cholinergic receptors historical

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Bibliographic Information

The action of certain esters and ethers of choline, and their relation to

muscarine. Dale, H. H.. London, J. Pharmacol (1914), 6 147-90.Journal language unavailable. CAN 9:633 AN 1915:633 CAPLUS

Abstract

In the action of choline, and, with varying degrees of intensity, in the action

of its esters (marked with acetylcholine, choline nitrous ester and cholinenitric ester) and certain ethers (choline ethyl ether), 2 distinct types of action

can be detected-a "muscarine" action, paralyzed by atropine, and a

"nicotine" action, paralyzed by excess of nicotine. The action of choline

nitrous ether is identical with "synthetic muscarine." Acetylcholine occurs

occasionally in ergot, but its instability renders it improbable that its

occurrence has any therapeutic significance. It appears to be hydrolyzed in

the blood.



Muscarine

Muscarine, L-(+)-muscarine, or muscarin is a natural product f ound in certainmushrooms, particularly in Inocybe and Clitocybe species, such as the deadly C.dealbata. It was f irst isolated f rom Amanita muscaria in 1869. It was the f irstparasympathomimetic substance ever studied and causes prof ound activation of theperipheral parasympathetic nervous system that may end in convulsions and death.Muscarine has no eff ects on the central nervous system because it does not cross theblood-brain barrier due to its positively charged (polar) nitrogen atom.Muscarine mimicsthe action of the neurotransmitter acetylcholine at metabotropic receptors that are also

known under the name muscarinic acetylcholine receptors.Muscarine poisoning is characterizedby increased salivation, sweating (perspiration), and tear f low (lacrimation) within 15 to 30minutes af ter ingestion of the mushroom. With large doses, these symptoms may be f ollowed byabdominal pain, severe nausea, diarrhea, blurred vision, and labored breathing. Intoxicationgenerally subsides within 2 hours. Death is rare, but may result f rom cardiac or respiratoryfailure in severe cases. The specif ic antidote is atropine.Muscarine is only a trace compoundin the f ly agaric Amanita muscaria; the pharmacologically more relevant compound f rom this

mushroom is muscimol.



Nicotine

Nicotine is an alkaloid f ound in the nightshade f amily of plants (S olanaceae),predominantly in tobacco, and in lower quantities in tomato, potato, eggplant(aubergine), and green pepper . Nicotine alkaloids are also f ound in the leaves of thecoca plant. Nicotine constitutes 0.3 to 5% of the tobacco plant by dry weight, withbiosynthesis taking place in the roots, and accumulates in the leaves. It is a potentneurotoxin with particular specif icity to insects; theref ore nicotine was widely usedas an insecticide in the past, and currently nicotine derivatives such asimidacloprid continue to be widely used.In lower concentrations (an averagecigarette yields about 1mg of absorbed nicotine), the substance acts as a stimulantin mammals and is one of the main f actors responsible f or the dependence-f ormingproperties of tobacco smoking. According to the American Heart Association,"Nicotine addiction has historically been one of the hardest addictions to break.



Some definitions Para- (prefix): A prefix with many meanings,

including: alongside of, beside, near,

resembling, beyond, apart from, andabnormal.For example, the parathyroid

glands are called "para-thyroid" because they

are adjacent to the thyroid. For another

example, paraumbilical means alongside theumbilicus (the belly button).The prefix "para-"

comes straight from the Greek.



Methacholine

Metacholine (also spelt methacholine) is a synthetic choline ester that actsas a non-selective muscarinic receptor agonist in the parasympatheticnervous system. It is highly active at all of the muscarinic receptors, but has littleeff ect on the nicotinic receptors. Metacholine has a charged quaternary aminestructure, rendering it insoluble to lipid cell membranes. Clinically, this means that it

will not cross the blood-brain barrier and has poor absorption f rom thegastrointestinal tract. It is broken down at a relatively slow rate within the body,due to its resistance to acetylcholinesterases.The primary clinical use of methacholine is to diagnose bronchial hyperreactivity, which occurs in asthma. This isaccomplished through the metacholine challenge test. Other therapeutic uses arelimited by its adverse cardiovascular eff ects, such as bradycardia andhypotension, which arise f rom its f unction as a cholinomimetic.Use of

metacholine, as well as all other muscarinic receptor agonists, is contraindicated inpatients with coronary insuff iciency, gastroduodenal ulcers, and incontinence. Theparasympathomimetic action of this drug will exacerbate the symptoms of thesedisorders.



Carbachol Carbachol (K ar-ba-kol key), also known as carbamylcholine (marketed under the brand names Carbastat,

Carboptic, Isopto Carbachol, Miostat), is classif ied as a cholinergic. Thus, it acts as an AChR agonist.It is primarily used f or various ophthalmic purposes, such as f or treating glaucoma, or f or use during ophthalmicsurgery. It is generally administered as an intraocular solution (i.e. eyedrop).

Carbachol is a choline ester and a positively charged quaternary ammonium compound. It is not wellabsorbed in the gastro-intestinal tract and does not cross the blood-brain barrier . It is usually administeredtopical ocular or through intraocular injection. Carbachol is not easily metabolized by cholinesterase, itsduration of action is 4 to 8 hours with topical administration and 24 hours f or intraocular administration.Since carbachol is poorly absorbed through topical administration, benzalkonium chloride is mixed in topromote absorption.Carbachol is a parasympathomimetic that stimulates both muscarinic and nicotinic

receptors. In topical ocular and intraocular administration its principal eff ects are miosis and increasedaqueous humour outf low.In the cat and rat, carbachol is well-known f or its ability to induce rapid eyemovement (REM) sleep when microinjected into the pontine reticular f ormation. Carbachol elicits this REMsleep-like state via activation of postsynaptic muscarinic cholinergic receptors(mAChRs).[edit

]IndicationsCarbachol is primarily used in the treatment of glaucoma, but it is also usedduring ophthalmic surgery. Carbachol eyedrops are used to decrease the pressure in the eye f or peoplewith glaucoma. It is sometimes used to constrict the pupils during cataract surgery.Topical occular administration is used to decrease intraocular pressure in people with primary open-angle glaucoma.

Intraocular administration is used to produce miosis af ter lens implantation during cataract surgery.Carbachol can also be used to stimulate bladder emptying if the normal emptying mechanism is notworking properly.In most countries carbachol is only available by prescription.



Definitions

A parasympathomimetic is a drug or poison that acts bystimulating or mimicking the parasympathetic nervous system(PNS). These chemicals are also called cholinergics becauseacetylcholine (ACh) is the neurotransmitter used by the PNS.

Chemicals in this f amily can act by either directly stimulating thenicotinic or muscarinic receptors, or they can act indirectly by inhibitingcholinesterase, promoting acetylcholine release, or other mechanisms.

Some Chemical weapons such as sarin or VX, Non-lethal riot controlagents such as tear gas, and insecticides such as Diazinon f all into thiscategory.



Definitions Sympathetic and parasympathetic divisions typically f unction in

opposition to each other. But this opposition is better termedcomplementary in nature rather than antagonistic. For an analogy, onemay think of the sympathetic division as the accelerator and theparasympathetic division as the brake.

The sympathetic division typically f unctions in actions requiring quickresponses.

The parasympathetic division f unctions with actions that do not require

immediate reaction.

Consider sympathetic as "f ight or f light" and parasympathetic as "restand digest".



1. Nerve Transmission1. Nerve Transmission

Peripheral nervous systemPeripheral nervous system

CNS

(Somatic)

CNS

(Autonomic)

Sympathetic

Parasympathetic

NA

Ach

(N)

Synapse

Ach (N)

Ach(N)

Ach

(N)

Ach

(M)

Adrenal

medulla

Adrenaline

Skeletal

muscle

Synapse

AUTONOMIC

Smooth muscle

Cardiac muscle



Bethanechol Bethanechol (be-Than-e-kol [key]) is a parasympathomimetic choline ester

that selectively stimulates muscarinic receptors without any eff ect on nicotinicreceptors. Its chemical structure is 2-((aminocarbonyl)oxy)-N,N,N-trimethyl-1-propanaminium. Unlike acetylcholine, bethanechol is not hydrolyzed bycholinesterase and will theref ore have a long duration of action.Bethanechol issometimes given orally or subcutaneously to treat urinary retention resultingf rom general anesthetic or diabetic neuropathy of the bladder, or to treatgastrointestinal atony (lack of muscular tone). The muscarinic receptors in the bladder and gastrointestinal tract stimulate contraction of the bladder and expulsion of urine, and increased gastrointestinal motility, respectively. Bethanechol should be usedto treat these disorders only af ter obstruction is ruled out as a possible cause.Use of bethanechol, as well as all other muscarinic receptor agonists, is contraindicated in

patients with asthma, coronary insufficiency, peptic ulcers, and incontinence.The parasympathomimetic action of this drug will exacerbate the symptoms of thesedisorders.Bethanechol is sold under the brand names Duvoid (Roberts), Myotonachol(Glenwood), and Urecholine (Merck Frosst).



Medicinal Importance of Ach Agonists

Types of direct acting muscarinic receptor agonists:a) Esters of choline(eg. acetylcholine, pilocarpine, carbachol, bethanechol chloride)-poorlyabsorbed,-variable susceptibility to hydrolysis by cholinesterase-affectsduration of actionb)

Alkaloids (eg. muscarine)-well absorbed, not used clinically-mushroompoisoning ( Amanita muscaria)i)

Acetylcholine-highly susceptible to hydrolysis-IV bolus lasts 5-20seconds-limited use in topical application in ophthalmologyii)

Pilocarpine-acts on smooth muscles of eye to constrict the pupil (miosis)-used to treat glaucoma-contracts ciliary muscles by stimulating muscarinicreceptors-rapid penetration (15-30 min) and long duration (8 hrs)-increased aqueous outflowiii)

Carbachol-carbamyl ester of choline-used mainly in ophthalmology for cataract surgery (causes rapid miosis)-decreases intraocular pressure byopening drainage angle of anterior chamber of eye - .: used in glaucoma(when resistant to pilocarpine or physostigmine)

Bethanechol Chloride-choline ester -persistent effects because it isresistant to cholinesterases-selectively stimulates urinary andgastrointestinal tracts-facilitates emptying of neurogenic bladder in patients

after surgery or parturition or with spinal cord injury



Pilocarpine has been used in the treatment of chronic open-angle glaucoma and acute angle-

closure glaucoma f or over 100 years.[1] It acts on a subtype of muscarinic receptor (M3) f ound

on the iris sphincter muscle, causing the muscle to contract and produce miosis. This opensthe trabecular meshwork through increased tension on the scleral spur. This action f acilitates

the rate that aqueous humor leaves the eye to decrease intraocular pressure.Pilocarpine is

also used to treat dry mouth (xerostomia). Pilocarpine stimulates the secretion of large

amounts of saliva and sweat. It may also cause hypotension and bradycardia in the

cardiovascular system, and bronchospasm and increased bronchial secretion in the lungs due

to its non-selective muscarinic action.

N

N

O

O

pilocarpine



N

N

O

O

pilocarpine

Pilocarpine is used to stimulate sweat glands in a sweat test to measure the concentration of chloride andsodium that is excreted in sweat. It is used to diagnose cystic f ibrosis (CF).

Pilocarpine is available under several trade names such as: Diocarpine (Dioptic), Isopto Carpine (Alcon),Miocarpine (CIBA Vision), Ocusert Pilo-20 and -40 (Alza), Pilopine HS (Alcon), Salagen (Pharmacia &Upjohn), Scheinpharm Pilocarpine (Schein Pharmaceutical), and Timpilo (Merck Frosst).

Adverse eff ectsUse of pilocarpine may result in a range of adverse eff ects, most of them related to its actionas a muscarinic receptor agonist. Pilocarpine has been known to cause excessive sweating, excessive

salivation, bronchospasm, increased bronchial mucus secretion, bradycardia, hypotension, and diarrhea.Thetherapeutic uses of pilocarpine are limited by its adverse eff ects.



Sweat Testing for Cystic FibrosisFrom Stacey Lloyd,

Diagnosing Cystic Fibrosis with Sweat Testing

For the past forty plus years, sweat testing has been the most effective, and therefore the most popular,

test for detecting cystic fibrosis. However, if a person tests positive for cystic fibrosis, a repeat of the

sweat test should be performed to confirm the diagnosis.

How Sweat Testing is Performed

The sweat test is performed by using an electrode filled with pilocarpine. The electrode is placed on the

inner forearm, and a second electrode is placed on the outer forearm. A current is run through the

electrodes delivering the pilocarpine under the skin.

Sweating testing is painless, however the person will feel a slight tingling sensation on the skin where

the eletrodes are placed.

The electrodes are removed and the arm is left to rest for about a one-half hour with the filter paper.

The filter paper will soak up any sweat released from the person's skin. Once the one-half hour is up, the

filter paper is placed into a flask and rinsed to release the sweat from the filter.

A digital chloridometer is used to measure the concentration of chloride ions in the fluid. If more than 60

mmol/liter is detected, cystic fibrosis is diagnosed.

Quick Fact: Many, many years ago, doctors would lick babies shortly after birth to determine if they had

cystic fibrosis!



Cystic f ibrosis

Cystic f ibrosis (CF) is the most common f atal genetic disease in the United States today. It causes the body toproduce a thick, sticky mucus that clogs the lungs, leading to inf ection, and blocks the pancreas, stopping

digestive enzymes f rom reaching the intestines where they are required to digest f ood.

CF is caused by a def ective gene, which codes f or a chloride transporter f ound on the sur f ace of the epithelial

cells that line the lungs and other organs. Several hundred mutations have been f ound in this gene, all of which

result in def ective transport of chloride, and secondarily sodium, by epithelial cells. As a result, the amount of

sodium chloride (salt) is increased in bodily secretions. The severity of the disease symptoms of CF is directlyrelated to the characteristic eff ects of the particular mutation(s) that have been inherited by the suff erer.

CF research has accelerated sharply since the discovery of CFTR in 1989. In 1990, scientists successf ully

cloned the normal gene and added it to CF cells in the laboratory, which corrected the def ective chloride

transport mechanism. This technique²gene therapy²was then tried on a limited number of CF patients.

However, this treatment may not be as successf ul as originally hoped. Further research will be required bef ore

gene therapy, and other experimental treatments, prove usef ul in combating CF.

cholinergic receptors historical

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