Uvod v farmakologijo perifernega živčevja
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1 Uvod v farmakologijo perifernega živčevja Prof. Lovro Stanovnik
2 Prenos v živčevju
3 Kriteriji, da je učinkovita endogena snov proglašena za mediator Dokaz, je snov in encimi za njeno sintezo prisotna na ustreznih mestih Izolacija te snovi iz perfuzata inervirane strukture med stimulacijo živca, ni je pa v perfuzatu, če stimulacije ni. Dokaz, da snov izzove učinke, ki so enaki učinkom ob stimulaciji živca. Dokaz, da so učinki mediatorskega kandidata blokirani z istimi snovmi, ki blokirajo tudi učinke stimulacije živca (običajno gre za kompetitivne antagoniste).
4 Razvoj koncepta nevrohumoralnega prenosa Začetek 1901 Lewandowski in Langley: podobni učinki ekstrakta supraren. in stim. simpatika 1905 Langley: receptive substances 1907 Dixon: Učinki muskarina podobni učinkom stimulacije vagusa 1910 Barger in Dale: razlike med učinki A in NA (učinek primarnih simpatkomim. aminov bolj podoben stimulaciji simp. kot učinki adrenalina A) 1914 Henry Dale: opis muskarinskih in nikotinskih učinkov ACh 1921 Otto Loewi: perfuzija žabjega srca fi stim. vagusa perfuzat na drugo srce fl frekvence (Vagusstoff) 1926 Loewi in Navratil: Vagusstoff = Ach
5 Prenos dražljajev v živčevju I Sinaptični prenos (nevrohumoralni prenos) Aksonsko prevajanje
6 Prenos dražljajev v živčevju II Sinaptični prenos Kemične sinapse Električne sinapse Pomen v razvoju kasneje število teh sinaps upada Pomen v patoloških razmerah
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9 Prenos dražljajev v živčevju III Nesinaptične interakcije: Efaptični prenos (pomen v patoloških razmerah, nevroni v neposredni bližini) Interakcije preko električnega polja Spremembe ionskega okolja zaradi dejavnosti nevronov (K + ) Aksonsko prevajanje
10 Razdelitev perifernega živčevja Fukcionalna: somatsko vegetativno Smer prenosa: eferentno aferentno
11 Razdelitev vegetativnega živčevja: anatomsko fukcionalna: PSy usmerjen Sy splošni učinki difuzno delovanje Eferentna sistema Aferentni del vegetativnega živčevja Vagus (3/4 vlaken) Somatski aferentni živci Mediatorji v aferentnem delu (tudi v somatskem): substanca P glutamat CGRP
12 Učinki aktivacije simpatika (fight and flight)
13 Učinki aktivacije parasimpatika
14 P Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani Centralni preklopi vegetativnega sistema Medula spinalis Medula oblongata (NTS nucleus tractus solitarii) Hipotalamus M A PSy Sy L
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16 Anatomska razporeditev vegetetativnega živčevja
17 Poseganje v nevrohumoralni prenos Farmakologija iskanje možnosti posega v fiziol. dogajanje (poznavanje!) 2 kriterija: dostopnost (možnost) za poseg terapevtska zanimivost različno število substanc z dol. učinki fi glede na ta kriterij primer blokatorji receptorjev β: b 2 - ni selektivnih b 1 - številna zdravila
18 Aksonsko prevajanje Pomen Na + in K + kanalov Modifikacija aktivnosti: Lokalni anestetiki Nekateri antiepileptiki Tetrodotoksin (Tetrodon - tropska riba) blokada Na + kanalov Saksitoksin (Saxidomus giganteus - školjka) Batrahotoksin (steroid) permeabilnost za Na + stalna depolarizacija Toksini škorpionov - inhibicija inaktivacije AP
19 Faze sinaptičnega prenosa kemične sinapse Sprejem prekurzorja v živčni končič Sinteza mediatorja Shranjevanje (skladiščenje) mediatorja Razgradnja znotraj živčnega končiča Depolarizacija ob akcijskem potencialu (AP) Vdor Ca ++ ob AP Sproščanje mediatorja Difuzija do receptorjev (R) Kombinacija z receptorji (pre-in post-sinapt.) Aktivacija R učinek Inaktivacija mediatorja Razgradnja Privzem
20 Faze sinaptičnega prenosa Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
21 Sinteza mediatorja Poteka v aksoplazmi Sledi prenos v vezikle ali zrnca ACh in biogeni amini sinteza v končiču Polipeptidi začetek sinteze v telesu nevrona bliže jedru Aksonski transport encimov za sintezo Pogosta povratna inhibicija (feed back) Možnost blokade encimov
22 Sinteza ACh Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
23 Sinteza NA in A Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
24 Prenos v mesto skladiščenja Že pred zadnjo stopnjo v sintezi (često) Poseben transportni sistem Možnost kompeticije za mesto na transporterju fi inhibicija transporta Izrivanje z mest vezave v granulih (veziklih)
25 Sproščanje mediatorja kontinuirno (počasno) sproščanje mepp vzdrževanje fiziol. odzivnosti efektorja udeleženi prenašalci difuzija pri nekaterih mediatorjih proces eksocitoze pomen Ca ++ - Ca kanali v bližini mesta 'pristanka' vezikla poleg osnovnega mediatorja se sproščajo tudi encimi, ATP modifikacija sproščanja presinaptični R za mediator, ki se sprošča - avto R za druge mediatorje (heteroreceptorji) v spl. zavora sproščanja
26 Dogajanja v sinapsi Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
27 Procesi sproščanja mediatorja Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
28 Vezava na receptor (R) Različne vrste receptorjev glede na: Transdukcijske mehanizme Ionski kanali Receptorji, sklopljeni s proteinom G (metabotropni R) R, vezani na kinaze (tirozinkinaza...) Intracelularni receptorji Lokalizacijo Postsinaptični R Presinaptični R
29 Razdelitev R glede na transdukcijske mehanizme Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
30 Funcija receptorjev (R) glede na njihovo lokalizacijo Postsinaptični R: Efektorni organi kontrakcija, sekrecija Drugi nevroni depolarizacija, hiperpolarizacija Presinaptični R (hetero R, avto R): Zmanjšanje sproščanja (sekrecije) mediatorja Povečanje sproščanja mediatorja
31 Presinaptični receptorji Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
32 Inaktivacija mediatorja Razgradnja npr. holinergična sinapsa Privzem (ponovni (re)uptake) noradrenergična, dopaminergična, serotonergična,... sinapsa: nevronski (privzem 1) ekstranevronski (privzem 2) Difuzija iz sinaptične reže Možnosti farmakološkega vpliva na prva dva procesa
33 Sinteza ACh Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
34 Inaktivacija NA Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
35 Katabolizem NA in A Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
36 Kotransmisija Daleov princip: En nevron en mediator Pogosto se poleg glavnega mediatorja iz istega nevrona sproščajo še drugi mediatorji kotransmiterji Posledice modulacija učinka osnovnega mediatorja: različno hitra inaktivacija podaljšano delovanje različno razmerje sproščanja glede na frekvenco impulzov različni receptorni mehanizmi različna hitrost nastopa učinka, različne tarče
37 Mediatorji v vegetativnem živčevju Glavna mediatorja: noradrenalin acetilholin Drugi mediatorji (neadrenergičen neholinergičen prenos NANC): Peptidni (snov P, nevropeptid Y, VIP...) nepeptidni (monoamini, ATP, adenozin, GABA, NO...) samostojni mediatorji ali kotransmiterji
38 Poimenovanje snovi, ki modificirajo delovanje vegetativnega živčevja Snovi z delovanjem, podobnim aktivaciji določenega sistema mimetiki: parasimpatikomimetiki simpatikomimetiki Snovi, ki zmanjšajo učinke aktivacije vegetativnega sistema litiki: parasimpatikolitiki simpatikolitiki
39 Poseganje v holinergično sinapso Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
40 Posegi v NA sinapso Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
41 Faze sinaptičnega prenosa Sprejem prekurzorja v živčni končič Sinteza mediatorja Shranjevanje (skladiščenje) mediatorja Razgradnja znotraj živčnega končiča Depolarizacija ob akcijskem potencialu (AP) Vdor Ca ++ ob AP Sproščanje mediatorja Difuzija do receptorjev (R) Kombinacija z R (pre-in post-sinapt.) Aktivacija R učinek Inaktivacija mediatorja Razgradnja Privzem
42 Poseganje v sintezo mediatorja Sistem Holinergični Adrenergični Snovi (zdravila) inhibitorji holin acetiltransferaze a-metil tirozin Učinek Minimalno izpraznjenje zalog ACh Izpraznjenje zalog noradrenalina
43 Metabolna transformacija po isti poti kot prekurzor mediatorja Sistem Adrenergični Snovi (zdravila) metildopa Učinek Lažni prenašalec (a-metil noradrenalin) spodrine noradrenalin
44 Blokada transportnega sistema na membrani živčnega končiča (blokada privzema) Sistem Snovi (zdravila) Učinek Holinergični Adrenergični vesamikol, hemiholinij kokain, imipramin Blokada privzema holina in zmanjšanje zalog ACh Kopičenje noradrenalina ob receptorjih
45 Blokada transportnega sistema v membrani zrnc Sistem Snovi (zdravila) Učinek Holinergični Adrenergični vesamikol rezerpin Blokada shranjevanja ACh Razgradnja noradrenalina z mitohondrijsko MAO, zmanjšanje zalog v adrenergičnih končičih
46 Spodrivanje mediatorja v živčnem končiču Sistem Holinergični Snovi (zdravila) strup črne vdove Učinek Holinomimetičnemu učinku sledi blokada Adrenergični amfetamin, tiramin Simpatomimetičen
47 Blokada sproščanja mediatorja Sistem Snovi (zdravila) Učinek Holinergični botulinus toksin Antiholinergičen Adrenergični bretilium, gvanetidin Antiadrenergičen
48 Aktivacija postsinaptičnih receptorjev Sistem Holinergični Muskarinski Nikotinski Adrenergični a 1 a 2 Snovi (zdravila) muskarin, metaholin nikotin fenilefrin klonidin Učinek Holinomimetičen Simpatomimetičen Simpatomimetičen (na periferiji) Znižana aktivnost simpatika (CŽS) b 1,2 b 1 b 2 izoproterenol dobutamin terbutalin Neselektiven b-adrenomimetičen Selektivna stimulacija srca Selektivna inhibicija kontrakcije gladkih mišic
49 Blokada postsinaptičnih receptorjev Sistem Holinergični Muskarinski Nikotinski N M Nikotinski, N N Adrenergični a b 1,2 b 1 Snovi (zdravila) atropin tubokurarin trimetafan fenoksibenzamin propranolol metoprolol Učinek Muskarinska blokada Nevromuskularni blok Ganglijska blokada a- adrenergični blok b - adrenergični blok Selektivna adrenergična blokada srca
50 Inhibicija razgradnje mediatorja Sistem Holinergični Adrenergični Snovi (zdravila) antiholinesterazna sredstva (fizostigmin, DFP) inhibitorji MAO (pargilin, nialamid) Učinek Holinomimetičen Skromen direktni vpliv na simpatik; potenciranje učinka tiramina
51 Adrenalin in noradrenalin Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
52 Učinki kateholaminov Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
53 Dogajanja v holinergičnih sinapsah Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
54 Učinki parasimpatika Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
55 Responses of Effector Organs to Autonomic Nerve Impulses I ORGAN SYM- EFFECT NA-R SUBTYPE Eye PARASYM- EFFECT ACh- R SUBTYPE Radial muscle, iris Contraction (mydriasis)++ a 1 Sphincter muscle, iris Contraction (miosis)+++ M 3, M 2 Ciliary muscle Relaxation for far vision + b 2 Contraction for near vision +++ M 3, M 2 Lacrimal glands Secretion + a Secretion +++ M 3, M 2 Heart Sinoatrial node in heart rate ++ b 1 > b 2 fl in heart rate +++ M 2 >> M 3 Atria in contractility and cond. velocity ++ b 1 > b 2 fl in contractility ++, shortened AP duration M 2 >> M 3 Atrioventricular node in automaticity and conduction velocity ++ b 1 > b 2 fl in conduction velocity; AV block +++ M 2 >> M 3 His-Purkinje system Ventricle in automaticity and conduction velocity in contractility, conduction velocity, automaticity and rate of idioventricular pacemakers +++ b 1 > b 2 Little effect M 2 >> M 3 b 1 > b 2 M Slight fl in contractility 2 >> M 3
56 Responses of Effector Organs to Autonomic Nerve Impulses II ORGAN Blood Vessels (Arteries and arterioles) Coronary SYM- EFFECT Constriction +; dilation ++ NA-R SUBTYPE PARASYM - EFFECT ACh- R SUBTYPE a 1, a 2, b 2 No innervation Skin and mucosa Constriction +++ a 1, a 2 No innervation Skeletal muscle Constriction; dilation ++ a 1, b 2 Dilation (?) Cerebral Constriction (slight) a 1 No innervation Pulmonary Abdominal viscera Constriction +; dilation Constriction +++; dilation + a 1, b 2 No innervation a 1, b 2 No innervation Salivary glands Constriction +++ Renal Constriction ++; dilation ++ (Veins) Constriction ++; dilation ++ Endothelium a 1, a 2 Dilation ++ M 3 a 1, a 2, b 1 b 2 No innervation a 1, a 2, b 2 No innervation NO synthase M 3
57 Responses of Effector Organs to Autonomic Nerve Impulses III ORGAN SYM- EFFECT NA-R SUBTYPE PARASYM - EFFECT ACh- R SUBTYPE Lung Tracheal and bronchial smooth muscle Bronchial glands Relaxation b 2 Contraction M 2 = M 3 fl secretion, secretion a 1, b 2 Stimulation M 2, M 3 Stomach Motility and tone fl (usually) + a 1, a 2, b 1, b M 2 = M 3 Sphincters Contraction (usually)+ a 1 Relaxation (usually ) + M 3, M 2 Secretion Inhibition a 2 Stimulation ++ M 3, M 2 Intestine Motility and tone Decrease + a 1, a 2, b 1, b M 3, M 2 Sphincters Contraction+ a 1 Relaxation (usually)+ M 3, M 2 Secretion fl a 2 ++ M 3, M 2
58 Responses of Effector Organs to Autonomic Nerve Impulses IV ORGAN SYM- EFFECT NA-R SUBTYPE PARASYM - EFFECT ACh- R SUBTYPE Gallbladder and Ducts Kidney Relaxation + b 2 Contraction + M Renin secretion fl +; ++ a 1, b 1 No innervation Urinary Bladder Detrusor Relaxation + Trigone and sphincter Ureter b 2 Contraction +++ M 3 > M 2 Contraction ++ a 1 Relaxation ++ M 3 > M 2 Motility and tone a 1 (?) M Fat Cells Lipolysis+++; thermogenesis a 1, b 1, b 2, b 3 Inhibition of lipolysis a 2
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