1. Autonomic nervous system Cholinergic agonists (CHOLINOMIMETICS) Cholinergic antagonists (CHOLINOBLOCKERS)

2. Functional divisions within the nervous system

3. Efferent neurons of the autonomic nervous system

4. Sympathetic and parasympathetic actions

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. 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.

8. 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

9. 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.

10. 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

11. 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

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

13. 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.

14. Muscarinic receptors M1 M3

15. M-cholinoceptors Cholinoceptors Localization Effects of stimulation M2
Heart
Smooth muscle
Bradycardia, decrease in conduction, decrease in force of atrial contraction
Relaxation M3
Smooth muscles
Increase in tone, increase in peristalsis, decrease in sphincter tone and removal of content, bronchoconstriction
M1-M3
Exocrine glands
Secretion
Eye
miosis
spasm of accommodation
decrease in intraocular tension
M1-M5
CNS
Stimulation

16. 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

17. 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

18. 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)

19. 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)

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

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

22. Direct acting cholinergic agonists
ACETYLCHOLINE

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

24. Direct acting cholinergic agonists
ACETYLCHOLINE
3. Other actions
4. Clinical use very rare: eye drops to obtain miosis

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

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

27. Direct acting cholinergic agonists
PILOCARPINE
Secretagoge (sweat, tears, saliva)
Jaborandi - what causes slobbering
Sjögren’s syndrome
Dry mouth, lack tears
Glaucoma
Jaborandi (Pilocarpus pennatifolius)

28. Direct acting cholinergic agonists
PILOCARPINE

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

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

31. Mechanism of action

32. Reversible Tertiary nitrogen Good adsorbtion Penetrate BBB
Physostigmine
Tertiary nitrogen
Good adsorbtion
Penetrate BBB
Calabar Bean

33. 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

34. Reversible Quatenary nitrogen Poor adsorbtion Not penetrate BBB
Neostigmine
Quatenary nitrogen
Poor adsorbtion
Not penetrate BBB

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

36. Reversible Neostigmine Bronchial asthma
Intestinal inflammation, obstruction
Bladder obstruction
Peritonitis

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

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

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

40. Reversible
Rivastigmine
Alzheimer disease

41. Irreversible
Echothiophate
Glaucoma

42. Toxicology
Organophosphates

43. SLUDGEM Toxicology Salivation Lacrimation Urination Defecation
Gastrointestinal motility Emesis
Miosis
SLUDGEM

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

45. CHOLINERGIC BLOCKERS

46. Classification of cholinoblockers
I. M-cholinoblockers (Muscarinic antagonists)
Natural agents
Atropine
Hyoscine /Scopolamine/
Plathyphylline
Semisynthetic and synthetic
Homatropine
Propantheline
Methacinum
Ipratropium bromide /Atrovent/
Cyclopentolate
Pirenzepine

47. Classification of N-cholinoblockers
1. Ganglion blocking drugs
Hexamethonium /Benzohexonium/
Hygronium
Mecamylamine
Pempidine tosilate
Trimethaphan
2. Neuromuscular blockers
a) Nondepolarizing
Atracurium
Pancuronium
Tubocurarine
Vecuronium
b) Depolarizing
Succinylcholine
Dithylinum

48. Mechanism of action

49. Parasympatholythics
Eye
inability to focus for near vision, mydriasis, IOP ↑
Saliva
xerostomia
Bronchi
bronchodilation, secretion ↓
Heart
Rate ↑
GIT
secretion, peristalsis ↓ sphincter tone ↑
Bladder
detrusor ↓ sphincter tone ↑

50. Clinical uses of M-cholinoblockers
A-V block – Atropine
Colic, abdominal cramps – Atropine, Plathyphylline
Urinary frequency - Oxybutinin
Preanesthetic medication – Atropine, Hyoscine
Peptic ulcer – Pirenzepine (selective M1 cholinoblocker)
Bronchial asthma - Ipratropium bromide

51. Clinical uses of M-cholinoblockers
Therapeutic uses in ophthalmology: in iritis, keratitis and other inflammatory diseases and trauma of eye - Atropine
Diagnostics in ophthalmology – Atropine, Homatropine, Cyclopentolate
Prevention of motion sickness - Hyoscine
Muscarinic poisoning – Atropine
Organophosphate poisoning - Atropine

52. Pharmakokinetics Tertiary nitrogen Good adsorbtion Penetrate BBB
ATROPINE
Tertiary nitrogen
Good adsorbtion
Penetrate BBB
Atropa belladonna

53. Dose-dependent effects of atropine
Main effects
ATROPINE
Smooth muscle relaxation
Antisecretory
Dose-dependent effects of atropine

54. Therapeutic uses ATROPINE Ophtalmological tests
Spasmolythic (as an antispasmodic agent to relax the GIT and bladder)
Antisecretory (during dental operations, tuberculosis, to block secretions in the upper and lower respiratory tracts prior to surgery)
Mushroom poisoning
Organophosphates poisoning
Heart block, bradycardia
Resuscitation (asystole)

55. Adverse effects
ATROPINE

56. Contraindications ATROPINE Narrow-angle glaucoma Pyloricstenosis
Prostatichypertrophy
Drivers

57. Belladonna poisoning Dry mouth, difficulties in swallowing and talking
Dilated pupil, photophobia, blurred vision
Dry, flushed and hot skin
Difficulties in micturation
Constipation
Hypotension, weak and rapid pulse
Excitement, psychotic behavior,delirium, hallucination
ANTICHOLINESTERASE DRUGS ARE ANTIDOTES

58. Pharmakokinetics Tertiary nitrogen Good adsorbtion Penetrate BBB
SCOPOLAMINE
Tertiary nitrogen
Good adsorbtion
Penetrate BBB
Solanaceae family

59. Therapeutic uses
SCOPOLAMINE

60. Therapeutic uses
TROPICAMIDE
Eye examination

61. Therapeutic uses
IPRATROPIUM
Bronchial asthma
COPD

62. Therapeutic uses
TRIHEXYPHENIDYL
Parkinson’s disease

63. Nicotine
Dose-dependent effect

64. Ganglion blocking drugs
Hexamithonium
Hygronium
Mecamylamine
Trimethaphan
Interfere with postsynaptic transmission of Ach
Block action of Ach on nicotinic receptors
Used rarely
severe adverse effects:
Orthostatic (postural) hypotension, tachycardia, dry-mouth, GIT atony, urine retention, digestive problems, sexual dysfunction: failure of erection and ejaculation

65. Nondepolarizing (competitive)
Neuromuscular Blocking Drugs
Depolarizing
(non-competitive)
Nondepolarizing (competitive)
Atracurium
Pancuronium
Tubocurarine
Succinylcholine
Dithylinum

66. Tubocurarine

67. Clinical uses of nondepolarizing myorelaxants
In surgery
General anesthesia to produce paralysis, to permit intubation of the trachea,
To optimize the surgical field by inhibiting spontaneous ventilation, and causing relaxation of skeletal muscles.
Because the appropriate dose of neuromuscular-blocking drug may paralyze muscles required for breathing (i.e., the diaphragm), mechanical ventilation should be available to maintain adequate respiration.

68. Side effects of nondepolarizing myorelaxants
Stimulation of histamine release,
Hypotension,
Flushing,
Tachycardia
Arrest of breathing. Because the appropriate dose of neuromuscular-blocking drug may paralyze muscles required for breathing (i.e., the diaphragm), mechanical ventilation should be available to maintain adequate respiration.

69. Succinylcholine

70. Succinylcholine
It has a rapid onset (30 seconds) but very short duration of action (5–10 minutes) because of hydrolysis by various cholinesterases (such as butyrylcholinesterase in the blood).
Used in short lasting surgical invasions
It cause side effects:
fasciculations (a sudden twitch just before paralysis occurs).
post-operative pain

71. TOXICITY
RESPIRATORY PARALYSIS - neuromuscular blockers induce a respiratory paralysis. If mechanical ventilation is not provided, the patient will asphyxiate.
2. MALIGNANT HYPERTHERMIA - Malignant hyperthermia susceptibility, an autosomal dominant disorder of skeletal muscle, is one of the main causes of death due to anesthesia. Depolarizing neuromuscular blocking drugs (succinylcholine) can trigger malignant hyperthermia.
Malignant hyperthermia is a result of excessive release of Ca2+ from sarcoplasmic reticulum.
The clinical features of malignant hyperthermia are hyperthermia, metabolic acidosis, tachycardia, accelerated muscle metabolism and contructures.