Autonomic nervous system

Kolinerg Farmakologi
Associate Professor Daniela Gabriele Grimm
Department of Pharmacology, Aarhus
University, DK

Nervous System
Peripheral

Somatic motor
Nervous system

Central

Autonomic (Visceral functions, involuntary such as heart, gut)

(Having the will control

ex. Skeletal muscle
voluntary)

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

Ganglion near
target organ

M, Ach.
Parasympathetic

N, Ach

Medulla
Spinalis

Truncus sympaticus

N, Ach

Adrenoceptor, NA
Sympathetic

N, Ach, motor end plate

(Contact between nerve & muscle)
Preganglionic fibre
Postganglionic fibre
Ach = acetylcholine, NA = noradrenaline (norepinephrine), N = Nicotinic receptor, M = Muscarinic receptor

Autonomic
nervous
system

Parasympathetic stimulation
- Bradycardia
- Vascular dilatation in the viscera
- Contraction of bronchi
- Relaxation of the Intestine
- Miosis-small pupil

rest and digest

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

Ach
Ach

Ach

NA
NA
NA

Ach

Ach

Adrenaline

NA
NA
NA

Ach

Post- and presynaptic receptors

Balance between the tone of sympaticus and parasympaticus
Sympathetic
neuron

Parasympathetic
neuron

NA

Ach

nerve

M1/2

2
M3

1
Target organ
Physiological
effects (Smooth muscle)

Physiological effects glands,

endothelial cells

Eye-contraction in the light is parasympathetic

Dilation in the dark sympathetic

PARASYMPATHETIC SYSTEM
Preganglionic and postganglionic neurons are cholinerg

Transmitter ACh nicotine RC Transm ACh muscarinic Rc

Transmitter Ach

nicotinic Rc sceletal muscle

somatomotoric nerve

-> all somatic motor end-plates on skeletal

muscle

target organs

Sympathethic system
Transmitter ACh nicotine RC Transmitter NA

1 2
1 2

all symathetic

Organs

Preganglionic transmitter is Aceytlcholine

(cholinergic neuron)
Postganglionic transmitter is Noradrenaline

Norepinephrine

Cholinergic Synapsis
Inhibitors (Anticholinergics)
Hemicholinium
(Inhibits choline uptake)

Ack
M
Vesamicol
AcCoA
(VesicleKact
Membranblockade) P

Aktions
potentiale

acetylcholin
mitochondria
acetyl-CoA
cholinacetyltransferase
neuropeptid

botulinum
(Block the release of Ach)

Receptor antagonists

Activators
(Cholinergic agents)
Direct receptor
agonist
Indirect agonist

(M-type)

Cholinergic receptor typesmuscarinic receptor - subtypes

ACh

M1 , M3 , M5
a bg

PLC
IP3

K+

ACh
a b
g

G-protein coupled

Ca2+

a b
g

M2 , M4
AC

cAMP

Gi inhibition of adenylyl cyclase reduction of CAMP

Function of cholinoceptor subtypes

Eye

M3

Bronchi
Heart

M3
M2

-m. constrictor pupilae

-m. ciliaris

-SA node
-arteries
-AV node
-ventricles

contraction (miosis)
contraction
contraction, secretion
reduced frequency
decreased contractility
decreased conduction velocity
mildly impaired contractility

Vascular

M3

- skin, mucous membranes

skeletal muscles
-coronary

vasodilation (NO mediated)

contraction

Glands (no sweat)

M3

secretion

Termoregulatoric
glands

M?

secretion

Function of cholinoceptor subtypes

Stomach, bowel,
bladder

M3

secretion and motility

increased tone
relaxation

Uterus

M3

contraction

Nerve Terminals

M3

inhibition of NA release from sympathetic

-wall
-sphinx

Brain

M1
M4
M5

nerves
cortex, hippocampus
forebrain, striatum
substantia nigra

Alzheimer (M1), schizophrenia (M1 cortex), Parkinson(M4,M5)

What stimulates cholinergic receptors

Muscarinic (M)

Nicotinic (N)

Acetylcholine

Agonist
stimulates

Carbachol
(Against bladder spasms)

Pilocarpine
Muscarine

Antagonists blocker Muscarinic

Nicotine

Atropine, Scopolamine
Tropicamide
Ipratropium, Oxybutynin, Benztropine

Cholinergic agonists
(Cholinomimetics)

Direct

Indirect
(cholinesterase inhibitors)

Muscarine

Nicotine

Acetylcholine- Acetylcholine
Fast decomposition
Nicotine
Carbachol
Bethanechol
Pilocarpine
Muscarine

Edrophonium
Physostigmine
Neostigmine
Pyridostigmine

short acting

(reversible)

Organophosphates
Parathion
(irreversiblemay cause poisoning)

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

Clinical applications of
cholinomimetics I

Eye Glaucoma - Pilocarpine

Myastenia gravis (autoimmune neuromuscular
muscle weakness)
Edrophonium, pyridostigmine, neostigmine
Demens
Alzheimers
Donepezil, rivastigmin, galantamin delayed
disease progression
Antidot
Intox. / overdose of atropine

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

Myasthenia gravis
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 200400 cases per million it is one of the less common autoimmune
disorders.
MG must be distinguished from congenital myasthenic syndroms that
can present similar symptomatology but offer no response to
immunosuppressive interventions.

Symptoms of MG

Fatiguability: Muscles become progressively weaker during

periods of activity and improve after periods of rest. Muscles
that control 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 and
assisted ventilation to sustain life. If respiratory muscles are
already weak, crises may be triggered by infection, fever
Since the heart muscle is only regulated by the autonomic
nervous system, it is generally unaffected by MG.

More about MG

autoimmune disorder: antibodies directed against the body's

own proteins. Up to 75% of patients have an abnormality of
the thymus; 25% have a thymoma, a tumor (either benign or
malignant) of the thymus.
Autoantibodies against the nicotinic acetylcholine receptor
(nAChR), the receptor in the motor end plate for the
neurotransmitter acetylcholine that stimulates muscular
contraction.
auto-antibodies against MuSK protein (muscle specific
kinase), a tyrosine kinase receptor which is required for the
formation of the neuromuscular junction.
Common in families with other autoimmune diseases.

The Eye

Glaucoma

A disease in which the optic nerve is damaged, leading to progressive,

irreversible loss of vision. It is often, but not always, associated with
increased pressure of the fluid in the eye (above 22 mmHg or 2.9 kPa).
An untreated glaucoma leads to permanent damage of the optic nerve
and resultant visual field loss, which can progress to blindness.

Use of cholinomimetics
Glaucoma:
Acute narrow angle : Pilocarpine + neostigmine, laser
Glaukoma simplex: -blocker, prostaglandine analogon,
-agonist, pilocarpine

Pilocarpine
Neostigmine
Physostigmine
Kontraktion of M. sphincter pupillae and
M. ciliaris

Miosis(contraction) and accomodation

Improved drainage of chamber fluid

What is Alzheimers
dementia?

most common cause of dementia the loss of intellectual

and social abilities severe enough to interfere with daily
functioning. Healthy brain tissue degenerates -> steady
decline in memory and mental abilities.
No part of normal aging, but the risk of the disorder
increases with age. About 5 percent of people between the
ages of 65 and 74 have Alzheimer's disease, while nearly
half the people over the age of 85 have M. Alzheimer.
Although there's no cure, treatments may improve the
quality of life for people with Alzheimer's disease.

Causes

Combination of genetic, lifestyle and environmental factors to trigger the

onset of symptoms. While the causes of Alzheimer's are poorly
understood, its effect on brain tissue is clear. Alzheimer's disease
damages and kills brain cells.
Two types of brain cell (neuron) damage are common in people who
have Alzheimer's:
Plaques. Clumps of a normally harmless protein called beta-amyloid
may interfere with communication between brain cells. Although the
ultimate cause of neuron death in Alzheimer's isn't known, mounting
evidence suggests that the abnormal processing of beta-amyloid protein
may be the culprit.
In people with Alzheimer's, threads of tau protein undergo
alterations that cause them to become twisted. Many researchers believe
this may seriously damage neurons, causing them to die.

Treatment of Alzheimer's dementia

Donepezil (Aricept)
Rivastigmin (Exelon)
Galantamin (Reminyl)

Donepezil
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

Acetylcholinesterase inhibitors
- Can reduce the progression of Alzheimer's
possible: also effective against dementia
- side effects: abdominal pain, diarrhea.
- Contraindications: urinary obstruction
asthma, COPD

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)

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 effects
stimulation anxiety, nightmares, convulsions
-then, depression coma, respiratory depression, death

Treatment of acute poisoning with

irreversible cholinesterase
inhibitor

Alkylphosphates ISOFLUROPHATE
Respiration Insufficiency
Decontamination
Atropine NE frequently to control
muscarinic symptoms
Pralidoxime = reactivation of
acetylcholinesterase in plasma

Cholinergic receptors
Muscarinic (M)

Nicotinic (N)

Acetylcholine

Agonists

Carbachol
Pilocarpine
Muscarine

Antagonists

Atropine, Scopolamine
Tropicamide
Ipratropium

Nicotine

Muscarinic antagonists
Atropine/
scopolamine

Tropicamid

Ipratropium

Naturally occurring alkaloids

- Absorbed and distributed easily
- T = 2 hours, the eye,
however, effect of
several days of atropine (48-72 h) ...

Synthetic tertiary amine

- Lipophilic, easy abs and
distribution
- Nearly as potent as the
neighborhood close relationship
Synthetic, quaternary amine
- Hydrophilic
- Poor absorption (10-30%)
District near relations have generally
pronounced effect on the abdominal
organs

Mechanism of cholinoceptor
blocking drugs

Included in reversible substrate competition with

Ach on M-receptors = competitive antagonist
More effective against externally applied agonist
than 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 Nreceptors

Physiological effects of
muscarinic antagonists

Peripheral

Eye
Inhibition of m. sphincter pupillae and m. ciliaris pupillary
dilation and accommodation palsy impeded drainage of
chamber fluid
Glands
Antisecretoriy, dry mouth
Thermoregulatory glands
Temperature rise (can not sweat ..) = atropine fever
Smooth muscle-relaxant
Spasmolyse (intestinal, urinary, respiratory tract), little effect on
blood vessels
Heart
Tachycardia (fast heart rhythm)

Central

Smaller doses drowsiness, sedation

Larger doses CNS depression (drowsiness, lethargy, weakness)

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

Muscarinic receptor blocking

agents - Contraindications

Narrow-angle glaucoma
Prostate-hypertrophy (enlargement of the
prostate)
Hiatus hernia-(esophagus hernia)
Non-congenital pyloric stenosis
Delayed gastric emptying
Heart Disease

Muscarinic antagonists
poisoning / 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

Cholinoreceptor types
-Nicotinic receptorsAcetylcholine
NM

Autonom ganglion
Motor end plate
(striated muscle)

Neuromuscular blocking
agents

Drugs that block the normal neuromuscular

transmission and thereby cause paralysis of
the muscles
Paralysis of skeletal muscle is sought in
connection with

Intubation
Surgeries
Respiratory Treatment
Anticonvulsant Modes (tetanus)

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 skeletal

muscle relaxation in surgery.

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

Effects of NMB

Initially, muscle weakness, rising to relax

paralysis
With suxameton seen initially transient
fasciculation of dorsal and abdominal
muscles
Small muscle groups to relax first, followed by
large
Diaphragm (and thus respiration) is the last to
be involved
Reversal occurs in reverse order

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)

Scopolamine I

Scopolamine (levo-duboisine, and hyoscine), is

a tropane alkaloid drug with muscarinic antagonist
effects. It is obtained from plants of the family
Solanaceae (nightshades).
Scopolamine is one of three main active
components of belladonna and stramonium
tinctures and powders used medicinally along with
atropine and hyoscyamine.
Scopolamine was isolated from plant sources by
scientists in 1881 in Germany and description of
its structure and activity followed shortly thereafter.

Scopolamine II

anticholinergic properties and has legitimate

medical applications in very minute doses.
For the treatment of motion sickness, the dose,
gradually released from a transdermal patch, is
only 330 microgrammes (g) per day.
In rare cases, unusual reactions to ordinary doses
of scopolamine have occurred including
confusion, agitation, rambling speech,
hallucinations, paranoid behaviors, and
delusions.

Have a nice day!