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Action Potential

a. b. a. Action Potential. Pharmacologic manipulation of the cholinergic system. Ca 2+. Na +. Muscarinic Receptor. ACH. Choline Acetyltransferase. Acetylcholinesterase. Acetyl CoA +. Acetylcholine. Choline. Na +. H +. Nicotinic Receptor. ACH. Choline. Acetate. Choline.

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Action Potential

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  1. a b a Action Potential 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. O O C H C H 3 3 C C H C H N C H C C H C H N 2 2 3 2 2 H C O O 3 C H 3 A c e t y l c h o l i n e ( M i o c h o l ) O C H C H 3 3 C C H C H N C H 2 3 H N O 2 C H 3 B e t h a n e c h o l ( U r e c h o l i n e ) Direct acting cholinergic receptor agonists:Esters 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 H C O 3 C H 3 M e t h a c h o l i n e (Provocholine)

  3. Direct acting cholinergic receptor agonists:Alkaloids 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 3 2 N C H 2 O N N O P i l o c a r p i n e C H 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. NH 3 Phospho - (+) G lipase C q PIP 2 IP Diacylglycerol COOH 3 2+ Increase Ca Activate Protein Kinase C Response Receptor agonists activate signal transduction pathways O C H 3 C C H C H N C H 2 2 3 C H O 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. Stereochemistry of cholinergic drugs Acetylcholine + + trans cis

  7. 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

  8. 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

  9. Stereochemistry of cholinergic drugs (+)-muscarine Protonated pilocarpine

  10. Nicotine pKa 6.16 • Dibasic • Nicotinic receptors less stereoselective pKa 10.96

  11. 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

  12. 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 M=Muscarinic N=Nicotinic Why are antimuscarinic drugs contraindicated in glaucoma?

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