Cholinergic receptors &drugs

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Cholinergic receptors & drugs:

Cholinergic receptors & drugs Dr.Kumarasingam PG Pharmacology


INTRODUCTION Ach - first neurotransmitter identified (Otto Loewi, 1921) Important role in movement: causes muscle contraction Also found in brain: important role in attention, learning & memory

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Basal forebrain nuclei (especially the nucleus of Meynert ) are the major source of ACh in brain Cholinergic pathways project from basal nuclei throughout cortex Activation of this neural system is associated with alertness, attention, learning & memory

2 main types of ACh receptor::

2 main types of ACh receptor: 1.Nicotinic receptor – nicotine is an agonist 2.Muscarinic receptor – muscarine (toxin found in mushrooms, e.g. Amanita muscaria ) is an agonist both types of receptor can be activated by ACh

(the ‘master key’ for both types of ‘lock’):

nicotine muscarine muscarinic receptor nicotinic receptor (the ‘master key’ for both types of ‘lock’) ACh

Nicotinic receptors:

Nicotinic receptors Location : neuromuscular jn , all autonomic ganglia, brain. Subtypes : muscular type Nm, neuronal type Nn , central.

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Receptor Type Other Names Location Structual Features Postreceptor Mechanism N M Muscle type, end plate receptor Skeletal muscle neuromuscular junction Pentamer ( α 2 βδγ ) 2 NA + , K + depolarizing ion channel N N Neuronal type, ganglion receptor Postganglionic cell body, dendrite α and β subunits only as α 2 β 2 or α 3 β 3 NA + , K + depolarizing ion channel

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MOA : ligand gated ion channel family of receptor opening of cation (Na+) channel end plate depolarisation

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Function : Nm – contraction of skeletal muscle Nn – transmission of impulse through autonomic ganglia, firing of postganglionic neuron, secretion of NE & E from adrenal medulla. Central – release dopamine & glutamate from adrenal medulla

Muscarinic receptors:

Muscarinic receptors Location : neuro effector junction at smooth muscle & glands. Subtypes : M1, M2, M3, M4 & M5 Depending upon – pharmacological specificities, molecular cloning.

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Receptor Type Other Names Location Structural Features Mechanism M1 Gastric Sympathetic ganglia, cns , gastric paracrine cells G protein - linked IP 3 ,DAG cascade M2 M 2a , Cardiac M 2 Heart,nerves, smooth muscle G protein -linked Inhibition of cAMP production, activation of K + channels

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Receptor Type Other Names Location Structual Features Mechanism M 3 glandular Glands, smooth muscle, endothelium G protein-linked IP 3 , DAG cascade M 4 CNS G protein-linked Inhibition of cAMP production M 5 CNS G protein-linked IP 3 , DAG cascade

MOA : M1, M3 & M5 – Odd numbers:

MOA : M1, M3 & M5 – Odd numbers Ach + Gq Activation PLC Hydrolyses the PIP2 IP3 - ca 2+ DAG - PKc Cytosolic Ca2+ ( phosphorylate ) CAM specific protein (Contraction) response

MOA : M2 & M4 – Even numbers:

MOA : M2 & M4 – Even numbers R + Gi protein (-) adenylate cyclase Reduce intra cellular cAMP ↓ force of contraction

Classification :


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Choline esters Acetylcholine Methacholine Carbachol Bethanechol Natural Alkaloids Muscarine Pilocapine Arecoline

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Esters of Choline


Direct Esters of choline – mostly activate muscarinic receptors methacholine bethanechol Alkaloids – activate both muscarinic and nicotinic receptors pilocarpine nicotine

Properties of choline esters:

Properties of choline esters Choline Ester Susceptibility to Cholinesterase Muscarinic Action Nicotinic Action Acetylcholine ++++ +++ +++ Methacholine + ++++ None Carbachol Negligible ++ +++ Bethanechol Negligible ++ None

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Effects of Muscarinic Agonists:

Effects of Muscarinic Agonists

Effect of direct-acting cholinoceptor stimulants:

Effect of direct-acting cholinoceptor stimulants Organ Response Eye Sphincter muscle of iris Ciliary muscle Contraction (miosis) Contraction for near vision Lung Bronchial muscle Bronchial glands Contraction ( bronchoconstriction ) Stimulation

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Organ Response Heart Sinoatrial node Atria Atrioventricular node Ventricles Decrease in rate (negative chronotropy ) Decrease in contractile strength (negative ionotropy ), Decrease in conduction velocity, Increase in refractory period Small decrease in contractile strength

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Organ Response Blood vessels Arteries Veins Dilation (via EDRF), Constriction (high-dose effect) Dilation (via EDRF), Constriction (high-dose effect) Urinary bladder Detrusor Trigone and sphincter Contraction Relaxation

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Organ Response Gastrointestinal tract Motility Sphincters Secretion Increase Relaxation Stimulation Glands Sweat, salivary, lacrimal, nasopharyngeal Secretion

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Acetylcholine has no clinical utility Ultrashort action It is easily hydrolyzed by: Acid in the stomach Acetylcholine esterase in blood Widespread activity


Cholinesterase True Acetyl cholinesterase Pseudo acetyl cholinesterase Synaptic cleft, Neuronal membrane, RBC, placenta Synthesised – liver, found – plasma / intestine Hydrolysis – Ach / methacholine Succinylcholine , benzoylcholine , butyrylcholine RBC – connected with Ion transport mechanism Genetic variations Placenta – vasodilatation – facilitates nutrition for embryo Atypical pseudocholinesterase - apnoea

Alkaloids (pilocarpine and nicotine):

Alkaloids ( pilocarpine and nicotine) Highly lipid soluble well absorbed from GI tract Cross BBB brain both muscarinic and nicotinic receptor activation

Pilocarpine (pilocarpus microphyllus):

Pilocarpine ( pilocarpus microphyllus ) Muscarinic action, through ganglionic muscarinic R ↑ secretion – sweating / salivation CVS small dose – fall BP ( muscarinic ) Higher dose - ↑ BP / ↑ HR ( ganglionic )


EYE Circullar muscle contraction - Miosis Ciliary muscle contraction open pores of canal of schlemm drainage of aqueous humour ↓ IOP open angle glaucoma

Other drugs used in gluacoma:

Other drugs used in gluacoma β blockers Timolol Betaxolol Levobunolol Miotics Physostigmine α agonist Adrenaline Apraclonidine Brimonidine Carbonic anhydrase inhibitors Acetazolamide Prostaglandine Latanoprost

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S/E Stinging sensation in eye Painful spasm of accommodation Sweating USEs : Open angle glaucoma, Xerostomia followed by radiation Sjogren syndrome Counteract with mydriatics Dose : 5-10 mg tds Lower in hepatic impairment

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Physostigmine Neostigmine Pyridostigmine Edrophonium Rivastigmine Donepezil Tacrine Dyflos Echothiophate Parathion Malathion Diazinon Tabun , Sarin , Soman Carbaryl Propoxur

Removal of Acetylcholine from the synaptic cleft::

Removal of Acetylcholine from the synaptic cleft: In order to ready the synapse for another impulses: 1)      The neurotransmitters, which are released from the synaptic vesicles, are hydrolyzed by enzyme present in the synaptic cleft “ Acetylcholinestrase ” giving choline , which poorly binds to acetylcholine receptors.   Acetylcholine + H2O Choline + H+ acetate 2)      The empty synaptic vesicles, which are returned to the axonal terminal bulb by endocytosis , must be filled with acetylecholine . Acetylcholinestrase

ACh is broken down in the synaptic cleft by the enzyme acetylcholinesterase (AChE):

ACh is broken down in the synaptic cleft by the enzyme acetylcholinesterase ( AChE )


MECHANISM OF ACTION Acetylcholinesterase inhibitors - inhibit the enzyme acetylcholinesterase ( AChE ), responsible for breakdown of ACh This results in increased cholinergic activity (at both nicotinic and muscarinic receptors)

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+ H2O


(1) Ach + AchE = gorge Ach-enzyme complex Acetylated enzyme H2O Free enzyme + Acetic Acid + Choline


(2) Ach-enzyme complex + carbamates Carbamylated enzyme + H2O Free enzyme + carbamic acid (slow reaction) Edrophonium & Tacrine – attach in anionic site & does not involve hydrolysis BUT diffusion action brief.


(3) Ach-enzyme complex + phosphates Phosphorylated enzyme + Oxime Oxime-phosphonate + free enzyme (extremely slow reaction) Organophosphates - attach in esteratic site & phosphorylated enzyme undergo ‘ageing’ – become totally resistant to hydrolysis

‘Ageing’ on Phosphorylated enzyme:

‘Ageing’ on Phosphorylated enzyme


EFFECTS OF ACETYLCHOLINESTEASE INHIBITION By inhibiting cholinesterase, the indirect acting agonists “amplify“ of endogenous acetylcholine. Therefore, the indirect agents have muscarinic and nicotinic effects. Lipid soluble agent : Physostigmine , organophosphates Muscarinic & CNS action Skeletal muscle less prominent Lipid insoluble agent : Neostigmine , other ammonium compounds Skeletal muscle & ganglia Muscarinic effect less prominent

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EYE : miosis GI : diarrhea, urination, vomiting, salivation RESPIRATORY : bronchoconstriction , increased bronchial secretion CNS : tremor, anxiety, convulsions, coma CARDIOVASCULAR : bradycardia , hypotension SKELETAL MUSCLE : fasciculation

Pharmacokinetics :

Pharmacokinetics Physostigmine Rapidly absorbed in g.i.t / parenteral Eye – penetrate the cornea Cross the BBB Disposed after hydrolysed by chE Neostigmine & congeners Poorly absorbed orally Cornea / BBB – penetration low Partially hydrolysed & partially excreted unchanged in urine Organophosphates Absorbed all sites – including intact skin & lung Hydrolysed & oxidised in the body Little is excreted unchanged form


Uses Myasthenia gravis Alzheimer’s disease Postoperative paralytic ileus / urinary retention Cobra bite – prevent respiratory paralysis Belladonna poisoning Tricyclic antidepressants, phenothiazines – over does glaucoma

Myasthenia gravis:

Myasthenia gravis Autoimmune disorder Nicotinic receptor antibodies obliterate the nicotinic receptors – muscle endplate Population of nicotinic receptors are reduce


MOA AchE Hydrolysis the Ach + Anti AchE Inhibit AchE Frequency of Ach-NR interaction Muscle contraction

Treatment :

Treatment Neostigmine – 15mg oral 6 hourly Pyridostigmine Corticosteroids – prednisolone Azathioprine / cyclosporine Plasmapheresis Thymectomy

Alzheimer’s disease:

Alzheimer’s disease Neurodegenerative disorder Cardinal features Dementia Progressive loss of memory Cognitive functions Loss of short-term memory Treatment Tacrine Rivastigmine Galantamine by inhibiting the breakdown of acetylcholine, by blocking the enzyme acetylcholinesterase .

Organophosphate poisoning:

Organophosphate poisoning Bronchoconstriction Bronchial secretions Sweating Salivation, Lacrimation Bradycardia Hypotention Miosis , Blurring of vision Urinary incontinenc Muscular fasciculation Tachycardia Hypertension Restlessness Insomnia Tremors, Ataxia Confusion Convulsions Respiratory depression Circulatory collapse Signs and symptoms :

Treatment :

Treatment Termination of further exposure Maintain airway Supportive measures Specific antidotes Atropine – 2mg i.v every 10 mins Cholinesterase reactivators – pralidoxime 1-2g i.v Within 24 hrs

Delayed neurotoxicity of organophosphorus compounds:

Delayed neurotoxicity of organophosphorus compounds Fluorine containing group – dyflos , mipafox , triorthocresylphosphate They share with triarylphosphates Severe polyneuropathy Mild sensory disturbances Ataxia Weakness Muscle fatigue & twitching Reduced tendon reflexes Flaccid paralysis & muscle wasting

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Not dependent upon inhibition – AchE Neurotoxic esterase Specificity for hydrophobic esters Myopathies – necrotic lesion & end plate cytostructure changes

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