Dipyrone

Dipyrone Nathan K. Evanson University of Cincinnati, Cincinnati, USA ã 2007 Elsevier Inc. All rights reserved.

Introduction Dipyrone is an analgesic/antipyretic drug that has been in use since 1922. At present, its use is banned in the United States, because of a small risk of agranulocytosis associated with its use Huguley (1964). Despite this risk, dipyrone is widely used in other areas of the world, especially Europe and South America. It is available without prescription in places such as Brazil and Turkey, and is sometimes referred to as ‘‘Mexican aspirin’’.

Nomenclature Name of the Clinical Form Related Names Source: EMTREE

dipyrone methylmelubrin; methampyrone; metamizol; analgin; sulpyrin; Alginodia; Algocalmin; Bonpyrin; Conmel; Divarine; Dolazon; D-Pron; Dya-Tron; Espyre; Farmolisina; Feverall; Fevonil; Keypyrone; Metilon; Minalgin; Narone; Nartate; Nevralgina; Nolotil; Novacid; Novaldin; Novalgin; Novemina; Novil; Paralgin; Pyralgin; Pyril; Pyrilgin; Pyrojec; TegaPyrone; Unagen.; 2,3 dimethyl 1 phenyl 5 pyrazolone 4 methylaminomethanesulfonate; 2,3 dimethyl 1 phenyl 5 pyrazolone 4 methylaminomethanesulfonate sodium; 4 methylaminophenazone methanesulfonate sodium; [(2,3 dihydro 1,5 dimethyl 3 oxo 2 phenyl 1h pyrazol 4 yl)methylamino]methanesulfonate sodium; alginotia; algocalmin; algopyrin; alipyrone; analgetin; barone; bonpyrin; dipirona; diprofarn; diprone; dipyron; dipyrone calcium; duralgina; dypirone; fevonil; metamisol; metamizol sodium; metamizole; metapyrin; metham pyrone; methamizole; methapyrone; metilon; narone; nartrate; noramidazophen; noramido pyrine methanesulfonate; noramidopyrine methane sulfonate; noramidopyrine methane sulfonate sodium; noramidopyrine methanesulfanate sodium; noramidopyrine methanesulfonate; noramidopyrine methanesulfonate calcium; noramidopyrine methanesulfonate sodium; noramidopyrine methanesulfonic acid; noramidopyrinium methanesulfonate sodium; novaldin; novalgetol; novalgin; novamidazophen; novamidoazophen; novaminsulfon; novaminsulfone; novaminsulfone sodium; novapyrine; novemina; novil; oxiquinazine; pydirone; pyralgin; pyralgina; pyretin; pyridone;

1

2

Dipyrone

sodium noramidopyrinium methansulfonate; sodium(antipyrinylmethylamino)methanesulfonate hydrate; sulpyrine; vitalgin; ww17d2 [(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1Hpyrazol-4-yl)methylamino]methanesulfonicacid sodium salt monohydrate; (antipyrinylmethylamino)-methanesulfonic acidsodium salt; 1-phenyl-2,3-dimethyl-5pyrazolone-4methylaminomethanesulfonatesodium; noraminopyrine methanesulfonate sodium; 4methylamino-1,5-dimethyl-2-phenyl-3-pyrazolone sodium methanesulfonate; sodium methylaminoantipyrine methanesulfonate. 5907-38-0

Chemical Names

CAS Number

Basic Chemistry Chemical Structure Structure

Chemical Formula Properties Physical Properties Molecular Weight Solubility

C13 H16 N3 O4 S. Na

Dipyrone is a white or almost white crystalline powder. It hydrolyzes in aqueous solution to 4-methyl-aminoantipyrine. Hydrolysis is accelerated by lower pH Ergun et al (2004). 333.342 1 g/1.5 ml in water. Also soluble in methanol, less so in ethanol. Nearly insoluble in ether, benzene, acetone, or chloroform The Merck Index (2001).

Human Pharmacokinetics After an oral dose, dipyrone is almost completely hydrolyzed to 4-methyl-aminoantipyrine (MAA). The dose is almost completely absorbed as MA A. MAA and 4-aminoantipyrine (AA) levels are correlated with the analgesic effect of dipyrone Levy et al (1995). The main metabolites of dipyrone are MAA, AA, 4-formyl-amino-antipyrine and 4-acetyl-antipyrine.

Dipyrone

Pharmacokinetic Properties

Value

Units

Prep. and Route of Admin.

Absorption Bioavailability

85

%

Tablets, oral

bioavailability

89

%

Drops, oral

bioavailability

54

%

Suppository, rectal

bioavailability

87

%

Solution, Levy et al (1995) intramuscular injection

Distribution Volume of Distribution

33.5

l

Intravenous

Levy et al (1995)

volume of Distribution

1.19

Oral

Levy et al (1995)

Plasma Protein Binding Plasma Protein Binding Plasma Protein Binding Plasma Protein Binding Metabolism Plasma dHalf-Life

57.6

l/kg lean mass %

Value is for 4-methylaminoantipyrine. All four metabolites can cross the blood-brain barrier Levy et al (1995). Value is for 4-methylaminoantipyrine

Levy et al (1995)

Value for 4-methylaminoantipyrine.

47.9

%

Levy et al (1995)

Value for 4-amino-antipyrine.

17.8

%

Levy et al (1995)

Value for 4-formyl-aminoantipyrine.

14.2

%

Levy et al (1995)

Value for 4-acetyl-antipyrine.

3.8

hrs

plasma Halflife

2.1

hrs

Bio Half-Life

2.4

hrs

Clearance

170

ml/min

Clearance

132

ml/min

Oral

Levy et al (1995)

Clearance

820

ml/min

Oral

Clearance

479

ml/min

Oral

Clearance

281

ml/min

Oral

Levy et al (1995) Levy et al (1995) Levy et al (1995)

Clearance

300

ml/min

Oral

Reference Comments

Levy et al (1995) Levy et al (1995) Levy et al (1995)

Volz and Kellner (1980) intramuscular Volz and Kellner (1980) Oral or Volz and intramuscular Kellner (1980) Oral Levy et al (1995)

Compared to oral formulations, absorption is slower and incomplete. Maximum plasma concentration and the time needed to reach it are similar to oral formulations.

Oral

Value for 4-methylaminoantipyrine after single dose. Value for 4-methylaminoantipyrine after multiple doses. Value for 4-amino-antipyrine after single dose. Value for 4-amino-antipyrine after multiple doses. Value for 4-acetyl-antipyrine after single dose.

3

4

Dipyrone

Clearance Clearance Routes of Elimination

Levy et al Value for 4-acetyl-antipyrine after (1995) multiple doses. 221 ml/min Oral Levy et al Value for 4-formyl-amino(1995) antipyrine after single dose. 662 ml/min Oral Levy et al Value for 4-formyl-amino(1995) antipyrine after multiple doses. Dipyrone is excreted almost completely in the urine as metabolites Volz and Kellner (1980)

Targets-Pharmacodynamics Dipyrone itself likely has little activity. The ability of dipyrone to inhibit prostaglandin production is likely due to the metabolite 4-methyl-aminoantipyrine Brogden (1986), which is rapidly produced when dipyrone is dissolved in water. Although the mechanism of action for dipyrone was historically assumed to be inhibition of prostaglandin synthesis, it has only very weak action against cyclooxygenase (COX)-1 and cyclooxygenase (COX)-2. Dipyrone does, however inhibit the COX-3 splice variant of COX-1 Chandrasekharan et al (2002), Simmons et al (2004). This suggests that the analgesic and antipyretic effects of dipyrone may be mediated by inhibition of this enzyme. Target Name(s): COX-3 splice variant of COX-1

Therapeutics Dipyrone is effective as an analgesic and as an antipyretic. Because of the possibility of agranulocytosis, it has been recommended that dipyrone (where available) should only be used in severe pain and the absence of alternatives Sweetman (2002). However, there is controversy over the actual risk posed by use of dipyrone Brogden (1986). Indications Prep. and Route of Admin.

Reference

Comments

g

Oral, divided doses of 0.5–1 g each.

Sweetman (2002)

Can also be used intramuscular, intravenous, and as a suppository.

mg/ kg

Oral

Brune (1988)

Value

Units

Pain Dosage

0.5–4

Fever Dosage

5

Contraindications Dipyrone is contraindicated in aspirin sensitivity, pregnancy, breastfeeding, and porphyria Sweetman (2002).

Dipyrone

Adverse Effects Agranulocytosis, shock Sweetman (2002). The most common side effect is rash, but toxic epidermal necrolysis, exfoliative dermatitis, Stevens-Johnson syndrome and anaphylactic shock have also been reported Brogden (1986). Agent-Agent Interactions Agent Name

Mode of Interaction

Cyclosporine

Dipyrone can reduce blood levels of cyclosporine, so blood levels of cyclosporine should be regularly checked if dipyrone is given.

Pre-Clinical Research In animal studies, dipyrone is much less effective in models of inflammatory pain (such as yeast-induced paw edema) than for other types of pain (such as that induced by phenylquinone injection) Hoffmeister et al (1974). It is also a potent antipyretic. Dipyrone is highly bioavailable after oral dosing, and is eliminated mainly in the urine. Pharmacokinetics The pattern of dipyrone metabolism is similar between the rat and human, but metabolism in the dog is dissimilar Volz and Kellner (1980). It is highly bioavailable after oral administration, and has relatively high LD50 values in animals. Rat

Value

Units

Prep. and Route of Admin.

Absorption Bioavailability Distribution Volume of Distribution Plasma Protein Binding Metabolism Plasma Half-Life

2.7

hrs

Intravenous

Plasma Half-Life>

2.4

hrs

Oral

Reference

Comments

Volz and Kellner (1980) Volz and Kellner (1980)

Bio Half-Life Clearance Routes of Elimination

Dog

Value Absorption Bioavailability Distribution Volume of Distribution

Units

Prep. and Route of Admin.

Reference

Comments

5

6

Dipyrone Plasma Protein Binding Metabolism Plasma Half-Life Plasma Half-Life Plasma Half-Life Bio Half-Life Clearance Routes of Elimination

5.2 4.4 5.4

hrs hrs hrs

Intravenous Oral Rectal

Volz and Kellner (1980) Volz and Kellner (1980) Volz and Kellner (1980)

Potency

Cell Line/ TypeEffects

Exp. End Point

Reference

Comments

Sf9 Inhibition of COX-1

Chandrasekharan et al (2002)

mM

Sf9 Inhibition of COX-2

Chandrasekharan et al (2002)

mM

Sf9 Inhibition of COX-3 splice variant of COX-1

Chandrasekharan et al (2002)

The IC50 value is for canine cyclooxygenase overexpressed in Sf9 insect cells. The IC50 value is for canine cyclooxygenase overexpressed in Sf9 insect cells. The IC50 value is for canine cyclooxygenase overexpressed in Sf9 insect cells.

Value

Units

Dog EC50

350

mM

EC50

>1000

EC50

52

Mouse LD50 2891

Organ/ Tissue

Prep. and Route of Admin.

LD50

2083

LD50

2197

ED50

652

ED50

49.8

EC50

~100

mg/ kg mg/ kg mg/ kg mg/ kg mg/ kg mM

Oral

EC50

~100

mM

Rat ED50

>150

mg/ kg

Oral

Inhibition of edema

ED50

10

mg/ kg

Oral

Antipyresis

Subcutaneous Intravenous Subcutaneous Subcutaneous Macrophage

Macrophage

Inhibition of tail flick Analgesia Inhibition of prostaglandin synthesis Increased leukotriene production

Hoffmeister et al (1974) Hoffmeister et al (1974) Hoffmeister et al (1974) Hoffmeister et al (1974) Hoffmeister et al (1974) Brune (1988)

Radiant heating of tail. Phenylquinone writhing test. Value is for 4methyl-aminoantipyrine.

Brune (1988)

Value is for 4-methylaminoantipyrine. Increased leukotriene production may be a result of shunting arachidonic acid from the cyclooxygenase pathway into the lipoxygenase pathway rather than any specific effect of the drug.

Brune and Alpermann (1983) Brune and Alpermann (1983)

Carrageenan-induced edema test. Inhibition of yeastinduced fever.

Dipyrone ED50

1120

ED50

362

ED50

459

ED50

10.9

mg/ kg mg/ kg mg/ kg

mg/ kg

Subcutaneous Subcutaneous

Inhibition of tail flick Analgesia

Subcutaneous

Analgesia

Subcutaneous

Analgesia

Hoffmeister et al (1974) Hoffmeister et al (1974) Hoffmeister et al (1974)

Hoffmeister et al (1974)

Radiant heating of tail. Silver nitrate-induced arthritis. Yeast-induced paw edema-dose at which animals were resistant to at least 100 mm Hg of pressure to the paw. Phenylquinone writhing test.

Other Research Available from Sigma-Aldrich (cat #D8890).

Journal Citations Brogden, R.N., 1986. Pyrazolone derivatives. Drugs, 32 (Suppl. 4), 60–70. Brune, K., 1988. The pharmacological profile of non-opiod (OTC) analgesics: Aspirin, paracetamol (acetaminophen), ibuprofen, and phenazones. Agents Actions Suppl., 25, 9–19. Brune, K., Alpermann, H., 1983. Non-acidic pyrazoles: Inhibition of prostaglandin production, carrageenan oedema and yeast fever. Agents Actions, 13(4), 360–363. Chandrasekharan, N.V., Dai, H., Roos, K.L., Evanson, N.K., Tomsik, J., Elton, T.S., Simmons, D.L., 2002. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc. Natl. Acad. Sci. USA, 99(21), 13926–13931. Ergun, H., Frattarelli, D.A.C., Aranda, J.V., 2004. Characterization of the role of physicochemical factors on the hydrolysis of dipyrone. J. Pharm. Biomed. Anal., 35(3), 479–487. Hoffmeister, V.F., Kronegerg, G., Chlichting, U., Wuttke, W., 1974. Zur pharmakologie des analgetikums propiramfumarat [N-(1-methyl-2-piperidino-athyl)-N-(2-pyridyl)-propionamid-fumarat]. Arzneimittelforschung, 24, 600–624. Huguley, C.M., 1964. Agranulocytosis induced by dipyrone, a hazardous antipyretic and analgesic. JAMA, 189(12), 162–165. Levy, M., Zylber-Katz, E., Rosenkranz, B., 1995. Clinical pharmacokinetics of dipyrone and its metabolites. Clin. Pharmacokinet., 28(3), 216–234. Volz, M., Kellner, H.M., 1980. Kinetics and metabolism of pyrazolones (propyphenazone, aminopyrine and dipyrone). Br. J. Clin. Pharmac., 10, 299S–308S. Simmons, D.L., Botting, R.M., Hla, T., 2004. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol. Rev., 56(3), 387–437.

Book Citations The Merck Index 2001 Dipyrone (Entry # 3385). O’Neil, M.J. (Ed.), The Merck Index, Edition 13, pp. 589–590, Merck Research Laboratories, Whitehouse Station, NJ. Sweetman, S.C., 2002. Sweetman, S.C. (Ed.), Martindale: The complete Drug Reference, Edition 33, p. 34, Pharmaceutical Press, London.

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