Drugs and Poisons in Humans - A Handbook of Practical Analysis (Part 27)

Introduction:Phenothiazine drugs, including chlorpromazine and levomepromazine, have been being widely used as neuroleptics (major tranquilizers), antiparkinsonian drugs and antihistaminics for a long time [1]. Table 1.1 shows chemical structures of representative phenothiazines. These drugs show blocking action on D2 receptors of dopaminergic neurons; there is close relationship between the receptor blocking and tranquilizing actions. The dopamine D2 receptor-blocking actions provoke extrapyramidal symptoms, such as muscular stiffness, tremor and ptyalism. Orthostatic hypotension, arrythmia and icterus are occasionally found after administration of phenothiazines as side effects. The number of phenothiazine poisoning cases is relatively small, as compared with the extensive...
Nội dung trích xuất từ tài liệu:
Drugs and Poisons in Humans - A Handbook of Practical Analysis (Part 27) 3.1II.3.1 Phenothiazines by Akira Ishii and Yoshinao KatsumataIntroductionPhenothiazine drugs, including chlorpromazine and levomepromazine, have been beingwidely used as neuroleptics (major tranquilizers), antiparkinsonian drugs and antihistaminicsfor a long time [1]. > Table 1.1 shows chemical structures of representative phenothiazines.These drugs show blocking action on D2 receptors of dopaminergic neurons; there is closerelationship between the receptor blocking and tranquilizing actions. The dopamine D2 recep-tor-blocking actions provoke extrapyramidal symptoms, such as muscular stiffness, tremorand ptyalism. Orthostatic hypotension, arrythmia and icterus are occasionally found after ad-ministration of phenothiazines as side effects. The number of phenothiazine poisoning cases is relatively small, as compared with theextensive use of this group of drugs [2]. However, until now, many phenothiazine poisoningcases, including fatal ones [3, 4], were reported. Phenothiazines were analyzed by various methods, such as GC, GC/MS, HPLC and LC/MS. The methods by GC and GC/MS are relatively simple, but most of the methods reportedused packed columns or wide-bore capillary columns [5, 6], which did not give high sensi-tivity. Hattori et al. [7] reported a highly sensitive method for detecting phenothiazine in bodyfluids using GC-surface ionization detection (SID)a. Although the SID detector has an advan-tage in that each compound having a tertiary amino group can be analyzed with high sensitiv-ity and specificity, it is not a detector commonly available. In this chapter, the methodsof qualitative and quantitative analysis of phenothiazines in human body fluids using usefulGC/MS and LC/MS are presented.GC/MS analysisReagents and their preparationi. ReagentsChlorpromazine, triflupromazine, promethazine and thioridazine can be purchased fromSigma (St. Louis, MO, USA). Pure powder of levomepromazine was donated by MitsubishiWelpharma, Osaka, Japan. Other common chemicals were of the highest purity commercially available.© Springer-Verlag Berlin Heidelberg 2005256 Phenothiazines ⊡ Table 1.1 Structures of phenothiazine drugs TIC and mass chromatograms (MCs) for 5 phenothiazines. 1: triflupromazine; 2: promethazine; 3: chlorpromazine; 4: levomepromazine; 5: thioridazine. For the authentic sample, the mixture of 4 ng each of the compounds was directly injected into GC/MS. A 200-ng aliquot each of 5 compounds had been spiked into 1 mL whole blood or urine and extracted with a Sep-Pak C18 cartridge; the residue was dissolved in 100 µL methanol and a 2- µL of it was injected into GC/MS. GC/MS analysis 257ii. PreparationEach drug is dissolved in methanol to prepare 1 mg/mL solutionb. Many of the phenothiazinedrugs are in the forms of hydrochloride salt. For example, to prepare 1 mg/mL solution of thefree form of chlorpromazine, the amount of chlorpromazine hydrochloride to be dissolved in1 mL methanol is calculated as follows. 1 mg (MW of the free form 318.9 MW of the salt form 355.4) = 1.11 mg The 1 mg/mL solution of each phenothiazine drug is diluted with methanol appropriately,according to need.GC/MS conditionsGC column: an Rtx-1 fused silica capillary column (30 m × 0.32 mm i.d., film thickness0.25 µm, Restek, Bellefonte, PA, USA)c GC conditions; instrument: a Shimadzu GC-17A gas chromatograph connected to MS(Shimadzu Corp., Kyoto, Japan)d; column (oven) temperature: 150 °C (1 min) →15 °C/mine →290 °C (10 min); injection temperature: 270 °C; interface temperature; 270 °C; carrier gas: He;its flow rate: about 1.5 mL/min; injection: splitless mode for 1 min followed by the split mode. MS conditions; instrument: a Shimadzu QP-5050A quadrupole mass spectrometerf; mea-surement: scan mode; ionization: positive ion EI; ionization current: 60 µA; electron energy:70 eV; scan range: m/z 50–400; scan speed: 1,000 amu/s.Procedurei. A 10-mL volume of methanol and 10 mL distilled water are passed through a Sep-Pak C18 cartridge; this procedure is repeated twice (in total 3 times) to activate the cartridgeg.ii. To 1 mL of whole blood or urine, are added 8 mL distilled waterh, internal standard (IS) solution and 1 mL of 1 M sodium bicarbonate solution. For IS, a non-target phenothiazine drug (200 ng)i is selected for use.iii. The mixture solution is poured into the cartridge, followed by washing with 10 mL distilled water twice and by elution with 3 mL of chloroform/acetonitrile (8:2).iv. The upper aqueous layer of the eluate is removed wit ...