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Trasmissione Colinergica
Trasmissione Colinergica
SYSTEM
PARASYMPATHETIC
CHOLINERGIC
SYMPATHETIC
NORADRENERGIC
SYMPATHETIC
DOPAMINERGIC
SYMPATHETIC
b A schematic representation of
the quaternary structure, showing
the arrangement of the subunits in
the muscle-type receptor, the
location of the two acetylcholine
(ACh)-binding sites (between an
α- and a γ-subunit, and an α- and
a δ- subunit), and the axial cation-
conducting channel
Adapted from Karlin, Nature 2002
NICOTINIC EFFECTS
Ganglioni Neuronal
Muscular
c (α4)2 (β2)3
(α1)2β1δε
(α4)2 (β4)3 (α7)5
Increased cationic
(Na+and K +/Ca 2+) permeability
Excitatory effect
Sympathetic Skeletal
and muscle Central
parasympathet contractio effects
ic effects n
MUSCARINIC RECEPTORS
M1 M3 M5 M2 M4
Gq Gi
protein-coupled protein-coupled
↑ IP3, DAG ↓ cAMP
Excitatory effect Inhibitory effect
• CNS • Smooth
muscle • CNS
• Gastric • Gastric • CNS • PNS • CNS
and and (substanti • Heart (forebrain)
salivary salivary a nigra) • Smooth
glands glands muscle
MUSCARINIC EFFECTS
HEART Detrusor contraction
Chronotropic and dromotropic Sphincteric relaxation
negative effect
SWEAT GLANDS
Weak inotropic negative effect
Induction of secretion
VASCULAR BEDS
SALIVARY GLANDS
Vasodilation
Induction of serous secretion
BRONCHIAL TREE
EYE MUSCLES
Bronchoconstriction
Myosis (sphincter of the pupil)
Increase of secretions
Accommodation (ciliary muscle)
GASTROINTESTINAL TRACT
CENTRAL NERVOUS
Increase of peristalsis
SYSTEM
Increase of secretions
Increase of motor activity,
Sphincteric relaxation
tremor,
MALE REPRODUCTIVE SYSTEM improvement of memory,
Erection hypothermia
BLADDER
DRUGS OF THE CHOLINERGIC
SYNAPSIS
DIRECT-
ACTING
MUSCARINIC NICOTINIC
GANGLIONIC NEUROMUSCULAR
Agonists Antagonis
ts
Depolarizin Non
Stimulant
Blockers g Depolarizin
s
Blockers* g Blockers
CLINICAL USES
PILOCARPINE
• Glaucoma
• Ocular and oral dryness in Sjögren syndrome
• Oral dryness after radiotherapy of head and neck cancer
BETHANECHOL M3 agonist
• Urinary retention resulting from general anaesthetic,
diabetic neuropathy (sporadic use)
METHACOLINE
• Bronchial challenge test used to make diagnosis of
asthma
Muscarinic Antagonists
• Vegetal
alkaloids
• Tertiary amines
• High
liposolubility
• BEE entrance
ATROPINE SCOPOLAMINE • Similar kinetics
(HYOSCYAMINE) (HYOSCINE) and clinical
• Occurs in the plant • Occurs in the plant uses
Atropa belladonna Hyoscyamus niger
Muscarinic Antagonists
CLINICAL USES
CARDIOVASCULAR
Increase of heart rate → Sinus bradycardia Atropine
OPHTALMOLOGICAL
Dilation of the pupil → Retinal examination Atropine, Scopolamine,
Homatropine, Tropicamide,
Cyclopentolate
RESPIRATORY
Bronchodilation → Acute asthma/ COPD Ipratropium, Tiotropium
worsening
Bronchodilation → Pre-anaesthetic medication Atropine
Muscarinic Antagonists
CLINICAL USES
GASTROENTEROLOGICAL AND GENITOURINARY
Reduction of smooth muscle and secretory Hyoscine butylbromide
activity of gut → Irritable bowel syndrome,
diverticular disease, renal cramps, abdominal
cramps
Reduction of detrusor smooth muscle tone, Oxybutynin
spasms → Overactive bladder
NEUROLOGICAL
Antidote for cholinesterase inhibitor poisoning Atropine, Pralidoxime
Parkinsonism in antipsychotic therapy (Atropine),
Benzatropine,
Orphenadrine
Prevention of motion sickness and Scopolamine
postoperative
nausea and vomiting
Muscarinic Antagonists
SIDE EFFECTS
• Dryness of mouth and skin
• Tachycardia
• Constipation
• Difficulties of urination Increasing
• Tachycardia doses of the drug
• Mydriasis
• Blur vision
• Confusion and memory deficit
• Agitation
• Hallucination
• Delirium
Neuromuscular Blockers
NON
DEPOLARIZIN
G BLOCKERS
DEPOLARIZING BLOCKERS
Flaccid paralysis
Neuromuscular Blockers
PHARMACOKINETICS
http://www.us.elsevierhealth.com/media/us/samplechapters/9780323053747/ Chapter%2012.pdf
Depolarizing Neuromuscular Blockers
CLINICAL USES
SUCCINYLCHOLINE/SUXAMETHONIUM
• Peculiar use also during electrical or pharmacological
convulsive therapy, thanks to its ultrashort duration of
action
DRUGS OF THE CHOLINERGIC
SYNAPSIS
INDIRECT-
ACTING
ANTICHOLINERGICS CHOLINOMIMETICS
BOTULINUM TOXIN
The light chain of botulinum toxin cleaves specific sites on the SNARE
proteins in the neuronal terminal, preventing complete assembly of the
synaptic fusion complex and thereby blocking acetylcholine release
Inhibitors of Acetylcholine Release
BOTULISM
Release of
Afferent transmitters (e.g.
Peripheral pain stimulus signals glutammate) →
towards CNS CENTRAL
SENSIBILIZATIO
Neuronal feedback →
N
PERIPHERAL
BoNT-A may block the SENSIBILIZATION
transmitter release in the and increasing afferent input
peripheral terminations, with towards CNS PAIN
direct reduction of peripheral
sensibilization and indirect
reduction of central
sensibilization
Locally injected
No systemic use
Different formulations for different clinical indications:
• Blepharospasm
• Facial hemispasm
• Cervical dystonia
• Spasticity after stroke
• Equinus foot in children affected by cerebral palsy
• Underarm hyperidrosis
• Chronic migraine
• Neurogenic urinary incontinence
Inhibitors of Acetylcholine Esterase
CHOLINESTERASES
Family of enzymes that catalyses the hydrolysis of
acetylcholine into choline and acetic acid, in order to
allow the cholinergic neuron to return to its resting state
after activation
Acetylcholinesterase (AchE)
• In the neuromuscular junctions, peripheral and central
cholinergic synapses, red blood cell membranes
• High selectivity for Ach and its esters
Pseudocholineserase/Butyrylcholinesterase (BuChE)
• In the liver, skin, brain, gastrointestinal smooth muscle,
plasma
• It metabolizes the synthetic compound butyrylcholine
more quickly than Ach
Inhibitors of Acetylcholine Esterase
Acidic
site
Esterasic
site Ser
Glu
Hys
CLINICAL USE
Diagnostic test of myasthenia gravis
Reversible inhibition Irreversible inhibition
Active enzyme
NEOSTIGMINE DYFLOS
Phosphorilate
d enzyme
Anionic
site
Catalytic
site
Reactivatio
n
Slow Reactivated
Hydrolys enzyme
Modified from Rang and Dale, 2005 is
Reversible Inhibitors of Acetylcholine
Esterase
Compound Chemical Structure AchE Inhibition Application