Autonomic Nervous System -

“Autonomic Pharmacology”
 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 –
 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)
Autonomic Pharmacology is Practical
Mimic or Block
transmitters
Nerves to organ O
release neurotransmitter N, Drug A blocks
and N increases receptors for
the activity of organ O
+ neurotransmitter N

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

Atropine blocks muscarinic

receptors
and decreases intestinal motility
 For a definite clinical outcome!

Sympathetic nerves Propranolol blocks

release β-adrenergic
Noradrenaline receptors
and increase that respond to NA
Blood Pressure

Propranolol blocks β-adrenergic

receptors
and decreases Blood Pressure
Autonomic Drugs are very
much Clinically Relevant
Autonomic drugs are used
for the
treatment of Angina
Autonomic drugs are used
for the
treatment of Heart
Failure
Autonomic drugs are used for th
treatment of HighBlood
Pressure

• Autonomic drugs also used for

treatment of
- Anaphylactic shock
- Septic shock
- Benign prostatic hypertrophy
- Alzheimer’s disease
- Asthma
 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
 Autonomic Pharmacology

I. Anatomy of Peripheral Nervous System –

Recall
 Organization of
Nervous System - Recall

Central Nervous System Peripheral Nervous System

“Brain and spinal cord”

Autonomic Nervous System Somatic Nervous System

Afferent Division Efferent Division

Sympathetic Parasympathetic
“thoracolumbar” “craniosacral”
 Peripheral Nervous System
Controls
Controls
smooth &
skeletal cardiac
muscle muscle &
glands

Somatic
Nervous Autonomic
System Nervous
System

One Two
Neuron Preganglionic Neuron
Efferent Efferent
Limb Postganglionic Limb
Recall Differences - Somatic Vs ANS
 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
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
 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
 AUTONOMIC NERVOUS SYSTEM
• SYMPATHETIC
– Fight or Flight

• PARASYMPATHETIC
– Rest and Digest

Next slide –
Distriibution:
Parasympathetic Nervous System (Craniosacral Outflow)
SA & AV Node Bronchi/Bronchial
Sphincter Muscle of Iris Glands
Ciliary Muscle
Stomach

Small Intestines
Lacrimal Gland
Bile Ducts
Gallbladder

Submaxillary & Kidney

Sublingual
Glands
Large Intestines

Bladder
Parotid Gland

Genitalia
 Radial Muscle of Iris
Sympathetic Nervous System Ciliary Muscle
(Thoracolumbar Outflow) Sublingual/Submaxillary
& Parotid Gland
SA & AV Nodes
Pilomotor Muscles His-Purkinje System
Sweat Glands Myocardium
Bronchi/Bronchial
Glands
Stomach

Kidneys
Blood Vessels

Intestines

Paravertebral Ganglia Bladder//Genitalia

Prevertebral Ganglia
 ADRENAL
MEDULLA

Chromaffin Cells

Epinephrine
(+) Dilates Airways (+) Mental Alertness

(+) ACTH & TSH

(+) Cardiac Output

(+) Muscle Contraction & Efficiency (+) Glycogenolysis

(+) Fatty Acid Release (-) Intestinal Motility

 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
Impulse conduction across synapse
 Somatic
Motor Fiber Skeletal
Ach Muscle

Sympathetic GanglionPostganglionic Fiber:

Smooth Muscle
Ach Adrenergic NE Cardiac Cells
Gland Cells
Sympathetic Ganglion
Ach Ach Sweat
Glands
Sympathetic
EPI/NE
Ach
Adrenal Gland Smooth Muscle
Para- Ganglion Cardiac Cells
sympathetic Ach Ach Gland Cells
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)
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.
 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
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
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.
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
 Differences between 2 AChEs
True AChE Pseudo AChE
Distribution All cholinergic Plasma, liver,
sites, RBCs, Intestine and
gray matter white matter
Action on:
Acetycholine Very Fast Slow
Methacholine Slower Not hydrolyzed

Inhibition More sensitive More sensitive to

to Organophosphates
Physostigmine
Function Termination of Hydrolysis of
Ach action Ingested Esters
 Cholinergic receptors - 2 types

• Muscarinic (M) and Nicotinic (N):

Nicotinic (N) –
Muscarinic ligand gated
(M) - GPCR
Acetylcholine (cholinergic receptors)
Amanita muscaria
– 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
 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
 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
Muscarinic Receptor
Subtypes
M1 M2 M3
Location Autonomic ganglia, Heart and CNS SMs of Viscera,
Gastric glands and CNS Eye, exocrine
glands and
endothelium
Functions excitatory postsynaptic Less impulse Visceral SM
potential (EPSP) & generation, less contraction,
Histamine release & velocity of Constriction of
acid secretion with CNS conduction, pupil,
learning and motor decreased contraction of
functions contractility, Cilliary muscle
less Ach and
release vasodilatation
Agonists Oxotremorine and MCN Methacholine Bethanechol
and MCN-343A
Antagonis Pirenzepine Methoctramine Darifenacin
ts & Triptramine
 Acetylcholine (cholinergic receptors)
– Muscarinic Receptors

• Selectively stimulated by Muscarine and

blocked by Atropine

M1 M2 M3

Ganglia Heart Glands and

Smooth Muscles
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
 Nicotinic (NM and NN) Receptor -
comparison
NM (Muscle type) NN (Ganglion type)
1. Location: Skeletal Muscle 1. Location: In autonomic ganglia of
end plates all type (ganglion type) –
Sympathetic, Parasympathetic and
2. Function: Stimulate skeletal also Adrenal Medulla
muscle (contraction) 2. Function: Depolarization and
3. MOA: Postsynaptic and postganglionic impulse – stimulate
Excitatory (increases Na+ and all autonomic ganglia
K+ permeability) 3. MOA: Excitatory – Na+, K+ and
Ca+ channel opening
4. Agonists: ACh, carbachol 4. Agonists: ACh, CCh, nicotine
(CCh), suxamethonium – Selectively stimulated by
– Selective stimulation by phenyl phenyl piperazinium (DMPP)
trimethyl ammonium (PTMA)
5. Antagonists: mecamylamine,
5. Antagonists: tubocurarine, trimetaphan
hexamethonium
 Sites of Cholinergic transmission
and types of Receptors
Site Types Selective Selective
agonist antagonist
All Postganglionic
Parasympathetic Muscarini Muscarine Atropine
Postganglionic sympathetic to c
sweat gland & BV
Ganglia (Both Para and NN DMPP Hexamethoniu
sympathetic and also m
Adrenal Medulla

Skeletal Muscle NM PTMA Curare

CNS Muscarini Muscarine Atropine
c Oxotremorin
e
Ganglia Concept - summary
Sympathetic and Parasympathetic Effects on Body Tissues
 Organs With Dual Innervations

• Dual innervations
➢ Innervations by both
❖Sympathetic fibers
❖Parasympathetic fibers
• Most visceral organs receive dual innervations
• Effects of dual innervations
➢ Antagonistic
➢ Complementary
➢ Cooperative
 Organs With Dual Innervations

• Antagonistic :
– Sympathetic and parasympathetic fibers innervate the
same cells.
• Actions counteract each other.
– Heart rate.
• Complementary:
– Sympathetic and parasympathetic stimulation produces
similar effects.
• Cooperative:
– Sympathetic and parasympathetic stimulation produce
different effects that work together to produce desired
effect.
• Micturition.
Organs Without Dual Innervations

• Regulation achieved by increasing or decreasing

firing rate.
• Organ receive only sympathetic innervations-
➢Adrenal medulla
➢Sweat glands
➢Most blood vessels.
❖Nonshivering thermogenesis.
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.
 Classification - Direct-acting (receptor
agonists )
• Choline Esters
– Natural: Acetylcholine
– Synthetic: Methacholine, Carbachol and
Bethanechol
• Alkaloids: Pilocarpine, Muscarine, Arecholine
– Synthetic: Oxotremorine
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)
 Question…
• What side effects might you expect to
see in a patient taking a cholinergic drug?
 Ach actions - Muscarinic
1. Heart: M2
– Hyperpolarization of SA node, reduction in impulse generation and
Bradycardia
– Slowing of AV conduction and His-purkinje fibres – partial or
complete block
– Atrial fibrillation and flutter – nonuniform vagal innervations
– Decrease in ventricular contractility
2. 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
 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
 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)
Bethanecol Uses: Postoperative and postpartum urinary
obstruction, neurogenic bladder and GERD (10-40 mg oral)
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
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 )
 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)
Early Onset Mushroom Poisoning
• Occurs ½ to 1 hour Volvariella volvacea

• 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.
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
 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)
 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
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)
 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
Anti-ChEs (MOA) – contd.
If You Want to Know More …

Please follow the coming

Slides!
Hydrolysis of acetylcholine by AChE

O
C Phe 338
Glu 327 O
H
N
N O CH3
N CH3
His 440 O CH3
OH Anionic site
Trp 86

Ser 203 HN

Esteratic site
Hydrolysis of acetylcholine by AChE

O
C
Glu 327 O
H
N Phe 338
N
CH3
His 440
N CH3
O HO CH3
Anionic site
O
Trp 86
HN
Ser 203

Esteratic site
Hydrolysis of acetylcholine by AChE

O
C
Glu 327 O
H
N Phe 338
N
CH3
His 440 choline
O N CH3
HO CH3

O Anionic site
Trp 86

Ser 203 HN

Esteratic site
Hydrolysis of acetylcholine by AChE

O
C
Glu 327 O
H
N Phe 338
N
O H
His 440 H
O

O Anionic site
Trp 86

Ser 203 HN

Esteratic site
Hydrolysis of acetylcholine by AChE

O
C
Glu 327 O
H
N Phe 338
N

O
His 440 acetate
OH

OH Anionic site
Trp 86

Ser 203 HN

Esteratic site
 Pharmacologic manipulation of AChE: No
inhibition

Na+
Muscarini
ACH
c
ACH
Receptor
Acetylcholinesteras
ACH e
ACH ACH
Action Potential ACH
ACH
ACH

ACH
ACH
ACH
Choline Acetate

Presynaptic neuron
Postsynaptic target
 Pharmacologic manipulation of AChE: Inhibition by
drugs
ACH
ACH
Na+
ACH
Muscarini
ACH
c
ACH
Receptor
Acetylcholinesteras
ACH e
ACH
ACH ACH
Action Potential ACH
ACH
ACH ACH
ACH ACH
ACH
ACH

Presynaptic neuron
Postsynaptic target
 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
 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
 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
 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
 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
 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 0.5-2.5 mg IM/SC
oral/parenteral 15-30 mg orally
0.1-1% eye drop
Duration of 4-6 Hrs 3-4 Hrs
action
 Therapeutic Uses – cholinergic drugs
1. Myasthenia gravis:
• Edrophonium to diagnose
• 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
 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 a method of removing blood plasma from the body by
withdrawing blood, separating it into plasma and cells, and transfusing
the cells back into the bloodstream. It is performed especially to
remove antibodies in treating autoimmune conditions.
Myasthenia Gravis - Images
 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
 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
 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
 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
 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
Thank you