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Cholinergic drugs
The document provides an overview of the nervous system and cholinergic transmission. It discusses the organization and functions of the sympathetic and parasympathetic nervous systems. It describes the cholinergic receptors (muscarinic and nicotinic), cholinergic transmission, and the actions of cholinergic drugs including choline esters, alkaloids, anti-cholinesterases, and their therapeutic uses and side effects. In summary, it provides a comprehensive review of the cholinergic nervous system, receptors, transmission, and pharmacology of drugs that act on this system.
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Cholinergic drugs
- 2. Nervous System: Overview NervousSystem (NS) Central Nervous System(CNS) Cerebrum, Cerebellum, Brainstem, Spinal Cord Peripheral Nervous System (PNS) Somatic Nervous System Autonomic Nervous System (ANS) Sympathetic Nervous System Parasympathetic Nervous System
- 3.
- 4. Sympathetic vs ParasympatheticNS Sympathetic NS Parasympathetic NS Thoracolumbar outflow Most ganglions are nearer to vertebral column Shorter preganlionic fibres Craniosacral outflow Ganglions are within or near to target organ Longer preganglionic fibers Preganglionic NT: Acetylcholine Preganglionic NT: Acetylcholine Postganlionic NT: Norepinephrine (Noradrenaline); Acetylcholine at some sites Postganglionic NT: Acetylcholine; Nitric oxide at some sites
- 5. Cholinoceptors • Muscarinic (GProtein Coupled Receptor) • SelectiveAgonist: Muscarine • Antagonist: Atropine • Five Subtypes: M1-M5 • M1, M3, M5: excitatory • Nicotinic (Ligand gated cation channel) • SelectiveAgonist: Nicotine • Antagonist: d-tubocurarine • Two subtypes: NN & NM • Usually excitatory
- 6. CholinergicTransmission Site Type ofReceptor Selective Agonist Selective Antagonist All postganglionic parasympathetic(parasym). Few postganglionic sympathetic (sym)1 Muscarinic Muscarine Atropine Ganglia (sym. & parasym.) Adrenal Medulla Nicotinic (NN) Dimethyl Phenyl Piperazinium (DMPP) Hexamethonium Skeletal Muscles Nicotinic (NM) PhenylTrimethyl Ammonium (PTMA) d-tubocurarine CNS (cortex, basal ganglia, spinal cord, others) Muscarinic Muscarine/ Oxotremorine Atropine Nicotinic Carbachol d-tubocurarine
- 7. CholinergicTransmission • Synthesised fromAcetyl CoA and Choline in presence of Choline Acetyl Transferase • Stored in vesicles • Released when impulses arrives by exocytosis • Degraded by Acetylcholinesterase (AChE)
- 8. Muscarinic Cholinoceptors Features M1M2 M3 Location & Function Autonomic ganglia: depolarization1 Gastric glands: increased secretion CNS (learning, memory, motor function) Heart: Decrease rate, force Nerve endings: Decrease ACh release CNS: tremor, analgesia Visceral smooth muscle: contraction Visceral smooth muscle: contraction Iris: constriction of pupil Ciliary muscle: contraction2 Exocrine glands: secretion Vascular endothelium: vasodilatation Nature Gq protein coupled Gi/G0 protein coupled Gq protein coupled Transducer mechanism IP3/DAG – increaseCa++ PLA2 increasd – PG synthesis K+channel opening, decreased cAMP IP3/DAG – increase Ca++ PLA2 increasd – PG synthesis Agonists Oxotremorine, MCN 343A Methacholine Bethanechol Antagonists Pirenzepine,Telenzepine Methotramine, Triptiramine Solifenacin, Darifenacin
- 9. Nicotinic Cholinoceptors Features NMNN Location & Function Neuromuscular junction: depolarization of muscle end plate – contraction of skeletal muscle Autonomic ganglia: depolarization – postganglionic impulse Adrenal medulla: catecholamine release CNS: site specific excitation or inhibition Nature Intrinsic ion channel, pentamer of α2 β ε or γ and δ, each with 4 transmembrane segments Intrinsic ion channel, pentamer of only α or α,β subunit, each with 4 transmembrane segments Transducer mechanism Opening of cation channels (Na+ K+) Opening of cation (Na+ K+ Ca++) channels Agonists PTMA, nicotine DMPP, nicotine Antagonists Tubocurarine, α-Bungarotoxin Hexamethonium,Trimethaphan
- 10. Cholinergic (Cholinomimetic / Parasympathomimetic)Drugs Cholinergic Agonists Anti-cholinesterases Choline esters Alkaloids Reversible Irreversible Acetylcholine Pilocarpine Carbamates: Physostigmine, Neostigmine, Pyridostigmine, Edrophonium, Rivastigmine, Donepezil, Galantamine Carbamates: Carbaryl, Propoxur Methacholine Arecoline Organophosphates: Dyflos, Echothiophate, Malathion, Diazinon, Tabun, Sarin, Soman Carbachol Muscarine Bethanechol Acridine:Tacrine
- 11. MuscarinicActions of CholinergicAgonists(ACh) Organ Receptor Involved Mechanism Effect Heart M2 Hyperpolarization of SA Node Bradycardia, cardiac arrest M2 Increased Refractory Period at AV node and His-Purkinje Fibres Delayed conduction, Prolonged P-R interval, Heart Block Blood Vessels PLc – IP3/DAG mediated EDRF (NO release):Vasodilation Fall in BP, flushing M3 Vasoconstriction Release of NO – dilatation of cavernous sinus Erection of penis
- 12. MuscarinicActions of CholinergicAgonists (ACh) Organ Receptor Involved Mechanism Effects Smooth Muscle M3 + M2 Increased tone and peristalsis of GIT, sphincters relaxed Abdominal cramps, evacuation of bowels M3 Increased peristalsis in ureters, detrusor contracts, trigone & sphincter relaxes Voiding of bladder M3 Constriction of bronchial muscles Bronchospams, dyspnoea, asthamatic attack
- 13. MuscarinicActions of CholinergicAgonists (ACh) Organ Receptor Involved Mechanism Effects Glands M3 + M2 Increased secretion Salivation, sweating, lacrimation, increased tracheobronchial and gastric secretions Eyes M3 Contraction of circular muscle of iris Miosis Contraction of ciliary muscle Blurring of near vision, increased aqueous outflow, decreased intra ocular pressure in glaucomatous eye
- 14. Nicotinic Actions ofCholinergic Drugs (ACh) Organ Receptor Involved Mechanism & Effects Autonomic Ganglia NN • Stimulation of sym. & parasym. ganglia (higher doses) Skeletal Muscles NM • Iontophoreic application of ACh to muscle end plate: contraction of fibres • Intra-arterial injection: twitching and fasciculations
- 15. CNS Action ofACh • Intravenous injection: No central effects • Direct injection into brain: arousal response followed by depression • Complex neurological and behavioural effects
- 16. Drug interactions Synergism Antagonism Anticholinesterases:potentiation Atropine, Atropine like substances Methacholine: potentiation (lesser extent) Adrenaline Carbachol, bethanechol: additive
- 17. Choline esters: Usesand Side Effects • Uses: • Rarely used (evanescent and non selective action) • Bethanechol: non- obstructive urinary retention, neurogenic bladder • Side effects: • Belching, colic • Involuntary urination/defecation • Flushing, sweating • Fall in BP • Bronchospasm
- 18. Cholinomimetic Alkaloids Pilocarpine • Source:Pilocarpus microphyllus • Prominent muscarinic actions; ganglionic action via M1 receptors • CVS Effects: • Small dose – fall in BP (muscarinic, ?M2) • Higher dose – rise in BP and tachycardia (ganglion mediated; M1) • Eyes: • Local application – penetrates cornea, miosis, ciliary muscle contraction, fall in intraocular tension (M3) • Use: As Miotics (counteract mydriatics used for refraction, along with mydriatics to prevent/break adhesions), In open angle glaucoma, • S/E: marked sweating, salivation, increased secretions
- 19. Arecholine • Source: betelnut Areca catechu • Muscarinic as well as Nicotinic actions • No therapeutic use Cholinomimetic Alkaloids
- 20. Muscarine •Source: mushrooms Amanitamuscaria, Inocybe sps. •Only muscarinic actions •Not used therapeutically, has toxicological importance Cholinomimetic Alkaloids
- 21. Mushroom Poisoning Early type(Muscarinic) HallucinogenicType Late type (Phalloidin) Toxic principle Inocybe and related sps. Muscimol; isoxazole (A. muscaria) Peptide toxin of A. phalloides,Galerina Mechanism Blocks M receptors in CNS Inhibit RNA and protein synthesis Features Muscarinic Hallucinogenic, central manifestations Damage to GIT, liver, kidney Presentation Within an hour of eating After hours of ingestion Treatment Atropine Nonspecific, Atropine contraindicated Supportive
- 22. Anti-cholinesterases (AChE) •Inhibits Cholinesterases(ChE) protects ACh from hydrolysis cholinergic effects •Some have additional direct action on Nicotinic receptors
- 23. AChE: Mechanism ofAction • Normally, after showing its activity, ACh is degraded by hydrolysis by Cholinesterase(ChE) into choline and acetic acid • Hydrolysis of AChEs is either slow (carbamates, about 30 mins) or extremely slow (organophosphates, days), hence the enzyme ChE is rendered inactive normal ACh at the junction cannot be hydrolysed prolonged action of ACh (cholinomimetic action) • Hydrolysis after ageing not possible, new ChE needs to be formed
- 24. AChE: PharmacologicalActions • Dueto amplification of endogenous Ach • Intensity of action on muscarinic, nicotinic and CNS varies among different agents Characteristics Example Muscarinic Nicotinic CNS Ganglia Skeletal Muscle Lipid soluble Physostigmine, organophosphates +++ + Less prominent +++ Lipid insolube Neostigmine Less prominent + +++ none
- 25. AChE: Pharmacological Actions •Ganglia: stimulation at low dose, blockade at high dose • Stimulation via M1 receptors • High dose: persistent depolarization depletion of ACh blockade of transmission • CVS: complex, unpredictable effects • Muscarinic: bradycardia, hypotension;Ganglionic: tachycarida, hypertension • Action on medullary centres(stimulation then depression), ganglion blockade at high doses • Skeletal Muscles: twitching and fasciculations at low dose, weakness and paralysis at high dose • Prolonged action of ACh on motor end plates and prejunctional fibres twitching and fasciculations • High dose: persistent depolarization neuromuscular transmission blockade weakness and paralysis • CNS: general arousal at low dose, excitement, confusion at high dose • Lipophilic agent: generalised alerting response, improved cognition inAlzheimer’s Disease • Higher doses: excitement, mental confusion, disorientation, tremors, convulsions, coma
- 26. AChE: Pharmacokinetics • Physostigmine: •Rapid absorption (oral, parenteral, topical in eye) • Crosses BBB, central effects • Metabolism by hydrolysis • Neostigmine: • Poor oral absorption (20-30 times parenteral dose) • Does not cross BBB, cornea • Partially hydrolysed and partially excreted unchanged in urine • Organophosphates: • Absorbed from all sites • Hydrolysed and oxidised and then excreted
- 27. AChE:Uses As Miotic • Glaucoma: •Increases tone of ciliary muscle and sphincter pupillae opening of trabeculae intra ocular tension (iot) falls in open angle glaucoma • Pilocarpine – rapid and short lasting (4-6hrs), 6-8hrly instillation required; fluctuation of iot in between seen, S/E: diminution of vision especially in dim light, spasm of accommodation, brow pain; nausea, diarrhoea, sweating, bronchospasm with higher concentration; also used in combination for angle closure glaucoma • Physostigmine 0.1% - supplement pilocarpine • Reversal of mydriasis after refraction • Prevent/break adhesions (iris-lens, iris-cornea): in conjunction with mydriatics
- 28. AChE:Uses • Myasthenia gravis(MG): •Treatment • Neostigmine 15 mg orally 6 hrly, adjusted according to response, dose requirement fluctuates in accordance to remission and exacerbation • Pyridostigmine • Atropine if muscarinic side effects seen, cholinergic weakness/crisis if dose adjustment not adequate • DiagnosticTests • AmeliorativeTest: Inj Edrophonium 2mg i.v. (test dose) followed by 8 mg i.v. after 30-60 sec. reversal of weakness and short lasting improvement of strength: +ve for MG • ProvocativeTest: hazardous – not performed • Demonstration of anti-NR antibodies in plasma or muscle biopsy specimen
- 29. AChE:Uses • Post-operative paralyticileus/urinary retention: Inj. Neostigmine 0.5-1 mg s.c. • Post-operative decurarization: Neostigmine 0.5-2 mg i.v. preceeded by atropine to block muscarinic effects rapidly reversal of muscle paralysis induced by competitive neuromuscular blockers • Cobra bite: Neostigmine + Atropine to prevent respiratory paralysis can be used • Belladona poisoning/Dhatura poisoning: Physostigmine 0.5-2 mg i.v. repeat as required (S/E – hypotension, arrhythmia, undesireable central effects: last resort), Neostigmine safer • Drug Overdose:TCA, phenothiazines, antihistaminics – Physostigmine (rare) • Alzheimer’s Disease: cerebroselective AChE (rivastigmine, donepezil, galantamine)
- 30. Phew!!!! • That willbe all for today • Please revise the topic…. • Next class:Thursday 31st December, 2015;Topic: Anticholinergics Drugs
Editor's Notes
- #6 GPCR: G-protein coupled receptors; i.e. the response is carried out by attached GTP protein to the interior surface of receptor M1 M3 M5: Gq coupled – Phospholipase C - IP3/DAG-Ca++; Gq – PLA2 – PG/LKT synthesis M2 M4: Gi mediated – opening of K+ channels (beta,gamma subunit)– inhibit adenylyl cyclase (alpha subunit) – hyperpolarization/reduced activity
- #7 1: sweat glands, hair follicles, blood vessels to skeletal muscles
- #9 1: release of Ach M2: SA node: decreased impulse generation; AV node: decrease velocity of conduction; Atrium: shortening of APD, decreased contractility; Ventricle: decreased contractility 2: loss of near accommodation, blurring of near vision
- #10 PTMA: phenyl trimethyl ammonium DMPP: dimethyl phenyl piperazinium
- #12 EDRF: endothelium dependent relaxing factor
- #29 Treatment: Acts by allowing ACh released from prejunctional endings to accumulate and act on receptors over a large area, as well as by directly depolarizing the end plate Only palliative treatment Other treatment: Corticosteroids, plasmapheresis (myasthenic crisis), thymectomy Diagnostic Tests Ameliorative Test: Inj Edrophonium 2mg i.v. (test dose) followed by 8 mg i.v. after 30-60 sec. reversal of weakness and short lasting improvement of strength: +ve Provocative Test: 0.5 mg d-tubocurarine i.v. marked weakness in myasthenic patients; hazardous – not performed Demonstration of anti-NR antibodies in plasma or muscle biopsy specimen