mcmp 407 action potential na + ca 2+ acetylcholinesterase pharmacologic manipulation of the...
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MCMP 407
Action Potential
Na+
Ca 2+
Acetylcholinesterase
Pharmacologic manipulation of the cholinergic system
Presynaptic neuronPostsynaptic target
Nicotinic
Receptor
Muscarinic
Receptor
Choline
Choline
Na+
Acetyl CoA
+ Acetylcholine
CholineAcetyltransferase
H+
ACH
ACH
Choline Acetate
MCMP 407
Direct acting cholinergic receptor agonists:Direct acting cholinergic receptor agonists:EstersEsters
COH3C
O
CH2 CH2 N
CH3
CH3
CH3
Acetylcholine(Miochol)
CO
O
CH CH2 N
CH3
CH3
CH3H2N
CH3
Bethanechol(Urecholine)
CO
O
CH2 CH2 N
CH3
CH3
CH3H2N
Carbachol(Isoptocarbachol)
COH3C
O
CH CH2 N
CH3
CH3
CH3
Methacholine
CH3
(Provocholine)
MCMP 407
Direct acting cholinergic receptor agonists:Direct acting cholinergic receptor agonists:Alkaloids and synthetic analogsAlkaloids and synthetic analogs
N
CH3
N
Nicotine(Nicorette)
OO
CH2
H2CH3C
N
NCH3
Pilocarpine(Isoptocarpine)
OH
H
H3CHO
H
N(CH3)3
(+)-Muscarine
MCMP 407
NH3
COOH
Gq
Phospho-lipase C
(+)
PIP2
IP3 Diacylglycerol
Increase Ca2+ Activate ProteinKinase C
Response
Receptor agonists activate signal transduction pathwaysReceptor agonists activate signal transduction pathways
M3 muscarinic
receptor
C O
O
CH2 CH2 N
CH3
CH3
CH3
CH3
Acetylcholine
MCMP 407
HO
OH
Molecular actions of acetylcholineMolecular actions of acetylcholineat muscarinic receptorsat muscarinic receptors
I
II
IV
V
VI
VII
C O
O
IIIAsp105
Thr189
Tyr381
N O
O
MCMP 407
MCMP 407
Stereochemistry of cholinergic drugsStereochemistry of cholinergic drugs
+
Acetylcholine
+
trans cis
MCMP 407
Stereochemistry of cholinergic drugsStereochemistry of cholinergic drugs
OH
H
H3CHO
H
N(CH3)3
OH
N(CH3)3
O
H3C H3C
OCH3
N(CH3)3
O
H3C H
(+)-muscarine (+)-methacholine
(-)-methacholine
MCMP 407
Stereochemistry of cholinergic drugsStereochemistry of cholinergic drugs
OH
H
H3CHO
H
N(CH3)3
OO
NH
N
H3C
(+)-muscarine Protonated
pilocarpine
MCMP 407
Stereochemistry of cholinergic drugsStereochemistry of cholinergic drugs
(+)-muscarine
Protonated
pilocarpine
MCMP 407
NicotineNicotine
N
CH3
N
pKa 6.16
pKa 10.96
Dibasic Nicotinic receptors less
stereoselective
MCMP 407
Varenicline tartrate (Chantix)Varenicline tartrate (Chantix)
42 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
NN
H2N
HOOCCOO
OH
OH
MCMP 407
Clinical pharmacology of cholinergic receptor agonistsClinical pharmacology of cholinergic receptor agonists
Drug ReceptorCholinesteraseSensitivity Clinical Use
Acetylcholine M, N Yes Intraocular use for miosis during surgeryCarbachol M, N No Intraocular use for miosis during surgery,
glaucomaPilocarpine M No GlaucomaBethanechol M No Urinary retention, post-operative ileus
M=Muscarinic
N=Nicotinic
Why are antimuscarinic drugs contraindicated
in glaucoma?
Varenicline N No Smoking cessation