The Cholinergic System

PART 1

The neurotransmitter of the cholinergic system is acetylcholine.

Acetylcholine is synthesized in the cytoplasm of presynaptic cholinergic

neurons, under the influence of the enzyme cholinacetylase or
acetylcholintransferase which promotes the formation of an ester bond between
acetic acid and choline.

Acetylcholine is then captured in the presynaptic storage vesicles from

where it is released into the synaptic cleft and attached to postsynaptic cholinergic
receptors. However, the effect of acetylcholine is quickly terminated by the
diffusion of the substance out of the synaptic space and, especially, by its rapid
metabolism under the influence of two enzymes, one specific for acetylcholine,
called acetylcholinesterase (cholinesterase) and another, less specific, called
pseudocholinesterase (or butyrylcholinesterase).

The effects of acetylcholine are achieved through specific receptors called

cholinergic receptors - muscarinic and nicotinic.

Nicotinic receptors are sodium channel receptors located in the central

nervous system and in most peripheral synapses. There are two types of nicotinic
receptors, some located in the vegetative ganglia, both sympathetic and
parasympathetic, and in the medullary adrenal gland, called NN- nicotinic ganglia
receptors and others in the somatic neuromuscular synapses (motor plaques),
called nicotinic muscular receptors note with NM.

Muscarinic receptors are G protein-coupled receptors. There are at least

five distinct types of muscarinic receptors marked with M1-5. M1, M3 and M5
receptors bind to a Gq and maybe a Gs protein, while M2 and M4 receptors bind
to a Gi protein.

The effects of acetylcholine are determined by the type of receptors on

which acetylcholine acts on.
 Effects determined via nicotinic receptors

• Stimulation of the parasympathetic ganglia receptors causes the release of

acetylcholine into the terminal parasympathetic synapses.
• Stimulation of the sympathetic ganglia receptors causes the release of
norepinephrine into the terminal sympathetic synapses.
• Stimulation of nicotinic receptors in the medullary adrenal gland causes
the release of adrenaline and noradrenaline into the bloodstream.
• Stimulation of NM receptors causes skeletal muscle contraction.

Effect determined via muscarinic receptors

• Digestive tract - increased digestive secretions (salivary section, secretion

of hydrochloric acid and pepsin in the stomach, secretion of intestinal
glands), promotes emptying of the stomach, increasing gastric peristalsis
and relaxing the pylorus, accelerates intestinal transit, accelerating
peristaltic movements and relaxing sphincters.
• Respiratory system - bronchoconstriction and increased tracheobronchial
secretion.
• Ureters - increases peristalsis,
• Cavitary organs - gallbladder and bladder - promote the evacuation of the
contents by contraction of the bladder muscles and relaxation of the
sphincters.
• Sweat glands - increased sweat secretion.
• Cardiovascular system - decreases heart rate, decreases excitability,
decreases atrioventricular conduction velocity and decreases myocardial
fiber contractility.
• Blood vessels - vasodilation by the release of nitrogen monoxide (NO)
from endothelial cells.
• Eyes - the contraction of the circular muscles of the iris with miosis, the
contraction of the ciliary muscles with the bulging of the lens and its
fixation for the close eye, the decrease of the intraocular pressure, the
increase of the lacrimal secretion.
 Parasympathomimetics

Parasympathomimetic drugs contain a number of substances able to

stimulate muscarinic receptors. The effects of these drugs are similar to the effects
of endogenous acetylcholine.

Acetylcholine has a quaternary (polar) ammonium structure that crosses

cell membranes with difficulty, which means that the substance has no systemic
effects if administered orally. Administered intravenously, acetylcholine has
mainly muscarinic effects and less nicotinic effects, because nicotinic receptors
are less sensitive to the action of acetylcholine.

Methacholine, carbachol and bethanechol stimulate muscarinic

receptors, even being selective for muscarinic receptors. However, these esters
are less sensitive to the action of cholinesterase, which ensures a longer
persistence in the body. They stimulate muscarinic receptors, even being selective
for muscarinic receptors. However, these esters are less sensitive to the action of
cholinesterases, which ensures a longer persistence in the body.

Pilocarpine has therapeutic interest. It is mainly used as an antiglaucoma

when administered in conjunctival instillations as an ophthalmic solution.

Muscarine is of toxicological interest. The name of the substance comes

from the fact that it was originally isolated from the fungus Amanita muscaria.
Due to the muscarine content, ingestion of poisonous fungi causes, 30-60
minutes after ingestion, typical muscarinic phenomena such as hypersalivation,
hyper lacrimation, nausea, vomiting, visual disturbances, abdominal colic,
diarrhea, bronchospasm, bradycardia, hypotension and shock. which respond
very well to treatment with muscarinic receptor blockers, for example with
atropine.

Arecoline is also of toxicological interest.

 Parasympatholytics

Parasympatholytic drugs contain a group of natural, semi-synthetic or

synthetic chemicals that block muscarinic receptors.

Atropine, a non-selective muscarinic receptor blocker, is a fat-soluble

alkaloid found in some plants, Atropa belladonna. The drug is well absorbed from
the digestive tract and mucous membranes, but relatively difficult to penetrate the
skin except the skin located posterior to the earlobe.

Effects of atropine

Heart. increases sinus frequency, tachycardia, increases excitability of

myocardial fibers, increases atrioventricular conduction velocity, increases
myocardial fiber contractility and decreases the intensity of vagal reflexes
predominantly in the atria and upper atrioventricular junction - useful therapeutic
block in the treatment -ventricular (digital block treatment). It prevents reflex
cardiac arrest that may occur during maneuvers such as pleural puncture, various
endoscopes (bronchoscopes, gastroscopes, etc.), intravenous administration of
irritating contrast agents, and the use of atropine as a preanesthetic.

Digestive system. Decreases salivary secretion - dry mouth. Inhibits

chlorhydropeptic secretion and motility. Decreased stomach motility is
accompanied by increased pyloric sphincter tone and much less cardiac sphincter
tone - delays stomach emptying and promotes gastroesophageal reflux. Favoring
gastroesophageal reflux causes atropine to aggravate reflux peptic esophagitis.
Decreases bowel motility, increases sphincter tone and decreases bowel secretion.

Respiratory system - decreases secretions and relaxes the bronchial

muscles, prevents the appearance of laryngospasm during general anesthesia
which allows the use of atropine as a pre-anesthetic. The bronchodilator effect is
accompanied by unwanted effects, which means that today atropine is no longer
used as an antiasthma.

Cavitary organs - relaxation of the propulsive muscles and increase the

tone of the sphincters - useful for the treatment of renal colic or bladder spasms
that occur during urinary tract infections or urological maneuvers. However, the
difficulty of emptying the bladder can be due to the bladder, especially in patients
with prostate adenoma.

Eyes - decreased tear secretion, relaxation of the circular muscle of the iris
with mydriasis and ciliary muscle and increased intraocular pressure.
 Skin - decreased sweat secretion with dry skin preventing thermolysis.
Compensator vasodilation occurs, the skin acquires red color.

Side effects - dry mouth, constipation, mydriasis, redness of the skin and
bladder tenesmus, photophobia, cycloplegia, and tachycardia.

The drug is contraindicated in glaucoma, hyperthyroidism, prostate

adenoma, paralytic ileus, pyloric stenosis, tachycardia, acute myocardial
infarction (except for the controversial excessive bradycardia) and in lactating
women (the drug is excreted in breast milk).

Scopolamine non-selectively blocks all muscarinic receptors, but crosses

biological membranes, including the blood-brain barrier, more easily than
atropine. Scopolamine is considered an effective drug in the treatment of motion
sickness, probably due to the intervention of nerve-central muscarinic
mechanisms in the production of this phenomenon, in transdermal administration.
The side effects are similar to those caused by atropine. Phenomena of
intoxication after transcutaneous administration have been described.

Butylscopolamine is a non-selective antimuscarinic, similar to atropine, but with

polar molecule - quaternary ammonium structure, it crosses with difficulty the
biological membranes. The main use of butylscopolamine is as an antispasmodic
in the treatment of various colic when it is usually given by injection. Side effects
are classic for atropine.

Orally administered propanteline, metantelin, butantelin block

muscarinic receptors in the stomach, thus decreasing atropine-like
chlorhydropeptic secretion. Having a polar molecule, it is difficult to absorb from
the digestive tract, which makes the systemic side effects of atropine very little
expressed. However, the side effects characteristic of parasympatholytics in the
digestive tract remain, such as delayed gastric emptying and promoting
gastroesophageal reflux or constipation.

Pirenzepine, a drug with a quaternary ammonium structure that selectively

blocks muscarinic M1-type receptors in the parasympathetic vegetative ganglia
in the stomach but also in the secretory glands of the stomach. Chlorhydropeptic
secretion decreases in the same way as quaternary ammonium
parasympatholytics, but by selectively blocking M1-type muscarinic receptors in
the stomach, it has virtually none of the side effects of atropine, either
systemically or digestively.

Homatropin and tropicamide are advantageous over atropine in ophthalmology

for eyes fundus examination (ophthalmoscopy) because the undesirable effects
characteristic of parasympatholytics administered in conjunctival instillations
disappear much faster.

Trihexyphenidyl and benzotropin are mainly used for the treatment of

extrapyramidal disorders caused by neuroleptic drugs and, less recently, in the
treatment of Parkinson's disease.

Ipratropium, a compound with a quaternary ammonium structure that is

administered by inhalation - achieves active concentrations in the bronchi but,
having a polar molecule, is practically not absorbed through the bronchial
mucosa. The drug is active in certain cases of bronchospasm with an important
cholinergic component such as reflex asthma, exercise asthma, cold asthma,
bronchospasm in patients with spastic bronchitis.