Download Cholinergic Drugs

MCMP 407
Pharmacologic manipulation of the cholinergic system
Na+
Muscarinic
Receptor
ACH
Choline
Acetyltransferase
Acetylcholinesterase
Acetyl CoA
+
Choline
Action Potential
Na+
Acetylcholine
H+
ACH
Nicotinic
Choline Acetate
Receptor
Choline
Presynaptic neuron
Postsynaptic target
MCMP 407
Direct acting cholinergic receptor agonists:
Esters
O
C
H3C
O
CH2
CH2
Acetylcholine
(Miochol)
O
CH3
C
H3 C
O
CH3
CH
O
N
CH3
CH3
C
H2N
Methacholine
(Provocholine)
N
CH3
CH3
O
CH2
CH2
N
CH3
CH
3
Carbachol
(Isoptocarbachol)
O
CH3
CH2
CH3
CH3
C
H2 N
CH
O
CH3
CH2
Bethanechol
(Urecholine)
N
CH3
CH3
MCMP 407
Direct acting cholinergic receptor agonists:
Alkaloids and synthetic analogs
H
N(CH3)3
H3CHO
O
H
H
(+)-Muscarine
O
N
CH3
N
Nicotine
(Nicorette)
H3C H2C
N
CH2
O
Pilocarpine
(Isoptocarpine)
N
CH3
MCMP 407
Receptor agonists activate signal transduction pathways
O
NH3
CH3
C O CH2
CH3
CH2
Acetylcholine
M3 muscarinic
receptor
(+) Phospho-
Gq
lipase C
PIP2
COOH
IP3
Diacylglycerol
Increase Ca2+
Activate Protein
Kinase C
Response
N
CH3
CH3
MCMP 407
Molecular actions of acetylcholine
at muscarinic receptors
VI
I
Tyr381
VII
Thr189
OH
II
O
O
C
Asp105
N
O
III
O
IV
HO
V
MCMP 407
MCMP 407
Stereochemistry of cholinergic drugs
Acetylcholine
+
+
trans
cis
MCMP 407
Stereochemistry of cholinergic drugs
H
N(CH3)3
H3CHO
H
O
H
O
(+)-muscarine
N(CH3)3
H 3C
H3C
O
H
(+)-methacholine
H
H3C
O
O
(-)-methacholine
N(CH3)3
CH3
MCMP 407
Stereochemistry of cholinergic drugs
NH
H
N(CH3)3
H3CHO
H
O
(+)-muscarine
N
O
H
O
Protonated
pilocarpine
H 3C
MCMP 407
Stereochemistry of cholinergic drugs
(+)-muscarine
Protonated
pilocarpine
MCMP 407
Nicotine
pKa 6.16
N
CH3
N
pKa 10.96
Dibasic
Nicotinic receptors less
stereoselective
MCMP 407
Varenicline tartrate (Chantix)
OH
HOOC
COO
OH
N
42 Nicotinic receptor
partial agonist
H2
Activates nicotinic receptor
N
much less than nicotine;
Blocks nicotine from binding
Well tolerated
Side effects:
• GI related (nausea,
constipation, gas, vomiting)
N
• Altered dreams
MCMP 407
Clinical pharmacology of cholinergic receptor agonists
Cholinesterase
Receptor Sensitivity
Clinical Use
Drug
Acetylcholine
Carbachol
M, N
M, N
Yes
No
Pilocarpine
Bethanechol
Varenicline
M
M
N
No
No
No
Intraocular use for miosis during surgery
Intraocular use for miosis during surgery,
glaucoma
Glaucoma
Urinary retention, post-operative ileus
Smoking cessation
M=Muscarinic
N=Nicotinic
Why are antimuscarinic drugs contraindicated
in glaucoma?