Pharmacology of diclofenac sodium (Voltaren®)

Pharmacology of Diclofenac Sodium (Voltaren®) By Dietrich W. Scholer. Irmgard Boettcher. Edmond C. Ku, and Alfred Schweizer

HE treatment of inflammatory conditions and rheumatic disorders is largely based on the use of nonsteroidal, anti-inflammatory agents. The choice of the appropriate drug, among a considerable number of compounds, depends ultimately on therapeutic efficacy and tolerability/safety profiles as observed under clinical conditions. This clinical activity profile can be predicted reasonably well by a careful preclinical evaluation including biochemical, pharmacologic, and toxicologic testing. Diclofenac sodium, or sodium-[0-[2,6-dichlorophenyl)-amino]-phenyl]-acetate, is the active ingredient of Voltaren~. Its chemical structure was rationally designed based on information on structure-activity relationships of anti-inflammatory drugs. By selection of appropriate physicochemical and steric properties (acidity constant, partition coefficient, spatial configuration'), a molecule with enhanced anti-inflammatory, antipyretic, and analgesic activities could be developed. 2 The following is a synopsis of the preclinical activity profile of diclofenac sodium in terms of pharmacologic activity (as assessed in animal models), preclinical tolerability, and biochemical mode of action. Although the main pharmacologic profile had been established and described in the literature some years ago,2 recent data on gastrointestinal tolerability, peripheral analgesic activity, and, particularly, biochemical sites of interaction underscore the interest in this compound.

T

ANTI-INFLAMMATORY ACTIVITY

The anti-inflammatory activity of diclofenac sodium was first evaluated in an acute model of inflammation using carrageenin-induced paw edema in the rat. 3 Administration of a single dose of diclofenac sodium in the range of 0.3 to 10 mg/kg p.o. induced a dose-dependent inhibition of edema formation (Fig. I). The dose resulting in a 40% inhibition (ED 40) amounted to 2 mg/kg p.o. More relevant to clinical use of the compound was its effectiveness in a model of subchronic inflammation. For this evaluation adjuvant arthritis was induced in rats· and the inhibitory effect of diclofenac 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 p.o. was an effective dose for 40% inhibition (Fig. 2). The anti-inflammatory potency of diclofenac sodium shown by the rat adjuvant arthritis model correlates well with the anti-inflammatory potency assessed under clinical conditions in humans (Fig. 3). Comparison of the potency of several anti-inflammatory agents in the rat model and in man results in a linear correlation between the rat ED40 value and the daily dose used in humans. ANALGESIC (ANTI-NOCICEPTIVE) ACTIVITY

Analgesic potency of diclofenac sodium has been estimated in the writhing model under three different experimental conditions in the mouse or rat 2; diclofenac sodium turned out to be active in all models, yielding a potency (ED",) between I and 4 mg/kg p.o. (Table 1). The analgesic activity of diclofenac sodium was mediated by peripheral pain receptors and not by central mechanisms, as indicated by additional experiments in the pain reflex assay in the perfused rabbit ear. s With this preparation, an analgesic (antinociceptive) effect of diclofenac sodium could be demonstrated at the 10 ~M level exclusively by action on peripheral pain receptors. The relevance of the experimental information on analgesic activity in animal models was illustrated by comparing the analgesic activity observed for several drugs in humans and in mice (Fig. 4). Decreasing potency in the mouse writhing model correlated well with increasing initial daily doses used in man. Diclofenac sodium

From the Research Departments, Pharmaceuticals Division. C1BA-GEIGY Corp, Summit. NJ. USA and C1BAGEIGY LId, Basle. Switzerland Dietrich W. Scholer, MD. Edmond C. Ku. PhD: Biology Research. Pharmaceuticals Division. C1BA-GE1GY Corp. Summit. NJ. USA: lrmgard Boettcher, PhD. Alfred Schweizer, PhD. Biology Research. Pharmaceuticals Division. C1BA-GEIGY. Ltd. Basle, Switzerland Address reprint requests to Dietrich W. Scholer, MD. Biology Research. CIBA-GEIGYCorp. Summit. NJ © 1985 by Grune & Strauon. Inc. 0049~/721851 J502-111215.0010

Seminars in Arthritis and RheumatIsm, Vol 15. No 2. Suppl 1 (November). 1985: pp 61-64

61

SCHOLER ET AL

62 ~

Inhibition 30

80

10

40

3

20

0

0.3

0.3

1

0.1 0 . 1

3

mg/kg p.o. Diclofenac N a ED 40 mg/kg - 2 mg/kg Fig. 1. Anti-inflammatory activity in the rat model of acute inflammation. Carrageenin paw edema. single oral dose of diclofenac Na (n - 60 to 80 ratsl.

belongs to the compounds with high activity under both experimental and clinical conditions. Onset and duration of analgesic activity are illustrated in Fig. 5. Diclofenac sodium is less potent than zomepirac but acts within 15 minutes and its analgesic effect lasts at least four to six hours (data in mice). ANTIPYRETIC ACTIVITY

Diclofenac sodium effectively suppressed yeast-induced fever in rats; a reduction by I.5°C was induced by 0.5 mgjkg p.o. compared to 185 mgjkg for acetylsalicylic acid, 55 mgjkg for naproxen, 24 mg/kg for ibuprofen, and 1.2 mgj kg for indomethacin. 2 TOLERABILITY

A first estimate of the tolerability of a compound in animals can be derived from the rela~

Piroxicam

Inhibition

60

0.3 I 3 10 30 lOa 300 Rat ED 40 mg/kg p.o. Anti-inflammatory Activity In Adj. Arthritis

Fig. 3. Anti-inflammatory activity in human v rat. Human maximum daily dose mg/kg orally.

tionship between acute lethal dose (LD so ) and desired pharmacologic potency (e.g., ED so for anti-inflammatory or analgesic activity). Given an arbitrary value of 100 for diclofenac sodium for the ratio between LD so and ED so for acute anti-inflammatory potency, the ratio for naproxen would be 30, for phenylbutazone and ibuprofen 10, and for indomethacin about 3. 2 Of particular importance is gastrointestinal tolerability. Total gastrointestinal blood loss was measured in rats during a ten-day treatment with diclofenac sodium (Fig. 6). Up to a dose of 7.5 mg/kg p.o., no increase in blood loss over control values was observed; thus diclofenac sodium has a substantial therapeutic ratio of about 35, calculated as the ratio between this threshold dose and the anti-inflammatory potency (the dose at ED 40 ) in the adjuvant arthritis model. In comparison, the therapeutic ratio of indomethacin was about 10. In essence, diclofenac sodium is, as judged by various preclinical parameters, a potent antiinflammatory, analgesic, and antipyretic compound and has a considerable safety margin in terms of gastrointestinal side effects or acute lethal toxicity.

40 Table 1. Antinociceptive (Analgesic) Activity of Diclofenac Sodium in Writhing Models 8

20

Model

0.1

0.3

1.0

BenzoqUInone Test Dosage at ED..

(Mouse)

Acetic ACId Test (Rat)

Dlclofenac Na (mg/kg orally)

4.3

2.5

3.0

mg/kg p.o. Diclofenac N a ED.o - 0.3 mg/kg p.o. Fig. 2. Anti-inflammatory activity in the rat model of subacute inflammation. Adjuvant arthritis. 4-day oral treatment. from day 11 to 14 (n - 60 ratsl.

Ethacrynic Acid Test (Rat)

1.4

80iclofenac sodium was given one hour before induction of the writhing syndrome.

63

PHARMACOlOGY OF DICLOFENAC SODIUM MeuuremeDt or

30

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( "Cr . labeled RBCI

Blood Loaml

0'=25~__~0'3_8_--1! .~

10

3

0.3

o

~1

I

0.1

0.3 1 3 10 30 100 300 Mice. ED50 mg/kg p.o. Anti-nociceptive Activity (Benzoquinone-writhing)

Fig. 4. Analge.ic activity in human " mouse. Human initial daily do.e mg/kg orally.

BIOCHEMICAL MODE OF ACTION

Like other nonsteroidal anti-inflammatory drugs, diclofenac sodium interacts with the arachidonic acid cascade at the level of cyclooxygenase. Inhibition of this key enzyme occurs in vitro in the micromolar range and prevents, consequently, the formation of thromboxanes, prostaglandins, and prostacyclin (Fig. 7). This classical site of interaction was reported for diclofenac sodium many years ago. z More recent investigations have revealed an additional site of interaction. Malmsten6 originally observed that diclofenac sodium, when incubated with human neutrophils, did not increase leukotriene formation as expected from a shunting effect due to cyclooxygenase inhibition alone. Detailed studies by Ku' indicated that diclofenac sodium had no inhibitory effect at the level of 5- and 15-lipoxygenases nor of the phospholipase A z but produced significant modulation of arachidonic acid release and uptake (Fig. 7). As reported in detail by Ku (page 36), decreased arachidonic acid release and increased

6 7.6 DloloreDaO Na mg/kg p.o. (10 Daya)

Thera~ulic = 0.-1. Blood 1.088 IThre.hold no.e) RatiO Adj. Arthnll. (£0.0)

10

=7

mg/kg 0.2 mg/kg

Fig. 6. Gastrointestinal tolerability in the rat. Ten-day treatment with diclofenac Na.

uptake (probably into triglycerides) limit the availability of arachidonic acid flowing into the cyclooxygenase and lipoxygenase pathways. Reduced formation of leukotrienes and 5-HETE was documented indeed experimentally (I) in vitro during incubation of micromolar concentrations of diclofenac sodium with rat polymorphonuclear leukocytes and macrophages, with guinea pig peritoneal leukocytes, and with human polymorphonuclear leukocytes and monocytes; and (2) ex vivo after oral pretreatment of rats with 6 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 after oral treatment with diclofenac sodium. The inhibitory effect of diclofenac sodium on l~ukotriene formation is of particular interest, given the suggested role of leukotrienes in the inflammatory process. The fact that macro-

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3

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4h

6h

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Fig. 5. Anelge.ic effect in the mouae writhing assay: onset and duration of action.

~E;:~:t'.::.. t unIn Pt.1N. 10 ,.M'" monocyloo) (IC.. -110 ..... ."tunlnPt.1N. -10pM"'monocyloo)

Fig. 7. Arachidonic acid ca.cade (simplified). Biochemical .it•• of interaction.

SCHOLER ET AL

64

phages are even more susceptible to diclofenac sodium than polymorphonuclear cells in terms of leukotriene inhibition implies a potential benefit of this agent in chronic inflammation. CONCLUSIONS

Diclofenac sodium has been profiled preclinically as a potent anti-inflammatory, analgesic, and antipyretic agent with good gastrointestinal

tolerability. Its mode of action includes potent cyclooxygenase inhibition and modulation of arachidonic acid release and uptake, resulting in a dual effect on the cyclooxygenase and Iipoxygenase pathway. Diclofenac sodium thus has the potential to effectively counteract the clinical symptoms of inflammation and to affect a wide range of inflammation-related mediators and cell functions.

REFERENCES I. Sallmann A: Chemische Aspekte von diclofenac. In: Wagenhauser FJ, ed. Polyarthritiden, International Symposium, Torremolinos, 1975. Bern: Hans Huber, 1976:295 2. Menasse R, Hedwall PR, Kraetz J, et al: Pharmacological properties of diclofenac sodium and its metabolites. Scand J Rheumatol1978; Suppl. 22:5-16 3. Winter CA, Risley EA, Nuss GW: Carrageenininduced edema in hind paw of the rat as an assay for inflammatory drugs. ProcSoc Exp Bioi Med 1963;162:544 4. Newbould BB: Chemotherapy of arthritis induced in rats by mycobacterial adjuvant. Br J Pharmacol 1963; 21:127-136

5. Schweizer A, Brom R: Differentiation of peripheral and central effects of analgesic drugs. Int J Tiss React 1985;7:7983 6. Malmsten CL: The effects of some non-steroidal antiinflammatory drugs upon LTB 4 formation and granulocyte function in vitro. (Abstract) Prostaglandins and Leukotrienes 84, Washington, D.C., May 8-11,1984 7. Ku EC, Lee W, Kothari H, et al: Regulatory role of diclofenac sodium on arachidonic acid metabolism and release in cellular and animal systems. (Abstract, p. 27) Inflammation Research Association, Second International Conference, Ellenville, NY, October 21-25,1984