Chemical Carcinogens

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 that persists 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

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 metaplasia

Hyperplasia 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.

Multistage Carcinogenesis
Human chemical carcinogenesis is a multistage process that results from exposures, usually in the form of complex chemical mixtures, often encountered 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 Although most chemical carcinogens do not react directly with intracellular components, 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.

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

Multistage Carcinogenesis
Multistage chemical carcinogenesis can be conceptually divided into four stages:
1. 2. Tumor initiation Tumor promotion

3.
4.

Malignant conversion
Tumor progression

Multistage Carcinogenesis, Tumor Initiation

The primary genetic change that results from a chemical-DNA interaction is termed tumor initiation.
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 by forming 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

Multistage Carcinogenesis, Tumor Promotion

Tumor promotion comprises the selective clonal expansion of initiated cells. (epigenetic 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 to a tumor initiator (mutation rate rate of cell division)

Multistage Carcinogenesis, Tumor Promotion to

Malignant Conversion
The total dose of a tumor promoter is less significant than frequently repeated administrations,
if the tumor promoter is discontinued before malignant conversion has occurred, pre-malignant or benign lesions may regress Tumor promotion contributes to the process of carcinogenesis by the expansion of a population of initiated 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 as complete carcinogens, e.g., benzo[a]pyrene

Multistage Carcinogenesis, Tumor Promotion to

Malignant Conversion
Additional genetic changes (mutations) continue to accumulate 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

Multistage Carcinogenesis, Malignant Conversion

Malignant conversion is the transformation of a preneoplastic cell into one that expresses the malignant phenotype This process requires further genetic changes A prominent characteristic of 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 suppressor genes (e.g., p53).

Multistage Carcinogenesis, Tumor Progression

Tumor 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.

Common Chemical Carcinogens

Carcinogen
Occupational carcinogens
Soot and mineral oil Arsenic Asbestos Hair dyes and aromatic amines Benzene Nickel Formaldehyde Vinyl chloride Painting materials, non-arsenic pesticides, diesel exhaust, chromates chromates Skin cancer Lung cancer, skin cancer Lung cancer, mesothelioma Bladder cancer Leukemia Lung cancer, nasal sinus cancer Nasal cancer, nasopharyngeal cancer Hepatic angiosarcoma Lung cancer

Type of Cancer

Lifestyle carcinogens
Alcohol Tobacco Esophageal cancer, oropharyngeal cancer
Head and neck cancer, lung cancer, esophageal cancer, bladder cancer

Drug carcinogens
Alkylating agents Diethylstilbestrol Oxymetholone (Anadrol) Leukemia Liver cell adenoma, vaginal cancer in exposed female fetuses Liver cancer

IARC Classification of carcinogens

IARC (International Agency for Research on Cancer)
IARC class 1: The substance is carcinogenic to humans, e.g. arsenic, aflatoxin
B1, estrogens

IARC class 2A: The substance is probably carcinogenic to humans (sufficient

evidence 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., carbon
tetrachloride, chloroform

IARC class 3:

The substance is not classifiable as to its carcinogenicity to humans, e.g., chloroquine, diazepam, 5-fluorouracil
The substance is probably not carcinogenic to humans. This category is used for agents or mixtures for which there is evidence suggesting lack of carcinogenicity in humans and in experimental animals

IARC class 4:

Structure of Representative Chemical Carcinogens

Classification of Carcinogens According to the Mode of Action, Based on Reactivity with DNA

I.

Genotoxic Carcinogens

I.

Non-Genotoxic (Epigenetic) Carcinogens

Classification of Carcinogens According to 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

Genotoxic Carcinogens, Mechanism

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 from incomplete 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-tetrahydrobenz[a]pyrene} yl] - deoxyguanosine; BPdG)

Metabolic Activation of Benzo(a)pyrene, as a Representative Example

for Chemical Carcinogens (Genotoxic)

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

(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-7,8,9,10tetrahydroxybenz[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 and the exocyclic amino group of deoxyguanosine

Classification of Carcinogens According to the Mode of Action, Based on Reactivity with DNA
I. Epigenetic (non-genotoxic) Carcinogens
No 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

Epigenetic Carcinogens, Mechanisms

1.
2. 3.

Prolonged stimulation of cell proliferation, via chronic cytotoxicity or increased secretion trophic hormones
Inhibition of apoptosis in cells with DNA damage Impairment of DNA-replication fidelity and DNA-repairing machinery

4.
5. 6.

Dysregulated gene expression

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

Induction of metabolizing enzymes Dysregulated cell signaling via receptor- or non-receptor-mediated pathways

7.
8.

Persistent immunosuppression, leading to compromised immunosurveillance

Oxidative Stress
Indirect DNA damage Induction of cell proliferation signaling cascades

Epigenetic Carcinogens, Mechanisms

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 gene amplification Clonally expands existing cell populations

Examples: Epidermal growth factor, hepatocyte growth factor, estrogens

Epigenetic Carcinogens, Mechanisms

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

Epigenetic Carcinogens, Mechanisms

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

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

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 receptor binds to a particular nucleotide sequence on a gene altered transcription of certain genes

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. 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

2.

Kinase-linked Receptors,
Kinase cascade that transmits signals downstream from activated Ras protein
1. 2. Activated Ras binds to the N-terminal domain of Raf, a serine/threonine kinase. Raf binds to and phosphorylates MEK, a dualspecificity protein kinase that phosphorylates both tyrosine and serine residues. MEK phosphorylates and activates MAP kinase, another serine/threonine kinase. MAP kinase phosphorylates many different proteins, including nuclear transcription factors, that mediate cellular responses.

3. 4.

Chemical Carcinogens,
Representative Members

Modifying Factors in Chemical Carcinogenesis

I. Interaction with DNA
A great body of information indicates that interaction with DNA is the critical factor in chemical carcinogenesis. Several distinct sorts of data have been gathered. Relevant findings are as follows:
1. 2. 3. In general, carcinogens are mutagens, indicating that they have the potential to interact with DNA. Within groups of related carcinogenic chemicals, carcinogenic potency correlates best with ability to interact with DNA. 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

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
The sorts of genetic involvement which have been described are:

one.

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 of the natives in the immigrants' new homeland

Modifying Factors in Chemical Carcinogenesis

I. Biological behaviors of the chemical carcinogen:
1. Site of action: Chemicals can act both locally and distally, e.g., benzo(a)pyrene painting causes 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-naphthylamine bladder tumor; urethane lung tumor; zinc testis tumor; tin and nickel sarcoma, 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 cancer

5. 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

Modifying Factors in Chemical Carcinogenesis

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 and irreversible. 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

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 virally induced 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

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 Patient

Toxicokinetics vs Toxicodynamics:
The term "toxicokinetics" denotes the absorption, distribution, excretion, and metabolism 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

Antidotes, Definition and Types

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

Some anatomic and neurotransmitter features of autonomic and somatic motor nerves

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

Cholinergic Transmission
After release from the presynaptic terminal, ACh molecules may bind to and activate 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 is also 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,

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,

Nicotinic Receptors 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

Parasympathetic Nervous System,

Muscarinic Receptors for acetylcholine
I. Muscarinic receptors, mAChRs (the muscarinic actions of ACh are those that 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

Eye (iris sphincter muscle) Eye (ciliary muscle) SA node Atrium AV node Arteriole Bronchial muscle Bronchial secretion GIT (motility) GIT (secretion) GIT (sphincters) Gallbladder Urinary bladder (detrusor) Urinary bladder (trigone, sphincter) Penis Sweat glands Salivary glands Lacrimal glands Contraction (miosis) Contraction (for near vision) Bradycardia Reduced contractility Reduced conduction velocity Dilation (via nitric oxide) Muscle Contraction Increase Increase Increase Relaxation Contraction Contraction Relaxation Erection (but not ejaculation) Secretion (sympathetic cholinergic!) Secretion Secretion

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 ACh storage f) Cholinesterase inhibition, e.g., physostigmine, neostigmine g) Receptors agonists (chlinomimetic drugs) and antagonists (anticholinergic drugs)
latrotoxin +

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 motility 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 also 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

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-anesthetic preparation 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

Antichloinergic drugs

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
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 of ACh 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

"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, and hypertension 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

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 involves the substitution of oxygen for sulphur. Thus, parathion is oxidized to the more potent 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 to activation is slow. In insects, the opposite is usually the case, and those agents are very potent insecticides.

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 bowel 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 Patient

Toxicokinetics vs Toxicodynamics:
The term "toxicokinetics" denotes the absorption, distribution, excretion, and metabolism 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