Intro.

To ANS &
cholinomimmetic
drugs
A K Dubey M.D.
 Learning Objectives
To explain the differences between Parasympathetic
Nervous System and Sympathetic Nervous System and
their effects on the organs.
List the steps in the synthesis, storage, release and
inactivation of acetylcholine, and drugs that interface with
those processes. Explain their mechanisms. Describe the
types of receptors ,nicotinic and muscarinic.
To define that cholinomimmetic drugs can be either Direct
acting (directly stimulate Muscarinic receptors) or
Indirect acting drugs (Anticholinesterases) which inhibit
ChE enzyme increase synaptic Ach which in turn
stimulates the receptors (both muscarinic and nicotinic)
and to predict the uses, side effects & contraindications of
cholinergic drugs.
List the therapeutic uses of muscarinic agonists.
List the adverse side effects of muscarinic agonists
 Learning Objectives
Compare the two major cholinesterases:
acetylcholinesterase(AChE) and butyrylcholinesterase
(BuChE) as to anatomical locations, sites of synthesis and
function.
Relate the onset of action of anticholinesterases, routes of
administration, and the duration of action of
anticholinesterases with sites and type of attachment to
the enzyme.
Explain why anticholinesterases are reversible or
irreversible, and indicate which anticholinesterases are in
each category.
Describe the effects of accumulated acetylcholine at
Muscarinic and nicotinic receptors in the periphery and
the central nervous system.
List therapeutic uses for and adverse side effects of
anticholinesterases.
 Learning Objectives
Explain the role of enzyme aging in the enzyme-inhibitor
interaction.
Explain why anticholinesterase agents can be used as
insecticides (malathion, parathion) and chemical warfare
agents (sarin, VX series).
Explain why PRALIDOXIME is not effective reactivating all
phosphorylated AChE. j. Important or prototypic drugs:
physostigmine, neostigmine,
To list commonly used drugs in Myasthenia gravis:
describe mechanism of action, side effects and
contraindication of commonly used drugs; diagnosis of MG
with edrophonium and be able to differentiating between
cholinergic and myasthenia crisis in a known patient of MG
receiving drugs.
Important drugs-edrophonium, Neostigmine,
pyridostigmine, echothiophate and pralidoxime.
DIFFERENECES BETWEEN SYMPATHETIC &
PARASYMPATHETIC

SYMPATHETIC PARASYMPATHETIC

Thoracolumbar Craniosacral
outflow outflow

Ganglion Ganglion located

located close to close to the organ
origin; long of innervations;
postganglionic short post-
fibers ganglionic fibers
NT--Ach
NT---NE &
Epinephrine Conserve energy
 cholinergic
Neurotransmission
Which involves Ach, which helps with the following:
All preganglionic fibers
All autonomic ganglions
All post-ganglionic parasympathatic
fibers
Post-ganglionic sympathetic fibers to
sweat glands
Somatic fibers to the skeletal muscle
 Synthesis of Ach- within the nerve
endings
Choline is transported from outside
& combines with acetyl-CoA in
presence of enzyme ChAT (choline
ChAT

acetyl transferase) to form Ach

Choline + Acetyl-coA Ach
Storage- stored in vesicles-1000-
50,000 molecules per vesicle.
Release action potential leads to
depolarization & influx of Calcium
which facilitates extrusion of
 Cholinergic
Neurotransmission
Breakdown of Ach---Fast by
Acetylcholinesterase enzyme (AchE)
2 types of AchE- True & pseudo
Differences between true & pseudo
AchE??
True (synaptic & neuroeffector junction), Pseudo (blood/liver)
Cholinergic Receptors- Two types-
muscarinic(M) &Nicotinic(N)
 Cholinergic receptors
Receptors Signaling Locations Effects
M1 G q- PLC, Ganglion, CNS depolarization
Increased IP3,
DAG, Increased
calcium
M 2 Gi, Inhibition of Heart Negative
adenyl cyclase, chronotropy
decreased cAMP, ( HR),
opening of K dromotropy
channels ( conduction) and
ionotropy ( Force
of contraction)
effect
M 3 G q- PLC, Smooth muscles Contraction
Increased IP3, of glands,
DAG, Increased sphincter
calcium pupillae, GIT, Vasodilation via
Bladder release of N.O.
Blood vessels
endothelium
Nicotinic NM Ion channel, Neuromuscular End plate
influx of sodium junction depolarization
ion
 Cholinomimmetic drugs
Ach has no therapeutic use as it is
short acting (fast broken down by
acetyl ChE) and also has non-selective
action (acts on both M and N
receptors)
Drugs can be Direct acting or
Indirect acting.

Direct acting drugs directly bind with

M-receptors ; Indirect acting drugs
inhibit ChE enzyme, inhibit breakdown
of Ach & conc. Of Ach at synapses
which stimulates M-receptors &
 Cholinomimmetic drugs

CHOLINOMIMETIC (CHOLINERGIC)
DRUGS

Direct-acting Indirect-acting:
inhibit AchE
Stimulate Muscarinic receptors
DUMBBELS Organophosphates
(Irrev inhibitors) Muscarinic
Carbamates (Rev Inhibition)
(Intermediate long-acting)
Alkaloids- Pilocarpine
Choline esters- *Methacholine, *carbachol
*Bethanechol Edrophonium (Short-acting)
 Direct acting drugs
1. Alkaloids pilocarpine, muscarine
2. Esters of Ach- carbachol, bethanechol
Pharmacological actions--
. Eye: Miosis (stimulation of M3 present in
constrictor pupillae muscle) and increased
lacrimation and spasm of accommodation.
. Oral cavity: increased salivation (M3)
. Respiratory system: Bronchoconstriction and
Endothelium derived relaxing factor and N
increased secretions (M3)
. CVS 4 primary effects- vasodilatation (thru
EDRF), decrease in HR, decrease in conduction
& dec. in FOC: all mediated thru M2 receptors.
. GIT- increased secretions & peristalsis results in
nausea, vomiting, diarrhea, cramps.(M3
receptors)
. Urinary tract contraction of detrusor &
relaxation of trigone& sphincter(M3)
 Direct acting drugs-
contd
Therapeutic Uses
1. Post-operative urinary retention and
paralytic ileus- bethanechol 2.5mg sc
2. Xerostomia- pilocarpine
3. Glaucoma- pilocarpine
Contraindications: Guess??

Mushroom poisoning:
Mushrooms contain muscarine that
causes excessive
M-receptor stimulation. Treated with
*atropine which
 Indirect acting drugs/
Cholinesterase inhibitors
AKA Anticholinesterases: Both M
and N receptor stimulation
Can be reversible inhibitors or
Irreversible inhibitors ( what is the
difference??).
Reversible ChE inhibitors can be
alkaloids eg physostigmine or
carbamates eg neostigmine,
pyridostigmine, edrophonium
(ultrashort acting:8-10mins)
 Cholinesterase inhibitors

contd
Pharmacological actions similar to direct
acting( M-receptor stimulation) +with
additional nicotinic actions( Skeletal
muscle contraction followed by paralysis
in high dose).
Differences between drugs---

physostigmine- tertiary ammonium comp-

lipid soluble, enters CNS.
Neo/pyridostigmine -quaternary-
ammonium comp, water soluble.& have
additional direct action on NMJ
Uses--- postoperative paralytic ileus &
urinary retention, Glaucoma, Myaesthenia
Myaesthenia
gravis
Autoimmune disease due to antibodies
against nicotinic receptor at
neuromuscular junction characterized by
weakness & easy fatigability of skeletal
muscle.
Muscles involved: eyes and eyelids
(diplopia, ptosis)chewing, swallowing,
speaking, and breathing
Diagnosis
-Edrophonium test: by injecting 2-10mg iv
result
in increased muscle strength.
 Treatment of
Myaesthenia Gravis

Neostigmine,pyridostigmine,ambenoniu
m
Immunosuppressants eg
corticosteroids, cyclosporin
Thymectomy
Plasmapheresis
 A myesthenic patient receiving ChE
inhibitors develops severe weakness of
muscles- may be due to less of drugs
i.e. myesthenic crisis ( insufficient
therapy) or even high dose of drugs i.e.
cholinergic crisis ( excessive therapy).

How to differentiate??

The "edrophonium test" is infrequently performed to identify MG; its

Role of Edrophonium test??
application is limited to the situation when other investigations do not yield
a conclusive diagnosis. This test requires the intravenous administration of
edrophonium chloride (Tensilon, Reversol) or neostigmine (Prostigmin),
drugs that block the breakdown of acetylcholine by cholinesterase and
temporarily increases the levels of acetylcholine at the
neuromuscular junction. In people with myasthenia gravis involving the eye
Before prescribing bethanechol, you
question the patient to determine
the presence of which of the
following concurrent conditions
which might be contraindications?
A. Glaucoma

B. Nocturnal Enuresis

C. Mania

D. Epilepsy

E. Hypertension
 Which one of the following receptors
mediates the effects of pliocarpine
on smooth muscles of bronchi?
M1
M2
M3
M4
M5
 The calabar plant is native to Africa.
When ingested, its beans produce effect
similar to indirect acting cholinomimmetic
drug entering the CNS. Which of the
following drugs is most like the active
ingredient of calabar seeds?
Neostigmine
Physostigmine
Edrophonium
pilocarpine
A known patient of myasthenia gravis, who is
taking tab pyridostigmine 30 mg four times daily
orally, is brought to the emergency with severe
weakness of skeletal muscles and difficulty in
breathing. The doctor on duty performs
Edrophonium test and based on the results he
decides to increase the dose of pyridostigmine to
60mg four times a day.
A. The patient is suffering from
B. Cholinergic crisis

C. Myasthenic crisis

D. Adrenergic crisis
E. Glucose-6- phosphate dehydrogenase deficiency
F. Liver transglucosylase deficiency

 Mr G has been diagnosed with MG. you

are considering therapy with neostigmine
or pyridostigmine. These drugs may cause
which one of the following effects?
Bronchodilation
Cycloplegia
Diarrhea
Reduced gastric secretion
Irreversible inhibition of
acetylcholinesterase
 A 30-year-old woman undergoes abdominal
surgery. She develops paralytic ileus following
surgery. Mild cholinomimmetic stimulation with
bethanechol or neostigmine is often effective in
relieving paralytic ileus. Bethanechol and
neostigmine has significantly different effect on
which of the following?
Gastric secretion
Salivary glands
Sweat glands
Neuromuscular junction
Ureteral tone
 Cholinomimmetic drugs:
Must know
Parasympathomimmetic/Cholinergic drugs:
2 main categories- Direct acting drugs and
cholinesterase inhibitors (aka Indirect
acting).
Direct acting drugs: Pilocarpine,
Bethanechol, carbachol
Pilocarpine : used in glaucoma, Xerostomia
(dry mouth due to lack of saliva) following irradiation/
Sjoogrens syndrome, low dose paradoxical
rise in BP
Bethanechol: more resistant to hydrolysis,
selective muscarinic action, more selective
effect in GIT and urinary tract. Used for PO
paralytic ileus, PO urinary retention, Given
 Cholinomimmetic drugs: Must
know
Cholinesterase inhibitors can be reversible and
Irreversible Inhibitors of ChE.
Reversible inhibitors are alkaloids (Physostigmine- a
tertiary ammonium compound) and Carbamates:
Neostigmine, Pyridostigmine, Edrophonium)
Neostigmine mainly used in Myasthenia Gravis.,
PO paralytic ileus, PO urinary retention.
Physostigmine: used in glaucoma, treatment of
Atropine poisoning
Edrophonium is short acting (8-10min) and used for
diagnosing MG and differentiate between
Myasthenic crisis and cholinergic crisis in a MG
patient receiving drugs.
Alzheimers disease: Centrally acting
acetylcholinesterase inhibitors eg. Tacrine,
donepezil, rivastigmine and galantamine: FDA
approved
Botulinum toxin: degrades synaptobrevin and thus
prevents synaptic vesicle fusion with axon terminal
Study this topic again within 24 Hrs
Thank You