ANS

1. Autonomic Nervous System -
“Autonomic Pharmacology”
Department of Pharmacology
NEIGRIHMS, Shillong

2. Goal
To Learn about the drugs affecting the
autonomic nervous system
Be prepared to link mechanism of drug action
with knowledge mainly of cardiovascular anatomy,
physiology and neurobiology
to predict effects of drugs –

3. The autonomic nervous system
maintains the internal environment
of the body – called HOMEOSTASIS
Role of ANS in homeostasis
links to target organs -
(Cardivascular System, smooth
muscle of GI and glands)

4. +
Drug A decreases
activity of
organ O
Autonomic Pharmacology is Practical
Nerves to organ O
release neurotransmitter N,
and N increases
the activity of organ O
Mimic or Block
transmitters
Drug A blocks
receptors for
neurotransmitter N

5. +
Atropine blocks muscarinic
receptors
and decreases intestinal
motility
Atropine blocks
muscarinic
cholinergic
receptors
that respond to
ACh
Understanding actions of drugs that
influence the autonomic nervous
system allows prediction of their
effects!
Parasympathetic
nerves
release ACh
and increase
intestinal motility

6. For a definite clinical outcome!
Sympathetic
nerves
release
Noradrenaline
and increase
Blood Pressure
Propranolol
blocks
β-adrenergic
receptors
that respond to
NA
Propranolol blocks β-adrenergic
receptors
and decreases Blood Pressure

7. Autonomic Drugs are
very much Clinically
Relevant

8. Autonomic drugs are used
for the
treatment of Angina

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

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

11. Objectives
• Review the anatomy of the autonomic nervous system
• Know the neurotransmitters at autonomic synapses
• Understand the mechanism of neurotransmission in the
autonomic nervous system
• Be able to describe the distribution of adrenergic and
cholinergic receptors
• Describe general mechanisms by which drugs interact with
the autonomic nervous system

12. Autonomic Pharmacology
I. Anatomy of Peripheral Nervous System –
Recall

13. 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”

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

15. Recall Differences - Somatic Vs ANS

16. ANS - Organization
• Autonomic afferents:
– Mixed and nonmyelinated Nerves
– Cell bodies are located in the dorsal root ganglion
of Spinal Nerves and the sensory ganglia of
Cranial Nerves
– Mainly mediate visceral pain
– Also reflexes from CVS, visceral and respiratory

17. Organization of ANS –
Central Connections
• No Exclusive autonomic area in CNS
• Intermixing and integration of somatic and ANS occurs
• Hypothalamus is the organ to regulate
• Sympathetic – Lateral and Posterior sympathetic
• Parasympathetic – Anterior and Medial
• Many autonomic centres are located in mid brain
medulla

18. Organization of ANS – Efferent fibres
• Motor limb – Sympathetic
and Parasympathetic
• Most organs receive both
innervations
• Functionally antagonistic of
each other
• Overall – depends on the tone
at particular moment
• EXCEPTIONS:
– Most Blood vessels, sweat
glands and hair follicles –
Sympathetic
– Gastric and pancreatic glands,
cilliary muscles -
Parasympathetic

19. AUTONOMIC NERVOUS SYSTEM
• SYMPATHETIC
– Fight or Flight
• PARASYMPATHETIC
– Rest and Digest
Next slide –
Distriibution:

20. Parasympathetic Nervous System (Craniosacral Outflow)
Genitalia
Bladder
Large Intestines
Kidney
Bile Ducts
Gallbladder
Small Intestines
Stomach
Bronchi/Bronchial
Glands
SA & AV Node
Sphincter Muscle of Iris
Ciliary Muscle
Lacrimal Gland
Submaxillary &
Sublingual
Glands
Parotid Gland

21. Radial Muscle of Iris
Ciliary Muscle
SA & AV Nodes
His-Purkinje System
Myocardium
Bronchi/Bronchial
Glands
Stomach
Kidneys
Intestines
Bladder//Genitalia
Sublingual/Submaxillary
& Parotid Gland
Pilomotor Muscles
Sweat Glands
Blood Vessels
Sympathetic Nervous System
(Thoracolumbar Outflow)
Paravertebral Ganglia
Prevertebral Ganglia

23. Epinephrine
(+) Fatty Acid Release (-) Intestinal Motility
(+) Glycogenolysis
(+) ACTH & TSH
(+) Mental Alertness
(+) Muscle Contraction & Efficiency
(+) Dilates Airways
(+) Cardiac Output
ADRENAL
MEDULLA
Chromaffin Cells

24. Sympathetic Parasympathetic
Origin Dorso-lumber (T1 to L2 or 3) Craniosacral (S2-4)
Distribution Wide Head, neck and trunk
Ganglia Away from Organ supplied On or close to the organ
Postganglionic fibers Long Short
Pre and post fiber
ratio
1:20 to 1:100 1:1 or 1: 2
Transmitter Noradrenalin Acetylcholine
Duration Long and wider action Ach – rapid destroy
Function Tackling stress and emergency Assimilation of food and
conservation of energy

25. Enteric Nervous System
• Considered 3rd
Division of ANS
– Auerbach`s plexus or myenteric plexus
– Meissner`s plexus or submucous plexus
• Stimulation of these neurones causes release of – Ach, NE,
VIP, ATP, Substance P, 5-HT etc.
• May be excitatory or inhibitory in Nature

26. Enteric Nervous System

27. Neurohumoral
Transmission
• Neurohumoral transmission
means the transmission of
message across synapse and
neuroeffector junctions by
release of humoral (chemical)
messages
• Initially junctional
transmission was thought to
be Electrical
• But, Dale (1914) and Otto
Loewi (1921) provided direct
proof of humoral transmission
– vagusstoff and
acceleranstoff
• Many Neurohumoral
transmitters identified:
Acetylcholine, noradrenalin,

28. Neurohumoral
Transmission - Steps
1. Impulse Conduction
– Tetrodotoxin and
saxitoxin
1. Transmitter Release
2. Transmitter release on
postjunctional membrane
 EPSP and IPSP
1. Postjunctional activity
2. Termination of transmitter
action
– NET, SERT, DT

29. Impulse conduction across synapse

30. Ach
Ach
Ach
Ach NE
Ach
EPI/NE
Ach Ach
Somatic
Sympathetic
Sympathetic
Sympathetic
Para-
sympathetic
Postganglionic Fiber:
Adrenergic
Postganglionic
Fiber:Cholinergic
Adrenal Gland
MotorFiber
Sweat
Glands
Smooth Muscle
Cardiac Cells
Gland Cells
Smooth Muscle
Cardiac Cells
Gland Cells
Skeletal
Muscle
PreganglionicFiber:
Cholinergic
Ganglion
Ganglion
Ganglion

31. Cholinergic and Adrenergic System
• Accordingly:
– Cholinergic Drugs, i.e., they act by releasing
acetylcholine
• But also utilize nitric oxide (NO) or peptides for
transmission
– Noradrenergic (commonly called "adrenergic")
Drugs - act by releasing norepinephrine (NA)

32. Cotransmission
• Peripheral and central Neurons release more than one active
substance when stimulated
• In ANS, besides Ach and NA – neurones elaborate Purines
(ATP, adenosines), Peptides (VIP) or NPY, substance P, NO,
enkephalins etc.
• ACH and VIP, ATP with both Ach and NA
• Stored in same neurones, but distinct vesicles – ATP and NA in
same vesicle
• NANC – gut, vas deferens, urinary tract, salivary glands and
certain blood vessels.

35. Sites of Cholinergic Transmission
Acetylcholine (Ach) is major neurohumoral transmitter at
autonomic, somatic and central nervous system:
1. All preganglionic sites (Both Parasympathetic and
sympathetic)
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

36. Cholinergic
Transmission:
• Cholinergic neurons contain large
numbers of small membrane-bound
vesicles (containing ACh) concentrated
near the synaptic portion of the cell
membrane
• ACh is synthesized in the cytoplasm
from acetyl-CoA and choline by the
catalytic action of Choline
acetyltransferase (ChAT)
• Acetyl-CoA is synthesized in
mitochondria, which are present in large
numbers in the nerve ending
• Choline is transported from the
extracellular fluid into the neuron terminal
by a sodium-dependent membrane carrier
(carrier A). This carrier can be blocked by
a group of drugs called hemicholiniums
The action of the choline
transporter is the rate-limiting
step in ACh synthesis

37. Cholinergic Transmission:
• Synthesized, ACh is transported from the
cytoplasm into the vesicles by an antiporter
that removes protons (carrier B). This
transporter can be blocked by vesamicol
• Release is dependent on extracellular Ca2+
and occurs when an action potential reaches
the terminal and triggers sufficient influx of
Ca2+ ions
• The increased Ca2+ concentration
"destabilizes" the storage vesicles by
interacting with special proteins associated
with the vesicular membrane (VAMPs)
Fusion of the vesicular membranes with the
terminal membrane results in exocytotic
expulsion of ACh into the synaptic cleft
• The ACh vesicle release process is blocked
by botulinum toxin through the enzymatic
removal of two amino acids from one or more
of the fusion proteins. Black widow spider??

38. Cholinergic Transmission:
• After release - ACh molecules may bind to
and activate an ACh receptor
(cholinoceptor)
• Eventually (and usually very rapidly), all of
the ACh released will diffuse within range
of an acetylcholinesterase (AChE)
molecule
• AChE very efficiently splits ACh into
choline and acetate, neither of which has
significant transmitter effect, and thereby
terminates the action of the transmitter.
• Most cholinergic synapses are richly
supplied with AChE; the half-life of ACh in
the synapse is therefore very short. AChE
is also found in other tissues, eg, red blood
cells.
• Another cholinesterase with a lower
specificity for ACh, butyrylcholinesterase
[pseudo cholinesterase], is found in blood
plasma, liver, glial, and many other tissues

39. Differences between 2 AChEs
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
Inhibition More sensitive
to
Physostigmine
More sensitive to
Organophosphates
Function Termination of
Ach action
Hydrolysis of
Ingested Esters

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

41. Acetylcholine (cholinergic receptors)
– Muscarinic Receptors
1. Selectively stimulated by Muscarine and blocked by Atropine – all are G-
protein coupled receptors
2. Primarily located in heart, eye, smooth muscles and glands of GIT
3. Subsidiary M receptors are also present in ganglia for modulation
4. Autoreceptors (M type) are present in prejunctional cholinergic Nerve
endings – also in adrenergic nerve terminals leading to vasodilatation
when Ach is injected
5. Blood vessels: All blood vessels have muscarninc receptors although no
cholinergic innervations
Amanita
muscaria

42. 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 till today, 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

43. Muscarinic Receptors - Location
• M1: Ganglion Cells and Central Neurons (cortex,
hippocampus, corpus striatum)
– Physiological Role: Mediation of Gastric acid secretion and
relaxation of LES
• 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

44. M1 M2 M3
Location Autonomic ganglia,
Gastric glands and CNS
Heart and CNS SMs of Viscera,
Eye, exocrine
glands and
endothelium
Functions EPSP & 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
vasodilatationAgonists Oxotremorine and MCN
and MCN-343A
Methacholine Bethanechol
Antagonis
ts
Pirenzepine Methoctramine
& Triptramine
Darifenacin
Muscarinic Receptor
Subtypes

45. Acetylcholine (cholinergic receptors)
– Muscarinic Receptors
• Selectively stimulated by Muscarine and
blocked by Atropine
M1 M2 M3
Ganglia Heart Glands and
Smooth
Muscles

46. 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

47. Nicotinic (NM and NN) Receptor -
comparison
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)
1. Antagonists: tubocurarine,
hexamethonium
NN (Ganglion type)
1. Location: In autonomic ganglia of
all type (ganglion type) –
Sympathetic, Parasympathetic and
also Adrenal Medulla
2. Function: Depolarization and
postganglionic impulse – stimulate
all autonomic ganglia
3. MOA: Excitatory – Na+, K+ and
Ca+ channel opening
4. Agonists: ACh, CCh, nicotine
– Selectively stimulated by
phenyl piperazinium (DMPP)
1. Antagonists: mecamylamine,
trimetaphan

48. Sites of Cholinergic transmission
and types of Receptors
Site Types Selective
agonist
Selective
antagonist
All Postganglionic
Parasympathetic
Postganglionic sympathetic to
sweat gland & BV
Muscarini
c
Muscarine Atropine
Ganglia (Both Para and
sympathetic and also
Adrenal Medulla
NN DMPP Hexamethoniu
m
Skeletal Muscle NM PTMA Curare
CNS Muscarini
c
Muscarine
Oxotremorin
e
Atropine

49. Ganglia Concept - summary

50. Cholinergic Drugs or Cholinomimetic
or Parasympathomimetics
Drugs producing actions similar to Ach – by
interacting with Cholinergic receptors or
by increasing availability of Ach at these
sites.

51. Classification - Direct-acting (receptor
agonists )
• Choline Esters
– Natural: Acetylcholine
– Synthetic: Methacholine, Carbachol and
Bethanechol
• Alkaloids: Pilocarpine, Muscarine, Arecholine
– Synthetic: Oxotremorine

52. Cholinergic Drugs – Indirect acting
• Cholinesterase inhibitors or reversible
anticholinesterases:
– Natural: Physostigmine
– Synthetic: neostigmine, pyridostigmine, distigmine,
rivastigmine, donepezil, gallantamine, edrophonium,
ambenonium, demecarium
• Irreversible anticholinesterases:
– Organophosphorous Compounds (OPC) – Diisopropyl
fluorophosphate (DFP), Ecothiophate, Parathion,
malathion, diazinon (insecticides and pesticides)
– Tabun, sarin, soman (nerve gases in war)
– Carbamate Esters: Carbaryl and Propoxur (Baygon)

53. Question…
• What side effects might you expect to
see in a patient taking a cholinergic
drug?
• Hint… Cholinergic = “Colon-Urgent”

54. Ach actions - Muscarinic
1. Heart: M2
– Hyperpolarization of SA node, reduction in impulse generation and
Bradycardia
– RP in SAN and PF increased but atrial muscles fibers abbreviated
– Slowing of AV conduction and His-purkinje fibres – partial or
complete block
– Atrial fibrillation and flutter – nonuniform vagal innervations
– Decrease in ventricular contractility
1. 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
– Penile erection

55. Muscarinic action – contd.
3. Smooth Muscles: M3
– 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
5. Eye: M3
– Contraction of circular fibres of Iris – miosis
– Contraction of Ciliary muscles – spasm of accommodation,
increased outflow and reduction in IOP

56. Ach actions - Nicotinic
1. Autonomic ganglia:
– Both Sympathetic and parasympathetic ganglia are stimulated
– After atropine injection Ach causes tachycardia and rise in BP
1. 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)
Bethanecol Uses: Postoperative and postpartum urinary
obstruction, neurogenic bladder and GERD (10-40 mg oral)

57. Pilocarpine
• Alkaloid from leaves of Pilocarpus
microphyllus
• Prominent muscarinic actions
• Profuse salivation, lacrimation,
sweating
• Dilates blood vessels, causes
hypotension
• On Eyes:
– it produces miosis by contraction
of circular muscles of iris
– Contraction of cilliary muscles
• spasm of accommodation -
fixed for near vision
• Increased outflow of AH
• Lowers intraocular pressure (IOP) in
Glaucoma when applied as eye
drops
• Too toxic for systemic use

58. Pilocarpine –
contd.
• Used as eye drops in treatment of narrow angle and wide
angle glaucoma to reduce IOP
• Used to reverse mydriatic effect of atropine
• To break adhesion between iris and cornea/lens alternated
with mydriatic
• Pilocarpine nitrate eye drops ( 1 to 4% )
• CNS toxicity after systemic use
• Atropine used as antidote in acute pilocarpine poisoning ( 1-2
mg IV 8hrly )

59. Muscarine
• Alkaloid from mushroom Amanita muscaria
• Only muscarinic actions
• No clinical use
• Mushroom poisoning due to ingestion of poisonous
mushroom
= Early onset mushroom poisoning (Muscarine type)
= Late onset mushroom poisoning (neurogenic)

60. 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 mio acid receptors. No specific treatment – Atropine
is contraindicated.
Volvariella volvacea

61. Late Onset Mushroom
Poisoning
• Occurs within 6-15 hours
• Amanita phylloides – due to peptide toxins – Inhibit RNA and
protein 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
• Gastric lavage and activated charcoal

62. Cholinesterase
Inhibitors
“ANTICHOLINESTERA
SES”

63. Cholinesterase inhibitors - Classification
• Reversible anticholinesterases (Carbamates):
– Natural: Physostigmine
– Synthetic: Neostigmine, pyridostigmine, distigmine,
rivastigmine, donepezil, gallantamine, edrophonium,
ambenonium, demecarium
• Irreversible anticholinesterases:
– Organophosphorous Compounds (OPC) – Diisopropyl
fluorophosphate (DFP), Ecothiophate, Parathion,
malathion, diazinon (insecticides and pesticides)
– Tabun, sarin, soman (nerve gases in war)
– Carbamate: Carbaryl and Propoxur (Baygon)

64. Overall …
• Most reversible Anti-ChEs are Carbamic acid compounds –
Physostigmine, Neostigmine, pyridostigmine and
Edrophonium
 Physostigmine is tertiary amine (has tertiary amino N radical) – lipid
soluble
 Neostigmine – Quarternary amine (has tertiary amino N radical) - lipid
insoluble
 Exception: Tacrine – Acridine derivative
• Most Irreversible Anti-ChEs contain Phosphoric acid –
ORGANOPHOSPHATES – highly lipid soluble
• A few Irreversible Anti-ChEs are lipid soluble Carbamates - Carbaryl
and Propoxur

65. AChEs - MOA
• Acetylcholinesterase is the primary target
• Normally Acetylcholine - binds to the enzyme's active site and is
hydrolyzed, yielding free choline and the acetylated enzyme
• The active site has two subsites – anionic and esteratic
• The anionic site serves to bind a molecule of ACh to the enzyme
• Once the ACh is bound at anioic site, the hydrolytic reaction occurs at
a second region of the active site - esteratic subsite
• AChE itself gets acetylated by acetylation of serine site
• Acetylated enzyme reacts with water to form Acetic acid and choline
(Bond splits)

66. Anti-ChEs (MOA) – contd.
• Anticholinesterases also react with the enzyme ChEs in similar
fashion like Acetylcholine
– Carbamates – carbamylates the active site of the enzyme
– Phosphates – Phosphorylates the enzyme
• 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)
• 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 while
Organophosphates reacts only at esteratic site

67. Anti-ChEs (MOA) – contd.

68. If You Want to Know More …
Please follow the coming
Slides!

69. HN
Hydrolysis of acetylcholine by AChE
Trp 86
Esteratic site
O
N
CH3
CH3
CH3
O
OH
Ser 203
Phe 338
Anionic site
C
O
OGlu 327
N
H
N
His 440

70. O
O
HN
Hydrolysis of acetylcholine by AChE
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic site
HO
N
CH3
CH3
CH3
C
O
OGlu 327
N
H
N
His 440

71. O
O
HN
Hydrolysis of acetylcholine by AChE
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic site
HO
N
CH3
CH3
CH3
choline
C
O
OGlu 327
N
H
N
His 440

72. O
O
HN
Hydrolysis of acetylcholine by AChE
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic site
C
O
OGlu 327
N
H
N
His 440 H
O H

73. OH
HN
Hydrolysis of acetylcholine by AChE
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic site
OH
O
acetate
C
O
OGlu 327
N
H
N
His 440

74. Action Potential
Na+
Ca 2+
Acetylcholinester
ase
Pharmacologic manipulation of AChE: No
inhibition
Presynaptic neuron
Postsynaptic
Muscari
nic
Recepto
r
ACH
ACH
CholineAcetate
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH

75. Action Potential
Na+
Ca 2+
Acetylcholinester
ase
Pharmacologic manipulation of AChE:
Inhibition by drugs
Presynaptic neuron
Postsynaptic
Muscari
nic
Recepto
r
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH

76. Anti-ChEs – Pharmacological
Actions
• Qualitatively similar to directly acting cholinergics, but quantitatively
different – two important clinically used drugs:
– Lipid soluble agents (physostigmine) – more muscarinic and CNS effects
(stimulate ganglia) – less skeletal muscle effect
– Lipid insoluble ones like Neostigimine – more skeletal muscle effect, stimulate
ganglia but less muscarinic effect
• Ganglia: Stimulates ganglia through muscarinic receptors, but high doses
may cause persistent depolarization of Nicotinic receptors and block
transmission
• CVS: Complex action – muscarinic-bradycardia, ganglionic-tachycardia etc.
• Skeletal Muscle: Repetitive firing – twitching and fasciculation
– High doses – persistent depolarization and NM blockade

77. 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)
• Reversible anticholinesterase drug
• It indirectly prevents destruction of acetylcholine released from
cholinergic nerve endings and causes ACh accumulation
• Muscarinic action on eye causing miosis and spasm of accommodation on
local application
• Antagonises mydriasis and cycloplegia produced by atropine and
anticholinergic drugs
• Salivation, lacrimation, sweating and increased tracheobronchial
secretions.
• Increased heart rate & causes hypotension

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

79. Neostigmine
• Synthetic reversible anticholinesterase drug
• Quaternary ammonium compound and lipid soluble
• 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
• Stimulates autonomic ganglia in small doses
• Large doses block ganglionic transmission
• No CNS effects

80. Neostigmine – Uses and ADRs
• 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

81. Physostigmine and Neostigmine -
Summary
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

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

83. Myasthenia gravis
• Autoimmune disorder affecting 1 in 10,000 population
• 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
• Treatment:
– Neostigmine – 15 to 30 mg orally every 6 hrly
– Adjusted according to the response
– Dose requirement may fluctuate time to time – adjustment required
– Pyridostigmine – less frequency of dosing
– Other drugs: Corticosteroids (prednisolone 30-60 mg /day)
• Azathioprin and cyclosporin also Plasmapheresis
– Plasmapheresis

84. Myasthenia Gravis - Images

85. Myasthenic crisis
• Acute weakness and respiratory paralysis
– Tracheobronchial intubation and mechanical ventilation
– Methylprednisolone IV with withdrawal of AChE
– Gradual reintroduction of AChE
– Thymectomy
• Edrophonium is used for diagnosis of Myasthenic crisis
(disease itself) and cholinergic crisis (overdose of Anti-ChE)
– Improvement of symptoms – myasthenic crisis
– Worsening – Cholinergic crisis

86. Snake venom Poisoning
• Asian Cobra Bite
• Symptoms are similar to Myasthenia gravis
• Atropine sulfate 0.6 mg IV slowly – to
counteract Muscarinic action
• Edrophonium chloride (Tensilon) - 10 mg IV
over 2 minutes – reversal of occulomotor and
respiratory paralysis

87. AChE Poisoning (Organophopsphorous
Poisoning)
• Poisoning may be – Occupational, accidental,
Suicidal
• Symptoms:
– Fall in BP, bradycardia or tachycardia, cardiac arrhythmia
and vascular collapse
– Irrittion of Eye, lacrimation, salivation, colic, involuntary
defection, breathlessness, blurring of vision
– Muscular fasciculations and weakness
– Death due to respiratory paralysis – peripheral and central

88. Principles of Treatment
• Remove soiled clothes
• Wash soiled skin and eyes
• Prone Positioning and clear mouth and throat
• Intubation of airway
• Gastric lavage
• Atropine: All cases of AChE poisoning, 2mg IV every
`10 minutes – continue till atropinization occurs
• Cholinesterase reactivators: Oximes

89. Cholinesterase Reactivators - Oximes
• Pralidoxime (2-PAM), Obidoxime Diacetyl monoxime (DAM)
• Oximes have generic formula R-CH=N-OH
• Provides reactive group OH to the enzymes to reactivate the
phosphorylated enzymes
• PAM:
– Quaternary Nitrogen of PAM has a quaternary Nitrogen – gets
attached to Anionic site of the enzyme - unoccupied in
Organophosphorous poisoning
– and reacts with Phosphorous atom at esteratic site
– Forms Oxime-phosphonate complex making esteratic site free
– Not effective in Carbamate poisoning
– Available as 500 mg/20 ml infusion or 1 gm/vial for infusion
– Injected slow IV - 1-2gm

90. Khublei Shibun / Thank you