1 Autonomic Nervous System

2 Division of Nervous SystemCentral Nervous System (CNS) Peripheral Nervous System Autonomic (involuntary) Sympathetic/Adrenergic Parasympathetic/Cholinergic Somatic (voluntary) - innervates skeletal muscles

3 SYMPATHETIC PARASYMPATHETIC

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5 NEUROTRANSMITTERS

6 RECEPTORS ACETYLCHOLINE CHOLINERGIC (NOR)ADRENALINE ADRENERGICNICOTINIC MUSCARINIC (NOR)ADRENALINE ADRENERGIC

7 ANS Adrenergic transmission

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10 Adrenergic transmissionType of Receptor Second Messengers α1 phospholipase C activation, increased IP3, release of Ca2+ α2 inhibition of adenylyl cyclase, decreased cAMP β1 activation of adenylyl cyclase, increased cAMP, activation of protein kinase β2 β3 D1 increased cAMP D2 decreased cAMP, increased potassium currents, decreased calcium influx

11 Most important types of Gα subunitsAdrenergic transmission Most important types of Gα subunits of G proteins Second Messengers Localisation Gαs subunit activation of adenylyl cyclase, increased cAMP stimulating Gαi subunit inhibition of adenylyl cyclase, decreased cAMP inhibitory Gαq subunit phospholipase C activation, increased IP3 + DAG, Ca2+

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

14 Signal pathway connected with phospholipase Cagonist PLCb bg PIP2 aq + GTP IP3 DAG IP3R protein kinase 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

15 Sympathic Nervous System (Thoracolumbal system)Main mediator is norepinephrine (NE) (in vegetative ganglions acetylcholine) Receptors α: α1 blood vessels in skin + gut vasoconstriction bladder sphincter constriction ejaculation pilomotor muscles constriction mydriasis α2 GIT - ↓ motility and secretion; CNS – decreased sympathic activity – negative feedback

16 Sympathic Nervous System (Thoracolumbal system)Main mediator is norepinephrine (NE) (in vegetative ganglions acetylcholine) Receptors β: β1 heart – increased frequency, contractility, conductivity and excitability kidneys - ↑ excretion of renin β2 bronchi – dilation, blood vessels in skeletal muscles vasodilation bladder detrusor relaxation increased skeletal muscle and hepatic glycogenolysis uterine smooth muscle relaxation – tocolysis β3 adipocytes – increased lipolysis

17 α1: noradrenaline ≥ adrenaline α2: adrenaline > noradrenaline Affinity of NA, A to different subtypes of adrenergic receptors α1: noradrenaline ≥ adrenaline α2: adrenaline > noradrenaline β1: noradrenaline ≥ adrenaline β2: adrenaline > noradrenaline β3: noradrenaline = adrenaline

18 Noradrenaline, adrenalineacts 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)

19 Dopamine, dobutamine DOPAMINE acts mainly on D1, D2, β1, α1 receptors(dose-dependent); D1 – renal vasodilation, D2 – periheral arterial vasodilation in hemodynamic disorders that are due to cardiogenic shock DOBUTAMINE analogue of dopamine with significant effect on β1 receptors indications: cardiogenic shock, acute heart failure

20 Selectivity of sympathomimeticsα1 α2 β1 β2 D1 D2 NA adrenaline noradrenaline etylephrine dopamine, dobutamine ephedrine amphetamine nafazoline oxymetazoline phenylephrine clonidine, moxonidine, tizanidine salbutamol, fenoterol

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

22 Direct (act directly on the sympath. receptors) Sympathomimetics Direct (act directly on the sympath. receptors) endogenous catecholamines and their derivates (NE, epinephrine etc.) α1 phenylephrine, 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)

23 Sympatholytics INDIRECT-ACTING DIRECT-ACTING Alfa BetaRelease 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) 1 (hypertension, BPH) cardioselective (1) prazosin doxazosin terazosin alfuzosin tamsulosin urapidil atenolol metoprolol bisoprolol betaxolol acebutolol celiprolol + 2 mimetic.effect (vasodilation) 2 with  lytic effect (vasodilation) carvedilol labetalol yohimbine

24 Sympatholytics Direct - act directly on the sympath. receptors (blockade) α: non-selective (α1+α2): phentolamine, phenoxybenzamine (pheochromocytoma) selective α1: prazosin, doxazosin, terazosin (hypertension + benign prostatic hyperplasia), specifically against BPH: tamsulosin β: indications: hypertension, IHD, tachyarrhythmias, glaucoma non-selective (β1+ β2): propranolol, metipranolol, ... selective β1: metoprolol, bisoprolol, atenolol, ... hybrid (+ vasodilatative effect): carvedilol, labetalol, nebivolol, celiprolol Indirect  decrease the release of sympath. mediators guanethidine, rezerpine – obsolete antihypertensives

25 ANS. Cholinergic Transmission.

26 Cholinergic Transmissionpostganglionic parasympathetic neurons ganglia of the autonomic nervous system (sympathetic and parasympathetic) neuromuscular junction CNS

27 Cholinergic transmissionCNS basal ganglia interneurons in the striatum septo-hippocampal pathways postganglionic neurons in parasympathetic system ANS ganglia sympathetic parasympathetic neuromuscular junction

28 Cholinergic transmissionSynthesis 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

29 Receptors for Ach muskarinic: M1 = CNS, ganglions, stomach M2 = heartM3 = glands, smooth muscles M4,5 = CNS nicotinic: NM (muscular) = neuromuscular junction NN (neuronal) = veg. ganglions

30 Cholinergic transmissionType of Receptor Second Messengers Localisation M1 Gq , IP3 + DAG, Ca2+ stomach – secretion, ganglions M2 Gi, cAMP myocardium M3 smooth muscles, glands, eye, endothelium M4 M5 NN Na+ channel autonomic ganglia, CNS, adrenal medulla NM neuromuscular junction

31 Cholinergic transmission muscarinic receptors nicotinic receptors

32 Parasympathic nervous systemOrgan Effect eye m. sphincter pupillae contraction – miosis m.ciliaris contraction – near acomodation heart SA node  frequeny atrium  contractility AV node decreased conduction velocity ventricles vessels dilation (EDRF) – NO airways bronchial muscles glands bronchoconstriction stimulation of secretion GIT motility  motility sfincters relaxation secretion from glands  secretion urinary bladder detrusor contraction sfincter glands salivary, lacrimal, nasopharyngeal secretion sweat

33 Cholinergic TransmissionAcetylcholine receptor agonists = parasympathomimetics inderect (inhibitors of acetylcholinesterase) direct muscarinic nicotinic reversible irreversible

34 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

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

36 Direct Parasympathomimetics (2Direct 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)

37 Direct Parasympathomimetics (3. cevimeline, varenicicline)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)

38 Inhibitors of AcetylcholinesteraseIndirect parasympathomimetics (indirect-acting acetylcholine receptor agonists) Inhibitors of Acetylcholinesterase a. REVERSIBLE donepezil, rivastigmine, galantamine (cognitives; Alzheimer´s disease) neostigmine, physostigmine,pyridostigmine (myasthenia gravis, postoperational atonia of GIT and urinary bladder) edrophonium (diagnosis of myasthenia gravis) b. IRREVERSIBLE organophosphates

39 Indirect Parasympathomimeticsinhibitors 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

40 Indirect Parasympathomimetics (cognitives)mediator of parasympathicus = acetylcholine learning, memory (cognitive f.), motoric f. deficiency in CNS: Alzheimer´s disease, Parkinson´s disease ↑ availability of Ach – reversible inhibitors of Ach esterase selectively in CNS (cognitives) donepezil, rivastigmine, galantamine only slowing progression of disease ↓↓ efectivity at advanced stage of disease

41 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)

42 Indirect ParasympathomimeticsPhysostigma venenosum Areca catechu

43 Indirect Parasympathomimetics (reversible)edrophnium test with edrophonium - differential diagnoses of myasthenie gravis - test is positive if after i.v. application of edrophonium increases grip strength, improves ptosis, increases tone of facial muscles

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

45 Intoxication with Organophosphates= 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)

46 Cholinergic TransmissionAcetylcholine receptor antagonists = parasympatholytics 4´nitrogen 3´nitrogen atropine homatropine scopolamine (CNS penetration) oxybutine butylscopolamine solifenacine ipratropium (no CNS enetration)

47 Parasympatholytics block muscarinic receptorsIndications: decrease in bronchial secretion decrease in gastric acid secretion bronchodilation spasmolysis mydriasis increased heart rate

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

49 Parasympatholytics (with tertial nitrogene)= block muskarinic receptors With tertial nitrogene: penetrate through HEB  atropine: alkaloid (Atropa belladona, Durman), Ind.: premedication as antiemetic drug (n. vagus, reduction of bronchial secretion) in the past antidysrytmic drug – bradyarhyttmias causes mydriasis – not suitable for ↑ effect on eye organophosphate poisoning KI : glaucoma !!! ADRs: tachycardia, arrhythmia, urinary retention, constipation, photophobia, sweating inhibition, hyperthermia

50 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)

51 Parasympatholytics (with quarter nitrogen)2. With quarter nitrogen: don´t penetrate through HEB butylscopolamine: spasmolysis of smooth muscles of GIT and urogenit. tract (Ind.: colic pain, dysmenorea) oxybutynine: spasmolysis of smooth muscles of urinary bladder (Ind.: incontinence, hyperreflexion of detrussor, enuresis nocturna) ipratropium, tiotropium: select. bronchodilat. (Ind.: asthma, CHOPD, administration through inhalation)

52 acetylcholine autonomous neuromuscular CNS nervous system junction↑ Ach parasympathomimetics: glaucoma atony of the bladder, GIT ↑ Ach therapy of Alzheimer´s disease ↑ Ach myastenia gravis ↓ Ach parasympatholytics: Spasmolytics of GIT, bronchi, urogenital tract ↓ Ach periferal muscle relaxants, intoxication with organophosphates ↓ Ach therapy of Parkinson´s disease