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Autonomic nervous system

Kolinerg Farmakologi

Associate Professor Daniela Gabriele GrimmDepartment of Pharmacology, Aarhus

University, DK



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



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



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”



Adrenaline

NA

NA

NA

Ach

Ach

Ach

Ach

Ach

NA

NA

NA

Ach



–

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



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



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



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



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



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



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



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



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



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 neuromuscularmuscle 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



•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

http://en.wikipedia.org/wiki/Neuromuscular_disease



http://en.wikipedia.org/wiki/Fatigue_%28physical%29


http://en.wikipedia.org/wiki/Acetylcholine

http://en.wikipedia.org/wiki/Immunosuppressants

http://en.wikipedia.org/wiki/Cholinesterase_inhibitor







http://en.wikipedia.org/wiki/Acetylcholine

http://en.wikipedia.org/wiki/Fatigue_%28physical%29




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.

http://en.wikipedia.org/wiki/Chewing

http://en.wikipedia.org/wiki/Manner_of_articulation

http://en.wikipedia.org/wiki/Swallowing




http://en.wikipedia.org/wiki/Breath








http://en.wikipedia.org/wiki/Assisted_ventilation




http://en.wikipedia.org/wiki/Paralysis




http://en.wikipedia.org/wiki/Cardiac_muscle

















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.

http://en.wikipedia.org/wiki/Thymoma

http://en.wikipedia.org/wiki/Thymus



http://en.wikipedia.org/wiki/Receptor_%28biochemistry%29




http://en.wikipedia.org/wiki/Nicotinic_acetylcholine_receptor










http://en.wikipedia.org/wiki/Neuromuscular_junction












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 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.

http://en.wikipedia.org/wiki/Optic_nerve

http://en.wikipedia.org/wiki/Visual_field

http://en.wikipedia.org/wiki/Blindness

http://en.wikipedia.org/wiki/Blindness

http://en.wikipedia.org/wiki/Visual_field

http://en.wikipedia.org/wiki/Optic_nerve



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 …



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.



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”)



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 effectsstimulation→ anxiety, nightmares, convulsions

-then, depression → coma, respiratory depression, death

T t t f t i i ith



Treatment of acute poisoning withirreversible cholinesterase

inhibitor

Alkylphosphates ISOFLUROPHATE

Respiration Insufficiency

Decontamination

Atropine NE frequently to controlmuscarinic symptoms

Pralidoxime = reactivation ofacetylcholinesterase in plasma



Cholinergic receptors

Muscarinic (M)

Nicotinic (N)

Agonists Acetylcholine

Carbachol

PilocarpineMuscarine Nicotine

Antagonists Atropine, Scopolamine

Tropicamide

Ipratropium



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



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)



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 theprostate)

Hiatus hernia-(esophagus hernia)

Non-congenital pyloric stenosis

Delayed gastric emptying

Heart Disease



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



Cholinoreceptor

types

-Nicotinic receptors-

•Autonom ganglion

•Motor end plate

(striated muscle)

Acetylcholine

NM



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)



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.



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 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



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), 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.

http://en.wikipedia.org/wiki/Tropane_alkaloid


http://en.wikipedia.org/wiki/Medication

http://en.wikipedia.org/wiki/Muscarinic_antagonist





http://en.wikipedia.org/wiki/Solanaceae

















http://en.wikipedia.org/wiki/Atropine

http://en.wikipedia.org/wiki/Hyoscyamine














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.

http://en.wikipedia.org/wiki/Anticholinergic





http://en.wikipedia.org/wiki/Motion_sickness

http://en.wikipedia.org/wiki/Transdermal_patch



http://en.wikipedia.org/wiki/Microgram






http://en.wikipedia.org/wiki/Motion_sickness




Have

a nice

day!

dg f kolinerg f10 mm

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