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7/21/2019 DG F Kolinerg F10 Mm
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Autonomic nervous system
Kolinerg Farmakologi
Associate Professor Daniela Gabriele GrimmDepartment of Pharmacology, Aarhus
University, DK
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Nervous System
Peripheral Central
Somatic motor
Nervous system(Having the will control
ex. Skeletal musclevoluntary)
Autonomic
(Visceral functions, involuntary such as heart, gut)
Sympaticus-preganglionic neurons in
the grey substance T1-L3
-synapses in the Truncus
sympaticus
Thoracolumbar outflow
Parasympaticus-preganglionic neurons in the cranial nerves(III, VII, IX, X) and S2-S4 in the medulla
spinalis – craniosacral outflow-
synapse in ganglia near target organs
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Medulla
Spinalis
N, Ach, motor end plate(Contact
between
nerve & muscle)
N, Ach
M, Ach.Parasympathetic
N, Ach Adrenoceptor, NA
Sympathetic
Preganglionic fibre
Postganglionic fibre
Ach = acetylcholine, NA = noradrenaline (norepinephrine), N = Nicotinic receptor, M = Muscarinic receptor
Ganglion near
target
organ
Truncus sympaticus
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Autonomic
nervous
system
Sympathetic stimulation:- Tachycardia-rapid heart rate- Cardilatation in muscles- vascular contraction in viscera- Dilatation of bronchi- Contraction of the Sphinx- Mydriasis-large pupil
”fight or flight”
Parasympathetic stimulation- Bradycardia- Vascular dilatation in the viscera- Contraction of bronchi- Relaxation of the Intestine
- Miosis-small pupil
”rest and digest”
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Adrenaline
NA
NA
NA
Ach
Ach
Ach
Ach
Ach
NA
NA
NA
Ach
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–
β1
NA
Sympathetic
neuron
Post-
and presynaptic receptors
”
Balance between the tone of sympaticus
and parasympaticus”
nerve
Target organ
α2
–
M1/2
M3
Parasympathetic
neuron
Ach
M α
Physiological
effects
(Smooth
muscle)
Physiological
effects
–
glands,
endothelial
cellsEye-contraction in the light is parasympathetic
Dilation in the dark sympathetic
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PARASYMPATHETIC SYSTEMPreganglionic and postganglionic neurons are cholinerg
Transmitter ACh
nicotine RC
Transm ACh
muscarinic Rc
O O M target organs
Transmitter Ach nicotinic
Rc sceletal muscle
O somatomotoric nerve
-> all somatic motor end-plates on skeletalmuscle
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Sympathethic
system
Transmitter ACh nicotine RC Transmitter NA
all symatheticO O 12
1 2 Organs
Preganglionic
transmitter is
Aceytlcholine(cholinergic neuron)
Postganglionic transmitter is
NoradrenalineNorepinephrine
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Vesamicol(Vesicle-
Membranblockade)
botulinum(Block the release of Ach)
Receptor antagonists
Ack acetylcholin
M mitochondria
AcCoA acetyl-CoA
Kact
cholinacetyltransferase
P neuropeptid
Hemicholinium(Inhibits
choline
uptake)
Inhibitors
(Anticholinergics)
Direct receptor
agonist
Activators(Cholinergic agents)
Cholinergic
Synapsis
(M-type)Indirect agonist
Aktions
potentiale
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Cholinergic
receptor
types-
muscarinic
receptor
-
subtypes ACh
PLC
ACh
K+
Ca2+IP3
a bg
a gb
M1
, M3
, M5
M2
, M4
AC
cAMPa
b
g
G-protein coupled
Gi inhibition of adenylyl cyclase – reduction of CAMP
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Function
of cholinoceptor
subtypes
Eye
M3-m. constrictor
pupilae
contraction
(miosis)-m. ciliaris
contraction
Bronchi
M3
contraction, secretion
Heart
M2
-SA node reduced frequency
-arteries decreased contractility
-AV node decreased conduction velocity
-ventricles mildly impaired contractility
Vascular
M3
-
skin, mucous
membranes
vasodilation
(NO mediated)
skeletal
muscles-coronary
contraction
Glands
(no sweat) M3
secretion
Termoregulatoric
M?
secretionglands
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Stomach, bowel,
bladder
M3
secretion
and motility↑-wall increased tone
-sphinx relaxation
Uterus
M3
contraction
Nerve Terminals M3
inhibition of NA release from sympathetic
nerves
Brain M1
cortex, hippocampus
M4
forebrain, striatum
M5
substantia nigra
Alzheimer (M1), schizophrenia (M1 cortex), Parkinson(M4,M5)
Function
of cholinoceptor
subtypes
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What stimulates cholinergic receptors
Muscarinic
(M) Nicotinic
(N)
Agonist
stimulates
Acetylcholine
Carbachol(Against
bladder
spasms)
PilocarpineMuscarine Nicotine
Antagonists -
blocker -Muscarinic
Atropine, Scopolamine
Tropicamide
Ipratropium, Oxybutynin, Benztropine
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Cholinergic agonists(Cholinomimetics)
Direct Indirect( cholinesterase inhibitors )
Edrophonium short acting
Physostigmine
(reversible)
Neostigmine
Pyridostigmine
Organophosphates
Parathion(irreversible-
may cause poisoning)
Muscarine
Nicotine
Acetylcholine-Fast decomposition
Carbachol
Bethanechol
PilocarpineMuscarine
Acetylcholine
Nicotine
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Cholinoceptor
agonists
Acetylcholine: hydrolyzed rapidly (msec), low systemic effect, low lipid soluble
(neighborhood close ammonium group).
Carbachol: carbamate-choline, is not hydrolyzed by acetylcholinesterase.
Pilocarpine: tertiary amine, lipid soluble, renally
eliminated.
Muscarine: partially absorbed by the G-I
Nicotine: absorbed easily, also from the skin
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Clinical
applications
of
cholinomimetics
I
Eye Glaucoma -
Pilocarpine
Myastenia gravis (autoimmune neuromuscularmuscle weakness)
Edrophonium, pyridostigmine, neostigmine
Demens
Alzheimers
Donepezil, rivastigmin, galantamin → delayed
disease
progression
Antidot
Intox. / overdose of atropine
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Clinical
applications
of
cholinomimetics
II
General anesthesia, neuromuscular
blockade
Neuromuscular block (Suxamethon)
Inactivation of Nicotine receptors
Reversal of neuromuscular block (Neostigmine)
Indirect displacement of the NM-receptor antagonists
Gastrointestinal tract and urinary tract
Bladder
and bowel
atony
(Neostigmine)
Contraction, increased
peristalsis
Dry
mouth
(Pilocarpine)
Secretion
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•neuromuscular disease
with fluctuating muscle weakness and
fatiguability.
•autoimmune disorder: weakness is caused by circulating antibodies
that block acetylcholine receptors
at the post-synaptic neuromuscular
junction, inhibiting the stimulative effect of acetylcholine.
•
Myasthenia is treated medically with cholinesterase inhibitors
or
immunosuppressants, and, in selected cases, thymectomy.
• At 200–400 cases per million it is one of the less common autoimmune
disorders.
•MG must be distinguished from congenital myasthenic syndroms
thatcan present similar symptomatology but offer no response to
immunosuppressive interventions.
Myasthenia gravis
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Symptoms of MG
Fatiguability:
Muscles become progressively weaker duringperiods of activity and improve after periods of rest. Musclesthat contr ol eye and eyelid movement, facial expression,chewing, talking, and swallowing
are especially susceptible.The muscles that control breathing
and neck and limb
movements can also be affected.
Sudden and intermittent.
Myasthenic crisis: Paralysis
of the respiratory muscles andassisted ventilation
to sustain life. If respiratory muscles arealready weak, crises may be triggered by infection, fever…
Since the heart muscle
is only regulated by the autonomicnervous system, it is generally unaffected by MG.
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More about MG
autoimmune disorder: antibodies directed against the body'sown proteins. Up to 75% of patients have an abnormality ofthe thymus; 25% have a thymoma, a tumor (either benign ormalignant) of the thymus.
Autoantibodies
against the nicotinic acetylcholine receptor
(nAChR), the receptor
in the motor end plate
for theneurotransmitter
acetylcholine
that stimulates muscularcontraction.
auto-antibodies against MuSK
protein
(muscle specifickinase), a tyrosine kinase
receptor which is required for theformation of the neuromuscular junction.
Common in families with other autoimmune diseases.
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The Eye
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Glaucoma
A disease in which the optic nerve is damaged, leading to progressive,irreversible loss of vision. It is often, but not always, associated withincreased pressure of the fluid in the eye (above 22 mmHg or 2.9 kPa).
An untreated glaucoma leads to permanent damage of the optic nerveand resultant visual field loss, which can progress to blindness.
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Use
of cholinomimetics
Glaucoma:
Acute
narrow
angle : Pilocarpine + neostigmine, laser
Glaukoma simplex: β-blocker, prostaglandine analogon,α -agonist, pilocarpine
Pilocarpine
Neostigmine
Physostigmine
Kontraktion of M. sphincter pupillae and
M. ciliarisMiosis(contraction) and accomodation
Improved drainage of chamber fluid …
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What is Alzheimer’s
dementia?
most common cause of dementia
— the loss of intellectual
and social abilities severe enough to interfere with dailyfunctioning. Healthy brain tissue degenerates -> steadydecline in memory and mental abilities.
No part of normal aging, but the risk of the disorderincreases with age. About 5 percent of people between theages of 65 and 74 have Alzheimer's disease, while nearlyhalf the people over the age of 85 have M. Alzheimer.
Although there's no cure, treatments may improve thequality of life for people with Alzheimer's disease.
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A 1-year, randomized, placebo-controlled
study of donepezil
in patients with
mild to moderate AD.
Winblad B et al, Neurology 2001; 57: 489-495
Donepezil
•Acetylcholinesterase inhibitors
-
Can reduce the progression of Alzheimer's
possible: also effective against dementia
-
side effects: abdominal pain, diarrhea.
-
Contraindications: urinary obstruction
asthma, COPD
Treatment of Alzheimer's dementia
•Donepezil (”Aricept”)•Rivastigmin (”Exelon”)
•Galantamin (”Reminyl”)
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Contraindications agonists
Asthma (Bronchoconstriction)
Heart failure (reduced contractility)
Cardiac conduction abnormalities(bradycardia, decreased heart rate)
Peptic ulcer (ulcer) (increased secretion)
Iritis (inflammation
of the
iris)
Mechanical bowel-/ureterobstruction
(increased motility)
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The
cholinergic
syndrome-
"overstimulation"
Muscarinic
effects
-sweating, saliva-river
-bradycardia
(decreased
heart
rate), bronchospasm
-intestinal
spasm, diarrhea, urinary
outlet
-nausea, vomiting, pupillary
constriction
(MIOSIS)
Nicotine effects
stimulation of autonomic ganglia → BT increase
stimulation of motor endplates → cramps
Later ...
blocker of ganglia and endplates → BT case, paresis
(including respiratory blockade)
CNS effectsstimulation→ anxiety, nightmares, convulsions
-then, depression → coma, respiratory depression, death
T t t f t i i ith
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Treatment of acute poisoning withirreversible cholinesterase
inhibitor
Alkylphosphates ISOFLUROPHATE
Respiration Insufficiency
Decontamination
Atropine NE frequently to controlmuscarinic symptoms
Pralidoxime = reactivation ofacetylcholinesterase in plasma
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Cholinergic receptors
Muscarinic (M)
Nicotinic (N)
Agonists Acetylcholine
Carbachol
PilocarpineMuscarine Nicotine
Antagonists Atropine, Scopolamine
Tropicamide
Ipratropium
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Mechanism of cholinoceptor
blocking drugs
Included in reversible substrate
competition
with Ach on M-receptors = competitive antagonist
More effective against externally applied agonistthan endogenous free set Ach
Atropine
In low concentrations also partial agonist,antagonist at high doses only
Ipratropium
(Quatenary amin)
Have some blocking effect also on the N-
receptors
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Physiological effects of
muscarinic
antagonists
Peripheral
Eye
Inhibition of m. sphincter pupillae
and m. ciliaris
→ pupillary
dilation and accommodation palsy → impeded drainage ofchamber fluid
Glands
Antisecretoriy, ”dry mouth”
Thermoregulatory glands
Temperature rise (can not sweat ..) = ”atropine fever ”
Smooth muscle-relaxant
Spasmolyse (intestinal, urinary, respiratory tract), little effect onblood vessels
Heart
Tachycardia
(fast heart
rhythm)
Central
Smaller
doses
→ drowsiness, sedation
Larger doses → CNS depression (drowsiness, lethargy, weakness)
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Clinical application muscarinic
antagonists
Respiratory: Acute Asthma / COPD (Ipratropium bromide)
Cardiovascular: Sinus bradycardia, nerve blockage between the
heart chambers, asystole (cardiac arrest) (Atropine)
Premedication (scopolamine)
Mydriatika (pupillary enlargement) of iritis (no glaucoma)
Motion sickness (scopolamine
patch)
Parkinsonism (Biperidine)
Spasmolyse intestine (relaxer)
Overactive bladder
Urge incontinence, 17% of the population
Reversal of neuromuscular blockade (Glykopyrron (+
neostigmine))
Atropine: Myasthenia gravis (antidote to side), poisoning with
cholinesterase inhibitors
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Muscarinic receptor blocking
agents - Contraindications
Narrow-angle glaucoma
Prostate-hypertrophy (enlargement of theprostate)
Hiatus hernia-(esophagus hernia)
Non-congenital pyloric stenosis
Delayed gastric emptying
Heart Disease
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Muscarinic antagonistspoisoning / adverse effects
Undesirable -Accommodation
paresis -pupillary
dilation
-dry
mouth -nasal mucosal
dryness
-tachycardia -difficulty
urinating -urinary
retention
-Constipation
Poisoning-Confusion-Restlessness - Seizures-respiratory depression
-hallucinations-temperature rise-Facial
Antidot = Physostigmine
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Cholinoreceptor
types
-Nicotinic receptors-
•Autonom ganglion
•Motor end plate
(striated muscle)
Acetylcholine
NM
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Neuromuscular blocking
agents
Drugs that block the normal neuromusculartransmission and thereby cause paralysis ofthe muscles
Paralysis of skeletal muscle is sought inconnection with
Intubation
Surgeries
Respiratory
Treatment
Anticonvulsant
Modes
(tetanus)
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Neuromuscular blocking
drugs (NMB)
Depolarizing
succinylcholine
Non-depolarizing
Effect
Duration
Short duration
(vecuronium, pancuronium)
Intermediate
(atracurium)
Long duration (tubocurarine)
NMB are used to induce complete skeletalmuscle relaxation in surgery.
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Mechanims of Blockade
Nondepolarizing
drugs –
bind to nicotinic receptor and compete with Ach
Depolarizing drugs –
act as nicotinic agonists
and induce depolarization: Because skeletal
muscle tension cannot be maintained without
repolarization/depolarization of the endplate,continuous depolarization results in muscle
relaxation
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Effects of NMB
Initially, muscle weakness, rising to relaxparalysis
With suxameton
seen initially transient
fasciculation of dorsal and abdominalmuscles
Small muscle groups to relax first, followed by
large
Diaphragm (and thus respiration) is the last tobe involved
Reversal occurs in reverse order
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Reversal of neuromuscular block
Glykopyrron + neostigmine
Neostigmine
= indirect cholinergic agonist → ACH volume increased by the nicotinergic
(NM)
receptors at the motor endplate
Glykopyrron
= muskarin-receptorantagonist→
blockade of muscarinic
receptors (M), thereby
blocking the adverse effects associated with
muscarinic
stimulation (sweating and salivation,
bradycardia, bronchospasm, intestinal spasms,
urinary outlet, pupillary
constriction)
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Scopolamine I
Scopolamine (levo-duboisine, and hyoscine), isa tropane
alkaloid
drug
with muscarinic
antagonisteffects. It is obtained from plants of the familySolanaceae
(nightshades).
Scopolamine is one of three main activecomponents of belladonna and stramonium
tinctures and powders used medicinally along with
atropine
and hyoscyamine.
Scopolamine was isolated from plant sources byscientists in 1881 in Germany and description ofits structure and activity followed shortly thereafter.
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Scopolamine II
anticholinergic
properties and has legitimatemedical applications in very minute doses.
For the treatment of motion sickness, the dose,
gradually released from a transdermal
patch, isonly 330 microgrammes
(µg) per day.
In rare cases, unusual reactions to ordinary doses
of scopolamine have occurred includingconfusion, agitation, rambling speech,hallucinations, paranoid behaviors, anddelusions.
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Have
a nice
day!