The Cholinergic System and Cholinergic Drugs
CHOLINERGIC
SYSTEM
AND
CHOLINERGIC
DRUGS
Dr.
KHAN
IMU..BISHKEK
KYRGYZSTAN
Sympathetic
Vs
Parasympathetic
•
S
Y
M
P
A
T
H
E
T
I
C
F
i
g
h
t
o
r
F
l
i
g
h
t
•
I
n
c
r
e
a
s
e
B
P
&
H
R
,
g
l
u
c
o
s
e
,
p
e
r
f
u
s
i
o
n
t
o
s
k
e
l
e
t
a
l
m
u
s
c
l
e
s
,
M
y
d
r
i
a
s
i
s
,
B
r
o
n
c
h
o
d
i
l
a
t
a
t
i
o
n
•
P
A
R
A
S
Y
M
P
A
T
H
E
T
I
C
Rest
and
Digest
•
M
i
o
s
i
s
,
d
e
c
r
e
a
s
e
d
H
R
,
B
P
,
b
r
o
n
c
h
i
a
s
e
c
r
e
t
i
o
n
,
I
n
s
u
l
i
n
r
e
l
e
a
s
e
,
D
i
g
e
s
t
i
o
n
,
e
x
c
r
e
t
i
o
n
Sites
of
Cholinergic
Transmission
-
Summary
A
c
e
t
y
l
c
h
o
l
i
n
e
(
A
C
h
)
i
s
m
a
j
o
r
n
e
u
r
o
h
u
m
o
r
a
l
t
r
a
n
s
m
i
t
t
e
r
a
t
a
u
t
o
n
o
m
i
c
,
s
o
m
a
t
i
c
a
n
d
c
e
n
t
r
a
l
n
e
r
v
o
u
s
s
y
s
t
e
m
:
1.
All
preganglionic
sites
(Both
Parasympathetic
and
sympathetic)
2.
A
l
l
P
o
s
t
g
a
n
g
l
i
o
n
i
c
P
a
r
a
s
y
m
p
a
t
h
e
t
i
c
s
i
t
e
s
a
n
d
s
y
m
p
a
t
h
e
t
i
c
t
o
s
w
e
a
t
g
l
a
n
d
a
n
d
s
o
m
e
b
l
o
o
d
v
e
s
s
e
l
s
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
C
h
o
l
i
n
e
r
g
i
c
T
r
a
n
s
m
i
s
s
i
o
n
–
S
y
n
t
h
e
s
i
s
:
•
Cholinergic neurons contain large numbers of
small
membrane-bound
vesicles
(containing
ACh) concentrated near the
synaptic
portion of
the
cell
membrane
•
A
C
h
i
s
s
y
n
t
h
e
s
i
z
e
d
i
n
t
h
e
c
y
t
o
p
l
a
s
m
f
r
o
m
a
c
e
t
y
l
-
C
o
A
a
n
d
c
h
o
l
i
n
e
b
y
t
h
e
c
a
t
a
l
y
t
i
c
a
c
t
i
o
n
o
f
C
h
o
l
i
n
e
a
c
e
t
y
l
t
r
a
n
s
f
e
r
a
s
e
(
C
h
A
T
)
•
A
c
e
t
y
l
-
C
o
A
i
s
s
y
n
t
h
e
s
i
z
e
d
i
n
m
i
t
o
c
h
o
n
d
r
i
a
,
w
h
i
c
h
a
r
e
p
r
e
s
e
n
t
i
n
l
a
r
g
e
n
u
m
b
e
r
s
i
n
t
h
e
n
e
r
v
e
e
n
d
i
n
g
•
C
h
o
l
i
n
e
i
s
t
r
a
n
s
p
o
r
t
e
d
f
r
o
m
t
h
e
e
x
t
r
a
c
e
l
l
u
l
a
r
f
l
u
i
d
i
n
t
o
t
h
e
n
e
u
r
o
n
t
e
r
m
i
n
a
l
b
y
a
N
a
+
-
d
e
p
e
n
d
e
n
t
m
e
m
b
r
a
n
e
c
h
o
l
i
n
e
c
o
t
r
a
n
s
p
o
r
t
e
r
(
C
a
r
r
i
e
r
A
)
.
T
h
i
s
c
a
r
r
i
e
r
c
a
n
b
e
b
l
o
c
k
e
d
b
y
a
group of drugs called
hemicholiniums
T
h
e
a
c
t
i
o
n
o
f
t
h
e
c
h
o
l
i
n
e
t
r
a
n
s
p
o
r
t
e
r
i
s
t
h
e
r
a
t
e
-
l
i
m
i
t
i
n
g
s
t
e
p
i
n
A
C
h
s
y
n
t
h
e
s
i
s
C
h
o
l
i
n
e
r
g
i
c
T
r
a
n
s
m
i
s
s
i
o
n
–
R
e
l
e
a
s
e
:
•
S
y
n
t
h
e
s
i
z
e
d
,
A
C
h
i
s
t
r
a
n
s
p
o
r
t
e
d
f
r
o
m
t
h
e
c
y
t
o
p
l
a
s
m
i
n
t
o
t
h
e
v
e
s
i
c
l
e
s
b
y
a
n
a
n
t
i
p
o
r
t
e
r
t
h
a
t
r
e
m
o
v
e
s
p
r
o
t
o
n
s
(
c
a
r
r
i
e
r
B
)
.
T
h
i
s
t
r
a
n
s
p
o
r
t
e
r
c
a
n
b
e
b
l
o
c
k
e
d
b
y
v
e
s
a
m
i
c
o
l
•
Release
is
dependent on extracellular
Ca
2+
•
and occurs
when
an action potential reaches the
terminal and
triggers
sufficient influx of
Ca
2+
ions
•
T
h
e
i
n
c
r
e
a
s
e
d
C
a
2
+
c
o
n
c
e
n
t
r
a
t
i
o
n
"
d
e
s
t
a
b
i
l
i
z
e
s
"
t
h
e
s
t
o
r
a
g
e
v
e
s
i
c
l
e
s
b
y
i
n
t
e
r
a
c
t
i
n
g
w
i
t
h
s
p
e
c
i
a
l
p
r
o
t
e
i
n
s
a
s
s
o
c
i
a
t
e
d
w
i
t
h
t
h
e
v
e
s
i
c
u
l
a
r
m
e
m
b
r
a
n
e
(
V
A
M
P
s
a
n
d
S
N
A
P
-
s
y
n
a
p
t
o
s
o
m
e
a
s
s
o
c
i
a
t
e
d
p
r
o
t
e
i
n
)
Fusion of the vesicular membranes with the
terminal membrane results
in
exocytotic
expulsion
of ACh into the
synaptic
cleft
•
T
h
e
A
C
h
v
e
s
i
c
l
e
r
e
l
e
a
s
e
p
r
o
c
e
s
s
i
s
b
l
o
c
k
e
d
b
y
b
o
t
u
l
i
n
u
m
t
o
x
i
n
t
h
r
o
u
g
h
t
h
e
e
n
z
y
m
a
t
i
c
r
e
m
o
v
a
l
o
f
t
w
o
a
m
i
n
o
a
c
i
d
s
f
r
o
m
o
n
e
o
r
m
o
r
e
o
f
t
h
e
f
u
s
i
o
n
p
r
o
t
e
i
n
s
.
B
l
a
c
k
w
i
d
o
w
s
p
i
d
e
r
?
?
Cholinergic Transmission:
Destruction
•
After release
-
ACh molecules
may
bind to
and activate an ACh receptor
(cholinoceptor)
•
E
v
e
n
t
u
a
l
l
y
(
a
n
d
u
s
u
a
l
l
y
v
e
r
y
r
a
p
i
d
l
y
)
,
a
l
l
o
f
t
h
e
A
C
h
r
e
l
e
a
s
e
d
w
i
l
l
d
i
f
f
u
s
e
w
i
t
h
i
n
r
a
n
g
e
o
f
a
n
a
c
e
t
y
l
c
h
o
l
i
n
e
s
t
e
r
a
s
e
(
A
C
h
E
)
m
o
l
e
c
u
l
e
•
A
C
h
E
v
e
r
y
e
f
f
i
c
i
e
n
t
l
y
s
p
l
i
t
s
A
C
h
i
n
t
o
c
h
o
l
i
n
e
a
n
d
a
c
e
t
a
t
e
,
n
e
i
t
h
e
r
o
f
w
h
i
c
h
h
a
s
s
i
g
n
i
f
i
c
a
n
t
t
r
a
n
s
m
i
t
t
e
r
e
f
f
e
c
t
,
a
n
d
t
h
e
r
e
b
y
t
e
r
m
i
n
a
t
e
s
t
h
e
a
c
t
i
o
n
o
f
t
h
e
t
r
a
n
s
m
i
t
t
e
r
.
•
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
s
p
e
c
i
f
i
c
i
t
y
f
o
r
A
C
h
,
b
u
t
y
r
y
l
c
h
o
l
i
n
e
s
t
e
r
a
s
e
[
p
s
e
u
d
o
c
h
o
l
i
n
e
s
t
e
r
a
s
e
]
,
i
s
f
o
u
n
d
i
n
b
l
o
o
d
p
l
a
s
m
a
,
l
i
v
e
r
,
g
l
i
a
l
,
a
n
d
m
a
n
y
o
t
h
e
r
t
i
s
s
u
e
s
True
Vs
Pseudo
AChE
Distribution
True
AChE
All
cholinergic sites,
RBCs,
gray
matter
Pseudo
AChE
Plasma,
liver,
Intestine
and white
matter
Action
on:
Acetycholine
M
e
t
h
a
cho
l
i
ne
Function
Very
Fast
Slower
Termination
of
Ach
actio
I
nh
i
b
i
ti
on
More sensitive to
Physostigmine
Slow
Not
hydrolyzed
Hydrolysis
of Ingested
Esters
More sensitive to
Or
g
anop
h
o
s
pha
t
e
s
Cholinergic
receptors
-
2
types
•
M
u
s
c
a
r
i
n
i
c
(
M
)
a
n
d
N
i
c
o
t
i
n
i
c
(
N
)
:
Muscarinic
(
M)
-
GPCR
Nicotinic
(N)
–
ligand
gated
Muscarinic
Receptors
??
1
.
S
e
l
e
c
t
i
v
e
l
y
s
t
i
m
u
l
a
t
e
d
b
y
M
u
s
c
a
r
i
n
e
a
n
d
b
l
o
c
k
e
d
b
y
A
t
r
o
p
i
n
e
–
a
l
l
a
r
e
G
-
p
r
o
t
e
i
n
c
o
u
p
l
e
d
r
e
c
e
p
t
o
r
s
2
.
P
r
i
m
a
r
i
l
y
l
o
c
a
t
e
d
i
n
a
u
t
o
n
o
m
i
c
e
f
f
e
c
t
o
r
c
e
l
l
s
i
n
h
e
a
r
t
,
e
y
e
,
s
m
o
o
t
h
m
u
s
c
l
e
s
a
n
d
g
l
a
n
d
s
o
f
G
I
T
a
n
d
C
N
S
3.
Subsidiary
M
receptors
are
also
present
in
ganglia
for
modulation
–
long
lasting
late
EPSP
4.
A
u
t
o
r
e
c
e
p
t
o
r
s
(
M
t
y
p
e
)
a
r
e
p
r
e
s
e
n
t
i
n
p
o
s
t
g
a
n
g
l
i
o
n
i
c
p
r
e
j
u
n
c
t
i
o
n
a
l
c
h
o
l
i
n
e
r
g
i
c
N
e
r
v
e
e
n
d
i
n
g
s
–
i
n
h
i
b
i
t
s
A
C
h
r
e
l
e
a
s
e
1.
a
l
s
o
i
n
a
d
r
e
n
e
r
g
i
c
n
e
r
v
e
t
e
r
m
i
n
a
l
s
(
i
n
h
i
b
i
t
s
N
A
r
e
l
e
a
s
e
)
l
e
a
d
i
n
g
t
o
v
a
s
o
d
i
l
a
t
a
t
i
o
n
w
h
e
n
A
C
h
i
s
i
n
j
e
c
t
e
d
5.
B
l
o
o
d
v
e
s
s
e
l
s
:
A
l
l
b
l
o
o
d
v
e
s
s
e
l
s
h
a
v
e
m
u
s
c
a
r
n
i
n
c
r
e
c
e
p
t
o
r
s
a
l
t
h
o
u
g
h
n
o
c
h
o
l
i
n
e
r
g
i
c
i
n
n
e
r
v
a
t
i
o
n
s
–
E
D
R
F
–
S
M
r
e
l
a
x
a
t
i
o
n
-
V
a
s
o
d
i
l
a
t
a
t
i
o
n
Muscarinic
Receptors
-
Subtypes
•
P
h
a
r
m
a
c
o
l
o
g
i
c
a
l
l
y
-
M
1
,
M
2
,
M
3
,
M
4
a
n
d
M
5
•
M
4
and
M
5
are
present
in
certain
areas
of
Brain
and
regulate
other
neurotransmitters
•
M
1
,
M
3
and
M
5
fall
in
one
class,
while
M
2
and
M
4
in
another
class
•
However
-
M
1
,
M
2
and
M
3
are
major
ones
and
present
in
effector
cells
and
prejunctional
nerve
endings
in
Peripheral
organs
and
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
•
M
1
:
A
u
t
o
n
o
m
i
c
g
a
n
g
l
i
o
n
C
e
l
l
s
,
G
a
s
t
r
i
c
g
l
a
n
d
s
a
n
d
C
e
n
t
r
a
l
N
e
u
r
o
n
s
(
c
o
r
t
e
x
,
h
i
p
p
o
c
a
m
p
u
s
,
c
o
r
p
u
s
s
t
r
i
a
t
u
m
)
•
Physiological
Role:
Mediation
of
Gastric
acid
secretion
and
relaxation
of
LES
(vagal)
•
Learning,
memory
and
motor
functions
•
M
2
:
C
a
r
d
i
a
c
M
u
s
c
a
r
i
n
i
c
r
e
c
e
p
t
o
r
s
•
•
•
Mediate
vagal
bradycardia
Also
auto
receptors
in
cholinergic
nerve
endings
CNS
–
Tremor,
analgesia
•
M
3
:
V
i
s
c
e
r
a
l
s
m
o
o
t
h
m
u
s
c
l
e
s
,
g
l
a
n
d
s
a
n
d
v
a
s
c
u
l
a
r
e
n
d
o
t
h
e
l
i
u
m
.
A
l
s
o
I
r
i
s
a
n
d
C
i
l
i
a
r
y
m
u
s
c
l
e
s
Muscarinic
Receptor
Subtypes
Location
M
2
Heart
and
CNS
Functions
M
1
Autonomic
ganglia,
Gastric glands and
CNS
Depolarization
(late
EPSP) &
Histamine
release
& acid
secretion, relaxation of
LES, CNS
learning and
motor
functions
Less impulse generation,
less velocity of
conduction, decreased
contractility, less
ACh
release
(auto)
Agonists
A
n
t
a
g
o
n
i
s
t
s
O
x
o
t
r
e
m
o
r
i
ne
Pirenzepine
M
3
SMs
of Viscera, Eye,
exocrine glands
and
endothelium
Visceral
SM
contraction,
glandular
secretions,
Constriction of
pupil, contraction of
Cilliary muscle
and
vasodilatation
(EDRF
-
B
N
e
t
O
h
)
a
n
e
ch
o
l
Darifenacin
Transducer
IP3/DAG
and
PLA2
increase
–
Ca++
and
PG
Methacholine
Methoctramine
&
Triptramine
K+
channel opening and
decresed
cAMP
IP3/DAG
and
increase
–
Ca++ and
PG
synthesis
Acetylcholine
(cholinergic
receptors)
–
M
u
s
c
a
r
i
n
i
c
R
e
c
e
p
t
o
r
s
M1
G
an
g
l
i
a
,
gastric
gland
and
CNS
M2
Heart
Cho
l
i
n
e
r
g
i
c
Nerves
M3
Visceral
Smooth
Muscles,
Iris
and
cilliary
muscle
Selectively stimulated by
Muscarine
and blocked by
Atropine
Nicotinic
(N)
Receptors
•
•
•
N
i
c
o
t
i
n
i
c
r
e
c
e
p
t
o
r
s
:
n
i
c
o
t
i
n
i
c
a
c
t
i
o
n
s
o
f
A
C
h
a
r
e
t
h
o
s
e
t
h
a
t
c
a
n
b
e
r
e
p
r
o
d
u
c
e
d
b
y
t
h
e
i
n
j
e
c
t
i
o
n
o
f
N
i
c
o
t
i
n
e
(
N
i
c
o
t
i
a
n
a
t
a
b
a
c
u
m
)
–
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
TWO
Types:
N
M
and
N
N
–
based
on
location
Question
?
•
A
person
is
having
severe
cholinergic
symptoms
like
vomiting,
salivation
and
lacrimation
etc.
after
accidental
consumption
of
poisonous
mushroom.
What
subtype
of
receptor
is
involved
in
the
mediation
of
such
reaction
…..
????
•
A
n
s
w
e
r
:
M
3
Question…?
•
What
side
effects
might
you
expect
to
see
in
a
patient
taking
a
cholinergic
drug?
•
H
i
n
t
…
•
=
“Colon-Urgent”
….Cholinergic
C
h
o
l
i
n
e
r
g
i
c
D
r
u
g
s
o
r
C
h
o
l
i
n
o
m
i
m
e
t
i
c
o
r
P
a
r
a
s
y
m
p
a
t
h
o
m
i
m
e
t
i
c
s
D
r
u
g
s
p
r
o
d
u
c
i
n
g
a
c
t
i
o
n
s
s
i
m
i
l
a
r
t
o
A
c
e
t
y
l
c
h
o
l
i
n
e
b
y
–
1
)
i
n
t
e
r
a
c
t
i
n
g
w
i
t
h
C
h
o
l
i
n
e
r
g
i
c
r
e
c
e
p
t
o
r
s
o
r
2
)
i
n
c
r
e
a
s
i
n
g
a
v
a
i
l
a
b
i
l
i
t
y
o
f
A
c
e
t
y
l
c
h
o
l
i
n
e
a
t
t
h
e
s
e
s
i
t
e
s
C
l
a
s
s
i
f
i
c
t
i
o
n
-
D
i
r
e
c
t
-
a
c
t
i
n
g
(
r
e
c
e
p
t
o
r
a
g
o
n
i
s
t
s
)
M
a
g
o
n
i
s
t
:
>
>
.
.
N
a
g
o
n
i
s
t
M
i
x
e
d
a
c
t
i
n
g
M
u
s
c
a
r
i
n
,
n
i
c
o
t
i
n
e
m
e
t
h
a
c
h
o
l
i
n
e
b
e
t
h
o
n
i
c
h
o
l
a
c
e
t
y
l
c
h
o
l
i
n
e
P
i
l
o
c
a
r
p
i
n
c
a
r
b
a
c
h
o
l
•
•
C
h
o
l
i
n
e
r
g
i
c
D
r
u
g
s
–
I
n
d
i
r
e
c
t
a
c
t
i
n
g
R
e
v
e
r
s
i
b
l
e
N
a
t
u
r
a
l
:
P
h
y
s
o
s
t
i
g
m
i
n
e
S
y
n
t
h
e
t
i
c
:
N
e
o
s
t
i
g
m
i
n
e
,
P
y
r
i
d
o
s
t
i
g
m
i
n
e
,
,
R
i
v
a
s
t
i
g
m
i
n
e
,
D
o
n
e
p
e
z
i
l
,
,
E
d
r
o
p
h
o
n
i
u
m
,
,
I
r
r
e
v
e
r
s
i
b
l
e
a
n
t
i
c
h
o
l
i
n
e
s
t
e
r
a
s
e
s
:
O
r
g
a
n
o
p
h
o
s
p
h
o
r
o
u
s
C
o
m
p
o
u
n
d
s
(
O
P
C
)
–
D
i
i
s
o
p
r
o
p
y
l
f
l
u
o
r
o
p
h
o
s
p
h
a
t
e
(
D
F
P
)
,
E
c
o
t
h
i
o
p
h
a
t
e
,
P
a
r
a
t
h
i
o
n
,
m
a
l
a
t
h
i
o
n
,
d
i
a
z
i
n
o
n
(
i
n
s
e
c
t
i
c
i
d
e
s
a
n
d
p
e
s
t
i
c
i
d
e
s
)
T
a
b
u
n
,
s
a
r
i
n
,
s
o
m
a
n
(
n
e
r
v
e
g
a
s
e
s
i
n
w
a
r
)
Pilocarpine
•
A
l
k
a
l
o
i
d
f
r
o
m
l
e
a
v
e
s
o
f
J
a
b
o
r
a
n
d
i
(
P
i
l
o
c
a
r
p
u
s
m
i
c
r
o
p
h
y
l
l
u
s
)
•
Prominent
muscarinic
actions
•
Profuse
salivation,
lacrimation,
sweating
•
Dilates
blood
vessels,
causes
hypotension
•
H
i
g
h
d
o
s
e
s
:
R
i
s
e
i
n
B
P
a
n
d
t
a
c
h
y
c
a
r
d
i
a
(
g
a
n
g
l
i
o
n
i
c
a
c
t
i
o
n
)
•
O
n
E
y
e
s
:
p
r
o
d
u
c
e
s
m
i
o
s
i
s
a
n
d
s
p
a
s
m
o
f
a
c
c
o
m
m
o
d
a
t
i
o
n
•
Lowers
intraocular
pressure
(IOP)
in
Glaucoma
when
applied
as
eye
drops
•
Too
toxic
for
systemic
use
–
CNS
toxicity
•
Diaphoretic
(?),
xerostomia
and
Sjögren’s
syndrome
Pilocarpine
–
contd.
•
•
1.
Used
as
eye
drops
in
treatment
of
n
a
r
r
o
w
a
n
g
l
e
g
l
a
u
c
o
m
a
t
o
r
e
d
u
c
e
I
O
P
2.
To
reverse
mydriatic
effect
of
atropine
3.
To
break
adhesion
between
iris
and
cornea/lens
alternated
with
mydriatic
Pilocarpine
nitrate
eye
drops
(
1
to
4%
)
A
t
r
o
p
i
n
e
u
s
e
d
a
s
a
n
t
i
d
o
t
e
i
n
a
c
u
t
e
p
i
l
o
c
a
r
p
i
n
e
p
o
i
s
o
n
i
n
g
(
1
-
2
m
g
I
V
8
h
r
l
y
)
IMU ,,,dr khan
Pilocarpine
in
Glaucoma
•
•
•
Constriction of circular muscle
of
Iris
Contraction
of
ciliary
muscle
Spasm of accommodation
–
fixed
at
near
vision
M
us
c
ar
i
n
e
•
A
l
k
a
l
o
i
d
f
r
o
m
m
u
s
h
r
o
o
m
A
m
a
n
i
t
a
m
u
s
c
a
r
i
a
•
Only
muscarinic
actions
•
No
clinical
use
•
M
u
s
h
r
o
o
m
p
o
i
s
o
n
i
n
g
d
u
e
t
o
i
n
g
e
s
t
i
o
n
o
f
p
o
i
s
o
n
o
u
s
m
u
s
h
r
o
o
m
1
.
E
a
r
l
y
o
n
s
e
t
m
u
s
h
r
o
o
m
p
o
i
s
o
n
i
n
g
(
M
u
s
c
a
r
i
n
e
t
y
p
e
)
i
n
o
c
y
b
e
a
n
d
c
l
i
t
o
c
y
b
e
2
.
L
a
t
e
o
n
s
e
t
m
u
s
h
r
o
o
m
p
o
i
s
o
n
i
n
g
a
m
i
n
a
t
a
p
h
a
l
l
i
d
e
s
3
.
H
a
l
l
u
c
i
n
o
g
e
n
i
c
t
y
p
e
a
m
i
n
a
t
a
m
u
s
c
i
r
a
Mushroom
Poisoning
•
E
a
r
l
y
O
n
s
e
t
M
u
s
h
r
o
o
m
P
o
i
s
o
n
i
n
g
:
O
c
c
u
r
s
½
t
o
1
h
o
u
r
–
S
y
m
p
t
o
m
s
a
r
e
c
h
a
r
a
c
t
e
r
i
s
t
i
c
o
f
M
u
s
c
a
r
i
n
i
c
a
c
t
i
o
n
s
–
I
n
o
c
y
b
e
o
r
C
l
i
t
o
c
y
b
e
–
s
e
v
e
r
e
c
h
o
l
i
n
e
r
g
i
c
s
y
m
p
t
o
m
s
l
i
k
e
v
o
m
i
t
i
n
g
,
s
a
l
i
v
a
t
i
o
n
,
l
a
c
r
i
m
a
t
i
o
n
,
h
e
a
d
a
c
h
e
,
b
r
o
n
c
h
o
s
p
a
s
m
,
d
i
a
r
r
h
o
e
a
b
r
a
d
y
c
a
r
d
i
a
,
d
y
s
p
n
o
e
a
,
h
y
p
o
t
e
n
s
i
o
n
,
w
e
a
k
n
e
s
s
,
c
a
r
d
i
o
v
a
s
c
u
l
a
r
c
o
l
l
a
p
s
e
,
c
o
n
v
u
l
s
i
o
n
s
a
n
d
c
o
m
a
–
A
n
t
i
d
o
t
e
i
s
A
t
r
o
p
i
n
e
s
u
l
p
h
a
t
e
(
2
-
3
m
g
I
M
e
v
e
r
y
h
r
l
y
t
i
l
l
i
m
p
r
o
v
e
m
e
n
t
)
•
H
a
l
l
u
c
i
n
o
g
e
n
i
c
t
y
p
e
:
a
m
a
n
i
t
a
m
u
s
c
i
r
a
d
u
e
t
o
M
u
s
c
i
m
o
l
o
r
i
b
o
t
e
n
i
c
a
c
i
d
p
r
e
s
e
n
t
i
n
A
.
m
u
s
c
r
i
a
.
B
l
o
c
k
s
m
u
s
c
a
r
i
n
i
c
r
e
c
e
p
t
o
r
s
i
n
b
r
a
i
n
a
n
d
a
c
t
i
v
a
t
e
a
m
i
n
o
a
c
i
d
r
e
c
e
p
t
o
r
s
.
N
o
s
p
e
c
i
f
i
c
t
r
e
a
t
m
e
n
t
–
A
t
r
o
p
i
n
e
c
o
n
t
r
a
i
n
d
i
c
a
t
e
d
.
Late
Onset
Mushroom
Poisoning
•
Occurs
within
6
-
15
hours
•
Amanita
phylloides
(deadly
nightcap),
Galerina–
due
to
peptide
toxins
–
Inhibit
RNA
and
protein
synthesis
•
Irritability,
restlessness,
nausea,
vomiting,
bloody
diarrhoea
ataxia,
hallucination,
d
e
l
i
r
i
u
m
,
s
e
d
a
t
i
o
n
,
d
r
o
w
s
i
n
e
s
s
a
n
d
s
l
e
e
p
–
K
i
d
n
e
y
,
l
i
v
e
r
a
n
d
G
I
T
m
u
c
o
s
a
l
d
a
m
a
g
e
•
Maintain
blood
pressure,
respiration
•
Inj.
Diazepam
5
mg
IM
•
A
t
r
o
p
i
n
e
c
o
n
t
r
a
i
n
d
i
c
a
t
e
d
a
s
i
t
m
a
y
c
a
u
s
e
c
o
n
v
u
l
s
i
o
n
s
a
n
d
d
e
a
t
h
-
p
e
n
i
c
i
l
l
i
n
,
t
h
i
o
c
t
i
c
a
c
i
d
a
n
d
s
i
l
i
b
i
n
i
n
(
a
n
t
i
d
o
t
e
?
)
•
Gastric
lavage
and
activated
charcoal
D
E
L
A
Y
E
D
O
N
S
E
T
T
y
p
e
(
m
o
r
e
t
h
a
n
2
4
H
o
u
r
s
)
–
N
e
p
h
r
o
t
o
x
i
c
s
y
n
d
r
o
m
e
s
AChEs
-
MOA
•
•
•
•
•
•
•
Normally
Acetylcholinesterase
(AchE)
hydrolyses
A
c
e
t
y
l
c
h
o
l
i
n
e
T
h
e
a
c
t
i
v
e
s
i
t
e
o
f
A
C
h
E
i
s
m
a
d
e
u
p
o
f
t
w
o
s
u
b
s
i
t
e
s
–
a
n
i
o
n
i
c
a
n
d
e
s
t
e
r
a
t
i
c
T
h
e
a
n
i
o
n
i
c
s
i
t
e
s
e
r
v
e
s
t
o
b
i
n
d
a
m
o
l
e
c
u
l
e
o
f
A
C
h
t
o
t
h
e
e
n
z
y
m
e
O
n
c
e
t
h
e
A
C
h
i
s
b
o
u
n
d
,
t
h
e
h
y
d
r
o
l
y
t
i
c
r
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a
c
t
i
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c
c
u
r
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t
a
s
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c
o
n
d
r
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g
i
o
n
o
f
t
h
e
a
c
t
i
v
e
s
i
t
e
c
a
l
l
e
d
t
h
e
e
s
t
e
r
a
t
i
c
s
u
b
s
i
t
e
T
h
e
A
C
h
E
i
t
s
e
l
f
g
e
t
s
a
c
e
t
y
l
a
t
e
d
a
t
s
e
r
i
n
e
s
i
t
e
Acetylated
enzyme reacts
+
water
=
acetic
acid
and
choline
C
h
o
l
i
n
e
-
i
m
m
e
d
i
a
t
e
l
y
t
a
k
e
n
u
p
a
g
a
i
n
b
y
t
h
e
h
i
g
h
a
f
f
i
n
i
t
y
c
h
o
l
i
n
e
u
p
t
a
k
e
s
y
s
t
e
m
p
r
e
s
y
n
a
p
t
i
c
m
e
m
b
r
a
n
e
G
l
u
t
a
m
a
t
e
a
n
d
h
i
s
t
i
d
i
n
e
T
r
y
p
t
o
p
h
a
n
AChEs
-
MOA
•
Anticholinesterases
also
react
with
the
enzyme
ChEs
in
similar
fashion
like
Acetylcholine
•
Carbamates
–
carbamylate
the
active
site
of
the
enzyme
•
Phosphates
–
Phosphorylate
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)
•
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
h
y
d
r
o
l
y
s
i
s
–
a
g
i
n
g
•
Edrophonium
and
tacrine
react
only
at
anionic
site
–
short
acting
while
Organophosphates
react
only
at
esteratic
site
Physostigmine
•
Alkaloid
from
dry
ripened
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)
•
Penetrates
cornea
readily
on
local
application
in
eye
-
Muscarinic
action
on
eye
causing
miosis
and
spasm
of
accommodation
on
local
application
•
Salivation,
lacrimation,
sweating
and
increased
tracheobronchial
secretions
•
Increased
heart
rate
&
hypotension
Physostigmine
-
uses
1.
Used
as
miotic
drops
to
decrease
IOP
in
Glaucoma
2.
To
antagonize
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
6.
Atropine
is
antidote
in
physostigmine
poisoning.
A
D
R
s
–
C
N
S
s
t
i
m
u
l
a
t
i
o
n
f
o
l
l
o
w
e
d
b
y
d
e
p
r
e
s
s
i
o
n
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
(N
M
)
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
Vs
Neostigmine
Source
C
he
m
i
s
tr
y
Physostigmine
Natural
Tertiary
amine
Oral
absorption
CNS action
Eye
E
f
f
ect
Uses
Dose
Duration
of
action
Good
P
r
e
s
ent
Penetrates
cornea
Ganglia
Miotic
0.5-1
mg
oral/parenteral
0.1-1% eye
drop
4-6
Hrs
N
eo
s
t
i
gm
i
n
e
Synthetic
Quaternary
ammonium
compound
Poor
Absent
Poor penetration
Muscle
Mysthenia
gravis
0.5-2.5 mg
IM/SC
15-30
mg
orally
3-4
Hrs
Other
Drugs
•
Pyridostigmine:
Same
as
Neostigmine
-
less
potent
but
longer
acting
•
Edrophonium:
Same
as
Neostigmine
–
shorter
duration
of
action
(1-
-
30
minutes)
–
diagnostic
use
in
MG
•
Tacrine:
Acts
like
edrophonium,
lipid
soluble,
crosses
BBB
–
increases
brain
ACh
–
symptomatic
improvement
in
Alzheimer`s
disease
(AD)
•
Rivastigmine,
donepezil,
galantamine
–
all
used
in
AD
Myasthenia
gravis
(Myo
+
asthenia)
•
Autoimmune
disorder
affecting
1
in
10,000
population
(?) –
reduction
in
number
of
N
M
receptors
•
Symptoms:
Weakness
and
easy
fatigability
–
ptosis
to
diaphragmatic
paralysis
•
C
a
u
s
e
s
:
D
e
v
e
l
o
p
m
e
n
t
o
f
a
n
t
i
b
o
d
i
e
s
directed
to
Nicotinic
receptors
in
muscle
end
plate
–
reduction
in
number
by
1/3rd
of
N
M
receptors
•
Structural
damage
to
N
M
junction
Myasthenia
gravis
–
other
drugs
•
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)
–
immunosuppression
•
•
Inhibits
production
of
NR
antibodies
and
may
increase
synthesis
or
NRs
Azathioprin
and
cyclosporin
also
Plasmapheresis
Myasthenic
crisis
•
A
c
u
t
e
w
e
a
k
n
e
s
s
a
n
d
r
e
s
p
i
r
a
t
o
r
y
p
a
r
a
l
y
s
i
s
–
Tracheobronchial
intubation
and
mechnical
ventilation
–
Methylprednisolone
IV
with
withdrawal
of
AChE
–
Gradual
reintroduction
of
AChE
–
Thymectomy
•
T
h
e
p
r
o
b
l
e
m
–
o
v
e
r
t
r
e
a
t
m
e
n
t
V
s
a
c
t
u
a
l
d
i
s
e
a
s
e
(
o
p
p
o
s
i
t
e
t
r
e
a
t
m
e
n
t
s
)
–
Diagnosis
by
various
tests
–
Tensilon
Test
–
Injection
of
Edrophonium
–
2
mg
(observe)
–
after
half
a
minute
8
mg
(observe)
•
•
In
MG
–
symptoms
will
improve
In
overtreatment
–
symptoms
worsen
Overall
Therapeutic
Uses
–
cholinergic
drugs
–
Bethanechol,
Carbachol,
Distigmine.
To
lower
IOP
in
chronic
simple
glaucoma:
–
P
i
l
o
c
a
r
p
i
n
e
,
P
h
y
s
o
s
t
i
g
m
i
n
e
1.
M
y
a
s
t
h
e
n
i
a
g
r
a
v
i
s
:
E
d
r
o
p
h
o
n
i
u
m
t
o
d
i
a
g
n
o
s
e
a
n
d
N
e
o
s
t
i
g
m
i
n
e
,
P
y
r
i
d
o
s
t
i
g
m
i
n
e
&
D
i
s
t
i
g
m
i
n
e
t
o
t
r
e
a
t
2.
To
stimulate
bladder
&
bowel
after
surgery:
1.
1.
To
improve
cognitive
function
in
Alzheimer’s
disease:
Rivastigmine,
Gallantamine,
Donepezil.
2.
P
h
y
s
o
s
t
i
g
m
i
n
e
i
n
B
e
l
l
a
d
o
n
n
a
p
o
i
s
o
n
i
n
g
3.
Cobra
Bite
Pharmacotherapy
of
Organophosphate
Poisoning
•
•
C
o
m
p
l
e
x
e
f
f
e
c
t
s
–
M
u
s
c
a
r
i
n
i
c
,
N
i
c
o
t
i
n
i
c
a
n
d
C
N
S
S
i
g
n
s
a
n
d
s
y
m
p
t
o
m
s
:
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.
Irritability,
disorientation,
ataxia,
tremor,
convulsins
and
coma
•
Treatment
ABC
Airway amaintance
Breathing Give oxygen
Circulation :”two wide bore calunas then give normal saline
Pass NG tube
Pass foleys catheter
ANTIDOT PRALIDOXIME
Atropine – 2mg IV every 10 minutes till dryness of mouth
Mukhtiar khan IMU
KYRGYSTAN
/Thank
you
The cholinergic system plays a crucial role in the transmission of signals within the nervous system. Acetylcholine (ACh) is the primary neurotransmitter involved in cholinergic transmission, impacting various physiological functions. Cholinergic neurons synthesize ACh through a complex process involving acetyl-CoA and choline. The release of ACh into the synaptic cleft is regulated by intricate mechanisms, including vesicle fusion and calcium influx. Understanding cholinergic transmission is essential for comprehending the effects of cholinergic drugs and their implications in medical practice.
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CHOLINERGIC SYSTEM AND CHOLINERGIC DRUGS Dr. KHAN IMU..BISHKEK KYRGYZSTAN
Sympathetic VsParasympathetic SYMPATHETIC Fight orFlight Increase BP & HR, glucose,perfusion to skeletal muscles, Mydriasis,Bronchodilatation PARASYMPATHETIC Rest and Digest Miosis, decreased HR, BP , bronchiasecretion, Insulin release, Digestion,excretion
SitesofCholinergicTransmission-Summary Acetylcholine (ACh) is major neurohumoral transmitter atautonomic, somatic and central nervoussystem: 1. All preganglionic sites (Both Parasympatheticand sympathetic) 2. All PostganglionicParasympatheticsitesandsympathetictosweatglandandsome bloodvessels 3. SkeletalMuscles 4. CNS:Cortex,Basalganglia,spinalchordandothers ParasympatheticStimulation Acetylcholine(Ach)releaseatneuroeffectorjunction- biologicaleffects Sympathetic stimulation Noradrenaline (NA) at neuroeffector junction - biologicaleffects
Cholinergic Transmission Synthesis: 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 Na+- dependent membrane choline cotransporter (Carrier A). This carrier can be blocked by a group of drugs called hemicholiniums T h e action of the choline transporter is the rate-limiting step in ACh synthesis
Cholinergic Transmission Release: 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 and SNAP- synaptosome associated protein) 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??
Cholinergic Transmission: Destruction 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
True Vs PseudoAChE True AChE Pseudo AChE All cholinergic sites, RBCs, gray matter Plasma, liver, Intestine and white matter Distribution Action on: Acetycholine Methacholine Function Very Fast Slower Slow Not hydrolyzed Hydrolysis of Ingested Esters More sensitive to Organophosphates Termination of Ach actio Inhibition More sensitive to Physostigmine
Cholinergicreceptors-2types Muscarinic (M) and Nicotinic(N): Nicotinic (N) ligand gated Muscarinic (M) - GPCR
Muscarinic Receptors?? 1. Selectively stimulated by Muscarine and blocked by Atropine all areG- protein coupledreceptors 2. Primarily locatedinautonomiceffector cellsin heart,eye,smoothmuscles andglandsofGITandCNS 3. SubsidiaryMreceptorsarealsopresentingangliafor modulation long lasting lateEPSP 4. Autoreceptors(Mtype) arepresentinpostganglionic prejunctional cholinergicNerveendings inhibitsAChrelease 1.alsoin adrenergicnerveterminals(inhibitsNArelease)leading to vasodilatation when ACh isinjected 5. Bloodvessels:Allbloodvesselshavemuscarnincreceptorsalthoughno cholinergicinnervations EDRF SMrelaxation-Vasodilatation
Muscarinic Receptors -Subtypes Pharmacologically- M1, M2, M3, M4andM5 M4andM5arepresentincertainareasof Brainandregulateother neurotransmitters M1,M3andM5fallinoneclass,whileM2andM4inanotherclass However- M1,M2andM3aremajoronesandpresentineffector cellsand prejunctionalnerveendingsinPeripheralorgansandCNS Allsubtypeshavelittle agonistselectivitybut selectiveantagonistselectivity Mostorgansusuallyhavemorethanonesubtypebut onesubtypepredominatesin atissue
Muscarinic Receptors -Location M1:AutonomicganglionCells,GastricglandsandCentralNeurons(cortex, hippocampus, corpusstriatum) PhysiologicalRole:Mediation ofGastricacidsecretion andrelaxationof LES(vagal) Learning,memoryandmotor functions M2:Cardiac Muscarinicreceptors M3:Visceralsmoothmuscles,glandsandvascularendothelium.AlsoIrisandCiliary muscles Mediate vagalbradycardia Alsoautoreceptorsincholinergic nerveendings CNS Tremor,analgesia
Muscarinic ReceptorSubtypes M1 M2 M3 SMs of Viscera, Eye, exocrine glands and endothelium Visceral SM contraction, glandular secretions, Constriction of pupil, contraction of Cilliary muscle and vasodilatation (EDRF -BNetOh)anechol Darifenacin Autonomic ganglia, Gastric glands and CNS Depolarization (late EPSP) & Histamine release & acid secretion, relaxation of LES, CNS learning and motor functions Location Heart and CNS Less impulse generation, less velocity of conduction, decreased contractility, less ACh release (auto) Functions Agonists Antagonists Oxotremorine Pirenzepine Methacholine Methoctramine & Triptramine K+ channel opening and decresed cAMP IP3/DAG and increase Ca++ and PG synthesis Transducer IP3/DAG and PLA2 increase Ca++ and PG
Acetylcholine (cholinergicreceptors) MuscarinicReceptors Selectively stimulated by Muscarine and blocked by Atropine M1 M2 M3 Ganglia, gastric gland and CNS Visceral Smooth Muscles, Iris and cilliary muscle Heart Cholinergic Nerves
Nicotinic (N)Receptors Nicotinicreceptors:nicotinicactionsofACharethosethat can be reproduced by the injection of Nicotine (Nicotiana tabacum) Canbeblockedbytubocurarineandhexamethonium Ligand-gated ionchannels activation resultsinarapidincreaseincellularpermeability to Na+andCa++resulting- depolarizationandinitiation ofactionpotential TWOTypes:NMandNN basedonlocation
Question? Apersonishavingseverecholinergic symptomslike vomiting, salivationand lacrimation etc. after accidental consumption of poisonous mushroom. Whatsubtypeof receptorisinvolvedinthemediationof suchreaction ..???? Answer:M3
Question? Whatsideeffectsmight youexpectto seeinapatienttaking acholinergic drug? Hint = Colon-Urgent .Cholinergic
Cholinergic Drugs or Cholinomimeticor Parasympathomimetics DrugsproducingactionssimilartoAcetylcholineby 1)interacting with Cholinergic receptors or 2) increasing availability of Acetylcholine at thesesites
Classifiction - Direct-acting (receptoragonists) M agonist :>>.. N agonist Mixed acting Muscarin, nicotine methacholine bethonichol Pilocarpin acetylcholine carbachol
Cholinergic Drugs Indirectacting Reversible Natural:Physostigmine Synthetic: Neostigmine, Pyridostigmine,, Rivastigmine, Donepezil,, Edrophonium,, Irreversibleanticholinesterases: Organophosphorous Compounds (OPC) Diisopropyl fluorophosphate (DFP), Ecothiophate, Parathion, malathion, diazinon (insecticides and pesticides) Tabun, sarin, soman (nerve gases inwar)
Pilocarpine Alkaloidfromleavesof Jaborandi(Pilocarpusmicrophyllus) Prominent muscarinicactions Profuse salivation, lacrimation,sweating Dilates blood vessels, causeshypotension Highdoses:RiseinBPandtachycardia(ganglionicaction) OnEyes:producesmiosisandspasmof accommodation Lowersintraocularpressure(IOP)inGlaucomawhenappliedaseyedrops Tootoxic for systemicuse CNStoxicity Diaphoretic (?), xerostomiaand Sj gren s syndrome
Pilocarpine contd. 1. Usedaseyedropsintreatmentof narrow angle glaucoma toreduce IOP 2. Toreversemydriaticeffectofatropine 3. To break adhesion between iris and cornea/lens alternated withmydriatic Pilocarpinenitrateeyedrops(1to 4%) Atropine used as antidote in acute pilocarpinepoisoning(1-2mgIV8hrly)
Pilocarpine inGlaucoma Constriction of circular muscle of Iris Contraction of ciliary muscle Spasm of accommodation fixed at near vision
Muscarine Alkaloid frommushroom Amanita muscaria Only muscarinicactions No clinicaluse Mushroompoisoningdueto ingestionof poisonousmushroom 1.Early onset mushroom poisoning (Muscarinetype) inocybe and clitocybe 2.Late onset mushroom poisoning aminata phallides 3.Hallucinogenictype aminata muscira
MushroomPoisoning EarlyOnsetMushroomPoisoning:Occurs to1hour Symptomsarecharacteristicof Muscarinicactions Inocybe or Clitocybe severe cholinergic symptoms like vomiting, salivation, lacrimation, headache,bronchospasm,diarrhoeabradycardia,dyspnoea,hypotension, weakness,cardiovascularcollapse,convulsionsandcoma AntidoteisAtropinesulphate(2-3mgIMeveryhrlytill improvement) Hallucinogenictype:amanita muscira dueto Muscimolor ibotenic acid present in A. muscria. Blocks muscarinic receptors in brain and activate amino acid receptors. No specific treatment Atropine contraindicated.
Late OnsetMushroom Poisoning Occurswithin6- 15hours Amanitaphylloides(deadlynightcap),Galerina dueto peptidetoxins Inhibit RNA and proteinsynthesis Irritability, restlessness,nausea,vomiting,bloodydiarrhoeaataxia,hallucination, delirium,sedation,drowsinessandsleep Kidney,liverandGITmucosaldamage Maintain blood pressure,respiration Inj. Diazepam 5 mgIM Atropinecontraindicatedasit maycauseconvulsionsanddeath- penicillin, thioctic acid and silibinin(antidote?) Gastric lavage and activatedcharcoal DELAYEDONSETType (morethan24Hours) Nephrotoxicsyndromes
AChEs -MOA Normally Acetylcholinesterase (AchE)hydrolyses Acetylcholine TheactivesiteofAChEismadeupof two subsites anionic andesteratic Theanionicsiteservesto bindamoleculeof ACh to theenzyme Once the ACh is bound, the hydrolytic reaction occursat asecondregionofthe activesitecalled the esteraticsubsite TheAChEitselfgetsacetylatedat serinesite Acetylated enzyme reacts + water = aceticacid andcholine Choline - immediately taken up again by the high affinity choline uptake systempresynaptic membrane Tryptophan Glutamateand histidine
AChEs -MOA Anticholinesterasesalsoreactwith theenzymeChEsinsimilarfashionlike Acetylcholine Carbamates carbamylatetheactivesiteof theenzyme Phosphates Phosphorylate theenzyme Bothreactsimilarfashioncovalently with serine Carbamylated(reversibleinhibitors)reactswith waterslowlyandtheesteraticsite isfreedandreadyfor action 30minutes (lessthansynthesisof freshenzyme) But,Phosphorylated(irreversible)reactsextremelyslowlyornot at all takesmore time thansynthesisof freshenzyme Sometimesphosphorylated enzymelossesonealkylgroupandbecomeresistantto hydrolysis aging Edrophoniumandtacrinereactonlyat anionicsite shortactingwhile Organophosphatesreactonlyat esteraticsite
Physostigmine Alkaloidfromdryripenedseed(Calabarbean)ofAfricanplant Physostigma venenosum Tertiaryamine,lipid soluble,wellabsorbedorallyandcrossesBBB Hydrolyzedinliverandplasmabyesterases Longlastingaction(4-8hours) Penetratescorneareadily onlocalapplicationineye-Muscarinicactionon eyecausingmiosisandspasmof accommodationonlocalapplication Salivation,lacrimation,sweatingandincreasedtracheobronchialsecretions Increasedheartrate&hypotension
Physostigmine -uses 1. Usedasmioticdropsto decreaseIOPinGlaucoma 2. To antagonizemydriatic effectof atropine 3. Tobreakadhesionsbetweenirisandcorneaalternating with mydriatic drops 4. Belladonnapoisoning,TCAs&Phenothiazinepoisoning 5. Alzheimer sdisease-pre-senileorseniledementia 6. Atropineisantidote inphysostigminepoisoning. ADRs CNS stimulation followed bydepression
Neostigmine Synthetic reversible anticholinesterasedrug Quaternaryammoniumcompoundandlipidinsoluble Cannot crossBBB Hydrolysedbyesterasesinliver& plasma Shortdurationof action(3-5hours) Directactiononnicotinic(NM)receptorspresentinneuromuscularjunction(motor endplate)of skeletalmuscle Antagonises(reverses)skeletalmusclerelaxation(paralysis)causedby tubocurarine andother competitiveneuromuscularblockers Stimulates autonomic gangliainsmalldoses- Largedosesblockganglionic transmission No CNSeffects
Neostigmine Uses andADRs Usedinthetreatmentof MyastheniaGravisto increasemusclestrength Post-operative reversal ofneuromuscular blockade Post-operativecomplications gastricatonyparalytic ileus,urinarybladder atony Cobra snakebite Producestwitchings &fasciculationsof musclesleadingto weakness Atropineistheantidote inacuteneostigminepoisoning
Physostigmine VsNeostigmine Physostigmine Natural Tertiary amine Neostigmine Source Chemistr y Oral absorption CNS action Eye Effect Uses Dose Synthetic Quaternary ammonium compound Poor Absent Poor penetration Muscle Mysthenia gravis 0.5-2.5 mg IM/SC 15-30 mg orally 3-4 Hrs Good Present Penetrates cornea Ganglia Miotic 0.5-1 mg oral/parenteral 0.1-1% eye drop 4-6 Hrs Duration of action
OtherDrugs Pyridostigmine: Same as Neostigmine - less potent butlonger acting Edrophonium: Same as Neostigmine shorter duration ofaction (1--30minutes) diagnosticuseinMG Tacrine: Acts like edrophonium, lipid soluble, crosses BBB increasesbrainACh symptomaticimprovementinAlzheimer`s disease(AD) Rivastigmine,donepezil,galantamine allusedinAD
Myastheniagravis (Myo +asthenia) Autoimmune disorder affecting 1in 10,000population (?) reduction in number of NMreceptors Symptoms: Weakness andeasy fatigability ptosis todiaphragmatic paralysis Causes: Development ofantibodies directedto Nicotinicreceptorsin muscle end plate reduction in number by 1/3rd ofNM receptors Structural damage toNM junction
Myasthenia gravis otherdrugs Neostigmine 15to 30mg.orallyevery6hrly Adjustedaccordingto theresponse Pyridostigmine less frequency ofdosing Otherdrugs:Corticosteroids(prednisolone30-60mg/day) immunosuppression InhibitsproductionofNRantibodiesandmayincreasesynthesisorNRs Azathioprin and cyclosporinalso Plasmapheresis
Myastheniccrisis Acute weakness and respiratoryparalysis Tracheobronchial intubationand mechnical ventilation Methylprednisolone IVwith withdrawalofAChE Gradualreintroduction ofAChE Thymectomy Theproblem overtreatmentVsactualdisease(oppositetreatments) Diagnosisbyvarioustests TensilonTest Injection of Edrophonium 2mg(observe) afterhalfaminute 8mg(observe) In overtreatment symptoms worsen InMG symptomswill improve
OverallTherapeuticUsescholinergicdrugs 1. 2. 1. 1. 2. 3. Myastheniagravis:Edrophoniumto diagnoseandNeostigmine, Pyridostigmine & Distigmine totreat Tostimulatebladder& bowelafter surgery: Bethanechol, Carbachol,Distigmine. TolowerIOPinchronicsimpleglaucoma: Pilocarpine,Physostigmine To improvecognitivefunctioninAlzheimer sdisease:Rivastigmine, Gallantamine,Donepezil. Physostigmine in Belladonnapoisoning CobraBite
Pharmacotherapy ofOrganophosphate Poisoning Complexeffects Muscarinic,NicotinicandCNS Signs andsymptoms: 1. Irritationof eye,lacrmation, salivation,tracheo-bronchialsecretions,colic,blurring of vision, defaecation andurination 2. FallinBP ,tachyorbradycardia andCVScollapse 3. Muscularfasciculations,weakness,andrespiratoryparalysis 4. Irritability,disorientation,ataxia,tremor, convulsinsandcoma Treatment ABC Airway amaintance Breathing Give oxygen Circulation : two wide bore calunas then give normal saline Pass NG tube Pass foleys catheter ANTIDOT PRALIDOXIME Atropine 2mg IV every 10 minutes till dryness of mouth
Mukhtiar khan IMU KYRGYSTAN/Thank you
