This is the lecture presentation for general concept of autonomic nervous system and cholinergic drugs. The class is intended for BNS 1st year students.

1. Dr. Pravin Prasad
MBBS, MD Clinical Pharmacology
Assistant Professor, Dept. of Clinical Pharmacology
Maharajgunj Medical Campus
24th May, 2020 (11 Jestha 2077), Sunday
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2. By the end of this discussion, BNS 1st year
students will be able to:
Understand the basic organisation of Autonomic nervous system
List the receptors involved in parasympathetic nervous system
impulse transmission
Classify drugs used to mimic the activity of parasympathetic
nervous system
Explain the pharmacological basis of effects of cholinergic drugs
List the uses as well as side effects of parasympathetic drugs
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3. Nervous System: Overview
Nervous System (NS)
Central Nervous
System(CNS)
Cerebrum, Cerebellum,
Brainstem, Spinal Cord
Peripheral Nervous System
(PNS)
Somatic Nervous
System
Autonomic Nervous
System (ANS)
Sympathetic Nervous
System
Parasympathetic Nervous
System
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4. Autonomic Nervous System: Organization
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5. Sympathetic vs Parasympathetic NS
NE
ACh
ACh
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6. CholinergicTransmission
Site Type of Receptor
All postganglionic parasympathetic
Few postganglionic sympathetic1 Muscarinic
Ganglia,Adrenal Medulla Nicotinic (NN)
Skeletal Muscles Nicotinic (NM)
CNS (cortex, basal ganglia, spinal cord,
others)
Muscarinic
Nicotinic
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7. Cholinoceptors
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Characteristics Muscarinic Nicotinic
Selective agonist Muscarine Nicotine
Antagonist Atropine d-Tubocurarine
Subtypes
M1-M5
M1, M3, M5- excitatory
NN and NM
Usually excitatory

8. Muscarinic Cholinoceptors: Locations
M1 M2 M3
• Autonomic
ganglia
• Gastric glands
• CNS
• Heart
• CNS
• Visceral smooth
muscle
• Visceral smooth
muscle
• Iris
• Ciliary muscle
• Exocrine glands
• Vascular endothelium
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9. Nicotinic Cholinoceptors: Locations and
Functions
NM NN
• Neuromuscular junction:
contraction of skeletal
muscle
• Autonomic ganglia: depolarization
• Adrenal medulla: catecholamine
release
• CNS: site specific action
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10. CholinergicTransmission
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11. Cholinergic/Parasympathomimetic Drugs
Cholinergic Agonists Anti-cholinesterases
Choline esters Alkaloids Reversible Irreversible
Acetylcholine Pilocarpine Carbamates: Physostigmine,
Neostigmine,
Pyridostigmine,
Edrophonium, Rivastigmine,
Donepezil, Galantamine
Carbamates:
Carbaryl, Propoxur
Methacholine Arecoline Organophosphates:
Dyflos,
Echothiopate,
Malathion, Diazinon,
Tabun, Sarin, Soman
Carbachol Muscarine
Bethanechol Acridine:Tacrine
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12. MuscarinicActions of CholinergicAgonists (ACh)
Organ
Receptor
Involved
Mechanism Effect
Heart M2
Hyperpolarization of SA Node
Increased Refractory Period at AV
node and His-Purkinje Fibres
Bradycardia, cardiac arrest,
Delayed conduction, Prolonged
P-R interval, Heart Block
Blood
Vessels
Nitric Oxide(NO) release:
Vasodilation
Fall in BP, flushing
M3 Vasoconstriction
NO – dilatation of cavernous
sinus
Erection of penis
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13. MuscarinicActions of Cholinergic Agonists (ACh)
Organ
Receptor
Involved
Mechanism Effects
Smooth
Muscle
M3 + M2
Increased tone and peristalsis
of GIT, sphincters relaxed
Abdominal cramps, evacuation of
bowels
M3
Increased peristalsis in
ureters, detrusor contracts,
trigone & sphincter relaxes
Voiding of bladder
M3
Constriction of bronchial
muscles
Bronchospams, dyspnoea,
asthamatic attack
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14. MuscarinicActions of Cholinergic Agonists (ACh)
Organ
Receptor
Involved
Mechanism Effects
Glands M3 + M2 Increased secretion
Salivation, sweating, lacrimation,
increased tracheobronchial and gastric
secretions
Eyes M3
Contraction of circular
muscle of iris
Miosis
Contraction of ciliary
muscle
Blurring of near vision, increased
aqueous outflow, decreased intra ocular
pressure in glaucomatous eye
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15. Nicotinic Actions of Cholinergic Drugs (ACh)
Organ Receptor Involved Mechanism & Effects
Autonomic
Ganglia
NN • Stimulation at higher doses
Skeletal
Muscles
NM
• Contraction of muscle fibres
• Intra-arterial injection: twitching and
fasciculations
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16. Choline esters: Uses and Side Effects
Uses:
Rarely used (evanescent and
non selective action)
Bethanechol: non-obstructive
urinary retention, neurogenic
bladder
Side effects:
Belching, colic
Involuntary urination /
defecation
Flushing, sweating
Fall in BP
Bronchospasm
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17. Cholinomimetic Alkaloids:Pilocarpine
Prominent muscarinic actions
Stimulated ganglia via M1
receptors
Dose dependentCVS Effects
Small dose: fall in BP (M2)
High dose: rise in BP,
tachycardia (M1)
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18. Cholinomimetic Alkaloids:Pilocarpine
Eyes:
Local application – penetrates
cornea, miosis, ciliary muscle
contraction, fall in intraocular
tension (M3)
Use: as miotic
S/E: initial stinging, painful
spasm, marked sweating,
salivation, increased secretions
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19. Cholinomimetic Alkaloids
Arecholine
Source: Areca catechu (betel nut)
Muscarinic as well as Nicotinic
actions
No therapeutic use
Muscarine
Source: mushrooms Amanita
muscaria, Inocybe sps.
Only muscarinic actions
Has toxicological importance
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20. Mushroom Poisoning
Early type (Muscarinic) Hallucinogenic Type Late type (Phalloidin)
Toxic principle Inocybe and related sps.
Muscimol; isoxazole (A.
muscaria)
Peptide toxin of A.
phalloides, Galerina
Mechanism Stimulation of M receptors Blocks M receptors in CNS
Inhibit RNA and protein
synthesis
Features Muscarinic
Hallucinogenic, central
manifestations
Damage to GIT, liver,
kidney
Presentation Within an hour of eating After hours of ingestion
Treatment Atropine
Supportive
Atropine contraindicated
Supportive

21. Anti-cholinesterases (AChE)
Mechanism of action:
Inhibits Cholinesterase (ChE)
Protects ACh from hydrolysis
(Amplification of endogenous ACh)
Cholinergic effects seen
Additional direct action on Nicotinic
receptors
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22. AChE: PharmacologicalActions
Characteristics
(Example)
Muscarinic
Nicotinic
CNS
Ganglia
Skeletal
Muscle
Lipid soluble
(Physostigmine,
organophosphates)
+++ +
Less
prominent
+++
Lipid insoluble
(Neostigmine)
Less
prominent
+ +++ none
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23. AChE: PharmacologicalActions
Organ System Low dose High dose
Skeletal muscle
Twitching and
fasciculations
Weakness and
paralysis
Ganglia Stimulation Blockade
Central Nervous
System
General arousal confusion

24. AChE: PharmacologicalActions
Cardiovascular effects:
Muscarinic: bradycardia, hypotension
Ganglia stimulation: increase heart rate and BP
»High dose: transmission blockade
Medullary centres: stimulation followed by depression
Unpredictable and variable effects!!!

25. AChE: Individual compounds
Physostigmine:
Rapid absorption (oral, parenteral, topical in eye)
Crosses BBB, central effects
Metabolism by hydrolysis
Eye drops prepared freshly

26. AChE: Individual compounds
Neostigmine, Pyridostigmine:
Poor oral absorption (20-30 times parenteral dose)
Does not cross BBB, cornea
Partially hydrolysed and partially excreted unchanged in urine
Edrophonium:
Brief duration of action (10-30 mins)
Diagnostic purpose only

27. Neostigmine:Available formulations
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28. AChE: Individual compounds
Organophosphates:
Dyflos, Echothiophate
»Previously used as miotics
Absorbed from all sites
Hydrolysed and oxidised and then excreted
Has toxicological importance

29. AChE: Precautions
Use cautiously in:
Peptic ulcer
Hypertension
Asthma
Chronic Obstructive
Pulmonary Disease
Seizure patients
Contraindications:
Sick sinus
A-V conduction defects
Hypotensive states

30. AChE: Uses
As Miotic
Glaucoma:
Pilocarpine - rapid and short lasting (4-6hrs)
Physostigmine 0.1% - supplement pilocarpine
Reversal of mydriasis after refraction
Prevent/break adhesions: In conjunction with mydriatics
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31. AChE:Uses
Myasthenia gravis(MG)
 Treatment
Neostigmine
»15 mg orally 6 hourly
»Adjusted according to
response
»Dose requirement fluctuates
Pyridostigmine
DiagnosticTests
AmeliorativeTest
»Inj Edrophonium 2mg i.v. (test
dose) followed by 8 mg i.v.
after 30-60 sec
—Reversal of weakness and
short lasting improvement
of strength: +ve for MG
ProvocativeTest
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32. AChE:Uses
Alzheimer’s Disease:
CerebroselectiveAChE (Rivastigmine, Donepezil, Galantamine)
Post-operative paralytic ileus/urinary retention:
Inj. Neostigmine 0.5-1 mg s.c.
Post-operative decurarization:
Neostigmine 0.5-2 mg i.v.
Rapid reversal of muscle paralysis induced by competitive
neuromuscular blockers
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33. AChE:Uses
Belladona poisoning/Dhatura poisoning
Physostigmine 0.5-2 mg i.v. repeat as required, Neostigmine safer
Drug Overdose:
TCA, phenothiazines, antihistaminics
Physostigmine (rare)
Cobra bite:
Neostigmine + Atropine
To prevent respiratory paralysis can be used
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34. Conclusion
Autonomic nervous system: Sympathetic and Parasympathetic
Receptors in Parasympathetic Nervous System: Cholinergic (M1-M5) and
nicotinic (NN and NM)
Cholinergic drugs: Directly acting (Esters and alkaloids) and Indirectly acting
(Anticholinesterase)
Effects of drugs depends on the receptor involved
Cholinergic drugs are used as miotics, in Myaesthenia gravis, Alzheimer’s
Disease, post-operatively and in some toxic conditions
Organophosphates and mushroom have toxicological importance
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35. That will be all for today
Please revise the topic….
Next class: Anticholinergics Drugs
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