B Y TTRNG I HC Dc H NI****CQ|****NGUYN TH HNGKHO ST TC DNG KHNG MONG MUN CA GLUCOCORTICOID TRN BNH NHN MC BNH H THNG IU TR TI KHOA D NG -MIN DCH LM SNG -BNH VIN BCH MAI (KHO LUN TT NGHIP Dc s KHO 2001- 2006)Ngi hng dn:Th.s Bi c LpBSCKII Trng Thanh Lan Ni thc hin:B mn Dc lm sng -Trng i hc Dc H Ni Bnh vin Bch Mai Thi gian thc hin:01/2006-05/2006IH NI, 05/ 2006V-X-.-, i U . - j&eAMm&i in. eht thjnh iy, i Ltig, evi LiAiL ac. ti:^Ite. i l (Bi ^e.MqLfL(Be. i lduMMt idtUt. I I ^n i n g ,^uL Multn tinh htiq, dti ti hjiut tkt Uh. Lutl n-.Q eng. ht ehti thnh em. t t :th, e qi^l mtt ne. lm. ijcuijg.,ee. Im tnmt kh,ea phn. l%ut ^Mn. it hi^n)uje. '. Qli , du dt ti iu^ 5nttt h&e, fi ti. eA e./,- tcLUhiHLn)i nj. - Jtn. dleh. lm iMtt. -^nh ltL^aeh JHai IMLei fnhiL itt fifi*i. 3( Ujeh ttt. hfft. -it (Baeh JHai t &u Uitt eht- ti hsn. thnh. Uh UitL ll nhip, rt,.i eng, itt (%. t lt, tt ti nhi. ntii htt ^t. ia invluuLIxLu*lehtnAj.,tiiitltjC^ijg,^&tt.lrtOgip,it^t i tprig, thnh lm*Lq. eu&. sn l nhip,.'J Qlif n. 13 thM. 5 nnt 2006. Sinh ain (MJijit^ t t 'Taatjq.MC LCT VN .................................................................................................. 1PHN 1:TNG QUAN................................................................................. 21.1. Tng quan v bnh h thng................................................................... 21.1.1. Khi nim, c im, phn loi.......................................................21.1.2. Nguyn nhn v c ch bnh sinh................................................... 31.1.3.iu tr............................................................................................. 31.2. Tng quan v glucocorticoid................................................................... 51.2.1. Ngun gc....................................................................................... 51.2.2. Dc ng hc.................................................................................51.2.3. Phn loi.......................................................................................... 51.2.4.C ch tc dng............................................................................... 61.2.5. Tc dng.......................................................................................... 81.2.6.Ch nh..........................................................................................111.2.7.Chng ch nh...............................................................................111.2.8. Tc dng khng mong mun.........................................................121.2.9. Tng tc thuc............................................................................. 161.2.10.Mt s iu cn lu khi dng glucocorticoid...........................17PHN 2: I TNG V PHNG PHP NGHN cu................ 182.1. i tng nghin cu.............................................................................182.1.1. Tiu chun la chn..................................................................... 182.1.2. Tiu chun loi tr.........................................................................182.2. Phng php nghin cu.......................................................................182.3. X l kt qu.......................................................................................... 182.4. Ni dung nghin cu..............................................................................18PHN 3:KT QU NGHIN cu V BN LUN..............................203.1. Kho st chung v bnh h thng........................................................ 203.1.1. M hnh cc bnh h thng gp ti khoa c s dng GC............. 203.1.2. Phn loi bnh nhn theo la tui................................................. 213.1.3. Thi gian mc bnh..................................................................... 223.2. Thuc iu tr bnh h thng............................................................... 233.2.1. Tnh hnh s dng GC trongiu tr cc bnh h thng..............233.2.2.Cc nhm thuc c dng phi hp vi GC............................. 273.2.3. Tng tc gia GC vi cc thuc dng phi hp..........................293.3. Tc dng khng mong mun ca GC v bin php khc phc........ 303.3.1.So snh t l gp TDKMM trong tng bnh v gia cc bnh... 303.3.2.Cc tc dng khng mong mun gp.......................................323.3.3. Cc bin php khc phc TDKMM ca GC................................. 373.3.4. Cc nhm thuc dng iu tr TDKMM ca GC.....................39PHN 4:KT LUN V XUT.........................................................464.1. Kt lun.................................................................................................. 464.2. xut.................................................................................................... 47TI LIU THAM KHOPH LCCH GII CH VIT TTD- MDLS: GC KSKSRTH MC nNSAID SLE STTTDKMM VDC VNQM XCB CMDD ng -Min dch lm sngGlucocorticoidKhng sinhKhng st rt tng hpMineralcorticoidS lng bnh nThuc chng vim khng steroidLupus ban h thngS th tTc dng khng mong mun Vim da cVim nt quanh ng mch X cng b c ch min dichT VN Bnhhthng-bnhcnhhngrtlnncucsngcacon ngi k t khi mc, n c lin quan n ri lon h thng min dch trong c th.C n 50 nghn ngi M ch yu l ph n mc bnh h thng, c bit nhng ngitrong tui lm vicv nuicon[31].Mctiuiu trnhm bnh nychlluibnh bngcchs dngnhiunhmthuc khc nhau. Trong,glucocorticoidlnhmthucclachnutin.Tnhng nm1940,GC c dng trong iu tr bnh lin quan n min dch[27] v n khng nh c vai tr to ln ca mnh, khng nh Steroids - Keys to life (steroid - cha kho ca cuc sng)[32].Hin nay,GC khng chcdngtrongccbnh linquann min dch m n cn c s dng ph bin vd nhiu mc ch khc nhau ko theo slmdngcorticoidngycngtng.Chnhvth,nhngtcdngkhng mongmuncaGC xuthinngycng nhiuvngycngtrmtrnghn trn mi i tng, mi la tui v trn mi ng dng khc nhau.iu ny lmchobnhtnhthmphctp,nhhcmgludins phttrinv sckhovtrtuconngi.Lmsao hnch nhngtcdngkhng mongmuncaGC? cnlmtcuhilfn.ccinhncthvthy cmcnghimtrngdonhngTDKMMcaGCgyra,chngti tinhnhnghincuti;Khosttcdngkhngmongmunca glucocorticoidtrnccbnhnhnmcbnhhthngtikhoaDng- Min dch lm sng - Bnh vin Bch MaiVi mc tiu:1.KhostmhnhbnhhthngkhoaDng-Mindchlm sng - Bnh vin Bch Mai.2.KhosttnhhnhsdngGCtrongiutrbnhhthng,tc dng khng mong mun ca GC v bin php khc phc.T , gp phn s dng GC an ton, hp l, kinh t v hiu qu hn.PHNl TNG QUAN1.1. TNG QUAN V BNH H THNG1.1.1.Khi nim, c im, phn loi1.1.1.1. Khi nim [9]Bnh h thng l mt nhm bnh c biu hin vim mn tnh lan to hay ri rc tchc lin kt v tn thng l kt qu ca s gii trng hp nhng mucopolysaccharidtrongchtcbncathnhphntokeotrongtchc lin kt.1.1.1.2. c im ca cc bnh h thng [2], [9], [13]Vimkodinhiuni,nhiubphn,nhhngnhiunth chung.^ Tnthnggiiphubnh:thoihodngt huyt,tchcbnhc nhiu lympho xm nhp.Tng Yglobulinmu,gim bth,cmt hay nhiuloit khngth, hoc c dng t bo T t phn ng chng li nhiu t chc,Rilonhthngmindchnnchunhhngcacoiticoidvcc thuc c ch min dch.Yutkhiphtthngxyrasaunhimtrng,nhimc,chn thng.Bnh c khuynh hng duy tr v t pht trin qua nhiu t tin trin.1.1.1.3. Phn loi [9]Theo G.Klempeper (c) nhm bnh ny gm c 4 bnh:Lupus ban h thng X cng b h thng Vim da c hay vim da v c Vim nt quanh ng mchNgoira,mtsnginghxpthmvonhmnyccbnhnh: vim khp dng thp, cc bnh khp ca ct sng, hi chng Sjogren.. .[8].1.1.2.Nguyn nhn v c ch bnh sinh [9]Cnhiugithuytnhngchonnayhunhthngnhtxpnhm bnh ny vo cc bnh t min dch trn mt c a c bit.1.1.2.1. Nhng bng chng v t min dch ca bnhCcbnhnyctrngbisxuthinnhngt khngthtrong huytthanh:khngthkhngnhn,khngthkhngccacidnhn(ADN, ARN...),khnghiston,khngcchuytcu(hngcu,tiucu,bchcu). ngthilngbthgimrrttrongmu.Phthinccphchp min dch trong mu v t chc.T l cc t bo lympho T v B thay i trong mu.Cthgybnhthcnghimtrnscvtbngphngphpmin dch.iu tr bng cc thuc c ch min dch c kt qu.1.1.2.2.Yu t c aHu ht cc bnh h thnggp ph n, tr tui hoc trung nin. Mt s trng hp c tnh cht gia nh.1.1.2.3. Nguyn nhn trc tip gy bnhHin nay, ngi ta vn cha bit chnh xc nguyn nhn gy bnh nhng tathycvaitrcaccyuttmin,yutnghnghip,yutdi truyn, mi trng sng...c nh hng n cc bnh .1.1.3.iu tr[9]1.13.1. Mc tiu iu trBnh hthngl nhmbnhmntnh,xenkgiacct tintrin l thi k lui bnh.Mc ch iu tr ch nhm kim sot cc t cp ca bnh v duy tr trng thi lui bnh vi s lng thuc t gy tc dng ph nht.1.1.3.2. Phc iu tr^ Thuc chng vim v c ch min dch,Thuc iu tr triu chng,Trnh cc yu t nguy c.1.1.43. Cc thuc s dngCorticoid:da trn tcdng chngvim v tcdng cch min dch ca GC lm gim cc phn ng vim,gim cc triu chng ca bnh.Liu dng tu thuc mc nng nh ca bnh, nn chn loi GC vi liu ph hp ci thin tin lng ca bnh.Thucchngvimkhngsteroid:mithuctrongnhmnyucthsdngcdatrntcdngchngvimcandocchenzym cyclooxygenase,gimtng hp prostaglandin-cht trunggiangyphn ng vim v do n lm bn vngmng lyzosom, ngn gii phng cc enzym phn gii, c ch qu trnh vim.Thuc khng st rt tng hp:Chloroquin (Nivaquin), Delagyl...Hinnay,vnchabitcthc ch tcdngca nhmthucny.Mts tcgichorng,ccthucnyctcdnglmnnhmnglyzosom,c ch qu trnh phn bo,cch gii phng cc enzym v cytokin thc y qu trnh vim;thayicn bngacid-baseca t bo,do hn ch kh nng hnh thnh khng th.Thuccch mindch:Dobnh hthngclinquan n t mindchnnvics dng cc thuc CMD c hiu qu.Cc thucnyc nhiu tcdngphnnchcdngkhibnhnhnkhngpngviGC.Cc thuchaydngnh:azathiopiin,cyclophosphamid,cyclosporin,chlorambucid...Cc thuc khc:Danazol, globulin min dch...Cc thuc iu tr triu chng: hi chng Raynaud, nhim trng, tnghuyt p...Ngoira,iutrccbnhtrncns dngccphngphp iu tr c bit nh:Boluscortison:truynliucaomethylprednisolon1000-1500 mg/ngy trong 3 ngy lin tip.Lc huyt tng.Ringvibnhxcngbtacthsdngccthucginmch, vitamin E, iod, D-penicillamin kt hp steroid...1.2. TNG QUAN V GLUCOCORTICOID1.2.1.Ngun gc [3],[6]CcGC t nhindovngb thngthnsnxut ragmc2chtl hydrocortison (cortisol) v cortison.Cc GC tng hp nh methylprednisolon, dexamethason...1.2.2.Dc ng hc[3],[24]Cc GC t nhin v dn xut ca n thng c dng qua ng ung. Ngoi ra, n cn cs dng qua ng tim bp, tim tnh mch, tim di da,phunmvbitrnda.Nichung,nhpthuttquangtiuho. Phnbvottcccmtrongcth,quacnhauthaivsammt lng nh.Thuc lin kt vi protein huyt tng trn 90%qua hai protein l CBG(globulingnvicorticosteroid)valbumin.Trong,chyul globulin.Cc GC c chuyn ho gan v thi tr qua thn l ch yu.1.2.3.Phn loiCnhiucchphnloiGCdatheongungc,theocimtc dng hoc theo thi gian tc dng...1.23.1.Theo ngun gc [3]GC t nhin do c th sn xut ra nh hydrocotison...GC tng hp nhmethylprednisolon...1.2.3.2. Theo thc hnh [22]Loi gi nc mnh l cc cht khng c delta Ci_2-V d:cortison, hydrocortison, Auocortison...^ Loi gi nc t l cc cht c delta Ci_2 .V d:prednisolon, dexametheson, triamcinolon... 1.233.Theo ng dng thuc ng ungng tim: tim tnh mch, tim bp, tim ni khp...Dng ti ch:kh dung, bi ngoi da, tht hay np hu mn...1.23.4. Theo tc dng dc lLoi n thun ch c tc dng GC nh:betamethason...Loi km theo tc dng MC rt t nh : methylprednisolon... Loi km tc dng MC va nh :prednison, prednisolon... Loi km tc dng MC nhiu nh :cortison, hydrocoitison... /.2.5.5.Theo thi gian tc dng [3], [24]Bng 1.1:Phn loi GC theo thi gian tc dngPhn loi Tc dng ngn Tc dung trung bnhTc dng diThi gian tc dng 8 h - 12h 1 2 h - 3 6 h 36h-72hV d CortisonCortisolPrednisolonMethylprednisolonTriamcinolonFludrocortisonBetamethasonDexamethason1.2.4.C ch tc dng [4],[5], [14], [28]Transcotin1.GC t dovo t boBo tngNhnGR- GC c phosphoryl ho v di chuyn6.GR c phc hiCc GR chc nng nh monome hay dimeHnh 1.1:C ch phn t tc dng ca GC[28](GR:Receptor ca GC;Hps:Cc protein lin kt)GC tn ti trongmu as dnglin kt viproteingnGC(CBG) vmt phn nh dngt do.GC a lipidd khuychtnqua mng t bo, gnvoreceptortrongbotng.Ccreceptorlchiu,chcilcvi GC,khngtophccviandrogen,estrogen,Cortison,prednison(ring cortisonvprednisonchlinktcvireceptorkhichuynhosang cortisol hay prednisolon hot tnh).Saukhinhnphnphiliintch,phchpGC-receptortinvo nhn,kthpviChromatinti.TinhntbophchpGC-Re- Chromatinkchthchsaom mcRNAquatrunggianRNA-polymerase tng hp RNA thng tin.T to iu kin tng hp nhng protein c hiu c tc dng dc l, quy nh nhng tc dng ca GC.15n20phtsaukhiphchpGC-receptorvonhnthybin ivnchuyn glucosequa mng,cch hp thu,cch st nhp acetat volipid nhn.Sau khi phc hp GC - receptor vo nhn1 - 2gi, nhiu tc dng c ch chuyn ho xut hin.Thi gian tip xc gia cortisol v receptor ngn (Mhnh bnh h thnggp khoa D ng-Min dch lmsng-Bnh vin Bch Mai,>Tui ca bnh nhn,>Gii tnh,>Thi gian mc bnh.18Kho st v thuc iu tr bnh h thng:>Cc loi GC c dng ti khoa (tnbit dc, hot cht, hmlng v ng dng),>Liu dng GC,>Thi gian dng GC ti bnh vin,>Cc nhm thuc phi hp,>Tng tc gia GC v cc thuc phi hp.Cc tc dng khng mong mun ca GC v bin php khc phc.19PHN 3KT QU NGHIN ctru V BN LUN3.1. KHO ST CHUNG V BNH H THNG3.1.1. M hnh cc bnh h thng gp ti khoa c s dng GCtngthigian khc nhau,tl bnh nhn mcccbnh h thngs khc nhau. Trong nm 2005, qua hi cu trn 436 bnh n, chng ti thu c kt qu trong bng 3.2:Bng 3.2:M hnh cc bnh h thng gp ti khoa c s dng GCBnhChtiuSLE XCBVNC>M TngNam N Nam N Nam N Nam Nam Nn 21 335 16 37 4 12 2 9 43 393T l% 5,90 94,10 30,19 69,81 25,00 75,00 18,18 81,82 9,86 90,14Tng 356 53 16 11 436T l% gia cc bnh81,65 12,16 3,67 2,52 100,00x' = 35,904; p < 0,05Vi s liu t bng, ta c biu : 81,65%2,52%-3,67%16% SLE XCB 0VDC nVNQMHnh3.5:Biu th hin m hnhbnh h thng khoa c s dngGC20Trong 4 bnh h thng theo phn loi ca G.Kempeper th bnh SLE gp nhiunhttrongnm2005,chimn81,65%nhiuhnsoviktqu nghincucangNgcTrcvTrnNgcntrong10nm(1979- 1988) l 59,00%[4].iu ny c th biu hin c phn no rng t l mc bnhSLEtngln.Ktquchngtithucvmiquanhgiagii tnh v t lmc bnh cng tng t nghin cu ,ccbnh nhn mcbnh h thng ch yu l n, trong t l n gp trong bnhSLE l rt cao chim 94,10%.Hinnay vncha gii thch c r rng tisao cc bnh h thng li gp n nhiu hn, c gi thuyt cho rng l do yu t hormon.Trong nghincuny,chngtithytlmcbnhphthucgiitnh vitin cy 95%(x^ = 35,904; p < 0,05).3.1.2.Phn loi bnh nhn theo la tuiCcbnh hthngclinquan n ccyu t t mindch,yu t c a v tui ca bnh nhn cng c nh hng n t l mc bnh.Kt qu thu c khi kho st v la tui ca bnh nhn c th hin trong bng 3.3:Bng 3.3:Phn loi bnh nhn theo la tui^ nhL \tul\^ SLE XCB VDC VNQM Tngn T l%n T l% n T l%n T l%n T l%60 8 2,34 2 3,78 2 12,50 3 27,28 15 3,44Tng 356 100,00 53 100,00 16 100,00 11 100,00 436 100,00=104,241; p< 0,0521Tl%80604020063,53 0.09 60TuiHnh 3.6:Biu biu hin phn loi bnh nhn theo la tuiTheobngtrn,slngbnhnhnmcccbnhhthngcaonht tronglatui18-40,chim63,53%.Ktqunyphhpviccnghin cu trc y v dch t bnh h thng,cc bnh nhn ch yu l n trong tuilmvicvnuidycon[8],[31].Cthtrongtuinyltui sinh,hmlngEstrogentngcaohnsovicclatuikhcnntl mc bnhcao hn[11].T l mc tng la tui trong 4 bnh cs khc bitv khc nhauc ngha thng k vi tincy95%=104,241;p 150mg prednisolon/ngy iu tr.Khi bnh nhn khng p ng tt vi thuc,bc s chuynsangdngliu bolus(truyn tnhmchSolumedrol500/l/ngy trong3ngylintip,sauchuynsangungprednisolon5mg/vinX8 vin/ngy).ThngthngsaumttdngGC liucaotrong2tunu, bc s s gim liu mt cch t tvi mc ch gim TDKMM v c th theo25dipngcabnhnhnkhigimliuGC.Ktquchngtithuc cngphhpviiu,liudngcabnhnhnlcravinliutrung bnh15-50 mg prednisolon/ngy chim80,30%s bnhn hicu v dng qua ng ung.3.1.13.Thi gian bnh nhn dng GC ti bnhvinThigiandngGCquytnhtnsutxuthinccTDKMMvn cng gn nh bng thi gian bnh nhn iu tr ti bnh vin.Trong thi gian ny,bnh nhnthngdngliuGC cao theongtim tnh mch v tl gp tai bins nhiu hn so vi khi ngoi tr.Chng ti khost thi gian bnh nhn dng GC ti bnh vin, kt qu thu c th hin trong bng 3.7: Bng 3.7:Thi gian bnh nhn dng GC ti bnh vinrhi gian dng GC (ngy)SLE VDC VNQMn T l % : n n T l % n T l %20 106 29,77 27 50,94 8 50,00 2 18,18Tng 356 100,00 53 100,00 16 100,00 11 100,00= 93,555; p < 0,05 >20ngy 11-20ngy Nhm chn knh calci: niedipin, amlodipin, diltiazem...6,4mmolA),chim 5,96%.KhikhostccbinphpkhcphcTDKMMny,chngtithu c kt qu trong bng 3.16.Bng 3.16:TDKMM tng ng huyt v bin php khc phcTDKMM tng ng huytBnh n khng c can thipBnh n c can thipThuc iu trInsulinGliclazid(Diamicron)n 5 21 13 10T l % 19,23 80,77 61,90 38,4643Quabngtrntathy,khigpTDKMMtngnghuyt,80,77% bnhnhnccanthipbngcchsdngccthucgyhnghuyt. Trongkhostny,chngtithybcschobnhnhndng1 trong2 thuchnghuytlinsulinvgliclazid hockthpc2loi,trong insulin cs dng nhiu hn, chim 61,90%.ng ch l t l bnh nhn khngccanthipchimti19,23%.Khitraoiviccbcs iutr khoaD-MDLS,ccbcschorngnubnhnhnctngnghuyt nh,chacnthitdngccthuciutrngayvkhibnhnhnngng thuc, nng glucose trong mu s v mc bnh thng.33.4.8. Lot d dy t trngyl mt TDKMM gp kh nhiu,trn83bnh nhn,chim19,04% viccbiuhinbnhnhnthy nngrtvngthngv hi, chua,au vngthngv...Trongchc32bnhnhn(chim34,41%)clmxt nghimcnlmsngnisoid dyvcchnonvimddy,cnli chltheocmgiccabnhnhn.khcphccctcdngtrn,cc bc s dng cc nhm thuc trong bng 3.17.Bng 3.17:Cc nhm thuc iu tr TDKMM lot d dy t trngSTT Nhm thuc Thuc s dng n T l%1 AntacidGastropulgitePepsan70 84,342c ch bm protonOmeprazol (Losec, Helizol) Esomeprazol (Nexium)56 67,473 Khng th th H2CimetidinRanitidin (Dudine, Zan tac)23 27,7144Qua bngta thy,khibnh nhnccmgicnngrtddy, chua. Antacidlnhmthuccbnhnhnsdngnhiunhtchim84,34%, tip theol nhm c ch bm proton,chim 67,47%.c bit,c 47bnh n c s dng phi hp hai nhm antacid v nhm c ch bm proton hoc nhm khngththH2.Trong khi khost,chngti thyc7bnh nhncbin chngxuthuyttiuhovciutrbngCimetidin400mg/ng/ngy quangtim tnh mch.Vi cc bnh nhn ny,sau mt thigianiu tr ti bnh vin, h ht cm gic nng rt vng thng v v khi iu tr ngoi tr vn c dng cc thuc d phng lot d dy t trng.45PHN 4 KT LUN V XUT4.1. KT LUNSau khi hon thnh ti, chng ti rt ra mt s kt lun sau:V bnh h thng90,14% bnh nhn mc bnh h thng l n.M hnh bnh h thng:SLE (81,65%);XCB(12,16%);VDC (3,67%) v VNQM (2,52%).63,53% bnh nhn trong tui t 18 n 40.