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Ans (parasympathetic)


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Ans (parasympathetic)

  1. 1. Nervous system Peripheral Nervous System CNS PNS
  2. 2. PNS • Consists of bundles of sensory and motor neurons • It relaying information between the central nervous system and muscles or sensory organs.
  3. 3. ANS • Auto: Self; Nomos:Governing involuntary and maintain homeostasis • Each autonomic fibres made up of two neurons • It innervates the heart, smooth muscles and endocrine glands • ANS controls visceral functions such as circulation, digestion, excretion etc., Somatic nervous system • Voluntary control • Somatic fibres made up of single motor neuron, connect CNS to skeletal muscle • It innervates skeletal muscle • Controls skeletal muscle tone E
  4. 4. ANS • Afferent (Sensory) Sensory organs to CNS • Efferent (Motor) CNS to effector cells. • Motor responses are auto regulatory in nature. Regulates unconscious body functions such as: – All exocrine and some endocrine secretions – heart rate – Blood pressure – Some metabolic functions
  5. 5. Divisions:- –Sympathetic –Parasympathetic
  6. 6. Arise from Length of pre / postganglionic fibres Ganglion
  7. 7. Branching of axons NT released by preganglionic axons NT released by post ganglionic axons
  8. 8. Sympathetic Para sympathetic Arise from thoracolumbar division T1 –L2 craniosacral division III,VII,IX,X, S2-S4 of spinal Length of postganglionic fibres long postganglionic fibres short postganglionic fibres Ganglion Away from effector organ Near or on effector organ Pre ganglion fibres Myelinated Myelinated Post ganglion fibres NonMyelinated Myelinated – Ciliary muscle Non myelinated to other Neurotransmitter released by preganglionic axons cholinergic Cholinergic Neurotransmitter released by post ganglionic axons adrenergic cholinergic Branching of axons highly branched Influences many organs few branches Localized effect
  9. 9. Anger, Alert, Aggressive Flushing of Face Bronchodilatation Mydriasis In. Cardiac output Inc. Muscle tone Lipolysis-Energy Liver Glucogenolysis More energy prod Large B vessels dilate to speed up blood flow
  10. 10. Parasympathetic system • ACh is a first neurotransmitter to be discovered • It a main NT at the neuromuscular junction • It is synthesized from two common chemicals Acetyl Co enzyme A and Choline. • It is metabolized by Acetylcholine esterase.
  11. 11. • Cholinomimetics, mimic the action of Ach c/s parasympathomimetics” • All parasympathetic fibres release Ach. • External Ach is no therapeutic value due to its ultra short acting. • Hypothalamus is major controlling centre
  12. 12. N M Choline + Acetate Pyu PDH Ac Co A Ach by exocytosis Hemicholine - AChE PDH: Pyruvate dehyrogenase AChE: Acetylcholine esterase
  13. 13. Metabolism:- In synaptic cleft, Ach is rapidly hydrolyzed by acetyl cholinesterase (AChE) enzyme Two type of cholinesterases. True And Pseudo cholinesterase True cholinesterase: • Found in cholinergic neurons, ganglia, RBCs and NMJ. • Highly specific for Ach, other acetylesters (methacholine and bethanechol)
  14. 14. Pseudo cholinesterase/ butyrylcholinesterase / Plasma choline esterase : • Synthesized in liver • found in plasma and intestine . • Actions are non specific • It hydrolyzed Ach, benzoylcholine and butyrylcholine esters • Genetically variation • atypicalcholine esterase slowly hydrolyzesis • Typical choline (Fast acetylates)
  15. 15. N receptors • The cholinergic receptors are divided into Nicotinic and Muscarinic. • Nicotinic receptors located – NMJ and Autonomic ganglia – brain (located presynaptically) facilitatory role in release of other NT like DA and Glutamate. • N receptor subtypes are muscle type (NM), neuronal type (NN) and central nicotinic receptors.
  16. 16. Nicotinic receptors NM NN Central N Location Skeletal NMJ post synaptic All autonamic ganglia and adrenal medulla Sensory nerve terminals presynaptically Function Contraction of Sk. muscle NE & E from adrenal medulla Facilitate release of Dopamine, glutamate Mechanism Ligand gated channel Ligand gated channel
  17. 17. • N receptors are inotropic receptors • Quaternary structure indicate five sub units (two alpha, beta, delta and gamma) • Ach binding sites between α and γ subunit, and α and δ subunit
  18. 18. Mechanism of action • Ach interacts with nicotinic Ach receptor, it opens Na+ channel and Na+ ions flow into the membrane • Causes a depolarization, and result in EPP. • It cause excitatory on skeletal muscle. Response is fast and short lived.
  19. 19. Muscarinic • Parasympathetic neuroeffector junction of all smooth muscle and glands. • M receptors are linked to G-protein (metabotrophic) • Responses are slower and longer lived • More sterospecific and structure specific then „N‟
  20. 20. Types of M receptors • 5 types of “M” receptors • M1,M3,M5 (Odd) are excitatory effect through IP3,DAG. • M2,M4 are inhibitory effect cAMP and opening of K+ channels. • M1,M2,M3 are well characterized.
  21. 21. M1 (Neuronal and gastric) M2 (Cardiac) M3(Glandular) M4 M5 Distrib ution Ganglia, gastric parietal cells, CNS (cortex, hippocampus) Myocardium, smooth muscle, presynaptic PNS,CNS Exocrine glands, visceral smooth muscle, vascular endothelium Neostriatum Substanti a nigra Functi on Gastric acid secretion, GI motility, CNS excitation SA node rate of impulse generation AV node velocity and decrease atrial and ventricular contraction Exocrine secretions. Smooth muscle contraction (expect urinary, Blood vessels - - Mech G protein (Gq), IP3,DAG,depolari zation Gi cAmp, opening of K+ channels G protein (Gq), IP3,DAG,depolari zation Gi cAmp, opening of K+ channels G (Gq), IP3,DAG, depolariz Agoni st Oxotremorine Methacholine Bethanechol - - Anta gonist Pirenzepine, Telenzepine Methoctramine,Tripi tramine 4-DAMP, Hexa hydrosiladifenidol
  22. 22. • Ach is more effective with “M” receptors. • “N” receptor activation require larger doses. • At high dose it acts on “N” receptors cause release of NE & Epinephrine from adrenal medulla. M N
  23. 23. Ach- contraction circular muscle of iris- Miosis . (M3) Contraction of ciliary muscle (M3) - suspensory ligaments loose- eye accommodated for near vision Miosis Accommodated for near vision Inc. drainage Lacrimal gland (M3) inc. secretion LENS Ciliary muscle Circular muscle Radial muscle
  24. 24. • Parasympathetic supply only upto SA node, atria and AV node. • Ventricular myocardium has M receptors but no innervation. • SA node M2 receptors activation: – heart rate (-ve chronotrophic) – contractile strength(-ve inotrophic) • AV node M2 activation: conduction velocity and refractory period
  25. 25. RP RP
  26. 26. • Bronchial smooth muscle mucous gland contain M3 receptors Bronchoconstriction Inc. bronchial secretions
  27. 27. Gastric parietal cells M1- Acid secretion GIT smooth muscle, sphincters and gastric gland – M3 • GIT smooth muscle- tone, motility • Sphincters – Relaxation • Glands – secretions Pancreas – Acini cells M3 secretion of pancreatic juice.
  28. 28. Detrusor muscle (M3)- Contraction Relaxation of sphincter . Emptying of urinary bladder. Vascular bed of erectile tissue is dilated, venous sphincters closed. Erection of penis.
  29. 29. • Arteries have no parasympathetic, but M receptors. • Release EDRF, cause vasodilatation. • Exogenous Ach cause fall in BP, it evoke baroreceptor reflex, result sympathetic discharge at heart. • Bardycardia initial, after followed by tachycardia.
  30. 30. CENTRAL NERVOUS SYSTEM Brain PARASYMPATHETIC Spinal cord Stimulates salivation VII Constricts bronchi X Slows heartbeat X Stimulates activity Contracts bladder Stimulates erection of sex organs S Stimulates gallbladder Gallbladder Contracts pupil III
  31. 31. Parasympathomimetics Directly acting Indirectly acting 1. Ach 2. Synthetic choline esters Reversible Irreversible Methacholine Carbamates Carbachol 1. Natural alkaloids 1. Organophosphates Bethanechol 3. Natural alkaloids 2. Quaternary 4.Miscellaneous 2. Carbamates Acridine Tacrine • Edrophonium • Neostigmine • Pyridostigmine • Ambenonium • Demecarium • Rivastigmine • Popoxour • Carbaryl • Tremorine • Oxotremorine • Muscarine • Nicotine • Pilocarpine • Arecoline • Physostigmine • Ecothophate • Isoflurophate • Paraoxon • Parathion • Malathion • Diazon
  32. 32. • Methacholine:- Seldom used therapeutically Use to supra ventricular tachycardia but now not using better drugs available. Muscarinic Mycocardium (3Ms) • Bethanechol:- (Urocholine) resistant to True/Pseudocholinestrase , t½ long • Uses:- i) To reverse post operative atony of baldder ii) To treat GIT atony iii) to treat salivary gland malfunction iv) intra cerebroventricular inj beneficial effect in Alzheimer's disease
  33. 33. Carbachol: – Totally resistances to true/Pseudo chE – N and M action – Avoided therapeutic use bcoz of Large nicotinic action Precautions : for all cholinesters – Never give IV • Sudden rise  cardiac collapse CI: – Bronchial asthma – Peptic ulcers – MI – Hyperthyrodism
  34. 34. Pilocarpine (natural) • Obtained from the leaves of Pilocrapus microphyllus. • Tertiary amine cross BBB • Prominent Muscarinic action. • Increases all the secretions . • Have complex effect on CVS, small doses decreases BP but larger doses have opposite action. (Ganglionic stimulation NN stimulation)
  35. 35. • Penetrates cornea • Promptly causes miosis • Ciliary muscle contracts and IOP reduces. • Uses:  0.5 - 4% eye drops for open angle glaucoma.  To counteract mydriatics after refraction testing.  To prevent or break adhesions of iris with lens • A/E: stinging sensations, painful spasms of accomodation.
  36. 36. • Muscarine :source Amantia muscaria Not used therapeutically • Arecoiline: Found in Beetel nuts Areca catechu Muscrinic as well as nicotinic action Not used therapeutically
  37. 37. Side effects:- result of over stimulation of the parasympathetic system . • Cardiovascular: – Bradycardia, hypotension, conduction abnormalities (AV block and cardiac arrest) • CNS: – Headache, dizziness, convulsions • Gastrointestinal: – Abdominal cramps, increased secretions, nausea, vomiting
  38. 38. • Respiratory: – Increased bronchial secretions, bronchospasms Other: – Lacrimation, sweating, salivation, loss of binocular accommodation, miosis
  39. 39. Physostigmine Physostigma venenosum
  40. 40. Physostigmine and Neostigmine Physostigmine Neostigmine Source Natural alkaloid Synthetic Chemistry Tertiary amine Quaternary amine CNS action Present Absent Oral absorption Good Poor Applied to eye Cross cornea No Action on cholino receptors Absent Present Prominent effect on Autonomic effectors Skeletal muscles (Post operative decurization) Post operative paralytic ileus / urinary retention (1mg SC) Use Glaucoma Myasthenia gravis
  41. 41. Belladona (Atropine) poision • Physostigimine specific antidote for atropine • It cross BBB dec central action and peripheral action • Poison :- 0.5- 1mg IM dose. • 2mg IV/IM initially and additional dose if required
  42. 42. Rivastigmine & Tacrine • Lipophilic • Cross BBB • Cerebroselective ChE • Used for Alzheimer‟s Disease
  43. 43. Glaucoma • Glaucoma is an increased intraocular pressure. • If persistent it leads to optic nerve damage result in blindness. • Glaucoma is caused by impaired drainage or inc. aqueous humor.
  44. 44. • Out flow of aqueous humor: Produced by ciliary epithelium Posterior chamber Flow to anterior chamber by passing betn lens and iris Out through pupil Leaves anterior chamber by flowing through trabecu-lar- mesh work Drainage through canal of Schlemm Episcleral venous plexus Systemic circulation
  45. 45. LENS
  46. 46. 3 Types of glaucoma 1.Primary (after trauma) 2.secondary (followed by cataract operation) 3.congenital.(By birth) -Primary / secondary glaucoma Physostigmine in combination with pilocarpine used. -Congenital glaucoma hardly respond to drug therapy, except surgery. Primary glaucoma is subdivided to 2 types 1. Narrow angle 2. Open angle
  47. 47. • Narrow angle (Closed angle, Acute congestive) • Iris physically blocking canal of Schlemm. • It is medical emergency, drugs may control acute attack but long term surgical (partial iridectomy)
  48. 48. • Wide angle (Open angle, Chronic simple):- • Angle is remain wide but trabecular meshwork losses potency due to degeneration. • So outflow of aqueous humor is impeded. • surgery is not useful.
  49. 49. Cholinomimetics decrease the IOP in both types. In closed angle:- Pulling the Iris, opening of angle In open angle : contraction of longitudinal Ciliary muscle  inc. drainage
  50. 50. Group Mech Dose Directly acting Cholinomimetics Pilocarpine Ciliary muscle contraction, opening of trabecular meshwork, Inc drainage 0.5 - 4% topical 3times a day or ocular inserts Reversible Anti AChE Physostigmine Demecuronium Same 0.25 - 5% topical 2 a day 0.25 - 5% topical 2 a week Irreversible Ecothiophate Only one drug used clinically Same 0.05 - 0.25% once in 2weeks 0.03% topically Beta blockers (DOC for Open) Timolol Betaxolol Levobunolol Carteolol Dec. aqueous humor by blocking β2 present in ciliary epithelium 0.25% - 0.5% topical 2 a day 0.25% - 0.5% topical 2 a day 0.25% - 0.5% topical 1 a day 1% solution topically Non seletive α agonist Epinephrine Dipivefrine α1 Blood α 2 Aqueous secretion 0.5 - 2% topically 0.1%opically 2 or 3 a day Seletive α2 agonist Apraclonidine Brimonidine Dec formation by α2 agonist Potent ocular hypotensive ≠ BBB no systemic side effects 0.5 -1% topically 0.5 -1% topically Restricted use for acute IOP
  51. 51. Group Mech Dose Carbonic anhydrase inhibitors Acetazolamide Dorzolamide Reduce aqueous humor by dec. formation of HCO3 ions in ciliary epithelium 250 – 500mg 3 a day orally 2% soln. 3 a day Hypertonic solutions © Manitol (20%) Glycerol (10%) Reduce IOP  intaocular dehydration by osmatic action IV Infusion Prostaglandins (O) Latanopost Facilitate outflow via uveoscleral Acute glaucoma Pilocarpine nitrate 4% eye drops with physostigmine salicylate1% Install 2drops every 10min initially then longer intervals 2Hrs Inj. Manitol 20% 100ml slow IV Acetazolamide 500mg orally 1tab 2 a day
  52. 52. Myasthenia gravis • Autoimmuno disorder • Occurs 1 in 10,000 • It is associated with production of IgG antibody that binds to Ach receptors at post junctional motor end plate • Fast moving muscles are affected first
  53. 53. Symptoms –Ptosis –Diplopia –Slurring of speech –Difficulty in swallowing Diagnosis Edrophonium test: 1-2mg IV Very shorting anti ChE (5min) Improve –Myasthenia crisis Worsen - Cholinergic crisis
  54. 54. R Myasthenia gravis Tab. Neostigmine 15mg – 6hrly Or Tab. Pyridostigmine 60mg – 8hrly Tab. Prednisolone 20mg 1tab 8hrly Tab. Atropine 0.5mg OD(to dec M action) Plasmapheresis-removal antibodies Thymectomy-Produce antibodies
  55. 55. Organophosphates INSECTICIDES • Echothiophate • Isoflurophate • Parathion, Malathion CHEMICAL WEAPONS Chemical warfare agents-nerve gases • Tabun • Serin • Soman
  56. 56. Mechanism of Action Phosphorylating the active Site of serine. Covalent modification Duration: days Irreversible action By the loss of one of the alkyl group the phosporylated enzyme may become resistant to hydrolysis thus causing irreversibility.
  57. 57. Uses of AChE Ecothiophate • Quaternary compound • Water soluble • Don‟t cross BBB • Used as miotic and management of glaucoma (Ophthalmic solution 0.05- 0.25%) • Potent and longer acting • No local irritation Isofluorophosphate : • oil in character cause local irritation
  58. 58. Effects • Cardiovascular: Bradycardia, hypotension • Gastrointestinal: Nausea, vomiting, diarrhea • Urinary tract: Incontinence, urinary urgency • Glands: Salivation, lacrimation, sweating • Eye: Miosis, blurred vision • Respiratory bronchoconstriction, bronchial secretion
  59. 59. Toxicity of AChE Inhibitors 2. Skeletal Muscle: Fasciculations, weakness, paralysis 3. CNS: Ataxia, confusion, convulsions, coma, paralysis 4. Death: Respiratory depression due to bronchoconstriction, increased secretions, paralysis of diaphragm and intercostals muscles and central respiratory depression
  60. 60. Treatment of AChE Poisoning Atropine Reverses muscarinic but not nicotinic AchE reactivating drugs Pralidoxime (Pyrindine 2-Aldoxime Methylcholride 2-PAM):
  61. 61. HON=CH H20 N=CH Oxime Oxime Phosphonate complex
  62. 62. General supportive Removal of clothes, washing of contaminated skin, gastric lavage , artificial respiration, If convulsions  Diazeepam Pradlidoxime 1-2g Slow IV infusion over 15- 30min to reactive and regeneration of AChE 2 mg IV repeated every 10 mins till signs of full atropinization i.e. dilatation of pupils, tachycardia R Organo Phosphorus poison Diacetylmonoxime cross BBB
  63. 63. Thank Q