Kaj so to zdravi možgani?
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1 Farm acevts ska kem mija 3 Serotoninergični sistem 2 Antidepresivi izr. prof. dr. Marko Anderluh 18. april 2013
2 Depresija Kaj so to zdravi možgani?
3 Edvard Munch (1893): Skrik "One evening I was walking along a path, the city was on one side and the fjord below. I felt tired and ill. I stopped and looked out over the fjord the sun was setting, and the clouds turning blood red. I sensed a scream passing through nature; it seemed to me that I heard the scream. I painted this picture, painted the clouds as actual blood. The color shrieked. This became The Scream." Depresija?
4 Vincent van Gogh (1882): Na vratih večnosti Depresija?
5 Vincent van Gogh ( ): Lobanja z gorečo cigareto Depresija?
6 Depresija - Anksioznost Depresija Anksioznost duševna motnja, ki jo Tesnoba: občutje negotovosti, označujejo žalostno pričakovanja česa neugodnega, g razpoloženje, pobitost, brez stvarnega zunanjega razloga, spremljano z vegetativnimi pojavi pesimizem, obupanost, (npr. pospešen p srčni utrip in pomanjkanje notranjih pospešeno dihanje, drhtenje); sin. spodbud, včasih tesnoba in Anksioznost samomorilna nagnjenja Generalizirana anksiozna motnja Kronična, recidivirajoča, epizoda Panična motnja Distimija (kronična) Socialna anksiozna motnja Bipolarna a (manično č depresivna) es (socialna fobija) Akutna stresna reakcija Posttravmatska stresna motnja Obsesivno-kompulzivna motnja
7 Izguba energije Depresija Težave pri koncentraciji Brezvoljnost Motnje spanja Motnje teka in telesne teže Izguba veselja do aktivnosti Samomorilske misli Žalostno počutje Občutek krivde Fizična neaktivnost Vsaj 5 od vseh navedenih znakov traja 5 tednov ali več depresija!
8
9 Hipoteze nastanka depresije Hipoteza monoaminskega pomanjkanja: pomanjkanje monoaminskih prenašalcev (MAP) serotonina, noradrenalina, dopamina v centralnem živčevju Serotonin (5-HT):v Raphe nuclei, uravnavanje razpoloženja, spanja in v spolnosti Noradrenalin: v Locus coeruleus, uravnava procese budnosti, pozornosti in koncentracije, učinkuje na krvni pritisk in pulz, vpliva na občutke zadovoljstva in z nagrado pogojeno vedenje Dopamin:v Substantii nigri, kognitivne funkcije, učenje, razpoloženje, občutek ugodja, evforije Hipoteza nevrotransmiterskih receptorjev: Povečano/zmanjšano število in občutljivost (downregulation) serotoninergičnih in adrenergičnih receptorjev posledica adaptacije na znižane nivoje MAP v sinaptični špranji
10 Hipoteze nastanka depresije
11 < < < < Molekularni nivo nastanka depresije < < < <
12 Antidepresivi Triciklični antidepresivi = SNRI = Neselektivni zaviralci privzema 5-HT in NA SSRI = Selektivni zaviralci privzema 5-HT NRI = selektivni zaviralci privzema NA NDRI = Neselektivni zaviralci privzema NA in DA NaSSA = NA in 5-HT antidepresivi MAOI = inhibitorji MAO
13 Antidepresivi
14 Triciklični antidepresivi (TCA) = NSRI podobno kot MAOI ena prekretnic v farmakoterapiji depresivnih motenj, imipramin že leta 1957 dve skupini: terciarni amini (amitriptilin, imipramin, doksepin, klomipramin) zavirajo predvsem privzem serotonina v presinaptične nevrone sekundarni amini (desimipramin, nortriptilin, protriptilin) zavirajo predvsem privzem noradrenalina v presinaptične nevrone
15 Triciklični antidepresivi
16 Triciklični antidepresivi MAPROTILIN
17 Triciklični antidepresivi Primerjava z antispihotiki (fenotiazini) večji kot med aromatoma vzrok za 5-HT + NA vs. DaA selektivnost
18 5-HT/NA selektivnost Triciklični antidepresivi
19 Triciklični antidepresivi - metabolizem
20 Triciklični antidepresivi - metabolizem
21 Triciklični antidepresivi
22 Stranski učinki TCA Antiholinergični H1 Antihistaminergični - muskarinski Kardiotoksični ič i (adenergični 1) CNS
23 Ostali NSRI selektivneje kot triciklični antidepresivi, ni zaviranja privzema dopamina močnejši učinek in pogosteje remisije, manj str. učinkov
24 SSRI = Selektivni zaviralci privzema 5- načrtovanje HT
25 SSRI = Selektivni zaviralci privzema fenoksifenilalkilamini najpogosteje predpisovani antidepresivi, zlati standard d terapije depresivnih motenj - začetek zdravljenja ravno s SSRI Zapoznelo delovanje!? serotonina
26 SSRI = Selektivni zaviralci privzema Farmakokinetični parametri serotonina Očiščenje pred uvedbo MAOI po terapiji s SSRI!
27 SSRI = Selektivni zaviralci privzema fenilalkilamini serotonina
28 Selektivni zaviralci privzema NA/5-HT SAR
29 SNRI = selektivni zaviralci privzema noradrenalina Po mehanizmu neselektivni: delujejo selektivneje kot triciklični antidepresivi, ni zaviranja privzema dopamina
30 SNRI = selektivni zaviralci privzema metabolizem noradrenalina
31 Noradrenergični in selektivni serotoninergični antidepresivi (NaSSA) NaSSA N N N N N mianserin mirtazapin Tetraciklični i antidepresiv i mianserin i in novejši mirtazapin delujejo zaviralno na 1- in 2- adrenergične receptorje ter praktično vse serotoninergične receptorje, na delovanje
32 Noradrenergični in selektivni serotoninergični antidepresivi (NaSSA) Metabolizem
33 Primerjava struktur
34 Zaviralci monoaminooksidaz (MAOI) prvi klinično uporabljeni antidepresivi: prvi klinično uporabljeni antidepresivi: izoniazid in iproniazid
35 Zaviralci monoaminooksidaz (MAOI) Večinoma neselektivni več str. Učinkov. Moklobemid reverzibilen in MAO-A selektiven MAOI Cl O N H moklobemid N O
36 Zaviralci monoaminooksidaz (MAOI) Potencialna nevarnost? Hipertenzivna Potencialna nevarnost? Hipertenzivna kriza
37 Literatura predavanj Foye s Principles of Medicinal Chemistry, 6. izdaja: 14., 21. poglavje
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