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Autonomic Nervous System

Autonomic Nervous System. Division of Nervous System. Central Nervous System (CNS) Peripheral Nervous System Autonomic ( involuntary ) Sympathetic / Adrenergic Parasympathetic / Cholinergic Somatic ( voluntary ) - i nnervates skeletal muscles. SYMPATHETIC. PARASYMPATHETIC.

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Autonomic Nervous System

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  1. Autonomic Nervous System

  2. Division of Nervous System • CentralNervousSystem (CNS) • PeripheralNervousSystem • Autonomic(involuntary) • Sympathetic/Adrenergic • Parasympathetic/Cholinergic • Somatic(voluntary) - innervatesskeletalmuscles

  3. SYMPATHETIC PARASYMPATHETIC

  4. NEUROTRANSMITTERS

  5. RECEPTORS ACETYLCHOLINE CHOLINERGIC NICOTINIC MUSCARINIC (NOR)ADRENALINE ADRENERGIC

  6. ANS Adrenergic transmission

  7. Adrenergic transmission

  8. Adrenergic transmission

  9. Signal pathway connected with adenylyl cyclase agonist agonist AC bg bg as ai - + GTP GTP ATP cAMP AC – adenylyl cyclase cAMP – cyclic adenosine monophosphate ATP – adenosine triphosphate GTP – guanosine triphosphate PKA – protein kinase A PDE – phosphodiesterase Pi – inorganic phosphate PDE 5’-AMP PKA ATP ADP protein protein cellular response P Pi phosphatase

  10. Signal pathway connected with phospholipase C agonist PLCb bg PIP2 aq + GTP DAG IP3 IP3R proteinkinase C endoplazmatic reticulum effect Ca2+ protein phosphorylation PLCb – phospholipase C beta PIP2 – phosphatidylinositol biphosphate (membranous phospholipid) IP3 – inositol trisphosphate IP3R – receptor for IP3 DAG – diacylglycerol GTP – guanosine triphosphate Ca2+-calmodulin calmodulin-dependent protein kinase

  11. SympathicNervousSystem (Thoracolumbalsystem) Main mediatorisnorepinephrine (NE) (in vegetativeganglions acetylcholine) Receptorsα: α1bloodvessels in skin + gutvasoconstriction bladdersphincterconstriction ejaculation pilomotormusclesconstriction mydriasis α2GIT - ↓ motility and secretion; CNS – decreasedsympathicactivity– negative feedback

  12. SympathicNervousSystem (Thoracolumbalsystem) • Main mediatorisnorepinephrine (NE) (in vegetativeganglionsacetylcholine) Receptorsβ: β1heart – increasedfrequency, contractility, conductivity and excitability kidneys - ↑ excretion of renin β2bronchi – dilation, bloodvesselsin skeletalmusclesvasodilation bladderdetrusorrelaxation increasedskeletalmuscle and hepaticglycogenolysis uterinesmoothmusclerelaxation – tocolysis β3adipocytes – increasedlipolysis

  13. Affinity of NA, A to differentsubtypes of adrenergic receptors α1: noradrenaline ≥ adrenaline α2: adrenaline > noradrenaline β1: noradrenaline ≥ adrenaline β2: adrenaline > noradrenaline β3: noradrenaline = adrenaline

  14. Noradrenaline, adrenaline NORADRENALINE • acts mainly on α receptors • in hemodynamic disorders that are due to vasodilation (septic shock) • also cardiogenic shock ADRENALINE • acts mainly on α and β receptors • in anaphylactic shock (action on α receptors reduces oedemas and action on β2 recetors causes bronchodilation) • cardiac arrest (effect on β1 receptors in the heart)

  15. Dopamine, dobutamine DOPAMINE • actsmainly on D1, D2, β1, α1 receptors (dose-dependent); D1 – renalvasodilation, D2 – periheralarterialvasodilation • in hemodynamic disorders that are due to cardiogenicshock DOBUTAMINE • analogue of dopaminewithsignificanteffect on β1 receptors • indications: cardiogenicshock, acuteheartfailure

  16. Selectivity of sympathomimetics

  17. Alfa Beta inh. reuptake of mediator IMAO Sympathomimetics INDIRECT-ACTING DIRECT-ACTING release of mediator 1+ 2 nonselective1+2 NOR, ADR, DOP 1 (nasal decongescants) 1 • fenylephrine • nafazoline • tetryzoline • oxymetazoline • xylometazoline • dobutamine (cardiogenic shock) 2 (asthma) • salbutamol • fenoterol • terbutaline • formoterol • salmeterol 2 (hypertension) • -metydopa • guanfacine • clonidine

  18. Sympathomimetics Direct (act directly on the sympath. receptors) endogenous catecholamines and their derivates (NE, epinephrine etc.) α1phenylephrine, nafazoline, oxymetazoline (mydriasis, decongestion of mucosa) α2 clonidine, α-metyldopa (hypertension) β1 dopamine, dobutamine (acute heart failure - cardiogenic shock) β2 short lasting effect – salbutamol, fenoterol, terbutaline long lasting effect – salmeterol, formoterol, clenbuterol indications: asthma bronchiale, tocolysis Indirect (increase the release of sympath. mediators) amphetamine, metamphetamine (penetration to CNS, abuse) tyramine (found in many foods, interaction with MAOI) cocaine (vasoconstriction, cardiac stimulation, local anesthetic properties, abuse) Mixed-acting ephedrine, pseudoephedrine (viral and allergic rhinitis)

  19. Alfa Beta Sympatholytics INDIRECT-ACTING DIRECT-ACTING Release of mediator noselective nonselective • rezerpine (in the past hypertension, psychotic symptoms; now better drugs) • guanethidine • sotalol • timolol • metipranolol • propranolol • pindolol • bopindolol (prodrug) • ergot alcaloides • tolazoline • phentolamine (pheochromocytoma) • phenoxybezamine (pheochromocytoma) cardioselective (1) 1 (hypertension, BPH) • prazosin • doxazosin • terazosin • alfuzosin • tamsulosin • urapidil • atenolol • metoprolol • bisoprolol • betaxolol • acebutolol • celiprolol +2 mimetic.effect (vasodilation) 2 with  lytic effect (vasodilation) • carvedilol • labetalol • yohimbine

  20. Sympatholytics Direct- actdirectly on thesympath. receptors (blockade) α: non-selective (α1+α2): phentolamine, phenoxybenzamine(pheochromocytoma) selectiveα1: prazosin, doxazosin, terazosin(hypertension + benignprostatic hyperplasia), specificallyagainst BPH: tamsulosin β: indications: hypertension, IHD, tachyarrhythmias, glaucoma non-selective (β1+ β2): propranolol, metipranolol, ... selectiveβ1: metoprolol, bisoprolol, atenolol, ... hybrid (+ vasodilatativeeffect): carvedilol, labetalol, nebivolol, celiprolol Indirect decreasethereleaseofsympath. mediators guanethidine, rezerpine – obsoleteantihypertensives

  21. ANS.Cholinergic Transmission.

  22. Cholinergic Transmission • postganglionic parasympathetic neurons • ganglia of the autonomic nervous system (sympathetic and parasympathetic) • neuromuscular junction • CNS

  23. Cholinergic transmission CNS basal ganglia interneurons in the striatum septo-hippocampal pathways postganglionic neurons in parasympathetic system ANS ganglia sympathetic parasympathetic neuromuscular junction

  24. Cholinergic transmission • Synthesis in terminal part of neuron AcCoA + choline Ach 2. Storage in vesicles and the release of Ach Propagation of AP through voltage-dependent Na+ channels activation of voltage-dependent Ca2+ channels fusion of the vesicles with the membrane Ach release in the synapse 3. Removal of Ach from synapse Degradation of Ach with acetylcholinesterase (reuptake, diffusion into the surrounding area), reuptake of choline residues into the neuron Degradation of Ach in plasma, tissues – butyrylcholinesterase (atypic form of BCh esterase = ↓ activity !!!) acetyl-cholintransferase

  25. Receptors for Ach • muskarinic: M1 = CNS, ganglions, stomach M2 = heart M3 = glands, smooth muscles M4,5 = CNS • nicotinic: NM (muscular) = neuromuscular junction NN (neuronal) = veg. ganglions

  26. Cholinergic transmission

  27. Cholinergic transmission muscarinic receptors nicotinic receptors

  28. Parasympathic nervous system

  29. Cholinergic Transmission Acetylcholine receptor agonists = parasympathomimetics direct inderect (inhibitors of acetylcholinesterase) muscarinic nicotinic reversible irreversible

  30. Parasympathomimetics (Acetylcholine receptor agonists) Stimulation of muscarinic receptors direct binding to receptors M1, M2, M3 indirect inhibition of acetylcholinesterase indications - xerostomia - Sjögren syndrome - postoperative atony of bladder and gastrointestinal tract - glaucoma

  31. Direct Parasympathomimetics (1. plant alkaloids: pilocarpine, muscarine, nicotine) Pilocarpus jaborandi Amanita muscaria

  32. Direct Parasympathomimetics (2. choline esters: acetylcholine, bethanechol, carbachol) • Analogues of acetylcholine are more stable to acetylcholinesterase as acetylcholine • activate all muscarinic receptor subtypes local administration bethanechol, carbachol, pilocarpine, metacholine • glaucoma • increased salivation, mydriasis suppression • bronchoprovoking test (diagnosis of asthma, bronchial damage)

  33. Direct Parasympathomimetics (3. cevimeline, varenicicline) Cevimeline Treatment of dry mouth in patients with radiation therapy for head and neck and patients with Sjögren syndrome (dry eyes, dry mouth, arthritis) Varenicicline Treatment of smoking cessation (reduces craving and withdrawal effects)

  34. Indirect parasympathomimetics (indirect-acting acetylcholine receptor agonists) Inhibitors of Acetylcholinesterase a. REVERSIBLE donepezil,rivastigmine, galantamine (cognitives;Alzheimer´sdisease) neostigmine, physostigmine,pyridostigmine (myastheniagravis, postoperationalatonia of GIT and urinarybladder) edrophonium(diagnosis of myastheniagravis) b. IRREVERSIBLE organophosphates

  35. Indirect Parasympathomimetics • inhibitors of acetylcholinesterase (AchE) – blockade of Ach degradation in synapses effect on M and also N receptors • „ false substrates“ AchE 1. carbamates - REVERSIBLE inhibitors of AchE - carbamyl residues binding to the active site of AChE several hours to days 2. organophosphates - IRREVERSIBLE inhibitors of AchE - phosphate binding to the active site is covalent - irreversible

  36. IndirectParasympathomimetics(cognitives) • mediator of parasympathicus = acetylcholine • learning, memory (cognitive f.), motoric f. • deficiency in CNS: Alzheimer´sdisease, Parkinson´sdisease • ↑ availability of Ach – reversibleinhibitors of Ach esteraseselectively in CNS (cognitives) • donepezil, rivastigmine, galantamine • onlyslowingprogression of disease • ↓↓ efectivity atadvancedstage of disease

  37. Indirect Parasympathomimetics (reversible) CARBAMATES physostigmine(Physostigma venenosum) - tertiary amine - penetrates through hematoencephalic barrier - CNS irritation neostigmine, pyridostigmine - quaternary nitrogen indication - postoperative atony of bladder and gastrointestinal tract - myasthenia gravis (N receptors on neuromuscular junction)

  38. Indirect Parasympathomimetics Physostigma venenosum Areca catechu

  39. Indirect Parasympathomimetics (reversible) edrophnium test withedrophonium - differentialdiagnoses of myastheniegravis - test is positive if after i.v. application of edrophonium increases grip strength, improves ptosis, increasestone of facialmuscles

  40. Indirect parasympathomimetics(irreversible) organophosphates:  quasi-reversible covalent bondto Ach esterase (later irreversible), cummulation of Ach • insecticides (accidental and intentional poisoning), • chemical weapons (Sarin, Tabun)  ↑ resorption through mucosa + skin  ↑ lipophilia = ↑ penetration to CNS

  41. IntoxicationwithOrganophosphates = cholinergic syndrome:lacriamation, salivation, sweatting, diarrhoea, relaxation of sfincters, bradycardia, miosis, rhonchus, cyanosis, spasms, paralysis of breathing therapy:rinse affected with water (gloves!!!), ensure vital functions, atropine + obidoxime i.v.as antidote as soon as possible !!! (reactivator of Ach esterase)

  42. Cholinergic Transmission Acetylcholine receptor antagonists = parasympatholytics 3´nitrogen 4´nitrogen oxybutine butylscopolamine solifenacine ipratropium (no CNS enetration) atropine homatropine scopolamine (CNS penetration)

  43. Parasympatholytics • blockmuscarinic receptors • Indications: • decrease inbronchialsecretion • decreaseingastricacidsecretion • bronchodilation • spasmolysis • mydriasis • increased heart rate

  44. Parasympatholytics (accidental or intentional poisoning)(belladonna alkaloids: atropine, hyoscyamine, scopolamine) Atropa belladona Lobelia inflata

  45. Parasympatholytics (with tertial nitrogene) = blockmuskarinicreceptors Withtertialnitrogene: penetratethrough HEB  atropine: alkaloid (Atropabelladona, Durman), Ind.:premedication as antiemeticdrug (n. vagus, reduction of bronchialsecretion) in thepastantidysrytmicdrug – bradyarhyttmias causesmydriasis – notsuitablefor↑ effect on eye organophosphatepoisoning KI : glaucoma !!! ADRs: tachycardia, arrhythmia, urinaryretention, constipation, photophobia, sweatinginhibition, hyperthermia

  46. Parasympatholytics • atropine poisoning:atropa belladona (black plants similar to bilberries) – dry red skin, dry mucosas, mydriasis, blurred vision, tachycardia, at children risk of spasms • therapy: prognosis usually good,symptomatic (cooling, hydration of the patient), in case of spasms and CNS symptoms diazepam, in severe cases inhibitors of acetylcholinesterase  homatropine: in the past diagnostic mydriasis (advantage = short lasting effect); now prefered tropicamide (short duration of action, 4-8 hours)

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