Analytical Toxicologyfor Clinical, Forensic andPharmaceutical Chemists

EditorsH. Brandenberger

R. A. A. Maes

W

Walter de GruyterBerlin • New York

1997

Contents

Part 1 Chapters of General Nature

1.1 Emergency Toxicology (M. Schmidt and M. Roth)1.1.1 Introduction1.1.2 Role and Location of the Laboratory1.1.3 Types of Intoxication

1.1.3.1 Intoxications of known origin . . .1.1.3.2 Intoxications of unknown origin .

1.1.4 Causes of Intoxications1.1.4.1 Legal drugs

Illegal drugsOther substances

1.1.5Data and indicesClinical status of the patientPathological indicesOther indices

1.1.6

1.1.71.1.8

1.1.4.21.1.4.3Request1.1.5.11.1.5.21.1.5.31.1.5.4Sampling1.1.6.1 Blood

Random urineGastric contentOther specimensSpecimen collection

Transport and Preservation of SamplesAnalytical Techniques Used in Emergency Toxicology1.1.8.1 Spot tests

ImmunoassaysGas chromatography (GC)Gas chromatography - mass spectrometry (GC-MS)Liquid chromatography (LC and HPLC)Thin layer chromatography (TLC)Preparation of the sample

1.1.6.21.1.6.31.1.6.41.1.6.5

1.1.8.:

1.1.9 Expression of Results and Interpretation

.8.3

.8.4

.8.5

.8.6

.8.7

.9.1 Identification of substances

.9.2 Quantitative determination

.9.3 Follow-up of the patient . .1.1.10 Organisation of the Laboratory

.10.1 Emergencies

.10.2 Techniques and equipment

.10.3 Personnel1.1.11 Conclusion

333455557788889999

101010111111111212131314141414141515151515

XII Contents

1.2 Therapeutic Drug Monitoring (A. D. Fraser) 171.2.1 Introduction 171.2.2 Concept of a Therapeutic Range 181.2.3 Individual Drugs 20

1.2.3.1 Phenytoin 201.2.3.2 Carbamazepine 211.2.3.3 Sodium valproate (valproic acid) 22

1.2.4 Audit of Therapeutic Drug Monitoring Programmes 231.2.5 Discontinuation of Antiepileptic Drug Therapy 241.2.6 Summary 251.2.7 Additional Remarks (added in proof) 25

1.3 Special Aspects of Forensic Toxicology (H. Brandenberger) 311.3.1 History 311.3.2 Differences between Forensic and Clinical Toxicology 33

1.3.2.1 Goals of the analytical investigations 331.3.2.2 Mandators of the analytical investigation 341.3.2.3 Specimens submitted for analysis 341.3.2.4 Containers, labeling, sample delivery 351.3.2.5 Analytical investigations 361.3.2.6 Book keeping and reporting of results 371.3.2.7 Fate of analytical specimens 37

1.3.3 Instrumentation of a Laboratory for Forensic Toxicology 381.3.4 Staff of a Laboratory for Forensic Toxicology 391.3.5 Concluding Remarks 40

1.4 Analytical Aspects of Doping in Sports(D. de Boer, T. J. A. Seppenwoolde-Waasdorp and R. A. A. Maes) 431.4.1 Introduction 431.4.2 Doping Control Procedure 431.4.3 Selection of Biological Specimen 441.4.4 Doping List 44

1.4.4.1 Stimulants 451.4.4.2 Narcotic analgesics 481.4.4.3 Anabolic agents 491.4.4.4 Diuretics 511.4.4.5 Peptide hormones and analogs 521.4.4.6 Blood doping 531.4.4.7 Pharmacological, chemical and physical manipulation . 531.4.4.8 Alcohol 541.4.4.9 Marijuana 541.4.4.10 Local anesthetics 541.4.4.11 Corticosteroids 541.4.4.12 Beta-blockers 551.4.4.13 Sedatives 551.4.4.14 Nicotine 561.4.4.15 Miscellaneous 56

Contents XIII

1.4.5 Analytical Procedures 561.4.5.1 Group analysis 561.4.5.2 Sample preparation 561.4.5.3 Immunoassays 581.4.5.4 Thin layer chromatography 591.4.5.5 High performance liquid chromatography 591.4.5.6 Gas chromatography 601.4.5.7 Mass spectrometry 601.4.5.8 Hematological techniques 61

1.4.6 Horse Doping Control 611.4.7 Chirality 611.4.8 Quality Control 621.4.9 Analytical Developments 63

1.4.9.1 Historical overview 631.4.9.2 Group analysis 641.4.9.3 Immunological techniques 641.4.9.4 Mass spectrometry 64

1.4.10 Development of Doping Epidemics and the Role ofthe Analytical Tools 65

1.5 Pharmacokinetics as Applied to Drug and Doping Research(T. B. Vree) 731.5.1 Introduction 731.5.2 Elimination 731.5.3 Sampling 741.5.4 Number of Samples 751.5.5 Analysis 751.5.6 Doping Research 761.5.7 The Site of Metabolism 781.5.8 Reconstruction of the Pharmacokinetic Process 811.5.9 Doping Control 831.5.10 Conclusion 85

1.6 The Future of Immunochemical Drug Analysis(T. Takatori and M. Nagao) 871.6.1 Introduction 871.6.2 Immunochemical Analysis of Psychotropic Drugs 87

1.6.2.1 Radioimmunoassay for diazepam 871.6.2.2 Radioimmunoassay for haloperidol 91

1.6.3 Immunochemical Analysis of Paraquat 931.6.4 Conclusions 97

1.7 The Future of Instrumental Analysis in Toxicology(H. Brandenberger) 991.7.1 History 991.7.2 Outlook on Future General Strategy 100

XIV Contents

1.7.3 Screening Test for Dithiocarbamates as an Examplefor a Preliminary Test on Instrumental Basis 101

1.7.4 New Extraction Techniques 1031.7.4.1 Solid phase extractions 1031.7.4.2 Supercritical fluid extractions 1041.7.4.3 Extractive dialysis 104

1.7.5 Fractionation Methods 1051.7.5.1 Established techniques 1051.7.5.2 Supercritical fluid chromatography (SFC) 1061.7.5.3 Capillary electrophoresis (CE) 1071.7.5.4 Capillary electrochromatography (CEC) 1081.7.5.5 Chiral separations 1081.7.5.6 Identification by retention indicies or with on-line

spectrometric methods 1091.7.6 Trace Analysis by Mass Specific Detection in the

Negative Ion Mode 1091.7.7 Chromatographic Separations with On-line Identification Methods 1111.7.8 "Dual-MS", a Combination of Positive EI-MS with Negative

CI-MS at Low Source Pressure I l l1.7.9 GC-FTIR and the Need for Derivatization 1131.7.10 Summary and Concluding Remarks 115

Part 2 Chapters Concerned with Special Poison Classes 119

2.1 Natural Gases and Vapors (H. Brandenberger) 1212.1.1 General Remarks and Classification 1212.1.2 The Elemental Gases 122

2.1.2.1 Hydrogen and nitrogen 1222.1.2.2 Oxygen 1222.1.2.3 Ozone 1222A.2.4 Halogens (fluorine and chlorine) 123

2.1.3 The Products of Reduction 1232.1.3.1 General remarks 1232.1.3.2 Methane (and other hydrocarbons) 1242.1.3.3 Ammonia 1242.1.3.4 Hydrogen sulfide 1242.1.3.5 Phosphine and arsine 1242.1.3.6 Hydrogen halogenides 125

2.1.4 The Products of Oxidation 1252.1.4.1 The oxides of carbon 1252.1.4.2 The oxides of nitrogen (NOX) 1262.1.4.3 The oxides of sulfur 1262.1.4.4 The oxides of the halogens 127

2.1.5 Phosgene and Nitrosyl Chloride 1272.1.6 Hydrocyanic Acid (Hydrogen Cyanide, Prussic Acid)

and Related Compounds 127

Contents XV

2.1.7 Chemical Investigation of Gas Samples 1282.1.8 Procedures for Investigating Biological Materials 1292.1.9 Examples for the Analysis of Biological Materials 130

2.1.9.1 Determination of hydrocyanic acid (respectivelycyanide) by head space GC 130

2.1.9.2 Determination of the blood hemoglobin saturationindex with carbon monoxide by GC 130

2.1.9.3 Determination of the blood hemoglobin saturationindex with carbon monoxide by atomic absorptionanalysis of Fe 131

2.2 Carbon Monoxide (T. Kojima) 1332.2.1 Introduction 1332.2.2 Determination of CO 1342.2.3 Formation of CO in Humans 1362.2.4 Interpretation of COHb Saturations in Blood from the Left

and Right Heart Cavities of Cadavers 1372.2.5 Treatment of Acute CO Intoxication 138

2.3 Determination of Alcohol Levels in the Body 141(H. Brandenberger, R. Brandenberger and K. Haider)2.3.1 Introduction 1412.3.2 Toxic Effects of Ethanol 142

2.3.2.1 Acute intoxications 1422.3.2.2 Chronic intoxications 1422.3.2.3 Mixed intoxication of ethanol and drugs 143

2.3.3 Biological Specimens for Ethanol Analysis 1432.3.4 Review of Methods for Blood Alcohol Analysis 145

2.3.4.1 Interferometric analysis 1452.3.4.2 Chemical oxidation 1452.3.4.3 Enzymatic oxidation 1462.3.4.4 Gas chromatography 1462.3.4.5 Other methods 147

2.3.5 Criteria for Selection of Analytical Methods 1482.3.6 Detailed Procedures for Blood Alcohol Analysis

by two Different Gas Chromatographic Methods 1492.3.7 Analysis for Ethanol in Tissue Samples 1502.3.8 Identification of Additional Volatiles 1512.3.9 Computer Program for the Collection and Processing

of Data and Presentation of Results of Forensic AlcoholAnalysis by two Different Gas Chromatographic Methods 153

2.3.9.1 Program description 1532.3.9.2 Structure of the program 1552.3.9.3 Listing of variables 1552.3.9.4 Program listing 1582.3.9.5 Sample output 174

XVI Contents

2.4 Volatile Hydrocarbons (T. Nagata and K. Kimura) 1772.4.1 General Aspects 1772.4.2 Toxicity 1772.4.3 Therapy 1782.4.4 Chemical Analysis 178

2.4.4.1 Sampling 1782.4.4.2 Analytical methods 178

2.4.5 Specific Hydrocarbons 1802.4.5.1 Aliphatic hydrocarbons 1802.4.5.2 Aromatic hydrocarbons 1802.4.5.3 Gasoline and kerosene 181

2.4.6 Halogenated Hydrocarbons 1822.4.7 Other Important Volatiles 184

2.5 Volatile Halogenated Compounds (R. J. Flanagan) 1872.5.1 General Introduction 1872.5.2 Volatile Substance Abuse (VSA) 1902.5.3 Clinical Toxicology of Volatile Halogenated Compounds 192

2.5.3.1 Fumigants and other toxic gases 1922.5.3.2 Halogenated solvents and inhalational anaesthetics . . . . 1952.5.3.3 Occupational/Environmental toxicology 197

2.5.4 Pharmacokinetics of Volatile Substances 1972.5.4.1 Absorption, distribution and elimination 1972.5.4.2 Metabolism 198

2.5.5 Diagnosis of Poisoning due to Volatile Substances 2012.5.5.1 Clinical and circumstantial evidence 2012.5.5.2 Toxicological analyses 201

2.6 Pesticides (M. Geldmacher-v. Mallinckrodt and G. Machbert) 2152.6.1 General Remarks 215

2.6.1.1 Definition 2152.6.1.2 Classification of pesticides 2152.6.1.3 Toxicity for man 217

2.6.2 Organophosphorus Pesticides 2182.6.2.1 Chemical structure and physico-chemical properties . . . . 2182.6.2.2 Uses and route of exposure 2192.6.2.3 Absorption, distribution, metabolism, and

elimination 2192.6.2.4 Toxicology 2202.6.2.5 Biochemical and toxicological analyses 224

2.6.3 Carbamate Pesticides 2352.6.3.1 Chemical structure and physico-chemical properties . . . . 2352.6.3.2 Uses and route of exposure 2362.6.3.3 Absorption, distribution, metabolism, and elimination . . 2362.6.3.4 Toxicology 2372.6.3.5 Biochemical and toxicological analyses 239

Contents XVII

2.6.4 Chlorinated Hydrocarbon Insecticides 2422.6.4.1 Chemical structure and physico-chemical properties . . . . 2422.6.4.2 Uses and route of exposure 2452.6.4.3 Absorption, distribution, metabolism, and elimination . . 2462.6.4.4 Toxicology 2482.6.4.5 Biochemical and toxicological analyses 253

2.6.5 Bipyridylium Herbicides 2552.6.5.1 Chemical structure and physico-chemical properties . . . . 2552.6.5.2 Uses and route of exposure 2562.6.5.3 Absorption, distribution, metabolism, and elimination . . 2562.6.5.4 Toxicology 2562.6.5.5 Toxicological analyses 258

2.7 Glycols (M. Roth) 2652.7.1 Ethylene Glycol (1,2 Ethanediol) 265

2.7.1.1 Plasma bicarbonate 2652.7.1.2 The anion gap 2662.7.1.3 Gas chromatography of ethylene glycol 2672.7.1.4 Other methods 267

2.7.2 Other Glycols 267

2.8 Inorganic Anions (M. Roth) 2692.8.1 Nitrate (NOj) and Nitrite (NO2~) 2692.8.2 Chlorate (ClOf) and Chlorite (CIO 7) 2692.8.3 Methemoglobin as a Toxicity Index 270

2.8.3.1 Determination of methemoglobin 2702.8.4 Bromate (BrO3) 2722.8.5 Halogenides 272

2.8.5.1 Fluoride (F") 2722.8.5.2 Chloride (Cl ) 2722.8.5.3 Bromide (Br") 2732.8.5.4 Iodide (I ) 274

2.8.6 Sulfide (S2 ) 2752.8.6.1 Determination of sulfhemoglobin 275

2.8.7 Phosphate T 2752.8.8 Cyanide (CN ") 275

2.8.8.1 Cyanide intoxication 2752.8.8.2 Cyanide analysis 276

2.9 Non-Metals of Group 16 (M. Roth and M. Pelletier) 2812.9.1 Selenium 281

2.9.1.1 Introduction 2812.9.1.2 Analysis 282

2.9.2 Tellurium 283

2.10 Metals of Toxicological Significance (H. Brandenberger and M. Roth) 2852.10.1 Introduction 285

XVIII Contents

2.10.2 Qualitative Analysis for Metals in Biological Specimens 2862.10.2.1 Preliminary tests 2862.10.2.2 Color reactions 2862.10.2.3 Emission methods 2862.10.2.4 Electrochemical methods 2872.10.2.5 Thin-layer chromatography (TLC) 2872.10.2.6 Cation chromatography on columns 2872.10.2.7 Capillary electrophoresis 288

2.10.3 Lithium 2882.10.3.1 Toxicity 2882.10.3.2 Lithium determination 289

2.10.4 The Metals of the Group 2 (Alkaline Earths) 2892.10.4.1 Beryllium 2892.10.4.2 Magnesium 2912.10.4.3 Calcium and strontium 2922.10.4.4 Barium 292

2.10.5 Transition Metals from Groups 5 to 10 (Old NomenclatureGroups Vb to VIII b) with Technical and ToxicologicalImportance 2932.10.5.1 Group information 2932.10.5.2 Vanadium 2952.10.5.3 Chromium 2952.10.5.4 Molybdenum 2952.10.5.5 Manganese 2962.10.5.6 Cobalt 2962.10.5.7 Nickel 297

2.10.6 Iron 2972.10.6.1 Introduction 2972.10.6.2 Symptoms of acute iron intoxication 2982.10.6.3 Laboratory assessment of iron poisoning 298

2.10.7 Copper 2992.10.7.1 Toxicological importance 2992.10.7.2 Clinical significance 3002.10.7.3 Detection possibilities 3002.10.7.4 Copper analysis by atomic absorption 300

2.10.8 The Noble Metals Silver and Gold 3012.10.8.1 General remarks 3012.10.8.2 Toxic effects of silver 3022.10.8.3 Toxic effects of gold 3022.10.8.4 Determination of noble metals in body fluids 302

2.10.9 Zinc 3032.10.9.1 Physiological and toxicological importance 3032.10.9.2 Zinc analysis with atomic absorption 303

2.10.10 Cadmium 3032.10.10.1 Toxicological importance 3032.10.10.2 Analytical possibilities 3052.10.10.3 Cadmium determination by atomic absorption 305

Contents XIX

2.10.11 Mercury 3062.10.11.1 Introductory remarks 3062.10.11.2 Intoxications by metallic mercury 3062.10.11.3 Intoxications by mercury salts 3072.10.11.4 Intoxications by organic mercury derivatives 3082.10.11.5 Minamata disease 3092.10.11.6 Other ,,epidemic" intoxications with

organo-mercurials 3092.10.11.7 Mercury levels in man 3092.10.11.8 Methods for mercury analysis in biological samples . 3102.10.11.9 Choice of analytical method 3112.10.11.10 Mercury analysis by cold vapor atomic absorption . 3122.10.11.11 Differentiation between inorganic and various

types of organic mercury 3142.10.12 Boron 315

2.10.12.1 Toxicological importance 3152.10.12.2 Detection possibilities 3152.10.12.3 Quantitative determinations 316

2.10.13 Aluminium 3162.10.13.1 Introduction 3162.10.13.2 Causes of aluminium intoxication 3172.10.13.3 Clinical manifestations of aluminium intoxication .. . 3172.10.13.4 Analysis of aluminium 3182.10.13.5 Role of aluminium analysis in clinical toxicology . . . 318

2.10.14 Thallium 3192.10.14.1 Toxicological importance 3192.10.14.2 Determination by flame emission 3202.10.14.3 Determination by atomic absorption 3202.10.14.4 Other methods for thallium analysis 321

2.10.15 Germanium and Tin 3212.10.15.1 Toxicological importance of germanium 3212.10.15.2 Toxicological importance of tin 3212.10.15.3 Analysis for germanium and tin in biological samples 3222.10.15.4 Analysis of volatile hydrides by GC-MS^ 323

2.10.16 Lead '. ". 3242.10.16.1 Occurrence and possible function 3242.10.16.2 Toxicity of lead 3252.10.16.3 Indirect screening for lead intoxication 3262.10.16.4 Direct chemical determination of lead 327

2.10.17 Arsenic 3272.10.17.1 General remarks 3272.10.17.2 Sources and toxicity of arsenic 3272.10.17.3 Arsenic in the human body 3282.10.17.4 Analytical possibilities 3292.10.17.5 Determination of arsenic and other

hydride forming elements by GC-MS 3302.10.17.6 Differentiation of individual compounds of arsenic . . 332

XX Contents

2.10.18 Antimony 3322.10.18.1 Occurrence, toxicological and medical importance . . 3322.10.18.2 Analysis 3332.10.18.3 Body levels 333

2.10.19 Bismuth 3332.10.20 Review and Preview 334

Part 3 Toxicological Drug Analysis 345

3.1 Barbiturates (H. Brandenberger) 3473.1.1 Introduction 3473.1.2 Sub-Classes of Barbituric Acids 3493.1.3 The Pharmaceutical Action of Barbituric Acids 3503.1.4 The Metabolic Fate of Barbituric Acids 3503.1.5 Barbiturate Dosages, Body Levels and Toxicity 3523.1.6 Preliminary Screening Tests 352

3.1.6.1 General remarks 3523.1.6.2 Color reactions: the Zwikker test 3533.1.6.3 Immunochemical assays 353

3.1.7 Extractions 3543.1.7.1 General remarks on liquid-liquid extraction 3543.1.7.2 Extraction procedure in a general search for drugs 3553.1.7.3 Extraction of barbituric acids 355

3.1.8 Ultraviolet-Spectrophotometry 3573.1.8.1 UV-spectrophotometric control of extraction 3573.1.8.2 The UV-spectra of barbiturates 3583.1.8.3 Quantification of barbiturates by UV-spectrometry . . . . 359

3.1.9 Chromatographic Separations 3603.1.10 Infrared Spectrophotometry 3603.1.11 Mass Spectrometry 363

3.1.11.1 Positive ion mass spectrometry of barbituric acids . . . . 3633.1.11.2 Negative ion mass spectrometry of barbituric acids . . . 3643.1.11.3 "Dual mass spectrometry" of barbituric acids 365

3.1.12 Concluding Remarks 365

3.2 Benzodiazepines (H. Schiitz) 3693.2.1 Introduction 3693.2.2 Structures of the Benzodiazepines 3723.2.3 Pharmacodynamic Properties of the Benzodiazepines 3733.2.4 Pharmacokinetics of the Benzodiazepines 3733.2.5 Benzodiazepine Doses, Serum Levels and Toxicity 3773.2.6 Screening of Benzodiazepines 378

3.2.6.1 Immunochemical methods 3783.2.6.2 TLC-methods 382

3.2.7 Separation of Benzodiazepines by Chromatographic Techniques . 3863.2.7.1 Thin layer chromatography (TLC) 386

Contents XXI

3.2.7.2 Gas chromatography (GC) 3883.2.7.3 High pressure liquid chromatography (HPLC) 389

3.2.8 Detection of Benzodiazepines by Spectroscopic Techniques 3913.2.8.1 Ultraviolet detection and quantification 3913.2.8.2 Infrared spectroscopy 3913.2.8.3 Mass spectrometry 392

3.2.9 Electroanalytical Methods 394

3.3 Hypnotics and Sedatives Not Belonging to the Classes ofBarbiturates and Benzodiazepines (H. Brandenberger) 3393.3.1 Introduction 3993.3.2 Inorganic Bromides 4003.3.3 Alcohols and Aldehydes 400

3.3.3.1 General remarks 4003.3.3.2 Chloral hydrate 4023.3.3.3 Analytical' detection 4023.3.3.4 Preliminary tests 4033.3.3.5 Derivatives of chloral hydrate 404

3.3.4 Linear Ureides and Amides 4053.3.4.1 Bromoureides 4053.3.4.2 Ureides without bromine 4063.3.4.3 Amides 4063.3.4.4 Analytical detection 4073.3.4.5 Preliminary tests 409

3.3.5 Piperidine-diones and Tetrahydropyridine-diones 4093.3.5.1 General remarks ." 4093.3.5.2 Advantages and disadvantages 4103.3.5.3 Metabolism \ 4113.3.5.4 Detection and dosage of piperidine-2.4-diones and

tetrahydropyridine-2,4-diones 4133.3.5.5 Detection of glutethimide and its metabolites 414

3.3.6 Quinazolinones 4143.3.6.1 General remarks 4143.3.6.2 Analysis for 3-phenyl-quinazolin-4(3H)-ones 415

3.3.7 Hypnotics. Sedatives and Tranquilizers with Urethane Structure . 4173.3.7.1 General remarks 4173.3.7.2 Hypnotics with carbamate structure 4183.3.7.3 Main tranquilizers with carbamate structure 419

3.3.8 Hypnotics with Different Structures 4193.3.9 Concluding Remarks 422

3.4 Anticonvulsants Not Belonging to the Classes of Barbiturates andBenzodiazepines (W. R. Kiilpmann) 4273.4.1 Genera] Introduction 4273.4.2 Carbamazepine 427

3.4.2.1 Introduction 4273.4.2.2 Methods 429

XXII Contents

3.4.2.3 Quality assessment 4313.4.2.4 Pharmacokinetics 4323.4.2.5 Medical interpretation 433

3.4.3 Ethosuximide 4333.4.3.1 Introduction 4333.4.3.2 Methods 4343.4.3.3 Quality assessment 4353.4.3.4 Pharmacokinetics 4353.4.3.5 Medical interpretation 436

3.4.4 Phenytoin 4373.4.4.1 Introduction 4373.4.4.2 Methods 4373.4.4.3 Quality assessment 4383.4.4.4 Pharmacokinetics 4393.4.4.5 Medical interpretation 440

3.4.5 Valproic Acid 4413.4.5.1 Introduction 4413.4.5.2 Methods 4413.4.5.3 Quality assessment 4423.4.5.4 Pharmacokinetics 4433.4.5.5 Medical interpretation 444

3.4.6 Other Antiepileptic Drugs 444

3.5 Neuroleptics (R. Whelpton) 4513.5.1 Introduction 4513.5.2 Pharmacokinetics 4533.5.3 Analysis 4563.5.4 Plasma Concentrations During Therapy and Overdose 470

3.6 Antidepressants (R. A. Braithwaite) 4813.6.1 Introduction 4813.6.2 Pharmacokinetics 4823.6.3 Analysis 4843.6.4 Drug Concentrations in Therapy and in Overdose 489

3.7 Beta-Blocking Drugs (M. S. Leloux) 4953.7.1 Introduction 4953.7.2 Sample Pre-Treatment Methods for Beta-Blocking Drugs 4963.7.3 Gas Chromatography of Beta-Blocking Drugs 4973.7.4 High Performance Liquid Chromatography of Beta-Blocking

Drugs 4983.7.5 Mass Spectrometry of Beta-Blocking Drugs 4983.7.6 Chiral Separation of Beta-Blocking Drugs 4993.7.7 Concluding Remarks 500

Contents XXIII

3.8 Analgesics, Antipyretics and Non-Steroidal Anti-Inflammatory Agents(B. Widdop) ' 5093.8.1 Opioid Analgesics 509

3.8.1.1 Pharmacological properties of opioid analgesics 5093.8.1.2 Toxic effects of opioid analgesics 509

3.8.2 Applications of Toxicological Analyses for Opioid Analgesics .. . 5103.8.2.1 Clinical applications 5103.8.2.2 Forensic applications 511

3.8.3 Individual Opioid Drugs 5113.8.3.1 Heroin (diamorphine) 5113.8.3.2 Morphine 5133.8.3.3 Codeine 5143.8.3.4 Methadone 5153.8.3.5 Propoxyphene 5163.8.3.6 Meperidine (Pethidine) 5183.8.3.7 Diphenoxylate 5193.8.3.8 Fentanyl 5203.8.3.9 Buprenorphine 521

3.8.4 Antipyretic and Non-Steroidal Anti-Inflammatory Agents 5223.8.4.1 Pharmacological properties of antipyretic and

non-steroidal anti-inflammatory drugs 5223.8.4.2 Toxic effects of antipyretic and non-steroidal

anti-inflammatory drugs 5223.8.5 Applications of Toxicological Analyses for Antipyretic and

Non-Steroidal Anti-Inflammatory Drugs 5233.8.6 Individual Antipyretic and Non-Steroidal

Anti-Inflammatory Drugs 5233.8.6.1 Aspirin (acetylsalicylic acid) 5233.8.6.2 Paracetamol (acetaminophen) 5243.8.6.3 Pyrazolan derivatives 5263.8.6.4 Indole derivatives 5273.8.6.5 Propionic acid derivatives 5293.8.6.6 Fenamates 5323.8.6.7 Piroxicam 533

3.9 Antihistamines (H. Brandenberger) 5433.9.1 General Remarks 5433.9.2 Diphenhydramine 5453.9.3 Other Aminoalkyl Ethers 5483.9.4 Antihistamines with Alkylamine Structure 5493.9.5 Antihistamines with Ethylenediainine Structure 5513.9.6 Antihistamines with Piperazine Moiety 553

3.9.6.1 Hydroxyzine 5533.9.6.2 Further members with piperidine moiety 555

3.9.7 Antihistamines with Phenothiazine Structure 5553.9.7.1 General remarks 5553.9.7.2 Promethazine 557

XXIV Contents

3.9.7.3 Recommendations for a search for antihistamines withphenothiazine or aza-phenothiazine structure 558

3.9.8 Concluding Remarks 560

3.10 Volatiles Used and Abused as Anesthetics (H. Brandenberger) 5633.10.1 General Remarks 5633.10.2 Analytical Considerations 566

3.10.2.1 Sampling procedures 5663.10.2.2 Gas chromatographic separations 5673.10.2.3 Identification of separated compounds 5673.10.2.4 Trace detection 571

3.10.3 Some Important Volatile Solvents and Anesthetics 5713.10.3.1 Nitrous oxide 5713.10.3.2 Gaseous hydrocarbons 5723.10.3.3 Volatile chlorinated hydrocarbons (solvents) 5723.10.3.4 Freons 5753.10.3.5 Halogenated hydrocarbon anesthetics 5763.10.3.6 Ethers 5763.10.3.7 Halogenated anesthetics with ether structure 576

3.10.4 Concluding Remarks 577

3.11 Digitalis (= Cardiac) Glycosides (J. Hallbach and H. Vogel) 5793.11.1 General Remarks 579

3.11.1.1 Definition of digitalis glycosides 5793.11.1.2 Chemical structure and physico-chemical

properties 5793.11.2 Uses and Route of Exposure 580

3.11.2.1 Therapeutic use of cardiac glycosides 5813.11.2.2 Absorption, distribution, metabolism, influences

on the pharmacodynamic behaviour, andelimination 581

3.11.3 Toxicity for Man 5843.11.3.1 Mechanism of toxic action 5843.11.3.2 Overdosing 5843.11.3.3 Acute toxic effects 5843.11.3.4 Delayed clinical effects 5843.11.3.5 Biochemical effects 5853.11.3.6 Treatment of overdosing and intoxication 585

3.11.4 Analyses 5853.11.4.1 Determination of digitalis compounds 5853.11.4.2 Determination of cardiac glycosides in blood

and urine by chromatography 5863.11.4.3 Quantification of cardiac glycosides in blood

by immunoassay 5873.11.5 Other Biological Analyses 590

3.11.5.1 Potassium and sodium 5903.11.5.2 Magnesium 591

Contents XXV

3.11.6 Influence of Endogenous Digitalis Like Factors 5913.11.7 General Interpretation of Results 592

3.12 Cyclosporins (D. W. Holt) 5973.12.1 Introduction 5973.12.2 Measurement 5973.12.3 Clinical Problems 6003.12.4 Activity of the Cyclosporins and Their Metabolites 6023.12.5 Other Biological Effects of the Cyclosporins 6043.12.6 Conclusions 605

3.13 Anticoagulants (M. Geldmacher-v. Mallinckrodt) 6093.13.1 General Remarks 6093.13.2 Heparin 610

3.13.2.1 Chemical structure 6103.13.2.2 Uses and route of exposure 6103.13.2.3 Metabolism and elimination 6113.13.2.4 Toxicology 6113.13.2.5 Management of intoxication 6123.13.2.6 Relevant laboratory analyses 612

3.13.3 Coumarin Derivatives 6133.13.3.1 Chemical structure 6133.13.3.2 Uses and route of exposure 6143.13.3.3 Metabolism and elimination 6143.13.3.4 Toxicology 6153.13.3.5 Management of intoxication 6163.13.3.6 Relevant laboratory analyses 617

3.14 Alkaloids (Y. Kuroiwa and T. Yoshida) 6213.14.1 Introduction 6213.14.2 Isolation and Identification of Alkaloids 624

3.14.2.1 Isolation of alkaloids 6243.14.2.2 General qualitative analysis of alkaloids 625

3.14.3 General Qualitative and Quantitative Methods forAlkaloids Analysis 6273.14.3.1 Gas chromatography (GC) 6273.14.3.2 High performance liquid chromatography (HPLC) . . 6283.14.3.3 GC-mass spectrometry (GC-MS) and HPLC-MS . . . 6303.14.3.4 Immunoassay 630

3.14.4 Alphabetical Listing of Toxic Alkaloids - Occurrence.Metabolism and Analysis 6303.14.4.1 Aconitum alkaloids 6303.14.4.2 Belladonna alkaloids, atropine and scopolamine . . . . 6313.14.4.3 Cinchona alkaloids, quinidine and quinine 6333.14.4.4 Colchicum alkaloids, colchicine 6353.14.4.5 Conium alkaloids 6363.14.4.6 Ergot alkaloids 637

XXVI Contents

3.14.4.7 Glycoalkaloids 6393.14.4.8 Nicotinum alkaloids, nicotine 6403.14.4.9 Opium alkaloids 6413.14.4.10 Psilocybe alkaloids 6463.14.4.11 Rauwolfia alkaloids 6473.14.4.12 Strychnos alkaloids 6493.14.4.13 Xanthines 650

3.14.5 Future Perspectives of Alkaloids Toxicology andToxicological Analysis 652

3.15 Stimulants (D. de Boer, T. J. A. Seppenwoolde-Waasdorp andR. A. A. Maes) 6633.15.1 Testing in General 663

3.15.1.1 Introduction 6633.15.1.2 Screening assays in general 663

3.15.2 Cocaine 6653.15.2.1 Introduction 6653.15.2.2 Metabolism and distribution 6653.15.2.3 Detection methodologies 670

3.15.3 Amphetamines 6723.15.3.1 Introduction 6723.15.3.2 Metabolism and distribution 6733.15.3.3 Detection methodologies 675

3.15.4 Conclusions 678

3.16 Designer Drugs (G. L. Henderson) 6853.16.1 Introduction 6853.16.2 The Fentanyls 685

3.16.2.1 Toxicological importance 6853.16.2.2 Chemistry 6863.16.2.3 Metabolism 6873.16.2.4 Blood and tissue levels 6873.16.2.5 Analytical considerations 6883.16.2.6 Extraction methods 6883.16.2.7 Screening methods 6883.16.2.8 Confirmation methods 689

3.16.3 Ring-Substituted Amphetamines 6903.16.3.1 Toxicological importance 6903.16.3.2 Chemistry 6913.16.3.3 Metabolism 6923.16.3.4 Blood and tissue levels 6923.16.3.5 Analytical considerations 6923.16.3.6 Screening tests 6923.16.3.7 Confirmation tests 692

3.16.4 Aminorex Derivatives 6933.16.4.1 Toxicological importance 6933.16.4.2 Chemistry 694

Contents XXVII

3.16.4.3 Metabolism 6953.16.4.4 Blood and tissue levels 6953.16.4.5 Analytical considerations 6953.16.4.6 Extraction methods 6953.16.4.7 Screening tests 6963.16.4.8 Confirmation tests 696

3.16.5 Gamma-Hydroxybutyrate 6963.16.5.1 Toxicological importance 6963.16.5.2 Chemistry 6973.16.5.3 Metabolism 6973.16.5.4 Blood and tissue levels 6973.16.5.5 Analytical considerations 6983.16.5.6 Extraction methods 6993.16.5.7 Screening tests 6993.16.5.8 Confirmation tests 699

Part 4 Blood Level Data 705

4.1 Blood Level Data (D. R. A. Uges) 7074.1.1 Introductory Remarks 7074.1.2 List of Therapeutic and Toxic Reference Values 707

Index 719