10- forensic & clinical toxicology

8/8/2019 10- Forensic & Clinical Toxicology

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Toxicology II course PHTX 943for pharmacy students

9th semester

Lecture 10

Forensic & Clinicaltoxicology

Dr. Ola Ahmed Heikal


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Forensic toxicology

Fundamentals Forensic toxicology refers to the use toxicology for the purpose of law

The most common application is to identify any chemical that may serve ascausative agent in inflicting death or injury on humans or causing damageto the property

The systematic approach is the use fundamental toxicology knowledge inconjunction with the sophisticated tools of analytical toxicology to providethat data needed to understand the hazards of the toxic substances morecompletely

The duties of forensic toxicologist

1- Qualitative and quantitative analysis of drugs or poisons in the biological specimendetected at autopsy

2- Interpretation of the results regarding to physiological effect of the detected chemicals on thedeceased at the time of death

3- Establishment of the cause of death with combined efforts of pathologists
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Determines which toxic substances are present, in what concentrations,and the probable effect of those chemicals on the person, to proof of guilt or

innocence in court of law

The forensic toxicologist must

Example :-Detection of ethanol in victims or industrial accidents not due to postmortem changes

- Intoxication of CO in fire victims to determine weather the death is before or after the fire started

Sample underinvestigation mayonly containmicrograms ornanograms


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Investigation of toxicity related death / injury

1-Collection of information and specimen :

Age , sex, his/her medical history, Identification of any

medication taken before death

Many different body fluids and specimens should becollected since xenobiotics have different affinities for bodytissues ( hair , bone marrow , vitreous humor , GIT content ,urine )

Specimen should be collected before embalming whichmay destroy evidence yielding false positive results ( ethanol acomponent of embalming )

Preservation of the specimen by sod. Fluoride can prevent

the production of postmortem ethanol

Chain of custody : ( documentation practice)

Labeling and all handling documentation that exist fromthe beginning of the data/ specimen collection to theanalysis in a typical toxicology worksheet that enablesthe toxicologist to introduce the analytical results into alegal form

The basic phases in conducting an investigation of a suspected toxicant-induced /related death or in living victims of criminal poisoning

Each handler of the sample must sign the formWhen it is arrived to the lab , the sheet has tobe checked for all signatures


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Investigation of toxicity related death / injury ( Cont.)

The basic phases in conducting an investigation of a suspected toxicant-induced / related death or in living victims of criminal poisoning

2- Toxicological analysis

The decision concerning analytical method employeddepend greatly on

The sample volume

The nature of the toxicant: ( parent , metabolite or both ) :

Biotransformation must be taken in consideration whendoing analysis and making interpretation

1- low concentration of toxic parent may reflectbiotransformation rather than low level of exposure

( Heroin & Benzodiazepines and Phenothiazines )

2- Conversely , low level of non-toxic parent compoundmay be associated with sufficient Conc.

Of metabolite that causes the insult

The substance also is diluted by its dispersal throughthe body; Sample under investigation may only containmicrograms or nanograms


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Many of the drugs , such benzodiazepines , phenothiazines , are available throughIllicit sources and can be purchased illegally . When administrated , they causesedation , incapacitate the victim while also producing amnesia about the eventthat occurred .

Benzodiazepines &phenothiazines These drugs have usually are eliminated fromthe body at the time the victim can bring for allegation

Examples of criminal poising of livings :


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Pharmacokinetic considerations of some important drugsconcerning forensic toxicological analysis

The knowledge of absorption, distribution, metabolism of a poison in the biologicalfluid is crucial for identification and confirmation of the ingestion of the poison when

the toxicologist testimony is required as proof of guilt or innocence in court of law.Toxicologist is known as expert witness

Opiatest 1/2 Major metabolite t ( metabolite ) Interpretation

Heroin 6 min. Morphine &

6- monoacetyl morphine

M = 2hr average.

1-8 hr.

6-MAM = 40 min .

morphine isdetected asmetabolite

Morphine 8 hr. Morphine -3 glucuronide or

Morphine -6 glucuronide conjugate

1-8 hr. similar tomorphine

10% freemorphine

90% detected as

glucuronideconjugate

Codeine 2- 4 hr. 10% 15% -as conjugated or freemorphine

40-70 % as conjugated or free codeine

Norcodeine

Morphine isdetected asmetabolite

To differentiate between codeine use ( cough syrup ) legitimate use and heroin use (illegal ) basedon morphine : codeine ration

Following heroin use : morphine exceed codeine in the 1st 24 hr. which is reversed after this timeMorphine : codeine ratio < 0.5 is indication to use of codeine


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Pharmacokinetic considerations of some important drugsconcerning Forensic toxicological analysis

Cannabis ; the main active constituent is 9 Tetrahydrocannabinol : (9 THC)Item t 1/2 Major metabolite Detection

9 Tetrahydrocannabinol(9 THC)

20-36 hr 11 hydroxyl - 9 THC& 11- nor 9 THC -9carboxylic acid as free ortheir glucuroindconjugated form

In urine

2-5 days after acute use

10- 46 days after chronicuse

The slow release of THC and its metabolites is a result of

- High enter hepatic circulation- High plasma protein binding

This leads toPlasma conc.9 THC high peak plasma concentrations ( 0.03-0.12g/ml ) within 3 min after

administration followed by rapidly fall in concentration to 0.003-0.01 g/ml within onehour even to 0.0006 g/ml after 4 hr Thus

Urine analysis is preferred for detectionFluctuation in elimination vary from ve to +ve values when measured after several daysof abstinence so conc. Of THC COOH metabolite should be expressed per mg

creatinine and 50% increase from previous value implies reuse (Creatinine level drops belownormal when people dilute their urine. Labs test creatinine levels to ensure that the sample is valid and the subject didn'tdrink unusual amounts of water.


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Some Notes concerning drug concentration and distribution

1- As a rule , the highest concentration of a poison are found at the site ofadministration

High concentration of drug toxicant GIT and liver indicates oral digestion Compounds located in tissues surrounding an injection sites indicates a

fresh IM Or Iv injection

Detection of drug combustion breakdown products within fluids / tissues revealthat smoking was the route of drug administration ( product of crack pyrolysis ; is

unhydroecgonine methylester , high conc.of the product Indicates that smoking is the route of cocaineadministration )

Urine analysis is of great value followed by blood ( heart & peripheral )and tissues ( kidney and liver )

Laboratory analysis :

Qualitative : 1-Colorimetric screen tests 2- Enzymatic Immunoassay

Quantitative : Chromatographic techniques ( TLC, GC, HPLC , GC/Ms)


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Analytical scheme for toxicant detection

VC : Volatile screen ; detection of ethanolDAS : Drug of abuse screenGDS : General drug screen ( when the cause of death is not clear )

includes : ANS ( Acid./Neutral drug screen ) , barbiturates , muscle relaxantsBDS : Basic drug screen ( Amphetamine , cocaine)


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Clinical Toxicology

Analytical toxicology approaches used in forensic toxicology play an importantrole In clinical testing

The methods and the instrumentation used in a clinical toxicology laboratoryare similar to those used in forensic toxicology

Clinical toxicology laboratory serves the following purposes :

- Diagnosis and treatment toxicoses- Monitoring of treatment effectiveness- Identification of the nature of exposure- Quantification of toxicant

Basic operating rules in the treatment of toxicoses

1- Ensure airway so that breathing are adequate2- Ensure adequate circulation, by administer i.v fluids3- Prevention of absorption (Removal of unabsorbed materials limit further

absorption ,

5- Enhancement of Excretion4- Using of specific antidotes


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Diagnosis of toxidrome

A toxidrome is a group of symptoms associated with some drugs or class of drugsRecognition of a toxidrome can help with the selection of the therapeutic step


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Prevention of absorption

External / skin decontamination : This entails the complete removal of clothingand gentle washing of the victim

Internal decontamination : Reducing the absorption of toxicants into the systemiccirculation

-Gastric lavage ( use of nasogastric or orogastric tube to flush GIT )- Activated charcoal (bind to drugs that undergo enterohepatic circulation;barbiturates, digoxin, carbamazepines; CBZ)

- Emesis- Cathartics

Emesis

Emesis :1-Syrup of ipeca :It induces vomiting by directly irritating The stomach and bystimulating the chemoreceptor trigger zone

The onset of vomiting is within 20 to 30 minutes

Contraindications :

-Not recommended with ingestion of strong acids or alkalis- The danger of aspiration is great leading to asphyxia

2-Apomorphine ( morphine derivative)- It acts quickly within 2-3 min. subcutaneously

Nasogastric tube
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Prevention of absorption

Cathartics : ( sorbitol , magnesium citrate , polyethylene glycol )

Sorbitol :

It is commonly used as cathartic and with charcoal formulations

It increases the gut motility to improve excretion of the poison charcoal complex

Because of the diarrhea induced by this agent ( and other cathartics) carefulmonitoring of fluid and electrolytes is necessary

Contraindications :

It is not recommended with poisoning compounds that cause perfuse diarrhea( as organphosphorous compounds , carbonates , and arsenic)

I n hypotensive patients , when dehydration and electrolyte balance is present

With corrosive substances


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Enhancement of excretion

1- Forced diuresis : it is useful to enhance renal elimination of poisons whichare primarily excreted in urine

- Saline : Is administered to expand the extra cellular fluid volume- Furosemide : Added to enhance diuresis- Acid diuresis : Acidification of urine with ammonium chloride to eliminate

weak basic drugs ( amphetamine , quinidine , phencyclidine )

Alkaline diuresis : Administration of sod. Carbonate to removal of weakacids ( salicylates, barbiturates , isoniazide )

2- Hemodialysis : Usually a procedure in which blood is taken from a patient'scirculation to have a process applied to it before it is returned tothe circulation.

The dialysate is flowing in the opposite direction to blood flow

3- Hemoperfusion : The technique involves passing large volumes of blood overan adsorbent substance.

The adsorbent substance most commonly used in hemoperfusion are resins and

activated charcoal


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Using specific antidotes

An effective agents that can alter the distribution and or metabolismof a toxicant

A- Antidotes That act chemically :

1- By chemical detoxification :i- Chelating agents : ( Metals ) BAL, ( Succimer) , EDTA

2- Enzymatic detoxification :i- Sodium thiosulphate : Increase the conversion of

cyanide to thiocyanate by rhodanase enzyme

thus being easily excreted by the kidney

ii- Methylene blue : Converts the metheamoglobin to hemoglobinacting on methylene blue reeducates enzyme

iii- Ethanol : Prevention of formation of toxicmetabolite of ethylene glycol and methanol by competitivebinding to alcohol dehydrogenase enzyme

iV- N- acetylcysteineand methionine : antidote acts on toxic metaboliteas paracetamol metabolite ( NAPQI)

V- 2-PAM : Removes the phosphorylated group from thecholinesterase enzyme


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Using specific antidotesB- Antidotes That act pharmacologically :

1- Antagonisms at characterized pharmacological receptors

- Naloxone , naltrexone : opiate antidote- Flumazanil : benzodiazepines- Atropine : Organophosphorous and carbamate pesticides- Chloropromazine : amphetamine antidote ( dopamine blocker)

C- Functional antidotes :

- Diazepam as anticonvulsants ( stimulants , organophosphorous)- IV fluid in hypotension

Example cyanide antidote

NaNO2 + Hemoglobin = MethaemoglobinHCN + Methaemoglobin = CyanmethaemoglobinNa2S2O3 + HCN + O2 = HSCN

Sodium nitrite reacts with hemoglobin to form methaemoglobin. The latter removescyanide ions from various tissues and couples with them to become

cyanmethaemoglobin, which has a relatively low toxicity. The function of Sodiumthiosulfate is to convert cyanide to thiocyanate, by an enzyme known as rhodanase

10- forensic & clinical toxicology

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