1. MCMP 407 Action Potential Na + Ca 2+ Acetylcholinesterase Pharmacologic manipulation of the cholinergic system Presynaptic neuron Postsynaptic target Nicotinic Receptor    Muscarinic Receptor Choline Na + Acetyl CoA + Acetylcholine Choline Acetyltransferase H+H+ ACH CholineAcetate

2. MCMP 407 Direct acting cholinergic receptor agonists: Esters CH 3 CH 3 H 2 N Carbachol (Isoptocarbachol) C OH 3 C O CHCH 2 N CH 3 CH 3 CH 3 Methacholine CH 3 (Provocholine)

3. MCMP 407 Direct acting cholinergic receptor agonists: Alkaloids and synthetic analogs N CH 3 N Nicotine (Nicorette) O O CH 2 H 2 CH 3 C N N CH 3 Pilocarpine (Isoptocarpine) O H H H 3 C HO H N(CH 3 ) 3 (+)-Muscarine

4. MCMP 407 Receptor agonists activate signal transduction pathways M 3 muscarinic receptor C O O CH 2 CH 2 N CH 3 CH 3 CH 3 CH 3 Acetylcholine

5. MCMP 407 Molecular actions of acetylcholine at muscarinic receptors I II IV V VI VII III Asp105 Thr189 Tyr381

6. MCMP 407

7. Stereochemistry of cholinergic drugs + Acetylcholine + transcis

8. MCMP 407 Stereochemistry of cholinergic drugs O H H H 3 C HO H N(CH 3 ) 3 O H N(CH 3 ) 3 O H 3 C H 3 C O CH 3 N(CH 3 ) 3 O H 3 C H (+)-muscarine(+)-methacholine (-)-methacholine

9. MCMP 407 Stereochemistry of cholinergic drugs O H H H 3 C HO H N(CH 3 ) 3 O O NH N H 3 C (+)-muscarineProtonated pilocarpine

10. MCMP 407 Stereochemistry of cholinergic drugs (+)-muscarine Protonated pilocarpine

11. MCMP 407 Nicotine pKa 6.16 pKa 10.96 uDibasic uNicotinic receptors less stereoselective

12. MCMP 407 Varenicline tartrate (Chantix) u  4  2 Nicotinic receptor partial agonist uActivates nicotinic receptor much less than nicotine; Blocks nicotine from binding uWell tolerated uSide effects: GI related (nausea, constipation, gas, vomiting) Altered dreams

13. MCMP 407 Clinical pharmacology of cholinergic receptor agonists DrugReceptor Cholinesterase SensitivityClinical Use AcetylcholineM, NYesIntraocular use for miosis during surgery CarbacholM, NNoIntraocular use for miosis during surgery, glaucoma PilocarpineMNoGlaucoma BethanecholMNoUrinary retention, post-operative ileus M=Muscarinic N=Nicotinic Why are antimuscarinic drugs contraindicated in glaucoma? VareniclineNNoSmoking cessation