Introduction to ANS (autonomous nervous system) & cholinergic drugs

Introduction to ANS (Autonomous Nervous System) & Cholinergic drugs

1. Introduction to ANS (Autonomous Nervous System ) & Cholinergic drugs presented By Dr. Manoj Kumar Assistant Professor Department of Pharmacology Adesh Medical College & Hospital Ambala Can’t .

2. Introduction to ANS Neurons = A cell that received & send electrical signal over long distance. Nervous system = Brain + Spinal Cord + Ganglia + Receptor organ. CNS = Brain + Spinal Cord. PNS = Other then Brain + Spinal Cord ANS = Heart muscles, smooth muscles. Sympathetic nerves system = adjust stress & prepare the body for fight or flight. Parasympathetic nerves system = adjust stress free, rest and digest. 2

3. Introduction to ANS Con.. Somatic = ( voluntary ) neuron association with skittle muscle influence voluntary movement. Involuntary nerves = that control muscles of internal organs- heart, blood vessels, exocrine glands, lungs, stomach, viscera Reflex = muscles contraction in response to stretching. Hypothalamus = control – 1. Body temperature 2. Hunger 3. Thirst 4. Body equilibrium. Maintains homeostasis Endocrinal, metabolic, immunological, emotional activities , somatomotor , Integrates sensory. 3

4. Introduction to ANS Con .. Afferent nerves = nerve that care impulse toward CNS. Efferent nerves = nerve that care impulse away from CNS. Pre- ganglionic neuron = myelinated Post- ganglionic neurons = non- myelinated Ganglion = junction b/w pre & postganglionic fibers. Nerve conduction = generate nerve impulse Nerve transmission = transfer impulse one nerve to another nerve or muscles. 4

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6. Neurotransmitters Sympathetic: ADRENERGIC Central: EPINEPHRINE Peripheral: NOREPINEPHRINE Parasympathetic: CHOLINERGIC Acetylcholine 7

7. Cholinergic drugs .

8. Cholinergic system Acetylcholine is the principal NT at nm junction. Synthesize, store, release ACh Sites of ACh release Ganglia: pre-ganglionic fibres of ANS (both sympathetic & para -sympathetic) Post-ganglionic parasympathetic nerve endings Sweat glands Skeletal muscles Adrenal medulla CNS: brain, spinal cord 9

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10. Synthesis of acetylcholine 11

11. Steps in Cholinergic transmission Synthesis Storage of NT Release Post junctional effects Termination of action 12

12. Cholinesterases ACh is hydrolyzed to choline & acetic acid by cholinesterases 2 types True cholinesterases At neurons, ganglia, nm junction Pseudocholinesterases / Butyryl cholinesterases In plasma, liver 13

13. Cholinergic Receptors 2 types Muscarinic Present in heart, smooth muscles, glands, eyes, CNS GPCRs M 1 -M 5 Agonist – Muscarine ; Antagonist – Atropine Nicotinic Present in nm junction, autonomic ganglia, adrenal medulla Ion channels 5 subunits N M (on NM junction of skeletal muscles), N N (on autonomic ganglia, adrenal medulla) Agonist – Nicotine, Antagonist – Curare 14

14. Cholinergic receptors Receptor Location M 1 Ganglia; Gland; CNS, Parietal cell of stomach M 2 Heart; Pre-synaptic; CNS M 3 Glands; Smooth ms; CNS, E yes M 4 CNS M 5 CNS N M Skeletal muscle NM junction N N Autonomic ganglia Adrenal medulla CNS 15

15. CHOLINERGIC RECEPTORS G-Protein coupled Receptors MUSCARINIC NICOTINIC Ligand gated ion Channels

16. Cholinomimetic Agents Choline esters Acetylcholine Methacholine Bethanechol Carbachol Alkaloids & related drugs Muscarine Pilocarpine Arecholine 17 Parasympathomimetic drugs/ agonists Directly acting ( ACh like) agents

17. Cholinomimetic Agents Reversible AntiChEs Tertiary Physostigmine Tacrine Quarternary Neostigmine Pyridostigmine Edrophonium Irreversible anticholinesterases Organophosphates Miotics Dyflos (DFP) Ecothiophate Insecticides Malathion ( Licel ), Parathion Diazinon (Tik-20) War gases: Sarin , Soman , Tabun Carbamates : Propoxur ( Bagyon ) 18 Indirectly acting agents ( ACh enhancers/amplifiers)

18. Cholinergic drugs Chemicals that act at the same site as ACh Mimic actions of ACh Acetylcholine Muscarinic actions Heart (M2): Depress SA, reduces heart rate, force of contraction, decrease conduction velocity Blood vessels: relax vascular smooth muscles, dilates blood vessels of skin & mucous membrane,  BP 19

19. Acetylcholine Smooth muscle:  tone of all other non-vascular smooth muscles GIT:  peristalsis (M3) Urinary bladder (M3): contract detrussor , relax trigone of bladder, promotes voiding of urine Bronchus (M3): contraction: Bronchospasm Secretory glands: Enhance secretions (  GI secretions-M1) Eye (M3): miosis (circular muscles of iris), accommodation, drainage of aqueous humor, ciliary muscle contraction 20

20. Acetylcholine Nicotinic actions: NMJ Contraction of skeletal muscles Autonomic ganglia Stimulation of symp & parasymp ganglia, adrenal medulla CNS Neurotransmitter Produce alerting response 21

21. Acetylcholine Uses PO: Destroyed in GIT N ot used therapeutically Esters of ACh Carbachol : longer DOA Used in glaucoma Bethanechol : hypotonia of bladder & GI smooth muscles, post op paralytic ileus, urinary retention Adverse effects Diarrhea, flushing, salivation, sweating, bradycardia, hypotension, Bronchospasm, syncope 22

22. Alkaloids P ilocarpine Natural source: Stimulates cholinergic receptors Tertiary amine (crosses BBB) Miosis , spasm of accommodation,  IOP  Sweat, salivary secretions Adverse effects: burning sensation, painful spasm of accommodation, brow ache, corneal edema Uses: glaucoma, break adhesions between iris & lens, counter dryness of mouth . 23

23. Glaucoma Increased IOP Causes Blockage of drainage of aqueous humor Increased formation of aqueous humor Management Decrease formation of aqueous humor Timolol , betaxolol , levobunolol Adrenaline, acetazolamide , Apraclonidine , brimonidine . Increase drainage of aq humor Carbachol , pilocarpine , physostigmine , latanoprost 24

24. Alkaloids Arecoline C hief alkaloid of areca or betel nuts Muscarinic & nicotinic receptors Enhances salivary secretion No therapeutic indication Muscarine Quaternary amine Muscarinic receptors Found in mushrooms (Amanita muscaria ) Small amounts  edible Large amounts  poisonous E ffects : fall in BP, temporary pause of heart beat , Antidote : ATROPINE 25

25. Anticholinesterases The agents inhibiting the action of acetylcholinesterase are called anti acetylcholinesterase ( AntiCHEs ) or Cholinesterase inhibitors 26

26. Anticholinesterases Reversible AntiChEs Tertiary Physostigmine Tacrine Quarternary Neostigmine Pyridostigmine Edrophonium Irreversible anticholinesterases Organophosphates Miotics Dyflos (DFP) Ecothiophate Insecticides Malathion ( Licel ), Parathion Diazinon (Tik-20) War gases: Sarin , Soman , Tabun Carbamates : Propoxur ( Bagyon ) 27

27. Action of anticholinesterases 28

28. Physostigmine - only anticholinesterase capable of crossing the blood brain barrier. Is more lipid soluble. Used as an antidote for overdosage of anticholinergics such as: atropine, antihistamines, TCA, phenothiazines . G laucoma. Pyridostigmine - drug of choice for patients with Myasthenia gravis.

29. Neostigmine - prototype anticholinesterase agent. Used for long-term treatment of myasthenia gravis and as an antidote for tubocurarine and other non- depolarizing agents in surgery. Donepezil - Used in the treatment of mild to moderate Alzheimer’s disease. Helps to increase or maintain memory and learning capabilities.

30. Cobra bite – edrophonium (prevent respiratory paralysis. atropine poisoning – Physostigmine (antogonizes both central and peripheral effects ). Alzheimer’s Disease – Donepezil , galantamine , tacrine, rivastigmine .

31. Myasthenia Gravis ( Myo + asthenia) Autoimmune disorder Reduction in number of free N M receptors Causes: Development of antibodies directed to Nicotinic receptors at muscle end plate Reduction in number by 1/3rd of N M receptors Structural damage to NM junction Weakness & easy fatigability on repeated activity, with recovery after rest 32

32. Myasthenia gravis – Treatment Neostigmine : improve muscle contraction by allowing ACh released from prejunctional endings to accumulate . Neostigmine – 15 to 3 mg. orally every 6 hrly  Dose frequency is Adjusted according to the response Pyridostigmine – less frequency of dosing

33. Other drugs: Corticosteroids (prednisolone 30-60 mg /day induces remission and 10 mg daily or on alternate days can be used for maintenance therapy. ) – immunosuppression Inhibits production of NR antibodies . Both azathioprine and cyclosporine also inhibit NR- antibody synthesis by affecting T-cells. Removal of antibodies by plasmapheresis (plasma exchange) is another therapeutic approach .

34. Anticholinesterases Uses Glaucoma Reverse effects of mydriatic To prevent/break adhesions between iris & lens Myasthenia gravis Reverse effects of muscle relaxants Post op paralytic ileus/ urinary retention Belladona (atropine) poisoning: Physostigmine DOC Alzheimer’s disease 36

35. Cholinergic Agents : Adverse Effects Adverse effects are a result of overstimulation of the PNS. Cardiovascular : – Bradycardia , hypotension, conduction abnormalities (AV block and cardiac arrest) CNS: – Headache, dizziness, convulsions Gastrointestinal: – Abdominal cramps, increased secretions, nausea, vomiting Respiratory: Increased bronchial secretions, bronchospasm Other: Lacrimation , sweating, salivation, miosis 37

36. Drug Adverse Effects of Cholinergic Agents “MSLUBDD” M any S mart L adies U ltimately B ring D isaster for D udes ! M iosis S alivation L a c rimation U rination B ronchoconstriction D efaecation D ecreased heart rate

37. Acute toxic effects of irreversible cholinesterase inhibitors (OP poisoning ) These agents are lipid soluble Can enter the body by the eye,skin, respiratory system and GI tract. organophosphate insecticides (malathion, parathion) or nerve gases (sarin, tabun, soman) These agents cause excessive cholinergic stimulation (muscarinic) and neuromuscular blockade

38. Cholinergic crisis occurs because the irreversible anticholinesterase poison binds to the enzyme acetylcholinesterase and inactivates it. Thus , acetylcholine remains in cholinergic synapses causing excessive stimulation of muscarinic and nicotinic receptors.

39. Treatment of OP poisoning Emergency treatment includes: Decontamination of clothing Flushing poison from skin and eyes Activated charcoal and lavage for GI ingestion Atropine to counteract the muscarinic effects (2mg IV every 10 min till pupil dilates, max 50-100 mg )

40. To relieve the neuromuscular blockade by nicotinic effects, give pralidoxime, a cholinesterase reactivator. Pralidoxime causes the anticholinesterase poison to release the enzyme acetylcholinesterase. Give Pralidoxime as soon as possible as if too much time passes, the poison bond becomes too strong (aging) for the pralidoxime to work. Other oximes- obidoxime, diacetylmonoxime