41 Poisoning and drug of abuse

Wolf Rüdiger Külpmann

41.1 Introduction

Poisonings are diseases. They can be caused directly by exogenous administration of poison or indirectly by the formation of poisons (e.g., methanol) within the body itself or by exceeding the capacity of the body’s detoxification mechanism (e.g., in paracetamol ingestion). In general, the following applies: ”all things are poison and nothing is without poison; the dose alone makes a thing not poison” (Paracelsus).

Exogenous poisoning may be viewed from a clinical viewpoint (medical or clinical toxicology) or from a forensic medical viewpoint (forensic toxicology).

Exogenous poisoning occur intentionally or unintentionally. Intentional poisoning is brought on by an outside person (e.g., murder or premeditated health impairment by poisoning), or by the affected person himself/herself (e.g., attempted suicide or self inflicted injury). Unintentional poisoning is caused by an outside person or the affected person himself/herself and is the result of carelessness or a random event. Unintentional poisoning occurs at the work place (occupational or industrial poisoning), at home (domestic poisoning) or is caused by therapeutic drugs.

Poisonings are common events. In hospitals with medical and pediatric inpatient services, the proportion of poisonings among all admissions is 5–8%. Approximately 10% of the cases presenting to emergency room departments are patients with acute poisonings. Poisonings more frequently affect younger individuals. Accordingly, the peak in the age distribution of suicidal poisonings due to hypnotics falls into the age range between 20–30 years /1/.

Tab. 41-1 – Substances involved in poisonings under in-patient treatment summarizes the types and prevalence of substances leading to poisonings. The distribution may differ regionally. For instance, poisonings with plant pesticides occur more frequently in rural areas whereas chlorinated hydrocarbons account for a higher percentage in industrial regions.

Tab. 41-2 – Causes of poisonings presents an overview of the main causes of poisonings. A rapid change in the spectrum of the individual drugs is possible, for example, as a result of changes in the statutory regulations within the scope of amendments to laws such as the German Controlled Substances Act.

A different picture is obtained when tobacco and alcohol abuse including their sequelae are taken into account (Tab. 41-3 – Deaths due to poisoning). The number of drug based deaths in 2008 corresponds to approximately 30% of fatalities related to car accidents in the same year.

Improvements in emergency medical care and the development of modern intensive therapy, especially resuscitation techniques, optimized detoxification measures and antidote therapy have contributed to the more favorable prognosis of exogenous poisoning.

Clinical toxicological analysis comprises methods concerned with the qualitative detection and quantitative determination of poisons as well as methods that measure the effects exerted by the poisons.

41.1.1 Qualitative analysis

The main tasks of qualitative analysis is to detect or to rule out the presence of one or several poisons in toxicologically relevant concentrations. The valuable role played by qualitative toxicological analysis is based on studies which show that, on average, the clinical diagnosis made at the time of specimen collection is, in comparison to the results of clinical-toxicological examinations, correct in only 22%, partially correct in 36% and wrong in 42% of the cases /1, 3/. When choosing the specimen, one must be aware of the fact that, immediately after ingestion of the toxic compound, the relevant substance may only be detectable in the blood but not (yet) in the urine.

41.1.2 Quantitative analysis

Quantitative determination of poisons in the blood allows conclusions as to the severity of the poisoning in many cases and is important for the indication for poison elimination therapy, thus allowing effective therapy monitoring.

41.1.3 Methods of detecting the effects exerted by poisons

Indirect evidence of poisons is based on their typical effects in the body such as:

• The formation of CO hemoglobin resulting from carbon monoxide inhalation (also contained in fire gases: Section 15.5.2 – Carboxyhemoglobin)
• The formation of methemoglobin resulting from the effects exerted by substances which cause oxidation of hemoglobin (aniline derivatives, sulfonamides, nitrous gases) (see Section 15.5.1 – Methemoglobin, hemiglobin)
• The inhibition of serum (pseudo) cholinesterase by phosphorus compounds contained in plant pesticides (e.g., parathion) and carbamates
• The prolongation of the prothrombin time, for example by phenprocoumon or superwarfarines (rotenticides)
• The decrease in blood glucose concentration following the administration of anti diabetics such as insulin or oral anti diabetics.

41.1.4 General laboratory analyses

In addition, biochemical and hematological analyses are necessary in poisonings:

• In the form of baseline assessment (Tab. 41-4 – Laboratory program in suspected exogenous intoxication)
• For differential diagnostic purposes in regard to endogenous intoxications (Tab. 41-5 – Laboratory investigations in suspected endogenous intoxications)
• For tracing specific organ damage (Tab. 41-6 – Relation of noxious agents with clinical findings in tissue damage due to acute poisonings)
• For monitoring poison elimination therapy (Tab. 41-7 – Investigations used in elimination therapy monitoring in acute poisonings).

The availability of a well equipped and functional emergency laboratory on a 24-h basis is indispensable in these settings. Typical results of laboratory investigations as seen in some acute poisoning cases are listed in Tab. 41-8 – Typical laboratory findings in acute poisonings.

41.2 Indication for investigations

Suspicion of poisoning is raised by the medical history and by clinical symptoms.

41.2.1 Medical history

The following should be kept in mind:

• Important questions regarding the intake of poison include: what? How much? When? How taken in?
• Answers to these questions are not always available and are often provided reluctantly. They may be incomplete, unreliable or intentionally wrong. They can be influenced by the motives underlying the poisoning or by the clinical condition of the patient. Thus, the information obtained by self medical history or third party medical history in retrospect corresponds to the actually ingested and detected poisons only by approximately 60%.

41.2.2 Clinical symptoms

Main clinical symptoms allow initial diagnostic guidance (Tab. 41-9 – Main clinical symptoms in poisonings related to drugs).

Poisoning should generally be considered in:

• All unconscious patients, especially in those less than 50 years of age
• Disease entities whose symptoms resemble those of a certain type of poisoning
• Patients with a conspicuous odor on the breath, often ethanol
• All patients who present with sudden vomiting and/or diarrhea
• All diseases starting out with circulatory compromise
• Unexpectedly occurring arrhythmias without any indication of the presence of cardiac disease
• Conspicuous (bruised) skin changes occurring at certain sites in comatose patients found after a longer period of time, as seen, for example, in severe poisonings with hypnotics
• The event of simultaneously occurring acute illness in several individuals or concomitant illness of domestic animals
• The fact that the patient’s medical history suggests the intake or administration of a poison
• Patients where there is no indication of preceding trauma
• Small children with sudden onset of illness
• Work related exposure to toxic products
• Conditions associated with the development of smoke and fumes or in the case of exposure to wild fires (i.e., toxic gases)
• Confused patients unable or unwilling to provide any information
• Patients known to have remarked on the weariness of living or known to have mentioned suicidal intentions
• The event that empty medication bottles or other bottles and containers with suspicious contents were found in the surroundings of the patient
• Every case with unclear symptoms, especially in children.

Ethanol: quantitative measurement of blood ethanol levels should be performed whenever underlying acute poisoning is suspected. Ethanol is concomitantly involved in many instances of poisoning. Ethanol and drugs are the sole or partial cause of trauma in many cases. Therefore, intoxication involving these substances must always be ruled out in victims of accidents.

41.2.3 Selection of investigations

The selection of toxicological investigation methods can be based on the type of poisoning if symptoms are sufficiently pronounced. This condition is met in approximately 65% of cases. In numerous cases, however, two poisons are involved, resulting in clinical symptoms that are difficult to diagnose.

Ethanol often represents the second poison. In approximately 17% of cases, three or more poisons are involved. Therefore, the spectrum of investigations should be sufficiently wide and should always include the determination of ethanol /8/. A summary of typical symptoms in poisoning with certain therapeutic drugs is presented in Tab. 41-10 – Typical poisonings with therapeutic drugs. Examples of clinically important poisonings not related to drugs are listed in Tab. 41-11 – Important poisonings not related to drugs.

Intoxications with poisons featuring a delayed onset of their effect (as is the case, for example, with amanitin, methanol, paracetamol, paraquat and salicylate) are found to be associated with a high mortality rate, thus calling for corresponding toxicological investigations and immediate treatment even in the absence of clinical symptoms and before clinical and/or laboratory findings are available.

If no guiding information or symptoms exist as to the type of the underlying poison in suspected cases of acute intoxication, a systematic search by laboratory toxicological investigations is necessary instead of a targeted request of certain single analyses.

41.3 Method of determination

The methods for the detection and determination of poisons in body fluids and tissues originate from the field of forensic toxicology. After specimen preparation, appropriate detection and determination methods are used depending on the relevant poison. The following methods are of special importance /10, 11, 12, 13/:

• Preliminary color tests
• Immunoassay
• Thin layer chromatography
• Gas chromatography with an N- and P-sensitive or a mass-specific detector (MSD)
• Gas chromatographic vaporization analysis (headspace GC) for the detection of volatile solvents
• High performance liquid chromatography (HPLC)
• Liquid chromatography tandem mass spectrometry (LC-MS/MS)
• Atomic absorption spectrophotometry (AAS) for the determination of heavy metals
• Spectral photometry (UV/VIS).

Further methods which may prove to be important include chromometric gas analysis, ion-selective electrode (ISE) potentiometry for the determination of bromide, cyanide or fluoride, fluorescence spectral photometry, infrared spectroscopy and voltammetry (e.g., for the determination of thallium).

Simple toxicological methods which can also be performed in the emergency laboratory of a larger hospital are listed in:

• Tab. 41-12 – Toxicological screening program whereby 80% of the acute poisonings occurring in the emergency unit can be detected
• Ref. /14, 15/.

41.4 Specimen

In view of the large number of possible poisons and the large number of circumstances under which toxicological investigations may become necessary, it is difficult to provide generally applicable specifications as to the most appropriate specimen. In case a basic toxicological investigation is to be conducted in an adult patient, at least the following specimens need to be provided:

• Heparin anticoagulated blood: 10 mL
• Urine: 50–100 mL
• Stomach contents (if available): 50–100 mL

Stomach contents refer to vomited matter, aspirated stomach contents or the first portion of the gastric lavage fluid.

Specimen collection should be carried out before initiation of treatment or the administration of drugs:

• Drugs may interfere with toxicological analyses in many ways
• The use of hyperbaric oxygen leads to rapid dissociation of CO hemoglobin in the blood, thus making the diagnosis of CO poisoning impossible.

Specimens containing a significant concentration of volatile compounds must be placed in tight containers and kept separate, both during transport and storage, from other biological samples in which these compounds may possibly occur at a low concentration.

For blood ethanol determination, blood collection must be performed without using alcohol disinfectant and, during transport, the blood sample needs to be sealed airtight.

41.4.1 Blood sample for the detection of addictive substances

Due to the high prevalence of HIV infection and viral hepatitis in drug users, special care must be taken during blood collection to ensure strict adherence to hygiene regulations.

41.4.2 Urine sample for the detection of addictive substances

The urine sample should be collected under supervision. In many cases, patients try to manipulate the sample by:

1. Diluting it with water (or previous excessive drinking)

2. Adding interfering substances such as toilet cleaner

3. Adding methadone

4. Slipping in a brought sample.

Manipulation can be detected by:

ad 1) Determination of the creatinine concentration, osmolality or specific density of the sample

ad 2) pH measurement, detection of chromate and nitrite

ad 3) Detection of the methadone metabolite EDDP in the urine instead of methadone. Since EDDP is not easy to obtain, it cannot be added to the urine after urination and therefore is a reliable indicator for methadone consumption

ad 4) Taking the temperature. A brought (false) sample is colder than fresh urine (Tab. 41-13 – Properties of fresh urine).

New tips on how to (allegedly) manipulate drug evidence continuously appear on notorious sites on the Internet. Reagents for the detection of adulterant substances which allow testing for interference free analysis are commercially available.

41.4.3 Saliva sample for the detection of addictive substance

Saliva can easily be obtained under supervision, thus making it easier to rule out manipulation than in urine sampling. The saliva sample can be examined, evaluated and documented using a portable analyzer unit with an integrated camera.

41.4.4 Hair sample for the detection of addictive substances

The detection of drugs in hair is used in forensic medicine. Since addictive substances are continuously incorporated into hair, sectional examination of a bush of hair provides insight into the drug abuse of the tested individual during the past weeks and months.

41.4.5 Serum sample for the detection of addictive substances

Contrary to the above-mentioned specimens, blood collection is an invasive method which the individual to be tested does not have to tolerate. However, it allows to maintain a continuous chain of custody more easily than in urine sampling. As a rule, the serum level of a substance reflects the current poisoning situation more accurately than the urine concentration. On the other hand, a substance is usually detectable in urine for a longer period of time than in blood due to the high concentration and the larger volume of the urine sample. Most immunochemical methods are only approved for urinalysis.

41.4.6 Test request form

The accompanying laboratory test request form should include the following data:

• Name and age of the patient
• Type and amount of specimens
• Time of sample collection
• Level of urgency of the requested investigation
• Analytical concerns
• Data from the medical history concerning the intake of poison
• Main clinical symptoms
• Therapeutic drugs taken by the patient and premedication
• Tentative diagnosis
• Telephone number for communication of the findings.

41.5 Toxicological investigations in acute poisoning

Medical care of patients suspected to have acute poisoning usually starts with establishing a tentative diagnosis and maintaining functions vital to life. Further patient outcome may depend on how close the tentative diagnosis is to the final one as well as on how much time is required to establish the final diagnosis and to initiate most adequate treatment /16/. The results of clinical toxicological investigations are very important for establishing the tentative diagnosis as well as for arriving at the final one.

Since a toxicological laboratory is usually not available on a 24-h basis within a hospital setting, clinical toxicological investigation often involves two steps as agreed with the person responsible for carrying out the laboratory tests.

41.5.1 Screening in the hospital laboratory

Acute poisonings occurring more frequently in the emergency area of the hospital and their medical implications should guide the composition of screening programs consisting of readily available (i.e., anytime) rapid tests and simple determinations. The necessary analyses should be selected by the attending physician in consultation with the person responsible for carrying out the laboratory tests, taking into account the medical history, main clinical symptoms and type of poisoning. Refer to:

• Tab. 41-9 – Main clinical symptoms in poisonings related to drugs
• Tab. 41-10 – Typical poisonings with therapeutic drugs
• Tab. 41-11 – Important poisonings not related to drugs.

In acute poisonings, on average 5–6 of the analysis methods in the toxicological screening program are requested per case (Tab. 41-12 – Toxicological screening program whereby 80% of the acute poisonings occurring in the emergency unit can be detected). The performance of these tests necessitates a mean period of 30 min. of direct personnel time per poisoning case.

41.5.2 Further toxicological investigations

Further qualitative and quantitative toxicological investigations are performed in toxicological laboratories as soon as possible using the methods listed in Section 41.3 – Method of determination in order to confirm and supplement toxicological screening. Further and more detailed toxicological investigation is only urgently necessary in 10–20% of patients admitted to the hospital with suspected acute poisoning, for example, if:

• The clinical presentation of the poisoning is severe
• Poison elimination or antidote therapy are under consideration
• There is significant discrepancy between the results of the toxicological screening and the clinical picture
• No explanation can be found for the condition of the patient by clinical examinations and the results of the toxicological screening
• Additional forensic concerns are present.

41.5.3 Specific investigations in life threatening situations due to poisoning

If there are definite reasons to suspect poisoning with any of the substances listed in Tab. 41-14 – Examples of poisonings which may be life threatening and require dedicated medical care, immediate and specific investigation must be conducted since the result of the analysis is essential for the (continued) administration of an antidote. This is true especially if there is a prolonged latency phase between poison intake and the occurrence of clinical symptoms. Refer to Section 41.2.1 – Medical history.

41.5.4 Systematic search for poisoning by toxicological analyses

A systematic search for poisoning by toxicology laboratory investigations is necessary if general suspicion has been raised concerning the presence of possible poisoning yet there are no indications regarding the type of poison involved. The diagnostic strategy is presented in Fig. 41-1 – Systematic toxicological analysis procedure.

41.6 Assessment of toxicological results

The assessment of toxicological results requires close cooperation between the laboratory and the clinician. In general, toxicological results should only be interpreted in conjunction with the clinical picture. Pharmacokinetic and toxicokinetic aspects must be taken into account.

The recommendations of the German Medical Association regarding quality assurance are to be observed /38/. Inter laboratory surveys regarding external quality control are performed by accredited institutions.

41.6.1 Acute poisonings

41.6.1.1 Qualitative investigations

Blood

The negative result of toxicological investigation in the blood rules out with high probability the presence of underlying acute poisoning with that particular substance. If a poison is detected in the blood, the probability that this substance exerts a toxicological effect is generally higher than if it is found in the urine only.

Urine

In the case of negative results of urinalysis and suspected acute intoxication, one has to be aware of the fact that the poison may not yet have been excreted into urine immediately after intake. Moreover, it has to be considered that metabolites may not be detected by a some methods (e.g., immunoassay) and the excretion rate may be reduced in more acid or alkaline urine: more ionized compounds reveal poorer tubular reabsorption and thus increased excretion. Acid compounds (e.g., phenobarbital or salicylate), are excreted more in alkaline than in acid urine. Alkaline compounds (e.g., morphine) on the contrary, are excreted at higher rates given a low urinary pH. However, the role of urinary pH regarding the excretion rate has been discussed controversially.

In severe poisonings involving therapeutic drugs, the quantity of non metabolized (i.e., parent) substance excreted in the urine almost always is sufficiently high for detection by qualitative analysis. In milder cases of poisonings, qualitative urinalysis for the parent substance can give a negative result and further testing has to be performed to include the detection of metabolites and conjugates as seen, for example, in conjunction with benzodiazepines /17/.

Positive results of qualitative toxicological screening tests are of significant value for confirming the tentative clinical diagnosis of acute poisoning or for determining whether a patient has taken in several poisons.

The interaction between several poisons simultaneously present within the body may significantly alter the clinical picture of the intoxication due to summation, potentiation or subtraction effects exerted by the individual components. Directly opposite effects, for instance, are observed if amphetamines and benzodiazepines or barbiturates and strychnine are taken in simultaneously. On the other hand, barbiturates and ethanol, for example, exert a similar, additive effect /1/.

If, in the case of severe intoxications, several poisons are detected and it is not possible based on the medical history and the clinical presentation to identify the predominant poison, quantitative poison determination must be conducted as soon as possible.

41.6.1.2 Quantitative investigations

In general, the same analytical criteria that are valid in clinical chemistry (e.g., precision, accuracy, detection limit, specificity) are valid for quantitative measurements in toxicology.

The following reference intervals of a substance in the blood or serum should be available for the transverse assessment of a quantitative toxicological analysis result:

• Intake within the physiological range (no exposure) (reference interval for a reference population of defined health)
• Intake within the therapeutic range
• Intake within the toxic range
• Intake within the lethal range.

For guideline levels for:

• Drugs within the therapeutic range, refer to Tab. 40-2 – Therapeutic ranges
• Drugs within the toxic range, refer to Tab. 41-15 – Specific poisonings
• Industrial poisons, refer to Tab. 41-16 – Examination of workers exposed to industrial poisons.

For longitudinal assessments and plausibility control, one should keep in mind that in acute poisoning the occurrence of extreme values must be anticipated at all times; in every single case, such extreme values require thorough, joint assessment made by the clinician and the laboratory.

In poisonings without complications, there is often good correlation between the quantity of poison taken in, the blood concentration of the poison, as well as the duration and intensity of the toxic effect.

Unexpectedly low poison concentrations may be found in the blood if:

• A patient is examined soon after the poison was taken in and poison absorption has not or has only partially begun
• A drug withdrawal syndrome is present
• Mixed intoxication is present
• Metabolites which escaped detection are responsible for the clinical picture
• Other additional causes are present accounting for the patient’s condition, such as intracranial pressure elevation in the case of subdural hematoma (e.g., if a slightly drunk person fell).

High poison concentrations in the blood are found in severe acute poisonings and in patients who suffer from drug addiction and show comparably mild symptoms due to tolerance development.

Poison elimination therapy is indicated if, as a prerequisite, a high blood concentration of the poison is found corresponding to the severity of the poisoning (Tab. 41-17 – Threshold levels requiring hemoperfusion).

The efficacy of poison elimination measures can be assessed by repeatedly determining the blood levels of the poison and by calculating its clearance and its elimination half life. The half life determined in acutely poisoned patients may deviate significantly from the known standard half life of the therapeutic drugs due to the presence of other drugs or of underlying pathological conditions such as shock and hepatic or renal failure.

41.6.1.2.1 Paracetamol

Paracetamol (acetaminophen) poisonings may cause severe liver cell damage with acute hepatic failure /21/. Therapy with N-acetyl cysteine which is life saving in many cases is indicated if the measured blood concentration of the poison, before treatment, falls within the hepatotoxic range in relationship to the point in time of ingestion (Fig. 41-2 – Semilogarithmic plot for prognosis of paracetamol intoxication). See also Fig. 18.6-4– Biochemical effects of ethanol.

41.6.1.2.2 Salicylate

In salicylate poisoning, as in paracetamol intoxication, there is a correlation between serum concentration and the severity of poisoning taking into account the point in time of ingestion (Fig. 41-3 – Salicylate concentration depending on the time of ingestion and influence on the severity of intoxication).

41.6.1.2.3 Cyanide

Cyanide is an extremely toxic compound and can, even in low concentrations, cause blockage of cellular respiration by binding to Fe³⁺ of the cytochrome oxidases (Tab. 41-18 – Cyanide concentration in the blood). Alkaline cyanides are used for producing/cleaning noble metals. Organic cyanides include, for example, acetonitrile and plant cyanogenic glycosides (e.g., in seeds of prunus varieties: bitter almond, apricot) and sodium nitroprusside which is used for treating high blood pressure. Hydrocyanic acid is used for rodent control in ships and warehouses. It is contained in fire gases and in tobacco smoke. Known as ”Zyklon B”, it was used in the Holocaust.

Cyanide is detected using test tubes or test strips and determined by absorption spectrometry or potentiometry. If the patient was exposed to fire gases, cyanide as well as CO hemoglobin must be determined.

Antidotes to cyanide include: sodium thiosulfate, hydroxocobalamin and methemoglobin forming agents (e.g., 4-dimethylaminophenol).

41.6.1.2.4 Ethanol

In Germany, 9.5 million individuals consume ethanol in a way which is harmful to health; 1.3 million individuals are considered to be alcohol addicts (Tab. 41-3 – Treatment cases in the hospital because of psychotropic substances 2017). Binge drinking has drastically increased in adolescents in recent years: 9500 young people had to be admitted to hospitals as inpatients in the year 2000 and 23,165 in 2007. Due to alcohol abuse during pregnancy, 10,000 disabled children are born each year, including 4000 showing all symptoms of fetal alcohol syndrome. The number of children suffering from alcohol induced prenatal damage is twice as high as that of children born with trisomy 21 /35/.

With ethanol there is a clear relationship between the amount of alcohol consumed, blood alcohol concentrations, and the effects on driving performance /42/.

Poisoning

Tab. 41-19 – Stages of ethanol intoxication provides guidelines regarding the assessment of blood alcohol concentrations. Numerous individual physical and mental factors such as, for example, age, gender, physical constitution, fatigue, ethanol tolerance, hypersensitivity to ethanol, initial rising phase and elimination phase have an impact on the severity of clinical symptoms. Similar symptoms as in ethanol poisoning may be generated by other causes, for example, the effect of therapeutic and illicit drugs, metabolic decompensation or head trauma. The effect of therapeutic drugs can be enhanced by ethanol. Illicit drugs and alcohol are often consumed in conjunction.

Determination of ethanol levels in the blood or serum is indispensable for assessing alcohol intoxication /22/. The serum ethanol concentration (mmol/L) is converted into blood alcohol concentration (BAC) (g/kg corresponding to per mil) using the following formulas:

Legend

C_B: Blood ethanol concentration (g/kg)

C_H: Serum ethanol concentration (g/L)

C_S: Serum ethanol concentration (mmol/L)

Ds: Serum density (1.026 g/kg)

Mr: Relative molar mass of ethanol (46.07)

w: water distribution coefficient between serum and blood (1.20)

41.6.1.2.5 Carbon monoxide

For the dependence of clinical symptoms on the COHb concentration, please refer to Section 15.5.2 – Carboxyhemoglobin (COHb).

41.6.1.2.6 Methemoglobin forming agents

See Section 15.5.1 – Methemoglobin.

41.6.1.2.7 Methanol

Methanol poisoning is caused by the (inadvertent) consumption of cleaning agents (e.g., windshield washer fluid transferred into a water bottle), industrial alcohol denatured with methanol or adulterated alcoholic beverages. Severe methanol poisoning can cause blindness and death. It results from formic acid, a methanol metabolite, and is characterized by metabolic acidosis and hyper osmolality. Like other volatile alcohols and ketones, methanol is determined by gas chromatographic vaporization analysis. For specific treatment, ethanol and fomepizole are used to delay the formation of formic acid (Tab. 41-14 – Examples of poisonings which may be life-threatening and require dedicated medical care).

41.6.1.2.8 Plants

Severe poisonings by plants are rare, but are often suspected in children. Important poisonous plants in Germany are listed in Tab. 41-20 – Poisonous plants and trees in Germany (selection).

The diagnosis is usually based on macroscopic and microscopic characteristics. In addition, thin layer chromatography, HPLC, GC-MS and LC-MC/MS are used for identification in special cases. Depending on their cross reactivity, cardiac glycosides can be detected using digoxin or digitoxin immunoassays.

The use of alleged drugs from traditional Chinese medicine can cause poisonings for the following reasons:

• Confusion of names and ambiguity of designations
• Addition of undeclared high potency drugs
• Heavy metal contamination
• Microbial contamination (aflatoxins).

Poisoning by plants in Germany refer to Reference /41/.

41.6.1.2.9 Mushrooms

Most cases of severe mushroom poisonings in Germany are caused by death caps (Amanita phalloides) which are confused with champignon mushrooms (Agaricus bisporus). Toxicological investigation is based on macroscopic and microscopic characteristics and on the determination of the extremely toxic α-amanitin by immunoassay. If mushroom poisoning is suspected, treatment (symptom based and using silibinin) must start immediately and should not wait for laboratory findings or symptoms (due to severe gastroenteritis followed by hepatolysis) which typically occur after a latency period. Poisonings by other mushrooms do not play a major role in Germany. Gastrointestinal disorders shortly after a mushroom meal are usually caused by bacterial contamination of the dish.

41.6.1.2.10 Poisonous animals

Bees and wasps are considered to be the most important poisonous animals in Europe, although their stings usually do not result in life threatening poisoning. In sensitized individuals, however, a single sting can cause an immediate allergic reaction, sending them to anaphylactic shock which may ultimately lead to death. In the most general sense, toxicological laboratory investigations do not play a role regarding animal venoms because the venoms occur in very low concentrations and usually consist of numerous different proteins. As a rule, the diagnosis is based solely on the identification of the animal.

41.6.2 Brain death

The differential diagnosis between intoxication induced coma and irreversible loss of cerebral function due to severe poisonings and other causes may during the course of events become problematic since in both conditions flat lines may occur in the EEG.

Prior to terminating the maintenance of vital functions in severely brain damaged patients, the presence of drugs which might cause depression of CNS function (e.g., barbiturates, benzodiazepines, tricyclic antidepressants) should therefore be excluded by qualitative or quantitative blood determination. This also applies to drugs which are often administered as part of the treatment in these patients /23/.

41.6.3 Chronic poisonings

Chronic poisonings are observed, for example, in individuals who are regularly exposed to the effects of industrial poisons. Individuals working in such environments are per regulations subject to regular check-ups regarding their health status. A listing of toxic working materials, the usually scheduled toxicological and other investigations as well as the permissible concentrations in the blood and urine are presented in Tab. 41-16 – Examination of workers exposed to industrial poisons.

Carbon monoxide

Chronic exposure to carbon monoxide can cause numerous neurological symptoms /24/. Related to the total blood hemoglobin concentration, blood CO hemoglobin levels above 10% as measured by spectrophotometric methods are considered to be definitely pathological. In heavy smokers, blood CO hemoglobin levels up to 10% may be found.

Aluminium

Excessive aluminium accumulation in hemodialysis patients receiving oral Al(OH)₃ as a phosphate binder may lead to pronounced structural bone changes as well as lethal encephalopathy /25/. Continuous monitoring of these patients by means of aluminium determination in serum and dialysis fluid is advisable (Section 11.2 – Aluminum).

41.6.4 Dependence on addictive substances

Dependence on addictive substances can be described as a condition which results from the interaction between a pharmacological drug and the body and which is characterized by certain behavior patterns and reactions. These reactions include the urge to consume the addictive substance periodically or continuously in order to experience its mental effects or avoid the unpleasant effects of its absence.

Important addictive substances are listed in Tab. 41-21 – Recommendations for the detection of addictive substances /27/.

Changes in the drug scene can be assessed based on the number of hard drug users as first time offenders (Tab. 41-22 – Hard drug users as first time offenders).

As a rule, the detection of popular addictive substances is initially performed by immunoassay in the urine (drug screening) (Tab. 41-21). Positive results require verification analysis using a different method with a higher specificity and sensitivity than screening, for example gas chromatography mass spectrometry or liquid chromatography tandem mass spectrometry (LC-MS/MS). It should be noted that some addictive substances are difficult or even impossible to detect by immunoassay.

41.6.4.1 Amphetamines/stimulants

This group comprises amphetamines and methamphetamines as well as so-called designer drugs (Ecstasy) such as:

• Methylenedioxyamphetamine (MDA)
• Methylenedioxymethamphetamine (MDMA)
• Methylenedioxyethylamphetamine (MDEA)
• Methylbenzodioxazolylbutanamine (MBDB)
• Benzodioxazolylbutanamine (BDB)
• p-methoxyamphetamine (PMA)
• p-methoxymethylamphetamine (PMMA).

These substances are often consumed on techno parties and can cause lethal hyperthermia. Hepatopathy, coagulopathy, rhabdomyolysis, renal failure and arrhythmia have also been observed. The recently increasingly popular PMA and PMMA are characterized by a delayed onset of effect. Users who are unaware of this delay and mistake it for ineffectiveness consume another dose which may lead to life threatening poisoning. In many cases, the immunoassays used for detecting this substance group in the urine are only sensitive to the calibration substance (e.g., amphetamine or methamphetamine) and may show very low analytic sensitivity to designer drugs.

This also applies to:

• Pep pills such as 1-benzyl piperazine which is legally available as anthelmintic. It is chemically related to amphetamine, is said to have Ecstasy-like effects and can cause cerebral seizures.
• Khat (Catha edulis) is a shrub the fresh leaves of which are known and dealt with as ”Khat”. Chewed or kept inside the mouth for a while, the leaves release amphetamine-related substances (methcathinone, pseudoephedrine). The consumption of ”Khat” is widespread in East-Africa and Yemen and among immigrants from those areas.

It is a general problem that new compounds which differ minimally from amphetamines in regards to chemical properties are created in increasingly shorter periods. Their effects are of similar quality and may even be more potent than those of listed illicit stimulants. A detailed systematic pharmacological analysis of these substances regarding their risks and adverse and long term effects of their use is usually not available or possible. These substances are freely available as long as they are not explicitly banned. At March of 2011, this applies to 16 compounds in Europe and 51 in Japan (International Narcotics Control Board of the United Nations). A typical example of this is mephedrone (4-methyl-N-methcathinone). The compound was of major significance because it was legally available as ”fertilizer” in Switzerland via the Internet until its ban on December 01, 2010. In Germany, the substance has been banned since the beginning of 2010. The options for detection of such compounds by the established amphetamine immunoassay cannot be assessed and must be evaluated on a case-by-case basis (see also THC/cannabinoids).

41.6.4.2 Cannabis

Cannabis is increasingly used both medically and recreationally. With widespread use, there is growing concern about how to identify cannabis impaired drivers /43/. Cannabis contains 9-tetrahydrocannabiol (THC) 5.9% or 13.4%. There is no relationship between THC concentrations measured in blood, oral fluid or breath and standard deviation of lateral position (SDLP) and car following (coherence) over a 5-hour period /43/.

41.6.4.3 Barbiturates/methaqualone

Since barbiturates have been included in the German Controlled Substances Act, their importance in the drug scene has declined markedly. The same applies to methaqualone. The detection limit of immunochemical screening tests for barbiturates in urine varies considerably depending on the different barbiturates. The urinalysis for some barbiturates which are completely metabolized in the body will have negative results.

41.6.4.4 Benzodiazepines

In Germany, approximately 1.4 million adults, including 70% women, are considered to be addicted to therapeutic drugs. Approximately 1–2% of the adults take benzodiazepines for a year or longer on a regular basis and 10–17% take them at least once a year /35/. About 50 different benzodiazepines are available at present. Most of them are only detectable based on their degradation products and conjugates in urine. It is therefore recommended to hydrolyze the urine before the immunoassay screening test in order to improve the detection limit. However, compounds such as flunitrazepam which are already effective in low concentrations may escape detection despite hydrolysis.

The detection limit of screening tests does not correlate with the potency of the individual benzodiazepine but depends on the chemical affinity of the antibody to the relevant epitope. The detection period is influenced by the elimination rate of the relevant benzodiazepine and ranges between 2–4 h (midazolam) and 40–250 h (flurazepam).

41.6.4.5 Buprenorphine

This substitution agent for the treatment of heroin addicts is detectable in urine by a specific immunoassay.

Cocaine: the body rapidly converts cocaine to benzoylecgonine, ecgonine methylester and ecgonine. Screenings for the detection of cocaine in urine use immunoassays which either exclusively and specifically determine benzoylecgonine or concurrently determine cocaine.

Immunoassays which exclusively determine benzoylecgonine should generally be preferred because benzoylecgonine is an indicator of the addictive substance’s passage through the body, whereas cocaine can also be added to the urine retrospectively.

41.6.4.6 Dextromethorphan

This freely available antitussive is no longer considered an opioid. It has similar pharmacodynamic properties as LSD, ketamine or psilocybin and cannot be detected by opiate immunoassay. The prevalence of dextromethorphan abuse is not known, but a withdrawal and dependence syndrome has been described.

41.6.4.7 γ-Hydroxybutyric acid (GHB)

This compound is referred to as Liquid Ecstasy in the drug scene. Ingested in low doses, it has similar effects as stimulants (e.g., euphorization and increased stimulation). It has often been added to beverages as an incapacitating drug (”knockout drops”), for example, in discotheques. It is detectable in the blood or urine only for a short time using GC-MS and might be found in hair later on. γ-Butyrolactone (solvent) and 1,4-butanediol (plasticizer) are rapidly converted to GHB, thus having indirectly the same effect as GHB.

41.6.4.8 Ketamine

Ketamine is chemically related with phencyclidine. It is used medically in anesthesia as an anesthetic and analgesic. Ketamine is abused as a hallucinogenic and probably also as an incapacitating drug. The immunoassay for phencyclidine detection can yield a positive result in the presence of ketamine. Specific detection is performed using HPLC or GC-MSD.

41.6.4.9 LSD (lysergic acid diethylamide)

LSD is a hallucinogenic and psychedelic substance. It can be specifically determined in urine by immunoassay.

41.6.4.10 Mescaline

This psychedelic drug obtained from the peyote cactus has been popular in Mexico and the Southwestern United States for a long time. The substance is detectable by GC-MS. 4-Bromo-2,5-dimethoxyphenethylamine (street name: Venus) is related to mescaline and has a similar effect.

41.6.4.11 Methadone

Methadone is an opioid used for substitution treatment in heroin addicts. In most cases, methadone specific immunoassays are used for direct detection. In addition, an immunoassay is available which specifically detects EDDP (a methadone metabolite produced in the body) in urine. Detection by 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) immunoassay does not allow pretended intake of the substitution agent by retrospectively adding methadone to the urine (see concomitant use under Section 41.6.4.12).

41.6.4.12 Nicotine/tobacco

Nicotine is usually taken in by smoking tobacco (16 million smokers in Germany). However, it is also used as a pesticide in agriculture and is contained in transdermal patches. Nicotine intake can be detected by immunoassay based on urinary excretion of the nicotine metabolite cotinine. Determination of nicotine and cotinine is also possible using HPLC and GC-MSD.

Smoking is harmful not only due to the vasoconstrictive effect of nicotine and its addiction potential but also because of numerous other compounds such as benzene, cyanide, heavy metals and 40 carcinogenic substances thought to cause 40% of all cancer deaths. They are contained in the side stream smoke and, therefore, are also harmful to passive smokers (Tab. 41-3 – Treatment cases in the hospital because of psychotropic substances 2017). The above mentioned toxicants promote the development of chronic bronchitis and cause pregnancy complications /35/.

41.6.4.13 Opiates

In Germany, 120,000–150,000 individuals are thought to be addicted to heroin. Heroin has recently been approved for substitution in special cases. Heroin (diacetylmorphine, diamorphine) is rapidly metabolized to 6-acetylmorphine and, more slowly, to morphine. Besides from heroin, however, morphine can also be metabolized from codeine and may even be detectable in urine in some cases following the consumption of poppy-seed cake. Opiate dependence screening uses the immunoassay for the detection of morphine and morphine derivatives. A positive opiate test result only substantiates the initial suspicion of heroin abuse and should be verified using a specific immunoassay for the detection of 6-acetylmorphine. As in all immunoassays for the detection of addictive substances, adequate reliable evidence is required and can be provided, for example, by gas chromatography mass spectrometry. The morphine/opiate immunoassay does not detect opioids such as dextropropoxyphene, fentanyl, methadone, oxycodone, pentazocine, pethidine (meperidine), tilidine and tramadol.

Concomitant use in substitution treatment of heroin addicts

Treatment must be closely monitored by surprise urine analysis. The concomitant use of other substances such as flunitrazepam in addition to methadone is common and can lead to severe poisoning and death. On the other hand, methadone intake for substitution treatment must be monitored to prevent the patient from stockpiling and selling on the drug in order to purchase, for example, heroin.

The application of phamacogenetics in the management with opioids has the potential to tailor pain medication based on individual’s genetic background. A review /26/ presented a shortlist of candidate genes that merit further study.

41.6.4.14 Phencyclidine

This compound has a sedative and analgesic effect. Whereas abuse by smoking phencyclidine in cigarettes is relatively common in the United States, no significant abuse has been found in Germany. A specific phencyclidine immunoassay is available.

41.6.4.15 Psilocybin/psilocin

These hallucinogens are taken in by eating certain mushrooms such as Psilocybe mexicana. They are detected using HPLC or GC-MSD.

41.6.4.16 THC/cannabinoids

Cannabinoids are the most common addictive substances besides nicotine and ethanol. In Germany, they are used by 600,000 individuals to an extent harmful to health /35/. The most important active ingredient inhaled by smoking hashish or marihuana is tetrahydrocannabinol (THC). The body metabolizes THC to form various compounds which are excreted in urine. The most important metabolite, 11-nor-Δ9-THC-9 carboxylic acid, is also the primary target of the immunoassay antibodies. Detection is possible for only 1–2 days in singular abuse and for several weeks in chronic abuse. Passive smokers usually show negative test results /40/.

Since about 2008, herbal blends (as well as bath salts or fertilizers), initially known as ”Spice” and later, since 2010, as Lava red, have been offered on the Internet. They contain undeclared cannabimimetic compounds such as JWH-018 and CP-47-497 (Spice) or JWH-122 (Lava red). These compounds are more potent than hashish and not detectable by the THC immunoassay. The cannabimimetic compounds in Spice as well as JWH-122 and another approximately 100 related substances have already been banned; however, in a further step, the German Controlled Substances Act should be amended accordingly as soon as possible.

41.6.4.17 Tricyclic antidepressants (TCA)

Immunochemical screening tests for the detection of TCA in serum are commercially available. They detect not only the TCA themselves, but also their metabolites as well as some tetra cyclic antidepressants and phenothiazines. Therefore, the immunoassays only substantiate an initial suspicion to be verified by other methods (e.g., gas chromatography analysis). Immunochemical methods are not suited for the quantitative determination of an unidentified TCA.

41.6.5 Significance of the detection of addictive substances

The detection and determination of addictive substances in the blood or urine of patients is important for:

• Providing evidence of addiction
• Recognizing withdrawal syndrome
• Monitoring withdrawal treatment
• Excluding illicit concomitant use of other substances in case of substitution therapy (e.g., as seen in heroin addicts enrolled in methadone programs).

Patients with strong addiction usually reveal high blood levels of the addictive substance although toxic symptoms need not be present because of this. High serum concentrations resulting in coma in non-addicted individuals are often measured in addicts who are but sleepy. Extremely high blood concentrations are usually required to cause coma in an addict /16/.

41.6.6 Withdrawal syndromes

In sedative and hypnotic drug abuse, withdrawal syndromes usually start two days after the last drug intake, in ethanol abuse after 1–3 days and in benzodiazepine abuse typically 6–7 days after the last dose. Negative detection of the addictive substances in the blood is typical for the diagnosis of this condition /16/ which tends to be associated with severe mental and physical alterations in affected patients. Minimal quantities of the addictive substance may be detected in the blood in underlying strong addiction.

41.6.7 Monitoring of withdrawal treatment

Withdrawal treatment in addicts is monitored by testing the urine for the absence of a particular addictive substance over a prolonged period of time. If withdrawal treatment is successful, the addictive substance concentration declines continuously and finally remains below the detection limit. The laboratory should be informed about therapeutic drugs administered to the patient to avoid false positive findings due to cross reactions in the immunoassay.

Drugs

As a rule, immunoassays for drug screening are not suited for finding out whether an individual, who tested positive for a drug, continues to use the addictive substance. When screening tests are used, in particular for detecting substances such as stimulants, barbiturates, benzodiazepines and opiates, an unequivocal result is not obtained until a sample collected under supervision tests negative. The cross reactivity of the individual compounds and their metabolites is concentration dependent and varies to such an extent that a decrease in the measured signal compared with a previous sample cannot be taken as solid evidence of abstention, for the following reasons, among others:

• A patient no longer takes diazepam which is detectable at high analytic sensitivity, but instead the potent flunitrazepam which is rapidly excreted and detectable at low sensitivity.
• The calibration curves are steep in the lower concentration range and very flat in the upper range. Therefore, imprecision may yield false differences in the upper range.
• A 24-h urine specimen is usually not available. Drug excretion in random specimens can vary significantly due, for example, to drinking habits or urine pH.

Adequate experience of the analyzing specialist provided, the current and previous findings can be compared on a semi-quantitative basis if immunoassays for the specific detection of certain individual substances (e.g., EDDP, benzoylecgonine) or for the detection of chemically closely related compounds (e.g., THC metabolites) are used. In cannabinoid detection, however, it must be kept in mind that the excretion pattern of the THC metabolites changes as a function of the time of intake.

Since, on the other hand, the cross reactivity of the metabolites with the antibody varies, the results obtained from samples collected within a narrow time frame should be assessed with reservation.

Quantitative results based on immunoassays for the detection of drugs in urine should in no case be communicated as diagnosis to the individual or entity requesting the test. The question as to whether the patient continues to take the addictive substances can most likely be reliably answered by performing a specific quantitative serum analysis using, for example, gas chromatography mass spectrometry.

Ethanol

The serum ethanol concentration reflects the current degree of intoxication of the tested individual. Detection in urine can be performed for monitoring withdrawal treatment since a qualitative result is usually sufficient. The enzymatic determination in morning urine allows a discrete way of monitoring alcohol consumption during the preceding evening which the patient may possibly have spent outside the treatment facility. The urine 5-hydroxytryptophol concentration is a measure of alcohol intake during the past 24 hours, the serum or urine ethyl glucuronide concentration is a measure for the past 3 days and the carbohydrate deficient transferrin (CDT) for the past 3 weeks. In chronic abuse situations, the γ-glutamyl transferase (GGT) activity and mean cellular volume (MCV) are elevated (see also Section 18.6.8.4 – Carbohydrate-deficient transferrin (CDT) and alcohol abuse).

41.6.8 Other abuse

41.6.8.1 Abuse of organic solvents

The abuse of organic solvents by inhalation (sniffing) may result in sudden death. Acutely poisoned patients may present with numerous neurological symptoms ranging from simple sleepiness to unconsciousness with seizure activity /28/. Blood analysis by gas chromatography for detecting the underlying presence of volatile poisons is diagnostically valuable in these cases.

41.6.8.2 Laxatives and diuretics

These substances are occasionally ingested clandestinely, especially by women, in order to reduce the body weight for cosmetic reasons. Relatively simple qualitative screening of the urine for such substances may help to avoid lengthy and futile clinical as well as laboratory investigations /29/.

41.6.8.3 Neuroenhancement

Neuroenhancement is the use of substances by healthy individuals to enhance mood or cognitive function. This method of brain doping is used, for example, by students, managers, physicians or soldiers in wartime deployment who, in the absence of medical indication, take certain substances to enhance their intellectual performance, reduce fear of failure and delay fatigue. More specifically, this term applies to the application of prescription drugs for the above mentioned purpose and not in accordance with the intended use. The drugs originate from different pharmacological active agent groups and some have a considerable addiction potential (Tab. 41-23 – Drugs for neuroenhancement).

Methylphenidate, modafinil and piracetam are most commonly used at the moment. In a wider sense, neuroenhancement also refers to the consumption of alcohol, caffeine and cigarettes as well as illicit drugs (e.g., cocaine, Ecstasy). In an international study, 20% of the sampled population and 5% of working individuals in Germany admitted to having practiced neuroenhancement.

41.7 Comments and problems

Immunoassays

The analytical specificity of immunoassays in clinical-toxicological analyses is not 100%. In general, the occurrence of false positive results must be anticipated. Their prevalence should be less than 5% /30/. For instance, certain pheno­thia­zines may mimic the presence of tricyclic antidepressants in the blood /31/.

A positive test result should, therefore, always be verified by means of a second, independent method (e.g., gas chromato­graphy/mass spectrometry or LC-MS/MS) /32/.

Screening tests

Screening tests (e.g., for the detection of benzodiazepines) in the urine, detect the individual substances at different detection limits corresponding to the cross reactivity with the antibodies in use, yet independently of the pharmacological potency and regardless of the speed and extent of metabolization. Accordingly, therapeutic doses of certain benzodiazepines, for example, may fail to be detected /33/.

Detection limit may be improved by using concentrating techniques such as, for example, urinary column extraction methods and cleavage of conjugates.

Strip tests: immunochromatographic strip tests are only recommended if instrumental immunoassays are not readily available and the analyzing specialist has sufficient experience with the subjective, visual evaluation of the test results.

Specimen and test method: if immunoassays are not used for urinalysis as intended by the manufacturer but for the analysis of serum, for example after acetone precipitation, the user is responsible for this deviation from intended use.

Assessment of individual results in a toxicological screening program

The assessment of the results obtained in a screening program must take into account which substances are generally not considered within the scope of the program. For instance, the following substances cannot be detected by the investigation methods listed in Tab. 41-12 – Toxicological screening program whereby 80% of the acute poisonings occurring in the emergency unit can be detected: barbituric acid free hypnotics like chloral hydrate, zolpidem, tetra cyclic antidepressants or certain alkaloids (e.g., strychnine). If it is necessary to include such substances in the investigation, the methods listed in Section 41.3 – Method of determination may be used; among these, gas chromatography mass spectrometry and HPLC (and, in the future, LC-MS/MS) are of most practical value for use in clinical laboratories.

Poison control centers (PCCs)

Poison control centers provide information day and night, free of charge and should be consulted by the clinician and the laboratory personnel in all unclear cases in regard to the following concerns:

• First aid measures in the event of poisoning
• Interpretation of signs suggestive of poisoning
• Composition and toxicity of drugs, household substances, chemicals, addictive and other substances
• Analytical advice
• Therapeutic approach.

For PCC contact addresses, please refer to the Internet and the official pharmaceutical catalog of your country.

Forensic aspects

All samples submitted for clinical toxicological investigation should be stored for 3–4 weeks in the refrigerator or kept deep frozen with unequivocal labeling tags for identification in case forensic investigation might follow later on.

41.8 Pathophysiology

It can be assumed that mild to moderately severe poisonings in otherwise healthy individuals will not result in significant pharmacokinetic alterations. As part of severe poisonings, changes in absorption, biological availability, protein binding and elimination of drugs and poisons may occur /34/.

Delayed absorption has been described for a number of drugs due to a decrease in gastrointestinal tract motility and the formation of poorly soluble masses of tablets. A significant rise in biological availability may result in the case of substances which are subject to pronounced first pass metabolism if saturation of this metabolism occurs.

A decrease in the protein binding of a drug may lead to an increase in its toxic effect since the drug’s free portion which is responsible for therapeutic efficacy is on the rise under such circumstances. Furthermore, a decrease in the protein binding leads to a rise in the volume of distribution. Subsequently, as a result of this increased volume of distribution, prolongation of the half life may occur.

Moreover, it needs to be taken into account that shock and hypothermia lead to a decrease not only in hepatic clearance but also in the volume of distribution and the renal elimination rate by causing a decrease in cardiac output and changes in perfusion.

The diffusion of drugs into the central nervous system may be altered as a result of a shift in the blood pH. In addition, changes in urinary pH have a significant impact on renal clearance.

Intrahepatic metabolism is the important process of elimination for the majority of drugs and other orally ingested extrinsic substances. Since most poisonous substances are lipophilic, groups with polar functionality are initially introduced into the molecule. Quite frequently, these metabolic products in addition are conjugated (e.g., with glucuronic acid). Due to these alterations of the chemical structure, water solubility increases, thus leading to a significant rise in renal excretion.

Metabolites usually reveal no efficacy or, in comparison to the original substance, only a markedly reduced one. Yet active and/or toxic metabolites may also be formed. Paracetamol poisoning is an example of this. Even at therapeutic doses, a small portion of paracetamol taken is converted into a toxic metabolite as a result of the catalytic effect exerted by the cytochrome P-450 system; this metabolite is detoxified by reacting with glutathione. At toxic doses, however, the toxic metabolite is produced in such large quantities that extracellular glutathione supplies become inadequate. Intracellular SH compounds react with the metabolite, thus causing liver damage, in particular /34/. The metabolite can be detoxified and the damage prevented by early substitution treatment involving the administration of an SH donor such as, for example, N-acetylcysteine.

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Further reading

• Dart RC (ed): Medical toxicology. 3rd edition. Philadelphia PA: Lippincott Williams and Wilkins, 2004.
• Karschner EL, Swortwood-Gates MJ, Huestis MA. Identifying and quantifying cannabinoids in biological matrices in the medical and legal canabis era. Clin Chem 2020; 66 (7): 888–914.
• Külpmann WR (ed): Clinical toxicological analysis. Weinheim: Wiley-VCH, 2009.
• Moffat AC, Osselton MD, Widdop B (eds): Clarke’s analysis of drugs and poisons. 3rd edition. London: Pharmaceutical Press, 2004.
• Watson ID, Proudfoot AT. Poisoning and laboratory medicine. London: ACB Venture Publ, 2002.