ans lecture 4new
DESCRIPTION
TRANSCRIPT
![Page 1: ans lecture 4new](https://reader033.vdocument.in/reader033/viewer/2022061202/547ad72cb4af9f554e8b4632/html5/thumbnails/1.jpg)
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
![Page 2: ans lecture 4new](https://reader033.vdocument.in/reader033/viewer/2022061202/547ad72cb4af9f554e8b4632/html5/thumbnails/2.jpg)
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)
![Page 3: ans lecture 4new](https://reader033.vdocument.in/reader033/viewer/2022061202/547ad72cb4af9f554e8b4632/html5/thumbnails/3.jpg)
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
![Page 4: ans lecture 4new](https://reader033.vdocument.in/reader033/viewer/2022061202/547ad72cb4af9f554e8b4632/html5/thumbnails/4.jpg)
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
![Page 5: ans lecture 4new](https://reader033.vdocument.in/reader033/viewer/2022061202/547ad72cb4af9f554e8b4632/html5/thumbnails/5.jpg)
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
![Page 6: ans lecture 4new](https://reader033.vdocument.in/reader033/viewer/2022061202/547ad72cb4af9f554e8b4632/html5/thumbnails/6.jpg)
MCMP 407
![Page 7: ans lecture 4new](https://reader033.vdocument.in/reader033/viewer/2022061202/547ad72cb4af9f554e8b4632/html5/thumbnails/7.jpg)
MCMP 407
Stereochemistry of cholinergic drugsStereochemistry of cholinergic drugs
+
Acetylcholine
+
trans cis
![Page 8: ans lecture 4new](https://reader033.vdocument.in/reader033/viewer/2022061202/547ad72cb4af9f554e8b4632/html5/thumbnails/8.jpg)
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
![Page 9: ans lecture 4new](https://reader033.vdocument.in/reader033/viewer/2022061202/547ad72cb4af9f554e8b4632/html5/thumbnails/9.jpg)
MCMP 407
Stereochemistry of cholinergic drugsStereochemistry of cholinergic drugs
OH
H
H3CHO
H
N(CH3)3
OO
NH
N
H3C
(+)-muscarine Protonated
pilocarpine
![Page 10: ans lecture 4new](https://reader033.vdocument.in/reader033/viewer/2022061202/547ad72cb4af9f554e8b4632/html5/thumbnails/10.jpg)
MCMP 407
Stereochemistry of cholinergic drugsStereochemistry of cholinergic drugs
(+)-muscarine
Protonated
pilocarpine
![Page 11: ans lecture 4new](https://reader033.vdocument.in/reader033/viewer/2022061202/547ad72cb4af9f554e8b4632/html5/thumbnails/11.jpg)
MCMP 407
NicotineNicotine
N
CH3
N
pKa 6.16
pKa 10.96
Dibasic Nicotinic receptors less
stereoselective
![Page 12: ans lecture 4new](https://reader033.vdocument.in/reader033/viewer/2022061202/547ad72cb4af9f554e8b4632/html5/thumbnails/12.jpg)
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
![Page 13: ans lecture 4new](https://reader033.vdocument.in/reader033/viewer/2022061202/547ad72cb4af9f554e8b4632/html5/thumbnails/13.jpg)
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