Transcript Bibliographic Information The action of certain esters and ethers of

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 choline
nitric 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 found in certain
mushrooms, particularly in Inocybe and Clitocybe species, such as the deadly C.
dealbata. It was first isolated from Amanita muscaria in 1869. It was the first
parasympathomimetic substance ever studied and causes profound activation of
the peripheral parasympathetic nervous system that may end in convulsions and
death. Muscarine has no effects on the central nervous system because it does
not cross the blood-brain barrier due to its positively charged (polar) nitrogen
atom.Muscarine mimics the action of the neurotransmitter acetylcholine at
metabotropic receptors that are also known under the name muscarinic
acetylcholine receptors.Muscarine poisoning is characterized by increased
salivation, sweating (perspiration), and tearflow (lacrimation) within 15 to 30
minutes after ingestion of the mushroom. With large doses, these symptoms
may be followed by abdominal pain, severe nausea, diarrhea, blurred vision,
and labored breathing. Intoxication generally subsides within 2 hours. Death is
rare, but may result from cardiac or respiratory failure in severe cases. The
specific antidote is atropine.Muscarine is only a trace compound in the fly agaric
Amanita muscaria; the pharmacologically more relevant compound from this
mushroom is muscimol.
Nicotine
•
Nicotine is an alkaloid found in the nightshade family of plants
(Solanaceae), predominantly in tobacco, and in lower quantities in
tomato, potato, eggplant (aubergine), and green pepper. Nicotine
alkaloids are also found in the leaves of the coca plant. Nicotine
constitutes 0.3 to 5% of the tobacco plant by dry weight, with
biosynthesis taking place in the roots, and accumulates in the leaves. It
is a potent neurotoxin with particular specificity to insects; therefore
nicotine was widely used as an insecticide in the past, and currently
nicotine derivatives such as imidacloprid continue to be widely used.In
lower concentrations (an average cigarette yields about 1mg of
absorbed nicotine), the substance acts as a stimulant in mammals and
is one of the main factors responsible for the dependence-forming
properties 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, and
abnormal.For example, the parathyroid
glands are called "para-thyroid" because they
are adjacent to the thyroid. For another
example, paraumbilical means alongside the
umbilicus (the belly button).The prefix "para-"
comes straight from the Greek.
Methacholine
•
Metacholine (also spelt methacholine) is a synthetic choline ester that
acts as a non-selective muscarinic receptor agonist in the
parasympathetic nervous system. It is highly active at all of the
muscarinic receptors, but has little effect on the nicotinic receptors.
Metacholine has a charged quaternary amine structure, rendering it
insoluble to lipid cell membranes. Clinically, this means that it will not
cross the blood-brain barrier and has poor absorption from the
gastrointestinal 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 is accomplished through the metacholine
challenge test. Other therapeutic uses are limited by its adverse
cardiovascular effects, such as bradycardia and hypotension, which
arise from its function as a cholinomimetic.Use of metacholine, as well
as all other muscarinic receptor agonists, is contraindicated in patients
with coronary insufficiency, gastroduodenal ulcers, and incontinence.
The parasympathomimetic action of this drug will exacerbate the
symptoms of these disorders.
Carbachol
•
Carbachol (Kar-ba-kol key), also known as carbamylcholine (marketed under the brand names
Carbastatｨ, Carbopticｨ, Isopto Carbacholｨ, Miostatｨ), is classified as a cholinergic. Thus, it acts
as an AChR agonist. It is primarily used for various ophthalmic purposes, such as for treating
glaucoma, or for use during ophthalmic surgery. 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 well absorbed in the gastro-intestinal tract and does not cross the
blood-brain barrier. It is usually administered topical ocular or through intraocular
injection. Carbachol is not easily metabolized by cholinesterase, its duration of action is
4 to 8 hours with topical administration and 24 hours for intraocular administration.
Since carbachol is poorly absorbed through topical administration, benzalkonium
chloride is mixed in to promote absorption.Carbachol is a parasympathomimetic that
stimulates both muscarinic and nicotinic receptors. In topical ocular and intraocular
administration its principal effects are miosis and increased aqueous humour outflow.In
the cat and rat, carbachol is well-known for its ability to induce rapid eye movement
(REM) sleep when microinjected into the pontine reticular formation. Carbachol elicits
this REM sleep-like state via activation of postsynaptic muscarinic cholinergic receptors
(mAChRs).[edit]IndicationsCarbachol is primarily used in the treatment of glaucoma,
but it is also used during ophthalmic surgery. Carbachol eyedrops are used to decrease
the pressure in the eye for people with 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 after lens implantation during cataract surgery.
Carbachol can also be used to stimulate bladder emptying if the normal emptying
mechanism is not working properly.In most countries carbachol is only available by
prescription.
Definitions
• A parasympathomimetic is a drug or poison that acts by
stimulating or mimicking the parasympathetic nervous
system (PNS). These chemicals are also called
cholinergics because acetylcholine (ACh) is the
neurotransmitter used by the PNS.
• Chemicals in this family can act by either directly
stimulating the nicotinic or muscarinic receptors, or they
can act indirectly by inhibiting cholinesterase, promoting
acetylcholine release, or other mechanisms.
• Some Chemical weapons such as sarin or VX, Non-lethal
riot control agents such as tear gas, and insecticides such
as Diazinon fall into this category.
Definitions
• Sympathetic and parasympathetic divisions typically
function in opposition to each other. But this opposition is
better termed complementary in nature rather than
antagonistic. For an analogy, one may think of the
sympathetic division as the accelerator and the
parasympathetic division as the brake.
•
The sympathetic division typically functions in actions
requiring quick responses.
• The parasympathetic division functions with actions that do
not require immediate reaction.
• Consider sympathetic as "fight or flight" and
parasympathetic as "rest and digest".
1. Nerve Transmission
Peripheral nervous system
Skeletal
muscle
CNS
(Somatic)
Ach
(N)
CNS
(Autonomic)
Synapse
Ach (N)
NA
Sympathetic
Adrenaline
Parasympathetic
Ach
(N)
Adrenal
medulla
AUTONOMIC
Synapse
Ach
(N)
Ach
(M)
Smooth muscle
Cardiac muscle
Bethanechol
• Bethanechol (be-Than-e-kol [key]) is a parasympathomimetic choline
ester that selectively stimulates muscarinic receptors without any effect
on nicotinic receptors. Its chemical structure is 2-((aminocarbonyl)oxy)N,N,N-trimethyl-1-propanaminium. Unlike acetylcholine, bethanechol is
not hydrolyzed by cholinesterase and will therefore have a long duration
of action.Bethanechol is sometimes given orally or subcutaneously to
treat urinary retention resulting from general anesthetic or diabetic
neuropathy of the bladder, or to treat gastrointestinal 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 used to treat these disorders only after
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 these disorders.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)-poorly
absorbed, -variable susceptibility to hydrolysis by cholinesterase -affects
duration of actionb)
Alkaloids (eg. muscarine)-well absorbed, not used clinically -mushroom
poisoning (Amanita muscaria)i)
Acetylcholine-highly susceptible to hydrolysis -IV bolus lasts 5-20
seconds -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 muscarinic
receptors -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 by
opening drainage angle of anterior chamber of eye - .: used in glaucoma
(when resistant to pilocarpine or physostigmine)
Bethanechol Chloride-choline ester -persistent effects because it is
resistant to cholinesterases -selectively stimulates urinary and
gastrointestinal tracts -facilitates emptying of neurogenic bladder in patients
after surgery or parturition or with spinal cord injury
O
O
N
N
pilocarpine
•
Pilocarpine has been used in the treatment of chronic open-angle glaucoma
and acute angle-closure glaucoma for over 100 years.[1] It acts on a subtype
of muscarinic receptor (M3) found on the iris sphincter muscle, causing the
muscle to contract and produce miosis. This opens the trabecular meshwork
through increased tension on the scleral spur. This action facilitates 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 nonselective muscarinic action.
O
O
N
N
pilocarpine
•Pilocarpine is used to stimulate sweat glands in a sweat test to measure the
concentration of chloride and sodium that is excreted in sweat. It is used to diagnose
cystic fibrosis (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 effectsUse of pilocarpine may result in a range of adverse effects, most of them
related to its action as a muscarinic receptor agonist. Pilocarpine has been known to
cause excessive sweating, excessive salivation, bronchospasm, increased bronchial
mucus secretion, bradycardia, hypotension, and diarrhea.The therapeutic uses of
pilocarpine are limited by its adverse effects.
Sweat Testing for Cystic Fibrosis
From 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 fibrosis
Cystic fibrosis (CF) is the most common fatal genetic disease in the United States today. It
causes the body to produce a thick, sticky mucus that clogs the lungs, leading to infection,
and blocks the pancreas, stopping digestive enzymes from reaching the intestines where
they are required to digest food.
CF is caused by a defective gene, which codes for a chloride transporter found on the
surface of the epithelial cells that line the lungs and other organs. Several hundred
mutations have been found in this gene, all of which result in defective 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 directly
related to the characteristic effects of the particular mutation(s) that have been inherited by
the sufferer.
CF research has accelerated sharply since the discovery of CFTR in 1989. In 1990,
scientists successfully cloned the normal gene and added it to CF cells in the laboratory,
which corrected the defective chloride transport mechanism. This technique—gene
therapy—was then tried on a limited number of CF patients. However, this treatment may
not be as successful as originally hoped. Further research will be required before gene
therapy, and other experimental treatments, prove useful in combating CF.