Pharmacology of diclofenac sodium

Pharmacology of Diclofenac Sodium

DIETRICH W. SCHOLER, M.D. EDMOND C. KU, Ph.D. Summit,

New

Diclofenac sodium is the active ingredient in Voltaren, a nonsteroidal anti-inflammatory drug designed by selection of appropriate physicochemical and sterlc properties. Its pharmacologic activity, specifically its effects in acute and subchronic inflammation, and its analgesic activity have been assessed in animal models. The tolerability of the compound as judged by several parameters (i.e., ratio between the acute lethal dose or the dose inducing gastrointestinal blood loss and the desired pharmacologic activity) Is favorable in comparison with other nonsteroidal anti-inflammatory drugs, Diclofenac sodium acts by potent cycle-oxygenase inhibition, reduction of arachidonic acid release, and enhancement of arachidonic acid uptake. It thereby results in a dual inhibitory effect on both the cycle-oxygenase and lipoxygenase pathways.

Jersey

IRMGARD BOETTCHER, Ph.D. ALFRED SCHWEIZER, Ph.D. Basle,

Switzerland

From Biology Research, Pharmaceuticals Division, CIBA-GEIGY Corporation, Summit, New Jersey, and CIBA-GEIGY Limited, Basle, Switzerland. This article is modified from Semin Arthritis Rheum 1985; 15 (suppl 1): 61-64, with permission from Grune and Stratton, Inc. Requests for reprints should be addressed to Dr. Dietrich W. Scholer, Biology Research, Pharmaceuticals Division, CIBA-GEIGY Corporation, Summit, New Jersey 07901. Voltaren is a registered maceuticals.

trademark

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Inflammatory and associated rheumatic disorders are treated mainly with nonsteroidal anti-inflammatory drugs. The choice of the appropriate nonsteroidal anti-inflammatory drug depends ultimately on therapeutic efficacy, tolerability, and safety under clinical conditions. A clinical activity profile can be predicted reasonably well by a careful preclinical evaluation that includes biochemical, pharmacologic, and toxicologic testing. Diclofenac sodium, or sodium-[o-[2,6-dichlorophenyl)-amino]-phenyl]acetate, is the active ingredient of Voltaren. Its chemical structure was designed based on information about the structure-activity relationships of other anti-inflammatory drugs. Consequently, a molecule with enhanced anti-inflampatory, antipyretic, and analgesic activities could be developed by selection of appropriate physicochemical and steric properties (acidity constant, partition coefficient, spatial configuration) [l]. This report outlines the preclinical activity profile of diclofenac sodium in terms of pharmacologic activity (as assessed in animal models), preclinical tolerability, and biochemical mode of action. The main pharmacologic profile of diclofenac was established and described in the literature almost a decade ago [2]. However, recent data on gastrointestinal tolerability, peripheral analgesic activity, and, particularly, biochemical sites of interaction have aroused new interest in this compound. ANTI-INFLAMMATORY ACTIVITY The anti-inflammatory activity of diclofenac sodium was first evaluated in a model of acute inflammation, that of carrageenin-induced paw edema in rats [3]. A single oral dose of diclofenac in the range of 0.3 to 10 mg/kg induced a dose-dependent inhibition of edema formation (Figure 1). An oral

dose

of 2 mg/kg

resulted

in 40

percent

inhibition.

The effectiveness of the compound in subchronic inflammation, which

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(Adjuvant Arthritis, 4 Day Oral Treatment, from Day 11 to 14, n = 50 Rats) % Inhibition

(Carrageenin Paw Edema, Single Oral Dose of Diclofenac Na, n = 60-80 Rats) % Inhibition

60

60

I I

0.3

I

I

I

1 3 mg/kg p.o. Diclofenac Na ED,,mg/kg - 2 mg/kg

I

10

J igure 1. Anti-inflammatory activity in a rat model of acute inflammation. EDdo = dose inducing 40 percent inhibition.

is more relevant to its clinical use, was evaluated in a model of adjuvant arthritis induced in rats [4]. The inhibitory effect of dicldfenac sodium was measured after four days of oral treatment. A steep and linear dose-response curve was obtained, reflecting high potency; 0.3 mg/kg by mouth was an effective dose for achieving 40 percent inhibition (FigCre 2). There is good correlation between the anti-inflammatory potency of diclofenac sodium shown by the rat adjuvant arthritis model and that assessed under clinical conditions in humans (Flgure 3). Comparison of the potency of several anti-inflammatory agents in the rat model and in humans results in a lihear correlation between the rat 40percent inhibition value and the daily dose prescribed for humans.

I

I

1.0 mg/kg p.o. Diclofenac Na ED,, - 0.3 mglkg p.o.

0.1

0.3

3.0

Figure 2. Anti-inflammatory activity in a rat model of subacute inflammation. EDdo = dose inducing 40 percent inhibition.

Human Daily Dose mg/kg p.o.

0.3 -

PiroZcam

0.1

I 0.3

0.1

I 1

I 3

I 10

I 30

1 100

I 300

Rat ED,, mg/kg p.o. Anti-inflammatory Activity In Adj. Arthritis

ANALGESIC ACTIVITY The analgesic potency of diclofenac sodium has been estimated in the writhing model in mice or rats under three different experimental conditions [2]. Diclofenac sodium turned out to be active in all models, showing a potency (dose inducing a 50 percent effect) of between 1 and 4 mg/kg when administered orally (Table I). The analgesic activity of diclofenac sodium was mediated by peripheral pain receptors rather than by central mechanisms, as shown by additional experiments in the pain reflex assay in the perfused rabbit ear [5]. With this assay, an analgesic (antinociceptive) effect of diclofenac sodium could be demonstrated at the IO PM level, indicating an action on peripheral pain receptors, The relevance of the experimental information on analgesic activity in animal models was shown by comparing the analgesic activity of various drugs in humans and in

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Figure 3. Anti-inflammatory activity in humans versus rats. EDdo = dose inducing 40 percent inhibition.

TABLE I

Analgesic Activity of Diclofenac Sodium in Writhing Models* Dose lnduclng 50 Percent Effect

Test

(model)

@B/k@)

4.3 Benzoquinone (mouse) 2.5 Acetic acid (rat) 1.4 Ethacrynic acid (rat) l Diclofenac sodium was administered orally, one hour before induction of the writhing syndrome.

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Initial Dose

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mice (Figure 4). Decreasing potency in the mouse writhing model correlated well with increasing initial daily doses used in humans. Diclofenac sodium is among those compounds with high activity under both experimental and clinical conditions. The onset and duration of analgesic activity are illustrated in Figure 5. In the mouse writhing model, diclofenac sodium was less potent than zomepirac but acted within 15 minutes; in this model, its analgesic effect lasted at least four to six hours.

mQ/kg p.o.

30 r

ANTIPYRETIC 0.11 I I I , 0.1 0.3 1 3 10 30 Mouse, ED= mg/kg p.o. Anti-nockxptive (Benzoquinon?wnthing)

Diclofenac sodium effectively suppressed yeast-induced fever in rats; a reduction of 15°C was induced by an oral dose of 0.5 mg/kg, as compared with 185 mg/kg for acetylsalicylic acid, 55 mg/kg for naproxen, 24 mg/kg for ibuprofen, and 1.2 mg/kg for indomethacin [2].

I 100 300 Activity

.

activity in numans igufe 4. Analgesic f&,, = dose inducing a 50 percent effect.

versus

mice.

TOLERABILITY

The first estimate of the tolerability of a compound in animals can be derived from the relationship between the acute lethal dose and the desired pharmacologic potency (e.g., effective dose for anti-inflammatory or analgesic activity). If diclofenac sodium were assigned an arbitrary value of 100 for the ratio between the lethal dose and the median effective dose for acute anti-inflammatory potency, then the value for naproxen would be 30, for phenylbutazone and ibuprofen 10, and for indomethacin about

ED50

3

15min

lh Cpds.

2h are Gjvep

at Time

4h 0 min. p.o.

6h I

igure 5. Analgesic effeci in the mouse writhing assay: nset and duration of actioq EDSo = dose inducing a 50 percent effect; Cpds = compounds.

10 Day Treatment

with Diclofenac

ka

Measurement of Total G.I. Blood Loss (51CR - labeled RBC)

PI.

Gastrointestinal tolerability is of particular importance. Total gastrointestinal blood loss was measured in rats during 10 days of treatment with diclofenac sodium (Fig ure 6). No increase in blood loss over controt values was observed with oral doses of up to 7.5 mg/kg; thus, diclofenac sodium has a substantial therapeutic rat/o of about 35, calculated as the ratio between this threshold dose and the anti-inflammatory potency (the dose at 40 percent inhibition) in the adjuvant arthritis model. In comparison, the therapeutic ratio of indomethacin is about 10. In essence, as judged by various preclinical criteria, diclofenac sodium is a potent anti-inflammatory, analgesic, and antipyretic compound. Moreover, the drug has a wide margin of safety for gastrointestinal side effects and acute lethal toxicity. BIOCHEMICAL

I

I 5 Na mgikg

i 0 Diclofeeac

Therapeutic Ratio

=

I 7.5 p.o. (IO Days)

G.-l. Blood Loss(Threshold Adj. Arthritis (ED,,)

Dose)

10

=

7 mglkg 0.2 mgikg

I

Figure 6. Gastrointestir?al kr 40 percent inhibitiip

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ACTIVITY

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tolerability in the rat. EDdo = dost

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MODE OF ACTION

As with other nonsteroidal anti-inflammatory drugs, diclofenac sodium interacts with the arachidonic acid cascade atthe level of cycle-oxygenase. Inhibition of this key enzyme occurs in vitro in the micromolar range so that diclofenac prevents the formation of thromboxanes, prostaglandins, and prostacyclin (Figure 7). In fact, this classical site of interaction was reported for diclofenac sodium several years ago [2]. An additional site of interaction has been disclosed more recently. Malmsten [6] originally observed that diclo80 (suppl

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acid cascade

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(simplified)

Phosphoiipids 4 Arachidonic

acid

LdCE~=~/

\ Cycio-oxygenase

77 Leukotrienes

5-HETE

Thromboxane

11

Prostaglandins

\ Protiacyciin

Biochemical sites of interaction of diciofenac sodium: Dual effects on cycle-oxygenase and iipoxygenase pathway products l

no effect on phosphoiipase

A,

* minimal inhibition of .!I- and Wipoxygenase (Cm > 100 and 5,000 PM, respectively) * potent (I& l

Figure tion.

7.

Biochemical

sites of interac-

fenac sodium, when incubated with human neutrophils, did not increase leukotriene formation as expected from the shunting effect due to cycle-oxygenase inhibition. Detailed in vitro studies by Ku et al [-/1 indicated that diclofenac sodium did not have an inhibitory effect at the level of 5 and 15lipoxygenases nor on phospholipase A2 but did produce significant modulation of arachidonic acid release and uptake (Figure 7). Diclofenac decreased arachidonic acid release and increased uptake (probably into triglycerides), thus limiting the availability of arachidonic acid entering into the cycle-oxygenase and lipoxygenase pathways [8]. Reduced formation of leukotrienes and of 5-hydroxyeicosatetraenoic acid has been documented experimentally in two models: (1) in vitro during incubation of micromolar concentrations of diclofenac sodium with rat polymorphonuclear leukocytes and macrophages, guinea pig peritoneal leukocytes, and human polymorphonuclear leukocytes and monocytes; and (2) ex vivo after oral pretreatment of rats with 8 to 30 mg/kg of diclofenac sodium. As a biologic correlate of reduced leukotriene formation, the influx of polymorphonuclear leukocytes into carrageenin-soaked implanted sponges was decreased in rats following oral treatment with diclofenac sodium.

inhibition 2-5 /Al)

of cycio-oxygenase

reduction of arachidonic acid availability by stimulation of uptake into triglycerides (E&o - 80pM for human PMN, 10 PM for monocytes) and inhibition of release (I&-8Ot.~MforhumanPMN-10kMformonocytes)

Given the suggested role of leukotrienes in the inflammatory process, the inhibitory effect of diclofenac sodium on leukotriene formation in these in vitro and animal models is of particular interest. The fact that macrophages are even more susceptible to diclofenac sodium than are polymorphonuclear cells in terms of leukotriene inhibition suggests a potential benefit of this agent in chronic inflammation. COMMENTS

Preclinical evaluations of diclofenac sodium reveal that the drug is a potent anti-inflammatory, analgesic, and antipyretic agent with good,gastrointestinal tolerability. It acts by means of potent cycle-oxygenase inhibition and modulation of arachidonic acid release and uptake (reducing release and increasing uptake, probably into triglycerides). This results in a dual inhibitory effect on cyclooxygenase and lipoxygenase pathways. Diclofenac sodium has the potential to affect a wide range of inflammation-related mediators and cell functions and thus to effectively counteract the clinical signs and symptoms of inflammation.

REFERENCES 1.

2.

Saiimann A: Chemische Aspekte von diciofenac. in: Wagenhauser FJ, ed. Poiyarthritiden, international Symposium, Torremoiinos, 1975. Bern: Hans Huber, 1976: 296-301. Menasse R, Hedwaii PR, Kraetz J, et al: Pharmacological proper-

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26, 1666

3.

ties of diciofenac sodium and its metabolites. Stand J Rheumatol [suppi] 1978; 22: 5-l 6. Winter CA, Risiey EA, Nuss GW: Carrageenin-induced edema in hind paw of the rat as an assay for inflammatory drugs. Proc

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Volume

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4. 5.

6.

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Sot Exp Biol Med 1963; 162: 544-547. Newbould BB: Chemotherapy of arthritis induced in rats by mycobacterial adjuvant. Br J Pharmacol 1963; 21: 127-136. Schweizer A, Brom R: Differentiation of peripheral and central effects of analgesic drugs. Int J Tissue React 1965; 7: 79-63. Malmsten CL: The effects of some non-steroidal anti-inflammatory drugs upon LTB& formation and granulocyte function in vitro (abstr). In: Proceedings of the 1964 Prostaglandins and

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28,1986

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ET AL

7.

6.

Leukotrienes Meeting, Washington, DC, May 6-11, 1964. Ku EC, Lee W, Kothari H, et al: Regulatory role of diclofenac sodium on arachidonic acid metabolism and release in cellular and animal systems (abstr). In: Proceedings of the Inflammation Research Association, Second International Conference, Ellenville, NY, October 21-25, 1964. Ku EC, Lee W, Kothari HV, Kimble EF, Liauw L, Tjan J: The effects of diclofenac sodium on arachidonic acid metabolism. Semin Arthritis Rheum 1965; 15: 36-41.

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