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Razlikovanje norepinefrina i epinefrina u indikacijama

Razlikovanje norepinefrina i epinefrina u indikacijama



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Norepinefrin je manje beta2 adrenomimetik od epinefrina, pa je selektivniji pa ima manje bronhospazma pa bi stoga mogao biti bolji u liječenju zatajenja srca i različitih šokova.

Međutim, nisam siguran.

Imam neku intuiciju da su neki od njih na neki način analogni drugima.

PubMed o norepinefrinu u farmakologiji

  • Simpatomimetici
  • Adrenergički alfa agonisti
  • Vazokonstriktorna sredstva

PubMed o epinefrinu u farmakologiji

  • Bronhodilatatori (beta2)
  • Midriatici (beta2)
  • Adrenergički alfa agonisti
  • Simpatomimetici
  • adrenergički beta-agonisti (ovo uzrokuje prve dvije indikacije)
  • Vazokonstriktorna sredstva

što je logično jer je epinefrin neselektivni beta2. Međutim, nisam siguran uključuje li ta svojstva sve prihvaćene indikacije.

To mi sugerira da se norepinefrin može bolje koristiti u akutnim situacijama. Međutim, znam da se injekcije epinefrina više daju alergičnim osobama za nošenje zbog anafilaktičkog šoka. Zašto? Vjerojatno zbog cijene. Kako se indikacije za norepinefrin razlikuju od onih u epinefrinu?


Razlike u djelovanju/indikaciji su zbog različitog afiniteta dviju molekula prema različitim adrenergičkim receptorima. Stranica wikipedije o Ardenergičkom receptoru ima tablicu koja to sažima.

Wikipedia ne navodi reference za to. Možda ćete pogledati neke od sljedećih starih članaka.

  • Podtipovi α- i β-adrenergičkih receptora

    Na periferiji, α1-receptori su smješteni postsinaptički, posredujući ekscitatorne učinke kateholamina na α-receptore. α2-adrenoreceptori su, s druge strane, autoreceptori uključeni u regulaciju oslobađanja noradrenalina (noradrenalina). U središnjem živčanom sustavu, i α1- i α2-receptori postoje na postsinaptičkim stanicama; postoje i 2 glavna podtipa β-adrenoceptora. β1-receptori imaju visok afinitet i za noradrenalin i za adrenalin (epinefrin) i nalaze se u srcu, mozgu i masnom tkivu. β2-receptori imaju nizak afinitet za noradrenalin i uključeni su u posredovanje opuštanja vaskularnih i drugih glatkih mišića te u mnogim metaboličkim učincima kateholamina.

  • Podtipovi β-adrenergičkih receptora: svojstva, distribucija i regulacija

NE=noradrenalin, EPI= adrenalin, ISO=izoprenalin


Iako su norepinefrin i epinefrin strukturno povezani, imaju različiti učinci. Noradrenalin ima specifičnije djelovanje koje uglavnom djeluje na alfa receptore za povećanje i održavanje krvnog tlaka, dok epinefrin ima šire učinke. Norepinefrin se kontinuirano oslobađa u cirkulaciju na niskim razinama, dok se adrenalin oslobađa samo tijekom stresa.

Norepinefrin je također poznat kao noradrenalin. To je i hormon i najčešći neurotransmiter simpatičkog živčanog sustava. Epinefrin je također poznat kao adrenalin. Uglavnom se stvara u meduli nadbubrežne žlijezde pa djeluje više kao hormon, iako se male količine stvaraju u živčanim vlaknima gdje djeluje kao neurotransmiter.

Norepinefrin protiv epinefrina: Sinteza i djelovanje u tijelu

Prirodni norepinefrin se uglavnom stvara unutar živčanih aksona (osovina živca), pohranjuje se unutar vezikula (male vrećice ispunjene tekućinom), a zatim se oslobađa kada akcijski potencijal (električni impuls) putuje niz živac. Noradrenalin putuje kroz jaz između dva živca gdje se veže na receptor na drugom živcu i stimulira taj živac da reagira. Ovo je norepinefrin koji djeluje kao neurotransmiter. Norepinefrin uzrokuje vazokonstrikciju (suženje krvnih žila) pa je koristan za održavanje krvnog tlaka i njegovo povećanje u vrijeme akutnog stresa.

Norepinefrin se također stvara u meduli nadbubrežne žlijezde gdje se sintetizira iz dopamina i oslobađa se u krv kao hormon.

Epinefrin se proizvodi od norepinefrina unutar moždine nadbubrežne žlijezde (unutarnjeg dijela nadbubrežne žlijezde, male žlijezde povezane s bubrezima). Naša nadbubrežna moždina pomaže nam da se nosimo s fizičkim i emocionalnim stresom. Sinteza epinefrina se povećava tijekom stresa. Epinefrin djeluje na gotovo sva tjelesna tkiva, ali njegovi učinci su različiti ovisno o tkivu, na primjer, epinefrin opušta cijevi za disanje, omogućujući lakše disanje, ali skuplja krvne žile (održava krvni tlak i osigurava da su mozak i srce prokrvljeni krvlju ). Epinefrin također povećava broj otkucaja srca i snagu kontrakcije, protok krvi u mišiće i mozak te pomaže pretvorbu glikogena (pohranjenog oblika energije) u glukozu u jetri.

Epinefrin difundira kroz medulu nadbubrežne žlijezde u krv koja perfundira nadbubrežne žlijezde i zatim se prenosi po cijelom tijelu.

Norepinefrin protiv epinefrina: Epinefrin ima širi raspon učinaka

Norepinefrin uglavnom djeluje na alfa receptore, iako do određenog stupnja stimulira beta receptore. Jedna od njegovih najvažnijih uloga je povećanje brzine srčanih kontrakcija, a zajedno s epinefrinom, on je u osnovi odgovora bori se ili bježi.

Epinefrin je relativno nespecifičan, stimulira alfa, beta 1, beta 2 i beta 3 receptore manje-više podjednako. Vezivanjem na te receptore epinefrin pokreće niz promjena, a sve su usmjerene ili na povećanje potrošnje energije u tijelu ili na stvaranje veće količine energije na raspolaganju za korištenje, na primjer, stimuliranje lučenja glukagona iz alfa stanica gušterače.

Norepinefrin protiv epinefrina: Upotreba u medicini

U medicini se norepinefrin koristi za povećanje i održavanje krvnog tlaka u akutnim situacijama u kojima je nizak krvni tlak značajka (kao što su srčani zastoj, spinalna anestezija, septikemija, transfuzije krvi, reakcije na lijekove). Obično se koristi uz druga sredstva.

Epinefrin se koristi u medicini za liječenje niskog krvnog tlaka povezanog sa septičkim šokom, za hitno liječenje alergijskih reakcija i u operaciji oka za održavanje proširenja zjenice. Također je dostupan u autoinjektoru za osobe s poviješću teških alergijskih reakcija.

U medicini se norepinefrin koristi za povećanje ili održavanje krvnog tlaka tijekom akutnih medicinskih situacija koje uzrokuju nizak krvni tlak, a epinefrin se koristi u hitnom liječenju alergijskih reakcija, za liječenje niskog krvnog tlaka tijekom septičkog šoka i u operaciji oka za održavanje dilatacije učenik.

Adrenalin uglavnom proizvodi moždina nadbubrežne žlijezde kao hormon, iako se male količine proizvode u živcima i djeluju kao neurotransmiter. Noradrenalin se uglavnom proizvodi u živcima, iako se male količine također proizvode u srži nadbubrežne žlijezde. I norepinefrin i epinefrin oslobađaju se tijekom odgovora bori se ili bježi.


Epinefrina

Farmakološka klasa: Simpatomimetik (izravno djelovanje)

Terapijski razred: Bronhodilatator, midrijatik

C kategorija rizika za trudnoću

Akcijski

Stimulira alfa- i beta-adrenergičke receptore, uzrokujući opuštanje glatkih mišića srca i bronha te proširenje skeletnih mišića. Također smanjuje proizvodnju očne vodice, povećava otjecanje očne vodice i širi zjenice kontrakcijom mišića dilatatora.

Dostupnost

Auto-injektor za I.M. injekciju: 1:2 000 (0,5 mg/ml)

Injekcija: 0,1 mg/ml, 0,5 mg/ml, 1 mg/ml

Oftalmološke kapi: 0.5%, 1%, 2% Otopina za inhalaciju (kao racepinefrin): 2,5% (ekvivalentno 1% epinefrina)

Indikacije i doze

➣ Reakcija preosjetljivosti bronhodilatacijske anafilaksije

odrasli: 0,1 do 0,5 ml otopine 1:1 000 subkutano ili I.M., ponavljano q 10 do 15 minuta p.r.n. Ili 0,1 do 0,25 ml otopine 1:10 000 I.V. polako tijekom 5 do 10 minuta može ponoviti q 5 do 15 minuta p.r.n. ili slijedi kontinuirana infuzija od 1 mcg/minuti, povećana na 4 mcg/minuti p.r.n. Za hitno liječenje, EpiPen isporučuje 0,3 mg I.M. adrenalina 1:1 000.

djeca: Za hitno liječenje, EpiPen Jr. isporučuje 0,15 mg I.M. adrenalina 1:2 000.

Odrasli i djeca u dobi od 4 i starija: Jedna do tri duboke inhalacije otopine za inhalaciju s ručnim nebulizatorom, ponavljano q 3 sata p.r.n.

➣ Za vraćanje srčanog ritma u srčanom zastoju

odrasli: 0,5 do 1 mg IV., ponavljano svakih 3 do 5 minuta, ako je potrebno. Ako nema odgovora, može dati 3 do 5 mg IV. q 3 do 5 minuta.

odrasli: Jedna kap u zahvaćeno oko jednom ili dva puta dnevno. Prilagodite dozu kako bi zadovoljila potrebe pacijenta.

➣ Za produljenje učinaka lokalne anestezije

Odrasli i djeca: Koncentracija 1:200 000 uz lokalni anestetik

Kontraindikacije

• Preosjetljivost na lijek, njegove komponente ili sulfite

• Dilatacija srca, srčana insuficijencija

• Cerebralna arterioskleroza, organski moždani sindrom

• Šok upotrebom općih anestetika i halogeniranih ugljikovodika ili ciklosporina

• Upotreba MAO inhibitora u posljednjih 14 dana

Mjere opreza

• hipertenzija, hipertireoza, dijabetes, hipertrofija prostate

Uprava

• Kod anafilaksije koristite I.M. put, a ne potkožni put, ako je moguće.

☞ Ubrizgajte EpiPen i EpiPen Jr. samo u anterolateralnu stranu bedra. Nemojte davati injekcije u stražnjicu ili davati IV.

☞ Imajte na umu da se sve otopine epinefrina ne mogu davati IV. Provjerite oznaku proizvođača.

• Za I.V. injekcije, dajte svaku dozu od 1 mg tijekom najmanje 1 minute. Za kontinuiranu infuziju, koristite brzinu od 1 do 10 mcg/minuti, prilagođavajući se željenom odgovoru.

• Koristite Epi-Pen Jr. za pacijente manje od 30 kg (66 lb).

☞ Nemojte davati u roku od 14 dana od MAO inhibitora.

Nuspojave

CNS: nervoza, tjeskoba, tremor, vrtoglavica, glavobolja, dezorijentacija, uznemirenost, pospanost, strah, vrtoglavica, astenija,cerebralno krvarenje, cerebrovaskularna nezgoda (CVA)

životopis: lupanje srca, prošireni pulsni tlak, hipertenzija, tahikardija, angina pektoris, promjene EKG-a,ventrikularna fibrilacija, šok

GU: smanjeno izlučivanje mokraće, retencija mokraće, disurija

Respiratorno: dispneja, plućni edem

Koža: urtikarija, bljedilo, dijaforeza, nekroza

ostalo: krvarenje na mjestu injekcije

Interakcije

Droga-droga. Alfa-adrenergički blokatori: hipotenzija zbog nesuprotstavljenih beta-adrenergičkih učinaka

Antihistaminici, hormon štitnjače, triciklički antidepresivi: teški simpatomimetički učinci

Beta-adrenergički blokatori (kao što je propranolol): vazodilatacija i refleksna tahikardija

Srčani glikozidi, opći anestetici: povećan rizik od ventrikularnih aritmija

diuretici: smanjen vaskularni odgovor doksapram, mazindol, metilfenidat: pojačana stimulacija CNS-a ili presorski učinci

Alkaloidi ergota: smanjena vazokonstrikcija

Guanadrel, gvanetidin: pojačani presorski učinci epinefrina

levodopa: povećan rizik od aritmija

levotiroksin: potenciranje djelovanja epinefrina

MAO inhibitori: povećan rizik od hipertenzivne krize

Dijagnostički testovi za lijekove. Glukoza: prolazna elevacija

Mliječna kiselina: povišena razina (s dugotrajnom upotrebom)

Praćenje bolesnika

☞ Pratite vitalne znakove, EKG te kardiovaskularni i respiratorni status. Pazite na ventrikularnu fibrilaciju, tahikardiju, aritmije te znakove i simptome šoka. Pitajte pacijenta o anginoznoj boli.

• Procijenite učinak lijeka na temeljni problem (kao što je anafilaksija ili napad astme) i ponovite dozu prema potrebi.

☞ Nadgledajte neurološki status, posebno zbog smanjene razine svijesti i drugih znakova i simptoma cerebralnog krvarenja ili CVA.

• Pratite unos i izlaz tekućine, pazeći na zadržavanje mokraće ili smanjeno izlučivanje mokraće.

• Pregledajte mjesto ubrizgavanja zbog krvarenja ili nekroze kože.

Poučavanje bolesnika

• Naučite pacijenta koji koristi auto-injektor kako pravilno koristiti štrcaljku, kada ubrizgati lijek, a kada ponoviti doze.

• Podučite pacijenta koji koristi ručni nebulizator pravilnoj upotrebi opreme i lijeka. Objasnite indikacije i za početnu dozu i za ponovljene doze.

☞ Obavijestite pacijenta da lijek može uzrokovati ozbiljne nuspojave. Recite mu koje simptome treba prijaviti.

• Ako će pacijent sam davati lijek izvan zdravstvenog okruženja, objasnite potrebu za hitnom procjenom od strane pružatelja zdravstvene skrbi kako bi se osiguralo da je temeljni poremećaj ispravljen.

• Prema potrebi, pregledajte sve druge značajne i po život opasne nuspojave i interakcije, posebno one povezane s gore navedenim lijekovima i testovima.


Kemijska koordinacija i integracija

Koji hormon kod ljudi djeluje kao blagi hormon rasta?

Prolaktin je laktogeni hormon. Potiče rast i diferencijaciju dojke i proizvodnju mlijeka. Stoga posredno kontrolira rast.

Kateholamin kod normalne osobe izaziva

Sržina nadbubrežne žlijezde luči dva hormona nazvana adrenalin ili epinefrin i noradrenalin ili noradrenalin. Oni se obično nazivaju kateholaminima. Oni se brzo luče kao odgovor na stres bilo koje vrste i tijekom izvanrednih situacija i nazivaju se hitnim hormonima ili hormonima borbe ili bijega. Ovi hormoni povećavaju budnost, širenje zjenica, piloerekciju (dizanje dlačica), znojenje itd. Oba hormona povećavaju otkucaje srca, snagu srčane kontrakcije i brzinu disanja. Kateholamini također potiču razgradnju glikogena, lipida i proteina.

Tijekom širenja živčanog impulsa, akcijski potencijal proizlazi iz kretanja


Inotropi i vazopresori

Iz odjela za kardiologiju, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Kanada.

Iz Odjela za kardiologiju, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Kanada.

Inotropni i vazopresorni agensi sve više postaju terapijski kamen temeljac za liječenje nekoliko važnih kardiovaskularnih sindroma. U širem smislu, ove tvari imaju ekscitatorno i inhibitorno djelovanje na srce i glatke mišiće krvnih žila, kao i važne metaboličke učinke, središnji živčani sustav i presinaptički autonomni živčani sustav. Općenito se primjenjuju uz pretpostavku da će kratkoročni do srednjoročni klinički oporavak biti olakšan povećanjem minutnog volumena srca (CO) ili vaskularnog tonusa koji je bio ozbiljno ugrožen kliničkim stanjima koja su često po život opasni. Klinička učinkovitost ovih lijekova uglavnom je istražena kroz ispitivanje njihovog utjecaja na hemodinamske krajnje točke, a klinička praksa je djelomično vođena stručnim mišljenjem, ekstrapolacijom iz studija na životinjama i preferencijama liječnika. Naš je cilj revidirati mehanizme djelovanja uobičajenih inotropa i vazopresora te ispitati suvremene dokaze o njihovoj primjeni u važnim srčanim stanjima.

Kardiovaskularni učinci uobičajenih inotropa i vazopresora

Kateholamini

Od početnog otkrića epinefrina, glavne djelatne tvari iz nadbubrežne žlijezde, 1 okarakterizirana je farmakologija i fiziologija velike skupine endogenih i sintetskih kateholamina ili “simpatomimetika”. 2 Kateholamini posreduju u svom kardiovaskularnom djelovanju pretežno putem α1, β1, β2, i dopaminergičkim receptorima, čija gustoća i udio moduliraju fiziološke odgovore inotropa i presora u pojedinim tkivima. β1- Stimulacija adrenergičkih receptora rezultira pojačanom kontraktilnošću miokarda kroz Ca 2+ posredovano olakšavanje vezanja kompleksa aktin-miozin s troponinom C i pojačanu kroničnost kroz aktivaciju Ca 2+ kanala (slika 1). β2- Stimulacija adrenergičkih receptora na vaskularnim glatkim mišićnim stanicama kroz različite unutarstanične mehanizme rezultira povećanim unosom Ca 2+ u sarkoplazmatski retikulum i vazodilatacijom (slika 1). Aktivacija α1-adrenergički receptori na stanicama glatkih mišića arterija rezultiraju kontrakcijom glatkih mišića i povećanjem sistemskog vaskularnog otpora (SVR Slika 2). Konačno, stimulacija D1 i D2 dopaminergički receptori u bubrežnoj i splanhničkoj vaskulaturi rezultiraju bubrežnom i mezenteričnom vazodilatacijom kroz aktivaciju složenih sustava sekundarnih glasnika.

Slika 1. Pojednostavljena shema postuliranog intracelularnog djelovanja β-adrenergičkih agonista. Stimulacija β-receptora, putem stimulativne Gs-GTP jedinice, aktivira sustav adenil ciklaze, što rezultira povećanom koncentracijom cAMP. U srčanim miocitima, β1-aktivacija receptora kroz povećanu koncentraciju cAMP aktivira Ca 2+ kanale, što dovodi do Ca 2+ posredovanih pojačanih kronotropnih odgovora i pozitivne inotropije povećanjem kontraktilnosti sustava aktin-miozin-troponin. U glatkim mišićima krvnih žila, β2-stimulacija i povećanje cAMP-a rezultira stimulacijom cAMP-ovisne protein kinaze, fosforilacijom fosfolambana i pojačanim unosom Ca 2+ u sarkoplazmatski retikulum (SR), što dovodi do vazodilatacije. Preuzeto iz Gillies et al 3 uz dopuštenje izdavača.

Slika 2. Shematski prikaz postuliranih mehanizama unutarstaničnog djelovanja α1-adrenergički agonisti. α1- Stimulacija receptora aktivira drugačiji regulatorni G protein (Gq), koji djeluje kroz sustav fosfolipaze C i proizvodnju 1,2-diacilglicerola (DAG) i, preko fosfatidil-inozitol-4,5-bifosfata (PiP).2), inozitol 1,4,5-trifosfata (IP3). IP3 aktivira oslobađanje Ca 2+ iz sarkoplazmatskog retikuluma (SR), koji sam po sebi i preko protein kinaza ovisnih o Ca 2+ -kalmodulinu utječe na stanične procese, što u glatkim mišićima krvnih žila dovodi do vazokonstrikcije. Preuzeto iz Gillies et al 3 uz dopuštenje izdavača.

Kontinuum postoji između učinaka pretežno α1-stimulacija fenilefrina (intenzivna vazokonstrikcija) do β-stimulacije izoproterenola (izrazito povećanje kontraktilnosti i otkucaja srca Tablica). Specifični kardiovaskularni odgovori su dodatno modificirani refleksivnim autonomnim promjenama nakon akutnih promjena krvnog tlaka, koje utječu na broj otkucaja srca, SVR i druge hemodinamske parametre. Adrenergički receptori mogu biti desenzibilizirani i smanjeni u određenim stanjima, kao što je kronično zatajenje srca (HF). 4 Konačno, relativni afiniteti vezanja pojedinih inotropa i vazopresora za adrenergičke receptore mogu se promijeniti hipoksijom 5 ili acidozom 6 što prigušuje njihov klinički učinak.

Stol. Nazivi inotropnih i vazopresorskih lijekova, klinička indikacija za terapijsku upotrebu, standardni raspon doza, vezanje na receptore (kateholamini) i glavne kliničke nuspojave

Dopamin

Dopamin, endogeni središnji neurotransmiter, neposredni je prekursor norepinefrina u putu sinteze kateholamina (slika 3A). Kada se primjenjuje terapijski, djeluje na dopaminergičke i adrenergičke receptore izazivajući mnoštvo kliničkih učinaka (Tablica). Pri niskim dozama (0,5 do 3 μg · kg −1 · min −1 ), stimulacija dopaminergičkog D1 postsinaptički receptori koncentrirani u koronarnom, bubrežnom, mezenteričkom i cerebralnom krevetu i D2 presinaptički receptori prisutni u vaskulaturi i bubrežnim tkivima pospješuju vazodilataciju i povećan protok krvi u ta tkiva. Dopamin također ima izravne natriuretičke učinke svojim djelovanjem na bubrežne tubule. 7 Međutim, klinički značaj dopamina "bubrežne doze" donekle je kontroverzan jer ne povećava brzinu glomerularne filtracije i nije dokazan zaštitni učinak na bubrege. 8 U srednjim dozama (3 do 10 μg · kg −1 · min −1), dopamin se slabo veže na β1-adrenergičkih receptora, koji potiču oslobađanje norepinefrina i inhibiraju ponovnu pohranu u presinaptičkim simpatičkim živčanim završecima, što rezultira povećanom kontraktilnošću i kronotropijom srca, uz blago povećanje SVR-a. Pri većim brzinama infuzije (10 do 20 μg · kg −1 · min −1 ), α1- dominira vazokonstrikcija posredovana adrenergičkim receptorima.

Slika 3. A, Put sinteze endogenog kateholamina. Lijevo, kemijske strukture Desno, nazivi spojeva s konverzijskim enzimima (kurziv) i kofaktorima (podebljano). B, Kemijske strukture i nazivi uobičajenih sintetiziranih kateholamina.

Dobutamin

Dobutamin je sintetski kateholamin s jakim afinitetom za oba β1- i β2-receptora, na koje se veže u omjeru 3:1 (Tablica Slika 3B). Sa svojim srčanim β1-stimulativno djelovanje, dobutamin je snažan inotrop, sa slabijim kronotropnim djelovanjem. Vezivanje glatkih mišića krvnih žila rezultira kombiniranim α1-adrenergički agonizam i antagonizam, kao i β2-stimulacija, tako da je neto vaskularni učinak često blaga vazodilatacija, osobito pri nižim dozama (≤5 μg · kg −1 · min −1). Doze do 15 μg · kg −1 · min −1 povećavaju kontraktilnost srca bez značajnog utjecaja na periferni otpor, vjerojatno zbog proturavnotežnih učinaka α1-posredovana vazokonstrikcija i β2- posredovana vazodilatacija. Vazokonstrikcija progresivno dominira pri većim brzinama infuzije. 9

Unatoč blagim kronotropnim učincima pri niskim do srednjim dozama, dobutamin značajno povećava potrošnju kisika u miokardu. Ovaj fenomen oponašanja vježbanja temelj je na kojem se dobutamin može koristiti kao sredstvo farmakološkog stresa za dijagnostičko snimanje perfuzije, 10 ali obrnuto, može ograničiti njegovu korisnost u kliničkim stanjima u kojima je indukcija ishemije potencijalno štetna. Tolerancija se može razviti nakon samo nekoliko dana terapije, 11 i maligne ventrikularne aritmije mogu se primijetiti pri bilo kojoj dozi.

Norepinefrin

Norepinefrin, glavni endogeni neurotransmiter koji oslobađaju postganglijski adrenergični živci (Tablica Slika 3A), moćan je α1agonist adrenergičkih receptora sa skromnom aktivnošću β-agonista, što ga čini snažnim vazokonstriktorom s manje snažnim izravnim inotropnim svojstvima. Norepinefrin prvenstveno povećava sistolički, dijastolički i pulsni tlak i ima minimalan neto utjecaj na CO. Nadalje, ovaj agens ima minimalne kronotropne učinke, što ga čini privlačnim za upotrebu u okruženjima u kojima stimulacija otkucaja srca može biti nepoželjna. Koronarni protok je povećan zbog povišenog dijastoličkog krvnog tlaka i neizravne stimulacije kardiomiocita koji oslobađaju lokalne vazodilatatore. 12 Produljena infuzija norepinefrina može imati izravan toksični učinak na srčane miocite induciranjem apoptoze putem aktivacije protein kinaze A i povećanog citosolnog priljeva Ca 2+. 13

Epinefrin

Epinefrin je endogeni kateholamin s visokim afinitetom za β1-, β2-, i α1-receptori prisutni u glatkim mišićima srca i krvnih žila (Slika 3A Tablica). β-adrenergički učinci su izraženiji pri niskim dozama i α1-adrenergički učinci pri većim dozama. Koronarni protok krvi se pojačava povećanjem relativnog trajanja dijastole pri višim otkucajima srca i stimulacijom miocita da otpuštaju lokalne vazodilatatore, koji u velikoj mjeri utječu na izravnu α1-posredovana koronarna vazokonstrikcija. 14 Arterijski i venski plućni tlakovi se povećavaju zbog izravne plućne vazokonstrikcije i povećanog protoka plućne krvi. Visoke i produljene doze mogu uzrokovati izravnu srčanu toksičnost kroz oštećenje arterijskih stijenki, što uzrokuje žarišne regije nekroze trake kontrakcije miokarda, i kroz izravnu stimulaciju apoptoze miocita. 15

Izoproterenol

Izoproterenol je snažan, neselektivan, sintetski β-adrenergički agonist s vrlo niskim afinitetom za α-adrenergičke receptore (Tablica Slika 3B). Ima snažna kronotropna i inotropna svojstva, sa snažnim sistemskim i blagim plućnim vazodilatacijskim učincima. Njegov stimulativni utjecaj na udarni volumen je protutežan β2- posredovani pad SVR-a, što rezultira neto neutralnim utjecajem na CO.

Fenilefrin

Sa svojom snažnom sintetskom α-adrenergičkom aktivnošću i praktički bez afiniteta za β-adrenergičke receptore (Tablica Slika 3B), fenilefrin se prvenstveno koristi kao brzi bolus za trenutnu korekciju iznenadne teške hipotenzije. Može se koristiti za podizanje srednjeg arterijskog tlaka (MAP) u bolesnika s teškom hipotenzijom i popratnom aortalnom stenozom, za ispravljanje hipotenzije uzrokovane istodobnim unosom sildenafila i nitrata, za smanjenje gradijenta izlaznog trakta u bolesnika s opstruktivnom hipertrofičnom kardiomiopatijom i za ispraviti vagalno posredovanu hipotenziju tijekom perkutanih dijagnostičkih ili terapijskih postupaka. Ovaj agens praktički nema izravne učinke na brzinu otkucaja srca, iako ima potencijal inducirati značajne baroreceptorno posredovane refleksne reakcije nakon brzih promjena u MAP-u.

Inhibitori fosfodiesteraze

Fosfodiesteraza 3 je intracelularni enzim povezan sa sarkoplazmatskim retikulumom u srčanim miocitima i glatkim mišićima krvnih žila koji razgrađuje cAMP u AMP. Inhibitori fosfodiesteraze (PDI) povećavaju razinu cAMP inhibirajući njegovu razgradnju unutar stanice, što dovodi do povećane kontraktilnosti miokarda (slika 4). Ovi agensi su snažni inotropi i vazodilatatori, a također poboljšavaju dijastoličku relaksaciju (luzitropiju), smanjujući tako predopterećenje, naknadno opterećenje i SVR.

Slika 4. Osnovni mehanizam djelovanja PDI. PDI dovode do povećane intracelularne koncentracije cAMP, što povećava kontraktilnost u miokardu i dovodi do vazodilatacije u glatkim mišićima krvnih žila.

Milrinon je PDI koji se najčešće koristi za kardiovaskularne indikacije (Tablica). U svom parenteralnom obliku, ima dulje poluvrijeme (2 do 4 sata) od mnogih drugih inotropnih lijekova. Ovaj lijek je osobito koristan ako su adrenergički receptori smanjeni ili desenzibilizirani u uvjetima kronične HF ili nakon kronične primjene β-agonista. Amrinon se koristi rjeđe zbog važnih nuspojava, koje uključuju trombocitopeniju ovisnu o dozi.

Vazopresin

Izoliran 1951., 16 nonapeptidni vazopresin ili "antidiuretski hormon" pohranjen je prvenstveno u granulama u stražnjoj hipofizi i oslobađa se nakon povećanog osmolaliteta plazme ili hipotenzije, kao i boli, mučnine i hipoksije. Vasopresin se sintetizira u manjem stupnju u srcu kao odgovor na povišeni stres srčane stijenke 17 i u nadbubrežnoj žlijezdi kao odgovor na povećano lučenje kateholamina. 18 Svoje cirkulacijske učinke ostvaruje kroz V1 (V1a u glatkim mišićima krvnih žila, V1b u hipofizi) i V2 receptori (sustav bubrežnih sabirnih kanala Tablica). V1a stimulacija posreduje stezanje glatkih mišića krvnih žila, dok V2 receptori posreduju u reapsorpciji vode povećavajući propusnost bubrežnih sabirnih kanala.

Vazopresin uzrokuje manju izravnu koronarnu i cerebralnu vazokonstrikciju od kateholamina i ima neutralan ili inhibitorni učinak na CO, ovisno o dozi ovisnom povećanju SVR-a i refleksnom povećanju vagalnog tonusa. Povećanje vaskularne osjetljivosti na norepinefrin modulirano vazopresinom dodatno povećava njegove presorske učinke. Sredstvo također može izravno utjecati na mehanizme uključene u patogenezu vazodilatacije, kroz inhibiciju ATP-aktiviranih kalijevih kanala, 19 slabljenje proizvodnje dušikovog oksida, 20 i poništavanje regulacije adrenergičkih receptora. 21 Presorski učinci vazopresina relativno su očuvani tijekom hipoksičnih i acidotičnih stanja, koja se obično razvijaju tijekom šoka bilo kojeg porijekla.

Sredstva za preosjetljivost na kalcij

Senzibilizatori kalcija su nedavno razvijena klasa inotropnih sredstava, a najpoznatiji je levosimendan (Tablica). 22 Ova sredstva imaju dvostruki mehanizam djelovanja koji uključuje preosjetljivost kontraktilnih proteina na kalcij i otvaranje ATP-ovisnih kalijevih (K+) kanala. Vezanje ovisno o kalciju na troponin C pojačava ventrikularnu kontraktilnost bez povećanja unutarstanične koncentracije Ca 2+ ili ugrožavanja dijastoličke relaksacije, što može povoljno utjecati na energiju miokarda u odnosu na tradicionalne inotropne terapije. Otvaranje K+ kanala na glatkim mišićima krvnih žila dovodi do arteriolarne i venske vazodilatacije i može dati određeni stupanj zaštite miokarda tijekom ishemije. 23 Kombinacija poboljšane kontraktilne učinkovitosti i vazodilatacije osobito je korisna tijekom akutnih i kroničnih stanja HF, za koje se levosimendan sve češće koristi u nekim zemljama.

Dokazi za upotrebu inotropa i vazopresora u kardiovaskularnim bolestima

Kardiogeni šok koji komplicira akutni infarkt miokarda

Inotropi i vazopresori se rutinski koriste u uvjetima kardiogenog šoka koji komplicira akutni infarkt miokarda (AMI). Svi ti agensi povećavaju potrošnju kisika u miokardu i mogu uzrokovati ventrikularne aritmije, nekrozu kontrakcijske trake i širenje infarkta. Međutim, sama kritična hipotenzija ugrožava perfuziju miokarda, što dovodi do povišenih tlakova punjenja lijeve klijetke (LV), povećane potrebe miokarda za kisikom i daljnjeg smanjenja koronarnog perfuzijskog gradijenta. Stoga, hemodinamske koristi obično nadmašuju specifične rizike inotropne terapije kada se koriste kao most za konačnije mjere liječenja.

Inotropni agensi mogu poboljšati mitohondrijalnu funkciju u neinfarktnom miokardu koji je poremećen tijekom AIM-a kompliciranog šokom. 24 Međutim, slobodni citosolni Ca 2+, koji je značajno povišen u postishemijskim srčanim miocitima, dodatno se povećava davanjem dopamina, što dovodi do aktivacije proteolitičkih enzima, proapoptotičkih signalnih kaskada, oštećenja mitohondrija i eventualnog poremećaja i nekroze membrane. 25 Stoga bi se trebale koristiti najniže moguće doze inotropnih i presornih sredstava za adekvatnu podršku perfuziji vitalnog tkiva uz istovremeno ograničavanje štetnih posljedica, od kojih neke možda neće biti odmah vidljive.

Smjernice American College of Cardiology/American Heart Association za liječenje hipotenzije koja komplicira AMI predlažu upotrebu dobutamina kao lijeka prve linije ako se sistolički krvni tlak kreće između 70 i 100 mm Hg u odsutnosti znakova i simptoma šoka. Dopamin se predlaže pacijentima koji imaju isti sistolički krvni tlak u prisutnosti simptoma šoka. 26 Međutim, nedostaju konačni dokazi koji podupiru upotrebu specifičnih sredstava u ovom okruženju. Umjerene doze ovih sredstava maksimiziraju inotropiju i izbjegavaju prekomjerni α1-adrenergičku stimulaciju koja može rezultirati ishemijom krajnjeg organa. Pokazalo se da namjerna kombinacija dopamina i dobutamina u dozi od 7,5 μg · kg −1 · min −1 poboljšava hemodinamiku i ograničava važne nuspojave u usporedbi s bilo kojim pojedinačnim lijekom primijenjenim u dozi od 15 μg · kg −1 · min −1. 27 Umjerene doze kombinacija lijekova potencijalno mogu biti učinkovitije od maksimalnih doza bilo kojeg pojedinačnog lijeka.

Kada je odgovor na srednju dozu dopamina ili kombinacije dopamina/dobutamina neadekvatan, ili je bolesnikov sistolički krvni tlak

Tijekom ranog šoka, razine endogenog vazopresina značajno su povišene kako bi se pomogla u održavanju perfuzije krajnjeg organa. 29 As the shock state progresses, however, plasma vasopressin levels fall dramatically, which contributes to a loss of vascular tone, worsening hypotension, and end-organ perfusion. Proposed mechanisms to explain this phenomenon include depletion of neurohypophyseal stores, 30 baroreceptor and generalized autonomic dysfunction during prolonged shock, 31 and endogenous norepinephrine-induced inhibition of vasopressin release. 32 Vasopressin therapy may thus be effective in norepinephrine-resistant vasodilatory shock, improving MAP, cardiac index, and LV stroke work index and reducing the need for norepinephrine, resulting in decreased cardiotoxicity and malignant arrhythmias. 33 Vasopressin may also attenuate interleukin-induced generation of nitric oxide, have a modest inotropic effect on the myocardium via V1a-mediated increases in intracellular Ca 2+ , and improve coronary blood flow due to catecholamine sparing. 34

In the only study to date that examined vasopressin use in cardiogenic shock after AMI, this agent was found to increase MAP without adversely impacting cardiac index and wedge pressure. 35 Cardiac power index, an important determinant of outcome in cardiogenic shock after AMI, was not adversely affected by vasopressin but decreased when norepinephrine was used. Further studies to validate the use of vasopressin in this setting are needed.

Congestive HF

Inotropic therapy is used in the management of decompensated HF to lower end-diastolic pressure and improve diuresis, thus allowing traditional medical therapy (eg, angiotensin-converting enzyme inhibitors, diuretics, and β-blockers) to be reinstituted gradually. Patients with decompensated HF unresponsive to diuresis often have diminished concomitant peripheral perfusion, clinically apparent as cool extremities, narrowed pulse pressure, and worsening renal function. They may have markedly elevated SVR despite hypotension due to the stimulation of the renal-angiotensin-aldosterone system, as well as release of endogenous catecholamines and vasopressin. In this setting, reversal of systemic vasoconstriction is often achieved through the use of vasodilators (such as sodium nitroprusside) and inotropes with peripheral vasodilatory properties to improve hemodynamic parameters and clinical symptoms.

The use of positive inotropes (parenteral inotropes and oral PDIs) in chronic HF has been consistently demonstrated to increase mortality. 36,37 A proposed central mechanism involves a chronic increase in intracellular Ca 2+ , which contributes to altered gene expression and apoptosis and an increased likelihood of malignant ventricular arrhythmias. 38 As a result, the current American College of Cardiology/American Heart Association guidelines for diagnosis and management of chronic HF in the adult do not recommend the routine use of intravenous inotropic agents for patients with refractory end-stage HF (class III recommendation) but do state that they may be considered for palliation of symptoms in these patients (class IIb recommendation). 39 The European Society of Cardiology acute HF guidelines also stress that few controlled trials with intravenous inotropic agents have been performed. 40 However, these guidelines do point out that in an appropriate clinical setting of hypotension and peripheral hypoperfusion, particular agents may be indicated with slightly different levels of recommendation (dobutamine and levosimendan, class IIa PDIs and dopamine, class IIb). 41

The most commonly recommended initial inotropic therapies for refractory HF (dobutamine, dopamine, and milrinone) are used to improve CO and enhance diuresis by improving renal blood flow and decreasing SVR without exacerbating systemic hypotension. Dobutamine stimulation of β1- i β2-receptors can achieve this goal at low to medium doses by modestly increasing contractility with usually mild systemic vasodilation. Unfortunately, β-adrenergic receptor responses are often blunted in the failing human heart. A chronic increase in activation of the sympathetic nervous system and increased circulating catecholamine levels results in a phosphorylation signal that leads to uncoupling of the surface receptor from its intracellular signal transduction proteins (desensitization), as well as increased receptor targeting for endocytosis (decreased receptor density). 42 PDIs such as milrinone, acting through a non–β-adrenergic mechanism, are not associated with diminished efficacy or tolerance with prolonged use. This drug causes relatively more significant right ventricular afterload reduction through pulmonary vasodilation and less direct cardiac inotropy, which results in less myocardial oxygen consumption. Milrinone can cause severe systemic hypotension, necessitating the coadministration of additional pressor therapies. Direct randomized comparisons of milrinone and dobutamine have been small and have demonstrated similar clinical outcomes. 43,44

Several major clinical trials have evaluated the safety and efficacy of levosimendan in HF syndromes. Two early studies demonstrated a mortality benefit in patients given levosimendan versus placebo early (within 14 days) in the setting of LV failure complicating AMI (RUSSLAN [Randomized Study on Safety and Effectiveness of Levosimendan in Patients With Left Ventricular Failure due to an Acute Myocardial Infarct]) 45 and at 180 days in the setting of chronic HF when compared with dobutamine therapy (LIDO [Levosimendan Infusion versus Dobutamine in Severe Low-Output Heart Failure]). 46 However, in larger multicenter randomized trials in the setting of acute decompensated HF (REVIVE II [Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy] and SURVIVE [Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support]), 47,48 levosimendan use significantly improved symptoms but not survival.

In some patients, complete inotropic dependence manifested by symptomatic hypotension, recurrent congestive symptoms, or worsening renal function may develop after discontinuation of parenteral therapy. Inotropic support may become necessary until cardiac transplantation or implantation of an LV assist device can be instituted. Long-term therapy is also used as a “bridge to decision” in patients who are not presently destination-therapy candidates but may become so in the future. Inotrope-dependent HF patients who do not go on to definitive therapy have a poor prognosis, with 1-year mortality ranging from 79% to 94%. 49 Long-term inotropic therapy is associated with an increased risk of line sepsis, arrhythmias, accelerated functional decline due to worsening nutritional status, and direct acceleration of end-organ dysfunction, such as the development of eosinophilic myocarditis from an allergic response to chronic dobutamine exposure. 50 Inotropic home therapy has been used effectively for palliation of symptoms in patients who are not candidates for LV assist device support or transplantation, enabling those individuals to die in the comfort of their own homes. 51

The majority of HF patients can be weaned off inotrope infusions successfully after diuresis of excess volume and careful adjustment of concomitant oral medications. General recommendations have been to keep patients in the hospital and on a stable oral HF regimen for 48 hours before discharge to ensure adequacy of the initiated therapy. 52

Cardiopulmonary Arrest

Inotropic and vasopressor agents are a mainstay of resuscitation therapy during cardiopulmonary arrest. 53 Epinephrine, with its potent vasopressor and inotropic properties, can rapidly increase diastolic blood pressure to facilitate coronary perfusion and help restore organized myocardial contractility. However, it is not clear whether epinephrine actually facilitates cardioversion to normal rhythm, and its use has been associated with increased oxygen consumption, ventricular arrhythmias, and myocardial dysfunction after successful resuscitation. 54 Repeated high-bolus doses (5 mg) appear no more effective than repeated standard doses (1 mg) at restoring circulation. 55

The finding that endogenous vasopressin levels are greater in patients successfully resuscitated from sudden cardiac death than in nonsurvivors sparked interest in the use of vasopressin for this indication. 56 Experimentally, the use of vasopressin during cardiopulmonary collapse has demonstrated a more beneficial effect than epinephrine on cerebral and myocardial blood flow, 57 resulting in more sustained increases in MAP. 58 Clinically, its use has been associated with a higher rate of short-term survival in patients experiencing out-of-hospital ventricular fibrillation. 59 However, in a larger trial of 1186 patients with out-of-hospital cardiac arrest who were randomized to 2 injections of either 40 U of vasopressin or 1 mg of epinephrine (followed by additional treatment with epinephrine if needed), patients with asystole but not those with ventricular fibrillation or pulseless electrical activity were significantly more likely to survive to hospital admission with vasopressin administration. 60 The mechanism of benefit may stem from the ability of vasopressin to retain its potent vasoconstricting properties under severely acidotic conditions, in which catecholamines have limited efficacy. The current American Heart Association guidelines for adult cardiac life support have incorporated vasopressin as a 1-time alternative to the first or second dose of epinephrine (1-time bolus of 40 U) in patients with pulseless electrical activity or asystole and for pulseless ventricular tachycardia or ventricular fibrillation. 53

Postoperative Cardiac Surgery

Pharmacological support may be necessary during and after weaning from cardiopulmonary bypass in patients who have developed a low-CO syndrome, arbitrarily defined as a cardiac index <2.4 L · min −1 · m −2 with evidence of end-organ dysfunction. 3 Causes of low CO include cardioplegia-induced myocardial dysfunction, precipitation of cardiac ischemia during aortic cross-clamping, reperfusion injury, activation of inflammatory and coagulation cascades, and the presence of nonrepaired preexisting cardiac disease. Therapy should be instituted promptly in addition to other measures, including optimization of volume status, reduction of SVR with propofol infusion, temporary pacing, and intra-aortic balloon counterpulsation. Although no single agent is universally superior in this setting, dobutamine has the most desirable side-effect profile of the β-agonists, whereas PDIs increase flow through arterial grafts, reduce MAP, and improve right-sided heart performance in pulmonary hypertension. 3 As is the case in HF, concomitant vasopressor therapy may be necessary.

Several studies have examined the role of prophylactic inotropic or vasopressor therapy in weaning from cardiopulmonary bypass or to improve hemodynamic status in general. Preemptive milrinone administration before separation from cardiopulmonary bypass was found to attenuate postoperative deterioration in cardiac function and reduce the need for additional inotropes. 61 In off-pump bypass surgery patients, the use of preemptive milrinone significantly ameliorates increases in mitral regurgitation and improves hemodynamic indexes that often deteriorate with off-pump surgery. 62 Milrinone and dobutamine were both found to be effective in improving general hemodynamic parameters compared with placebo in a European multicenter, randomized, open-label trial. 63

The development of a systemic inflammatory response during cardiopulmonary bypass may cause severe generalized vasodilation, known as “vasoplegia syndrome,” which can result in increased early mortality, especially in heart transplant recipients. 64 This syndrome is associated with prolonged cardiopulmonary bypass time, orthotropic heart transplantation, and LV assist device insertion and is characterized by severe persistent hypotension, metabolic acidosis, decreased SVR, and low intracardiac filling pressures, with normal or elevated CO. Preoperative risk factors include preoperative angiotensin-converting enzyme inhibitor, calcium channel blocker, or intravenous heparin use and poor LV function. 64–66 Development of vasoplegia syndrome may be related to the release of vasodilatory inflammatory mediators, extensive complement activation, or vasoactive substance depletion, such as vasopressin. Although catecholamine therapy is often ineffective, methylene blue (through a nitric oxide–inhibition mechanism) and vasopressin have been shown to improve outcomes. 65–67

Right Ventricular Infarction

Significant right ventricular free-wall ischemia leads to immediate dilation of the right ventricle within a constrained pericardium. A rapid increase in intrapericardial pressure and intraventricular septal shift alters LV geometry, impairing LV filling and contractile performance. 68,69 These combined effects result in a drop in CO that may exacerbate shock. 70 Excessive intravenous fluid beyond a right atrial pressure >15 mm Hg to improve a “preload-dependent” right ventricle can result in deterioration of LV performance. Dobutamine improves myocardial performance in this setting. 71 Close observation is essential to monitor for exacerbation of hypotension and atrial arrhythmias, which can profoundly worsen hemodynamics.

Bradyarrhythmias

Owing to their chronotropic effects, β-adrenergic agonists can be useful for transient emergency treatment of bradyarrhythmias if atropine is ineffective. 53 The use of the β-agonists dobutamine, dopamine, or isoproterenol can stabilize the patient to allow time for a temporary pacemaker to be inserted. These agents are also useful under the same circumstances to treat bradycardia-induced torsade des pointes. Finally, isoproterenol has also been used to suppress the trigger for ventricular fibrillation in patients with the Brugada syndrome who do not wish to have cardioverter-defibrillator implantation to prevent sudden cardiac death. 72

Adjuvant Issues

Patient Monitoring During Parenteral Inotropic and Vasopressor Therapy

Patients requiring treatment with inotropes and vasopressors generally require monitoring in an intensive care or step-down setting because of the potential for development of life-threatening arrhythmias.

Invasive Blood Pressure Monitoring

In shock, continuous blood pressure monitoring with an arterial line is essential both to monitor the status of the underlying illness and because inotropes and vasopressors have the potential to induce life-threatening hypotension or hypertension. Chronic HF patients undergoing hemodynamic tailoring with a low-dose β-agonist or PDI can usually be monitored noninvasively.

Pulmonary Artery Catheter Use

Consensus on pulmonary artery catheter use during treatment with inotropic therapy is lacking. Although this tool can be helpful diagnostically, its routine use has never been shown to improve outcomes. 73 This may reflect an absence of effective evidence-based therapies to be used in response to pulmonary artery catheter data in the treatment of critically ill patients. 74 In the ESCAPE trial (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness), which examined pulmonary artery catheter use in patients with severe HF, catheter insertion was deemed safe but was not associated with improved rates of mortality or hospitalization. 75 Inotropic titration with pulmonary artery catheter data in isolation can result in inappropriate stimulation of CO, thus negatively impacting prognosis in heterogeneous intensive care unit patient populations. 76 Titration of inotropic therapy should be guided by the adequacy of end-organ perfusion, based on multiple clinical parameters.

Goals of Inotropic and Vasopressor Therapy

The use of inotropes and vasopressors has not been shown in randomized, controlled studies to ultimately lead to improved patient outcomes, at least in part because no clinical trials have been conducted with study size and power adequate to test their effect on improving survival. In the absence of such data, the definitive goals of therapy must be considered of primary importance, and the role of inotropic therapy should be kept in a supportive context to allow treatment of the underlying disorder. Such therapy includes prompt percutaneous or surgical revascularization and the institution of mechanical support (intra-aortic balloon counterpulsation or LV assist device) to improve coronary perfusion, CO, or both.

Zaključci i preporuke

In conclusion, inotropes and vasopressors play an essential role in the supportive care of a number of important cardiovascular disease processes. To date, prospective examination of their impact on clinical outcomes in randomized trials has been minimal, despite their widespread use in cardiovascular illness. However, the recently published TRIUMPH (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock) international randomized trial of N G -monomethyl l -arginine in cardiogenic shock has shown that such trials are not only feasible but necessary to validate findings of smaller studies. 77,78 A better understanding of the physiology and important adverse effects of these medications should lead to directed clinical use, with realistic therapeutic goals. The following broad recommendations can be made:

Smaller combined doses of inotropes and vasopressors may be advantageous over a single agent used at higher doses to avoid dose-related adverse effects.

The use of vasopressin at low to moderate doses may allow catecholamine sparing, and it may be particularly useful in settings of catecholamine hyposensitivity and after prolonged critical illness.

In cardiogenic shock complicating AMI, current guidelines based on expert opinion recommend dopamine or dobutamine as first-line agents with moderate hypotension (systolic blood pressure 70 to 100 mm Hg) and norepinephrine as the preferred therapy for severe hypotension (systolic blood pressure <70 mm Hg).

Routine inotropic use is not recommended for end-stage HF. When such use is essential, every effort should be made to either reinstitute stable oral therapy as quickly as possible or use destination therapy such as cardiac transplantation or LV assist device support.

Large randomized trials focusing on clinical outcomes are needed to better assess the clinical efficacy of these agents.

We would like to thank Uchewnwa Genus for her assistance during the preparation of this article.

Otkrivanja

Dr Overgaard is supported by a Heart and Stroke Foundation of Canada (HSFC)/AstraZeneca Canada Inc fellowship award. Dr Džavík is supported in part by the Brompton Funds (Toronto, Canada) Professorship in Interventional Cardiology. Dr Džavík has received research funding from Arginox Inc and speaker’s honoraria from Datascope Inc.


Norepinefrin

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norepinefrin, također tzv noradrenalin, substance that is released predominantly from the ends of sympathetic nerve fibres and that acts to increase the force of skeletal muscle contraction and the rate and force of contraction of the heart. The actions of norepinephrine are vital to the fight-or-flight response, whereby the body prepares to react to or retreat from an acute threat.

Norepinephrine is classified structurally as a catecholamine—it contains a catechol group (a benzene ring with two hydroxyl groups) bound to an amine (nitrogen-containing) group. The addition of a methyl group to the amine group of norepinephrine results in the formation of epinephrine, the other major mediator of the flight-or-flight response. Relative to epinephrine, which is produced and stored primarily in the adrenal glands, norepinephrine is stored in small amounts in adrenal tissue. Its major site of storage and release are the neurons of the sympathetic nervous system (a branch of the autonomic nervous system). Thus, norepinephrine functions mainly as a neurotransmitter with some function as a hormone (being released into the bloodstream from the adrenal glands).


Fundamental Aspects of Catecholamine Biology

– Called epinephrine in U.S., adrenaline in U.K.

Stolz (1904) and Dakin (1905)

– Synthesized racemic adrenaline

– First hormone with identified chemical structure

Lewandowsky (1899), Langley (1904), and Elliott (1904)

– Adrenal extracts mimic the effects of sympathetic nerve stimulation

– The concept of neurochemical transmission is born

– Structure activity relationships of “sympathomimetic amines”

– Primary amines (like NE) more closely resemble sympathetic stimulation than secondary amines (like E)

– Stimulation of sympathetic nerves releases an adrenaline-like substance

– NE identified as the adrenergic neurotransmitter

– Based on differential potencies for stimulatory and excitatory actions of sympathomimetic agonists the concept of distinct alpha and beta receptors is proposed

– Identified NE uptake (and reuptake) into sympathetic nerve endings

NE, norepinephrine E, epinephrine.

Blaschko and Welch (1953), Hillarp (1953)

– Storage in subcellular organelles

– Protein phosphorylation activates hepatic phosphorylase inactivated by dephosphorylation

De Robertis and Vaz Ferreira (1957), Coupland (1965)

– Catecholamine action through stimulation of adenylyl cyclase cyclic AMP as second messenger phosphodiesterase system metabolizes cyclic AMP

– Eventually established (several groups) that cyclic AMP activated phosphorylation

Rodbell a (1972), Gilman a (1981)

– G-protein transducers between receptor activation and cellular effect

– Inhibitory G proteins cyclic GMP nitrous oxide

Lefkowitz a and Kobilka a (1983)

– Beta adrenergic receptor coupled to G proteins desensitization associated with beta receptor phosphorylation

AMP, adenosine monophosphate.

– Circulating hormone of the adrenal medulla

– Neurotransmitter within the CNS (brainstem)

– Neurotransmitter at peripheral sympathetic nerve endings

– Neurotransmitter within the CNS

– Neurotransmitter within the CNS

– Peripheral neurotransmitter in selected areas (small intensely fluorescent cells in sympathetic ganglia and in carotid body)

– Autocrine or paracrine function (kidney, gut) after synthesis from circulating DOPA

CNS, central nervous system DOPA, 3,4-dihydroxyphenylalanine.

Innervates smooth muscle and glands

Innervates striated muscle

Synapse in ganglia outside the CNS

Direct innervation from the CNS

Preganglionic fibers are myelinated postganglionic are unmyelinated

Somatic nerves are myelinated

Ground plexus of terminal fibers in innervated tissues

Dispersion of central outflow at level of the ganglia

Discrete innervation of motor units

Representative functions: cardiac stimulation vasomotor tone glandular secretion heat conservation and dissipation visceral smooth muscle contraction

Function: voluntary movement

CNS, central nervous system.

Short preganglionic nerves

Long preganglionic nerves

Ganglia in paravertebral chains and preaortic area

Ganglia in innervated organs

Thoracolumbar outflow: preganglionic fibers originate in the intermediolateral cell column of the spinal cord, exit the spinal cord from T1-L2 and synapse in paravertebral and preaortic ganglia or the adrenal medulla

Craniosacral outflow: preganglionic fibers originate in the midbrain, the medulla oblongata exiting the neuraxis in cranial nerves III, VII, IX, X, and in the pelvic nerves from S2 to S4 regions of the spinal cord

Preganglionic dispersion: each preganglionic neuron synapses with many postganglionic sympathetic nerves

Much less preganglionic dispersion except for the vagal innervation of the enteric plexuses


What are catecholamines, and what do they do?

Catecholamines are hormones that the brain, nerve tissues, and adrenal glands produce. The body releases catecholamines in response to emotional or physical stress.

Catecholamines are responsible for the body’s “fight-or-flight” response. Dopamine, adrenaline, and noradrenaline are all catecholamines.

Unusually high or low levels of individual catecholamines can cause medical issues. High or low levels of multiple catecholamines can indicate a serious underlying medical issue.

This article outlines how catecholamines function and what high or low levels may indicate about a person’s health. It also discusses some ways in which a doctor may test a person’s catecholamine levels.

Share on Pinterest Dopamine, adrenaline, and noradrenaline are the main types of catecholamine.

Catecholamines are hormones that also function as neurotransmitters. The body produces them in the brain, nerve tissues, and adrenal glands. The adrenal glands are located just above the kidneys.

The main types of catecholamine are dopamine, adrenaline, and noradrenaline. These hormones function in the following ways:

Dopamine

This neurotransmitter sends signals throughout the nervous system. It helps regulate the following:

Adrenaline, or epinephrine

This neurotransmitter is responsible for the fight-or-flight response. When a person experiences stress, the body releases adrenaline to allow increased blood flow to the muscles, heart, and lungs.

Noradrenaline, or norepinephrine

This neurotransmitter helps the body respond to stress. Noradrenaline release increases a person’s heart rate and blood pressure. It is also involved in mood regulation and the ability to concentrate.

Catecholamine levels that are too low or too high can sometimes indicate an underlying health issue.

The main reason a doctor will test a person’s catecholamine levels is to check for the presence of certain tumors, such as a neuroendocrine tumor or a neuroblastoma. The following sections will look at these in more detail.

Neuroendocrine tumors

Neuroendocrine tumors are those that develop from cells in the hormonal and nervous systems. These tumors can produce high levels of catecholamines.

Pheochromocytomas are neuroendocrine tumors present in adrenal glands. Around 80–85% of pheochromocytomas grow in the inner layer of the adrenal glands, while the remaining 15–20% grow outside of this area.

Some possible symptoms of a pheochromocytoma include:

Although generally benign, some pheochromocytomas may continue to grow without treatment. The symptoms may worsen as the tumor grows, causing possible damage to the kidneys and heart.

Tumor growth also increases the risk of a stroke and heart attack.

Neuroblastoma

A neuroblastoma is a type of cancer that occurs in specialized nerve cells called neuroblasts. Most of the time, this cancer develops in an adrenal gland or in the nerve tissues that run alongside the spinal cord. Neuroblastomas can cause increased levels of catecholamines.

Neuroblastomas are the most common cancer in infants and account for 6% of all childhood cancers. They are rare in people over the age of 10.

Some possible symptoms of a neuroblastoma include:

To test a person’s catecholamine levels, a doctor will order a blood or urine test.

A person having a catecholamine urine test will need to collect their urine in a bottle over the course of 24 hours. This bottle contains a small amount of acid that helps preserve the urine. The person should keep the urine sample cool until they can return it to their doctor.

A catecholamine blood test involves drawing blood from a person’s arm or hand and sending the sample for analysis.

Additional testing

Once a doctor receives a person’s catecholamine test results, they can determine whether or not further testing is necessary.

Tests for pheochromocytomas can produce false positives. This occurs when the test result indicates that a person has a pheochromocytoma when they do not.

Because of this possibility, the doctor will take into account other aspects of a person’s health, such as their:

In some cases, the doctor may conduct additional or repeated tests to confirm a diagnosis.

If the doctor suspects that a person has a tumor, they will order an imaging test, such as an MRI or CT scan. If imaging tests confirm the presence of a tumor, the doctor may order a biopsy test to determine the tumor type.

High or low levels of individual catecholamines can lead to a range of symptoms. The sections below outline these in more detail.

Abnormal dopamine levels

High dopamine levels may lead to the following symptoms:

Chronically high levels of dopamine may be related to the following conditions:

Scientists have also linked a lack of dopamine to some degenerative conditions, such as Parkinson’s disease.

Abnormal adrenaline levels

A person with high levels of adrenaline may experience the following symptoms:

  • anksioznost
  • a rapid heartbeat
  • heart palpitations
  • tresući se
  • visoki krvni tlak
  • sweating
  • a pale face
  • extreme headache

Having low adrenaline levels could inhibit a person’s ability to respond appropriately to stressful situations.

Abnormal noradrenaline levels

High levels of noradrenaline can cause the following symptoms:

Low levels of noradrenaline may cause the following symptoms or conditions:


Sažetak

Monitoring dopamine and norepinephrine (or other structurally similar neurotransmitters) in the same brain region necessitates selective sensing. In this Viewpoint, we highlight electrochemical and optical strategies for advancing simultaneous real-time measurements of dopamine and norepinephrine transmission. The potential for DNA aptamers as recognition elements in the context of field-effect transistor sensing for selective and simultaneous neurotransmitter monitoring in vivo is also discussed.

SPECIAL ISSUE

This article is part of the Monitoring Molecules in Neuroscience 2016 special issue.

It is no coincidence that neurotransmitters and other small molecules involved in biological signaling are closely structurally related. Evolution over millennia has imparted biological systems with finely tuned efficiency in the form of intertwined synthesis motifs. Amino acids are used as building blocks of proteins but also as neurotransmitters or their precursors. Glutamate is a prime example. Furthermore, decarboxylation of glutamate yields γ-aminobutyric acid (GABA). Together, glutamate and GABA are responsible for a majority of interneuronal communication in the central nervous system.

Less abundant but no less important are the catecholamine neurotransmitters dopamine, norepinephrine, and epinephrine, synthesized from the amino acid tyrosine in stepwise fashion (Figure 1). Dopamine neurons are located in the midbrain substantia nigra and ventral tegmental area. These neurons project densely to the dorsal and ventral striatum, respectively. A highly localized anatomy coupled with ease of electrochemical detection largely underlies the predominance of neurochemical investigation of dopamine signaling. Norepinephrine is also detected electrochemically. In contrast to dopaminergic projections, noradrenergic axons, originating from brain stem locus coeruleus and medullary (A1/A2) neurons, project diffusely to most brain regions, including those innervated by the dopamine system.


ASJC Scopus subject areas

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Cambridge University Press, 2007. 642 p.

Research output : Book/Report › Book

T2 - Neurobiology and therapeutics

N2 - This book was first published in 2007. Norepinephrine is a chemical neurotransmitter. Drugs that directly manipulate central nervous system (CNS) norepinephrine are being developed targeting noradrenergic neurons to deliver therapeutic effects. Noradrenergic drugs have been proven effective for depression and ADHD, and new disease indications are being identified. A team of experts provides the reader with a thorough understanding of the anatomy, physiology, molecular biology, pharmacology and therapeutics of norepinephrine in the brain, including an extensive review of the role of norepinephrine in brain diseases. The book is divided into four sections: the basic biology of norepinephrine the role that norepinephrine plays in behavior evidence of norepinephrine's role in CNS diseases, and the pharmacology and therapeutics of noradrenergic drugs in the treatment of psychiatric and neurological disorders.

AB - This book was first published in 2007. Norepinephrine is a chemical neurotransmitter. Drugs that directly manipulate central nervous system (CNS) norepinephrine are being developed targeting noradrenergic neurons to deliver therapeutic effects. Noradrenergic drugs have been proven effective for depression and ADHD, and new disease indications are being identified. A team of experts provides the reader with a thorough understanding of the anatomy, physiology, molecular biology, pharmacology and therapeutics of norepinephrine in the brain, including an extensive review of the role of norepinephrine in brain diseases. The book is divided into four sections: the basic biology of norepinephrine the role that norepinephrine plays in behavior evidence of norepinephrine's role in CNS diseases, and the pharmacology and therapeutics of noradrenergic drugs in the treatment of psychiatric and neurological disorders.


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