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Cholinergic pharmacology _ Complete presentation.pptx
- 1. Cholinergic Pharmacology Priscilla K.Mante, PhD Department of Pharmacology, KNUST. 1
- 2. Central nervous system(CNS) Peripheral nervous system (PNS) Motor (efferent) division Sensory (afferent) division Somatic nervous system Autonomic nervous system (ANS) Sympathetic division Parasympathetic division Nervous System 2
- 3. Autonomic Nervous System(ANS) • Autonomic nervous system – unconsciously perceived visceral sensations – involuntary inhibition or excitation of smooth muscle, cardiac muscle or glandular secretion 3
- 4. Divisions of theANS • 2 major divisions – parasympathetic – sympathetic • Dual innervation – one speeds up organ – one slows down organ – Sympathetic NS increases heart rate – Parasympathetic NS decreases heart rate 4
- 5. Sources of DualInnervation • Sympathetic (thoracolumbar) division • Parasympathetic (craniosacral) division 5
- 6. Neurotransmitters and Receptors •Acetylcholine (ACh) and noradrenaline (NA) are the two major neurotransmitters of the ANS • Cholinergic fibers – ACh-releasing fibers • Adrenergic fibers – NA-releasing fibres • Neurotransmitter effects can be excitatory or inhibitory depending upon the receptor type 6
- 7. ANS Fibres Two neuronsneeded to connect CNS to organ •Preganglionic neurons •postganglionic neurons 7
- 8. ANS Neurotransmitters • Adrenergic •Cholinergic 8
- 9. Neurotransmitters and Receptors •ACh is released by all preganglionic axons and all parasympathetic postganglionic axons • NA is released by sympathetic postganglionic axons 9
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- 13. 13 Agents affecting cholinergictransmission • α-ketoacids,naphthoquinones – direct inhibition of the enzyme ChAT • Hemicholinium – blocks choline uptake, thereby blocking synthesis of Ach. • Vesamicol – blocks the specific transport process of Ach into the vesicles so there will not be vesicular release of Ach. • These compounds are poisonous and not used for any therapeutic purpose
- 14. 14 Agents affecting cholinergictransmission • Latrotoxin(a toxin from the black widow spider) – produces an explosive release of Ach, causing muscular spasm. • Botulinum toxin( a toxin from Clostridium botulinum) – is able to bind to the neuron and interferes with the trafficking proteins as they come together to promote the fusing of the vesicles to the membrane. prevents vesicular docking
- 15. 15 Agents affecting cholinergictransmission • Calcium – is involved in the vesicular release. Its uptake is important in the fusion of vesicles to membrane of neuron. • Physostigmine – inhibits acetylcholinesterase causing Ach concentrations in the synaptic cleft to increase and rebind to muscarinic and nicotinic receptors.
- 16. 16 Agents affecting cholinergictransmission • Atropine – blocks muscarinic actions of Ach. • D-Tubocurarine – blocks the nicotinic actions, which are primarily at the endplate of the neuromuscular junction. Higher doses tend to block nicotinic receptors at the autonomic ganglion.
- 17. Sites of drugaction 17
- 18. Assignment Other Drugs thataffect cholinergic neurotransmission • 1. • 2. • 3. 18
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- 21. 21 CHOLINESTERASES . • ChE area group of enzymes which share a common property of hydrolyzing ester bonds but they differ in their substrate specificity. • The ChE found largely in the post synaptic membranes at the cholinergic synapses is called acetylcholinesterase (“True or specific” ChE) • Their function is to rapidly hydrolyse (terminate) the activity of Ach released from cholinergic nerve endings. • A rich source of ChE is the basement membrane in the synaptic cleft, RBC
- 22. 22 Cholinesterases • Another groupof ChE called butyrylcholinesterase or non-specific or pseudocholinesterase is found – in the plasma. – the intestine and – in the liver. • Acetylcholine is hydrolysed by AchE but not pseudo- ChE whereas Butyrylcholine is hydrolysed by pseudo- ChE but not by AchE.
- 23. Cholinergic Receptors (Cholinoceptors): Types 1.Muscarinic receptors 2. Nicotinic receptors 23
- 24. Subtypes and characteristicof cholinoceptors Receptor Type (Muscarinic) Location M1 Nerves M2 Heart, nerves, smooth muscle M3 Exocrine glands, smooth muscle, endothelium M4 CNS M5 CNS 24
- 25. 25 Muscarinic receptors • G-proteininduced changes in membrane-bound effector • M1, M3 and M5 act through inositol triphosphate pathway • Activation of other muscarinic receptors leads to an inhibition of adenylate cyclase and reduction of cAMP (M2 and M4) • Muscarinic responses are typically slow, long lasting and may be either inhibitory or excitatory
- 26. Nicotinic Receptor Subtypes Receptor Type (Nicotinic) Location NMSkeletal muscle neuromuscular junction NN Postganglionic cell body (ganglion), dendrite, adrenal medulla 26
- 27. 27 Nicotinic receptors • Ligandgated ion channels and their activation causes a rapid increase in cell permeability to Na+ and Ca2+ • Nicotinic receptor activation produces short lived excitatory responses • An excess of ACh or Nicotine (nicotinic agonist) at nicotinic receptor can cause receptor desensitization – Receptor will no longer respond to agonist and physiological response does not occur
- 28.
- 29. ANS Neurotransmitters • Adrenergic •Cholinergic 29
- 30. The major groupsof cholinoceptor- activating drugs Cholinoceptor stimulants Direct-acting (receptor agonists) Indirect-acting (cholinesterase inhibitors) Muscarinic Nicotinic Choline esters Alkaloids Ganglionic Neuromuscular 30
- 31. Cholinergic stimulants • Two(2) types –Direct • occupy and activate receptors –Indirect • inhibit acetylcholinesterase –levels of Ach increase –Ach stimulates receptors 31
- 32. Direct – ActingCholinergic Agonists (Cholinomimetics/Parasympathomimetics) • Muscarinic receptor agonists – Choline Esters – Alkaloids • Nicotinic receptor agonists – Ganglionic – Neuromuscular 32
- 33. 33 Muscarinic receptor agonists Cholineesters • There are three main structural features of the choline ester muscarinic agonists. – positively charged quaternary nitrogen N+. • the center of the cationic head and it is thought to fit into a depression in the receptor surface called the anionic site. • Alterations in the molecule to reduce the charge on the quartenary N or increase the size of the cationic head will reduce the muscarinic receptor stimulating potency of the molecule.
- 34. Structure and mechanismsof cholinergic agonists Acetylcholine 34 Cationic Head Muscarinic receptor Anionic site (-)
- 35. 35 Structure and mechanismsof cholinergic agonists – acetate ester (acetylcholine) or carbamate carbamylcholine or bethanechol. • The ester group bears an overall negative charge. It fits into a depression which bears a positive charge and is called the esteratic site. • The ester group in acetylcholine is an excellent substrate for cholinesterase enzymes so Ach is broken down very quickly in vivo. • The carbamate is hydrolyzed very slowly so carbamylcholine and bethanechol have much longer durations of action.
- 36. Structure and mechanismsof cholinergic agonists Acetylcholine 36 Ester group (-) Muscarinic receptor Esteratic site (+)
- 37. 37 Structure and mechanismsof cholinergic agonists – The alkyl chain – provides a bridge of correct length between the cationic head and the acetyl group of the Ach molecule and hence allows simultaneous attachment to the cationic head and ester (acetyl) group to the muscarinic receptor site. • Shortening or lengthening it reduces the potency of ACh molecule. • Apart from providing the correct length between the ends of the Ach molecule the alkyl chain also provides sites for formation of Van der Waals forces between the molecule and the receptor.
- 38. Structure and mechanismsof cholinergic agonists Acetylcholine 38 Ester group (-) Cationic Head Alkyl chain
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- 41. Properties of cholineesters Choline Ester Susceptibility to Cholinesterase Muscarinic Action Nicotinic Action Acetylcholine chloride ++++ +++ +++ Methacholine chloride + +++ + Carbachol chloride Negligible ++ +++ Bethanechol chloride Negligible ++ None 41
- 42. 42 Muscarinic receptor agonists Alkaloids:Muscarine • Muscarine mimics the actions of acetylcholine at smooth muscles, cardiac muscles, and glands • Muscarine is found in various mushrooms – Amanita muscaria: content of muscarine is very low – Inocybe sp: content of muscarine is high – Clitocybe sp: content of muscarine is high
- 43. 43 Muscarinic receptor agonists Alkaloids:Pilocarpine • Naturally occurring in the leaflets of a shrub Maranham jaborandi • Difficult to account for the muscarinic activity in terms of structure because it bears no relationship to Ach • Has muscarinic receptor stimulating potency and little nicotinic activity • Particularly potent on glandular tissues e.g. sweat and salivary glands • Used to treat glaucoma
- 44. Lesson Two Assignment Kindlycheck for this lesson’s assignment on myclass. Thank you. 44
- 45.
- 46. Muscarinic Effects :SLUDGE • Salivation • Lacrimation • Urination • Defaecation • Gastric distress • Emesis 46
- 47. Effect of direct-actingcholinoceptor agents Organ Response •Eye Sphincter muscle of iris Ciliary muscle Contraction (miosis) Contraction for near vision •Lung Bronchial muscle Bronchial glands Contraction (bronchoconstriction) Stimulation – increased secretions 47
- 48. Organ Response •Heart Sinoatrial node Atria Atrioventricularnode Ventricles Decrease in rate (negative chronotropy) Decrease in contractile strength (negative inotropy), Decrease in refractory period Decrease in conduction velocity, Increase in refractory period Small decrease in contractile strength 48
- 49. Organ Response •Blood vessels Arteries Veins Dilation(via EDRF), Constriction (high-dose effect) Dilation (via EDRF), Constriction (high-dose effect) •Urinary bladder Detrusor Contraction - urination 49
- 50. Organ Response •Gastrointestinal tract Motility Sphincters Glands Increase- diarrhoea Relaxation Stimulation-increased secretions •Glands Sweat, salivary, lacrimal, nasopharyngeal Secretion 50
- 51. Indirect-Acting Cholinergic Agents •Inhibit Acetylcholinesterase • Build up of Ach at ganglia, neuroeffector and neuromuscular junctions • Amplify effects of endogenous Ach • chief use: insecticides 51
- 52. Acetylcholinesterase Inhibitors (Peripherally-acting) 1. Simplealcohols (e.g. edrophonium) 2. Carbamic acid esters (e.g. neostigmine) 3. Organophosphates (e.g. ecothiophate) 52
- 53. Duration of Actionof Cholinesterase Inhibitors • Determined mostly by length of binding to enzyme –simple alcohols - short • bind to enzyme reversibly –carbamates – intermediate • bond with AchE ;longer lasting e.g. 30 mins –organophosphates - long • bond irreversibly; very long acting 53
- 54. Short acting -Edrophonium (Tensilon) • Short acting alcohol type • Uses –Diagnosis of myasthenia gravis* • Muscle strength tested after administration • Marked improvement is a positive test *Look up the pathogenesis of myasthenia gravis 54
- 55. Medium acting –Neostigmine, etc • Neostigmine and pyridostigmine - are quaternary ammonium compounds. Physostigmine (eserine) - tertiary amine, occurs naturally in the Calabar bean*. • These drugs are all carbamyl, all possess basic groups that bind to the anionic site. • Carbamylated enzyme is very much slower to hydrolyse 55
- 56. Long acting/Irreversible- Organophosphates •Phosphorylates AchE enzyme • Covalent phosphorus-enzyme bond strong • After some time the bond “ages” or gets stronger • Enzyme may be rejuvenated with pralidoxime, esp. before “ageing” • Pralidoxime – AchE Reactivator • E.g. Dyflos, parathion, ecothiophate 56
- 57. Signs and symptomsof organophosphate poisoning Muscarinic manifestations Nicotinic manifestations CNS manifestations •Bronchoconstriction •Increased bronchial secretions •Sweating •Salivation, Lacrimation •Bradycardia •Hypotension •Meiosis, Blurring of vision •Urinary incontinence •Muscular fasciculation •Tachycardia •Hypertension •Restlessness •Insomnia •Tremors, Ataxia •Confusion •Convulsions •Respiratory depression •Circulatory collapse 57
- 58. Therapeutic uses ofcholinesterase inhibitors Uses •Alcohols Edrophonium Myasthenia gravis, ileus •Organophosphates Ecothiophate Glaucoma 58
- 59. Uses •Carbamates and related agents Neostigmine Pyridostigmine Physostigmine Ambenonium Demacarium Myastheniagravis, ileus Myasthenia gravis Glaucoma Myasthenia gravis Glaucoma 59
- 60. Some Insecticides • Organophosphates –parathion –malathion –Diazinon –dyflos •Carbamate –Carbaryl (Sevin) 60
- 61. Assignment 2 Recap •Structure of ChE and modified choline esters 61
- 62.
- 63. Antimuscarinic Drugs (Parasympatholytics) • Alkaloids– naturally occurring – atropine – Hyoscine (scopolamine) • Tertiary amines – dicyclomine – benztropine – cyclopentolate – tropicamide • Quaternary amines - ipratropium - propantheline – hyoscine butylbromide 63
- 64. Antimuscarinic Drugs • Tertiaryamines & alkaloids –lipid soluble –good absorption from mucous membranes and skin –penetration into brain –highly selective for muscarinic receptor • quaternary amines - opposite of above 64
- 65. Atropine & Scopolamine •Plant origin –Atropine - Atropa belladonna –Scopolamine/Hyoscine - Hyoscyamus niger/ Datura stramonium • Compete with Ach for muscarinic receptors 65
- 66. Atropine • Non-selective competitive antimuscarinicagent • Tertiary amine – lipid soluble 66
- 67. Atropine - Eye •Relaxes pupillary sphincter muscle – due to unopposed sympathetic effects – mydriasis or dilation • Paralysis of the ciliary muscle - cycloplegia • Reduction in lacrimal secretion - dry eyes • Intraocular pressure may rise –unimportant in normal individuals – can be dangerous in narrow-angle glaucoma. 67
- 68. Atropine Heart & CardiovascularSystem • Tachycardia due to blockade of vagal slowing –Opposes Ach effects on SA depolarization –Opposes Ach effects on AV conduction The tachycardia is modest, up to 80–90 beats/min in humans. This is because there is no effect on the sympathetic system; only inhibition of tonic parasympathetic tone. • Ventricles are less affected • Overall - little affect on overall BP 68
- 69. Atropine • Respiratory tract –somebronchodilation –reduction of respiratory secretions –a quaternary drug (Ipatropium) is given as an aerosol to patients with asthma • Genitourinary tract - urethra and bladder relaxation • Sweat glands - suppressed by atropine 69
- 70. Atropine - GIT •Dry mouth • Slight, if any, decrease in gastric secretion • GI motility decreased –decreased gastric emptying –constipation 70
- 71. Atropine - CNSEffects • Mainly excitatory effects • Mild restlessness at low doses • Hallucinations in toxic doses • Inhibits involuntary movements in Parkinson’s disease • In atropine poisoning, marked excitement and irritability result in hyperactivity and significant rise in body temperature, accentuated by the loss of sweating. 71
- 72. Antimuscarinic Drugs: Contraindications • Narrow-angleGlaucoma • Urinary retention esp. in patients with Benign prostatic hypertrophic 72
- 73. Therapeutic Uses ofAnticholinergics • Antiparkinsonism effects - Benztropine • Motion sickness - scopolamine given via transdermal patch • Eye examinations - usually something short-acting (e.g. phenylephrine) is preferred, rather than atropine • Asthma - ipatropium aerosol • Peptic ulcer - pirenzepine 73
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- 75. 75 Ganglion Stimulants • Mostof these have no therapeutic uses but have useful pharmacological activities and are used experimentally. • E.g. – Nicotine – Lobeline – Epibatidine – Varenicline – Tetramethyl ammonium (TMA) – Dimethylphenylpiperazinium (DMPP)
- 76. 76 Nicotine Nicotine is atertiary amine that can act as an agonist at nicotinic receptors 1. in autonomic ganglia including the adrenal medulla 2. at the neuromuscular junction 3. on sensory nerve endings 4. in the CNS Note: High dose Ach exhibits nicotinic action
- 77. 77 • Alkaloid obtainedfrom Nicotina tabacum • Most effects are antagonistic to each other and therefore the effects of nicotine are generally very difficult to analyze • Exhibits tachyphylaxis • Possesses Central effects • CVS blood pressure • Respiratory System respiration • Neuromuscular junction stimulates the neuromuscular junction • GIT G.I. tract motility and HCl release NICOTINE
- 78. 78 Toxic Effects ofNicotine • Rapidly absorbed through skin and can enter placenta readily • Kills by causing respiratory arrest – At high doses, desensitizes nicotinic receptors – Desensitizes nicotinic receptors at motor endplate region to cause paralysis of diaphragm and intercostal muscles
- 79. 79 Ganglion Blockers • Ganglionblocking drugs are used experimentally to study autonomic function, Some that were previously used clinically are now obsolete. • Since ganglion blockers inhibit both sympathetic and parasympathetic output the major factor that determines the net effect of a ganglion blocker is the predominant tone in the tissue affected. • These are drugs have been used in the treatment of hypertension. But their uses have been replaced by other drugs and are now widely used in experimental pharmacology. • These drugs produce blockade without stimulating the ganglia.
- 80. 80 • CVS effects • BP by preventing the passage of nerve impulses across sympathetic ganglia • fall in BP is mainly due to reduced peripheral resistance • Cardiac output • effects on the heart are variable and depend on the initial level of the vagal tone. – If the initial rate is high then these drugs will reduce the heart rate. • the more usual effects are bradycardia. • reduce BP better in the upright position – cause orthosthatic hypotension • produce postural hypotension Hexamethonium (C6)
- 81. 81 • Eye Incomplete mydriasis– blockade of sympathetic and parasympathetic nerve supply to the iris Cause partial paralysis of accommodation and so patients may suffer from blurred vision and difficulty in focusing the eye • Glandular secretions ↓ secretions of digestive juices from the stomach and intestine by blocking the parasympathetic ganglion ↓ saliva and sweat and therefore patients may complain of dry mouth
- 82. 82 •GIT ↓ tone andmotility on all parts of the git results in slowing of gastric emptying after meals constipation paralytic ileus in very high doses •Urinary bladder Blockade of the parasympathetic ganglia produce difficulty in emptying of the bladder and this may lead to serious urinary retention • Sex organs Serious consequence in the sexual performance of the male, often producing complete impotence – ejaculation and erection are affected
- 83. Uses of GanglionBlockers • Treatment of hypertension (rarely used) • Produce controlled hypotension during surgery in order to reduce bleeding 83
- 84. 84 Other Blockers • Mecamylamine •Pentolinium • Pempidine • Trimethaphan
- 85. Neuromuscular Blockers • Interferewith transmission at the Neuromuscular Junction (NMJ) • Used as adjuncts to general anesthesia • 2 types –Non-depolarizing - typified by tubocurarine –Depolarizing - typified by succinylcholine 85
- 86. Non-depolarizing Blockers Curare • SouthAmerican Indian arrow poison • crude material called curare • active principle is tubocurarine • prevents access of Ach to its receptor (competitive antagonist) • prevents depolarization of end-plate • relaxes skeletal muscles 86
- 87. Tubocurarine/D-Tubocurarine • limited distributionin the body • acts for > 30 mins • jaw & eye paralyzed first • larger muscle (trunk & limbs) paralyzed second • diaphragm paralyzed last • releases histamine - lowers BP • Effect reversed by Anticholinesterases • Sugammadex* 87
- 88. Other Non-depolarizing Agents •Atracurium • Doxacurium • Mivacurium • Pancuronium • Vecuronium • Pipecuronium • Rocuronium • Gallamine 88
- 89. Depolarizing Blockers Succinylcholine • Consistsof 2 Ach molecules end-to-end • Produces a depolarizing block – Phase I - depolarizes the end-plate & adjacent muscle – Phase II - with continued presence, it desensitizes the end-plate to Ach • Metabolized by plasma pseudocholinesterases 89
- 90. Succinylcholine • Blockade lastsonly 10 to 15 minutes in normal patients • Blockade NOT overcome by Ach or AChE inhibitors • Side effects – Bradycardia. This is preventable by atropine – Hyperkalaemia – Increased intraocular pressure. 90
- 91.