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1. N-Cholinomimetics and N-Cholinoblockers,
Anticholinesterases
ass. Askarov O.O.

3. Efferent innervation of the body occurs
via autonomic nerves (innervating visceral
organs, blood vessels and glands) and
motor nerves of skeletal muscles.
Autonomic innervation is subdivided into
cholinergic (parasympathetic) and
adrenergic (sympathetic).
There are two main mediators:
acetylcholine and norepinephrine).

4. •The efferent pathway of the autonomic nerves
consists of two neurons: preganglionic and
ganglionic (postganglionic).
•The bodies of preganglionic neurons in the
cholinergic system have craniosacral localization.
Cranial nuclei are located in the midbrain and
medulla oblongata. Cholinergic fibers are inside the
pairs of cranial nerves (III, VII, IX, X).
•In the sacral part preganglionic neurons originate
from the lateral horns of the spinal cord gray
substance.

6. •In the adrenergic system, the bodies of
preganglionic neurons are mainly located in the
lateral horns of the thoracolumbar part of the
spinal cord.
•Axons of preganglionic neurons terminate at the
autonomic ganglia in the synaptic contacts with
ganglionic neurons.
•Sympathetic ganglia are located outside the
bodies organs, and parasympathetic are mostly
located inside the organs.

7. •Choline is accumulated in cholinergic
presynaptic nerve endings via an active
transport mechanism linked to a Na+ pump.
Acetylcholine is synthesized from choline
and acetyl-CoA and accumulated in synaptic
vesicles.
•Ach is released from synaptic vesicles.
•Ach interacts with its receptors, but it is
inactivated by acetylcholinesterase.

9. Types of cholinergic receptors:
N are nicotine-sensitive
M are muscarine-sensitive
Nn (1) are:
in ganglia,
in the carotid
sinus,
in the adrenal
medulla.
Nm(2) are in skeletal
muscles
•M1 are located in the
Central nervous system,
enterochromaffin cells of
the stomach.
•M2 are in the heart.
•M3 are in smooth muscles
of organs, glands of
external secretion,
endothelium of vessels.

10. N1 –
1,3,5
N2 – 6
M – 2
AR – 4

11. Classification of ChM:
Direct cholinomimetics:
N, M-ChM: Acetylcholine, Carbacholine
M-ChM: Pilocarpine, Aceclidine
N-ChM: Cytisine (Tabex),
Nicotine (Nicorette)
Indirect cholinomimetics (anticholinesterase
drugs): Neostigmine, Galantamine,
Rivastigmine

12. Nicotine is an alkaloid of tobacco leaves.
It is used in experimental pharmacology to
analyze the mechanism of drugs action.
Nicotine affects both central and peripheral
N-cholinoceptors. It has a two-phase effect
because it stimulates N-CR in low doses
but it blocks them when it is used in high
doses.
Tolerance and dependence develop to
nicotine.

13. •Nicotine interacts with N-CR of the autonomic
ganglia and changes the functions of organs.
•N. stimulates the chemoreceptors of the
sinocarotid zone and reflexively activates
respiratory and vasomotor centers. In high
doses N. causes the inhibition of these centers.
•In low doses N. stimulates N-cholinoceptors of
the chromaffin cells of the adrenal glands and
increases the release of epinephrine. In high
doses it causes the opposite effect.

14. •Nicotine has a marked effect on the
CNS. It increases the release of
dopamine into the Central nervous
system, a person experiences the
pleasure of smoking. If a person does
not smoke, dopamine levels drop and
the person feels unwell. Dependence
to nicotine develops.

18. EFFECTS OF NICOTINE
Effects Low doses High doses
The heart rate ↓ ↑
Blood pressure ↑ ↓
Intestinal
motility
↑ ↓
The secretion of
exocrine glands
↑ ↓

20. ACUTE POISONING
Abdominal pain, vomiting, nausea, diarrhea,
Raised sweating,
Headache, dizziness, visual impairment,
hearing disorders, disorientation.
In severe cases: lowering of blood pressure,
oppression of the heart, oppression of the
respiratory center.
Help: Adsorbents, gastric lavage;
Anticholinergics; artificial ventilation,
symptomatic therapy

21. • N. in low doses can be used for the treatment of tobacco dependence. It
stimulates receptors and helps stop Smoking. We can used for example:

22. •Cytisine is sometimes used in clinical
practice as respiratory stimulant of reflex
action. It stimulates receptors of carotid
sinus. It stimulates receptors of adrenal
medulla, increases the release of
epinephrine and increases arterial pressure.
•Indications: depression of breathing
(morphine poisoning, carbon monoxide,
drowning, injury), to aid “quitting”
smoking.

23. •Cytisine is an analeptic because it restores
depressed breathing and reduced pressure.
It is effective only after intravenous
administration.

24. •Anticholinergics block the cholinergic
receptors, prevents their interaction with
acetylcholine and disrupts the conduction of
nerve impulses.
N-Cholinoblockers:
N-cholinoblockers
Ganglionblockers
Neuromuscular relaxants (curare-like drugs)

25. •Ganglionic blockers block sympathetic and
parasympathetic ganglia, N-CR of the adrenal
medulla and carotid body.
Classification
Bis-Quaternary ammonium salts do not penetrate
the BBB
1. Short-acting drugs (5-20 minutes): Trepirium
iodide
2. Average duration (3-4 hours): Azametonium
bromide, Hexamethonium benzolsulfonate
3. Long-acting (tertiary amines): Pachycarpine (6-
8 hours)

26. •They dilate arterial and venous vessels,
decrease blood pressure, reduce preload
and postload of the heart, improve blood
circulation in organs (lower limbs),
improve tissue trophism .
•They reduce smooth muscle tone
(intestine, bronchi, except myometrium),
secretion of exocrine glands (salivary,
gastric). But they can increase tone of
uterine and stimulate labor.

27. Indications for the use:
Obliterating endarteritis, pulmonary edema,
arterial embolism, hypertensive crisis.
Short-acting drugs can be used for controlled
hypotension during operation. They are
administered IV drip, dilate vessels, decrease
arterial pressure and reduce hemorrhage during
thyroidectomy and mastectomy. In neurosurgery
they reduce the possibility of the development of
brain edema.
Spastic pain (colic), bronchospasm, gastric and
duodenal ulcer.

28. SIDE EFFECTS:
Orthostatic collapse develops after an
abrupt change of the body’s position in
space. Marked and rapid decrease in the
arterial pressure develops after transition
from horizontal to vertical position.
 Syncope.
Constipation, urinary retention.
Accommodation disorder, mydriasis.
Dysarthria, dysphagia.

29. •DRUGS BLOCKING NEUROMUSCULAR
TRANSMISSION (NEUROMUSCULAR
RELAXANTS, PERIPHERAL MUSCLES
RELAXANTS)
•They inhibit neuromuscular transmission on the
level of postsynaptic membrane, interacting
with N-cholinoceptors of the endplates.
•Curare was the first muscle relaxant. Its extract
was obtained from plants in South America and
used as an arrow poisoning.

32. CLASSIFICATION
Antidepolarizing (nondepolarizing)
drugs: Tubocurarine, Pancuronium,
Pipecuronium bromide,
Atracurium besilate,
Mivacurium chloride
Depolarizing drug – Suxamethonium
iodide
Mixed effect- Dioxonium

33. DURATION OF ACTION:
Short-acting:
Mivacurium chloride (15 min),
Suxamethonium iodide (5-8 min)
Average duration:
Atracurium besilate(15-35 min)
Long-acting:
Pipecuronium bromide (50-120 min)

34. Antidepolarizing drugs block N-ChR and prevent
depolarizing effect of acetylcholine. They act
competitive. If the concentration of acetylcholine
in the area of block is increased significantly this
will lead to restoration of the neuromuscular
transmission.
Depolarizing drug excite N-ChR and causes steady
depolarization of the postsynaptic membrane. In
the beginning, depolarization development is
manifested by muscular fasciculations. Soon after
a myoparalytic effect develops.

38. Muscles are relaxed in a certain sequence:
Muscles of the face and neck;
The lower and upper limbs;
Muscles of the trunk;
Respiratory muscles;
The diaphragm.
Myoparalytic action range: the range between doses in
which drugs paralyze more sensitive muscles, and doses
that cause respiratory arrest.
Artificial ventilation of the lungs is required when using
muscle relaxants

39. Antagonists:
Antagonists of the antidepolarizing
drugs are anticholinesterase drugs
(Neostigmine, Galanthamine).
The action of depolarizing drug
(suxamethonium) can be reversed by
the administration of fresh citrated
blood, containing plasma
cholinesterase, which hydrolyzes
suxamethonium.

40. INDICATIONS FOR THE USE
In anaesthesiology during the
performance of most operations on the
organs of the thoracic and abdominal
cavities, on the upper and lower limbs;
Tracheal intubation, bronchoscopy,
reduction and reposition of bone fracture
fragments;
The treatment of tetanus and epilepsy.

41. SIDE EFFECTS:
Tachycardia (pancuronium), fluctuations
in blood pressure,
 Allergic reactions,
 Arrhythmia, increase in intraocular
pressure, muscular pains, long-term
apnoea (suxamethonium).

42. Comparative characteristics
of Pipecuronium and Suxamethonium
Effects Pipecuronium Suxamethonium
Effect on the
endplate
membrane
Stabilization Depolarization
Muscle
fasciculations
Absent Observed at the
beginning of the
action
Interaction with
Neostigmine
Antagonism Sinergism

43. Anticholinesterases
The action of these drugs is directed to acetylcholinesterase
in a cholinergic synapse.
Anticholinesterase drugs bind to active centers of
acetylcholinesterase and impair hydrolysis of acetylcholine.
The mediator is accumulated in synapses
and stimulates M and N – cholinoceptors.
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.

44. Irreversible anticholinesterases (Armine, Ecothiophate,
Organophosphate and carbamate insecticids, nerve gases for
chemical war Tabun, Sarin, Soman inhibit activity of the
enzyme without its restoration.
Pharmacological effects of Anticholinesterase drugs:
44
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)

45. 45
Influence on skeletal muscles:
Anticholinesterase drugs facilitate neuromuscular
transmission due to indirect stimulation
of postjunctional N– cholinoceptors
and increase tone of striated muscles.
Influence on the CNS:
At small doses, anticholinesterase drugs take stimulatory effect,
whereas at high doses they produce inhibitory effect on the CNS.

46. 46
However, only tertiary structure compounds pass cross
the blood-brain barrier well.
Physostigmine Galantamine
Aminostigmine Tacrine
Donepezil
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

47. Therapeutic use of Anticholinesterase drugs
Anticholinesterase drugs are used for:
1. Treatment of glaucoma: Physostigmine, Armine, Echothiophate
2. Stimulation of peristalsis in postoperative atony of the intestines,
paralytic obstruction, atony of the urinary bladder and
uterine inertia (powerless labor):
Neostigmine, Distigmine, Physostigmine
3. Treatment and diagnostics of myasthenia gravis:
(chronic autoimmune disease causing muscle weakness:
autoantibodies reduce number of free Nn receptors)
Neostigmine, Pyridostigmine, Ambenonium, Edrophonium

48. 4. As pharmacological antagonists in overdoses of
nondepolarizing muscle relaxants: Neostigmine
5. Treatment of overdoses of drugs with anticholinergic action
(atropine, phenothiazines, tricyclic antidepressants):
Physostigmine, Galantamine
6. Treatment of Alzheimer’s disease:
Tacrine, Donepezil, Rivastigmine

49. Hypersalivation
Nausea, spastic stricture of muscles of the intestine and urinary bladder,
diarrhea
Bronchospasm and apnoe
Bradycardia, arrhythmia
Frequency of urination
Miosis
Twitchings of tongue and skeletal muscles
49
Adverse effects of anticholinesterase drugs:

50. Cholinesterase reactivators
50
Drugs of this group restore
acetylcholinesterase inhibited by anticholinesterases
with irreversible action (organophosphates & carbamates).
The main acetylcholinesterase reactivators are:
Isonitrozine
Trimedoxime
bromide
Alloxime Pralidoxime Obidoxime

51. Reactivators contain oxime group (=N-OH).
They attach to the anionic site of
acetylcholinesterase which remains unoccupied
in the presence of organophosphate inhibitor.
Its oxime end reacts with the phosphorous
atom attached to the esteratic site: the
oxime:phosphonate diffuses away leaving the
reactivated ChE.
51
Mechanism of acetylcholinesterase reactivator action:

52. Acetylcholinesterase reactivators are
used as specific antagonists of
organophosphorous compounds.
They are ineffective as an antidotes to
carbamate antiChEs (Physostigmine,
Neostigmine, Carbaryl, Propoxur) in
which case the anionic site of the enzyme
is not free to provide attachment to it.
52

53. Atropine as well as reactivators is the basic
pharmacological antidote in anticholinesterase
poisoning.
Atropine inhibits bronchospasm, bronchorrhea,
bradycardia and blockade of heart conductive
system.
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54. Thank you for your attention!!!