1Cholinergic Drugs - 1Richard D. YeProfessor of PharmacologyCollege of MedicineTel. 996-5087Room 4143, COMRBE-mail: [email protected] “Nicotinic actions” -- similar to those induced by nicotine; action mediated by nicotinic cholinergic receptors:• stimulation of all autonomic ganglia (NN)• stimulation of voluntary muscle (NM)• secretion of epinephrine from the adrenal medulla (NN)Cholinergic receptors: Nicotinic vs. Muscarinic2The “Muscarinic actions” -- reproduced by injection of muscarine, from Amanita muscaria. Similar to those of parasympathetic stimulation• Neural (M1): CNS, PNS, gastric parietal cells (excitatory; Gq)• Cardiac (M2): atria & conducting tissue; presynaptic (inhibitory; Gi)• Glandular (M3): exocrine glands; smooth muscle (excitatory; Gq)Cholinergic receptors: Nicotinic vs. MuscarinicMultiple muscarinic cholinergic receptorsdistributed in different tissues. Therefore, the “muscarinic actions” are dependent on the receptors in different tissues and cells.Nicotinic acetylcholine receptor: Structure• All nAchRs have a pentameric structure, consisting of subunits in different combinations:A total of 9 different α subunits and 4 different β subunits have been identified• In skeletal muscle: α1(2), β, γ, δ (γ is replaced by ε in adult muscle)• In autonomic ganglion: α3, α5, α7, β2, β4• Other combinations of α and β subunits are found among the nAchRs in CNS• nAchRs with different composition have different affinities for some ligands. For example,α-bungarotoxin binds to nAchR in motor end plate with high affinity3Nicotinic acetylcholine receptor: Function• Ligand-gated ion (Na+) channel• Acetylcholine binds to the α subunits at the boundary of αand γ, and α and δ subunits.• Channel opening requires binding of 2 acetylcholine molecules, with positive cooperativity. • Structurally and functionally similar to the sodium channel, which can be blocked by local anesthetics• Acetylcholine binds to the α-subunits of the receptor makingthe membrane more permeable to cations (sodium) and causing a local depolarization. The local depolarization spreads to an action potential, or leads to muscle contraction when summed with the action of other receptors. The ion channel is open during the active state. • Nicotine in small doses stimulates autonomic ganglia and adrenal medulla. When large doses are applied, the stimulatory effect is quickly followed by a blockade of transmission.• In addition to α-bungarotoxin, there are other blocking agents for autonomic ganglions that include hexamethonium, tetraethylammonium, mecamylamine, and trimethaphan. Blocking at this level stops all autonomic outflow and produces a broad effect.4AgonistMuscarinic acetylcholine receptors (mAChR)AgonistAgonistM1“neural”M2“cardiac”M3“glandular”Gq Gi Gq↑ IP3, DAGDepolarization↑ IP3Stimulation↑ Intracellular Ca2+↓ cAMPInhibition (↓ Ca2+ channel)↑ K+conductance↓ K+ conductanceMostly excitatoryCNS excitationGastric acid secretionGastrointestinal motilityMostly inhibitoryCardiac inhibitionPresynaptic inhibitionNeural inhibitionMostly excitatoryGlandular secretionContraction of visceralsmooth muscleVasodilation (via NO)Excitation (slow EPSP) Slow IPSPIntracellular signaling triggered by acetylcholine in the HeartMain molecular players: M2, heterotrimeric G Protein Gi, Adenylyl cyclase5• Adrenal extracts are known to produce a rise in blood pressure due to its content of epinephrine.• In 1900 Reid Hunt observed that, after depleting epinephrine the adrenal extracts produced a fall in blood pressure instead of a rise. • Later studies comparing various choline derivatives found that Ach was 100,000 times more potent than choline in lowering blood pressure in rabbits.Effects of Ach on blood pressureTwo kinds of effects produced by Ach. A. Ach causes a fall in BP due to vasodilation.B. A larger dose of Ach also produces bradycardia, further reducing BP.C. Atropine blocks the effect of Ach in lowering BP.D. Still under the influence of atropine, a much larger dose of Ach causes a rise in BP and tachycardia.Sir Henry Hallett Dale(Nobel laureate, 1936)A, B: Muscarinic effects of Ach (M)C: Muscarinic antagonistic effect (M)D. Stimulation of sympathetic ganglia (NN)(Arterial pressure of ananesthetized cat wasmeasured)6ThoracolumbarCranialSacralCNS Pre-ganglionic Ganglion Post-ganglionicParasympatheticAchNicotinicAchNicotinicAchNicotinicAchNicotinicAchNicotinicEpiSympatheticSympatheticSympatheticSympathetic (adrenal medulla)Motor (somatic)AchAchMuscarinicMuscarinicNEAdrenergic(α, β)DDopaminergic(D1)AchNicotinicCardiac & smoothmuscles, gland cells,nerve terminalsCardiac & smoothmuscles, gland cells,nerve terminalsSweat glandsRenal vascularsmooth muscleReleased intobloodSkeletal muscleAch = acetylcholine NE = norepinephrineEpi = epinephrineD = dopamineEffectorsIntracellular signaling triggered by acetylcholine in the endotheliumeNOS●NOL-ArgL-CitrulineMajor molecular players: M3, heterotrimeric G Protein Gq, Ca(2+)-CaM, eNOS, NOeNOS Nitric oxide synthase7Nitric oxide (NO): A signaling molecule for SMC relaxationRobert F.FurchgottLouis J.IgnarroFeridMuradAcetylcholineSMC relaxationNO is internally produced gas through deaminationof arginine.NO production is mediated by NO synthase. Thereare 3 types of NOS: nNOS and eNOS are calcium-dependent and constitutive; iNOS is calcium-inde-pendent and inducible.NO acts in paracrine and autocrine manner.NO binds to guanylyl cyclase and increases cGMP.SecondmessengerInhibition of PDE causes sustained levelof cGMP that maintains SMC relaxation.Sildenafil (Viagra)is an inhibitor forPDE 5.Experiments that examines the functions of muscarinic receptorsM1 - Neurotransmission in Cortex and Ganglia (-/-) mice - abrogation of pilocarpine – induced seizuresM2 - Agonist-mediated bradycardia, tremor, autoinhibition of release in severalbrain regions (-/-) mice - loss of oxytremorine-induced tremors; loss ofagonist-induced bradycardia; diminished hypothermia M3 - Smooth muscle contraction, gland secreation, pupil dilation, food intakeand possibly weight gain(-/-) mice - loss of agonist-induced bronchoconstriction, higher basal pupil dilation, reduction of agonist-induced salivationM4 and M5 – Central Nervous System (CNS) roles.8Classes of cholinergic stimulantsDirect-actingReceptor agonistsCholine estersACETYLCHOLINEBETHANECOLAlkaloidsPILOCARPINECholinesterase
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