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- 3.6
II.3.6 Barbiturates
by Masaru Terada and Ritsuko Watanabe
Introduction
Barbiturates are being widely used as antiepileptics, hypnotics and anaesthetics ( > Figure 6.1
and > Table 6.1). The incidence of barbiturate poisoning cases tends to increase in Japan
( > Figure 6.2) [1]. A majority of the barbiturate drugs is being controlled by the Narcotics
⊡ Figure 6.1
Structures of barbiturates.
© Springer-Verlag Berlin Heidelberg 2005
- 302 Barbiturates
⊡ Figure 6.2
Incidence of fatal barbiturate poisoning cases. Since fatal cases due to Vegetamin® tablets
containing phenobarbital are many, its incidence rate is also shown in this figure.
and Psychotropics Control Law in Japan; thus they are also important drugs in view of forensic
toxicology. The analysis of barbiturates in human specimens is being made by GC [2–6], GC/
MS [3, 6, 7–9], HPLC [10–13], LC/MS/MS [14], capillary electrophoresis [15] and immu-
noassays [16, 17]. In this chapter, usual methods for analysis of barbiturates by GC and HPLC
are presented.
⊡ Table 6.1
Properties and doses of barbiturates
Action type Compound Route Therapeutic Maximum
dose (g) dose (g)
long-acting barbital oral 0.3 0.5
phenobarbital oral 0.03–0.2 0.25
phenobarbital sodium suppository 0.015–0.03 0.2
metharbital oral 0.1
Intermediate amobarbital oral 0.1–0.3 0.5
acting amobarbital sodium i.v./i. m. 0.25–0.5
short-acting pentobarbital calcium oral 0.05–0.1 0.5
pentobarbital sodium i.v. 0.1 0.5
secobarbital sodium i.v. 0.1–0.2
hexobarbital oral 0.1–0.4 0.5
ultrashort-acting thiopental sodium i.v. 0.3–0.5
(anaesthetic) thiamylal sodium i.v. 0.3–0.5 1.0
- GC analysis 303
⊡ Figure 6.3
Methylation reaction of phenobarbital with TMAH.
GC analysis [3, 6]
Reagents and their preparation
• Barbital, phenobarbital sodium, amobarbital sodium, pentobarbital sodium, secobarbital
sodium, hexobarbital, thiopental sodium and thiamylal can be purchased from Sigma
(St. Louis, MO, USA); pure powder of metharbital was donated by Dainippon Pharmaceu-
tical Co., Ltd., Osaka, Japan.
• Each barbiturate is dissolved in methanol to prepare 1 mg/mL stock standard solution and
stored at –20 °C.
• An on-column methylation reagent, 0.2 M trimethylanilium hydroxide (TMAH) (Pierce,
Rockford, IL, USA), is diluted with methanol to prepare 4 mM TMAH or 0.4 mM TMAH
solution to be used as an on-column methylation reagent ( > Figure 6.3)a.
• Diethyl ether b used is of a special grade as pure as that used for analysis of the autoxidation
value (AV) and peroxide value (POV) (Dojin Laboratories, Kumamoto, Japan). Other
organic solvents are of the highest purity commercially available.
• For calibration curves, various concentrations (4–200 ng/mL) of each barbiturate are pre-
pared by diluting each 1 mg/mL solution with methanol, and a 10-µL each is evaporated to
dryness under a stream of nitrogen, followed by addition of 0.2 mL serum.
GC conditions
Instrument: a Shimadzu GC-14A gas chromatograph (Shimadzu Corp., Kyoto, Japan).
Column: a methylsilicone fused silica wide-bore capillary columnc (DB-1, 15 m × 0.53 mm
i. d., film thickness 1 µm, J & W Scientific, Folsom, CA, USA).
Column temperature: 60 °C → 8 °C/min → 250 °C; injection temperature: 250 °C d; carrier
gas (flow rate): He (15 mL/min); make-up gas (flow rate): He (30 mL/min); detectors: an FID
and a nitrogen-phosphorus detector (NPD).
- 304 Barbiturates
Procedure
i. A 0.2-mL volume of serume, 1.3 mL distilled water, 1.0 mL of 0.2 M sodium acetate/acetic
acid buffer solution (pH 6.0) and 6.0 mL of ethyl acetate/diethyl ether (1:1, v/v)f are placed
in a glass centrifuge tube with a ground-in stopper.
ii. The tube is shaken vigorously for 5 min.
iii. It is centrifuged at 800 g for 5 min, and the organic layer is transferred to a glass vial with a
conical bottom.
iv. The organic extract is evaporated to dryness under a stream of nitrogen with warming at
40 °C; the residue is dissolved in 0.4 mL of 0.4 mM TMAH methanolic solution.
v. A 1–2 µL aliquot of it is injected into GC; in this method, external calibration method is
used. An external calibration curveg is constructed by spiking various concentrations of a
barbiturate into serum. The peak area of a peak obtained from a test specimen is applied to
the calibration curve to obtain its concentration in a specimen. For identification by GC/
MS, mass spectra are presented in > Table 6.2.
⊡ Table 6.2
Mass spectra of free forms and methyl derivatives of barbiturates
Compound M. W. CI mode EI mode Other fragment ions
(isobutane) base peak
MH+
metharbital 198 155 170, 112, 169
methylmetharbital 212 213 169 184, 126, 112
allobarbital 208 167 124, 80, 141, 106, 53
methylallobarbital 236 237 195 138, 194, 110, 221
amobarbital 226 156 141, 157, 55, 98
methylamobarbital 254 255 169 184, 112, 126
pentobarbital 226 141 156, 157, 55, 98
methylpentobarbital 254 255 169 184, 112, 126
secobarbital 238 167 168, 97, 124, 55
methylsecobarbital 266 267 196 195, 181, 138, 223
hexobarbital 236 221 81, 157, 80, 79, 155, 108, 53
methylhexobarbital 250 251 235 81, 79, 169
mephobarbital 246 218 117,118,146,103
methylmephobarbital 260 261 232 117, 146, 175, 77
phenobarbital 232 204 117, 146, 161, 77, 115
methylphenobarbital 260 261 232 117, 146, 175, 77
cyclobarbital 236 207 141, 81, 79, 67
methylcyclobarbital 264 265 235 169, 79
thiamylal 254 184 168, 167
thiopental 242 172 157, 173, 97, 69
Instrument: a Shimadzu QP-1000EX GC/MS instrument: column: DB-1 (15 m × 0.25 mm i.d., film thickness 0.25 µm);
column temperature: 60° C (3 min) → 8° C/min → 290° C; injection temperature: 250° C; carrier gas (flow rate):
He (1 mL/min); electron energy: 70 eV (EI), 200 eV (CI); reagent gas: isobutane.
- GC analysis 305
Assessment and some comments on the method
The GC analysis of barbiturates without any derivatization gives very low sensitivities, even if
a non-polar fused silica wide-bore capillary column (DB-1) is used, except for metharbital
and hexobarbital. The sensitivities of most barbiturates are enhanced several-fold to several
ten-fold by the methyl-derivatization ( > Figs. 6.4 and 6.5, and > Table 6.3). The on-column
methylation is very rapid and simple. The detection limits of the methyl-derivatives of
barbiturates were 60–90 pg on-column with an NPD and 14–19 ng on-column with an FID.
Methylmephobarbital is identical with methylphenobarbital; this means that discrimination
⊡ Figure 6.4
Gas chromatograms of free forms (A) and methyl-derivatives (B) of barbiturates using an NPD.
Amounts of barbiturates used for the free and derivatized forms were 2 and 1 ng on-column,
respectively. 1: metharbital; 2: allobarbital; 3: amobarbital; 4: pentobarbital; 5: secobarbital;
6: hexobarbital; 7: phenobarbital.
- 306 Barbiturates
⊡ Figure 6.5
Gas chromatograms for methyl derivatives of barbiturates spiked into distilled water (A) and
human serum (B), and for blank human serum (C) using an NPD. The amount of each barbiturate
spiked into distilled water or 0.2 mL plasma was 0.5 µg. The peak numbers are the same as
specified in > Figure 6.4.
between mephobarbital and phenobarbital becomes impossible after methylation of these
compounds. It should be cautioned that the peak of thiopental overlaps that of methylcyclo-
barbital.
HPLC analysis [10]
Reagents and their preparation
• Each barbiturate is dissolved in methanol to prepare 10 µg/mL standard solution and
stored at –20 °C.
• As internal standard (IS) solution, 5-(4-methylphenyl)-5-phenylhydantoin (Sigma) is dis-
solved in methanol to prepare 10 µg/mL solution.
- HPLC analysis 307
⊡ Table 6.3
Retention times and detection limits for main barbiturates and their methyl derivatives
measured by GC-NPD
Compound Retention time Detection limit
(min) (pg/on-column)
metharbital 6.86 139
methylmetharbital 6.30 52
allobarbital 9.13 667
methylallobarbital 7.61 46
amobarbital 10.7 667
methylamobarbital 9.27 61
pentobarbital 11.0 667
methylpentobarbital 9.61 60
secobarbital 11.6 435
methylsecobarbital 10.2 48
hexobarbital 12.3 169
methylhexobarbital 11.9 52
mephobarbital 12.8 306
methylmephobarbital 12.2 57
phenobarbital 13.5 1,670
methylphenobarbital 12.2 57
cyclobarbital 13.7 1,360
methylcyclobarbital 12.4 89
thiopental 12.4 80
• Calibration curves: 10, 25, 50, 100, 500 and 1,000 µL of the standard solution of each bar-
biturate were separately placed in glass centrifuge tubes together with 50 µL of IS solution,
and evaporated to dryness under a stream of nitrogen, followed by addition of 0.5 mL se-
rum each.
HPLC conditions
Column: a reversed phase columnh (ODS-80 Ts, 10 cm × 4.6 mm i.d., particle diameter 2 µm,
Toso, Tokyo, Japan).
Mobile phase: 8 mM phosphoric acid solution/acetonitrile (3:7, v/v).
Detection wavelength: 215 nm; flow rate: 0.4 mL/min; temperature: room temperature.
Procedure
i. A 0.5-mL volume of blood (urine)i, 50 µL IS solution, 0.5 mL distilled water, 0.1 mL of
0.2 acetic acid/sodium acetate buffer solution (pH 6.0) and 3 mL of ethyl acetate/diethyl
ether (1:1, v/v) are placed in a 10-mL volume glass centrifuge tube with a ground-in stopper.
- 308 Barbiturates
ii. The tube is well voltex-mixed or shaken for 2 min.
iii. It is centrifuged at 800 g for 5 min, and the organic layer is transferred to a glass vial with a
conical bottom.
iv. The organic extract is evaporated to dryness under a stream of nitrogen with warming at
40 °C. The residue is dissolved in 100 µL of the mobile phase.
v. A 10-µL aliquot of the above solution is injected into HPLC. The peak area ratio obtained
from a test specimen is applied to the calibration curvej to calculate its concentration,
which had been constructed with the spiked serum according to the above procedure.
Assessment and some comments on the method
In this method, the authors used an HPLC column with a particle diameter of 2 µm in place of
5 µm; the smaller diameter gives various advantages, such as higher sensitivity, rapid analysis
and a smaller amount of the flow of mobile phase. The detection limit for most barbiturates
⊡ Figure 6.6
HPLC chromatograms for blood extracts in the presence (b) and absence (a) of barbiturates. The
concentration of each barbiturate spiked into blood was 0.1 µg/mL. 1: barbital; 2: allobarbital;
3: metharbital; 4: phenobarbital; 5: cyclobarbital; 6: pentobarbital; 7: hexobarbital;
8: amobarbital; 9: secobarbital; 10: thiopental; 11: IS [5-(4-methylphenyl)-5-phenylhydantoin].
- Toxic and fatal concentrations 309
⊡ Table 6.4
Retention times and detection limits for main barbiturates measured by HPLC
Compound Retention time (min) Detection limit (µg/mL)
barbital 3.8 0.05
allobarbital 5.1 0.05
metharbital 5.9 0.05
phenobarbital 6.1 0.05
cyclobarbital 7.1 0.05
pentobarbital 10.6 0.05
hexobarbital 10.6 0.05
amobarbital 10.9 0.05
secobarbital 14.2 0.05
thiopental 21.8 0.5
was about 0.05 µg/mL except for thiopental (0.5 µg/mL) ( > Table 6.4). The peak of pentobar-
bital overlaps that of hexobarbital; the peak of amobarbital appears very close to these peaks
( > Figure 6.6).
Toxic and fatal concentrations
Therapeutic, toxic and fatal blood concentrations of some barbiturates are shown in > Table 6.5
[18, 19]. Every concentration shows a wide variation according to individuals. By single admin-
istration, the dose (route), peak blood concentration and its time are: phenobarbital 50 mg (oral),
1.9 µg/mL after 3 h [6]; amobarbital 120 mg (oral), 1.8 µg/mL after 2 h [20]; pentobarbital 100 mg
(oral), 1.2–3.1 µg/mL after 0.5–2 h [21]; thiopental 400 mg (intravenous), 28 µg/mL after 2 min,
7 µg/mL after 15 min, and 3 µg/mL after 90 min [22]. The minimum fatal doses are: amobarbital,
about 1.5 g; pentobarbital, about 1 g; phenobarbital, about 1.5 g; and thiopental, about 1 g [19].
⊡ Table 6.5
Blood concentrations of main barbiturates (µg/mL)
Compound Therapeutic Toxic conc. Fatal conc. Reference
conc.
amobarbital 1–5 10–30 13–96 [18]
2–12 >9 9–72 [19]
pentobarbital 1–3 >5 10–169 [18]
1–10 >8 8–73 [19]
phenobarbital 10–40 40 – 60 >80 [18]
2–30 4–90 4–120 [19]
thiopental 1–42 >7 10–400 [18]
4.2–134 6–392 [19]
- 310 Barbiturates
Survived and fatal poisoning cases
Survived phenobarbital poisoning case [23]
A 26-year-old male ingested 2–3 g of phenobarbital plus phenytoin. Upon arrival at a hospital,
blood phenobarbital concentration was as high as 107 µg/mL. As emergency treatments, 30 g
of activated charcoal and 30 g of sodium sulfate were administered orally. The concentration of
blood phenobarbital decreased to 72 µg/mL after 24 h; he thereafter recovered without any
complication.
Fatal thiopental poisoning cases
Case 1 [24]: a 21-year-old female received intravenous administration of 17 mL of Thiobal
(thiopental sodium solution) for artificial abortion at a women’s clinic, and fell into a shock
state 20 min after. Although various emergency treatments were made, she died 2 h after. The
blood concentration of thiopental of this victim was 8.2 µg/mL.
Case 2 [25]: a 26-year-old male (son) and a 54-year-old female (mother). At their wit’s end
due to domestic violence by the son, his father intended to commit triple-suicide. He injected
about 12 mL (about 1.75 g thiopental) and about 15 mL (about 1.5 g thiopental) of thiopental
solution into his son and wife intravenously, respectively; both of them were killed. He intro-
duced car exhaust into his car room and also tried to inject the same solution intravenously by
himself to commit suicide, but his trials were abortive. The blood thiopental concentrations of
his son and wife were 6.9 and 4.4 µg/mL, respectively.
Case 3 [25]: a 25-year-old female was found dead in her room; she had committed suicide
by injecting an alate needle into a vein of the right dorsum pedis for drop infusion of thiopen-
tal (its amount infused not clear). The concentration of thiopental in her heart blood was
6.3 µg/mL; the amount administered was estimated to be about 1.5 g.
Fatal pentobarbital poisoning case [26]
A 3.2-year-old male. A doctor directed a nurse to inject 50 mg pentobarbital into the child
intramuscularly; but the nurse misunderstood the direction. She began intravenous injection
of 50 mL pentobarbital solution to the child. After injection of the 15 mL solution, he fell into
a shock state. In spite of efforts with various emergency treatments, he died 22 h later. The
pentobarbital concentration in his blood was 17.5 µg/mL (total amount injected estimated
about 500 mg).
Fatal poisoning cases due to a combined drug or multiple drugs
including a barbiturate
Case 1 [27]: a 40–45 year-old (estimated) female was found dead on a bed of a hotel. In her
room, 2 tablets of Vegetamin (a combined drug containing, phenobarbital, promethazine and
- Survived and fatal poisoning cases 311
chlorpromazine) and one capsule of Insumin (flurazepam) were found. From the stomach con-
tents, phenobarbital, promethazine and chlorpromazine were detected. Drug concentrations
in blood, the liver and kidney were: phenobarbital, 98.0, 106 and 105 µg/g; promethazine, 5.05,
38.2 and 6.92 µg/g; chlorpromazine, 1.68, 22.1 and 3.03 µg/g, respectively.
Case 2 [28]: A 30-year-old female was found dead by a passer-by at an open-air parking
lot close to her home almost in the nude with her clothes being scattered around her body. In
the previous night, the victim had drunk and eaten with her friends and left them. Twenty four
empty packages of Isomytal (amobarbital) were discovered at her home. From her blood, amo-
barbital at 10.6 µg/mL, phenobarbital at 28.6 µg/mL, promethazine at 2.8 µg/mL and chlor-
promazine at 0.9 µg/mL were detected.
Case 3 [29]: A 44-year-old male was found dead by his wife in his bedroom with smoke
from the right side of his mattress. She called an ambulance, but he had been dead. COHb
concentration in his blood was 1 %; burning wounds found in his whole body were negative for
vital reaction. From his stomach contents, amobarbital, bromisovalum and levomepromazine
were detected. The drug concentrations in blood, the liver, brain and urine were: amobarbital,
25, 47, 30 and 7 µg/mL (g); bromisovalum, 37, 70, 57 and 6 µg/mL (g); levomepromazine, 1.5,
19, 2.0 and not detectable µg/mL (g), respectively.
Notes
a) By the on-column methylation with TMAH, many compounds are methyl-derivatized
immediately ( > Figure 6.3). Except for barbiturate drugs, this method is applicable to
glutethimide, primidone and oxazolo-benzodiazepines. For thiopental, the derivatization
reaction causes some decomposition products together with the methylated product; the
analysis of the underivatized form of thiopental gives better results. The 4 mM and 0.4 mM
concentrations of TMAH are used for the FID and NPD, respectively.
b) It should be cautioned that thiopental is desulfurized and decomposed by a peroxide in-
cluded in diethyl ether.
c) Similar types of columns from other manufacturers, such as SPB-1, Ultra#1, CBP-1 and
CP-Sil5, can be used.
d) When the injection temperature is not high enough (not higher than 200 °C), the efficiency
of the on-column methylation is low.
e) Blood plasma and whole blood can be also used.
f) As extraction solvents, diethyl ether, ethyl acetate, chloroform and dichloromethane can be
used; however, the present ethyl acetate/diethyl ether (1:1, v/v) gave the cleanest back-
grounds with few impurity peaks for human specimens. For metharbital, diethyl ether,
ethyl acetate and dichloromethane give low extraction efficiencies (46–63 %).
g) Each calibration curve showed good linearity in the range of 0.2–10 ng on-column (0.2–
10 µg/mL). The detection limits of this method were 60–90 µg/mL in serum. The recovery
rates of 0.1–5.0 µg of barbiturates spiked into 0.2 mL serum were 83–111 %. Mass spectra,
retention times, detection limits and each GC chromatograms for underivatized and meth-
ylated barbiturates are shown in > Tables 6.2 and 6.3, and > Figure 6.5.
h) Similar types of ODS (octadecylsilane type silica gel) columns from other manufacturers,
such as Zorbax ODS and Hypersil, can be also used. However, the retention times may be
longer, because of 5 µm of particle diameter.
- 312 Barbiturates
i) For organ specimens, a 1-g aliquot of a tissue is minced and homogenized with 4 mL dis-
tilled water, followed by centrifugation at 12,000 g for 10 min. A 1-mL volume of the super-
natant fraction is processed like the blood (urine).
j) Linear relationship was observed in the range of 0.1–5 µg/mL for most barbiturates. The
recovery rates from blood were 95–104 %. In this method using urine as a test specimen,
interfering impurity peaks derived from urine appear until 10 min of retention time. The
retention times, detection limits, and HPLC chromatograms for barbiturates are shown
in > Table 6.4 and > Figure 6.6.
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nguon tai.lieu . vn
