, Nonacidic Acid they reduce the inflammation in arthritis. NSAIDs are used in , fluproquazone, azapropazonc all types of arthritis regardless of the etiology. Treatment with NSAIDs will quickly reduce the signs of inflammation which Clinically, it is not very important to remember the chemi- are pain, redness, swelling, heat and loss of function. How- cal classification and often it is better to remember the half- ever, they do nothing to treat the cause of the arthritis (unlike lives of the different NSAIDs as this will determine the dosing allopurinol for gout), or prevent initial tissue damage and interval. Drugs like piroxicam have a long half-life and are modify the outcome of the chronic arthritis (unlike gold for convenient as single day dose. However it may accumulate in rheumatoid arthritis). NSAIDs act quickly and the effect wears the elderly. with a slightly shorter half-life may be out quickly when the drug is discontinued. This is unlike Dis- taken twice daily and is also convenient to use. A drug with a ease Modifying Anti -Rheumatic Drugs (DMARDs) like gold, very short half-life is and requires frequent dosing. It which will continue to act for a while even after its administra- can sometimes be used for patients with arthritis requiring tion has been discontinued. surgery up till 24 hours before the surgery. Some NSAIDs with shorter half-lives are now available in a sustained release CLASSIFICATION formulation. However, sometimes the effect is not as long as There are many ways to classify NSAIDs and the simplest desired and the patient may have morning stiffness the next way is to follow the chemical structure. This is as given be- day as the drug wears out. low: NSAIDs are also available in injectable forms and are use- ful for rapid relief of acute rheumatic pains. Systemic Addle Acid side effects are the same as for oral formulations. Topical NSAIDs Arylcarboxilic acid in the form of gels and creams are available for the treatment - acetyl salicylate, , and of local rheumatic pain. This is quite effective and fairly popu- salicylsalicylate lar as some patients like to massage over a particu- Anthranilic - acid mefenemic acid, flufenamate acid, larly painful joint. It can be used together with an oral NSAID. (fenanrates) meclofenamate acid Side effects are mainly skin irritation or rash, and systemic Arylalkanoic acid side effects are mrnimal as the dose is small. Arylacctic acid - , Arylpropionic acid - naproxen, , , MECHANISMS OF ACTION , Since 1971, it has been known that most NSAIDs inhibit the syn- Heteroaryl - tolmetin, thesis of . The metabolism to Indole and indene - indomethacin, prostaglandins is shown in Fig 1. NSAIDs block the conversion of acetic acid arachidonic acid to endoperoxidase by inhibiting the enzyme cyclooxygenasetmt. NSAIDs have also been shown to inhibit the lipooxygenase pathway in arachidonic metabolism°. Another mecha- nism postulated is the inhibition of free radicalst4t. It has also been Department of Medicine shown that NSAIDs blunt neutrophil activationtsl. Another hypoth- Alexandra Hospital esis is that NSAIDs act via the calcium channel pathwayta. Clearly, Alexandra Road there is still much to be studied about the actual mechanism of Singapore 0314 action of the different NSAIDs.

S C Ng, MMed (Int Med) Adverse Effects Consultant All NSAIDs have possible adverse effects on all the major organ system. Generally the toxicities are dose related though some are idiosyncratic.

510 Fig t - Arachidonic Acid Metabolism

Phospholipids

Arachrdonic Acid

ooxl" enas Inhibition by NSAIDs

Endoperoxides PGGi, PGHi --Free Radicals i

Stable Pro st acyclin Prostaglandins A2 PGI, PGEI, PGE2

LTC4, LTD., Leucotriene LTE4 B.

Adapted from Ref I Gastrointestinal Complications Renal toxicities Gastrointestinal complications due to NSA1Ds are the most The most common renal toxicity is the so called reversible prevalent serious drug toxicity in the United States. The yearly NSAID nephropathy. This is the result of inhibition of renal hospitalization incidence for NSAID gastropathy was 1.58% prostaglandins and is characterized by elevation in scrum urea, in rheumatoid arthritis patients and the risk of gastrointestinal creatinine, potassium and an increase in body weight due to related death was 0.19% per year"'. The effect of NSAIDs on fluid retention. If recognized early and the drug discontinued, the gastrointestinal tract can be local or systemicts'. The local the renal function returns to normal usually within 3 days. effect of on the gastric mucosa is an endoscopically Renal prostaglandins are produced in the kidney in response to visible erosion. A prodiug like sulindac may have less local vasoconstriction caused by angiotensin II, norepinephrine and gastric toxicity because it has to be activated in the liver first. vasopressin. Yasodilatory renal prostaglandins especially Likewise enteric coated aspirin may have less local effect on E2 and act to maintain renal blood the gastric mucosa. The systemic effect is via the inhibition of flow and glomerular filtration rate. This action is not very gastric prostaglandins which have gastroprotective properties. important in normal circumstances but is vital in conditions All NSAIDs which inhibit cyclooxgenase may give this ad- causing decreased renal blood flow eg shock, congestive heart verse effect. NSAIDs which do not inhibit cyclooxygenase, failure, cirrhosis with ascites, nephrotic syndrome and in pa- for example salicylsalicylate, may potentially be safer. The tients with chronic renal disease. When such high risk patients main risk factors for serious gastrointestinal events are higher are given NSAIDs, inhibition of the renal prostaglandins will age, concomitant use of prednisone, previous NSAID GI side result in decreased renal perfusion and NSAID nephropathy. effect, prior GI hospitalization, level of disability and high Patients with advanced age, atherosclerotic cardiovascular dis- NSAID dose (more than 1.3 X recommended dose)t't. Hence it eases and who are taking concurrent diuretics are also at in- is not just a question of which NSAID is safer to use but creased risk for the development of reversible NSAID which patient is at higher risk of NSAID gastropathy. nephropathy. Treatment of acute gouty arthritis was reported Misoprostal (a ) may be used to pre- to be the most common clinical situation which precipitated vent NSAID induced gastric ulcers. Patients who develop gas- NSAID nephropathyt". Such high risk patients should have tric lesions may be treated with mtsoprostal while patients their renal function carefully monitored if they really need to with duodenal lesions respond to 112 Blockers. Those with take NSAIDs. It has been suggested that sulindac may be a difficult to treat lesions may respond to omeprazole. Patients renal sparing NSAID as the active drug is deactivated in the who had previous ulcers or bleeding yet need to continue on kidney and hence sparing the renal prostaglandins. However, NSAIDs have to be given concomitant long term ulcer treat- other investigators have reported patients who developed ment. Even then, there is no guarantee that there will not be NSAID nephropathy with sulindac. Recent studies demonstrate any further problems. These patients have to be monitored that the active drug is indeed excreted in patients' urine in carefully and if they do develop ulcers again, the NSAID has about 36% of the time"0'; hence these patients are indeed at to be withdrawn. There is no need to routinely cover patients risk of developing NSAID nephropathy just as with any other on NSAID with anti -ulcer drugs if they are elderly with dis- NSAID. Renal papillary necrosis is a more serious form of ability and on concomitant low dose steroids but they must be renal complication from NSAIDs. This is thought to be due to monitored carefully and gastroscoped if they develop any symp- renal medullary ischaemia from inhibition of renal toms or if the haemoglobin level drops. Such high risk patients prostaglandins. Initially compound were blamed but should never be given supra -maximal doses of NS AIDs. subsequently, it is recognized that any NSAID can cause this

511 complication. Risk factors are dehydration, old age and pre- Other mechanisms have been postulated including the mast existing renal disease. NSAIDs have also been blamed for cell and mediator release theory, platelet activation theory, etc. other renal problems including interstitial nephritis with These patients are often sensitive to many other NSAIDs. Drugs nephrotic syndrome. Such patients often have associated that do not inhibit cyclooxygenase like propoxyphene do not hypersensitivity phenomenon like rash and eosinophilia. cross react with aspirin. Salicylates and have Fenoprofen is the drug most often implicated though other been known to cause pulmonary edema. Ibuprofen has been drugs have been reported. reported to cause pleural effusion and naproxen has been re- Skin Complications ported to cause pulmonary infiltrates. The adverse skin reactions to NSAIDs are numerous. They Rare Toxicities include urticaria, macular papular lesions, vesiculubullous le- Though NSAIDs are often used in all types of rheumatic con- sions, fixed drug eruptions. photosensitivity reactions, erythema ditions for arthritis, NSAIDs can themselves cause lupus -like multiforme, exiolmtive dermatitis, Stevens Johnson Syndrome syndrome (phenylbutazone and ibuprofen) and vasculitis and toxic epidermal necrolysis. Adverse skin reactions were (indomethacin, naproxen and fenbufen). Other rare toxicities most commonll reported with piroxicam, zomepirac, sulindac, include alopecia (ibuprofen) and reversible gynecomastia meclofenamate and benoxaprofent" " However, the NSAIDs (sul indac). which are most often responsible for the serious even fatal skin toxicities are phenylbutazone and oxyphenylbutazoneort. A PRACTICAL GUIDE TO THE USE OF NSAIDs IN Haematologic Toxicities RHEUMA'l'OLOGY Doctors often choose an NSAID Here again, phenylbutazone and oxyphenytbutazonc arc most simply because they are fa- miliar with it and because it is often responsible for NSAID induced blood dyscrasiaso31 like cheap and easily available. Indeed there is no strong agranulocytosis and aplastic anaemia. The patients at high risk evidence to suggest that any one NSAID is superior to the for this complication are elderly (age over 60 years) women. other. However, there are other fac- tors to be taken into consideration - Mefenemic acid, a popular NSAID locally, has been reported concurrent illness, concur- rent drug therapy, past experience with NSAIDs and to cause haemolytic anaemia. Thrombocytopenia has also been the under- lying rheumatic disease. NSAIDs should not caused by NSAIDs. Another well known side -effect of NSAIDs be prescribed casu- ally to patients who have peptic ulcer disease, on platelets is the inhibition of platelet aggregation. NSAIDs kidney disease, congestive inhibit cyclooxygenase, blocking the synthesis of thromhoxane cardiac failure and other high risk factors as de- scribed above. Patients who have aspirin sensitivity as A2 which is important in platelet aggregation. This action is de- scribed above should never be given reversible in most NSAIDs except aspirin which irreversibly any NSAIDs again. Patients who have rheumatoid arthritis need long term acetylates cyclooxygenase. Currently low dose aspirin is com- NSAID therapy in anti-inflammatory monly used as an anti -platelet agent in the prevention of coro- doses. Such patients should be tried on an NSAID nary and cerebral thrombosis. The NSAIDs which do not have and the dose increased to the maximum recommended significant anti -platelet effect are the nonacetylated salicylates and kept at that dose for two weeks. If there is no good response, the is eg salicylsalicylateso"'. They may be safer to use in patients first NSAID discontinued with bleeding tendencies. and another NSAID is tried. Combining NSAIDs will only increase toxicity without increasing efficacyont. Concomitant Liver Complications use of Disease Modifying Anti -Rheumatic drug or drugs and Asymptomatic elevation of hepatic transaminases is not un- steroids are decided on an individual basis. common with the use of NSAIDs and hepatic toxicity is con- NSAIDs are also used for osteoarthritis. There has been sidered to be a class characteristic of NSAIDs o't. If detected much interest in articular cartilage and anti -rheumatic drugs early and the NSAID discontinued, the transaminitis is revers- recently". It has been demonstrated that proteoglycan synthe- ible. Sometimes the patient is symptomatic and develops nau- sis in osteoarticular cartilage culture is inhibited by salicylates sea, tender hepatomegaly and even jaundice and prolongation but not by ketotifen and that piroxicam downregulates the ex- of prothrombin time. The more serious complications are toxic pression of interleukin-1 in organ culture of osteoarthritic hepatitis, cholestatic jaundice and fulminant hepatic necrosis. synovial tissue. The clinical significance of these laboratory is responsible for the most serious hepatic findings is unclear. A clinical study suggested that patients toxicities and has been withdrawn from the market. given indomethacin for osteoarthritis of the hips had faster Phenylbutazone has also caused some fatalities from hepatic loss of joint space and required hip surgery earlier than pa- complications. The patients at increased risk to this are again tients given which is not an NSAID. More clini- the elderly. cal studies to address the question of chondroprotection are Central Nervous System Complications required before new guidelines for the use NSAIDs in Indomethacin has been known to cause many symptoms like osteoarthritis can be made. giddiness, confusion, drowsiness and even seizures°'". Other Patients with seronegative spondyloarthropathies require higher NSAIDs also cause cognitive dysfunction, memory loss, para- doses of NSAIDs to reduce pain and stiffness to enable them to do noia in the elderly eg ibuprofen. Salicylates in high doses can exercises to minimize flexion deformities. Fortunately these pa- also cause confusion, hallucinations and seizures. If not treated tients tend to be younger and do not suffer from complicating ill- early, salicylate overdosage can be fatal. Aseptic meningitis ness which put them at high risk for NSAID toxicides. has been reported with ibuprofen, sulindac and tolmetin. Patients with crystal arthritis like gout need supra maximal Ibuprofen has also been reported to cause amblyopia. It is well doses of NSAIDs during an acute attack. Unfortunately this known that salicylates in high doses cause tinnitus. group of patients are at increased risk of NSAID nephropathy Bronchopulmonary Complications and other complications. Alternate therapy with colchicine and Some patients have the well known triad of aspirin sensitivity, steroids should be considered for those patients who are at bronchial asthma and nasal polyposiso't. In these patients, in- increased risk of NSAID toxicity, for example those taking hibition of cyclooxygenase reduce bronchial prostaglandins and diuretics for congestive heart failure. Patients who have soft shunt arachidonic acid metabolism to the lipooxygenase path- tissue rheumatism may be given short term NSAID, physio- way. The leucotrienes C4 and D4 may precipitate bronchial therapy and advised rest or local steroid injections. Topical spasm. Generalized urticaria and angioedema can also occur. NSAIDs may also be used.

512 In all cases the benefits from the use of NSAIDs must 7. Pries IF, Williams CA, Bloch DA, Michel BA Non -steroidal Anti-inflammatory Ur ig- assocrned Gastropathy : Incidence and Risk Factor Models Am 1 Med 1991;91:213-22. outweigh the risk of toxicities. When managing a high risk 8. Soll AH. Non -steroidal Anthinflammatory drugs and peptic ulcer disease. Ann Intern patient, always consider alternate therapy and if an NSAID Med 1991; 114:307-19. must be used, always monitor the patient very carefully look- 9. Blackshear IL, Napier IS, Davidman M, Stillman MT. Renal Complications of Non - steroidal Arnim llanunatory Drugs: Identification and monitoring of those at Risk. Semen ing out for the complications discussed above. Arlhritta Rheum 1985: 14:163-75

10. Brandli ow, Sarkissian E, Ng SC, Paulus I IH. Individual variability in concentraboas of REFERENCES urinary sulindac sulfide Clin Pharmacol Ther 1991;50:650 5.

I. Schlegel SI. General Characteristics of Non -steroidal Ainbioflanmarory Drugs. In: Paulus I I. Stem RS, Bigby M. An expanded profile of cutaneous reactions to non -steroidal anti- HE, Furst DE. Dromgoole Sil. eels. Drugs For Rheumatic Disease. USA: Churchill inflammatory drugs. LAMA 1984; 252:1433-7. Livingstone 1987:203-26. 12 O'Brien WM, Bagby GPI Rare adverse reactions to non -steroidal anti-inflammatory drugs.

1 Rheumatil 2. Paulus HE, Furst DC Aspirin and other Non -steroidal Ante -inflammatory Drugs. In 1985;12:13-20. McCarty Dl. ed. Arthritis and Allied Conditions. 10th edition -USA- Ica & Febiger 13. Inman WH. Study of Fatal hove martow depression with reference to pheryibutazone publishers 1985'453-86 and oxyphenyl-butazone. Br Med.! 1977; 1.1500-5.

3. Dawson W, Boot IR. I larvcy 1. Walker 1R The pharmacology of Benoxaprofen with 14. Estes D, Kaplan K. Lack of Platelet Effects with the Aspirin analog Arthritis pal ocular reference to effects on lipooxygenase product formation. Eur J Rlmumalol Rheum 1980; 23:1303.

Inflamm 1982; 5:61-8. 15. Paulus HE. Government affairs : FDA arthritis advisory committee meeting. Arthritis 1. Puig -Patella P, Planas 1M. Synovial fluid degradation Induced by free radicals : In vitro Rheum 1982;25.1124. action of several free radical scavengers and anti-inflammatory drugs. iechem Pharmaeol 16. Boardman PL. Dudley lit:. Side effects of Indomediacin Ann Rheum Pis 1967,26-127-32. 197127 535-8. . Morassur P. Yang W, Kareh 1. Aspirin Intolerance. Saran Arthritis Rheum 1989;19:22-30. 5. Abramson S. Edelson HS, Kaplan H, et al. The neutrophal in Rheumatoid Arthritis . Its It, Miller DR. Combination use of non -steroidal anti-inflammatory drugs. Drug Intell Clin role and the inhibition of its activation by non -steroidal anti inflammatory drugs. Semen Pharm 1981; 15: 3-7. Arthritis Rheum 1983; 13.148-56. 19. Jubb RW. Anti -rheumatic Drugs and Articular Cartilage. UK: Reviews 6. Weissmann G, Korchak is. Abramson S. The cellular effects of non -steroidal anti-inflam- Tropical 1992. No 20 matory drugs (NSMD) cannot be due to the inhibition of prostaglandin (PG) release. Clin Res 1984. 32:556A.

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