Презентация на тему Cholinomimetic and anticholinesterase drugs

(sensory) and efferent nerve fibers which participate in regulation

Reflex principle underlies nerve regulation

is a response of an organism to irritation of

afferent innervation
Drugs inhibiting afferent nerve fibers
Drugs inhibiting afferent nerve

realized by the acetylcholine release from:
Preganglionic
nerve fibers
Postganglionic

Efferent
nerve fibers

Parasympathetic
and sympathetic
nerve systems

Parasympathetic
nerve system

Somatic
nerve system

of
adrenal medulla
Autonomic
ganglia
Cells
of internals
Striated muscles

ending from:
acetyl-CoA
choline


choline acetyl transferase catalyzes the

The synthesized neurotransmitter is transported into
into vesicles where is packed
(in vesicles acetylcholine is protected from degradation)

in the presynaptic membrane become opened,
providing influx of

It happens when an action potential arrives
at a nerve ending

Increase in endocellular concentration of calcium occurs
and in turn, it causes the fusion of vesicles with
membrane surface and release of their content
(Ach, co-transmitters- ATP) into the synaptic cleft
by exocytosis.

receptors
muscarinic
nicotinic


Binding of acetylcholine to
postsynaptic receptors

Binding of acetylcholine to
presynaptic receptors
results in discontinuation
of its release
(negative feedback
mechanism)

acetylcholine action), the acetylcholinesterase
terminates the Ach action by

choline

acetate

Choline formed is actively uptaken by the
axonal membrane (by a Na+:choline
cotransporter)
and is used for
acetylcholine resynthesis again.

Is removed

synapse

sensitivity to acetylcholine.

They are not homogeneous.

Two basic

and M5 subtypes lead to cellular excitation (stimulant receptors)
M2,

Localization of muscarinic receptors:

M1

M2

M3

On ganglion cells and
central neurones,
escpecially in cortex,
hyppocampus and
corpus striatum.
It plays a major role in
mediating gastric
secretion, relaxation of
LES, in learning, memo-
ry, motor functions

on effector cells
of myocardium
and presynaptic
membrane
(cholinergic nerve
ending)

on smooth muscles
of g.i.t., bronchi,
urogenital system,
on eye muscles,
on excretory glands

sensitivity to nicotine like to acetylcholine.
Nicotine is known

Localization of nicotinic receptors:

in the CNS,
adrenal medulla,
autonomic ganglia
neuromuscular junctions,
sinocarotid zones

In blood vessels non-innervated muscarinic receptors
(off- synaptic M - cholinoceptors) have been found.

NN receptors – are located on ganglionic
cells
NM receptors – at skeletal muscle
endplate

cholinomimetics
M –
cholinomimetics

Acetylcholine
Carbachol
Metacholine
Bethanecol

Pilocarpine
Aceclidine
N –
cholinomimetics



Lobeline &Cytitone
“Lobesil &Tabex
Nicotine (TTS,
Chewing

Neostigmine Physostigmine
Galantamine Pyridostigmine
Rivastigmine

reversible

irreversible

Armine
Ecothiophate
Dyplos
Malathion
Diazinon
Tabun, Sarin, Soman

action

Through Gq protein
activate
phospholipase “C”

hydrolyses
phosphatidylinositol -4,5-
bisphosphate (PIP2)

formation of
Diacylglycerol (DAG)
Inositol

depolarization
Secretion
Contraction
Stimulation or inhibition
of enzymes

influx of
Ca2+ ions,
production of
protein kinase C

- protein
inhibition of adenylyl cyclase
opening K+ channels,
result in hyperpolarization
Decrease

selective stimulatory effect on M - cholinoceptors.
Drugs of this

Ophthalmic effects:
narrowing of pupils,
decrease in intraocular pressure,
spasm of accommodation.

drugs
cause contraction of smooth muscle organs such as:
bronchi
stomach
intestines
biliary

urinary bladder
(stimulate detrusor
and relax the trigon)

uterus

of the myocardium
the drugs produce:
Slowing down of conduction

decrease in excitability
of heart cells

decrease in automatism
of heart cells

Finally these effects result in bradycardia

i.v
Stimulatory
action
M3
Muscarinic receptors
(extra-synaptic)

activation of
phosphatidylinositol
system

Increase in intracellular
concentration
of Ca2+

formation of
NO (EDRF)
Endothelium-derived
relaxing factor
from arginine

Vasodilation
(male erection)

cell membranes,
drugs increase secretion of :
Bronchial
glands
Salivary
glands
Gastric
glands
Sweat
glands
Lacrimal
glands

by stimulation of M3 – cholinoceptors
of the sphincter

Decrease in intraocular tension
caused by the sphincter pupillae contraction, increase in
iridocorneal angle, dilatation of Sсhlemm’s canal and
increase in intraocular fluid outflow from
anterior chamber of the eye

– cholinoceptors of the ciliary muscle.
Contraction of

drugs which directly stimulate N – cholinoceptors.
The main effects

Sinocarotid zones

Autonomic ganglia

CNS

Chromaffin cells of adrenal glands

action consisting of two phases. After the stimulation phase,

results in:
increase in
the sympathetic activity
in peripheral bood

increase in the parasympathetic
activity in smooth muscles
and excretory glands

Stimulation of N – cholinoceptors of the medullary substance of
adrenal glands causes increase in adrenaline secretion
that results in:

vasoconstriction

increase in arterial and
venous pressure

increase in total
peripheral resistance

increase in afterload and myocardial oxygen demand

cholinomimetics has been limited.

In the past, they were

release:
Their mechanism of action is based on “modulation”
of

Their main pharmacological effects are:

g.i.t. smooth muscle cells that can result in hyperperistalsis

These drugs are used for treatment of:
postoperative atony of

pains
Giddiness
Blood pressure decrease
The main contraindications are:

acetylcholinesterase
in a cholinergic synapse.
Anticholinesterase drugs bind to

The mechanism of acetylcholinesterase inhibition is reversible.
After inhibition, enzymatic activity of the enzyme
is restored and it continues to control
acetylcholine level in synapses.

nerve gases for chemical war Tabun, Sarin, Soman inhibit

Pharmacological effects of Anticholinesterase drugs:

These drugs produce:

М- cholinomimetic effects

N- cholinomimetic effects

They act on eyes, smooth muscles, secretion of excretory glands
and heart work like M-cholinomimetics.
(these effects were described above)

due to indirect stimulation
of postjunctional N– cholinoceptors
and

Influence on the CNS:

At small doses, anticholinesterase drugs take stimulatory effect,
whereas at high doses they produce inhibitory effect on the CNS.

blood-brain barrier well.

Quaternary compounds badly pass cross the blood-brain barrier
and practically don’t cause effects in the CNS.

Neostigmine Pyridostigmine bromide
Distigmine bromide Ambenonium chloride

for:
Treatment of glaucoma: Physostigmine, Armine, Echothiophate
Stimulation of peristalsis in

muscle relaxants: Neostigmine

5. Treatment of overdoses of drugs with

and urinary bladder, diarrhea
Bronchospasm and apnoe
Bradycardia, arrhythmia
Frequency of

Adverse effects of anticholinesterase drugs:

by anticholinesterases
with irreversible action (organophosphates & carbamates).
The

Isonitrozine

Trimedoxime
bromide

Alloxime

Pralidoxime

Obidoxime

the anionic site of acetylcholinesterase which remains unoccupied in

Mechanism of acetylcholinesterase reactivator action:

organophosphorous compounds.
They are ineffective as an antidotes to carbamate