TOXICOLOGY II. Toxic compounds in cases of intoxication at present

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TOXICOLOGY II. Toxic compounds in cases of
intoxication at present

• M. Balíková

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Toxicological cases in laboratory

• Clinical examination from reasons
• Diagnostics
• Therapy controls
• Prevention
• b) Clinical forensic development
• c) Forensic
• Autopsies (suicides, homicides)
• Traffic accidents
• Occupational injuries
• Violence associated with roberies, rapes,
  injuries
• Others

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CLINICAL TOXICOLOGY - SYMPTOMS

• Importance of anamnestic data, symptoms
• Differential diagnosis Is it poisoning?
• Preliminary results therapeutic action
• BUT
• nonspecific symptoms of intoxication

• Gastrointestinal problems
• Cramps (strychnin, cyanides, antidepressants,
  cocaine
• Hallucinations (LSD, psilocybine, MDMA,
  cannabis.)
• Mydriasis / Miosis

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Acute intoxications

• Intentional (suicides, homicides, associated with
  violence to others)
• Drug abuse
• Nonintentional (small children, accidental
  ingestion, expositions)

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FORENSIC TOXICOLOGY
Careful individual attitude Examination in
series not common Individual optimalization of
examination Principle in toxicology results
confirmation by another independent and specific
method if available The final toxicological
evidence defensible scientifically and legally
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Frequent toxic compoundsin acute intoxications

• Ethanol
• Pharmaceuticals
• Drugs of abuse
• Carbon oxide
• Volatiles
• Glycols
• Mushrooms, herbal toxins

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Ethylalcohol

• Hydrophilic compound, rapid resorption, in blood
  distributed in favour of plasma
• Pharmacokinetics
• rate of resorption gt rate of elimination
• elimination with zero order rate
  (0.12-0.2 g/kg/h)
• Metabolism 70 alcoholdehydrogenase, 25 MEOS,
  5 excreted in parent form
• Effects Narcotic fat solubility CNS
  depressant
• Endogenous bacterial production (0,001 0,002
  g/kg)
• Postmortem production (ethanol and other
  alcohols)

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Ethanol blood level and methods

• Breathanalysers indirect test
• Gas chromatography direct alcohol measurement
  in venous blood, specific forensic method
• Enzymatic method clinical cases O. K., but
  potentional interferences (lactate)
• Widmark method nonspecific (based on reduction
  of bichromate)

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Ethanol and driving

• Two general types of legislation in the world
• 1) Impairment
• 2) Per se
• In Czech Rep. Impairment type
• Jurisdiction
• 0.2 g/kg cut off value
• 0.5 g/kg impairment very probable,
  administrative sanctions
• 1.0 g/kg unfit for driving, dangerous, penal
  proceedings at court

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Methanol

• Lethal doses 5 100 ml
• Metabolites formaldehyde, formic acid
• Very slow oxidation, max level of formic acid 2
  days after ingestion
• Dangerous delayed effects
• at first narcotic
• later metabolic acidosis , retina damage,
  blindness, death

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Methanol poisoning

• Antidotum ethanol
• Competitive alcohols oxidation (long term ETOH
  infusion blood level maintenance 1.5 g/kg)
  protection from methanol oxidation
• Haemodialysis
• NaHCO3 infusion correction of pH

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Glycols - Diols

• Intoxications intentional ,accidental
• Antifreezers FRIDEX
• Solvents, also vehiculum in some pharmaceutical
  products (injections)
• Ethanediol and dimers, trimers, polymers
• Propanediol 1,2 and 1,3 isomers
• Butanediol- precursor of GHB
• Glycol monoalkyl ethers brake liquids
  (celosolve, carbitols)

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Ethylene-glycol

• Toxic oxidative metabolites
• glycolaldehyde, glycolic acid, glyoxylic acid,
  oxalic acid
• Toxic effects
• narcotic (alcohol)
• gradual development of acidosis
• renal failure, anuria
• Therapy as soon as possible as in methanol
  poisoning- ethanol as antidotum, haemodialysis,
  natrium bicarbonate

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Volatiles CNS depressants

• Hydrocarbons
• a) gaseous (propane, butane)
• b) liquid (toluene, chloroform)
• Fuels
• Various solvents
• Aenesthetics (ether, halothane)
• Intentional or accidental intoxications
• Drug abuse by inhalation, euphoria,
  hallucinations
• Dangerous overdoses, fatal intoxications

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Volatiles abuse

• Chronic abuse
• psychical addiction
• hepatorenal toxicity
• neurotoxicity
• cardiotoxicity
• Overdose
• agitation, cramps, coma, cardiac failure, death

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Volatiles metabolism

• Partly expired in parent form
• Only some produce known metabolites into urine
  (toluene 80-90 hippuric acid, butane only 1 as
  2-butanol)
• Only some can appear in urine in parent form
  (aromates)
• Some metabolites expired into air
  (dichloromethane 50 CO metabolite)
• Useful sample for toxicology blood
• Method gas chromatography

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Carbon oxide

• Burning of organic compounds at insuffient access
  of air
• Strong affinity to haemoglobin - in the same
  molar ratio as oxygen but 220 times stronger,
  competition for binding even low traces in air
  can be gradually bound
• Degree of poisoning correlates with time of
  exposition, physical activities

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Carbon oxide cont.

• Toxic effects
• reduction of oxygen transport in blood,
  neurotoxicity, potentional development of
  Parkinsonism in chronic exposition
• Endogenous levels COHb lt 0.5
• Smokers up to 10
• Light intoxication 10-20 COHb
• Severe intoxication 30-40 COHb
• Coma, respiratory failure 40 50 COHb
• Fatal 50 70 COHb

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Cyanides

• Hydrogen cyanide, HCN, boiling point 26 C,
  bitter almond like odor, colorless, very toxic
  gas or liquid (hydrocyanic acid)
• NaCN, KCN unstable in acidic media, hydrolysis to
  toxic HCN, unstable in air carbonates
• HCN present in exhaust gases, in tobacco and wood
  smoke, in smoke from burning nitrogen containing
  plastics
• HCN in air300 p.p.b. will kill a human in a few
  min
• LD50 in humans very individual (0.005 1 g)

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Cyanides cont.

• Biotransformation in the liver thiocyanates
• Toxic mechanism Inhibition of cytochromoxidase,
  cells can not accept oxygen, tissues hypoxia
• Therapy
• administration of compounds with Co or Fe(III)
• Amylnitrite, natrium nitrite as antidotum
  cyanomethaemoglobine production, enzyme block
  releasing
• Thiosulphate infusion metabolites SCN
• Oxygen ventilation

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Mercury

• Metallic form water insoluble
• Salts water soluble, partial resorption p. o.
• Fine particles in air dangerous entrance via
  lungs into blood, subsequent oxidation,
  cumulation in the brain, kidney potentional
  neurotoxicity, nefrotoxicity
• Elimination into urine very slow
• Organic mercury lipophilic, molecular effects,
  accumulation in CNS, embryotoxic
• Mercury in water sediments bacteria
  transformation into organic mercury-
  contamination of fish meat - dangerous

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Pesticides-1

• Insecticides
• Herbicides
• Fungicides
• Rhodenticides

Organic compounds of various structures, various
toxic mechanisms, various symptoms of
intoxication, various effects

Human acute intoxications in EUROPE at present
not frequent

• ORGANOPHOSPHATES (sarin, parathion, malathion...)
• CARBAMATES (aldicarb, carbofuran...)
• CHLORINATED HYDROCARBONS (chlophenothaneDDT,
  lindan, aldrin...)
• BIPYRIDINE DERIVATIVES (paraquat, diquat...)
• ANTICOAGULANS (warfarin, diolan...)

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Pesticides - 2

• Organophosphates
• irreversible potent acetylcholinesterase
  inhibition, respiratory difficulties,
  salivation, miosis, nausea, paralysis...
• antidotum atropine
• p-nitrophenol in urine marker of exposure to
  parathion
• Carbamates
• derivatives of methylcarbamic acid
• reversible inhibition of acetylcholinesterase
• antidotum atropine
• Polychlorinated hydrocarbons
• free radicals by biotransformation
• convulsions, nausea chronic neurotoxicity,
  hepato and nefrotoxicity
• Bipyridine derivatives
• paraquat, diquat (GRAMOXONE, ATRAZINE)
• contact toxicity, inflamation, bleeding, local
  necrosis, muscle stiffness, blurred vision,
  pulmonary fibrosis
• Anticoagulants
• warfarin, diolan (KUMATOX, TALON-G)

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Pharmaceuticals

• Accidental and intentional overdoses, suicides
• Combination with alcohol, mixtures of drugs
• Drug abuse narcotic and psychotropic
  substances
• Mostly organic substances with low molecular
  mass up to 400 Daltons
• Classification
• 1) Structure important for analytical
  toxicology, laboratory attitude
• 2) ATC system (WHO) Anatomical-Therapeutical-Che
  mical
• A Gastrointestinal tract (spasmolytics,
  anticholinergics.)
• B Blood system
• C Cardiovascular system (cardiotonica, ,
  antihypertensiva)
• D, G, H Dermatologica, urologica,
  gynekologica, hormones
• J, L Antibacterials, antivirotics,
  antimycotica, cytostatica
• M Muscle-sceletal system (antirevmatica,
  antiphlogistica, myorelaxancia)
• N Neurological system (anestetica,analgesica,an
  tiepileptica,psycholeptica)
• P Antiparasitica
• R Respiratory system (antiasthmatica,
  antitusica, antihistaminica..)
• S, V Varia

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Barbiturates

• Barbituráty
• Psychotropic substances CNS suppression
• The first derivative at the market barbital
• Common structure of various derivatives -
  barbiruric acid
• Acidic character after p. o. resorption mainly
  in small intestine
• Variable effect duration, therapeutic indication
• Short time effect pentobarbital halflife 20-30
  h)
• Long time effect phenobarbital halflife 2-6
  days)
• Thiobarbital (thiopental) i. v. anestheticum
• Thiobarbital, pentobarbital intracranial
  pressure reduction
• Phenobarbital sedative, antiepileptics
• Various barbiturates in pharmaceutical
  composites, analgesics, antiphlogistics
  (Spasmoveralgin, Alnagon,Bellaspon, Dinyl,
  Eunalgit)
• At present less prescription due to significant
  mortality at overdose, replacement by more safe
  substances

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Benzodiazepines

• Psychotropic substances with CNS sedation
• Frequent therapeutical indication
• Frequent abuse (sometimes with alcohol or
  illegal drugs)
• Potential criminal misuse
• More than 30 various structures with variable
  therapeutic indication
• sedatives (diazepam, alprazolam)
• hypnotics (nitrazepam, flunitrazepam),
• antiepileptics (clonazepam)
• Shortly active midazolam introduction into
  anesthesia (halflife 1-4 h)
• Long term active diazepam sedative (halflife
  21-37 h)
• At overdose accummulation in tissues,
  prolonged elimination
• Extensive biotransformation metabolites of
  phase I and II
• Identification of toxic substance important
  for differential diagnosis
• Plasma level monitoring no correlation to effect
• Addictive substances at chronic use, development
  of tolerance
• Low mortality when related to barbiturates
• Additive sedation at combination with alcohol
  and sedative drugs
• Coma state - antidote flumazenil (ANEXAT),
  short halflife 40-60 min

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Antidepressants
TCA tricyclic antidepressants (amitriptyline,
imipramine, trimipramine, clomipramine,
dibenzepine) Tetracyclic antidepressants
maprotiline, mianserine Frequent drugs at
suicidal attempts Pacients with psychiatric
treatment, endogenous depressions Lipophilic
substances with protein bounds, large Vd At
overdose drug accumulation prolonged
effect Normetabolites more potent related to
parent drug form Therapeutic effect CNS
sedation, inhibition of neurotransmiters
resorption Overdose cardiotoxicity,
neurotoxicity Symptoms of overdose Cardivascu
lar disturbances (hypotension) Coma, cramps,
hyperthermia Respiratory collaps, death Therapy
of overdose Symptomatic procedures Hemoelimination
, hemoperfusion
New types with lower toxicity Selective
serotonin reuptake inhibitors fluoxetine,
citalopram, sertraline, venlafaxine,
paroxetine.
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Phenothiazines
Antihistaminics promethazine,
dithiadene Neuroleptics chlorpromazine,
levopromazine, chlorprothixene,
thioridazine Treatment of
psychoses Frequent substances in overdose cases,
suicidal attempts Lipophilic substances bounded
to proteins Extensive biotransformation At
overdose accumulation in tissues, prolonged
effect Antipsychotic effect, CNS sedation,
affinity to neurotransmitters Symptoms of
overdose Delirium and coma Tachycardia,
bradycardia, arythmia, hypotonia Breath center
suppression Life endargement circulation and
respiratory failure Therapy symptomatic,
sometimes physostigmine recommended
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MAO Inhibitors
MAO inhibitors the first ones among
antidepressives Structurally hydrazines,
hydrazides, amides, amines Moclobemide
(AURORIX) Extenzive oxidation, hydrolysis Effect
mechanism Interaction with catabolism of
dopamine, noradrenaline, adrenaline, serotonine
with impact of neurotransmitters accumulation -
serotonine syndrom endargement of hyperpyrexia
and shock Potential interaction with other MAO
inhibitors amphetamines,TCA Symptoms of
overdose similar to overdose by amphetamines,
cocaine, caffeine ... agitation,
confusion, hallucination, convulsions, coma,
cardiovascular disturbances tachycardia,
hypertension, renal failure Phentermin
(ADIPEX) Treatment of obesite Methamphetamine
isomer Addictive potential
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Opiates and opioides
Opiates alkaloides of natural origine and
their structural synthetic analogs morphine,
codeine, dihydrocodeine, hydrocodone, oxycodone,
pholcodine, ethylmorphine) phenanthrene
structure Opioides synthetic origine,
another structure but similar effect,
interaction with opioide CNS receptors
methadone, buprenorphine, tramadol, pethidine,
fentanyl.... Narcotics in therapy part of
analgetics, antitussives Abuse illegal heroin
risk of fatal overdose Chronic abuse somatic
addiction, tolerance Effects Euphoria and
sedation of CNS, miosis, suppressed intestine
motility, constipation, respiration center
suppression, coma, hypothermia, hypotonia,
bradycardia, respiration and circulation collaps,
death Symptoms of fatal overdose lung and brain
edema Therapy Respiratory support, antidote
naloxone, short halftime, repeated administration
Naloxone antagonist of opiate receptors
careful dosing risk of abstinence syndrom
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Acetaminophen - Paracetamol
Part of pharmaceutical products (COLDREX,
KORYLAN, PANADOL) Overdose hepatotoxicity Assess
ment of hepatotoxic risk temporal profile of
serum level after resorption (4 h after
dose) hepatoprotective antidotum substance
with SH groups (N-acetylcysteine)
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Salicylates
Salicine glycoside in willow-tree rind laic
treatment of rheumatism Aspirine, Acylpyrine
acetylsalicylic acid Antipyretics, analgetics,
antiphlogistics, anticoagulants Metabolism
hydrolysis, conjugation) Effect
mechanism Irreversibile inactivation of
cyclooxygenase, local and systemic effects Toxic
effects Mucosal irritation, bleeding in GI,
vomitting Stimulation of respiratory center,
disturbances in electrolytic and acidobasic
balance, metabolic acidosis Rey syndrom in
children with virosis risk of encephalitis and
hepatodamage, risk at susceptive asthmatics
abstinence from salicylates application
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Theophylline
Methylxantines Theophylline, caffeine in
coffee, tea Theobromine - cacao Pharmaceutical
products Theophylline (1,3-dimethylxanthine)
antiasthmaticum, bronchodilatator Aminophylline
theophylline-ethylenediamine Theophylline-
narrow terapeutic window potential of
overdose Significant plasma level monitoring
(TDM) Adverse effects, overdose,
intoxication CNS stimulation cardiovascular
disturbances, arythmia (even fatal), convulsions,
GI
problems, vomiting , nausea
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Cardiotonics
Glycosides of digitalis Digoxine (C41H64O13),
Digitoxine (C41H64O14) Cardiotonics lipophilic
substances, localized in myocardium, bonded to
cardiac receptors, slow excretion. Digoxine
excreted rather faster when related to digitoxine

In cases of overdose digoxine level in
myocardium much higher than in plasma (100x). No
correlation between effect to plasma level TDM
control of therapeutic plasma level Laboratory
methods with respect to higher Mr (765, 781)
ICH, HPLC, not GC Toxicita Vomiting, nausea,
confusion, visual disturbances Ion balance
disturbance, hypokalemia Cardiac arythmia life
endargement, cardiac failure Digoxine fatal
intoxication death within 24 hours Digitoxine
fatal intoxication - dysrythmia prolonged to 5
days, prolonged toxic effects related to
digoxine
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Pharmaceticals with cardiovascular effects
Drugs affecting heart function directly Heart
glycosides Antidysrythmics amiodarone,
propafenol, verapamil, chinidine. Drugs
affecting circulation system Antihypertensiva Card
ioselective beta-blocking agents atenolol,
metoprolol, labetalol, pindolol, sotalol,
propafenone. Diuretics enhanced salts and
water excretion chlorothiazide,
furosemide. Therapeutic indication heart
ischemia, arythmia, heart failure,
cardiomyopatia, hypertension Toxic effects
dizziness, nausea, vasoconstriction, bradycardia
bronchoconstriction, coronar spasms,
hypotension, cardiac and circulatory failure
life endargement, death
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Abuse of addictive substancesPharmaceuticals,
illegal drugs

• CNS sedative substances, narcotics
• opiates/opioids, benzodiazepines....
• CNS stimulating substances
• amphetamines and derivatives, ephedrine,
  cocaine....
• Substances affecting perception, psychedelics,
  hallucinogens
• PEA derivatives (MDMA, PMA, DOB,
  mescaline.....),
• tryptamine derivatives (harmine,
  dimethyltryptamine....)
• ketamine, 9-THC, LSD, psilocybine, muscarine,
  atropine, scopolamine.......
• Tribe rituals - shaman leadership
  application of natural products
• New trends new synthetic drugs (NSD), dancing
  drugs
• stimulating and psychedelic effects
  
• PEA, tryptamine, piperazine structure analogues,
  
• synthetic cannabinoids
• NSD available via internet, frequent origine
  Asia, China
• Health risk of application of an illegal product
  no guarancy of its composition or
  content

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Correlation of anamnesis and toxicology findings