Cholinergic system

1. PART-1

2. CONTENT
1. HISTORY
2. INTRODUCTION
3. NEUROHORMONAL TRANSMISSION
4. SITES OF CHOLINERGIC TRANSMISSION
5. SYNTHESIS, STORAGE & DESTRUCTION OF Ach
6. CHOLINERGIC RECEPTORS
7. CLASSIFICATION OF CHOLINERGIC AGONISTS
8. ACTION OF CHOLINERGIC DRUGS
9. USE OF INDIVIDUAL DRUGS
10. MUSHROOM POISONING
1

3. HISTORY
• In 1900, Reid Hunt noted that suprarenal extracts free from
epinephrine caused a lowering of BP.
• Henry Hallett Dale first identified acetylcholine in 1914
as a parasympathetomimetic,
Otto Loewi showed its importance
as a neurotransmitter for which they
shared Nobel Prize in Medicine in 1936.
,Reid Hunt
Henry Hallett Dale
Otto Loewi
2

4. INTRODUCTION
Nervous system consist of a network of nerve cells and fibers that
transmits nerve impulses between different parts of the body.
Nervous system
Central
NS
BRAIN
SPINAL CORD
Peripheral
NS
Autonomic NS
Somatic NS
Sympathetic NS
Parasympathetic NS
Motor
3

5. INTRODUCTION…
Somatic NS Autonomic NS
Controls Voluntary functions .
Adjustment of external environment
Involutory functions.
Adjustment of internal environment.
1˚efferent NT Ach Ach, NA, Adr
Organ it supplied Skeletal muscles All other organs
Efferent Nerve fibers Myelinated (Chain of two motor neurons)
Pregang-Myelinated .
Postgang-Nonmylinated(Slow)
Distal most synapse Within CNS Outside CNS ( in ganglia)
Nerve section Paralysis and Atrophy Activity maintained
Difference between somatic and autonomic nervous system
4

6. INTRODUCTION…
• Sympathetic N.S is like the
accelerator for car, mobilizes
the body for action.
• Parasympathetic N.S is like breaks in
your car , slows the body down to
keep the rhythm- enabling the body
to conserve and store energy.
5

7. INTRODUCTION…
Sympathetic NS Parasympathetic NS
Location of preganglionic
cell bodies
Thoraco Lumbar outflow
T1 –L3
Cranio Sacral outflow
CN 3,7,9,10 & S2-4
Preganglionic neuron Short Long
Ganglia location Sympathetic Chain Near to effector organ
NT NA
Minor: ATP, NPY, DA, ACh
Ach
Minor: VIP, NO
Stability of transmitter NA stable, diffuses for wider
actions
ACh—rapidly destroyed
locally & action limited to
head, neck, trunk & external
genitalia
Difference between sympathetic and parasympathetic nervous system
6

8. INRTODUCTION…
• Cholinergic system is composed of organized nerve cells that use
Acetylcholine (Ach) as neurotransmitter, in the transduction of action
potential.
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9. NEUROHORMONAL TRANSMISSION
DEFINITION: Process of transmission of message by nerve,
across the synapses & neuroeffector junction
by the release of chemical messengers aka
neurotransmitters(NT)
8

10. STEPS IN NEUROHORMONAL TRANSMISSION
Impulse Conduction
Neurotransmitter release
NT action on postjunctional membrane
Postjunctional activity
Termination of NT action
9

11. STEPS IN NEUROHORMONAL TRANSMISSION
RMP of –70 Mv inside
* K+ permeability of axonal membrane and its high concentration inside.
* Na+ permeability & active export of this ion from the neuron.
* Na+ influx cause depolarization and overshoot resulting in reverse polarization
* Later K+ ions moves out ,thus repolarization is achieved
This ionic distribution is normalized during RP by the
activation of Na+ K ATPase channel
AP thus generated is transmitted to next excitable part
of the membrane & propagated without decrement.
1. Impulse Conduction
Stimulation

12. TETRODOTOXIN
SAXITOXIN
Selectively abolish increase in Na+ conductance
in nerve fibres and thus block impulse conduction.

13. STEPS IN NEUROHORMONAL
TRANSMISSION
The NT is stored in
prejunctional nerve
endings within
‘synaptic vesicles’
Nerve impulse causes
-Ca2+ influx
-promotes fusion of
vesicular and axonal
membranes.
All contents of the
vesicle are extruded by
exocytosis into
junctional cleft.
2.Transmitter release
Presynaptic
nerve ending
Ca influx
fusion of vesicular and
axonal membranes exocytosis to
synaptic cleft
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14. STEPS IN NEUROHORMONAL TRANSMISSION
3.Transmitter action on postjunctional membrane
NT combines with specific receptors on the postjunctional membrane
permeability to cations
Na+ or Ca2+ influx
depolarization f/b K+
efflux
EPSP
permeability to anions
Cl¯influx
Hyperpolarization
IPSP
13

15. STEPS IN NEUROHORMONAL TRANSMISSION
4.Postjunctional activity
Suprathreshold EPSP
Propagate postjunctional AP
Results in nerve impulse
IPSP
Stabilizes the postjunctional
membrane
Resists depolarizing stimuli
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16. STEPS IN NEUROHORMONAL TRANSMISSION
• Ach
Local degradation
• NPY
• VIP
Degraded as
Distant side
• GABA
• Glutamine
Reuptake by AA
transporter protien
• NE
• Dopamine
Reuptake by
Monoamine transporter
protien
• Enkephalins
5.Termination of NT action
• Serotonin
15

17. SITES OF CHOLINERGIC TRANSMISSION
16

18. SYNTHESIS AND STORAGE OF ACh
Na -Ch CoT
VAT
17

19. DESTRUCTION OF ACh
Acetylcholine
Choline Acetate
18

20. Types of cholinesterase
Acetylcholinesterase
(True)
Butyrylcholinesterase
(Pseudo)
Distribution All cholinergic sites, RBC, Grey matter Plasma, liver, intestine,white matter
Hydrolysis
Ach
Methacholine
Benzoylcholine
Butyrylcholine
Very fast
Slower than Ach
-
-
Slow
-
Hydrolysed
Hydrolysed
Function Termination of Ach action Hydrolysis of ingested esters
DESTRUCTION OF ACh
19

21. Ligand gated cation channels
Nm
Nn
CHOLINERGIC RECEPTORS
MUSCARINIC NICOTINIC
Gq protein coupled
M1
M3
M5
Gi/Go protein coupled
M2
M4
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22. Gq PROTIEN COUPLED RECEPTOR
21

23. Gi PROTIEN COUPLED RECEPTOR PATHWAY
βγ
α
−
+
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24. LOCATION AND FUNCTION
Autonomic
ganglia:
Increase in depolarization(late EPSP)
Gastric glands: Histamine release
Acid secretion
Enteric neurones intestinal secretion
CNS: Learning
memory
motor activity
Agonists Oxotremorine
Antagonists Pirenzepine
Telenzepine
M1 Receptors
23

25. SA Node Hyperpolarization
HR
AV Node: velocity of conduction
Atrium: RP & contraction
Ventricle: Slight in contraction
Visceral Smooth muscle: ↑ Contraction
Cholinergic nerve endings: ↓ Ach release
CNS: ↑ Tremors; hypothermia;
analgesia
Agonists Methacholine
Antagonists Methoctramine
Tripitramine
M2 Receptors
24

26. Visceral & bronchial smooth
muscle:
Contraction
Iris: constriction of pupil
Ciliary muscle: contraction
Exocrine glands: secretion
Vascular endothelium: release of NO •
vasodilatation
Agonists Bethanechol
Antagonists Solifenacin
Darifenacin
M3 Receptors
25

27. CNS cerebral vasodilatation
Facilitates DA release
Augmentation of drug-seeking behavior and reward
CNS Facilitate / inhibit NT release in
certain areas of brain
M4 Receptors
M5 Receptors
26

28. NICOTINIC RECEPTORS
Nm Nm
Location and
function
Neuromuscular junction:
depolarization of muscle end
plate
contraction of skeletal muscle
Autonomic ganglia: depolarization
—postganglionic impulse
Adrenal medulla: catecholamine
release
CNS: site specific excitation or
inhibition
Transducer
mechanism
Opening of cation (Na+, K+)
channels
Opening of cation (Na+, K+, Ca2+)
channels
Agonists PTMA, Nicotine DMPP, Nicotine
Antagonists Tubocurarine, Bungarotoxin Hexamethonium, Trimethaphan
28

29. CLASSIFICATION OF CHOLINERGIC DRUGS
(Cholinomimetic, Parasympathomimetic)
CHOLINERGIC AGONISTS
Choline esters Alkaloids Miscellaneous
Acetylcholine Muscarine Cevimeline
Methacholine Pilocarpine
Carbachol Arecoline
Bethanechol
28

30. ACTION ON HEART (M2)
Hyperpolarizes Rate of diastolic
depolarization
Bradycardia /
even cardiac arrest
RP &
conduction
is slowed
P-R interval
Partial /
complete
A-V block
Force of contraction
RP
Nonuniform vagal innervation
AF/
flutter
a.Muscarinic Actions
3
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31. ACTION BLOOD VESSALS (M3)
• Vasodilation,
• Site: skin of face, neck & salivary glands
• By release of NO from endothelium
• BP and flushing.
• In penis -dilation cavernosal vessels, there by causing erection.
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32. ACTION ON SMOOTH MUSCLES
1. Tone and peristalsis & sphincters relax
2. Causing abdominal cramps and evacuation of bowel
1.Ureter : Peristalsis
2.Urinary bladder : The detrusor muscle contracts ,bladder
trigone & sphincter relaxes causing voiding of bladder
1.Bronchial muscles constrict.
2. Bronchospasm, dyspnoea, precipitation of an attack of
bronchial asthma can occur in asthmatics
(M3>M2)
GIT
LUNGS
31

33. ACTION ON GLANDS (M3>M2)
• Secretion from all parasympathetically innervated glands
• in sweating, salivation, lacrimation, increased tracheobronchial
and gastric secretion.
• The effect on pancreatic and intestinal glands is not marked. Secretion of
milk and bile is not affected.
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34. ACTION ON EYE
• Contraction of circular muscle of iris resulting in miosis.
• Aqueous outflow, reduction in intraocular tension especially
in glaucomatous patients.
• Contraction of ciliary muscle causing spasm of
accommodation
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35. b.Nicotinic actions
1. AUTONOMIC GANGLIA
• Both sympathetic and parasympathetic ganglia are stimulated at higher doses.
• High dose of ACh, given after atropine causes tachycardia and BP due to
stimulation of sympathetic ganglia and release of catecholamines.
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36. 2.SKELETAL MUSCLES
• Contraction of the muscle fiber.
• lntraarterial injection of high dose can cause twitching and
fasciculations
• i.v. injection is generally without any effects due to rapid hydrolysis
of ACh.
35

37. C.CNS action
• ACh injected i.v. does not penetrate BBB & so no central effects seen
• Direct injection to the brain produces arousal response f/b depression.
• Cholinergic drugs which enter brain produce complex behavioral and
neurological effects.
36

38. ACETYLCHOLINE
• Acetylcholine rarely given systemically
• ACh is used topically for the induction of miosis during ophthalmologic surgery,
instilled into the eye as a 1% solution
37

39. METHACHOLINE
• Used in diagnosis of bronchial airway hyperreactivity in patients who do not have
clinically apparent asthma
• It is available as a powder, diluted with 0.9% NaCl & administered via nebulizer.
• Athmatic patients respond with intense bronchoconstriction and a reduction in
vital capacity.
38

40. CARBACHOL
Carbachol is used topically in ophthalmology for the
• treatment of glaucoma
• the induction of miosis during surgery
• it is instilled into the eye as a 0.01%–3% solution.
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41. Bethanechol
• Primarily affects the urinary and GI tracts.
• Use - Tx non obstructive urinary retention and inadequate emptying of the bladder, as in
 postoperative urinary retention,
 diabetic autonomic neuropathy,
 certain cases of chronic hypotonic/ myogenic/ neurogenic bladder;
Catheterization can thus be avoided.
• S/E : belching, colic, involuntary urination/defecation, flushing, sweating, fall in BP,
bronchospasm.
• Dose: 10–40 mg oral, 2.5–5 mg s.c.
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42. PILOCARPINE
• Alkaloid obtained from the leafs of Pilocarpus microphyllus and other species.
• sweating, salivation & other secretions .
• Small doses generally cause in BP (muscarinic),
• Higher doses elicit in BP and tachycardia
due to ganglionic stimulation
Eye –
miosis, ciliary muscle contraction & in IOT lasting 4-8 hrs.
41

43. PILOCARPINE…
USES:
1. Open angle glaucoma.
2. As a miotic in the eye as 0.5-4% drops.
- for refraction testing
-To prevent/ break adhesions of iris with lens /cornea.
• S/E- Initial stinging sensation in the eye & painful spasm of accommodation.
3. Tx xerostomia that follows head and neck radiotherapy/ Sjögren Sx
Sweating the m/c complaint. The usual dose is 5–10 mg three TID.
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44. CEVIMELINE
• Activate M1 and M3 receptors on lacrimal & salivary gland epithelia.
• The drug has a long-lasting sialagogic action , fewer S/E & better patient compliance
than pilocarpine .
• Used to Tx dry mouth in with Sjogren’s Sx
• The usual dose is 30mg TID.
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45. MUSHROOM POISONING
Muscarinic
TYPE
Hallucinogenic
TYPE
Phalloid
TYPE
Source Inocybe Amanita muscaria A. Phalloid, Galerina
Active
Ingradient
MUSCARINE MUSCIMOL & other ISOXAZOL compounds Peptide toxins
Features Onset within 1 hrs Block M receptors in brain,
Activate AA receptors causing
hallucination
Inhibit RNA &protein synthesis
Onset after many hrs due to
Damage to GI mucosa, liver &
kidney.
Tx Atropine No specific treatment Supportive Tx
Thioctic acid (Antidote)
44

46. SUMMERY:
• Two types of cholinergic receptors – muscarinic & nicotinc
• Muscarinic receptors- Smooth muscles/ Cardic muscles/Glands/CNS
• Nicotinic receptors- Skeletal muscles/ Ganglia/ CNS
• Cholinergic Drugs can be directly acting/ Indirectly acting
• Ach action on various organ systems.
• Uses of choline esters and cholinomimetic alkaloids.