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Drug toxicology. The main terms and concepts. Toxicodynamics
and Toxicokinetics of xenobiotics. Toxicology of opioid and non-
opioid analgesics, non-steroidal anti-inflammatory drugs
Topic of the lecture:
NATIONAL UNIVERSITY OF PHARMACY
DRUG AND ANALYTICAL TOXICOLOGY DEPARTMENT
DRUG AND ANALYTICAL TOXICOLOGY
Lecturer: Karpushyna Svitlana Anatoliivna,
Ass. Prof., PhD in Chemistry
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National University of PharmacyDrug and Analytical Toxicology Department
Plan of the lecture
1. Introduction into Drug Toxicology. The main terms and concepts. Classification of
poisons and intoxications.
2. The main sections of Toxicology: Toxicometry, Toxicodynamics, Toxicokinetics.
3. Metabolism of xenobiotics.
4. Toxicology of opioid analgesics.
5. Toxicology of non- opioid analgesics.
6. Toxicology of non-steroidal anti-inflammatory drugs.
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LITERATUREMain
1. Karpushina S.A. Toxicological chemistry. Lecture course / S.A. Karpushina, V.S. Bondar, I.O.
Zhuravel. – Kharkiv: NUPh: Golden pages, 2011. – 208 p.
2. Toxicology: Summary of lectures, practice and tests on toxicology / S.M.Drogovoz, T.O.
Kutsenko, A.Yu. Pozdniakova, V.A. Ulanova. Kharkiv : NUPh : Golden Pages, 2011.– 88 p.
3. Karpushyna, S.A. Workbook for practical lesons on drug and analytical toxicology / S.A.
Karpushyna, S.V. Baiurka. – Kh.: NUPh Publishing, 2019. – 87 p.
4. Karpushina S.A. Toxicological chemistry. Schemes and Tables: Handbook for students of
higher schools / S.A. Karpushina, V.S. Bondar. – Kharkiv : NUPh : Golden Pages, 2009.– 120
p.
Auxiliary
1. Flanagan, R. J. Developing Analytical Toxicology Services: Principles and Guidance [Electronic
resource] / R. J. Flanagan. – Geneva : World Health Organization, 2005. – 36 p. – Available at :
http://www.who.int/ipcs/publications/training_poisons/hospital_analytical_toxicology.pdf (date of
the application : (07.09.2017). – Developing Analytical Toxicology Services: Principles and
Guidance.
2. Clarke's analysis of drugs and poisons in pharmaceuticals, body fluids and postmortem
material: 4-th edition / A. C. Moffat; M.D. Osselton; B. Widdop [et al.]. – London, Chicago:
Pharmaceutical Press, 2011. – 2736 p.
3. Clarke’s Analytical Forensic Toxicology / Ed. by Sue Jickells, Adam Negrusz. – London:
Pharmaceutical Press, 2008. – 648 p.
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Introduction into drug toxicology.
The main terms and concepts.
Classification of poisons and intoxications.
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Directions of toxicology
The concept “Toxicology” originates from the Greek “toxicon” – poison and “logos” – science
The word “toxon” arises from the Greek "bow" – a means for poisoning arrows
Toxicology is the study of the interaction between chemical agents and
biological systems
Toxicology studies the properties of poisons, the mechanisms of their
action on animals and the human and develops methods for the
diagnosis, treatment and prevention of poisonings.
aconitum
mandrakecicuta
The main directions of toxicology are:
Preventive
toxicology Clinical
Theoretical
(experimental)
Drug toxicology studies the mechanisms of the drug action
of on the human body in toxic and subtoxic doses and develops
methods of diagnosis, treatment and prevention of drug
poisoning5
National University of PharmacyDrug and Analytical Toxicology Department
Poisons and their Classifications
Toxicant is a wide difinition used to denote substances that have a harmful (toxic) effect on
the body, and provoke other forms of the toxic process in the body and in biological
systems: cells (cytotoxicant), populations (ecotoxicant).
Poison is a substance, natural or synthetic, that causes damage to living tissues and has an
injurious or fatal effect on the body when administered the body.
“All things are poison and nothing is without poison, only the dose
permits something not to be poisonous.” This early observation
concerning the toxicity of chemicals was made by Paracelsus
(1493-1541).
Xenobiotic is a foreign substance for humans and animals, including medicine.6
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Poisons and their classifications
General classifications Special classification
Chemical classification –according to the
chemical structure (organic, inorganic,
elementoorganic, etc.)
Practical classification – according to the
usage (industrial poisons, pesticides, drugs, domestic
chemicals, etc.)
Hygienical classification – according to the
toxicity rate (extraordinarily toxic, highly-toxic,
moderately toxic, little toxic substances)
Toxicological classification – according to
nonorgan-directed toxicity (nervous-paralytic,
skin-rezorbtive, general toxic, teary and irritating,
psychotic poisons)
Pathophysiological classification –
according to the type of developing
hypoxia
Pathochemical classification –
according to the mechanism of cooperation
with enzymic systems
Biological classification – according to
the character of biological consequence of
poisoning
Classification according to the rate of
carcinogenic activity
Classification according to Target organ
toxicity (cardiac, nervous, hepatic, kidney, bloody
and stomach-intestinal poisons)
Criterions of
classifications
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Classification of poisons
according to the target organ toxicity
Cardiac glycosides, tricyclic antidepressants, some alkaloids
(quinine, aconitum etc.), barium, potassium salts
Narcotics, transquillisers, sedatives, hypnotics,
organophosphorous compounds, carbon monoxide, isoniazid
derivatives, ethanol
Chlorinated halocarbons, phenols, aldehydes
Heavy metal compounds, ethylene glycol, oxalic acid
Aniline and its derivatives, nitrites, arsenic compounds
Mineral acids and alkalies, heavy metal and arsenic
compounds
Cardiac poisons
Nervous poisons
Hepatic poisons
Kidney poisons
Stomach-intestinal poisons
Bloody poisons
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Poisonings their Classifications
Toxic action is the action of a substance (drug) that causes structural and functional
disorders in the body or its death.
Poisoning (Intoxication) is the disorder of vital important functions of an organism under the
action of a poison.
Forms of toxic process
Toxic process can manifest at different biological levels:
at the cellular level (structural and functional changes in
the cell and its organelles, mutations - genotoxicity)
at the level of the whole organism - intoxication; transient
toxic reactions; allobiosis - persistent change in the
reactivity of the organism: allergy, immunosuppression,
fatigue; special long-term toxic effects, developing only in
a part of the population and characterized by a long latent
period: carcinogenesis, embryotoxicity, impairment
reproductive functions, etc.
at the population and biogeocenological level - ecotoxic
effect
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Poisonings and their classifications
According to the
reason of origin
According to the
place of origin
According to the age
According to the rate
of development
Accidental: self-treatment, drug
overdose, drug abuse, alcohol
intoxication, incidents on industrial
premises or in daily life
Attempted: suicidal and criminal
Domestic
Hospital
Occupational
Adult
Children
Acute
Subacute
Chronic
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Organic solvent, etc.
Medication
Pesticide
Domestic chemical
Cosmetic mean
According to
the origin of poison
Lethal
Non-lethal
According to the eventual
result of disease
Poisonings and their classifications
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The main sections of Toxicology:
Toxicometry, Toxicodynamics, Toxicokinetics
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Toxicometryis a combination of methods for the quantitative assessment of toxicity of
poisons
The main toxicometric parameters of a substance are:
the median lethal dose, LD50, and
the median lethal concentration in air (LC50)
The LD50 is the dose of a substance that causes the death of 50% of
experimental animals for 14 days when administered orally, intraperitoneally,
intravenously, intramuscularly and expressed in units of mass of the substance,
referred to the unit of body mass of the experimental animal (mg/g).
Lethal dosage often varies depending on the method of administration. For instance, many
substances are less toxic when administered orally than when intravenously administered.
For this reason, LD50 figures are often qualified with the mode of administration, e.g.,
"LD50 i.v."
For gases and aerosols, lethal concentration (given in mg/m3 or ppm, parts per million) is
the analogous concept, although this also depends on the duration of exposure, which has
to be included in the definition.
CL50 is the concentration of a substance in an experiment that causes the death
of 50% of animals during two-, four-hour inhalation exposure.
The median lethal dose, LD50, and the median lethal concentration in air (LC50) are the most statistically
accurate values.
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LD50 (and LC50) is necessarily established for several (minimum four) species of laboratory animals in order to study interspecific sensitivity to the action of a poison.
Extrapolation of data obtained for laboratory animals to humans is an important aspect of preclinical toxicometry of developed drugs.
Dosing substances for mammals according to the constant of
biological activity (R)
Parameter mous
e
rat guinea
pig
rabbit dog cat human
R 3.20 3.62 2.63 2.20 1.44 1.47 0.57
Rhuman / (LD50) human = Ranimal / (LD50)animal
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Toxicology considers two aspects of the xenobiotic action:
influence of a poison on a body
Toxicodynamicsinfluence of a body on a poison
Toxicokinetics
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Toxicodynamics
describes the mechanisms of action of toxicants and manifestations of
various forms of the toxic process
The structural component within a living organism a
toxicant binds is called its “receptor” or “target”.
Targets (receptors) for exposure to toxicants can be:
elements of the extracellular space;
elements of the cells of the body;
elements of cell activity regulation systems
(enzymes)
Toxicity of drugs is determined by:
The ability of the drug to reach the target structure,
The nature and strength of the bonds between the
toxicant and the target structure
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The qualitative and quantitative characteristics of a developing toxic
process are determined by the chemical structure of the molecule and the
physicochemical properties of the toxicant:
molecule size,
molecule geometry (isomerism forms: structural, optical, geometric,
tautomerism)
water solubility,
lipid solubility (biological permeability of the toxicant is proportional to the
value of the lipophilicity coefficient Log P (octanol / water)),
acid-base nature of toxicant (pKa), the stability of the toxicant in the
environment (after ingestion, most xenobiotics undergo a
biotransformation at different rates).
the ability of a toxicant to chemical and intermolecular interaction
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Organophosphorus compounds inhibit the acetylcholinesterase enzyme via phosphorylation.
Oximes, that can displace the phosphoryl group from the enzyme active center, restore the
enzyme’s catalytic activity.
Oximes are used in treating the organophosphorus compound poisonings and called
cholinesterase reactivators, chemical antidotes.
Inhibited acetyl-cholinesterase Reactivated acetyl-cholinesterase
Cholinesterase reactivators
Pralidoxime (2-PAM) Dipiroxim Alloximum Isonitrosin
During the formation of strong bonds between a toxicant and a target molecule, destroying
the target-toxicant complex is sometimes possible only with the help of other compounds
that form even stronger complexes with the poison.
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Toxicokinetics studies patterns, as well as qualitative and quantitative characteristics of
absorption, distribution, protein binding (biotransport), biotransformation (metabolism) and
excretion of toxicants from the body
Basic toxicokinetic parameters:
C is the concentration of toxicant in blood plasma, μg (ng)/ml (l)
Vd is volume of distribution, l/kg (Vd = D/C0)
Fb% is plasma protein binding
t 1/2 is the half-life of a substance
CL is clearance (the volume of plasma from which a substance is completely removed per unit
time), mL/min are the usual units (CL = Vd ∙ k elimination for single-chamber model)
Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, and α, β‚
and γ globulins.
The less bound a drug is, the more efficiently it can penetrate a cell membrane. Only the unbound drug
fraction may exhibit activity.
The drug displacing each other and changing the clinical effect can be important in some case.
The common example displaing the importance of this effect is the anticoagulant Warfarin. Warfarin is
highly protein-bound (>95%) and has a low therapeutic index. A low therapeutic index indicates that
there is a high risk of toxicity when using the drug. So any potential increases in warfarin concentration
could be very dangerous and lead to hemorrhage. In horses, it is very true that if warfarin and
phenylbutazone are administered concurrently, the horse can develop bleeding issues which can be
fatal. The real problem is that phenylbutazone interferes with the liver's ability to metabolize warfarin so
free warfarin cannot be metabolized properly or excreted. This leads to an increase in free warfarin and
the resulting bleeding issues.
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Metabolism of xenobiotics
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Classification according to the type of chemical processes
(non-synthetic and synthetic routes)
Phase I of metabolism
(the non-synthetic routes) is the enzymatic transformation of
molecules. It includes the transformation of a
substance chemical structure resulting in a large increase in xenobiotic hydrophilicity, that accelerates its excretion from the body with the urine,
thereby reducing the time of its action and reducing toxicity.
Phase II of metabolism
(the synthetic routes) –
formation of endogenous compounds
(conjugates), which are more polar
and soluble in water, less toxic, easily
excreted in urine then products of
Phase I reactions
Сlassifications of xenobiotic metabolism processes
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Thus, one of the ways of natural detoxification is realized.
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Enzymes involved in Phase I of xenobiotic biotransformation can be classified
according to the type of reaction being activated:
Enzymes of the monooxygenase system: cytochrome P450 and flavin-
containing monooxygenase (FMO)
Prostaglandin synthetase (PGS), e.g. hydroperoxidases and other
peroxidases
Alcohol dehydrogenase and aldehyde dehydrogenase
Flavoprotein reductase
Epoxide hydrolases
Esterase and amidase
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Phases of metabolism and metabolic routes
Phase of
metabolism
Biochemical
reaction Examples
Phase I
Oxidation
Oxidation of alcohols to aldehydes and carboxylic acids
Hydroxylation of
aromatic and
cyclic compounds
benzene phenol
OH
R C
O
H
[O]
R COOH
R COH
[O]
R C
O
H
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Phase I N-, S-oxidation
Reduction
Hydrolysis
N
S
R
R
N
S
R
R
O
N
S
R
R
O O
1
2
1
2
[O]
1
2
[O]
sulphoxide
sulphone
NO2[H]
NH2
O C
O
N СH3 СH
СH2OH
OHN СH3 СH
СH2OH
HOOC+
atropine
tropine tropic acid
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N-, O-, S –
dealkylation
H3CO
O
HO
N CH3
O
HO
N CH3
HO
O
HN
HO
HO
codeine
morphine
normorphine
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Phase II Conjugation
Alkylation
Acetylation
N
NCl
O
OH
H
C6H5
H
N
NCl
O
O
H
C6H5
H
C6H9O6
oxazepam
oxazepam glucuronide
N N
CH3
pyridine N-methylpyridine
NH2
NHCOCH3
aniline acetanilide
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Toxicology
of opioid analgesics
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Opioids
can be defined as psychoactive chemicals that work by specific binding to
opioid receptors and narcotic analgesics in clinical manifestations
Opioids include
synthetic opioids
such as fentanyl and its
derivatives, promedol,
tramadol, methadone,
buprenorphine, naloxone,
naltrexone, etc.
natural opiates (morphine, codeine,
omponon which are
natural alkaloids found in
the resin of the opium
poppy, Papaver
somniferum)
semi-synthetic
opiates, they are morphine
derivatives
(heroin, dionin –
ethylmorphine,
apomorphine, etc.)
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National University of PharmacyDrug and Analytical Toxicology Department
Morphine hydrochloride and synthetic opioids: promedol, fentanyl, tramadol are narcotic
analgesics used for treatment of moderate to severe pain.
Codeine phosphate, dionin are used in headaches, neuralgias, cough, and they is are pain-
killing agents; analgesic effect of codeine is less pronounced than that of morphine.
Apomorphine as an strong the central nervous system stimulator, and especially the vomiting
center is used as an emetic and expectorant and in the treatment of alcoholism.
Methadone, buprenorphine are used in opioid replacement therapy.
Heroin (diacetylmorphine) is more toxic than morphine. Its use in medicine is prohibited in
many countries. Frequent and regular administration is associated with tolerance and physical
dependence.
Internationally, diacetylmorphine is controlled under Schedules I and IV of the Single Convention on Narcotic Drugs
Under the chemical names “diamorphine” or “diacetylmorphine”, heroin is a legally prescribed controlled drug in
the United Kingdom, and is supplied in tablet or injectable form for the same indications as morphine.
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Toxicokinetic data
Drug toxic dose lethal dose
Morphine 60 – 200 mg 200 – 400 mg
Codeine 300 – 800 mg 0.5 – 1 g
Fentanyl >100 mg/kg/hour 7.5 mg
Tramadol 400 mg 0.5 – 5 g
Methadone up to 50 mg,
but in cases of acquired
tolerance lethal dose may be
200 mg or more
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Mechanisms of toxic action
Depression of the respiratory centre resulting in development of non-
cardiogenic pulmonary edema.
The risk of cerebral edema due to expansion of its vessels.
Development of respiratory acidosis as a result of respiration suppression
and accumulation of CO2 in the blood.
Hypoxia of the nerve tissue resulting in convulsions.
Impaired function of the cardiovascular system arises from hypoxia due to
respiratory failure.
Violation of the vagus nerve and direct spasmogenic action on smooth
muscle resulting in bradycardia, increased tone of smooth muscles
(bronchus, sphincter of the gastrointestinal tract, etc.).
Stimulation of the vomiting centre.
Stimulation of the nucleus of the oculomotor nerve resulting in pupil
constriction (miosis).
symptoms of the central nervous system dysfunction (excitation which
changes increasing sleepiness).31
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Poisoning symptoms
Toxic effects of application include hyperemia of the face, dizziness,
nausea.
Then develops apathy, pallor of the skin, pupillary constriction (“point
pupil”), constipation, urinary retention, hypothermia, drowsiness,
bradycardia.
In severe poisoning symtompes include cyanosis of the skin and mucous
membranes, collapse, hypothermia, hypotension, hypertonicity of gastric,
intestinal, bladder, hypertonic muscles, possible clonic and tonic seizures,
confusion, respiratory depression, coma, acute respiratory failure and
pulmonary edema.
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Treatment of the poisoningAntidote therapy:
Use of opiate antagonists of a competitive type
naloxone (in acute opiate intoxication)
naltrexone (more prolonged action applied in opioid addiction)
Methods for enhancing natural processes of detoxification:
To prevent further absorption of morphine and remove it from the body repeated gastric lavage (with 5%
NaCl) is used regardless of the time that has passed since the adoption of the poison even in parenteral
morphine administration, emetics are contraindicated
introduction of activated charcoal or other enterosorbents to the stomach;
repeated washing the intestine with 5% NaCl every 8 h during the first day after hospitalization
stimulation of diuresis;
stimulation of biotransformation (with SH-group donors: lipoic acid, acetylcysteine) and glucuronidation
(with phenytoin)
Methods of artificial detoxification:
hemofiltration
therapy of respiratory failure syndromes (Bemegrid is not prescribed), toxic encephalopathy,
cardiovascular insufficiency, etc.
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National University of PharmacyDrug and Analytical Toxicology Department
Factors that influence the toxicity of OA
Factors that increase toxicity:
Concomitant use of OA and drugs that suppress the central nervous system may
increase the depression of the central nervous system and respiration.
OA are not compatible with antiparkinsonian drugs, muscle relaxants, β-adrenoblockers,
glucocorticosteroids, adrenocorticotropic hormone.
In combination with TCA they cause arrhythmogenic effect.
Inhibitors of MAO increase the effect of OA.
Combination of OA with alcohol is often fatal.
Factors that reduce toxicity:
Ascorbic acid facilitates the excretion of OA with urine.
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Toxicology
of non- opioid analgesics
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Classification of non-opioid analgesics (NOA) by mechanisms of action
NOA are drugs with a slow analgesic effect.
NOA differ from OA in that they are not addictive, and also
show antipyretic and anti-inflammatory effects.
Baraldas
Spasmalgon NEO
Non-opioid analgesics
With the central component of
actionPeripheral action
Spasmoanalgesics
Paracetamol
Ketorolac
medicines
containing
paracetamol:
Eferalgan,
Fermeaks)
Metamizole
Sodium
(Analgin)
Pentalgin
Tsitramon
Sedalgin
Tempalgin
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National University of PharmacyDrug and Analytical Toxicology Department
Toxicology of paracetamol
Acetaminophen overdose is one of the most common drug-related toxicities reported to poison
centres over the world.
Paracetamol is the main cause of acute liver failure in the United States (the II place), in
Germany and the United Kingdom (the I place).
To reduce the risk of hepatotoxicity, the Food and Drug Administration of USA (FDA) requires that
manufacturers limit the amount of acetaminophen in a pill to 325 mg
The FDA has also recommended that the healthcare professionals avoid prescribing and dispensing
products containing more than 325 mg of paracetamol per dose.
For adults the lethal dose is 5 – 15 g
For adolescents lethal dose is 13 – 25 g
Children under the age of 10 are much more resistant to
paracetamol poisoning.
Toxicokinetic data
The maximum recommended therapeutic dose of paracetamol is 4 g per a day in adults and 50 – 75 mg/kg/ a day in children.
Administration of a single dose greater than 7 g in an adult and 150 mg/kg in a child is considered potentially toxic to the liver
and kidneys due to the highly active metabolite, NAPQI.
Paracetamol (acetaminophen, panadol) is a derivative of p-aminophenol
Medical uses. Paracetamol shows antipyretic, anti-inflammatory and analgesic effect. It is used for
headaches, neuralgia, myalgia, as an antipyretic to relieve cold-related symptoms.
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Mechanism of toxic action
Acute overdoses of paracetamol can cause potentially fatal liver damage
Pathways of paracetamol metabolism glucuronidation which is catalyzed by UDP-
glucuronosyltransferases (UGTs), a phase II drug-metabolising enzymes;
sulphate conjugation which is catalyzed by adenosine 5'-phosphosulfate (APS) or 3'-phosphoadenosine-5'-phosphosulfate (PAPS), this biosynthesis of sulphate esters depends on liver sulfur reserves;
3-hydroxylation followed by conjugation and O-methylation of the hydroxyl group; these paths of biotransformation are of secondary importance;
oxidation to a highly reactive metabolite of N-acetyl-p-benzoquinone imine (NAPQI); is catalyzed by the cytochrome P450 mixed function oxidase enzymes.
The last biotransformation pathway is of little importance when receiving therapeutic doses of paracetamol, and it becomes much more important when taking large doses of the drug.
Glutathione of the liver quickly depletes this highly toxic substance by converting it into a cysteine or mercaptopurine conjugate.
When the glutathione content in the liver falls below the critical level (about 30 % of the normal stock), NAPQI covalently binds to macromolecules of hepatocytes, resulting in necrosis of the tissue.
MethemoglobinemiaNAPQI promotes the transition of hemoglobin to methnemoglobin
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Poisoning symptoms
Most people have few or non-specific symptoms in the first 24 hours following overdose. This may include
feeling tired, abdominal pain, or nausea.
This is typically followed by a couple of days without any symptoms after which yellowish skin, blood clotting
problems, and confusion occurs as a result of liver failure.
Additional complications may include kidney failure, pancreatitis, low blood sugar, and lactic acidosis.
If death does not occur, people tend to recover fully over a couple of weeks. Without treatment some cases
will resolve while others will result in death.
Treatment of the poisoning
Antidote therapy
Using Acetylcysteine (or Methionine)
If more than 150 mg/kg of paracetamol per os was taken and
the plasma level is unknown, and the clinical presentation of
poisoning indicates the paracetamol-induced hepatic failure, N-
acetylcysteine (NAC) therapy is carried out. NAC is a N-
acetylated derivative of the natural amino acid, L-cysteine. The
initial oral dose is 140 mg/kg in 5 % solution of NAC, then
another 17 doses of 70 mg/kg in the same solution are given
every 4 hours. NAC is prescribed intravenously in the event of
nausea and vomiting in the victim.
Methylene blue, Tocopherol, Sodium Nitrite are used
in methemoglobinemia
Gastric decontamination
(Gastric lavage, Activated charcoal,
Induced vomiting with syrup of ipecac has no role in the paracetamol overdose because vomiting decreases the effectiveness of oral administration of activated charcoal and acetylcysteine.
Liver transplantation
In people who develop
acute liver failure or who
are otherwise expected to
die from liver failure
Acetylcysteine
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National University of PharmacyDrug and Analytical Toxicology Department
Factors which increase hepatotoxicity of paracetamol
level of glutathione stock (decreases during exhaustion, fasting, chronic alcoholism)
drugs that can activate reactions that are mediated by cytochrome P-450 (some
psychotic agents, e.g. phenobarbital)
chronic liver disease (due to decreased paracetamol clearance)
Factors that influence the toxicity of paracetamol
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National University of PharmacyDrug and Analytical Toxicology Department
Toxicology of Metamizole Sodium
Metamizole Sodium (Analgin), a derivative of 5-pyrazolone, is a common analgesic and antipyretic
drug.
It is primarily used for perioperative pain, acute injury, colic, cancer pain, other acute/chronic forms
of pain and high fever unresponsive to other agents
However, its use has been associated with a risk of side-effects involving agranulocytosis and
aplastic anemia.
Toxicokinetic data
Metamizole therapeutic dose is 1–3 g, toxic dose is 10–15 g.
Agranulocytosis. Analgin causes hemolysis due to the formation of immune
complexes that are adsorbed on the erythrocyte membranes, which leads to their
damage and destruction.
Methemoglobinemia
Neurotoxicity of NOA is due to their ability to penetrate through the BBB (blood–
brain barrier) and suppress the central nervous system by reducing the production of
PGE2 (prostaglandin E2) which is involved in the regulation of cerebral circulation.
Mechanism of toxic action
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Poisoning symptoms
Toxic effects: Neuro-, hemato- and nephrotoxic in long-term use.
Easy form of overdosage causes nausea, ear noise, vomiting, fainting, hypothermia,
breathlessness, palpitations.
Heavy form of overdosage causes swelling, cyanosis, seizures, drowsiness, loss of consciousness,
pulmonary edema, hypotension, blood has a chocolate tint.
Treatment of the poisoning
Antidote therapy
methylene blue, in methemoglobinemia
Gastric decontamination
gastric lavage, enterosorption during the acute
period of the disease (activated charcoal and
other enterosorbents)
Forced alkaline diuresis
Hemosorption
Regular prolonged use of
Metamizole leads to myelotoxic
manifestations.
With long-term use of metamizol, it
is necessary to periodically conduct
a blood test.
Factors that influence the toxicity of Metamizole
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Toxicology
of non-steroidal anti-inflammatory drugs
National University of PharmacyDrug and Analytical Toxicology Department
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National University of PharmacyDrug and Analytical Toxicology Department
NSAIDs are medicines that simultaneously have anti-inflammatory, analgesic and
antipyretic effects, and when used for prolonged periods, they do not cause drug
dependence
Classification of NSAIDs by chemical structure
NSAIDs which are
derivatives of
Pyrazolone and
Indolacetic AcidCombined drugsSalicylic acid
Phenylpropionic acid
and phenylsalicylic
acid
Phenilbutazone
(antipyrine)
Indomethacin
Rheopyrin
Nimesulide
Aspirin
(Acetylsalicylic
acid, ASA)
Lysine-
acetylsalicylic
acid
Ketoprofen
Ibuprofen
Diclofenac
sodium
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National University of PharmacyDrug and Analytical Toxicology Department
Toxicology of Acetylsalicylic acid
The average number of acetylsalicylic acid tablets, which can
cause damage to the stomach, is 106 per year
Toxicokinetic data
The development of gastropathy
Aspirin has antiinflammatory effect due to inhibition of the cyclooxygenase enzyme
(COX) activity. This resulting in oppression of PGE2 prostaglandine ( they possess a
cytoprotective effect) synthesis and decreasing the amount of mucus protecting the
gastrointestinal mucosa
Damage to the cell membrane of the gastrointestinal epithelium, which leads to the
formation of ulcers, necrosis and perforation
Mechanism of toxic action
Therapeutic dose is 325–550 mg,
per os
Toxic dose Lethal dose
325–550 mg each 3 hours
325–650 mg each 4 hours
650–1000 mg each 6 hours
0.1-0.15 g/kg 5–30 g2–10 g (for children)
Pharmacological action: analgesic, antipyretic, anti-inflammatory, anti-aggregate.
Gastric Mucosal Erosion -
side effect of aspirin
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National University of PharmacyDrug and Analytical Toxicology Department
Poisoning symptoms
Toxic effects: Ray's syndrome ("white liver disease") and
aspirin asthma
Ray's syndrome is such a syndrome in children under the age of
13 years, accompanied by inflammation and cerebral edema,
rapid liver tissue damage and hepatic fat accumulation.
Clinical picture of poisoning:
nausea, vomiting, noise in the ears, fever
with increasing severity of poisoning there are
stupor, cramps and coma, non-cardiogenic pulmonary
edema, metabolic acidosis, toxic shock with renal failure.
“In chronic poisoning”, besides the symptoms of "salicylism”,
there are
dyspeptic disorders, gastrointestinal bleeding, "aspirin"
bronchial asthma, interstitial nephritis with renal insufficiency
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National University of PharmacyDrug and Analytical Toxicology Department
Treatment of the poisoning
Gastric decontamination
gastric lavage, enterosorption,
Forced diuresis
Hemodialysis is indicated at a concentration of salicylates in the blood of more
than 150 mg/ml and in the phenomena of metabolic acidosis (alkaline
bicarbonate hemodialysis). As a specific pharmacotherapy sodium bicarbonate is
used - 7.4 g per 1 liter of 5% glucose solution intravenously at a rate of 10-15 mg
/ kg per hour.
Symptomatic treatment: intravenous fluid therapy with crystalloids.
Hyperventilation and osmotic diuresis are indicated for pulmonary and brain
edema.
Smoking and prolonged use of NSAIDs promotes its toxicity.
Salicylates are unacceptable with simultaneous application with heparin
and other anticoagulants, hypoglycemic, diuretic, antihypertensive drugs.
ASA is unacceptable with atropine sulfate, vitamins B1, A, B12, papaverine
hydrochloride, other NSAIDs and preparations containing them.
While taking NSAIDs, alcohol should not be consumed, as the irritating
effect on the gastric mucosa increases.
Factors that influence the toxicity of salicylates
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Students' Individual Work Tasks
National University of PharmacyDrug and Analytical Toxicology Department
1. Toxicological characteristics of NSAIDs of phenylpropionic and
phenylacatic acid derivatives (ibuprofen, diclofenac sodium).
2. Toxicological characteristic of NSAIDs of pyrazolone derivatives
(phenylbutazone) and indolacatic acid (indomethacin).
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National University of PharmacyDrug and Analytical Toxicology Department
The knowledge of toxicometric parameters characterizing the degree of toxicity
and the risk of a poisoning, mechanism of drug toxicity, toxicodynamics,
treatment of the poisonings, factors that influence the drug toxicity is necessary
for searching the safe biologically active substances, medicines for effective
specific antidote therapy, to predict the effects of drug interactions when
combining medicines, a medicine and components of food, a medicine and
alcohol.
The knowledge of toxicokinetics, which includes the routes of administration,
absorption, distribution, cumulation, metabolism and excretion of xenobiotics, is
necessary for the toxicologist to correctly construct an algorithm for carrying out
the toxicological research and interpreting its results.
This topic gives the methodical basis for preparation of pharmacists specializing
in the biopharmacy, farmaco- and toxicokinetics, clinical pharmacy.
Сonclusions
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The knowledge of toxicometric parameters characterizing the degree of toxicity
and the risk of a poisoning, mechanism of drug toxicity, toxicodynamics,
treatment of the poisonings, factors that influence the drug toxicity is necessary
for searching the safe biologically active substances, medicines for effective
specific antidote therapy, to predict the effects of drug interactions when
combining medicines, a medicine and components of food, a medicine and
alcohol.
The knowledge of toxicokinetics, which includes the routes of administration,
absorption, distribution, cumulation, metabolism and excretion of xenobiotics, is
necessary for the toxicologist to correctly construct an algorithm for carrying out
the toxicological research and interpreting its results.
This topic gives the methodical basis for preparation of pharmacists specializing
in the biopharmacy, farmaco- and toxicokinetics, clinical pharmacy.
Thank you for your attention
National University of PharmacyDrug and Analytical Toxicology Department
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