Transcript TOXIC COMPOUNDS in ACUTE INTOXICATIONS at PRESENT

TOXICOLOGY
II. Toxic compounds in cases of
intoxication at present
M. Balíková
Toxicological cases in laboratory
a) 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 compounds
in 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 > 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 < 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 mercurycontamination of fish meat - dangerous
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Pesticides-1
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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 (chlophenothane=DDT,
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-Chemical :
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,antiepileptica,psycholeptica)
P – Antiparasitica
R – Respiratory system (antiasthmatica, antitusica, antihistaminica…..)
S, V – Varia
A C M N R – significant participation in drug overdose cases
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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
General danger at coma – vomit aspiration
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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:
Cardivascular disturbances (hypotension)
Coma, cramps, hyperthermia
Respiratory collaps, death
Therapy of overdose
New types with lower toxicity
Symptomatic procedures
Selective serotonin reuptake inhibitors
Hemoelimination, hemoperfusion
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
Assessment 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
Cardioselective 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 substances
Pharmaceuticals, 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
Pacient Anamnestic
data
Laboratory findings
M-26
years
G: prothiaden (dothiepine)
S: prothiaden 10590 ng/ml !!!
S: northiaden 455 ng/ml
(therapy 50-150 ng/ml)
F-20
years
M-21
years
F-21
years
Deep coma, serious
hypotensia, cardiac
dysrythmia, anuria.
Assumpted: drug
addict or epileptic
Somnolent
Assumpted: Alcohol,
Ibuprofen
Coma, convulsions
B: ethanol 2,7 g/kg
S: alprazolam 59 mg/ml
(therapy 5-50 ng/ml)
G: ibuprofen+codeine+fluoxetine
U: ibuprofen+metab.+ codeine+
fluoxetine+ salicylates+ caffeine
U:
methamphetamine+amphetamine+ephedrine+
bromazepam metabolites
G: acebutolol
U: acebutolol + metabolites
Coma, circulation
failure, death suicide
Sectral 20 tbl.x
400mg = 8 g
M-53
2 incidental gulps
S: EG 337 ng/ml
years
(cca 60 ml) of
U: EG 9640 ng/ml
FRIDEX - 45 min
before visiting a
doctor and sampling
for toxicology
G: gastric content; B: blood; S: serum; U: urine
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