This document discusses drugs that act on the autonomic nervous system. Autonomic drugs are used to treat conditions like angina, heart failure, and high blood pressure. They are also used for shocks and other conditions. The document reviews the anatomy and neurotransmitters of the autonomic nervous system including the sympathetic and parasympathetic divisions. It discusses cholinergic transmission and the types of cholinergic receptors, muscarinic and nicotinic. It provides details on specific muscarinic receptor subtypes and locations. The document summarizes the pharmacological effects and clinical uses of various cholinergic drugs including indirect-acting drugs that inhibit acetylcholinesterase as well as direct-acting cholinergic agonists

1. Drugs acting on Autonomic Nervous
System -
“Autonomic Pharmacology”

2. Autonomic drugs are used
for the
treatment of Angina

3. Autonomic drugs are used
for the
treatment of
Heart Failure

4. Autonomic drugs are used for
the
treatment of High Blood
Pressure
•Autonomic drugs also used for
treatment of
- Anaphylactic shock
- Septic shock
- Benign prostatic hypertrophy
- Alzheimer’s disease
- Asthma

5. Organization of
Nervous System -
Recall
Central Nervous System
“Brain and spinal cord”
Peripheral Nervous System
Autonomic Nervous System Somatic Nervous System
Afferent Division Efferent Division
Sympathetic
“thoracolumbar”
Parasympathetic
“craniosacral”

6. AUTONOMIC NERVOUS
SYSTEM
• SYMPATHETIC
– FightorFlight
• PARASYMPATHETIC
– Rest and Digest

7. Controls
skeletal
muscle
Controls
Peripheral Nervous System
Somatic
Nervous
System
Autonomic
Nervous
System
One
Neuron
Efferent
Limb
Two
Neuron
Efferent
Limb
smooth &
cardiac
muscle &
glands
Postganglionic
Preganglionic

9. Transmitters in ANS
• Neurotransmitter
• Autonomic:
A. Sympathetic:
• Preganglionic: Nicotinic (NN) Ach
• Postganglionic : Noradrenergic (NA) - ɑand ß (alpha and beta)
• Adrenal medulla (NN) Preganglionic and Postganglionic - Adrenaline in
blood stream
B. Parasympathetic:
• Preganglionic: Nicotinic (NN) Ach
• Postganglionic: Muscarininic (M)

11. Sites of Cholinergic Transmission
Acetylcholine (Ach) is major neurohumoral
transmitter at autonomic, somatic and central
nervous system:
1. All preganglionic sites
2. All Postganglionic Parasympathetic sites and
sympathetic to sweat gland and some blood vessels
3. Skeletal Muscles
4. CNS: Cortex Basal ganglia, spinal chord and others
Parasympathetic Stimulation – Acetylcholine (Ach) release
at neuroeffector junction - biological effects
Sympathetic stimulation – Noradrenaline (NA) at
neuroeffector junction - biological effects

12. Cholinergic Transmission –
Synthesis
Release
Action on
Receptor
Metabolism

14. True Vs Pseudo AChE
True AChE Pseudo AChE
Distribution All cholinergic sites,
RBCs, gray matter
Plasma, liver,
Intestine and
white matter
Action on:
Acetycholine
Methacholine
Very Fast
Slower
Slow
Not hydrolyzed
Function Termination of Ach
action
Hydrolysis of
Ingested Esters
Inhibition More sensitive to
Physostigmine
More sensitive to
Organophosphates

15. Cholinergic receptors - 2 types
• Muscarinic (M) and Nicotinic (N):
Muscarinic
(M) - GPCR
Nicotinic (N) –
ligand gated

16. Muscarinic Receptors - Subtypes
• Pharmacologically - M1, M2, M3, M4 and M5
• M4 and M5 are present in certain areas of Brain
and regulate other neurotransmitters
• M1, M3 and M5 fall in one class, while M2 and
M4 in another class
• However - M1, M2 and M3 are major ones and
present in effector cell and prejunctional nerve
endings in CNS
• All subtypes have little agonist selectivity but
selective antagonist selectivity
• Most organs usually have more than one
subtype but one subtype predominates in a
tissue

17. Muscarinic Receptors - Location
• M1: Ganglion Cells and Central Neurons
(cortex, hippocampus, corpus striatum)
– Physiological Role: Mediation of Gastric acid
secretion and relaxation of LES (vagal)
• Learning, memory and motor functions
• M2: Cardiac Muscarinic receptors
– Mediate vagal bradycardia
– Also auto receptors in cholinergic nerve endings
• M3: Visceral smooth muscles, glands and vascular
endothelium. Also Iris and Ciliary muscles

18. Muscarinic Receptor Subtypes
M1 M2 M3
Location Autonomic ganglia,
Gastric glands and
CNS
Heart and CNS SMs of Viscera,
Eye, exocrine
glands and
endothelium
Functions Histamine release
& acid secretion
with CNS learning
and motor
functions
Less impulse
generation, less velocity
of conduction,
decreased contractility,
less Ach release
Visceral SM
contraction,
Constriction of
pupil, contraction
of Cilliary muscle
and vasodilatation
Agonists Oxotremorine Methacholine Bethanechol
Antagonists Pirenzepine Methoctramine &
Triptramine
Darifenacin
Transducer IP3/DAG and PLA2
increase – Ca++ and
PG
K+ channel opening and
decresed cAMP
IP3/DAG and PLA2
increase – Ca++
and PG

19. Nicotinic (N) Receptors
• Nicotinic receptors: nicotinic actions of
ACh are those that can be reproduced by
the injection of Nicotine (Nicotiana
tabacum)
– Can be blocked by tubocurarine
and hexamethonium
• ligand-gated ion channels
– activation results in a rapid increase in
cellular permeability to Na+ and Ca++
resulting - depolarization and initiation of
action potential

20. Nicotinic Receptors
NM (Muscle type)
–
1. Location: Skeletal Muscle end plates
2. Function: Stimulate skeletal
muscle (contraction)
3. MOA: Postsynaptic and Excitatory (increases
Na+ and K+ permeability)
4. Agonists:
ACh, carbachol (CCh), suxamethonium
Selective stimulation by
Phenyl trimethyl ammonium (PTMA)
5. Antagonists:
Tubocurarine,
Atracurium,
vecuronium and pancuronium

21. NN (Ganglion type)
Location: In autonomic ganglia of all type
(ganglion type) – Sympathetic,
Parasympathetic and also Adrenal Medulla
Function: Depolarization and postganglionic
impulse – stimulate all autonomic ganglia
MOA: Excitatory – Na+, K+ and Ca+
channel opening
Agonists: ACh, CCh, nicotine
– Selectively stimulated by Dimethyl
phenyl piperazinium (DMPP)
5. Antagonists: Trimethaphan,
Mecamylamine and Hexamethonium

22. Classification of cholinergic drugs/
Parasympathomimetics
• 1. Direct-acting (receptor agonists)
• Choline Esters
– Natural: Acetylcholine (Ach)
– Synthetic: Methacholine, Carbachol and
Bethanechol
• Alkaloids: Pilocarpine, Muscarine,
Arecholine
– Synthetic: Oxotremorine

23. Cholinergic Drugs–2. Indirect acting
• Cholinesterase inhibitors or
reversible anticholinesterases:
1. Natural: Physostigmine
2. Synthetic: Neostigmine, Pyridostigmine,
Distigmine, Rivastigmine, Donepezil,
Gallantamine, Edrophonium, Ambenonium,
Demecarium
• Irreversible anticholinesterases:
1. Organophosphorous Compounds (OPC) –
Diisopropyl fluorophosphate (DFP),
Ecothiophate, Parathion, malathion, diazinon
(insecticides and pesticides)
2. Tabun, sarin, soman (nerve gases in war)
3. Carbamate Esters: Carbaryl and
Propoxur (Baygon)

24. Pharmacology of ACh Muscarinic
actions
Heart: M2
– SA node hyperpolarization (decrease in rate of diastolic
depolarizaton) - reduction in impulse generation and
Bradycardia
– AVN and PF – RP is increased – slowing of
conduction – partial/complete heart block
– Atrial fibres: Reduction in force of contraction and RP in
fibers abbreviated
– Atrial fibrillation and flutter – nonuniform vagal
innervations and variation in intensity of effect on RP in
diferent atrial fibres
– Decrease in ventricular contractility (less prominent)
Blood Vessels: M3
– Cholinergic innervations is limited – skin of face and neck
– But, M3 present in all type blood vessel – Vasodilatation by
Nitric oxide (NO) release – fall in BP and flushing
– Penile erection

25. Muscarinic action
3. Smooth Muscles: M3 - All are contracted
– Abdominal cramps, diarrhoea – due to increased
peristalsis and relaxed sphincters
– Voiding of Bladder
– Bronchial SM contraction – dyspnoea, attack of asthma
etc.
4. Glands: M3
– Increased secretions: sweating, salivation,
lacrimation, tracheobronchial tree and gastric
glands
– Pancratic and intestinal glands – less prominen
5. Eye: M3
– Contraction of circular fibres of Iris – miosis
– Contraction of Ciliary muscles – spasm of
accommodation, increased outflow and reduction
in IOP
Salivation
Lacrimation
Urination
Defecation

26. Ach actions – Nicotinic
1. Autonomic ganglia:
– Both Sympathetic and parasympathetic ganglia are stimulated
– After atropine injection Ach causes tachycardia and rise in BP
2. Skeletal muscle
– IV injection – no effect
– Application causes contraction of skeletal muscle
3. CNS:
– Does not penetrate BBB
– Local injection in CNS – complex actions
(Acetylcholine is not used therapeutically – non
specific)
Bethanecol Uses: Postoperative and postpartum urinary
obstruction, neurogenic bladder and GERD (10-40
mg oral)

27. Pilocarpine
• Alkaloid from leaves of Jaborandi (Pilocarpus
microphyllus)
• Prominent muscarinic actions
• Profuse salivation, lacrimation, sweating, Dilates blood vessels,
causes hypotension
• High doses: Rise in BP and tachycardia (ganglionic action)
• On Eyes: produces miosis and spasm of
accommodation
• Lowers intraocular pressure (IOP) in Glaucoma when applied as
eye drops
• Too toxic for systemic use – CNS toxicity
• Diaphoretic (?), xerostomia and Sjögren’s syndrome

28. Pilocarpine
1. Used as eye drops in treatment of wide angle
glaucoma to reduce IOP
2. Toreverse mydriatic effect of atropine
3. Tobreak adhesion between iris and
cornea/lens alternated with mydriatic
• Pilocarpine nitrate eye drops ( 1 to 4% )
• Atropine used as antidote in acute
pilocarpine poisoning ( 1- 2 mg IV 8 hrly )

29. Pilocarpine in Glaucoma
• Constriction of circular muscle of Iris
• Contraction of ciliary muscle
• Spasm of accomodation – fixed at near vision
In open-angle glaucoma, the
iris is in the right position, and
the uveoscleral drainage canals
are clear. But the trabecular
meshwork isn't draining
properly.
In closed-angle glaucoma, the
iris is squeezed against the
cornea, blocking the uveoscleral
drains and the trabecular
meshwork.

30. Muscarinic actions
• Alkaloid from mushroom Amanita muscaria
• Only muscarinic actions
• No clinical use
• Mushroom poisoning due to ingestion of
poisonous mushroom
1. Early onset mushroom poisoning
(Muscarine type)
2. Late onset mushroom poisoning
3. Hallucinogenic type

31. Mushroom Poisoning
• Early Onset Mushroom Poisoning: Occurs ½ to 1 hour
– Symptoms are characteristic of Muscarinic actions
– Inocybe or Clitocybe – severe cholinergic symptoms
like vomiting, salivation, lacrimation, headache,
bronchospasm, diarrhoea bradycardia, dyspnoea,
hypotension, weakness, cardiovascular collapse,
convulsions and coma
– Antidote is Atropine sulphate ( 2-3 mg IM every hrly
till improvement)
• Hallucinogenic type: due to Muscimol or ibotenic acid
present in A. muscria. Blocks muscarinic receptors in brain
and activate amino acid receptors. No specific treatment –
Atropine is contraindicated.

32. Late Onset Mushroom Poisoning
• Occurs within 6 - 15 hours
• Amanita phylloides (deadly nightcap)– due to peptide
toxins – Inhibit RNA polymerase II and therefore mRNA
synthesis
• Irritability, restlessness, nausea, vomiting, bloody diarrhoea
ataxia, hallucination, delirium, sedation, drowsiness and sleep
– Kidney, liver and GIT mucosal damage
• Maintain blood pressure, respiration
• Inj. Diazepam 5 mg IM
• Atropine contraindicated as it may cause convulsions and
death - penicillin, thioctic acid and silibinin (antidote?)
• Gastric lavage and activated charcoal

33. Cholinergic Drugs –Indirect acting
• Cholinesterase inhibitors or reversible
anticholinesterases:
1. Natural: Physostigmine
2. Synthetic: Neostigmine, Pyridostigmine,
Distigmine, Rivastigmine, Donepezil,
Gallantamine, Edrophonium, Ambenonium,
Demecarium
Tertiary amine N (lipid soluble) and quartenary
N+ (lipid insoluble).
• Irreversible anticholinesterases:
1. Organophosphorous Compounds (OPC) –
Diisopropyl fluorophosphate (DFP), Ecothiophate,
Parathion, malathion, diazinon (insecticides and
pesticides)
2. Tabun, sarin, soman (nerve gases in war)
3. Carbamate Esters: Carbaryl and Propoxur
(Baygon)
https://www.youtube.com/watch?v=W41HhX2
XHUk

36. Indirect acting Acetylcholinesterases
Glutamate and Histidine
Tryptophan

37. AChEs - MOA
• Normally Acetylcholinesterase (AchE) hydrolyses
Acetylcholine
• The active site of AChE is made up of
two subsites – anionic and esteratic
• The anionic site serves to bind a molecule of ACh to the
enzyme
• Once the ACh is bound, the hydrolytic reaction occurs at a
second region of the active site called the esteratic subsite
• The AChE itself gets acetylated at serine site
• Acetylated enzyme reacts + water = acetic acid and choline
• Choline - immediately taken up
again by the high affinity choline

38. AChEs - MOA
• Anticholinesterases also react with the enzyme ChEs in similar
fashion like Acetylcholine
• Carbamates – carbamoylates the active site of the enzyme
• Phosphates – Phosphorylates the enzyme
• Both react similar fashion covalently with serine
• Carbamylated (reversible inhibitors) reacts with water
slowly and the esteratic site is freed and ready for action – 30
minutes (less than synthesis of fresh enzyme)

39. • But, Phosphorylated (irreversible) reacts extremely slowly
or not at all – takes more time than synthesis of fresh
enzyme
– Sometimes phosphorylated enzyme losses one alkyl group
and become resistant to hydrolysis – aging
• Edrophonium and tacrine reacts only at anionic site – short
acting while Organophosphates reacts only at esteratic site
Irreversible
anticholinsterases
Mechanism
Strong covalent
bond , irreversible
in nature

40. Reversible Anticholinesterases –
Individual Drugs
• 2 (two) important clinically used drugs
–
– Physostigmine – lipid soluble, ganglion
acting and less action in skeletal muscle
• Also organophosphates
– Neostigmine – lipid insoluble, skeletal
muscle acting

41. Physostigmine
• Alkaloid from dried ripe seed (Calabar bean) of African
plant Physostigma venenosum
• Tertiary amine, lipid soluble, well absorbed orally and
crosses BBB, Hydrolyzed in liver and plasma by esterases
• Long lasting action (4-8 hours)
• It indirectly prevents destruction of acetylcholine
released from cholinergic nerve endings and causes ACh
accumulation

42. • Muscarinic action on eye causing miosis and spasm of
accommodation on local application
• Salivation, lacrimation, sweating and increased
tracheobronchial secretions
• Increased heart rate & hypotension

43. 1. Used as miotic drops to decrease IOP in Glaucoma
2. Toantagonize mydriatic effect of atropine
3. Tobreak adhesions between iris and cornea alternating with
mydriatic drops
4. Belladonna poisoning, TCAs & Phenothiazine poisoning
5. Alzheimer’s disease- pre-senile or senile dementia
6. Atropine is antidote in physostigmine poisoning.
ADRs –CNS stimulation followed by depression
Therapeutic uses:

44. Neostigmine
• Synthetic reversible anticholinesterase drug
• Quaternary ammonium compound and lipid insoluble
• Cannot cross BBB
• Hydrolysed by esterases in liver & plasma,Short duration of
action (3-5 hours)
• Direct action on nicotinic (NM) receptors present in
neuromuscular junction (motor end plate) of skeletal muscle
• Antagonises (reverses) skeletal muscle relaxation
(paralysis) caused by tubocurarine and other
competitive neuromuscular blockers

45. Neostigmine – Uses and ADRs
• Stimulates autonomic ganglia in small doses - Large
doses block ganglionic transmission
• No CNS effects
• Used in the treatment of Myasthenia Gravis to increase
muscle strength
• Post-operative reversal of neuromuscular blockade
• Post-operative complications – gastric atony paralytic
ileus, urinary bladder atony
• Cobra snake bite
• Produces twitchings & fasciculations of muscles leading to
weakness
• Atropine is the antidote in acute neostigmine poisoning

46. Physostigmine Vs Neostigmine
Physostigmine Neostigmine
Source Natural Synthetic
Chemistry Tertiary amine Quaternary ammonium
compound
Oral absorption Good Poor
CNS action Present Absent
Eye Penetrates cornea Poor penetration
Effect Ganglia Muscle
Uses Miotic Mysthenia gravis
Dose 0.5-1 mg
oral/parenteral
0.1-1% eye drop
0.5-2.5 mg IM/SC
15-30 mg orally
Duration of action 4-6 Hrs 3-4 Hrs

47. Myasthenia gravis (Myo +
asthenia)
• Autoimmune disorder affecting 1 in 10,000
population (?) – reduction in number of NM
receptors
• Causes: Development of antibodies directed to
Nicotinic receptors in muscle end plate –
reduction in number by 1/3rd of NM receptors
– Structural damage to NM junction
• Symptoms: Weakness and easy fatigability –
ptosis to diaphragmatic paralysis
• Treatment:
– Neostigmine – 15 to 30 mg. orally every 6 hrly
– Adjusted according to the response
– Pyridostigmine – less frequency of dosing
– Other drugs: Corticosteroids (prednisolone 30-60 mg
/day)
• Azathioprin and cyclosporin also Plasmapheresis

48. Overall Therapeutic Uses –
cholinergic drugs
1. Myasthenia gravis: Edrophonium to
diagnose and Neostigmine,
Pyridostigmine & Distigmine to treat
2. To stimulate bladder & bowel after surgery:
– Bethanechol, Carbachol, Distigmine.
3
.
To lower IOP in chronic simple
glaucoma:
– Pilocarpine, Physostigmine
4. To improve cognitive function in Alzheimer’s
disease: Rivastigmine, Gallantamine,
Donepezil.
5. Physostigmine in Belladonna poisoning
6. Cobra Bite

49. Pharmacotherapy of Organophosphate
Poisoning***
• Signs and symptoms:
1. Irritationof eye, lacrmation, salivation, tracheo-bronchial
secretions, colic, blurring of vision, defaecation and
urination
2. Fall in BP, tachy or bradycardia and CVS collapse
3. Muscular fasciculations, weakness, and respiratory
paralysis
4. Excitement, tremor, convulsins and coma
• Treatment:
– Decontamination – gastric lavage if needed
– Airway maintenance
– Supportive measures – for BP/fluid and electrolyte
– Specifc antidote – Atropine – 2mg IV every 10 minutes
till
dryness of mouth or atropinization (upto 200 mg/day)

50. Cholinesterase Reactivators -
Oximes
• Pralidoxime (2-PAM) and Obidoxime
Diacetyl monoxime (DAM)
• Oximes have generic formula R-CH=N-OH
• Provides reactive group OH to the enzymes
to
reactivate the phosphorylated enzymes –
million times faster
• PAM:
– Quaternary Nitrogen of PAM gets attaches to
Anionic
site of the enzyme and reacts with Phosphorous
atom at esteratic site
– Forms Oxime-phosphonate complex making
esteratic site free
– Not effective in Carbamate poisoning
– Dose: 1-2 gm IV slowly maximum 12 gms/24 hrs

51. Summary
• Biosynthesis of Acetylcholine
• Distribution of Muscarinic and Nicotinic receptors
• Classification of Anticholinesterases
• Mechanism of action of Anticholinesterases and
Aging
• Action of cholinomimetics on eye
• Physostigmine Vs Neostigmine
• Myasthenia gravis
• Neostigmine and its uses
• Use of Edrophonium
• Oximes
• Alzheimer`s disease drug names

52. Thank you