Introduction to ANS (autonomous nervous system) & cholinergic drugs
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- 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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- 7. Neurotransmitters Sympathetic: ADRENERGIC Central: EPINEPHRINE Peripheral: NOREPINEPHRINE • Parasympathetic: CHOLINERGIC Acetylcholine 7
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- 9. 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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- 12. Steps in Cholinergic transmission Synthesis Storage of NT Release Post junctional effects Termination of action 12
- 13. 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
- 14. Cholinergic Receptors 2 types Muscarinic Present in heart, smooth muscles, glands, eyes, CNS GPCRs M1-M5 Agonist – Muscarine; Antagonist – Atropine Nicotinic Present in nm junction, autonomic ganglia, adrenal medulla Ion channels 5 subunits NM (on NM junction of skeletal muscles), NN (on autonomic ganglia, adrenal medulla) Agonist – Nicotine, Antagonist – Curare 14
- 15. Cholinergic receptors Receptor Location M1 Ganglia; Gland; CNS, Parietal cell of stomach M2 Heart; Pre-synaptic; CNS M3 Glands; Smooth ms; CNS, Eyes M4 CNS M5 CNS NM Skeletal muscle NM junction NN Autonomic ganglia Adrenal medulla CNS 15
- 16. CHOLINERGIC RECEPTORS G-Protein coupled Receptors MUSCARINIC NICOTINIC Ligand gated ion Channels
- 17. Cholinomimetic Agents i. Choline esters Acetylcholine Methacholine Bethanechol Carbachol ii. Alkaloids & related drugs Muscarine Pilocarpine Arecholine 17 Parasympathomimetic drugs/ agonists A.Directly acting (ACh like) agents
- 18. Cholinomimetic Agents i. Reversible AntiChEs a) Tertiary Physostigmine Tacrine b) Quarternary Neostigmine Pyridostigmine Edrophonium ii. Irreversible anticholinesterases a) Organophosphates Miotics Dyflos (DFP) Ecothiophate Insecticides Malathion (Licel), Parathion Diazinon (Tik-20) War gases: Sarin, Soman, Tabun b) Carbamates: Propoxur (Bagyon) 18 B. Indirectly acting agents (ACh enhancers/amplifiers)
- 19. 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
- 20. 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
- 21. Acetylcholine Nicotinic actions: NMJ Contraction of skeletal muscles Autonomic ganglia Stimulation of symp & parasymp ganglia, adrenal medulla CNS Neurotransmitter Produce alerting response 21
- 22. Acetylcholine Uses PO: Destroyed in GIT Not 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
- 23. Alkaloids Pilocarpine 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
- 24. 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
- 25. Alkaloids Arecoline – Chief 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 – Effects: fall in BP, temporary pause of heart beat, Antidote: ATROPINE 25
- 26. Anticholinesterases The agents inhibiting the action of acetylcholinesterase are called anti acetylcholinesterase (AntiCHEs) or Cholinesterase inhibitors 26
- 27. Anticholinesterases i. Reversible AntiChEs a) Tertiary Physostigmine Tacrine b) Quarternary Neostigmine Pyridostigmine Edrophonium ii. Irreversible anticholinesterases a) Organophosphates Miotics Dyflos (DFP) Ecothiophate Insecticides Malathion (Licel), Parathion Diazinon (Tik-20) War gases: Sarin, Soman, Tabun b) Carbamates: Propoxur (Bagyon) 27
- 29. • 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. • Glaucoma. • Pyridostigmine - drug of choice for patients with Myasthenia gravis.
- 30. • 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.
- 31. • Cobra bite – edrophonium (prevent respiratory paralysis. • atropine poisoning – Physostigmine (antogonizes both central and peripheral effects). • Alzheimer’s Disease – Donepezil, galantamine, tacrine, rivastigmine.
- 32. Myasthenia Gravis (Myo + asthenia) Autoimmune disorder Reduction in number of free NM receptors Causes: Development of antibodies directed to Nicotinic receptors at muscle end plate Reduction in number by 1/3rd of NM receptors Structural damage to NM junction Weakness & easy fatigability on repeated activity, with recovery after rest 32
- 34. Myasthenia gravis – Treatment Neostigmine: improve muscle contraction by allowing ACh released fromprejunctional endings to accumulate. Neostigmine – 15to 30mg. orally every 6 hrly Dose frequency is Adjusted according to the response Pyridostigmine – less frequency of dosing
- 35. Other drugs: Corticosteroids (prednisolone 30-60 mg /day induces remission and 10mg daily or on alternate days can be used for maintenance therapy. ) – immunosuppression Inhibits production of NRantibodies . Both azathioprine and cyclosporine also inhibitNR- antibody synthesis by affecting T-cells. Removal of antibodies by plasmapheresis (plasma exchange) is another therapeutic approach.
- 36. 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
- 37. 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
- 38. Drug Adverse Effects of Cholinergic Agents “MSLUBDD” Many Smart Ladies Ultimately Bring Disaster for Dudes! Miosis Salivation Lacrimation Urination Bronchoconstriction Defaecation Decreased heart rate
- 39. 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
- 40. • 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.
- 41. 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)
- 42. • 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
Editor's Notes
- #15: Nicotinic selectively activated by nicotine, Muscarinic muscarine (from a toxic mushroom)
- #16: Pehle Khao Phir Dil Lagao: M1: GIT (gastric glands); M2: Heart; M3: in eye, Heart, Lungs (bronchus), bladder; M4, 5: CNS Blood vessels DONOT have muscarinic innervation; whenever there is stimulation of M3 receptors, release of NO, that causes VD
- #18: Directly acting: on muscarinic receptors Indirectly acting: increase the level of ACh at synapse
- #23: SC inj of Bethanechol in urine retention. Other ROA: oral Methacholine: highly sensitive to myocardium
- #24: ROA: oral, eye drops, spray, troche