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Toxicology II course PHTX 943

for pharmacy students

9th semester

Lecture 10

Forensic & Clinical


toxicology

Dr. Ola Ahmed Heikal


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 as
causative agent in inflicting death or injury on humans or causing damage
to the property

The systematic approach is the use fundamental toxicology knowledge in


conjunction with the sophisticated tools of analytical toxicology to provide
that data needed to understand the hazards of the toxic substances more
completely

The duties of forensic toxicologist


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

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

3- Establishment of the cause of death with combined efforts of pathologists


The forensic toxicologist must
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

Sample under
investigation may
only contain
micrograms or
nanograms

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

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 be


collected since xenobiotics have different affinities for body
tissues ( hair , bone marrow , vitreous humor , GIT content ,
urine )

 Specimen should be collected before embalming which


may destroy evidence yielding false positive results ( ethanol a
component 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 from


the beginning of the data/ specimen collection to the
analysis in a typical toxicology worksheet that enables
the toxicologist to introduce the analytical results into a Each handler of the sample must sign the form
legal form When it is arrived to the lab , the sheet has to
be checked for all signatures
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 employed
depend greatly on

 The sample volume

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

Biotransformation must be taken in consideration when


doing analysis and making interpretation

1- low concentration of toxic parent may reflect


biotransformation rather than low level of exposure

( Heroin & Benzodiazepines and Phenothiazines )

2- Conversely , low level of non-toxic parent compound


may be associated with sufficient Conc.
Of metabolite that causes the insult

 The substance also is diluted by its dispersal through


the body; Sample under investigation may only contain
micrograms or nanograms
Examples of criminal poising of livings :

Many of the drugs , such benzodiazepines , phenothiazines , are available through


Illicit sources and can be purchased illegally . When administrated , they cause
sedation , incapacitate the victim while also producing amnesia about the event
that occurred .

Benzodiazepines &phenothiazines These drugs have usually are eliminated from


the body at the time the victim can bring for allegation
Pharmacokinetic considerations of some important drugs
concerning forensic toxicological analysis
The knowledge of absorption, distribution, metabolism of a poison in the biological
fluid 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
Opiates
t 1/2 Major metabolite t ½( metabolite ) Interpretation

Heroin 6 min. Morphine & M = 2hr average. morphine is


6- monoacetyl – morphine 1-8 hr. detected as
6-MAM = 40 min . metabolite

Morphine 8 hr. Morphine -3 glucuronide or 1-8 hr. similar to 10% free


Morphine -6 glucuronide conjugate morphine morphine
90% detected as
glucuronide
conjugate
Codeine 2- 4 hr. 10% 15% -as conjugated or free Morphine is
morphine detected as
40-70 % as conjugated or free codeine metabolite
Norcodeine
To differentiate between codeine use ( cough syrup ) legitimate use and heroin use (illegal ) based
on morphine : codeine ration
Following heroin use : morphine exceed codeine in the 1st 24 hr. which is reversed after this time
Morphine : codeine ratio < 0.5 is indication to use of codeine
Pharmacokinetic considerations of some important drugs
concerning Forensic toxicological analysis

Cannabis ; the main active constituent is 9 –Tetrahydrocannabinol : (9 –THC)


Item t 1/2 Major metabolite Detection

9 – Tetrahydrocannabinol 20-36 hr 11 hydroxyl - 9 THC In urine


(9 –THC) & 11- nor 9 THC -9 2-5 days after acute use
carboxylic acid as free or 10- 46 days after chronic
their glucuroind use
conjugated form

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


- High enter hepatic circulation
- High plasma protein binding
This leads to
Plasma conc.
9 –THC high peak plasma concentrations ( 0.03-0.12g/ml ) within 3 min after
administration followed by rapidly fall in concentration to 0.003-0.01 g/ml within one
hour even to 0.0006 g/ml after 4 hr Thus

Urine analysis is preferred for detection


Fluctuation in elimination vary from –ve to +ve values when measured after several days
of abstinence so conc. Of THC –COOH metabolite should be expressed per mg
creatinine and 50% increase from previous value implies reuse (Creatinine level drops below
normal when people dilute their urine. Labs test creatinine levels to ensure that the sample is valid and the subject didn't
drink unusual amounts of water.
Some Notes concerning drug concentration and distribution

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


administration

 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 reveal
that 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 cocaine
administration )

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)


Analytical scheme for toxicant detection

VC : Volatile screen ; detection of ethanol


DAS : Drug of abuse screen
GDS : General drug screen ( when the cause of death is not clear )
includes : ANS ( Acid./Neutral drug screen ) , barbiturates , muscle relaxants
BDS : Basic drug screen ( Amphetamine , cocaine)
Clinical Toxicology
Analytical toxicology approaches used in forensic toxicology play an important
role In clinical testing

The methods and the instrumentation used in a clinical toxicology laboratory


are 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 adequate


2- Ensure adequate circulation, by administer i.v fluids
3- Prevention of absorption (Removal of unabsorbed materials limit further
absorption ,
5- Enhancement of Excretion
4- Using of specific antidotes
Diagnosis of toxidrome
A toxidrome is a group of symptoms associated with some drugs or class of drugs.
Recognition of a toxidrome can help with the selection of the therapeutic step
Diagnosis of toxidrome
Diagnosis of toxidrome
Prevention of absorption
External / skin decontamination : This entails the complete removal of clothing
and gentle washing of the victim

Internal decontamination : Reducing the absorption of toxicants into the systemic


circulation
-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 :
1-Syrup of ipeca :
It induces vomiting by directly irritating The stomach and by
stimulating the chemoreceptor trigger zone
Nasogastric tube
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
Emesis
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) careful
monitoring 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


Enhancement of excretion
1- Forced diuresis : it is useful to enhance renal elimination of poisons which
are 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 weak


acids ( salicylates, barbiturates , isoniazide )

2- Hemodialysis : Usually a procedure in which blood is taken from a patient's


circulation to have a process applied to it before it is returned to
the circulation.

The dialysate is flowing in the opposite direction to blood flow

3- Hemoperfusion : The technique involves passing large volumes of blood over


an adsorbent substance.
The adsorbent substance most commonly used in hemoperfusion are resins and
activated charcoal
Using specific antidotes
An effective agents that can alter the distribution and or metabolism
of 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 hemoglobin


acting on methylene blue reeducates enzyme

iii- Ethanol : Prevention of formation of toxic


metabolite of ethylene glycol and methanol by competitive
binding to alcohol dehydrogenase enzyme

iV- N- acetylcysteine and methionine : antidote acts on toxic metabolite


as paracetamol metabolite ( NAPQI)
V- 2-PAM : Removes the phosphorylated group from the
cholinesterase enzyme
Using specific antidotes
B- 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 = Methaemoglobin


HCN + Methaemoglobin = Cyanmethaemoglobin
Na2S2O3 + HCN + O2 = HSCN
Sodium nitrite reacts with hemoglobin to form methaemoglobin. The latter removes
cyanide ions from various tissues and couples with them to become
cyanmethaemoglobin, which has a relatively low toxicity. The function of Sodium
thiosulfate is to convert cyanide to thiocyanate, by an enzyme known as rhodanase

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