6. GAIA: FARMAKOEN IRAIZKETA
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1 6. GAIA: FARMAKOEN IRAIZKETA Lan hau Creative Commons-en Nazioarteko 3.0 lizentziaren mendeko Azterketa-Ez komertzial- Partekatu lizentziaren mende dago. Lizentzia horren kopia ikusteko, sartu helbidean.
2 Edukien indizea 2 1. Sarrera 2. Giltzurrunen anatomia eta fisiologia 3. Giltzurrun-iraizketa mekanismoak 4. Giltzurrun-argitzapena 5. Giltzurrun-iraizketa aldatu dezaketen faktoreak 6. Behazun iraizketa 7. Listu iraizketa 8. Esne bidezko iraizketa
3 Sarrera 3 Iraizketa Farmakoa edo bere metabolitoak gorputzetik kanporatzeko prozesua edo prozesu multzoak Farmakoen iraizketarako bide nagusiak: 1. Giltzurrunak (nagusia) 2. Giltzirrunetatik kanpo: Behazuna Listua Esnea
4 Giltzurrunen anatomia eta fisiologia 4 Wikispaces-en argitaratua Creative Commons Attribution Share-Alike 3.0 License lizentziarekin. ces.com/12.+urology
5 Giltzurrunen anatomia eta fisiologia 5 Nefrona: Glomeruloa Hurbileko tubuloa Henle-ren lakioa Urrineko tubuloa Hodi biltzailea
6 Giltzurrunen anatomia eta fisiologia 6 Wikispaces-en argitaratua Creative Commons Attribution Share-Alike 3.0 License lizentziarekin.
7 Giltzurrunen anatomia eta fisiologia 7 Jariaketa Birxurgapena Iragazketa Wikispaces-en argitaratua Creative Commons Attribution Share-Alike 3.0 License lizentziarekin.
8 Gernu-iraizketa mekanismoak 8 Iragazketa glomerularra Jariaketa tubular aktiboa Birxurgapen tubularra
9 Gernu-iraizketa mekanismoak 9 Iragazketa glomerularra Farmako baten iragazketa glomerularraren abiadura F g x C fu F g : C fu : Iragazketa glomerularraren fluxua ( ml/min) farmakoaren kontzentrazio askea plasman
10 Gernu-iraizketa mekanismoak 10 Jariaketa tubularra Garraio aktiboa Espezifikotasuna Ase daiteke Inhibizio lehiakorra (probenezid) P-glikoproteinaren eta beste garraiatzaileen parte-hartzea (OAT)
11 Gernu-iraizketa mekanismoak 11 Jariaketa tubularra Anioiak Azido folikoa Cefotaxima Norfloxacino Ampizilina Ceftazidima Penizilina G Ziprofloxazino Fenilbutanzona Cefazolina Cefotaxima Metotrexato Zidovudina Katioiak Amilorida Prokainamida Ranitidina Zimetidina Kinidina Trimetroprim Digoxina Kinina Bancomizina Jariaketa tubularra jasaten duten farmakoak
12 Gernu-iraizketa mekanismoak 12 Jariaketa tubularra Probeneciden eragina (PRO) ziprofloxazinoren (CIP) eta bere metabolitoaren (MI) kontzentrazio plasmatikoetan eta gernukontzentrazioetan boluntario osasuntsuetan. Landersdorfer CB et al. Br J Clin Pharmacol 2010; 69:
13 Gernu-iraizketa mekanismoak 13 Birxurgapen tubularra Barreiadura pasiboz (nagusia) Garraio aktiboa Azidoak A AH 10 ph pka Baseak BOH B 10 ph pka
14 Gernu-iraizketa mekanismoak 14 Birxurgapen tubularra Ionizatu gabeko farmakoaren barreiadura pasiboa Azidoak A AH 10 ph pka o pka 2: erabat ionizatuak birxurgapenik ez o pka > 8: ez ionizatuak erabateko birxurgapena o 3 < pka < 8,5: birxurgapena phren menpe Baseak BOH B 10 ph pka pka > 12: erabat ionizatuak birxurgapenik ez pka < 6: ez ionizatuak erabateko birxurgapena 6 < pka < 12: birxurgapena phren menpe
15 Gernu-iraizketa mekanismoak 15 AZIDOAK pka BASEAK Birxurgapenik ez Birxurgatze partziala Birxurgatze totala AZIDO GOGORRAK AZIDO AHULAK AZIDO OSO AHULAK BASE OSO AHULAK BASE AHULAK BASE GOGORRAK Birxurgatze totala Birxurgatze partziala Birxurgapenik ez
16 Iraizten den iragazitako frakzioa Iraizten den iragazitako frakzioa Gernu-iraizketa mekanismoak 16 Birxurgapen tubularra Base ahula Azido ahula 1,0 Farmako polarra 1,0 Farmako polarra 0,8 0,8 0,6 0,4 Polarrak ez diren farmakoak 0,6 0,4 Polarrak ez diren farmakoak 0,2 0, pka pka
17 Gernu-iraizketa mekanismoak 17 Birxurgapen sangre O OH tubularra O O B O OH O gernua O HO O - O Na + CH 3 CH 3 No ionizado A D O O - + H + O O CH 3 C Ionizatua Iraizketa Na + CO 2 + H 2 O Az Salizilikoaren (AS) giltzurrun argitzapenaren hazkuntza gernuaren pha bikarbonatoarekin igotzerakoan AS partzialki ionizatzen den azido ahula da (A). Bakarrik ionizatu gabeko forma pasatzen da gernura (B). Bikarbonatoa gehitzerakoan (D) gernuaren pha handitzen da eta ASren ionizazio maila ere handitzen da. Hori dela eta birxurgapena baxuagoa da eta gernu iraizketa handitzen da (C)
18 Gernu-iraizketa mekanismoak 18 Birxurgapen tubularra Salizilatoren erdibizitzaren eta gernuaren phren arteko erlazioa. Prescott LF. Br Med J (Clin Res Ed) 1982;285(6352):
19 Iraiztutako dosi % Gernu-iraizketa mekanismoak 19 Birxurgapen tubularra ph azidoa 30 ph normala 20 ph alkalinoa denbora(h) phren eragina metoxifenaminaren gernu iraizketan, farmakoa aho-bidetik administratu ondoren Iturri honetatik aldatua: Roy S et al. J Pharm Sci 1987;76:
20 Giltzurrun argitzapena 20 da/dt = Cl R Cp da/dt = denbora unitateko iraiztutako farmako kantitatea Cl R = (Cl FR + Cl SR ) (1- FR) Cl FR = Giltzurrun iragazketa bidezko argitzapena Cl SR = Jariaketa tubular bidezko argitzapena FR = Birxurgatzen den farmako frakzioa Cl FR = f u GFR fu = farmako frakzio askea, plasma proteinekin loturik ez dagoena GFR = Iragazketa glomerularraren abiadura Cl SR = (RBF f u Cl i )/(RBF + Cl i ) RBF = giltzurrunetako odol fluxua Cl i = farmako askearen berezko argitzapena
21 Giltzurrun argitzapena 21 Hainbat farmakoen giltzurrun bidezko argitzapena Farmakoa CLr (ml/min) Penizilina G 500 Cefalexina 250 Lidokaina 192 Amikacina 100 Furosemida 95 Indometacina 75 Amobarbital 37 Sulfadiazina 35 Eritromizina 20 Fenitoina 7 Propranolol 5
22 Giltzurrun iraizketa aldatu dezaketen faktoreak Farmakoaren kontzentrazio plasmatikoa 2. Proteina plasmatikoekin lotutako frakzioa 3. Giltzurrunetako odol-fluxua 4. Farmakoen arteko elkarrekintzak 5. Gernuaren ph-a 6. Gernu-fluxua 7. Faktore fisiopatologikoak : a) Adina b) Sexua c) Dieta d) Gaixotasunak: Giltzurrun gutxiegitasuna Bihotz-hutsegitea Obesitatea
23 Iraizketa abiadura Giltzurrun argitzapena Giltzurrun iraizketa aldatu dezaketen faktoreak: farmakoaren kontzentrazio plasmatikoa 23 B B A C A C C p Iraizketa abiaduran eta giltzurrun argitzapenean aldaketak kontzentrazio plasmatikoarekin, farmakoa A) Bakarrik iragazpen prozesuaz kanporatzen denean, B) Bakarrik iragazi eta jariatu C) Iragazten da eta birxurgapen aktiboa jasaten du C p
24 24 Giltzurrun iraizketa aldatu dezaketen faktoreak: lotura proteina plasmatikoekin Digitoxinaren giltzurrun argitzapenaren eta frakzio askearen arteko erlazioa perfundidutako arratoi-giltzurrun ereduan Hall S et al. J Pharmacol Exp Ther 1984;228:174-9.
25 25 Giltzurrun iraizketa aldatu dezaketen faktoreak: gernu-fluxua Digitoxinaren giltzurrun argitzapenaren eta gernu fluxuaren arteko erlazioa perfundidutako arratoi-giltzurrun ereduan Hall S et al. J Pharmacol Exp Ther 1984;228:174-9.
26 26 Giltzurrun iraizketa aldatu dezaketen faktoreak: farmakoen arteko elkarrekintzak Penizilina G eta aziklobir-ren arteko elkarrekintza Ye J et al. Pharmacol Rep. 2013;65:
27 27 Giltzurrun iraizketa aldatu dezaketen faktoreak: adina Kreatinina serikoaren eta adinaren arteko erlazioa (<1 urte duten haurrak). Bankomizinaren argitzapena eta adinaren arteko erlazioa jaioberrietan (PCA) Boer DP et al. Pediatr Nephrol 2010;25: Kimura T et al. Antimicrob Agents Chemother. Apr 2004; 48(4):
28 28 Giltzurrun iraizketa aldatu dezaketen faktoreak: adina Kreatinina argitzapenaren eta adinaren arteko erlazioa >65 urteko pertsonetan Ccr: kreatinina argitzapena C-G: Cockcroft Gault ekuazioa MDRD-4: Modification of Diet in Renal Disease (4 parametro) MDRD-6: Modification of Diet in Renal Disease (6 parametro) Pizzarelli F et al. Nephrol Dial Transplant 2009; 24:
29 29 Giltzurrun iraizketa aldatu dezaketen faktoreak: adina Vildagliptin farmakoaren parametro farmakozinetikoak pertsona osasuntsuei 100 mg administratu ondoren He YL et al. Br J Clin Pharmacol 2007;65:
30 30 Giltzurrun iraizketa aldatu dezaketen faktoreak: giltzurrun gutxiegitasuna Giltzurrun funtzio normala: Cl cr >80 ml/min G Gutxiegitasun arina: 30 < Cl cr < 50 ml/min G Gutxiegitasun moderatua: 10 < Clcr < 30 ml/min G Gutxiegitasun zorrotza: Cl cr < 10 ml/min Kreatinina argitzapena kalkulatzeko ekuazioak UNITATEAK GIZONEZKOAK EMAKUMEZKOAK Helduak - Jeliffe ml/min/1,73 m adina 20 Cl Cl cr =gizonezk x 0,9 cr S cr Helduak - Cockroft Gault ml/min Cl cr =gizonezk x 0,85 Cl cr (140 adina) Pisua 72 S cr Haurrak - Schwartz et al ml/min/1,73 m 2 Cl cr 0.45 azalera_cm S cr Haurrak: 0-1 urte ml/min/1,73 m 2 Cl cr 0.55 altuera_cm S cr 1-20 urte
31 31 Giltzurrun iraizketa aldatu dezaketen faktoreak: giltzurrun gutxiegitasuna Klinafloxazinoren giltzurrun argitzapenaren eta kreatinina argitzapenaren arteko erlazioa Randinitis EJ et al. Antimicrob Agents Chemother 2001; 45:
32 32 Giltzurrun iraizketa aldatu dezaketen faktoreak: giltzurrun gutxiegitasuna Kleijn HJ et al. Br J Clin Pharmacol 2011;72:
33 33 Giltzurrun iraizketa aldatu dezaketen faktoreak: giltzurrun gutxiegitasuna LBW: lean body weight (peso corporal magro) DWT: dosing weight (peso corporal) Kirkpatrick CMJ et al. Br J Clin Pharmacol 1999; 47:
34 34 Giltzurrun iraizketa aldatu dezaketen faktoreak: obesitatea Gizonezkoak Cl cr 137 Adina Pisua 12.1 Altuera 2 51Cr s Emakumezkoak Cl cr 146 Adina Pisua 9.74 Altuera 2 60Cr s
35 Behazun Iraizketa 35 Wikimedia Commons-en argitaratua Creative Commons Attribution/Share-Alike License lizentziarekin.
36 Behazun Iraizketa 36 Behazun iraizketan eragina duten faktoreak: Egitura kimikoa Pisu molekularra Polaritatea Yang X et al. Eur J Pharm Sci 2010;40:33-7
37 Behazun Iraizketa 37 Ziklo enterohepatikoa BEHAZUN IRAIZKETA DUODENOA HESTE-HESIA GIBELA ODOL ZIRKULAZIOA kondarrak
38 Kontzentrazioa Behazun Iraizketa 38 Ziklo enterohepatikoa Ziklo enterohepatikoa denbora
39 Behazun Iraizketa 39 Ziklo enterohepatikoa EPN: epinastina Ogiso T, Kasutani M, Tanaka H, Iwaki M, Tanino T. Biol Pharm Bull 2001;24:790-79
40 Behazun Iraizketa 40 Behazunetik iraizten diren farmakoak: Azenokumarol Cefotaxima Ceftriaxona Ziprofloxazino Kromoglikato Ibuprofeno Ketoprofeno Metotrexato Penizilina Rifanpizina
41 Listu Iraizketa 41 Azidoak R ph ph listu f pka plasma pka f listu plasma Baseak R pka ph pka ph listu plasma f plasma f listu R: listu/odol kontzentrazioen arteko erlazioa F plasma : farmako frakzio askea plasman F listu :farmako frakzio askea listuan
42 Listu Iraizketa 42 Listu bidez iraizten diren farmakoak Farmakoa R (listua/plasma) Litio 2,85 Metilprednisolona 5,20 Metroprolol 2,90 Lidokaina 1,78 Parazetamol 1,40 Sulfazetamida 0,92 Teofilina 0,75 Digoxina 0,66 Kafeina 0,55 Kinidina 0,51
43 Esne-bidezko iraizketa 43 Esnea (ph: 7,0) Plasma (ph: 7,4) Ionizatua Ionizatu gabea Ionizatua Ionizatu gabea Base ahulak [esnea] > [plasma] Ionizatu gabea Ionizatua Ionizatu gabea Ionizatua Azido ahulak [esnea] < [plasma] Plasmaren eta esnearen phren eragina farmakoen ionizazio mailan eta aien iraizketan esne-bidetik. Izaera basikoa duten farmakoan esnean metatzen dira
44 Esne-bidezko iraizketa 44 Moxidektin farmakoaren kontzentrazio vs denbora profilak plasman eta esnean Kurba Azpiko Azaleren erlazioa esnean eta plasman Korth-Bradley JM et al. Antimicrob Agents Chemother 2011; 55: Keyal S et al. J Clin Pharmacol 2010;50:
45 Esne-bidezko iraizketa 45 Esnean iraizten diren farmakoak: Azido nalidixiko Ampizilina Kafeina Karbamazepina Kloranfenikol Fenobarbital Metadona Metotrexato Morfina Teofilina Tolbutamida
46 Esne-bidezko iraizketa 46 Esne-bidezko iraizketa edoskitzean Arriskua mugatzen duten faktoreak: Amarekin erlazionatutako faktoreak Dosia Bioeraldatzerako/iraizketarako gaitasuna Farmakoaren administraziotik pasa den denbora Odolaren eta esnearen pha Ezaugarri fisikokimiko eta biofarmazeutikoak PM Liposolugarritasuna Ionizazio maila, pka Proteina plasmatikoei lotura Bularreko haurraren menpe dauden faktoreak Xurgapen, metabolismo edo iraizketan aldaketak
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