TRIPASS XR تري باس

 

Thus, inhibition of prostagiandin biosynthesis may be implicated as one of the

mechanisms involved in both the anti-inflammatory actions and gastrointestinal

side effects of the non-steroid anti-inflamrnatory agents. To reduce the gastrointestinal damage caused by such drugs it would therefore be desirable to selectively

inhibit prostagiandin production at the site of inflammation and not in the gastrointestinal tract.

Oral administration of aspirin, indornethacin, flurbiprofen or naproxen at antiinflammatory doses results in inhibition of prostacyclin synthesis in the gastric

mucosa and a reduction of prostagiandin concentrations in inflammatory exudates

collected from the same animals (Figure 3) (Whittle, Higgs, Eakins, Moncada &

Vane, 1980). The inhibition of gastric cyclo-oxygenase correlates closely with the

ulcerogenicity of these drugs. In contrast, sodium salicylate and BW755C, which

selectively reduce the generation of inflammatory prostaglandins without inhibiting

gastric mucosal cyclo-oxygenase, do have anti-inflammatory activity, yet are not

ulcerogenic. Thus, the development of anti-inflamrnatory compounds wh ich lack

topical irritancy and fail to inhibit prostagiandin production in the gastrointestinal

tract appears to be a feasible proposition. It is also possible that the gastrointestinal

side effects ofchronic corticosteroid administration are due to their interference with

arachidonic acid metabolism, although this area is less clearly defined than with the

aspirin-like compounds.

Conclusions

Dual inhibitors ofarachidonic acid peroxidation are likely to have significant clinical

advantages over selective cyclo-oxygenase inhibitors, by avoiding the potentiation of

leucocyte migration and by having a greater effect on leucocyte-mediated responses

in chronic inflammation. Compounds such as BW755C may have a steroid-like antiinflammatory activity without the systemic side effects normally associated with

steroid treatment. Furthermore, the demonstration that prostagiandin synthesis can

be selectively inhibited in different tissues indicates that well-tolerated non-steroid

anti-inflarnmatory drugs can be produced.

The potential therapeutic importance of dual inhibitors is also indicated in the

treatment ofother diseases. Indomethacin potentiates the release ofSRS-A and histamine from perfused lungs during anaphylactic challenge, while an analogue of

BW755C does not have this effect (Adcock, Garland, Moncada &Salmon, 1978). It is

possible that the development of a drug wh ich is equi-active in inhibiting both

enzymes may be the next step in the evolution of non-steroid drugs for the treatment

ofchronic inflammation and bronchoconstriction.

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CLINICAL EFFECTS AND

INTERACTIONS OF THE

NON-STEROIDAL

ANTI-INFLAMMATORY DRUGS

P.M.BROOKS

Department ofMedicine,

Flinders University,

South Australia 5042

The non-steroidal anti-inflammatory drugs still form the mainstay of drug therapy

for the rheumatic diseases. They do not eure or permanently reverse the inflammatory process but by reducing pain, swelling and stiffness they can improve

function and give considerable symptomatic relief.

A wide range of non-steroidal anti-inflammatory drugs is now available for use

(Table I). Classifying the sub-groups ofthis dass ofdrugs is difficult. The drugs have

much in common, they are all analgesic, in single dosage, and when given regularly

in ade quate dosage have an anti-inflammatory effect which develops over the course

of a few days. Significant differences can be shown between placebo and nonsteroidal anti-inflammatory drug in reduction of pain, morning stiffness and joint

Table 1 Non-steroidalanti-inflammatory drugs

I. Acidicagents

a. Aryl carboxylicacids

i Salicylicacids: aspirin, diflunisal

ii Anthranilic acids: flufenamic,mefenamic

b. Aryl alkanoic acids

i Aryl aceticacids: alclofenac, diclofenac

ii Aryl proprionic acids: ibuprofen, flurbiprofen, ketoprofen,naproxen, fenoprofen

iii Heteroarylaceticacids: tolmetin, fenclozicacid

iv Indole and indene acetic acids: indomethacin, sulindac

v Benzoxazole derivatives: benoxaprofen

c. Enolic acids

Phenylbutazone, oxyphenbutazone, azapropazone, feprazone

2. Non-acidicagents

i Proquazone

ii Diftalone

NON-STEROIDAL ANTI-INFLAMMATOR Y DRUGS 289

swelling in a number of rheumatic conditions (Champion, Day , Graham & Paull,

1975; Brooks & Buchanan, 1976), but significant differences between non-steroidal

anti-inflammatory drugs (NSAID) have been more difficult to demonstrate (Lee,

Anderson, Miller, Webb & Buchanan, 1976). The major differences between the

drugs often comes in their ability to produce side effects. Individual variation in

response to these drugs occurs (Huskisson, Woolf, Balrne, Scott & Franklin, 1976)

both in pain relief and the occurrence of side effects. Because of this a number of

NSAID often have to be tried before the appropriate one is found for that particular

patient and that particular rheumatic disease.

Salicylates

Salicylates are widely used for the treatment of rheumatic diseases desp ite weil

documented toxicity (Huskisson, 1977; Buchanan, Rooney & Rennie, 1979): The

recent development of enteric-coated and sustained release formulations have

enabled therapeutic plasma salic ylate levels to be maintained on a twice daily dosage

regime (Bensen, Laskin . Paton , Little & Farn , 1979). The newer ent eric-coated and

susta ined release salicylate preparations demonstrate good bioa vailability (Da y,

Paull, Champion & Graharn, 1976; Brooks, Roberts & Patel, 1978) and a reduced

incidence of gastric side effects and blood loss (Baum , 1970). Salicylate metabolism

has been found to be dose dependent (Levy, Tsuchiya & Amsel, 1972) and a great

variation in serum concentration and half-life of salicylate has been reported in

patients with rheumatoid arthritis (Paulus, 1970). Recently it has been shown that

plasma salicylate levels decrease on chronic dos ing due to the induction of salicylurate formation (Furst, Gupta & Paulus, 1977; Rurnble, Brooks & Roberts, 1980).

These recent advances in our understanding of salicylate metabolism only

emphasize the importance of serum salicylate determination in planning the

optimum dosage regime for patients with arthritis.

The other major problem with aspirin apart from its variable metabolism is the

production ofside effects. These are seen particularly in the renal and gastro intestinal

systems. The question as to whether aspirin alone causes analgesic nephropathy

remains unanswered. There is no doubt that aspirin administration increases the

excretion of renal tublar cells (Scott, Denman & Dorling, 1963) and decreases renal

blood flow (Beeley & Kendall, 1971; Kimberly, Bowden , Keiser & Plotz , 1978), but

these changes are often transient (Brooks & Cossum, 1978). Isolated case reports have

linked analgesic nephropathy and the ingestion of aspirin alone but no correlation

has been found in prospective studies of pat ients with rheumatoid arthritis between

aspirin consumption and impairment ofrenal function (Macklon, Craft, Thompson

& Kerr, 1974; New Zealand Rheumatism Study , 1974).

There is no doubt that aspirin increases faecal blood loss. but the linking ofaspirin

ingestion and chronic peptic ulceration or acute gastrointestinal bleeding is less c1ear

(New Zealand Rheumatism Association, 1974; Levy, 1974). Th ere is no evidence that

healing rates for gastric ulcers are dela yed by the continued use of aspirin (Piper.

Greig, Coupland. Hobbin & Shinn ers, 1975) and similarly there is no evidence of an

increa sed incidence of gastrointestinal bleeding in gastric ulcer pati ent s given aspirin

(Wood, Scott & SI. 1. Dixon, 1961). Considering the number of aspirin tablets

consumed the problem ofgastric bleeding with this drug is relatively small and it may

be that the drug itself, being a source of dyspepsia (Capell , Rennie, Rooney,

Murdoch, Hole, Dick & Buchanan, 1979) dissuades its prolonged use in most subjects

susceptible to peptic ulceration.

With careful monitoring salicylates still have a place in the initial management of

acute and chronic rheumatic diseases. They can be extremely effective in reducing

pain and swelling particularly in rheumatoid arthritis and with the use of enteric-

290 P.M.BROOKS

coated or sustained release preparations simple regimes can be instituted to increase

compliance and reduce side etfects.

Potential drug interactions at protein binding sites may occur with salicylates and

anti-coagulants (Prescott, 1969) and oral hypoglycaemic agents (Anderson, 1977). In

practice drug interactions of a protein binding nature rarely have c1inical

significance.