1. Autonomic nervous system ANS functions below the level of consciousness and control the visceral functions. ANS supplies all organs except skeletal muscles (supplied by somatic system).

2. Autonomic nervous system

4. TRANSMITTERS OF ANS: Acetylcholine is the nerve transmitter of preganglionic nerves of both parasympathetic and sympathetic nervous system. Acetylcholine is the nerve transmitter of postganlionic nerves of parasympathetic nerves system.

5. Autonomic nervous system TRANSMITTERS OF ANS: Norepinephrine is the major nerve transmitter of postganglionic nerves of sympathetic system. Acetylcholine is the nerve transmitter of postganlionic nerves of sympathetic nervous system supplying sweat glands.

6. Autonomic nervous system PARASYMPATHETIC NS: The preganglionic nerves arise from 1. Midbrain – III cranial nerve. 2. Medulla – VII, IX and X cranial nerve. 3. Sacral part of spinal cord – S - 2, 3, 4 SYMPATHETIC NS: The preganglionic fibers originate from the thoracolumbar region of the spinal cord.

18. Parasympathetic nervous system CHOLINERGIC TRANSMISSION: Acetylcholine is synthesized by the enzyme choline acetyltransferase (ChAT). Release of acetylcholine occurs by exocytosis with the influx of calcium ions. Inactivation by acetyl cholinesterase is the major mechanism for termination of action of Ach.

19. Autonomic nervous system Acetylcholine is hydrolyzed by the enzyme Cholinesterase There are two types of cholinesterase – Acetyl cholinesterase (true) – present at all neuromuscular junction. It hydrolyses specifically Acetylcholine. Butyryl Cholinesterase (Pseudo) – present in plasma and liver. It hydrolyzes procaine and suxamethonium.

20. Autonomic nervous system

23. Parasympathetic nervous system Acetylcholine acts on two types of receptors: Nicotinic receptors. Muscarinic receptors.

24. Autonomic nervous system Types of nicotinic receptors: Nicotinic nerve (NN) Nicotinic muscle (NM) Adrenal medulla, Autonomic ganglia Neuromuscular junction Opening of Na/K channel

25. Autonomic nervous system M1M2M3 Ganglia, GIT glands, CNS HeartSmooth muscle, Sweat / lacrimal glands ↑ PLC, ↑ IP3 & DAG ↑ Ca entry ↓ AC, ↓ cAMP, K channel open ↑ PLC, ↑ IP3 & DAG ↑ Ca entry Types of muscarinic receptors: M1, M2, M3, M4, M5

27. Autonomic nervous system ACETYLCHOLINE: No therapeutic implications Diffuse action Rapid hydrolysis

28. Autonomic nervous system ACETYLCHOLINE: HEART: M2 RECEPTORS Decrease in the heart rate Decrease in the conduction Decrease in the contraction BLOOD VESSELS: M3 Vasodilation via the release of nitric oxide

29. Autonomic nervous system ACETYLCHOLINE : GIT: M1/M3 Increase the tone and peristalsis. Increase the secretion of the GIT glands and lacrimal gland. Relax the sphincter. URINARY BLADDER: M3 Contraction of detrusor. Relaxation of trigone and sphincter.

30. Autonomic nervous system ACETYLCHOLINE : RESPIRATORY TRACT : Constriction of bronchus Increases the secretions of the respiratory tree.

31. Autonomic nervous system ACETYLCHOLINE : EYE : IRIS has parasympathetic innervation and acts on muscarinic receptors present on Circular or Sphincter muscle and Ciliary muscle (M 3 receptors ) Radial muscle has alpha 1 receptors.

32. Autonomic nervous system

35. ACETYLCHOLINE : EYE : It causes the spasm of accommodation by contraction of ciliary muscle which causes the zonula to relax, thus allowing the lens to become more convex. Thus vision is fixed for near objects.

36. Autonomic nervous system Nicotinic action of Acetylcholine : Autonomic ganglia ( N N ) – both parasympathetic and sympathetic are stimulated. Skeletal muscle ( N M ) : Contraction of the fibers.

37. Autonomic nervous system

38. CHOLINERGIC AGONISTS A.CHOLINE ESTERS – Acetylcholine, Methacholine, Carbachol, Bethanechol B.CHOLINOMIMETIC ALKALOIDS – Pilocarpine C.ANTICHOLINESTERASES

39. Autonomic nervous system

40. DRUGS AFFECTING CHOLINERGIC TRANSMISSION : A.ANTICHOLINESTERASES - Neostigmine B.INHIBITING CHOLINE CARRIER - Hemicholinium C.INHIBITION OF VESCICULAR STORAGE - Vesamicol D.INHIBITION OF RELEASE – Botulinium toxin

41. Autonomic nervous system Choline esters – Acetylcholine, Methacholine, Bethanechol poorly absorbed from the stomach poor lipid solubility poor BBB penetration

42. Autonomic nervous system

43. CHOLINE ESTERS: Methacholine and Bethanechol have no nicotinic actions Methacholine has prominent CVS action Carbachol and Bethanechol on GIT and Urinary bladder. Carbachol and Bethanechol are resistant to the hydrolysis by AchE

44. Autonomic nervous system CHOLINOMIMETIC ALKALOIDS – Pilocarpine Pilocarpine – stimulates only muscarinic receptors Used in chronic simple glaucoma, acute congestive glaucoma and as miotic.

45. Autonomic nervous system ANTICHOLINESTERASES AGENTS These agents inhibit the AchE present in the synaptic regions. Thus they prolong the existence of Ach released from the nerve endings. These are of two types Reversible Anti - ChE Irreversible Anti - ChE

46. ANS Irreversible Anti-ChE agents are insecticides and nerve gas poisons Insecticides – Organophosphorus compounds - Parathion, Malathion, Diazinon (TIK-20), Echothiopate Nerve gas poisons – Soman, Sarin, Tabun

47. Nerve Agents Organophosphate insecticides Cholinesterase inhibitors Pralidoxime Cholinesterase generator Chemical antagonist Enzyme active site

48. ANS ANTICHOLINESTERASES AGENTS Reversible : Short : Edrophonium Medium : Neostigmine, Physostigmine, Pyridostigmine, Tacrine

49. ANS ANTICHOLINESTERASES

50. ANS ANTI-CHOLINESTERASES AGENTS Mechanism of action : Acetyl cholinesterase (AchE) is an enzyme with anionic and esteratic site. Acetylcholine (Ach ) involves attraction of the positive charge N+ of Ach and anionic site; acetylation of serine leading to the acetylated enzyme. The acetylated enzyme reacts with the water to produce acetic acid and free enzyme within milliseconds.

51. ANS CHOLINESTERASES

52. ANS ANTICHOLINESTERASES

53. ANS Reversible anticholinesterases : Edrophonium, Neostigmine and Physostigmine They combine with the ChE and carbamylated enzyme is slow to hydrolyze and free the enzyme (~30 mins).

54. ANS Physostigmine : Naturally occurring alkaloid. Tertiary amine. Oral absorption is good. CNS action is present. Used in glaucoma and as antidote in atropine poisoning.

55. ANS Neostigmine : Synthetic Quaternary amine Poor oral absorption CNS action absent Prominent action on skeletal muscles Used in ileus, urinary retention, myasthenia gravis.

56. ANS Irreversible Anti-cholinesterases: Organophosphorus compounds - Parathion, Malathion The organophosphorus compounds reacts with esteratic site which is hydrolyzed extremely slowly with water or not at all. The phosphorylated enzyme undergo aging by the loss of one of the alkyl groups and become totally resistant to hydrolysis.

57. ANS CHOLINESTERASE REACTIVATORS : The phosphorylated ChE reacts very slowly or not at all with the water. If more OH groups in the form of Oximes are provided, reactivation occurs faster. Pralidoxime (PAM) attaches to the anionic site in presence of Organophosphorus compounds and set the enzyme free. PAM is ineffective in case of physostigmine poisoning as anionic site is not free.

58. ANS USES OF CHOLINOMIMETIC DRUGS: Open / Wide angle glaucoma. Miotics Myasthenia gravis Retention of urine Drug poisoning – Atropine, TCA. Alzheimer's disease – Donepezil, Galantamine, Rivastigmine, Tacrine

59. ANTICHOLINERGIC DRUGS ANTIMUSCARINIC OR PARASYMPATHOLYTICS: Natural alkaloids : Atropine, Scopolamine Synthetic : Homatropine, Ipratropium, Oxybutynin, Cyclopentolate, Tropicamide, Dicyclomine, Pirenzepine, Glycopyrrolate, Tolterodine Antiparkinsonism : Trihexyphenidyl, procyclidine, benztropine

60. ANS ATROPINE: PHARMACOLOGICAL ACTIONS : Atropine blocks the muscarinic receptors CNS : CNS stimulant action. High doses causes restlessness, hallucinations and disorientation.

61. ANS ATROPINE: CVS : The most prominent action is tachycardia --- due to blockade of M2 receptors It facilitates AV conduction No marked effect on the BP

62. ANS ATROPINE: EYE : Atropine causes mydriasis and cycloplegia (paralysis of accommodation) by blocking M3 receptors Vision is fixed for far objects.

63. ANS ATROPINE : SMOOTH MUSCLES : All smooth muscles that receive parasympathetic innervations are relaxed by atropine. GIT – Peristalsis is inhibited - Constipation Bronchus – dilatation Urinary bladder – retention of urine.

64. ANS ATROPINE : GLANDS : Atropine markedly decreases the secretions of the salivary and lacrimal glands, acid in the stomach. Body temperature increase. Atropine has a mild local anesthetic effect on the cornea.

65. ANS ATROPINE : PHARMACOKINETICS : Atropine is absorbed from the GIT. Freely penetrate the cornea Half life of 4 hours Scopolamine has better passage to brain than atropine.

66. ANS USES OF ANTIMUSCARINICS : ATROPINE OR SUBSTITUTES : Preanesthetic medication Peptic ulceration Antispasmodic Bronchial asthma – Ipratropium Mydriatic and cycloplegia Bradycardia

67. ANS USES OF ATROPINE / SUBSTITUTES : Anti-parkinsonism - Trihexyphenydyl Overactive Bladder – Oxybutynin, Tolterodine Motion sickness - Scopolamine Antidote to Organophosphorus poisoning.

68. ANS Adverse effects of atropine : Blurred vision, Confusion, Mydriasis, Constipation, urinary retention, tachycardia. May precipitate glaucoma or urinary retention.

69. ANS Ipratropium bromide Tiotropium bromide Inhalation for COPD and bronchial asthma Does not affect the mucociliary activity of the respiratory tract.

70. ANS As mydriatics: Cyclopentolate eye drops –long acting Tropicamide eye drops -- short acting As Antispasmodic / Anti-ulcer: Glycopyrrolate, Dicyclomine For Overactive Bladder : Tolterodine.

71. Autonomic nervous system