Section 2, Lecture 2 Cholinergic Receptor Agonists Muscarinic Receptors -smooth muscle -cardiac tissueparasymp. neuroeffector junctions -glands CNS- presynaptic parasymp. and symp. nerves and autonomic ganglia -activation of muscarinic receptors on presynaptic autonomic nerves inhibits further neurotransmission. -muscarinic receptors on symp. nerve terminals provides for communication between parasymp. and symp. nervous systems release of acetylcholine from parasymp nerves inhibits the release of NE from symp. Nerves.

2 -5 types of muscarinic receptors M 1 -M 5 Principal types M 1, M 2 M 3 Signal transduction: -Smooth muscle & glands: M 1 and M 3 via G-proteins: increased IP 3 and DAG -Vascular Smooth Muscle (endothelial cells): M 3 turns on nitric oxide synthase (NOS) Type of ReceptorPrincipal LocationsMechanism of Signal TransductionEffects Muscarinic M 1 ("neural")Autonomic ganglia, presynaptic nerve terminals, and central nervous system Increased inositol triphosphate (IP 3 ) and diacylglycerol (DAG) Modulation of neurotransmission M 2 ("cardiac")Cardiac tissue (sinoatrial and atrioventricular nodes) Increased potassium efflux or decreased cyclic adenosine monophosphate (cAMP) Slowing of heart rate and conduction M 3 ("glandular")Smooth muscle and glandsIncreased IP 3 and DAGContraction of smooth muscles and stimulation of glandular secretions Vascular smooth muscleIncreased cyclic guanosine monophosphate (cGMP) due to nitric oxide stimulation Vasodilation

3 L-Arg  NO ACh NOS NO Endothelial cells Smooth muscle cells G-protein GTPcGMP Muscle relaxation Guanlylate cyclase M3M3

4 -M 2 increases K + efflux and destruction of cAMP via increase in cyclic nucleotide phosphodiesterase activity Nicotinic Receptors Found at all autonomic ganglia, somatic neuromuscular junctions and CNS -ligand-gated sodium channels -autonomic ganglia activation of nicotinic receptors produces neuronal excitation leading to the release of neurotransmitters at postganglionic neuroeffector junctions -at neuromuscular junctions activation leads to depolarization and the release of Ca 2+ from the sarcoplasmic reticulum which results in muscle contraction.

5 Nicotinic N M (in muscles)Somatic neuromuscular junctions Increased sodium influx Contraction of muscles N N (in neurons)Autonomic gangliaIncreased sodium influx Excitation of postganglionic neurons Type of ReceptorPrincipal Locations Mechanism of Signal TransductionEffects

6 Cholinergic receptor agonists Direct acting agonists –bind and activate cholinergic receptors Indirect-acting agonists –increase synaptic [ACh] by either inhibiting AChE or increasing the release of ACh from terminals

7 Direct acting Choline esters ACh- rapidly hydrolyzed Effects and indicators: -intraocular use during cataract surgery where it produces miosis -in diagnostic angiography injected directly into coronary artery to produce vasodiation (M 3 -receptors) DrugReceptor Specificity Hydrolyzed by CholinesteraseRoute of AdministrationClinical Use Choline esters AcetylcholineMuscarinic and nicotinic YesIntraocularMiosis during ophthalmic surgery IntracoronaryCoronary angiography BethanecholMuscarinicNoOral or subcutaneousPostoperative or postpartum urinary retention CarbacholMuscarinic and nicotinic NoTopical ocularGlaucoma IntraocularMiosis during ophthalmic surgery

8 Pilocarpine Muscarinic receptor agonist Miosis-Pupillary constriction Atropine – Muscrinic recep. antagonist Pupillary dilatation Ocular effects

9 Direct acting plant alkaloids Muscarine- source mushrooms Nicotine- Indications: muscarine no current medical use; nicotine as dermal patches in smoking cessation programs Pilocarpine- source pilocarpus a shrub Effects and indications: Tratment of open-angle glaucoma Plant alkaloids MuscarineMuscarinicNoNone NicotineNicotinicNoOral or transdermalSmoking cessation programs PilocarpineGreater affinity for muscarinic than for nicotinic NoTopical ocular Oral Glaucoma Xerostomia Drug Receptor Specificity Hydrolyzed by CholinesteraseRoute of AdministrationClinical Use

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11 Indirect acting cholinergic agonists Reversible AChe inhibitors Carbamates- slow hydrolysis compared to ACh

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13 Irreversible inhibitors phosphoesters

14 Practice question What is the mechanism of signal transduction of the following receptors M 1 (neuronal) –Increased IP3 and DAG M 2 (Cardiac) –Increased potassuim efflux or decrease cGMP N M ( in muscles) –Increased soduim influx

15 What is the difference between direct- acting cholinergic agonists and indirect- acting agonists Direct-acting agonist: bind and activate cholinergic receptors Indirect-acting receptors: increase the synaptic concentration of Ach