PNS and Antidote for Pesticides F

7/28/2019 PNS and Antidote for Pesticides F

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Principles in Management of the PoisonedPatient

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


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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


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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


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Cholinergic

TransmissionAfter 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 intocholine 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


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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


Agonists: Ach, CCh, nicotine

Stimulate all autonomic ganglia

Antagonists: mecamylamine, trimetaphan


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Parasympathetic Nervous System,NicotinicReceptors for acetylcholine

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

Pre- and postsynaptic


Agonists: nicotine, ACh

Pre- and postsynaptic stimulation of many brain regions

Antagonists: methylaconitine, mecamylamine

4. On adrenal medulla

Ach stimulates secretion of adrenaline from adrenal medulla


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Parasympathetic Nervous System,MuscarinicReceptors for acetylcholine

II. 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


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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

Nasopharyngeal glands Secretion


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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

+


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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 motilitand 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).


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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

Antichloinergic drugs


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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.


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

both muscarinic and nicotinic agonist effect.


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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 inglaucoma.

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-brainbarrier) 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.


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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 makesthem 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 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 toactivation is slow.

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

insecticides.


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Insecticide Poisoning

Causes and symptoms

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

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PNS and Antidote for Pesticides F