Topic of the lecturetoxicchem.nuph.edu.ua/wp-content/uploads/2020/01/1_Drug... · 2020. 1. 21. ·...

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

1

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.

2

2


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.

33

http://www.who.int/ipcs/publications


Introduction into drug toxicology.

The main terms and concepts.

Classification of poisons and intoxications.

4 4


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


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

6

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


77

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


8


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

99

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


1010

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


1111


The main sections of Toxicology:

Toxicometry, Toxicodynamics, Toxicokinetics

1212


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.

1313


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

1414


Toxicology considers two aspects of the xenobiotic action:

influence of a poison on a body

Toxicodynamicsinfluence of a body on a poison

Toxicokinetics

1515


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

1616


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

1717


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.

1818


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.

1919

Metabolism of xenobiotics


2020

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


Thus, one of the ways of natural detoxification is realized.

2121


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

2222

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


2323

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


24

24

N-, O-, S –

dealkylation

H3CO

O

HO

N CH3

O

HO

N CH3

HO

O

HN

HO

HO

codeine

morphine

normorphine


2525

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


2626

Toxicology

of opioid analgesics


2727


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.)

2828


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.

2929


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

3030


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

31


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.

3232


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.

33


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.

34

Toxicology

of non- opioid analgesics


3535


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

3636


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.

37

37


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

38

38


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

39


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

40


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.


41


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.


Antidote therapy

methylene blue, in methemoglobinemia


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

42

Toxicology

of non-steroidal anti-inflammatory drugs


43


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

44


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


Therapeutic dose is 325–550 mg,

per os

Toxic dose Lethal dose

325–550 mg each 3 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

45


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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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


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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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

49

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


50

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