Pethidine: Clarke's Analysis of Drugs and Poisons Página 1 de 4

Printed from: Clarke's Analysis of Drugs and Poisons, London: Pharmaceutical Press. Electronic version, 2005.
Pethidine Narcotic Analgesic

Synonyms. Isonipecaine; Meperidine.

1-Methyl–4–phenyl–4–piperidinecarboxylic acid ethyl ester
C15H21NO2 = 247.3
CAS—57–42–1

An oily liquid which slowly crystallises.

Pethidine Hydrochloride
Proprietary names. Alodan; Centralgine; Demerol; Dispadol; Dolantine; Dolantin(a); Dolestine; Dolosal; Mefedina; Pethoid.
It is an ingredient of Mepergan and Pamergan P100.
C15H21NO2,HCl = 283.8
CAS—50–13–5

A white crystalline powder. M.p. 186° to 189°.

Soluble in water, acetone, and ethyl acetate; slightly soluble in alcohol and isopropanol; practically insoluble in ether and
benzene.

Dissociation Constant. pKa8.7 (20°).

Partition Coefficient. Log P(octanol/water), 2.7.

Colour Tests. Liebermann's Test—red–orange; Marquis Test—orange.

Thin–layer Chromatography. System TA—Rf 52; system TB—Rf 37; system TC—Rf 34; system TE—Rf 60; system
TL—Rf 11; system TAE—Rf 34; system TAF—Rf 40; system TAJ—Rf 14; system TAK—Rf 06; system TAL—Rf 72.
(Dragendorff spray, positive; acidified iodoplatinate solution, positive; Marquis reagent, brown.)

Gas Chromatography. System GA—pethidine RI 1754, M (nor-) RI 1885, M (nor-)-AC RI 2240, M (OH-) RI 2045, M
(OH-)-AC RI 2205, M (nor-OH-)-AC2 RI 2600; system GB—pethidine RI 1809, M (nor-) RI 1842, M (nor-)-AC RI 2256, M
(OH-) RI 2145; system GC—RI 2025; system GF—RI 1995; system GM—pethidine RRT 0.319, M (nor-) RRT 0.357 (both
relative to iprindole).

High Performance Liquid Chromatography. System HA—pethidine k 2.8 (tailing peak), M (nor-) k 1.7 (tailing peak),
pethidinic acid k 2.8 (tailing peak); system HC—pethidine k 0.55, M (nor-) k 2.04; system HX—RI 345; system HY—RI
281; system HZ—retention time 3.2 min; system HAA—retention time 11.8 min; system HAX—retention time 9.2 min;
system HAY—retention time 4.8 min.

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Ultraviolet Spectrum. Aqueous acid—251, 257 (A11=8.5a), 263 nm. No alkaline shift.

Infra–red Spectrum. Principal peaks at wavenumbers 1708, 1218, 1166, 1148, 688, 730 cm−1 (pethidine hydrochloride,
KBr disk).

Mass Spectrum. Principal ions at m/z 71, 70, 44, 57, 42, 247, 43, 246; norpethidine 57, 233, 42, 56, 158, 43, 160, 103;
pethidinic acid 71, 70, 57, 43, 219, 42, 218, 44.

Quantification

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GAS CHROMATOGRAPHY. In blood, plasma, or urine: pethidine and norpethidine, limit of detection 5 μg/L for pethidine and
2.5 μg/L for norpethidine, AFID—P. Jacob et al.,J. Pharm. Sci.,1982, 71, 166–168. In plasma: pethidine and norpethidine,
limit of detection 20 μg/L, ECD—P. Hartvig and C. Fagerlund,J. Chromatogr.,1983, 274(25) B Biomed. Appl., 355–360. In
urine: pethidine and its major metabolites, NPD—K. Chan et al.,J. Chromatogr.,1991, 565, 247–254. In urine: FID—F. Liu et
al.,J. Chromatogr.,1994, 658 B Biomed. Appl., 375–379. In urine: limit of detection 1 μg/L. NPD—S. W. Myung et
al.,Analyst,1999, 124, 1283–1286.
GAS CHROMATOGRAPHY–MASS SPECTROMETRY In plasma or serum: pethidine and norpethidine, limit of detection 170 ng/L for
pethidine and 500 ng/L for norpethidine—E. L. Todd et al.,J. Anal. Toxicol.,1979, 3, 256–259. In urine: pethidinic and
norpethidinic acids, limit of detection 500 μg/L—C. Lindberg et al.,Acta Pharm Suec.,1978, 15, 327–336. In urine: limit of
detection 20 μg/L—H. Y. Hu et al.,Yao Xue Xue Bao,1994, 1291, 116–121. In breast milk—L. Borgatta et al.,J. Clin.
Pharmacol.,1997, 37, 186–192. In blood: limit of detection 0.02 μg/L—A. Ishii et al.,J. Chromatogr. B Biomed. Sci.
Appl.,2001, 758, 117–121.

Disposition in the Body. Readily absorbed after oral administration and rapidly and extensively distributed throughout the
tissues. It undergoes considerable first–pass metabolism. The major metabolites are the N-demethylated derivative,
norpethidine, and the hydrolysis product, pethidinic acid, and its conjugates. Norpethidine is about half as active an analgesic
and about twice as toxic as pethidine; it may accumulate in the plasma on chronic administration, particularly in subjects with
renal failure. The excretion of pethidine and its metabolites is dependent on the urinary pH. In normal subjects, about 70% of
a dose is excreted in the urine in 24 h, up to 10% as unchanged drug, 10% as norpethidine, 20% as pethidinic acid, 16% as
conjugated pethidinic acid, 8% as norpethidinic acid, and 10% as conjugated norpethidinic acid; other metabolites identified
in the urine in minor amounts include the N-hydroxy and N-hydroxyphenyl derivatives and pethidine N-oxide. Urinary
excretion of pethidine and norpethidine may both be enhanced to about 30% of a dose if the urine is acid; in alkaline urine,
less than 5% is excreted as pethidine and norpethidine. In pregnant women and in women taking oral contraceptives, the
excretion of unchanged pethidine appears to be increased; less unchanged drug is eliminated in older subjects and, in subjects
with cirrhosis, excretion of pethidine is delayed. Pethidine and norpethidine are distributed in the CSF. Pethidine crosses the
placenta and is excreted in breast milk.Pethidine is a metabolite of phenoperidine.

THERAPEUTIC CONCENTRATION. In plasma, usually in the range 0.2 to 0.8 mg/L. Higher plasma concentrations are found in
elderly subjects.
Following a single oral dose of 50 mg to 6 subjects, a mean peak serum concentration of 0.14 mg/L was attained in 2 h; after
an IM injection of 50 mg to the same subjects, a mean peak serum concentration of 0.20 mg/L in 1 h was reported, and a
mean serum concentration of 0.52 mg/L was obtained 1 min after an IV injection of 50 mg. [J. E. Stambaugh et al.,J. Clin.
Pharmacol.,1976, 16, 245–256.]

Following multiple oral doses of 75 to 100 mg to 4 subjects, plasma concentrations of 0.16 to 0.54 mg/L (mean 0.36) of
pethidine and 0.13 to 0.48 mg/L (mean 0.27) of norpethidine were reported 1 to 4 h after a dose. [H. H. Szeto et al.,J.
Chromatogr.,1976, 125, 503–510.]

TOXICITY. The estimated minimum lethal dose is 1 g. Toxic effects are usually associated with blood concentrations greater
than 2 mg/L but fatalities involving pethidine are uncommon.
BIOAVAILABILITY. About 55%.
HALF–LIFE. Plasma half–life, pethidine 3 to 6 h, increased in neonates and in renal impairment; norpethidine about 20 h.
VOLUME OF DISTRIBUTION. About 4.4 L/kg.
CLEARANCE. Plasma clearance, about 17 mL/min/kg, decreased in subjects with liver disease and in the elderly.
DISTRIBUTION IN BLOOD. Plasma:whole blood ratio, about 0.9.
PROTEIN BINDING. In plasma, about 50 to 60%.
NOTE. For reviews of the pharmacokinetics of pethidine, see L. E. Mather and P. J. Meffin,Clin. Pharmacokinet.,1978, 3,
352–368, and D. J. Edwards et al.,Clin. Pharmacokinet.,1982, 7, 421–433; for a general review of pethidine, see K. S. Latta et
al.,Am. J. Ther.,2002, 9, 53–68.

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Dose. Usually 50 to 150 mg of pethidine hydrochloride, by mouth or 25 to 100 mg by IM injection every 4 h.

© Pharmaceutical Press 2005

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