01Introduction to ANS.pptx
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This document discusses the autonomic nervous system (ANS) and its sympathetic and parasympathetic divisions. It describes the roles and functions of the sympathetic and parasympathetic systems, including that the sympathetic system prepares the body for "fight or flight" while the parasympathetic system maintains essential functions at rest. Key neurotransmitters of each system are acetylcholine and norepinephrine. The document also examines cholinergic and adrenergic transmission in detail, including the receptors, synthesis and actions of acetylcholine and catecholamines.
01Introduction to ANS.pptx
- 1. Dr.K.Chandrakala Professor and HOD Guntur Medical College
- 7. Efferent (motor) nerves Two systems Autonomic nerves (unconscious) Eg cardiac output, respiration, etc Somatic nerves (voluntary)
- 8. Functions of the Sympathetic System Though continually active to some degree (e.g. in maintaining the tone of vascular beds), the sympathetic division has the property of adjusting in response to stressful situations, such as trauma, fear, hypoglycemia, cold, or exercise 1- Effects of stimulation of sympathetic division 2- Fight or flight response Sympathetic system is not essential to life
- 10. Functions of the parasympathetic system Parasympathetic division maintains essential bodily functions, such as digestive processes and elimination of wastes, and is required for life. It usually acts to oppose or balance the actions of the sympathetic division and is dominant over the sympathetic in “rest and digest” situations. Parasympathetic system is not a functional entity as such and never discharges as a complete system. If it did, it would produce massive, undesirable, and unpleasant symptoms. Instead, discrete parasympathetic fibres are activated separately, and the system functions to affect specific organs, such as stomach or eye.
- 12. Role of CNS in autonomic control of viscera 1- Reflex arcs (Baroreceptors for BP control) 2-Emotions and ANS (Rage, fear or pleasure) 3-Innervation by ANS A-Dual innervation B-Organs receiving only sympathetic innervation: adrenal medulla, kidney, pilomotor muscles, sweat glands and also blood pressure control Somatic NS: to skeletal muscle Ach is the neurotransmitter without interrupting ganglia
- 13. Chemical signaling between cells A- Local mediators: (histamine, PG’s). They act on the cells in their immediate environment. They are rapidly destroyed or removed, thus they do not enter the blood. B- Hormones: specialized endocrine cells secrete hormones into blood stream, exerting their effect on distal organs. C- Neurotransmitters: Ach, NE, and Epinephrine Second messenger system in intracellular response: 1. Actions on membrane receptors 2. Regulation involving second messenger molecules
- 14. ANS branches cholinergic fibres - acetylcholine adrenergic fibres noradrenaline (norepinepherine NE)
- 15. Functions and origins of the ANS
- 16. Action of ANS drugs Drugs to block ANS chemical transmission Drugs to mimic ANS action ANS drugs can modify a variety of effector tissues Cardiac muscle Blood pressure Exocrine glands
- 17. Cholinergic transmission Acetylcholine is at motor neuron and CNS nerve terminals Synthesized from Acetyl coA (mitochondria) Choline (dietary) Catalyzed by choline acetyl transferase (ChAT) Release is dependent on Calcium (Ca2+) Causes muscle contraction
- 18. Acetylcholine Identified 1921 Present at all NMJ and also CNS Synthesized in the axon terminal Diffuses across synaptic cleft Two receptor subtypes Nicotinic ACh receptors Muscarinic ACh receptors
- 19. The discovery of vagusstoff E.Chudler 2001
- 20. Neuromuscular Junction Synaptic End Plate T.Caceri Veterinary Histology 2003 1999 Sinauer Associates Inc
- 21. Characteristics of a neurotransmitter Synthesized in (or transported to) presynaptic terminal Stored in vesicles Regulated release Receptor located on postsynaptic membrane Termination of action
- 22. Presynaptic events Calcium influx releases synaptic vesicles from microtubules Movement of synaptic vesicles to sites of action Interaction of specific proteins Vesicle docking Membrane fusion Calcium dependent exocytosis
- 23. Fusion proteins regulate neurotransmitter release Vesicle proteins Synaptobrevin Presynaptic membrane proteins Syntaxins SNAP-25
- 24. Vesicular transport of NT – drug implications Toxins targeting neurotransmitter release Spider venom (excess ACh release) Botulinum (blocks ACh release) Tetanus
- 25. Postsynaptic events Boutons have multiple nerve terminals Simultaneous release Stimulation of contraction via AP Acetylcholine degraded after action ACETYLCHOLINESTERASE (AChE)
- 27. Cholinergic receptors Two classes for acetylcholine Nicotinic and muscarinic Nicotinic are ion channels Ionotrophic Muscarinic are G-protein coupled Metabotrophic
- 28. Nicotinic AChR are sodium channels 1999 Sinauer Associates Inc
- 29. Ionotropic AChR Consist of five polypeptide subunits Receptors vary in: subunit structure agonist sensitivity distribution Mediate fast synaptic transmission
- 30. Muscarinic AChR activate G-proteins 1999 Sinauer Associates Inc
- 31. Metabotropic AChR Five muscarinic AChR subtypes G protein coupled Slower synaptic transmission via intracellular signaling cascade
- 33. Mode of cholinergic drug action Cholinomimetics agonist antagonist Cholinesterase inhibitors Clinical applications
- 35. AChR agonists and antagonists Nicotinic AChR agonists Nicotine Nicotinic AChR antagonists Strychnine Snake toxins Bungarotoxin Muscarinic AChR agonist Muscarine Muscarinic AChR antagonists Atropine
- 36. Adrenergic transmission Catecholamines- Noncatecholamines Through sympathetic/adrenergic neurons
- 37. NE and E are released at nerve terminals and secreted by the adrenal medulla
- 39. Norepinephrine and epinephrine Catecholamines Synthesized from dopamine Present in CNS and sympathetic nerves Widely distributed, general behavioral arousal eg raise blood pressure etc Stress increases release of norepinephrine
- 40. Synthesis of norepinephrine (NA)
- 41. Synthesis of epinephrine (adrenaline)
- 42. Adrenergic receptors Four receptor subtypes a1, a2, b1, b2 G protein linked Bind either norepinephrine or epinephrine
- 44. Sympathetomimetic drugs Can act directly or indirectly Direct binding to receptors Epinepherine, dopamine (CNS and renal) Indirectly Drugs targeting synthesis and release of NE and NA eg DBH inhibitors, reserpine - depletes stores Drugs targeting reuptake at synapse eg cocaine, Tricyclic antidepressants
- 46. NE and E are released at nerve terminals and secreted by the adrenal medulla
- 47. Norepinephrine and epinephrine Catecholamines Synthesized from dopamine Present in CNS and sympathetic nerves Widely distributed, general behavioral arousal eg raise blood pressure etc Stress increases release of norepinephrine
- 48. Synthesis of norepinephrine (NA)
- 49. Synthesis of epinephrine (adrenaline)
- 50. Adrenergic receptors Four receptor subtypes a1, a2, b1, b2 G protein linked Bind either norepinephrine or epinephrine
- 51. Sympathetomimetic drugs Can act directly or indirectly Direct binding to receptors Epinepherine, dopamine (CNS and renal) Indirectly Drugs targeting synthesis and release of NE and NA eg DBH inhibitors, reserpine - depletes stores Drugs targeting reuptake at synapse eg cocaine, Tricyclic antidepressants
- 52. Importance of sympathetomimetic drugs Cardiovascular system Regulation of smooth muscle affects heart and blood pressure beta blockers Respiratory tract Smooth muscle relaxation – bronchodilation Isoproterenol, albuterol (asthma) Metabolic effects Liver effects, insulin secretion CNS Nervousness, emotional well-being, psychosis etc
- 53. Adrenergic Receptors ● ● ● Adrenergic receptors (or adrenoceptors) are a class of G- protein coupled receptors that are the target of catecholamines Adrenergic receptors specifically bind their endogenous ligands – catecholamines (adrenaline and noradrenline) ● Increase or decrease of 2ndmessengers cAMP or IP3/DAG Many cells possess these receptors, and the binding of an agonist will generally cause the cell to respond in a flight-fight manner. ● For instance, the heart will start beating quicker and the pupils will dilate
- 54. How Many of them ???? Alpha (α) Beta (β) Adenoreceptors α 1 β 3 β 2 β 1 α 2 α 2B α 2C α 2A α 1A α 1B α 1D
- 55. Differences - Adrenergic Receptors (α and β) ! ● Alpha (α) and Beta (β) ● ● Agonist affinity of alpha (α): ● adrenaline > noradrenaline > isoprenaline ● Antagonist: Phenoxybenzamine ● IP3/DAG, cAMP and K+ channel opening Agonist affinity of beta (β): ● isoprenaline > adrenaline > noradrenaline ● Propranolol ● cAMP and Ca+ channel opening
- 56. Potency of catecholamines on Adrenergic Receptors NA NA Iso Log Concentration Bronchial relaxation Iso Adr Aortic strip contraction Adr α β
- 57. Differences - α Vs β ● α Receptors: ● IP3/DAG ● cAMP ● K+ channel opening ● β Receptors: ● cAMP ● Ca+ channel opening
- 58. Recall: Adenylyl cyclas pathway PKA Phospholamban Increased Interaction with Ca++ Faster relaxation Troponin Cardiac contractility Other Functional proteins e: cAMP PKA alters the functions of many Enzymes, ion channels, transporters and structural proteins. Faster sequestration of Ca++ in SR
- 59. PKc Also Recall: Phospholipase C: IP3-DAG pathway
- 60. Beta receptors ● ● All βreceptors activate adenylate cyclase, raising the intracellular cAMP concentration Type β1: ● ● These are present in heart tissue, and cause an increased heart rate by acting on the cardiac pacemaker cells Type β2: ● ● ● ● These are in the vessels of skeletal muscle, and cause vasodilatation, which allows more blood to flow to the muscles, and reduce total peripheral resistance Beta-2 receptors are also present in bronchial smooth muscle, and cause bronchodilatation when activated Stimulated by adrenaline, but not noradrenaline Bronchodilator salbutamol work by binding to and stimulating the β 2 receptors ● Type β3: ● Beta-3 receptors are present in adipose tissue and are thought to have a role in the regulation of lipid metabolism
- 61. Differences between β1, β2 and β3 Location Beta-1 Heart and JG cells Beta-3 Adipose tissue Agonist Antagonist Dobutamine Metoprolol, Atenolol Beta-2 Bronchi, uterus, Blood vessels, liver, urinary tract, eye Salbutamol Alpha-methyl propranolol - - Action on NA Moderate Weak Strong
- 62. Clinical Effects of β-receptor stimulation ● β1: Adrenaline, NA and Isoprenaline: ● ● ● ● Tachycardia Increased myocardial contractility Increased Lipolysis Increased Renin Release ● β2: Adrenaline and Isoprenaline (not NA) ● ● ● ● ● ● Bronchi – Relaxation SM of Arterioles (skeletal Muscle) – Dilatation Uterus – Relaxation Skeletal Muscle – Tremor Hypokalaemia Hepatic Glycogenolysis and hyperlactiacidemia ● β3: Increased Plasma free fatty acid – increased O2 consumption - increased heat production
- 63. Adrenergic receptors - alpha ● Type α1 ● ● ● Blood vessels with alpha-1 receptors are present in the skin and the genitourinary system, and during the fight-or- flight response there is decreased blood flow to these organs Acts by phospholipase C activation, which forms IP3 and DAG In blood vessels these cause vasoconstriction ● Type α2 ● ● These are found on pre-synaptic nerve terminals Acts by inactivation of adenylate cyclase, cyclic AMP levels within the cell decrease (cAMP)
- 64. Differences between α1 and α2 Location Alpha-2 Prejunctional Function Alpha-1 Post junctional – blood vessels of skin and mucous membrane, Pilomotor muscle & sweat gland, radial muscles of Iris Stimulatory – GU, Vasoconstriction, gland secretion, Gut relaxation, Glycogenolysis Agonist Antagonist Phenylephrine, Methoxamine Prazosin Inhibition of transmitter release, vasoconstriction, decreased central symp. Outflow, platelet aggregation Clonidine Yohimbine
- 65. adrenoceptors Clinical effects ● Eye -- Mydriasis ● Arterioles – Constriction (rise in BP) ● Uterus -- Contraction ● Skin -- Sweat ● Platelet - Aggregation ● Male ejaculation ● Hyperkalaemia ● Bladder Contraction ● α 2 adrenoceptors on nerve endings mediate negative feedback which inhibits noradrenaline release
- 66. Molecular Basis of Adrenergic Receptors Also glycogenolysis in liver Inhibition of Insulin release and Platelet aggregation Gluconeogen esis
- 67. Dopamine receptors ● D1-receptors are post synaptic receptors located in blood vessels and CNS ● D2-receptors are presynaptic present in CNS, ganglia, renal cortex
- 68. Summary of agents modifying adrenergic transmission Step Actions Drug Synthesis of NA Inhibition α - methyl-p-tyrosine Axonal uptake Block Cocaine, guanethidine, ephedrine Vesicular uptake Block Reserpine Vesicular NA Displacement Guanethidine Membrane NA pool Exchange diffusion Tyramine, Ephedrine Metabolism MAO-A inhibition MAO-B inhibition COMT inhibition Moclobemide Selegiline Tolcapone Receptors α 1 α 2 β1 + β2 β1 Prazosin Yohimbine Propranolol Metoprolol
- 70. Adrenaline as prototype ● Potent stimulant of alpha and beta receptors ● Complex actions on target organs
- 71. Hear t ● ● Beta-1 mediated action - Powerful Cardiac stimulant - +ve chronotropic, +ve inotropic Acts on beta-1 receptors in myocardium, pacemaker cells and conducting tissue ● ● ● ● ● Heart rate increases by increasing slow diastolic depolarization of cells in SAN High doses cause marked rise in heart rate and BP causing reflex depression of SAN – unmasking of latent pacemaker cells in AVN and PF – arrhythmia (sensitization of arrhythmogenic effects by Halothane) Cardiac systole is shorter and more powerful Cardiac output is enhanced and Oxygen consumption is increased Cardiac efficiency is markedly decreased ● Conduction velocity in AVN, atrial muscle fibre, ventricular fibre and Bundle of His increased – benefit in partial AV block ● Reduced refractory period in all cardiac cells
- 72. Blood Vessels ● Seen mainly in the smaller vessels – arterioles – Vasoconstriction (alpha) and vasodilatation (beta) – depends on the drug ● Decreased blood flow to skin and mucus membranes and renal beds – alpha effect (1 and 2) - ● Increased blood flow to skeletal muscles, coronary and liver vessels - (Beta-2 effect) counterbalanced by a vasoconstrictor effect of alpha receptors
- 73. Blood Pressure ● Depends on the Catecholamine involved ● NA causes rise in Systolic, diastolic and mean BP (no beta-2 action) – unopposed alpha action ● Isoprenaline causes rise in systolic but fall in diastolic BP – mean BP falls (beta-1 and beta-2) ● Adr causes rise in systolic BP, but fall in diastolic BP – mean BP generally rises (slow injection) ● Decreased peripheral resistance at low conc. Beta receptors are more sensitive to Adr than alpha receptors
- 74. Blood Pressure – contd. ● Rapid IV injection of Adrenaline marked rise in Systolic and diastolic BP ● Large concentration alpha action predominates – vasoconstriction even in skeletal muscle ● But BP returns to normal in few minutes ● A secondary fall in mean BP occurs ● Mechanism – rapid uptake and dissipation of Adr – at low conc. Alpha action lost but beta action predominates – Dale`s Vasomotor reversal phenomenon
- 75. Dale`s Vasomotor Reversal Phenomenon
- 76. Actions of Adrenaline ❑ Respiratory: ● ● Powerful bronchodilator Relaxes bronchial smooth muscle (not NA) ● Beta-2 mediated effect ● Physiological antagonist to mediators of bronchoconstriction e.g. Histamine ❑ GIT : Relaxation of gut muscles (alpha and beta) and constricted sphincters – reduced peristalsis – not clinical importance ❑ Bladder: relaxed detrusor muscle (beta) muscle but constriction of Trigone – both are anti-voiding effect ❑ Uterus: Adr contracts and relaxes Uterus (alpha and beta action) but net effect depends on status of uterus and species – pregnant relaxes but non-pregnant - contracts
- 77. Actions of Adrenaline – contd. ● Skeletal Muscle: ● Facilitation of Ach release in NM junction (alpha -1) ● Beta-2 acts directly on Muscle fibres ● Abbreviated active state and less tension in slow conducting fibres and enhanced muscle spindle firing – tremor ● CNS: No visible clinical effect in normal doses – as low penetration except restlessness, apprehension and tremor ● Activation of alpha-2 in CNS decreases sympathetic outflow and reduction in BP and bradycardia - clonidine
- 78. Metabolic effects ● Increases concentration of glucose and lactic acid ● Calorigenesis (β-2 and β-3) ● Inhibits insulin secretion (α-2) ● Decreases uptake of glucose by peripheral tissue ● Simulates glycogenolysis - Beta effect ● Increases free fatty acid concentration in blood ● Hypokalaemia – initial hyperkalaemia
- 79. ADM E ● All Catecholamines are ineffective orally ● Absorbed slowly from subcutaneous tissue ● Faster from IM site ● Inhalation is locally effective ● Not usually given IV ● Rapidly inactivated in Liver by MAO and COMT
- 80. Clinical Question! ● Question: A Nurse was injecting a dose of penicillin to a patient in Medicine ward without prior skin test and patient suddenly developed immediate hypersensitivity reactions. What would you do? ● Answer: As the patient has developed Anaphylactic reaction, the only way to resuscitate the patient is injection of Adrenaline ● ● ● 0.5 mg (0.5 ml of 1:10000) IM and repeat after 5-10 minutes Antihistaminics: Chlorpheniramine 10 – 20 mg IM or IV Hydrocortisone 100 – 200 mg
- 81. Adrenaline – Clinical uses ● Injectable preparations are available in dilutions 1:1000, 1:10000 and 1:100000 ● Usual dose is 0.3-0.5 mg sc of 1: 10000 solution ● Used in: ● ● ● ● ● ● Anaphylactic shock… Prolong action of local anaesthetics Cardiac arrest Topically, to stop bleeding Hyperkinetic children – ADHD, minimal brain dysfunction Anorectic
- 82. CPR - Image
- 83. ADRs ● Restlessness, Throbbing headache, Tremor, Palpitations ● Cerebral hemorrhage, cardiac arrhythmias ● Contraindicated in hypertensives, hyperthyroid and angina poctoris ● Halothane and beta-blockers – not indicated
- 86. Noradrenali ne ● Neurotransmitter released from postganglionic adrenergic nerve endings (80%) ● Orally ineffective and poor SC absorption ● IV administered ● Metabolized by MAO, COMT ● Short duration of action
- 87. Actions and uses ● Agonist at α 1(predominant), α 2 and β 1Adrenergic receptors ● Equipotent with Adr on β 1, but No effect on β2 ● Increases systolic, diastolic B.P, mean pressure, pulse pressure and stroke volume ● Total peripheral resistance (TPR) increases due to vasoconstriction - Pressor agent ● ● ● Increases coronary blood flow Decreases blood flow to kidney, liver and skeletal muscles Uses: Injection Noradrenal bitartrate slow IV infusion at the rate of 2-4mg/ minute used as a vasopressor agent in treatment of hypovolemic shock and other hypotensive states in order to raise B.P ● ● Problems: Down regulation of receptors, Renal Vasoconstriction Septic and neurogenic shock (?)
- 88. Noradrenaline - ADRs ● Anxiety, palpitation, respiratory difficulty ● Acute Rise of BP, headache ● Extravasations causes necrosis, gangrene ● Contracts gravid uterus ● Severe hypertension, violent headache, photophobia, anginal pain, pallor and sweating in hyperthyroid and hypertensive patients
- 89. Isoprenalin e ● ● ● ● Catecholamine acting on beta-1 and beta-2 receptors – negligible action on alpha receptor ● Therefore main action on Heart and muscle vasculature Main Actions: Fall in Diastolic pressure, Bronchodilatation and relaxation of Gut ADME: Not effective orally, sublingual and inhalation (10mg tab. SL) Overall effect is Cardiac stimulant (beta-1) ● ● Increase in SBP but decrease in DBP (beta-2) Decrease in mean BP ● Used as Bronchodilator and for treatment of AV block, Stokes-Adam Syndrome etc. – but not preferred anymore
- 90. Summar y
- 91. Dopamin e ● Immediate metabolic precursor of Noradrenalin ● High concentration in CNS - basal ganglia, limbic system and hypothalamus and also in Adrenal medulla ● Central neurotransmitter, regulates body movements ineffective orally, IV use only, ● Short T 1/2 (3-5minutes)
- 92. Dopamin e ● MECHANISM: ● Agonists at dopaminergic D1, D2 receptors ● Agonist at adrenergic α1 and β1
- 93. Dopamin e ● In small doses 2-5 μg/kg/minute, it stimulates D1- receptors in renal, mesenteric and coronary vessels leading to vasodilatation (Increase in cAMP) ● Recall: Renal vasoconstriction occurs in CVS shock due to sympathetic over activity ● Increases renal blood flow, GFR an causes natriuresis ● Interaction with D2 receptors (present in presynaptic adrenergic neurones) – suppression of NA release (no alpha effect)
- 94. Dopamine – cond. ● Moderate dose (5-10 μg/kg/minute), stimulates β1- receptors in heart producing positive inotropic and chronotropic actions actions ● Releases Noradrenaline from nerves by β1- stimulation ● Does not change TPR and HR ● Great Clinical benefit in CVS shock and CCF ● High dose (10-30 μg/kg/minute), stimulates vascular adrenergic α1-receptors (NA release) – vasoconstriction and decreased renal blood flow
- 95. Why renal and mesenteric vasodilatation is useful in Shock? ● Increases renal blood flow, GFR an causes natriuresis ● In CVS shock – excessive sympathetic activity leading to ischemia of gut, sloughening and entry of Bacteria to systemic circulation - septicemia
- 96. Dobutamine - Derivative of Dopamine ● MOA: ● ● ● ● ● ● Acts on both alpha and beta receptors but more prominently in beta-1 receptor – increase in contractility and CO Does not act on D1 or D2 receptors – No release of NA and thereby hypertension Predominantly a beta-1 agonist with weak beta-2 and selective alpha-1 activity Racemic mixture consisting of both (+) and (−)isomers - the (+) isomer is a potent β 1agonist and α 1antagonist, while the (−)isomer is an α 1 agonist Overall beta-1 activity and weak beta-2 activity Increase in force of contraction and cardiac output but no change in heart rate ● ● Uses: Clinically give in dose of 2-8 mcg/kg/min IV infusion in Heart failure in cardiac surgery, Septic and cardiogenic shock, Congestive Heart failure ADRs: Tachycardia, hyperension, angina and fatal arrhythmia
- 97. Adrenergic agonists ● Selective Alpha-1 Agonists: ● Phenylepherine, Ephederine, Methoxamine, Metaraminol, Mephentermine ● Selective Alpha-2 Agonists: ● Clonidine, α-methyldopa, Guanfacine and Guanabenz ● Β -2 Adrenergic agonists: ● Salbutamol, Terbutaline, Salmeterol, Reproterol, Oxiprenaline, Fenoterol, Isoxsuprine, Rimiterol, Ritodrine, Bitolterol and Isoetharine
- 98. Therapeutic Classification ● Pressor agents: ● NA, Phenylephrine, ephedrine, Methoxamine, Dopamine ● Cardiac Stimulants: ● Adr, Dobutamine and Isoprenaline, Dopexamine ● Nasal Decongestants: ● Phenylepherine, Xylometazoline, Oxymetazoline, Naphazoline and Tetrahydrazoline and Phenylpropanolamine and Pseudoephidrine ● Bronchodilators: ● Isoprenaline, Salbutamol, Salmeterol, Terbutaline, Formeterol ● Uterine Relaxants: ● Ritodrine, Salbutamol, Isoxsuprine ● Anorectics ● Fenfluramine, Dexfenfluramine and Sibutramine ● CNS Stimulants: ● Amphetamine, Methamphetamine