chemical carcinogen

7/30/2019 Chemical Carcinogen

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Chemical Carcinogens


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Carcinogenesis, Definitions& Nomenclature

Carcinogenesis

The term refers to the process by which a normal cell is transformed into a

malignant cell and repeatedly divides to become a cancer

A chemical which can causes or induce this process is called a chemical

carcinogen

Cancer is a group of diseases in which there is a n uncontrolled proliferation of

cells that express varying degrees of fidelity to their precursor cell of origin

Cancer vs. neoplasia:

Cancer is a malignant neoplasm (tumor)

Neoplasia (new growth in Greek) is the formation of a neoplasm.

Neoplasm is genetically altered, relatively autonomous growth of tissue thatpersists in the same autonomous growth after cessation of the stimulus which

evoked the change

Neoplasm may be either benign or malignant.

Successful metastatic growth malignant

No metastasis

benign

Metastasis is a secondary growth of cells from the primary neoplasm


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Carcinogenesis, Definitions& Nomenclature, contd.

Neoplasia Nomenclature

For most benign neoplasms, the tissue of origin is followed by the suffix -oma,

e.g., adenoma (a collection of growths (-oma) of glandular origin.)

Malignant neoplasms derived from epithelial tissues are termed carcinomas with

antecedent tissue descriptor, e.g., hepatocellular carcinomas

For malignant neoplasms derived from tissues of mesenchymal origin, the term

sarcoma is added to the tissue descriptor, e.g., osteosarcoma

Neoplasia vs. hyperplasia, dysplasia and metaplasiaHyperplasia is a reversible increase in cell division caused by an external

stimulus, such as a hormonal imbalance or chronic irritation, which ceases when

the stimulus is removed. Hyperplasia involve normal cells

Dysplasia (or atypical hyperplasia) is a proliferation of abnormal cells with

variable size and shape. Dysplasia often occurs in the vicinity of cancerous cells.Dysplasia probably represents an intermediate stage in a multi-step pathway

leading from normal to neoplastic.

Metaplasia is the replacement of one type of differentiated cell by another in

response to a stimulus, usually a noxious stimulus. Metaplasia is often reversible,

Example: the replacement of bronchial columnar epithelium by squamous epithelium

in cigarette smokers.


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Multistage Carcinogenesis

Although most chemical carcinogens do not react directly with intracellularcomponents, they are activated to carcinogenic and mutagenic electrophiles

by metabolic processes evolutionarily designed to rid the body of toxins

Electrophilic chemical species are naturally attracted to nucleophiles like

deoxyribonucleic acid (DNA) and protein, and through covalent bonding to

DNA genetic damage results Once internalized, carcinogens are subject to competing processes of

metabolic activation and detoxification (individual variation!), although some

chemical species can act directly.

Human chemical carcinogenesis is a multistage process that results from

exposures, usually in the form of complex chemical mixtures, oftenencountered in the environment or through our lifestyle and diet

A prime example is tobacco smoke, which can cause cancers at multiple

sites including the lung, the bladder, and the head and neck


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Genotoxic vs. Epigenetic Events

Genotoxic carcinogen: one that reacts directly with DNA or with

macromolecules that then react with DNA.

Epigenetics: modifications in gene expression that are controlled by heritable

but potentially reversible changes in DNA methylation and/or chromatin

structure.

Epigenetic carcinogen: one that does not itself damage DNA but causes

alterations that predispose to cancer.

DNA methylation is a type of chemical modification of DNA that can be

inherited and subsequently removed without changing the original DNA

sequence. As such, it is part of the epigenetic code and is also the most well

characterized epigenetic mechanism


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Multistage Carcinogenesis

Multistage chemical carcinogenesis can be conceptually

divided into four stages:

1. Tumor initiation

2. Tumor promotion

3. Malignant conversion

4. Tumor progression


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Multistage Carcinogenesis, Tumor InitiationThe primary genetic

change that results from a

chemical-DNA interaction

is termed tumor ini tiation.

Initiated cells are

irreversibly altered and

are at a greater risk of

malignant conversion than

are normal cells

A chemical carcinogen

causes a genetic error by

modifying the molecular

structure of DNA

Thus can lead to a

mutation during DNA

synthesis, mainly byforming an adduct between

the chemical carcinogen or

one of its functional groups

and a nucleotide in DNA

DNA adduct formation that causes either the activation of a proto-oncogene or the

inactivation of a tumor suppressor gene can be categorized as a tumor-initiating event. This leads to genomic instability and an acceleration in the genetic changes taking place


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Multistage Carcinogenesis, Tumor Promotion

Tumor promotion comprises

the selective clonalexpansion of initiated cells.

(epigenet ic effect)

Selective, clonal growth

advantage causes a focus of

preneoplastic cells to form.

Tumor promoters (e.g.,croton oil, saccharin) are

generally non-mutagenic and

are not carcinogenic alone.

They reduce the latency

period for tumor formation

after exposure of a tissue toa tumor initiator (mutation

rate rate of cell division)

M lti t C i i


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Multistage Carcinogenesis, Tumor Promotion toMalignant Conversion

The total dose of a tumor

promoter is less significantthan frequently repeated

administrations,

if the tumor promoter is

discontinued before

malignant conversion has

occurred, pre-malignant orbenign lesions may

regress

Tumor promotion contributes

to the process of

carcinogenesis by the

expansion of a population ofinitiated cells, with a growth

advantage, that will then be at

risk for malignant conversion

Chemicals or agents capable of both tumor initiation and promotion are known ascomplete carcinogens, e.g., benzo[a]pyrene


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Multistage Carcinogenesis, Tumor Promotion toMalignant Conversion

Additional genetic changes

(mutations) continue toaccumulate

The accumulation of

mutations, and not

necessarily the order in

which they occur, constitutes

multistage carcinogenesis

This scenario is followed by

malignant conversion, tumor

progression, and metastasis

Carcinogenesis requires the

malignant conversion of

benign hyperplastic cells to a

malignant state, and invasion

and metastasis are

manifestations of further

genetic and epigenetic

changes


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Multistage Carcinogenesis, Malignant Conversion

Malignant conversion is the

transformation of apreneoplastic cell into one

that expresses the

malignant phenotype

This process requires

further genetic changes

A prominent characteristicof the malignant phenotype

is the propensity for

genomic instability and

uncontrolled growth.

During this process, further genetic and epigenetic changes can occur, again including

the activation of proto-oncogenes (e.g., ras) and the functional loss of tumor suppressorgenes (e.g., p53).


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Multistage Carcinogenesis, Tumor ProgressionTumor progression

comprises the expression of

the malignant phenotype and

the tendency of malignant

cells to acquire more

aggressive characteristics

over time.

Also, metastasis may involve

the ability of tumor cells to

secrete proteases that allow

invasion beyond the

immediate primary tumor

location.


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Common Chemical Carcinogens

Carcinogen Type of Cancer

Occupational carcinogens

Soot and mineral oil Skin cancer

Arsenic Lung cancer, skin cancerAsbestos Lung cancer, mesothelioma

Hair dyes and aromatic amines Bladder cancer

Benzene Leukemia

Nickel Lung cancer, nasal sinus cancer

Formaldehyde Nasal cancer, nasopharyngeal cancer

Vinyl chloride Hepatic angiosarcoma

Painting materials, non-arsenic pesticides, dieselexhaust, chromates chromates

Lung cancer

Lifestyle carcinogens

Alcohol Esophageal cancer, oropharyngeal cancer

Tobacco Head and neck cancer, lung cancer, esophagealcancer, bladder cancer

Drug carcinogens

Alkylating agents Leukemia

DiethylstilbestrolLiver cell adenoma, vaginal cancer in exposed female

fetuses

Oxymetholone (Anadrol) Liver cancer


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IARC Classification of carcinogens

IARC (International Agency forResearch on Cancer)

IARC class 1: The substance is carcinogenic to humans, e.g. arsenic, aflatoxinB1, estrogens

IARC class 2A: The substance is probably carcinogenic to humans (sufficientevidence of carcinogenicity in animals, but limited evidence of

carcinogenicity in humans), e.g., benzo[a]pyrene, adriamycin

IARC class 2B: The substance is possibly carcinogenic to humans , e.g., carbontetrachloride, chloroform

IARC class 3: The substance is not classifiable as to its carcinogenicity to

humans, e.g., chloroquine, diazepam, 5-fluorouracil

IARC class 4: The substance is probably not carcinogenic to humans. Thiscategory is used for agents or mixtures for which there is

evidence suggesting lack of carcinogenicity in humans and in

experimental animals


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Structure of Representative Chemical Carcinogens


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Classification of Carcinogens According to

the Mode of Action, Based on Reactivity with DNA

I. Genotoxic Carcinogens

I. Non-Genotoxic (Epigenetic) Carcinogens


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the Mode of Action, Based on Reactivity with DNA

I. Genotoxic Carcinogens

DNA-reactive (direct-acting) or DNA-reactive (indirectly acting ) metabolites

The interaction with DNA mutation due to alteration in the structure of DNA

inaccurate replication of that region of the genome

Genotoxic Carcinogens formation of DNA adducts (the most common), DNA strand

breaks, and DNA-protein cross-links

N7 of G is the most nucleophilic site in DNA, at which many ultimate carcinogens form

covalent adducts

+ = DNA Adduct Mutation Cancer


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Genotoxic Carcinogens, Mechanism


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Chemical Carcinogens and Their Activation

The first chemically identified carcinogens were the polycyclic aromatic hydrocarbons

(PAHs)

They are composed of variable numbers of fused benzene rings that form fromincomplete combustion of fossil fuels and vegetable matter (including tobacco), and they

are common environmental contaminants.

The PAHs are chemically inert, and require metabolism to exert their biologic effects

This is a multi-step process, it involves the following: initial epoxidation (cytochrome

P450, CYP1A1 is an inducible isoform), hydration of the epoxide (epoxide hydrolase),and subsequent epoxidation across the olefinic bond (CYP1B1; CYP3A4)

The result is the ultimate carcinogenic metabolite, a diolepoxide

The arene ring of benzo[a]pyrene-7,8-diol 9,10-oxide opens spontaneously at the 10

position, giving a highly reactive carbonium ion that can form a covalent addition

product (i.e., adduct) with cellular macromolecules, including DNA

Several DNA-adducts can be formed, the most abundant being at the exocyclic amino

group of deoxyguanosine ([7R]-N2-[10-{7,8,9-trihydroxy-7,8,9,10-tetrahydro-

benz[a]pyrene} yl] - deoxyguanosine; BPdG)


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Metabolic Activation of Benzo(a)pyrene,as a Representative Examplefor Chemical Carcinogens (Genotoxic)

(1) Benzo[a]pyrene-7, 8-dihydrodiol is further metabolized at the olefinic double bond by

cytochrome P450 to form a vicinal diolepoxide (7, 8-dihydroxy-9, 10 epoxy-7,8,9,10-

tetrahydroxybenz[a]pyrene)

(2) The highly unstable arene ring opens spontaneously to form a carbocation

(3) This electrophic species forms a covalent bond between the 10 position of the hydrocarbon andthe exocyclic amino group of deoxyguanosine

Procarcinogen Proximate Carcinogen Ultimate Carcinogen

(1) Cytochrome P450 catalyses initial epoxidation across the 1 - 2, 2 - 3, 4 -

5, 7 - 8 , 9 - 10 and 11 - 12 positions

(2) With the exception of the 1 - 2 and 2 - 3 oxides that convert to phenols,

epoxide hydrolase may catalyze the formation of dihydrodiols

N7(benzo[a]pyren-6-yl)guanine


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I. Epigenetic (non-genotoxic) CarcinogensNo direct chemical reactivity with DNA

They are non-mutagenic

Usually act as tumor promoters

There are no common chemical structural features between these chemicals

Their carcinogenic potential is generally lower than that of genotoxic

carcinogens


the Mode of Action,Based on Reactivity with DNA


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Epigenetic Carcinogens, Mechanisms

1. Prolonged stimulation of cell proliferation, via chronic cytotoxicity or increased secretion

trophic hormones

2. Inhibition of apoptosis in cells with DNA damage

3. Impairment of DNA-replication fidelity and DNA-repairing machinery

4. Dysregulated gene expression

Altered DNA methylation status in the genes that control cell growth and differentiation

5. Induction of metabolizing enzymes

6. Dysregulated cell signaling via receptor- or non-receptor-mediated pathways

7. Persistent immunosuppression, leading to compromised immunosurveillance

8. Oxidative Stress

Indirect DNA damage

Induction of cell proliferation signaling cascades


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Cell Replication is Essential for Multistage

Carcinogenesis

Decreases time available for DNA repair

Converts repairable DNA damage into non-repairable mutations

Necessary for chromosomal aberrations, insertions, deletions and geneamplification

Clonally expands existing cell populations

Examples: Epidermal growth factor, hepatocyte growth factor, estrogens


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Apoptosis

Programmed Cell Death (Apoptosis): Active, orderly and cell-type-specific

death distinguishable from necrotic cell death (passive process):

Induced in normal and cancer cells

Non-random event

Result of activation of a cascade of biochemical, gene expression and

morphological events

Tissue and cell specific

Growth factors and mitogens inhibit apoptosis


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Alteration of Gene Expression

Nuclear (hormone-like) receptors

Kinase cascades

Calcium-mediated signaling

Transcription factors

Gene methylation status (hypo enhanced gene expression; hyper gene

silencing)

The next four slides are just for your own information


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Intracellular Receptors

These receptors could be cytosolic or nuclear

Several biologic signals are sufficiently lipid-soluble to cross the plasma

membrane and act on intracellular receptors.

Examples of such ligands include corticosteroids, mineralocorticoids, sex

steroids, vitamin D, and thyroid hormone. They can stimulate the transcription of

genes in the nucleus by

binding to nuclear receptors

This binding of hormone exposes a normally hidden domain of the receptor

protein, thereby permitting the latter to bind to a particular nucleotide sequence

on a gene and to regulate its transcription.

End result is an alteration in gene transcription and therefore protein synthesis

Actions: slow-acting (hours), long lasting

N l R


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Nuclear Receptors, an example

Mechanism of glucocorticoid

action.

A heat-shock protein, hsp90,

binds to the glucocorticoid

receptor polypeptide in the

absence of hormone and

prevents folding into the active

conformation of the receptor.

Binding of a hormone ligand

(steroid) causes dissociation of

the hsp90 stabilizer and permits

conversion of glucocorticoid

receptor to the active

configuration.

The active glucocorticoid receptorbinds to a particular nucleotide

sequence on a gene altered

transcription of certain genes


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Kinase-linked Receptors,Activation of Ras following binding of a

hormone (e.g., EGF) to an RTK.

1. The adapter protein GRB2 binds to a specific

phosphotyrosine on the activated RTK and to

Sos, which in turn interacts with the inactive

RasGDP.2. The guanine nucleotide exchange factor

(GEF) activity of Sos then promotes formation

of active RasGTP.

Note that Ras is tethered to the membrane by a

farnesyl anchor

Ki li k d R t


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Kinase-linked Receptors,Kinase cascade that transmits signals

downstream from activated Ras protein

1. Activated Ras binds to the N-terminal domain of

Raf, a serine/threonine kinase.

2. Raf binds to and phosphorylates MEK, a dual-

specificity protein kinase that phosphorylates

both tyrosine and serine residues.

3. MEK phosphorylates and activates MAP

kinase, another serine/threonine kinase.

4. MAP kinase phosphorylates many different

proteins, including nuclear transcription factors,

that mediate cellular responses.

Ch i l


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Chemical

Carcinogens,Representative

Members

M dif i F t i Ch i l C i i


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I. Interaction with DNA

A great body of information indicates that interaction with DNA is the critical factor inchemical carcinogenesis.

Several distinct sorts of data have been gathered. Relevant findings are as follows:

1. In general, carcinogens are mutagens, indicating that they have the potential to interact

with DNA.

2. Within groups of related carcinogenic chemicals, carcinogenic potency correlates best

with ability to interact with DNA.3. Patients with DNA repair defects, such as xeroderma pigmentosum (defect in repair of

damage induced by UV and bulky aromatic chemicals), have increased incidence of

cancer.

Modifying Factors in Chemical Carcinogenesis



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I. Environment:

The most impressive feature of cancer epidemiology is a high degree of geographic

variability in the incidence of specific forms of cancer. This can easily be seen if one

compares incidences between countries or between regions within a country

II. Genetic factors:They influence some specific cancers, this influence is a major one.The sorts of genetic involvement which have been described are:

1. Single gene - probably directly involved in carcinogenesis. Example: retinoblastoma.

2. Single gene - predisposes to cancer. Example: xeroderma pigmentosum, a DNA repair defect

3. Familial predisposition, probably polygenic. Example: increased incidence of breast cancer in

women whose mother or sister have had breast cancer


Environment vs. Genetic factors : Some of the most productive studies that have been used were analyses of changes

in cancer incidence occurring when groups of people emigrate from one country to

another

In such studies (next slide), genetic factors are essentially held constant, and effects

of environment can be observed

In most cases, dramatic changes in cancer incidence are seen in the immigrant

populations, and such changes generally lead to a cancer incidence similar to that ofthe natives in the immigrants' new homeland


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I. Biological behaviors of the chemical carcinogen:

1. Site of action: Chemicals can act both locally and distally, e.g., benzo(a)pyrene paintingcauses skin tumor, whereas DMBA painting causes tumors of the skin and breast and also

leukemia

2. Tissue responsiveness: There appears to be a great variation in tissue responsiveness

2-naphthylaminebladder tumor; urethanelung tumor; zinctestis tumor; tin and

nickelsarcoma, etc

3. Species specificity: 2-naphthylamine causes bladder cancer in man, dog and hamster, but

only liver cancer in mouse and no effect in rats.

4. Sex specificity: Hepatocarcinogens are more effective in male rats

Female reproductive history: Late age at first pregnancy is associated with enhanced risk of

breast cancer, while zero or low parity is associated with increased risk of ovarian cancer5. Age: Many carcinogens are ineffective as transplacental carcinogens at preimplantation

but more effective after organogenesis begins, and more so at postnatal life before

immune system develops




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I. Biological behaviors of the chemical carcinogen:

1. Diet: Diet greatly influences the effect of carcinogens e.g., caloric restriction in general

reduces cancer incidence (and vice versa). Phenylalanine- and cysteine-deficient diets

reduce breast cancer in mice. Azodye induced liver tumors in rats are enhanced in the

presence of vitamin B6 but decrease in the presence of B2 The most common mechanism of diet-associated carcinogenesis in humans is the action of

major dietary constituents (mainly fat and carbohydrate) as promoting agents

2. Dose responsiveness. Carcinogen effect also appears to be dose dependent, additive andirreversible. Large single dose or fractional doses appear to induce the same incidence

of tumors

3. Latency. Carcinogenesis requires time. The latent period could be shortened by means

of large doses, but a certain minimum period called the "absolute minimum period of

latency" is required

The long latent period raises the question of whether factors other than true carcinogens

might act during the latent interval

Both in vivo and in vitro results suggest that transient short exposure to carcinogen causes

irreversible changes, but this must be followed by several cell divisions before neoplastic

cells become detectable

M dif i f t i h i l i i


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Modifying factors in chemical carcinogenesis

I. Life style

Unhealthy lifestyle habits such as: excess alcohol consumption; inhalation of tobacco

and related products; the ingestion of certain foods and their contamination by

mycotoxins (such as aflatoxin B1; a complete carcinogen); are responsible for higher

incidences of certain types of neoplasias in a number of population groups

I. Immune system

Immune system may have a protective role in tumor development (i.e.,

preventing tumor formation)

Small accumulations of tumor cells may develop and because of their possession

of new antigenic potentialities provoke an effective immunological reaction with

regression of the tumor

Mice with induced immunodeficiencies showed a high susceptibility to virallyinduced tumors and a greater tendency to develop spontaneous lymphomas

compared with immunocompetent mice

At the same time, the immune system also may function to promote or select

tumor variants with reduced immunogenicity, thereby providing developing

tumors with a mechanism to escape immunologic detection and elimination.

This is called: tumor-sculpting actions of the immune system on developing tumors

M dif i f t i h i l i i


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Modifying factors in chemical carcinogenesis

I. Inflammation

Inflammation caused by uncertain aetiology (e.g. ulcerative colitis, pancreatitis, etc)is one the modifying factors in chemical carcinogenesis

Inflammation orchestrates the microenvironment around tumours, contributing to

proliferation, survival and migration.

Cancer cells use selectins, chemokines and their receptors for invasion, migration and

metastasis.

On the other hand, many cells of the immune system contribute to cancer

immunology, suppressing cancer

Principles in Management of the Poisoned


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Principles in Management of the PoisonedPatient

Toxicokinetics vs Toxicodynamics:

The term "toxicokinetics" denotes the absorption, distribution, excretion, andmetabolism of toxins, toxic doses of therapeutic agents, and their metabolites.

The term "toxicodynamics" is used to denote the injurious effects of these

substances on vital function.

Volume of Distribution: The volume of distribution (Vd) is defined as the apparent volume into which a

substance is distributed

Vd is increased by increased tissue binding, decreased plasma binding and

increased lipid solubility.

Drug with high Vd extensive tissue distribution A large Vd implies that the drug is not readily accessible to measures aimed at

purifying the blood, such as hemodialysis.

Examples of drugs with large Vd (> 5 L/kg) include antidepressants,

antipsychotics, antimalarials, narcotics, propranolol, and verapamil. Drugs

with relatively small volumes of distribution (< 1 L/kg) include salicylate,phenobarbital, lithium, valproic acid, warfarin, and phenytoin

id


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Antidotes, Definition and Types

Types of Antidotes:

1. chemical antidotes combine with the poison to create a harmless compound. For

example, neutralization of acids by weak alkalis, e.g., (HCl NaHCO3)

2. Physical antidotes prevent the absorption of the poison; e.g., activated charcoal

3. Pharmacological antidotes counteract the effects of a poison by producing the

opposite pharmacological effects, e.g., ACHE inhibitors atropine

An antidote is a substance which can counteract a form of poisoning

Some anatomic and neurotransmitter features of


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Some anatomic and neurotransmitter features ofautonomic and somatic motor nerves

N.B. Parasympathetic ganglia are not shown because most are in or near the wall of the organ innervated

Cholinergic


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Cholinergic

Transmission

After release from the presynaptic

terminal, ACh molecules may bind to andactivate an ACh receptor (cholinoceptor).

Eventually (and usually very rapidly), all of

the ACh released will diffuse within range of

an acetylcholinesterase (AChE) molecule.

AChE very efficiently splits ACh into

choline and acetate, neither of which has

significant transmitter effect, and thereby

terminates the action of the transmitter.

Most cholinergic synapses are richly

supplied with AChE; the half-life of ACh in

the synapse is therefore very short. AChE isalso found in other tissues, eg, red blood

cells.

Another cholinesterase with a lower

specificity for ACh, butyrylcholinesterase

[pseudocholinesterase], is found in blood

plasma, liver, glia, and many other tissues

Parasympathetic Nervous System


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Parasympathetic Nervous System,Receptors for acetylcholine (cholinoceptors)

I. Nicotinic receptors, nAChRs (the nicotinic actions of ACh are those that can

be reproduced by the injection of nicotine)

1. At neuromuscular junctions of skeletal muscle (muscle type)

Postsynaptic

Excitatory (increases Na+ permeability)

Agonists: ACh, carbachol (CCh), suxamethonium

Stimulate skeletal muscle (contraction) Antagonists: tubocurarine, hexamethonium

2. On postganglionic neurons in the autonomic ganglia (ganglion type)

Postsynaptic

Excitatory (increases Na+ permeability)

Agonists: Ach, CCh, nicotine

Stimulate all autonomic ganglia

Antagonists: mecamylamine, trimetaphan

Parasympathetic Nervous System


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Parasympathetic Nervous System,NicotinicReceptors for acetylcholine

1. On some central nervous system neurons (CNS type)

Pre- and postsynaptic Excitatory (increases Na+ permeability)

Agonists: nicotine, ACh

Pre- and postsynaptic stimulation of many brain regions

Antagonists: methylaconitine, mecamylamine

2. On adrenal medulla

Ach stimulates secretion of adrenaline from adrenal medulla

P th ti N S t


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Parasympathetic Nervous System,MuscarinicReceptors for acetylcholine

I. Muscarinic receptors, mAChRs (the muscarinic actions of ACh are thosethat can be reproduced by the injection of muscarine)

Location:mAChRs are located

in tissues innervated by postganglionic parasympathetic neurons such as

On smooth muscle

On cardiac muscle

On gland cells

See next table for details.

in postganglionic sympathetic neurons to sweat glands

In the central nervous system

Muscarinic Autonomic Effects of Acetylcholine


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Muscarinic Autonomic Effects of Acetylcholine Eye (iris sphincter muscle) Contraction (miosis)

Eye (ciliary muscle) Contraction (for near vision)

SA node Bradycardia

Atrium Reduced contractility

AV node Reduced conduction velocity

Arteriole Dilation (via nitric oxide)

Bronchial muscle Muscle Contraction

Bronchial secretion Increase

GIT (motility) Increase

GIT (secretion) Increase

GIT (sphincters) Relaxation

Gallbladder Contraction

Urinary bladder (detrusor) Contraction

Urinary bladder (trigone, sphincter) Relaxation

Penis Erection (but not ejaculation)

Sweat glands Secretion (sympathetic cholinergic!)

Salivary glands Secretion

Lacrimal glands Secretion

Parasympathetic Nervous System,


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Parasympathetic Nervous System,Summary of Intervention Mechanisms

Cholinergic neurotransmission can

be modified at several sites,

including:

a) Precursor transport blockade, e.g.,

hemicholinium

b) Choline acetyltransferase inhibition,

no clinical example

c) Promote transmitter release, e.g.,choline, black widow spider venom

(latrotoxin)

d) Prevent transmitter release, e.g.,

botulinum toxin

e) Storage, e.g., vesamicol prevents AChstorage

f) Cholinesterase inhibition, e.g.,

physostigmine, neostigmine

g) Receptors agonists (chlinomimetic

drugs) and antagonists (anticholinergic

drugs)

latrotoxin

+

Muscarinic Agonists (, Cholinomimetics,


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Muscarinic Agonists (, Cholinomimetics,Parasympathomimetics)

Acetylcholine itself is rarely used clinically because of its rapid hydrolysis following

oral ingestion and rapid metabolism following i.v. administration.

Fortunately, a number of congeners with resistance to hydrolysis (methacholine,

carbachol, and bethanechol) have become available.

There are also several other naturally occurring muscarinic agonists such as muscarine

and pilocarpine.

Bethanechol is used (rarely) to treat gastroparesis, because it stimulates GI motilit

and secretion, but at a cost of some cramping abdominal discomfort. In addition, it

may cause hypotension and bradycardia. Bethanechol is also widely used to treat

urinary retention. This agent also occasionally is used to stimulate salivary gland

secretion in patients with xerostomia (dry mouth, nasal passages, and throat)

In rare cases, high doses of bethanechol have seemed to cause myocardial ischemia in

patients with a predisposition to coronary artery spasm Pilocarpine is more commonly used than bethanechol to induce salivation, and als

for various purposes in ophthalmology. It is widely used to treat open-angle

glaucoma, topically. Pilocarpine possesses the expected side effect profile,

including increased sweating, asthma worsening, nausea, hypotension, and

bradycardia (slow heart rate).

Antichloinergic drugs


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Nonselective Muscarinic Antagonists The classical muscarinic antagonists are derived from plants and are nonselective

competitive antagonists. Atropa belladonna contains atropine. Hyoscyamus niger

contains primarily scopolamine and hyoscine.

Clinically, atropine is used for raising heart rate during situations where vagal

activity is pronounced (for example, vasovagal syncope). It is also used for

dilating the pupils. Its most widespread current use is in pre-anestheticpreparation of patients; in this situation, atropine reduces respiratory tract

secretions and thus facilitates intubation.

Ipratropium (nonselective) is used by inhalation as a bronchodilator

Cyclopentolate and tropicamide (both are nonselective also) are developed for

ophthalmic use and administered as eye drops

Oxybutinin and tolterodine are new drugs developed for urinary incontinence




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Side effects of muscarinic antagonists include:

constipation,

xerostomia (dry mouth),

hypohidrosis (decreased sweating),

mydriasis (dilated pupils),

urinary retention,

precipitation of glaucoma,

decreased lacrimation,

tachycardia,

and decreased respiratory secretions

Selective Muscarinic Antagonists

Pirenzepine shows selectivity for the M1 muscarinic receptor.

Because of the importance of this receptor in mediating gastric acid release,

M1 antagonists such as pirenzepine help patients with ulcer disease or gastric

acid hypersecretion.

Cholinesterase Inhibitors


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Cholinesterase Inhibitors

The muscarinic and nicotinic agonists mimic acetylcholine effect by

stimulating the relevant receptors themselves.

Another way of accomplishing the same thing is to reduce the destruction ofACh following its release.

This is achieved by cholinesterase inhibitors, which are also called the

anticholinesterases.

They mimic the effect of combined muscarinic and nicotinic agonists.

Cholinergic neurotransmission is especially important in insects, and it was

discovered many years ago that anticholinesterases could be effective

insecticides, by overwhelming the cholinergic circuits (see War Gases

below)

By inhibiting acetylcholinesterase and pseudocholinesterase, these drugs

allow ACh to build up at its receptors. Thus, they result in enhancement of

both muscarinic and nicotinic agonist effect.

Cholinesterase Inhibitors Reversible


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Cholinesterase Inhibitors, Reversible "Reversible" cholinesterase inhibitors are generally short-acting. They bind AChE

reversibly. They include physostigmine that enters the CNS, and neostigmine and

edrophonium that do not.

Physostigmine enters the CNS and can cause restlessness, apprehension, andhypertension in addition to the effects more typical of muscarinic and nicotinic agonists.

Neostigmine is a quaternary amine (tends to be charged) and enters the CNS poorly;

its effects are therefore almost exclusively those of muscarinic and nicotinic stimulation.

It is used to stimulate motor activity of the small intestine and colon, as in certain types

of non-obstructive paralytic ileus. It is useful in treating atony of the detrusor muscle of

the urinary bladder, in myasthenia gravis, and sometimes in glaucoma. Some patients encounter muscarinic side effects due to the inhibition of peripheral

cholinesterase by physostigmine.

The most common of these side effects are nausea, pallor, sweating and bradycardia.

Concomitant use of anticholinergic drugs which are quaternary amines (e.g.,

glycopyrrolate or methscopolamine and which therefore do not cross the blood-brain

barrier) are recommended to prevent the peripheral side effects of physostigmine. Edrophonium (Tensilon) is a quaternary amine widely used as a clinical test for

myasthenia gravis.

If this disorder is present, edrophonium will markedly increase strength. It often

causes some cramping, but this only lasts a few minutes.

Ambenonium and pyridostigmine are sometimes also used to treat myasthenia.

Cholinesterase Inhibitors Irreversible


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Cholinesterase Inhibitors, Irreversible

Long-acting or "irreversible" cholinesterase inhibitors (organophosphates) are

especially used as insecticides. Cholinesterase inhibitors enhance cholinergic

transmission at all cholinergic sites, both nicotinic and muscarinic. This makes

them useful as poisons.

They bind AChE irreversibly. Example: organophosphates (e.g.,

phosphorothionates)

Many phosphorothionates, including parathion and malathion undergo enzymatic

oxidation that can greatly enhance anticholinesterase activity. The reaction involve

the substitution of oxygen for sulphur. Thus, parathion is oxidized to the morepotent and more water-soluble paraoxon.

Differences in the hydrolytic and oxidative metabolism in different organisms

accounts for the remarkable selectivity of malathion.

In mammals, the hydrolytic process in the presence of carboxyesterase leads to

inactivation. This normally occurs quite rapidly, whereas oxidation leading toactivation is slow.

In insects, the opposite is usually the case, and those agents are very potent

insecticides.

Insecticide Poisoning


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Insecticide Poisoning

Causes and symptoms

Exposure to insecticides can occur by ingestion, inhalation, or exposure to skin

or eyes.

The chemicals are absorbed through the skin, lungs, and gastrointestinal tract

and then widely distributed in tissues.

Symptoms cover a broad spectrum and affect several organ systems:

Gastrointestinal: nausea, vomiting, cramps, excess salivation, and loss of bowe

movement control

Lungs: increases in bronchial mucous secretions, coughing, wheezing, difficulty

breathing, and water collection in the lungs (this can progress to breathing

cessation)

Skin: sweating

Eyes: blurred vision, smaller sized pupil, and increased tearing

Heart: slowed heart rate, block of the electrical conduction responsible of

heartbeat, and lowered blood pressure

Urinary system: urinary frequency and lack of control

Central nervous system: convulsions, confusion, paralysis, and coma

Principles in Management of the Poisoned


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Principles in Management of the PoisonedPatient

Toxicokinetics vs Toxicodynamics:

The term "toxicokinetics" denotes the absorption, distribution, excretion, andmetabolism of toxins, toxic doses of therapeutic agents, and their metabolites.

The term "toxicodynamics" is used to denote the injurious effects of these

substances on vital function.

Volume of Distribution: The volume of distribution (Vd) is defined as the apparent volume into which a

substance is distributed

Vd is increased by increased tissue binding, decreased plasma binding and

increased lipid solubility.

Drug with high Vd extensive tissue distribution A large Vd implies that the drug is not readily accessible to measures aimed at

purifying the blood, such as hemodialysis.

Examples of drugs with large Vd (> 5 L/kg) include antidepressants,

antipsychotics, antimalarials, narcotics, propranolol, and verapamil. Drugs

with relatively small volumes of distribution (< 1 L/kg) include salicylate

chemical carcinogen

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