Presentation on theme: "Direct cholinomimetic (Parasympathomimetics) Drugs"— Presentation transcript:
1Direct cholinomimetic (Parasympathomimetics) Drugs Prof. Alhaider 1435 HCollege of MedicineDepartment of Pharmacology
2By the end of this lecture the student should know Classification of nervous system.Describe the various steps in cholinergic transmission.Mention the different types, locations and actions of cholinergic receptors.Describe the effects of acetylcholine on major organsClassify cholinomimetic drugs.Describe the kinetics, actions and uses of direct acting cholinomimetic drugs.
3Nervous system Central nervous system Peripheral nervous system Afferent DivisionEfferent DivisionAutonomic nervoussystemSomaticsystemEnteric nervous systemParasympathetic nervous systemSympathetic nervous system
4Why Acetylcholine is very important neurotransmitter? See the Next Figure
11Muscarinic receptorsType II receptors : G-protein linked receptorsLocated at all target organs that are innervated by parasympathetic fibers (e.g, heart, CVS, eye, bladder, etc).Five subclasses exist (M1 - M5)M1, M3, M5 are excitatory in function (stimulation).M2, M4 are inhibitory in function (inhibition).
12Pharmacological actions Locations Receptor CNS excitationGastric acid secretionActivation of phospholipase C IP3 &DAG CaCNSAutonomic gangliagastric parietal cellsM1 (Neural)ExcitatoryCardiac inhibitionPresynaptic inhibitionInhibition of adenyl cyclase( cAMP)Opening of K channelsHeartPresynaptic cholinergic fibersM2 (Cardiac)InhibitorySecretion of glandsSmooth muscle contractionVasodilatation (via NO)Activation of phospholipase C IP3 & DAG.Exocrine glandsSmooth musclesVascular endotheliumM3Glandular
13Subtypes and characteristics of Cholinergic Receptors (Both the Muscarenic and Nicotinic) Postrecptor mechanismStructural featuresLocationOther NameReceptor typeIP3,DAG cascade7 transmembrane segments,G protein linkedNervesM1aM1Inhibition of cAMP production, activation of K channels7 transmembrane segment,Gprotein-linkedHeart, nerves, smooth muscleM2a,cardiac M2M2IP3,DAG casaded→cytosolic calcium →↑released7 transmembrane segment ,G-protein linkedGlands,smooth muscle,endotheliumM2b glandular M2M3Inhibition of cAMP producation7membrane segment Gprotein linked? CNSm4IP3 ,DAG,cascadem51Na+,K+depolarizing ion channelPentamer(αβδγ)2Skeletal muscle neuromuscular junctionMuscle type,end plate receptorNMαandβsubunitss only as α2β2α3β3Postganglionic cell body,dendritesNeuronal type , ganglion receptorNN
14Nicotinic receptors Central cholinoceptor Muscarinic receptorsPeripheral cholinoceptorNicotinic receptorsCentral cholinoceptorG protein linked receptorsIon channel linked receptorsOn all peripheral organs that receive postganglionic parasympathetic fibersAutonomic ganglia (sympathetic & parasympathetic) stimulation ( Nn )Heart (M2) inhibitionexocrine glands (M3) contractionAdrenal medulla (Nn)release of catecholamines(Adrenaline & Noradrenaline)Smooth muscles (GIT, urinary tract, bronchial muscles)(M3) contractionSkeletal muscle (Neuromuscular junction)(Nm) ContractionExcitatory or inhibitoryAlmost excitatory
15Type I receptors : ion channel linked receptors 1 Type I receptors : ion channel linked receptors 1. Autonomic ganglia (Nn). 2. Adrenal medulla (Nn). 3. CNS (Nn) 3.Neuromuscular junction (Nm)Nicotinic receptors
16Based on the receptor type, Acetylcholine has two main effects: 1) Cholinergic (cholinomimetics) actions2) Nicotinic Actions
17Nicotinic Actions Skeletal muscles: Low conc. muscle contraction High conc. persistent depolarization & paralysis.Ganglia: stimulation of sympathetic & parasympathetic ganglia.Adrenal medulla release of catecholamines (A & NA).Nicotinic Actions
18Muscarinic actions Cholinergic actions Organs Contraction of circular muscle of iris (miosis)(M3)Contraction of ciliary muscles for near vision (M3)Eyebradycardia ( heart rate ) (M2)Release of NO (EDRF)HeartendotheliumConstriction of bronchial smooth musclesIncrease bronchial secretion M3LungIncreased peristalsisIncreased secretionContraction of sphincter M3GITContraction of musclesRelaxation of sphincter M3Urinary bladderIncrease of sweat, saliva, lacrimal, bronchial, intestinal secretions M3Exocrine glands
20Types of cholinomimetics (Parasympathomimetics) Direct cholinomimeticscause direct stimulation of cholinergic receptors.Indirect cholinomimetics (anticholinesterases)increase action of Ach indirectly by inhibiting acetylcholinesterase thus prevent the degradation of Ach (This will be the title of our lecture)
21Features of Good Directly Acting Cholinergic Drugs Since Ach is not specific and easily destroyed by Cholinesterase, thus it is very essential to obtain Cholinergic Drug that has low nicotinic activity, high muscarenic selectivity but with low susceptibility to cholinesterase. (See Figure)Which drug that has such features?
25Acetylcholine (Ach)Muscarinic and nicotinic agonistNot used clinically because AchIs not selective (N, M)Has short duration of action. Why?Due to rapid metabolism by acetycholinesterase
26Synthetic choline esters include drugs as bethanechol, carbacholQuaternary ammonium compounds (polar)Poor distributioncan not cross BBB (No CNS effects)Not metabolized by cholinesterase.Have longer duration of action than Ach.Never given I.V. or I.M BUT S.C.
28CarbacholOrally-S.C.Not metabolized by cholinesterases.Longer duration of action than AchMuscarinic actions on Eye, GIT, UT. (TableHas nicotinic actions (what are these actions?).Used forMainly in glaucomaUrinary retention & paralytic ileus (rarely used due to its nicotinic actions)
29BethanecholOrally-SCProminent muscarinic actions on GIT, UT.No nicotinic actionNot metabolized by cholinesterases.Longer duration of action than AchUsed forIn paralytic ileusIn urinary retention (in cases of post-operative atony, neurogenic bladder)
30PilocarpineNatural alkaloidsTertiary amine lipophilicPharmacokineticsIt is well absorbedGood distributionCross BBB (has central effects).Long duration of actionDirect muscarinic agonist(mainly on eye & secretion).
31better absorbed than Ach metabolized by cholinesterase PilocarpineBethanecholCarbacholAChTertiarynon polarQuaternary PolarChemistryCompletebetter absorbed than AchNOTAbsorptionmetabolized by cholinesteraseMetabolismby cholinesteraseLonger (++)Very shortDurationoral,eye dropsOralS.C.Oral,I.V.Administ.
32Pilocarpine Bethanechol Carbachol ACh Muscarinic Nicotinic +++ Receptors+++More on eye, secretionGIT, UrinarybladderEye, GITUrinary bladderNOTSelectivityNOGlaucomaXerostomiaParalytic ileusUrinary retentionUses
33Bethanechol Carbachol Pilocarpine ACh CompleteNOTAbsorptionhydrolyzed by cholinesteraseNOT hydrolyzed by cholinesteraseHydrolyzed bycholinesteraseMetabolismLonger (++)Very shortDurationOral, S.C.Oral,eye dropsoral,I.V.Administ.
34Bethanechol Carbachol Pilocarpine ACh Muscarinic Nicotinic +++ Receptors+++GIT, UrinarybladderEye, GITUrinary bladderMore on eye, secretionNOTSelectivityNOUrinary retentionParalytic ileusGlaucomaXerostomiaUses
35Cevimeline Direct acting muscarinic agonist at Glandular M3 Used orally for treatment of dry mouth symptomassociated with Sjogren's syndrome.
36Contraindications of cholinomimetics Bronchial asthma.Peptic ulcer.Angina pectorisIntestinal obstructionIncontinence
37Practice for Home: What are the the naturally occuring alkaloids (e Practice for Home: What are the the naturally occuring alkaloids (e.g: Pilocarpine and Oxotremorine and Muscarine) ? What is mushrooms poisoning? What are the differences between pilocarpine and bethanechol?.