Cholinergic Drugs

1
Pharmacologic manipulation of the cholinergic
system
Ca2
Na
Muscarinic Receptor
ACH
Choline Acetyltransferase
Acetylcholinesterase
Acetyl CoA
Acetylcholine
Choline
Na
H
Nicotinic Receptor
ACH
Choline
Acetate
Choline
Presynaptic neuron
Postsynaptic target
2
Direct acting cholinergic receptor
agonistsEsters
C
H
3
H
N
2
C
H
3
C
a
r
b
a
c
h
o
l
(
I
s
o
p
t
o
c
a
r
b
a
c
h
o
l
)
O
C
H
C
H
3
3
C
C
H
C
H
N
C
H
2
3
O
H
C
3
C
H
3
M
e
t
h
a
c
h
o
l
i
n
e
(Provocholine)
3
Direct acting cholinergic receptor
agonistsAlkaloids and synthetic analogs
H
N
(
C
H
)
3
3
H
O
H
C
3
O
H
H
(

)
-
M
u
s
c
a
r
i
n
e
C
H
H
C
H
C
3
2
3
N
C
H
2
O
N
N
O
C
H
P
i
l
o
c
a
r
p
i
n
e
3
(
I
s
o
p
t
o
c
a
r
p
i
n
e
)
N
N
i
c
o
t
i
n
e
(
N
i
c
o
r
e
t
t
e
)
4
Receptor agonists activate signal transduction
pathways
O
C
H
3
C
C
H
C
H
N
C
H
2
2
3
O
C
H
3
C
H
Acetylcholine
3
M3 muscarinic receptor
5
Molecular actions of acetylcholineat muscarinic
receptors
VI
Tyr381
I
VII
Thr189
V
II
IV
III
Asp105
6
(No Transcript)
7
Stereochemistry of cholinergic drugs
Acetylcholine


trans
cis
8
Stereochemistry of cholinergic drugs
H
N
(
C
H
)
N
(
C
H
)
3
3
3
3
H
C
H
C
H
O
3
3
H
C
3
O
O
O
H
H
H
()-muscarine
()-methacholine
N
(
C
H
)
3
3
H
H
C
3
O
O
C
H
3
(-)-methacholine
9
Stereochemistry of cholinergic drugs
N
H
H
N
(
C
H
)
N
3
3
H
O
H
C
H
C
3
3
O
O
O
H
H
()-muscarine
Protonated pilocarpine
10
Stereochemistry of cholinergic drugs
()-muscarine
Protonated pilocarpine
11
Nicotine
pKa 6.16

• Dibasic
• Nicotinic receptors less stereoselective

pKa 10.96
12
Varenicline tartrate (Chantix)

• ?4?2 Nicotinic receptor partial agonist
• Activates nicotinic receptor much less than
  nicotine Blocks nicotine from binding
• Well tolerated
• Side effects
• GI related (nausea, constipation, gas, vomiting)
• Altered dreams

13
Clinical pharmacology of cholinergic receptor
agonists
Cholinesterase
Drug
Receptor
Sensitivity
Clinical Use
Acetylcholine
M, N
Yes
Intraocular use for miosis during surgery
Carbachol
M, N
No
Intraocular use for miosis during surgery,
glaucoma
Pilocarpine
M
No
Glaucoma
Bethanechol
M
No
Urinary retention, post-operative ileus
Varenicline
N
No
Smoking cessation
MMuscarinic
NNicotinic
Why are antimuscarinic drugs contraindicated in
glaucoma?