1. Autonomic nervous system Cholinergic agonists (CHOLINOMIMETICS)
PhD. A.V. Aleksandrova

2. Functional divisions within the nervous system

3. Somatic N.S Autonomic N.S
What are the differences between the somatic and the autonomic nervous system?
Somatic N.S Autonomic N.S
Control skeletal muscles Control internal viscera
Voluntary Involuntary
Somatic nerve is one autonomic nerve is
fiber two fibers (Preganglionic & Postganglionic)

4. Efferent neurons of the autonomic nervous system

5. Sympathetic ANS
The 1st neuron of sympathetic division is located in the thoracolumbar region of the spinal cord (T1-L3) and the 2nd is disposed either in the paravertebral, or in the prevertebral ganglia. Postganglionic non-myelinated nerve fibres arising from neurones in the ganglia, innervate most organs of the body
The neurotransmitter released by sympathetic nerve endings is noradrenaline.

6. Parasympathetic system
The 1st neuron of parasympathetic system is located in the brain stem and in the sacral region of the spinal cord. The preganglionic fibres leave the central nervous system in the III, VII, IX and X pairs of cranial nerves and the third and fourth sacral spinal roots.
Ganglia are located either in the tissue of effector organ or near it. The nerve endings of the postganglionic parasympathetic fibres release neurotransmitter acetylcholine. All the preganglionic nerve fibres (sympathetic and parasympathetic;) are myelinated and release acetylcholine from the nerve terminals which depolarizes the ganglionic neurones by activating nicotinic receptors.

7. Parasympathetic Nervous System (craniosacral outflow)

8. Cholinergic nervous fibres are:
1) preganglionic (sympathetic and parasympathetic);
2) all postganglionic parasympathetic;
3) postganglionic sympathetic which supply sweat glands and vessels of skeletal muscles;
4) somatic nerves;
5) nerves which supply adrenal medulla and carotic sinuses;
6) neurons of CNS
Adrenergic nervous fibres are:
1) postganglionic sympathetic, except those which supply sweat glands and vessels of skeletal muscles;
2) neurons of CNS

10. Cholinergic transmission
Main NT is Acetylcholine (Ach).
A large number of peripheral ANS fibers which synthesize & release Acetylcholine are called CHOLINERGIC fibers. They include:
All pre-ganglionic efferent autonomic fibers.
Somatic motor fibers to skeletal muscles.
Most parasympathetic post ganglionic fibers.
A few sympathetic post ganglionic fibers– to sweat glands.
Some parasympathetic post ganglionic fibers utilize nitric oxide or peptides for transmission.

11. Fate of acetylcholine released by cholinergic fiber
ACh is released from the nerve into the synaptic cleft and binds to ACh receptors on the post-synaptic membrane, relaying the signal from the nerve.
Ach-esterase, located on the post-synaptic membrane, terminates the signal transmission by hydrolyzing ACh.
The liberated choline is reuptaken by the pre-synaptic membrane and used for resynthesis of ACh.

12. Cholinergic synapse
Nerve terminal of cholinergic fibre contains numerous vesicles with neurotransmitter acetylcholine (ACh) that is released from presynaptic membrane.
Release of acetylcholine depends on sufficient influx of Ca 2+, which occurs under the influence of action potential.  
ATP
negative feedback
ATP

13. Cholinergic receptor types
Two cholinergic receptor subtypes have been identified by selective agonists: muscarinic (M-cholinoceptors) and nicotinic (N-cholinoceptors). At least 5 subtypes of muscarinic receptors (M1 – M5) have been distinguished.
There are 3 main classes of N- cholinoceptors: the muscle, ganglionic, and CNS classes.
MUSCARINIC
NICOTINIC M1 M5 NM NN M2 M3 M4
Ganglions
Carotid sinus
Skeletal muscles
Adrenal glands
CNS
Eye
Heart
Smooth muscles
Exocrine glands
CNS

14. Muscarinic receptors High affinity to muscarine
M1 – gastric parietal cells, saliva, CNS
M2 - cardiac cells, smooth muscle,
CNS
M3 - bladder, exocrine glands, smooth muscle, eye, CNS
M1&M3 – Gq
M2 - Gi
Amanita muscaria

15. Nicotinic receptors High affinity to nicotine
NM- neuro-muscular junction
NN – ganglion, adrenal gland
CNS, carotid sinus

16. Mechanisms of impulse transmission
Muscarinic receptors belong to G-protein coupled receptors. Transmission of impulses through M1, M3, M5 cholinoceptors is realized by phospholipase C, inositol triphosphate and diacylglycerol
Stimulation of M2 and M4 cholinoceptors results in inhibition of adenylate cyclase and decrease in intracellular cAMP.
N- cholinoceptors are ion channel coupled. Their stimulation results in opening of Na+ channels that causes depolarization.

17. Muscarinic receptors M1 M3

18. Pharmacological actions gastric parietal cells
M-cholinoceptors
Pharmacological actions
Locations
Receptor
CNS excitation
Gastric acid secretion
CNS
gastric parietal cells
M1 Excitatory
Cardiac inhibition
(Bradycardia)
Heart
M2 Inhibitory
Secretion of glands
Smooth muscle contraction
Vasodilatation (via nitric oxide)
Exocrine glands
Smooth muscles
Vascular endothelium M3
Excitatory
memory, arousal, attention and
M4 & M5

19. Effects of stimulation
N-cholinoceptors
Cholinoceptors
Localization
Effects of stimulation NN
Autonomic ganglia
(parasympathetic and sympathetic)
Increase in parasympathetic and sympathetic reactions
Adrenal medulla
Increase in adrenaline release, increase in BP NM
Skeletal muscle
Increase in tone, contraction
Carotid sinus
Reflex respiratory centre stimulation
CNS
Stimulation

20. Peripheral cholinoceptor Nicotinic receptors Central cholinoceptor
Muscarinic receptors
Peripheral cholinoceptor
Nicotinic receptors
Central cholinoceptor
G protein linked receptors
Ion channel linked receptors
On all peripheral organs that receive postganglionic parasympathetic fibers
Autonomic ganglia (sympathetic & parasympathetic) stimulation ( Nn )
Heart (M2) inhibition
exocrine glands (M3) contraction
Adrenal medulla (Nn)
release of catecholamines
(Adrenaline & Noradrenaline)
Smooth muscles (GIT, urinary tract, bronchial muscles)
(M3) contraction
Skeletal muscle
(Neuromuscular junction)
(Nm) Contraction
Excitatory or inhibitory
Almost excitatory

21. Nicotinic actions Skeletal muscles:
Low conc. of nicotine  muscle contraction
High conc. of nicotine persistent depolarization & relaxation.
Ganglia:
stimulation of sympathetic& parasympathetic ganglia.
Adrenal medulla
release of catecholamines (A & NA).

22. Muscarinic actions Cholinergic actions Organs
Contraction of circular muscle of iris (miosis)(M3)
Contraction of ciliary muscles for near vision (M3)
Decrease in intraocular pressure
Eye
bradycardia ( heart rate ) (M2)
Release of NO (EDRF)
Heart
endothelium
Constriction of bronchial smooth muscles
Increase bronchial secretion M3
Lung
Increase motility (peristalsis)
Increase secretion
Relaxation of sphincter M3
GIT
Contraction of muscles
Relaxation of sphincter M3 - Urination
Urinary bladder
Increase of all secretions
sweat, saliva, lacrimal, bronchial, intestinal secretions M3
Exocrine glands

23. Cholinomimetics 1. Muscarinic agonists (M-cholinomimetics) Pilocarpine
I. Direct acting
1. Muscarinic agonists (M-cholinomimetics)
Pilocarpine
Oxothermorine
Aceclidine
2. Nicotinic agonists
Lobeline
Dimethylphenylpiperazinum (DMPP)
3. Muscarinic and nicotinic agonists
Acethylcholine
Carbachol
II. Indirect acting (muscarinic and nicotinic agonists – anticholinesterase agents)
1. Reversible
Neostigmine (Proserinum)
Physostigmine
Pyridostigmine
Edrophonium
Ambenonium chloride (Oxazylum)
Galanthamine
2. Irreversible (Organophosphates)
Echotiophate
Isoflurophate
Arminum
Drugs used in poisoning with organophosphates
1. Reactivators of acetylcholine esterase
Pralidoxime
Dipiridoxinum
Izonitrozinum
Obidoxime
2. M-cholinoblockers
Atropine

24. Pharmacological effects
Bradycardia, decrease in blood pressure
Raising the tone of smooth muscles of internal organs
Stimulation of intestinal motility
Reducing sphincter of alimentary canal and bladder
Increased secretory activity of the exocrine glands
Constriction of the pupil of the eye (miosis)
spasm of accommodation
Reducing intra ocular pressure
Relief of pulses in mionevralnomu skeletal muscle synapse, strengthening their contractility (anticholinergic drugs)
Stimulation of the central nervous system (means of penetrating the blood-brain barrier)

25. Main clinical usage 1. Glaucoma (Pilocarpine, Physostigmine, Armine)
2. Infants (Neostigmine)
3. Postoperative atony of the intestines and bladder (Neostigmine)
4. Paralysis, paresis, neuritis, polyneuritis (Neostigmine)
5. Dusturbances of skeletal muscle contractile function after cranial trauma, polio and stroke (Galanthamine hydrobromide)
6. Belladonna poisoning (Neostigmine, Physostigmine, Galanthamine)
7. Overdose nondepolarizing muscle relaxants (Neostigmine)
8. Xerostomia (Pilocarpine)
9. Respiratory depression (Cititon, Lobeline)

26. Side effects of cholinomimetics
1. Bradycardia
2. Bronchospasm
3. Intestinal cramps, colic, diarrhea
4. Hypersalivation
5. Blurred vision

27. Contraindications 1. Bradycardia, A-V block 2. Asthma
3. Gastric ulcer and 12 duodenal ulcer
4. Epilepsy (Neostigmine)
5.Pregnancy (Neostigmine)

28. Direct acting cholinergic agonists
ACETYLCHOLINE

29. Direct acting cholinergic agonists
ACETYLCHOLINE
Decrease in heart rate and cardiac output 2. Decrease in blood pressure

30. Direct acting cholinergic agonists
ACETYLCHOLINE
3. Other actions
4. Clinical use very rare: eye drops to obtain miosis
Muscarinic and nicotinic agonist not used clinically because Ach is not selective (N, M)
Has short duration of action. Why?
Due to rapid metabolism by acetycholinesterase

31. Direct acting cholinergic agonists
Stimulation of atonic bladder
Nonobstructive urinary retention
Neurogenic atony
Megacolon
Ophthalmology

32. Direct acting cholinergic agonists
PILOCARPINE
Tertiary nitrogen
Good adsorbtion
Penetrate BBB

33. Direct acting cholinergic agonists
PILOCARPINE
Natural alkaloids
Tertiary amine lipophilic
Pharmacokinetics
It is well absorbed
Good distribution
Cross BBB (has central effects).
Long duration of action
Direct muscarinic agonist
(mainly on eye & secretion).
Jaborandi (Pilocarpus pennatifolius)

34. Direct acting cholinergic agonists
PILOCARPINE

35. Pilocarpine Uses: Xerostomia (dry mouth).
Drug of choice in emergency glaucoma applied as eye drops.
Adverse effects:
Profuse sweating
Salivation
Bronchoconstriction
Diarrhea
CNS effects

36. Aceclidinum a synthetic preparation;
administered SC, IM, or topically (eye drops); not toxic;
does not penetrate CNS;
M-cholinomimetic;
used for the treatment of atonia of the intestine and urinary bladder, as well as for glaucoma.

37. Atropine Mushroom poisoning Miosis Hyper salivation
Excessive sweating, lacrimation
Cold, wet skin
Bradycardia
Polyuria
Diarrhea
Convulsions
Atropine

38. N-CHOLINOMIMETICS
They stimulate N-cholinoreceptors in zona carotis and initiate a reflexive increase
in the activity of the respiratory and vasomotor centers resulting in the short stimulation of breathing and elevation of BP.
They also stimulate N-cholinoreceptors in the adrenal medulla, increase the secretion of epinephrine, which causes vasoconstriction and the elevation of BP

39. NICOTINE
It is a tobacco alkaloid with a dose-dependent action on N-cholinoreceptors.
Effects of nicotine are manifested in tobacco smoking.
Nicotine causes dependence that leads to abuse of tobacco and results in the development of cardiovascular and lungs pathology.

40. Physiological effects of nicotine at CNS NN receptors
• ↑Emesis (vomiting) due to actions on chemoreceptor trigger zone of medulla oblongata
• Dependence (i.e. makes it hard to quit smoking)
• Respiratory depression (only at very high doses) due to actions on medulla oblongata - also contribution from blockade of diaphragm and intercostal muscles
• Tremors + convulsion (only at very high doses)

41. Physiological effects of nicotine at peripheral NN receptors
Many Effects of Nicotine Involve Ganglia
• ↑GI motility (nausea, diarrhea, vomiting) – Stimulation of parasympathetic ganglia
• ↑Heart rate, ↑blood pressure – Stimulation of sympathetic ganglia innervating heart and blood vessels – Release of EPI from adrenal medulla – Stimulation of chemoreceptors → reflex ↑heart rate, vasoconstriction

42. Lobeline is an alkaloid; is administered IV and acts during 3-5 min;
stimulates N-cholinoreceptors;
is used for emergency help in the respiratory arrest, asphyxia, asphyxia of newborns; is used to treat tobacco abuse in the form of combined tablets
is not used for collapse due to its ability to provoke
transitory a decrease in BP resulting from the stimulation of n.vagus center.

43. Cytitonum the name of a cytizine solution;
administered IV, acts 3-5 min;
stimulates N-cholinoreceptors; reflexly stimulates respiration and increases BP;
used for emergency help in respiratory arrest and collapse;
an ingredient of combined tablets against tobacco abuse.

44. Indirect acting cholinergic agonists
Reversible
Irreversible
Edrophonium
Neostigmine
Physostigmine
Rivastigmine
Galantamine
Echothiophate
Organophosphates
Arminum

45. Mechanism of action Mechanism of action:
Anticholinesterases prevent hydrolysis of Ach by antagonizing cholinesterase thus increase Ach concentrations and actions at the cholinergic receptors (both nicotinic and muscarinic).

46. Pharmacological effects of anticholinesterases
Muscarinic actions
Nicotinic actions
CNS actions:
Excitation, convulsion, respiratory failure, coma
only for lipid soluble anticholinesterases
physostigmine & phosphate ester except
Ecothiophate.

47. Reversible Reversible anticholinesterase Tertiary ammonium compound
Physostigmine
Reversible anticholinesterase
Tertiary ammonium compound
Non polar (lipid soluble)
Good lipid solubility
Good oral absorption
Has muscarinic & nicotinic actions
cross BBB (has CNS effects)
Calabar Bean

48. Reversible Physostigmine Indications 1. Atony of intestine
2. Atony of bladder
3. Glaucoma
4. Overdose of ATROPINE, ANTIPSYCOTICS, ANTIDEPRESSANTS
Side effects
Convulsions
Bradycardia
Paralysis of skeletal muscle

49. Reversible Quatenary nitrogen Poor adsorbtion Not penetrate BBB
Neostigmine
Quatenary nitrogen
Poor adsorbtion
Not penetrate BBB
Reversible anticholinesteras
Has muscarinic & nicotinic actions (prominent on GIT & urinary tract).

50. Reversible Neostigmine Indications Side effects Paralyzes Salivation
Myastenia gravis
Antidote of neuro-muscular blocker TUBOCURARINE
Salivation
Flushing
Decreased BP
Abdominal pain
Diarrhea
Bronchospasm

51. Contraindications Neostigmine Bronchial asthma
Intestinal inflammation, obstruction
Bladder obstruction
Peritonitis

52. Galantamine an alkaloid from Galanthus Woronowi; administered SC, IM;
penetrates into CNS;
has a reversible anticholinesterase action;
used for the treatment of paralysis, neuritis, early stages of Alzheimer’s disease and other
neurological diseases;
is not used in glaucoma due to its irritative action.

53. Reversible Quatenary nitrogen Poor adsorbtion Not penetrate BBB
Edrophonium
Quatenary nitrogen
Poor adsorbtion
Not penetrate BBB
Fast elimination
Duration min

54. Reversible Edrophonium Diagnosis of myasthenia gravis
Antidote of neuro-muscular blocker

55. Reversible Tertiary nitrogen Good adsorbtion Penetrate BBB
Rivastigmine
Tertiary nitrogen
Good adsorbtion
Penetrate BBB

56. Reversible
Rivastigmine
Alzheimer disease

57. Irreversible -Used for glaucoma. Mechanism
Echothiophate
Mechanism
-Irreversible anticholinesterase
-Binds to cholinesterase by strong covalent bond.
-Have very long duration of action
-Aging make bond extremely stable
-Used for glaucoma.

58. Toxicology
Organophosphates

59. SLUDGEM Toxicology Salivation Lacrimation Urination Defecation
Gastrointestinal motility Emesis
Miosis
SLUDGEM
Death is caused by breath insufficiency, bronchospasm and lungs edema

60. Toxicology Reactivation of acetylcholinesterase PRALIDOXIME
Not enter BBB
M-cholinoblocker
ATROPINE
Antimuscarinic only
Anticonvulsant
DIAZEPAM

61. Pralidoxime (PAM) cholinesterase reactivator
Acts by regeneration of cholinesterase enzyme.
reactivates recently inhibited enzymes before aging.
Uses
I.V.  over min for organophosphate intoxication.

62. Summary for cholinomimetics & their uses
Eye : treatment of glaucoma
Pilocarpine (direct muscarinic agonist)
Physostigmine -Ecothiophate (indirect cholinomimetics)
Urinary retention and paralytic ileus
Bethanechol (direct)
Neostigmine (indirect)
Myasthenia gravis (only indirect cholinomimetics)
Pyridostigmine, Neostigmine, Ambenonium
Xerostomia
Pilocarpine –Cevimeline (Sjogren’s syndrome)
Alzheimer’s disease: Rivastigmine, Donepezil