HA DC TR LIU

ThS. BS. Trn Trung Ngha31.NGUYN TC TR LIU HA DC TRONG TM THN

31.1.Phn loi:

31.2.Tc ng dc l:

31.3.C ch:

41.4.Tc dng ph:

41.5.Nhng yu t lin quan n bnh nhn:

82.THUC CHNG LON THN

82.1.Thuc chng lon thn in hnh:

162.2.Thuc chng lon thn khng in hnh:

232.3.Tc dng ph ngoi thp do thuc chng lon thn

313.THUC CHNG TRM CM SSRIs

343.2.Ch nh tr liu:

383.3.Thn trng v tc dng ph:

413.4.Tng tc thuc:

433.5.Liu lng v hng dn s dng:

454.THUC CHNG TRM CM TCAs:

454.1.Dc lc hc:

464.2.Ch nh tr liu:

474.3.Thn trng v tc dng ph:

484.4.Tng tc thuc:

494.5.Liu lng v hng dn lm sng:

515.CC THUC BENZODIAZEPINE (BZD) V CC THUC TC NG LN TH TH BENZODIAZEPINE:

525.1.Tc ng dc l:

535.2.Ch nh tr liu:

555.3.Flumazenil trong trng hp qu liu BZD:

565.4.Thn trng v cc tc dng ph ca BZD:

575.5.Dung np l thuc v cai nghin:

585.6.Tng tc thuc:

585.7.Giao thoa gia BZD zolpidem v zaleplon:

585.8.Liu lng v hng dn lm sng:

606.THUC IU HA KH SC

606.1.i cng v thuc iu hoa kh sc:

626.2.Lithium:

686.3.Valproate:

726.4.Carbamazepine v Oxcarbamazepine:

1. NGUYN TC TR LIU HA DC TRONG TM THN

1.1. Phn loi:Thuc dng tr liu cho cc ri lon tm thn c gi chung l thuc hng thn (psychotropic drug). Nhng thuc ny c m t theo p dng lm sng chnh yu ca thuc; VD: thuc chng trm cm, thuc chng lon thn, thuc n nh kh sc, thuc ng, thuc lm tng nhn thc, thuc kch thch. C mt kh khn vi cch tip cn ny l c nhiu thuc c nhiu ch nh khc. VD: thuc nhm SSRI c c tc dng chng trm cm v gii lo u, thuc i khng serotonine dopamine c tc dng chng lon thn v n nh kh sc.Thuc hng thn cn c sp xp theo cu trc ha hc (VD: thuc 3 vng), rtheo c ch (VD: c ch MAO), theo lch s (VD: thuc theo qui c, thuc th h u tin), tnh l thng (VD: thuc khng in hnh), theo ch nh (VD: thuc chng trm cm). Kh khn nhiu hn na l c nhiu thuc c dng iu tr cho cc bnh l thn kinh, v ni khoa cng c dng iu tr cho c cc ri lon tm thn.Thm vo , cc thut ng thuc hng thn cng m m. Cc thuc u tin thng dng iu tr tm thn phn lit c gi l thuc bnh thn. Khi c nhng thuc mi hn dng iu tr lo u, li phn bit thnh thuc bnh thn chnh v ph. Lc ban u, thuc chng trm cm l thuc chng trm cm 3 vng (TCAs) hoc IMAOs. Trong nhng nm 70, 80, nhng thuc chng trm cm mi hn xut hin th c gi l thuc chng trm cm th h th 2, th 3. Hin nay, nhng thuc c hn iu tr lon thn c gi l thuc an thn kinh (neuroleptics) qui c, in hnh, truyn thng. Thuc mi hn gi l thuc an thn kinh khng in hnh. Trong bi ny, hn ch s m m nay, cc thuc c sp xp thep c ch tc ng hoc cu trc tng t nhau thng nht, d tham kho v d hiu.

1.2. Tc ng dc l:

C yu t mi trng v di truyn u nh hng n p ng c tnh c nhn, v tnh dung np i vi thuc hng thn. Do , mt thuc c th khng chng minh c tnh hiu qu trn nhiu bnh nhn c bnh l trong vic ci thin triu chng. nhiu trng hp, nhn ra nhng yu t tin lng v kh nng ca thuc tr nn quan trng hn, nhng thng kh thc hin c. Ngay c trong cng mt nhm thuc, cc thuc cng kh phn bit vi thuc khc do c nhng khc bit tinh vi hn, v mt cu trc phn t, kiu tng tc vi h thng cht dn truyn thn kinh, khc bit v dc lc hc, c hay khng c chuyn ha cht hot ng, tnh kt ni vi protein. Nhng khc bit ny cng vi sinh ha ca tng bnh nhn to nn mt hnh nh tng i v hiu qu thuc, dung np, tnh an ton v t l gia nguy c li ch i vi tng bnh nhn. Tnh a bin ny, m nhiu yu t vn cha hiu r c, gy kh khn cho vic tin on hiu qu thuc. Tuy nhin, hiu bit v bn cht ca tng loi thuc lm tng kh nng thnh cng trong iu tr.

1.3. C ch:

C ch tc ng ca cc thuc hng thn vn cha c hiu r. Cch gii thch chun mc nht l cch thc thuc lm thay i tp trung ca cc th th dopamine, serotonine, norepinephrine, histamine gamma-aminobutyric acid (GABA). Nhng thay i c cho l do kt qu ca cc cht ng vn, i vn tc ng n ti hp thu cht dn truyn thn kinh, lm thun li cho s ch tit hoc c ch men chuyn ha. V d, mt thuc c th l cht ng vn, do kch thch hot ng sinh hc ca th th; hoc mt cht i vn s c ch hot ng sinh hc. Mt s thuc c c tnh ng vn tng phn v chng khng c kh nng tc ng ton vn n mt th th chuyn bit no . Mt s thuc hng thn cng c hiu qu lm sng thng qua c ch khc ch khng thng qua tng tc vi th th. V d: lithium tc ng bng cch c ch trc tip ln men inositol 1 phosphatase. Mt s hiu qu kt ni chc chn vi tc ng ca khe thn kinh (synaptic) chuyn bit. V d: hu ht cc thuc tr lon thn c kh nng phong ta th th dopamine type 2 (D2). Tng t, cc cht ng vn benzodiazepine kt ni vi phc hp th th gia th th benzodiazepine v th th GABA.

1.4. Tc dng ph:

Tc dng ph l nguy c khng th trnh khi khi iu tr bng thuc. Mc d khng th c kin thc bao qut v tt c nhng tc dng ph c th c ca thuc, nh lm sng khi k toa nn bit r nhng tc dng ph thng gp hn, cng nh nhng hu qu nguy him. Khng c mt ti liu no, k c nhng thng tin v sn phm, c tt c nhng tc dng ph nguy him phi iu tr c th c.Vic cn nhc nhng tc dng ph bao gm kh nng chc chn c th xut hin, nh hng ca tc dng ph n cht lng cuc sng, thi gian xut hin ca thuc, v nguyn nhn xut hin. Nh vy, phi bit rng, khng c thuc no chc chn lm ci thin v mt lm sng cho tt c bnh nhn; khng c tc dng ph no, lhng c vn no thng gp xut hin trn tt c bnh nhn. Khi c bnh l y khoa no cng xut hin hoc tin s c phn ng tri ngc tng t t bnh nhn vo nguy c cao b tc dng ph, vic lm hp l l phi xem xt li cht/thuc c k toa khng qui c xem c lin quan n tc dng ph khng.Cc tc dng ph c th do nhng tc ng dc l tng t vi tnh tr liu hoc do nhng c tnh khng thng gp. V d, tc dng ph thng gp ca TCAs l gy phong ta th th muscarinic acetylcholine hoc th th H2. Nu bnh nhn nhy cm vi nhng tc dng ny, nhng thuc thay th m khng gy ra tc dng ny c th c ch nh s dng. Nu tc dng ph l biu hin ca c ch tc ng c tin on ca mt thuc, th tc dng ph khi iu tr l iu khng th trnh khi. Do , tnh phong ta ti hp thu serotonine ca SSRIs c th gy nn, gy suy gim tnh dc. Tc dng phong ta D2 ca cc thuc iu tr lon thn c th gy tc dng ph ngoi thp. Tc dng ng vn th th benzodiazepine c th gy tht iu, gy ng ngy. Trong nhng trng hp ny, cc thuc thm vo thng phi gip nhng thuc iu tr u tin c dung np tt hn.

1.5. Nhng yu t lin quan n bnh nhn:

1.5.1. Tnh p ng vi thuc, v tnh nhy cm vi tc dng ph ca thuc c lin quan vi nhng yu t lin quan n bnh nhn. y chnh l l do ti sao m khng c mt cch tr liu no ph hp vi tt c mi ngi. Nhng yu t lin quan n bnh nhn l: chn on bnh, yu t di truyn, cch sng, tnh trng sc khe tng th, bnh l ng thi v tin s p ng thuc.

1.5.2. Chn on: Khng chn on chnh xc lm gim kh nng chn la mt loi thuc ti u. Chn on sai khng ch c th b mt c hi, m cn lm cho triu chng nng hn. Chn on v cho bnh nhn ang trong giai on trm cm ca ri lon lng cc thnh chn on trm cm n cc, c th gy ra cn hng cm hoc gy chu k nhanh khi dng thuc chng trm cm. Khi iu tr khng thnh cng hoc lm cho triu chng nng hn, nh lm sng cn nh gi li chn on.

1.5.3. p ng vi tr liu trong qu kh: mt thuc chuyn bit c chn ty theo p ng vi thuc trong qu kh ca bnh nhn (s tun th, hiu qu tr liu, tc dng ph), tnh p ng thuc trong gia nh bnh nhn, ph tc dng ph vi nhm bnh nhn c bit, ch nh tr liu trong thc hnh lm sng. Nu thuc tng c hiu qu tr liu cho bnh nhn hoc ngi thn trong gia nh bnh nhn, nn dng tr li loi thuc v thuc cng nhm. Tuy nhin, vn c mt s bnh nhn li khng p ng vi loi thuc m trc h p ng rt tt, khi dng tr li. Tin s c tc dng ph t mt thuc no cng l du ch im cho bit bnh nhn s khng tun th vi loi thuc .

S c ch nu bnh nhn nh c chi tit nhng thuc hng thn c dng: ch nh loi thuc, liu lng, thi gian dng, thuc kt hp. Tuy nhin, do vn bnh l tm thn m nhiu bnh nhn li c tr nh rt km. Gia nh ca bnh nhn l ngun lc gip tm hiu thm nhng thng tin ny.

1.5.4. p ng vi tr liu trong gia nh: thuc p ng c tnh ging nhau trong gia nh. Do , p ng thuc tt mt ngi thn no cng l iu c ch cho vic chn la thuc cho bnh nhn.

1.5.5. Bnh l phi hp: trong mt s trng hp, cc bnh l y khoa c th gy ra cc triu chng tm thn. Bnh nhn bnh tuyn gip cha c iu tr ng s c cc triu chng trm cm. Chng ngng th lc ng cng gy trm cm v suy gim nhn thc. Thuc c chn phi hn ch gy nng n mc ti thiu nhng bnh l y khoa c trc.

Dng thuc gii tr (thuc lc ), ung qu nhiu ru, thng s dng nc ung c caffein s lm phc tp va thm ch cn lm gim hiu qu tr liu bng thuc hng thn. Nhng cht ny c th c nhng nh hng tm thn quan trng v trong mt s trng hp, c th l nguyn nhn gy xut hin triu chng.

1.5.6. Tha thun v gio dc bnh nhn: bnh nhn nn c thng tin v k hoch tr liu, tc dng ph c th c, v li ch ca mi cch tr liu. Nu khuyn bnh nhn dng loi thuc c bit no, nn gii thch r rng l do ca li khuyn . Bnh nhn hu nh s tip tc dng thuc nu h hiu c y l do h phi dng thuc, l do thuc c ch nh cho h.

Mi lin minh tr liu gia bc s v bnh nhn lun lun hu ch. Cung cp cho bnh nhn bit v nhng iu khng mong i khi dng thuc, tc dng ph thng gp ca thuc, s gip ci thin s tun th iu tr. Nu bnh nhn tin tng vo kin thc ca bc s, vo kh nng phn on ca bc s, h s chp nhn dng th loi thuc no ch i hiu qu sp n.

Nghin cu cho thy, nu bnh nhn c thng tin v tc dng ph ca thuc, th t l xut hin tc dng ph cao hn nhng t l ngng iu tr li gim hn. Mt s bnh nhn cho rng iu tr bng thuc l thn dc, mt s khc li xem thuc nh k th. Do , khi lm tha thun tr liu vi bnh nhn, ngi than v bc s nn nu r l do iu tr, cng nh li ch ca vic iu tr v nguy c c th c khi iu tr.

1.5.7. Liu lng thi gian iu tr v theo di:

Liu iu tr c hiu qu ty theo c tnh ca thuc v cc yu t ca bnh nhn, nh tnh nhy cm v kh nng chuyn ha thuc, bnh kt hp v thuc ang dng ng thi, tin s dung loi thuc no. Nng thuc huyt tng ca nhiu thuc hng thn c th tng ln gp 10 ln. Do , liu hiu qu nht ca tng bnh nhn cn phi c th thch, cn c hng dn v kinh nghim tr liu vi khong liu iu tr. Mt s thuc c lin h r rt gia vic tng liu v p ng tr liu. Kh nng ca mt thuc c cho l liu tng ng cn c t c kt qu hin ti, ch khng phi l t c hiu lc ca thuc. V d: haloperidol c mnh nhiu hn so vi chlorpromazine, khong 5mg haloperidol c kh nng tr liu tng ng 100mg chlorpromazine. Tuy nhin, nhng thuc ny c hiu lc lm sng tng ng nhau.

Thuc phi c s dng vi liu t c hiu lc trong mt thi gian cn thit. Mc d tnh dung np v tnh an ton ca thuc lun cn c xem xt, nhng cn trnh vic dng liu thp hn liu iu tr v th nghim tnh tr liu khng y . Dng liu khng thch hp s lm bnh nhn c nguy c b tc dng ph m khng gip bnh nhn c c li ch tr liu.

Thi gian dng thuc thng c da vo thi gian bn hy ca thuc trong huyt tng v ph tc dng ph ca thuc. Thuc c tnh an thn nn c dng bui ti, hoc liu ban ngy thp hn liu bui ti. Ngc li vi nhng thuc c tnh kch thch. Hu ht ch dng thuc hng thn u da vo s nh chun nng thuc trong huyt tng hn l da vo kh nng chim ng ca thuc no. C nhiu bng chng cho rng c s phn ly ng k gia ng lc hc trong huyt tng v no. Da vo ng lc hc ca thuc trong huyt tng lp nn ch dng thuc s dn n hiu sai v ch dung thuc hp l.

Thng thng thuc hng thn nn c dng lin tc, ngoi tr trng hp dng thuc trong mt ng, kch ng cp tnh, lo u d di theo tnh hung. Sai lm thng gp khi dng thuc benzodiazepine hot lc cao, nh alprazolam (Xanax), clonazepam (Rivotril) l ch dng sau khi cn hong lon xut hin. Nhng thuc ny nn s dng trong ch u n ngn nga cn hong lon.

Mt s bnh nhn tng b ri lon tnh dc trong iu tr vi SSRIs khi dng thuc trong cc k ngh, nn thnh thong h ngng thuc thc hin hnh vi tnh dc trn vn. Vic s dng thuc SSRI ngt qung cng c hiu qu iu tr chng lon kh sc trc k kinh. Thuc nn c s dng 2 tun trc giai on hong th ca chu k kinh nguyt.

1.5.8. Thi gian iu tr:

Cu hi m bnh nhn thng xuyn t ra l: ti cn dng thuc trong bao lu?. Cu tr li ty thuc vo nhiu yu t: bn cht ca bnh l, thi gian ca triu chng, tin s gia nh v cn i mc bnh nhn dung np thuc vi li ch ca vic iu tr. C th gii thch hp l vi bnh nhn v nhng kh nng c th nhng trc ht, phi cho bnh nhn thy rng thuc gip ch cho h vi iu kin nhng tc dng ph c th chp nhn c. Khi vic tho lun ng tin cy v thi gian iu tr c thc hin th thnh cng trong tr liu chc chn s t c. Hu ht cc bnh l tm thn u tin trin mn tnh v ti pht, nn iu tr lu di l iu cn thit ngn nga bnh l ti din. Tuy nhin, cc thuc hng thn khng c cho l iu tr khi c cc bnh l tm thn nhng c th gip kim sot c bnh.

Vic iu tr c chia thnh 3 giai on: iu tr th nghim u tin, iu tr tip din v iu tr duy tr. Giai on u nn ko di t nht vi tun, chm p ng tr liu l c im ca hu ht cc thuc hng thn. Thi gian cn thit cho giai on th nghim thuc cng nn c a ra tho lun ngay t khi bt u iu tr bnh nhn khng mong i qu mc v s ci thin ngay lp tc cc triu chng. Hu ht bnh nhn u b tc dng ph sm trong qu trnh iu tr bng ha dc trc khi ht triu chng. Trong mt s trng hp, thuc cn lm cho cc triu chng nng hn. Bnh nhn v vy nn c t vn trc rng nhng phn ng xu ban u khng phi l iu tin on cho kt qu iu tr sau ny. V d: nhiu bnh nhn b ri lon hong lon thng s b run git ht hong, hoc tng cn hong lon sau khi bt u iu tr bng thuc chng trm cm 3 vng hay SSRIs. Thuc ng vn benzodiazepine l mt ngoi l gip hn ch triu chng lm sng ny. Vi thuc ng v chng lo u li c hiu qu ngay tc th.

Tuy nhin, vic bt u dng thuc khng gip bo v hon ton chng li ti pht. iu tr tip tc s gip vic bo v chng ti pht c n nh hn. Thi gian ti u nht cho giai on iu tr tip tc v iu tr duy tr thay i v ty thuc vo tin s bnh ca bnh nhn. V d: trm cm nng mn tnh khi pht sm c tin trin nng hn so vi trm cm nng mn tnh khi pht mun. Cng vi tnh khi pht sm ca bnh, tin s bnh din qua nhiu giai on, mc nng v di ca cc giai on ti din cng cn vic iu tr di hn, kh on trc c.

1.5.9. Xt nghim cn lm sng v theo di c tnh tr liu qua mu:

L xt nghim c bn xc nh bnh l v theo di iu tr.

Xt nghim cn lm sng khng gip chn on xc nh bnh l tm thn nhng l yu t nhm loi tr cc bnh l y khoa tim n c th gy ra triu chng tm thn hoc nh gi bin chng do iu tr thuc.

Cc xt nghim thng thc hin l: ECG, chc nng h to mu, chc nng gan, thn, tuyn gip, nht l vi cc loi thuc nh lithium, clozapine

Cc xt nghim khc cn c theo di l ng huyt, lipid mu, nht l khi iu tr bng cc thuc chng lon thn khng in hnh.

Cng cn theo di nng huyt tng ca thuc iu tr vi nhng loi c gii hn tr liu hp nh lithium. Vi lithium, nng huyt tng thp khng gip ci thin c triu chng; nng huyt tng cao hn gii hn li gy ra ng c nng.

Xt nghim cn lm sng cn gip sng lc nng cht gy nghin hoc thuc b lm dng.

1.5.10. Kt hp thuc:

Theo hng dn thc hnh ca Hip Hi Tm Thn Hoa K, nn trnh vic kt hp thuc trong iu tr tm thn. Mc d n tr liu l l tng nht nhng tr liu phi hp cng thng thy trong tm thn t rt lu (khong u nhng nm 50). Vic kt hp thuc, thc hnh tt vic tng liu hoc kt hp thuc n nay vn cn c tho lun rt nhiu trong y vn v ti cc hi tho khoa hc. S lng trung bnh ca cc thuc dng cng lc ngy cng tng cho n hin ti. Vi bnh nhn tm thn ni tr, s lng thuc trung bnh dng phi hp thng l 3 loi. Tuy nhin, vn hin nay l khi kt hp thuc, cc bc s li t linh ng trong vic gia gim liu thuc kt hp, hoc kt hp thuc nhng ch c 1 loi c hiu qu iu tr.

Fluoxetine olanzapine l kt hp thuc thng nht cho iu tr ri lon lng cc. Hu ht cc bnh nhn ri lon lng cc thng c kt hp nhiu thuc hng thn. Thuc i vn th th dopamine hoc thuc i vn th th serotonine dopamine thng c kt hp trong iu tr trm cm lon thn. Tng t, bnh nhn OCD ch p ng phn no vi SSRIs, nn thng c dng phi hp vi thuc i vn th th serotonine dopamine.

Cc thuc c kt hp cn nhm i khng li cc tc dng ph, iu tr cc triu chng chuyn bit v c th chuyn i t thuc ny sang thuc khc. Vic kt hp thuc nh vy gip duy tr tnh trng p ng tt ca bnh vi iu tr.

2. THUC CHNG LON THN

2.1. Thuc chng lon thn in hnh:

Thuc u tin c tm ra l Chlorpromazine, t nhng nm 50. C tc dng i vn vi th th D2, nn c gi l nhm thuc i vn th th dopamine (DRA dopamine receptor antagonist), cn c gi l thuc chng lon thn th h 1, thuc chng lon thn in hnh, thuc chng lon thn qui c.

Hin nay, nhm thuc ny khng cn l thuc chnh iu tr bnh tm thn phn lit hay cc bnh l c cc triu chng lon thn. Cc nhm thuc mi ngy cng thay th nhm DRA cng nhiu, nh thuc i vn serotonine dopamine (SDA serotonine-dopamine antagonist), thuc i vn tng phn dopamine (PDA partital dopamine antagonist) trong vai tr l thuc chn la hng u vi cc bnh l tng t. Khng ch do cc thuc mi ny t gy cc triu chng ngoi thp m cn iu tr triu chng m tnh trong tm thn phn lit, suy gim nhn thc, trm cm lon thn.

c chia nhm ty theo cu trc phn t ha hc. C cc nhm thuc sau: phenothiazine (chlorpromazine, promazine, triflupromazine), piperazine (acetophenazine, fluphenazine, trifluophenazine, perphenazine, thioridazine), thioxanthene (chlorprothixene), dibenzoxazepine (loxapine), digydroindole (molindone), butyrophenone (droperidol, haloperidol), diphenylbutylpiperidine (pimozide), rauwalfa alcaloid (reserpine).

Tt c cc thuc u hp thu qua ng ung, nhng dng dch hp thu tt hn so vi dng vin nn hay vin nang. Nng nh huyt thanh t c sau 1 4 gi ung hoc 30 60 pht sau khi dng ng tim. Ht thuc, ung caf, thuc khng acid, thc n lm cho nh hng n hp thu ca cc thuc. Sau 3 5 ngy dng thuc th t c nng iu tr. Thi gian bn hy ca a s thuc l khong 24 gi. Nu bnh nhn dung np thuc tt, vi tt c cc loi thuc, ch nn dng 1 ln trong ngy, ng ung khi bnh n nh. Hu ht cc thuc DRA u gn kt cao vi protein. Dng ng tim truyn s khi pht tc ng nhanh hn v ng tin cy hn. Tnh kh dng sinh hc ca dng thuc ng tim cng cao hn gp 10 ln ng ung. Hu ht cc thuc DRA c men CYP 2D6 v CYP 3A chuyn ha.

Nhng yu t nh hng n dc ng hc ca thuc chng lon thn

Tui thanh thi ca thuc gim ngi gi.

Bnh l ni khoaGim lng mu qua gan cng lm gim thanh thi thuc.

Bnh gan cng lm gim thanh thi.

Yu t gy thoi trinCarbamazepine, phenytoin, ethambutol, barbiturate

Cht c ch thanh thiSSRI, TCA, cimetidine, beta-bloquant, ciprofloxacine, ketoconazole.

Thay i tnh kt dnh vi proteinGim albumine huyt tng do suy dinh dng, suy gan.

Dng tim tc dng ko di ca haloperidol v fluphenazine c dng 1 ln mi 1 4 tun ty theo liu ca mi bnh nhn. C th phi dng u n n 6 thng mi t c nng c hiu qu, nn cn phi tip tc dng thuc ng ung trong thng u khi dng dng tc dng chm.

Tc ng ca thuc chng lon thn do kh nng c ch cht dn thuyn thn kinh h dopamine. Cc thuc DRA tc ng n khong 60% th th D2 trong no. Thuc DRA cng phong ta th th h noradrenergic, cholinergic, histaminergic ty theo tng loi thuc.

Mt s tnh nng chung ca DRA l ty vo tim lc ca mi thuc. Tim lc ca thuc l s lng thuc cn dng t c tc dng tr liu. Thuc c tim lc thp nh chlorpromazine, thioridazine c dng vi liu hnh trm miligram/ngy, c th gy tng cn, gy an thn nhiu hn thuc c tim lc cao nh haloperidol, fluphenazine, nhm ny ch cn dng t hn 10mg/ngy. Thuc c tim lc cao hu nh gy tc dng ph ngoi thp nhiu hn.

2.1.1. Ch nh tr liu:

Cc ch nh tr liu ca DRA

Giai on lon thn cp tnh trong tm thn phn lit v ri lon cm xc phn lit.

iu tr duy tr trong tm thn phn lit v ri lon cm xc phn lit

Hng cm

Trm cm lon thn

Ri lon hoang tng

Ri lon nhn cch ranh gii

Ri lon lon thn do s dng cht

Sng v sa st tm thn

Ri lon tm thn do bnh l c th

Tm thn phn lit tr em

Ri lon pht trin lan ta

Hi chng Tourette

Bnh Hungtington

Tm thn phn lit v ri lon cm xc phn lit: cc thuc DRA u c tc dng iu tr ngn hn v di hn kim sot tm thn phn lit v ri lon cm xc phn lit. Thuc c hiu qu iu tr triu chng cp tnh v ngn nga ti pht. Thuc c hiu qu ng kinh ngc vi cc triu chng dng tnh ca tm thn phn lit (nh: o gic, hoang tng, kch ng). Cc triu chng m tnh li hu nh t ci thin v c th nng hn v thuc gy hn ch din t bng nt mt, gy mt vn ng, cc tc dng ph ging triu chng m tnh.

Tm thn phn lit v ri lon cm xc phn lit c c im l giai on thuyn gim v ti pht. Thuc DRA lm gim nguy c ti nng ca triu chng lon thn sau khi c iu tr n nh bng thuc trong giai on cp tnh. Do , sau giai on lon thn u tin, bnh nhn phi iu tr duy tr t 1 2 nm; nu ti pht nhiu giai on lon thn, thi gian duy tr l 2 5 nm. Thm ch c mt s nh lm sng khuyn dng n sut i.

Hng cm: thuc DRA c hiu qu iu tr triu chng lon thn ca cn hng cm. V cc thuc chng hng cm (nh lithium) c khi pht hiu qu chm hn so vi thuc chng lon thn trong vic iu tr triu chng cp tnh, nn cch iu tr chun cho cn hng cm l kt hp thuc DRA hoc SDA vi lithium, lamotrigine, carbamazepine, valproate v sau dn dn b thuc chng lon thn.

Trm cm c triu chng lon thn: iu tr kt hp thuc chng lon thn v mt thuc chng trm cm l cch iu tr cho trm cm nng c lon thn. Ngoi cch ny, cn c th dng chong in (ECT electroconvulsive therapy).

Ri lon hoang tng: ri lon ny cng p ng tt vi iu tr bng thuc DRA.

Kch ng trm trng v hnh vi bo lc: vi nhng bnh nhn ny, ty theo chn on, c th iu tr bng DRA. Cc triu chng nh: cu knh qu mc, mt kim sot xung ng, gy hn nhiu, tng ng qu mc, kch ng, p ng vi iu tr ngn hn bng cc thuc DRA. Tr khuyt tt v tm thn, c bit l chm pht trin tm thn nng, ri lon t k, thng c giai on bo lc, gy hn, kch ng, cng p ng vi iu tr bng thuc chng lon thn. Tuy nhin, iu tr lp li thuc chng lon thn kim sot hnh vi xung ng tr em vn cn l iu ang bn ci.

Hi chng Tourette: thuc DRA cn c dng iu tr ri lon Tourette, bnh l thn kinh c biu hin bng nhng tic vn ng v pht m. Haloperidol v pimozide (Orap) l thuc thng c dng nht nhng nhng thuc DRA khc cng c hiu qu. Mt s nh lm sng li a dng clonidine iu tr bnh l ny v t c nguy c b tc dng ph v thn kinh. Pimozide cng t c dng hn v tc dng ph v tim mch.

Ri lon nhn cch ranh gii: nhng bnh nhn ny c nhng tri nghim v cc triu chng lon thn thong qua, nh: ri lon tri gic, tnh nghi ng, tng lin h, hung hng, c th cn phi c iu tr bng DRA. Bnh l ny cng cn iu tr bng thuc n nh kh sc.

Sng v sa st tm thn: khong 2/3 bnh nhn kch ng p ng vi iu tr bng DRA. Thuc c tim lc cao thng dng liu thp (VD: haloperidol 0.5 1mg/ngy). Cc thuc DRA cng c dng iu tr triu chng lon thn v kch ng trong sng. Tuy nhin, cn phi xc nh nguyn nhn gy sng, v sng do ng c cc thuc khng cholinergic c th tr nng nu dng cc thuc DRA c tim lc thp do c tc dng khng muscarinic ng k.

Ri lon lon thn c lin quan n cht: ng c cocain, amphetamine, phencyclidine hay nhng cht khc c th gy triu chng lon thn. V cc triu chng ny thng t gii hn theo thi gian nn cng cn trnh dng cc thuc DRA tr phi bnh nhn kch ng, gy hn d di. Thng ch dng benzodiazepine bnh nhn m du. Benzodiazepine nn c dng thay th DRA trong trng hp ng c phencyclidine trnh tc dng anticholinergic ca DRA. Nu bnh nhn c hoang tng, o gic nh trong cai ru, cc thuc DRA c th lm tng nguy c gy co git.

Tm thn phn lit tr em: bnh nhi cn c iu tr bng thuc chng lon thn mc d vn cn t nghin cu v iu ny. Cc nghin cu hin nay cn ngh iu tr vi nhng triu chng ri lon sm tr em c nguy c b tm thn phn lit nhm ngn nga cc triu chng bc pht. Cn xem xt k lng cc tc dng ph, c bit cc triu chng nhn thc v tnh trng thc tnh.

Cc ch nh khc v tm thn v bnh l khng phi tm thn: thuc DRA cn lm gim run git ca bnh l Huntington. Bnh nhn ny c th c triu chng o gic, hoang tng, hng cm, hng cm nh. Nhng triu chng ny p ng c vi thuc DRA v nn s dng thuc DRA c tim lc cao. Tuy nhin, cc nh lm sng nn ch n th cng trng lc ca bnh l ny c th l triu chng ca hi chng ngoi thp.

Thuc DRA cn dng iu tr ri lon kim sot xung ng nu cc can thip khc tht bi. Bnh nhn b ri lon pht trin lan ta cng c th tng ng qu mc, go tht, kch ng tn cng. Mt s triu chng ny c th p ng vi thuc DRA tim lc cao, nhng hin c t nghin cu cho thy li ch ca vic iu tr ny.

Cc bnh l thn kinh him gp nh: chng ma vung (ballismus) v chng ma vung na ngi (hemiballismus) vi biu hin vn ng y ti ca cc chi, cng p ng vi iu tr bng thuc chng lon thn. Ch nh khc ca DRA l bun nn, nn, nc v nga khng tr. Cc bnh l ni tit v ng kinh thy thi dng c biu hin lon thn c th p ng vi thuc chng lon thn.

2.1.2. Tc dng ph:Hu ht cc tc dng ph ca DRA l tc dng ph thn kinh. Cc thuc c tim lc thp thng c nhiu tc dng ph khng phi thn kinh hn cc thuc c tim lc cao. Ri lon vn ng do thuc l tc dng ph thng gp ca DRA (xem bi ring).

Hi chng c tnh do thuc chng lon thn: y l tc dng ph nguy him cht ngi ca DRA, c th xut hin bt k lc no trong qu trnh iu tr. Bao gm: st cao, cng c nng, lon trng lc c, mt vn ng, chng khng ni, l ln, kch ng, tng nhp tim v tng huyt p dn n suy tim mch. V cn lm sng, c tng bch cu, tng CPK (creatinine phosphokinase), tng men gan, tng myoglobin huyt tng v myoglobin niu, thng dn n suy thn. Cc triu chng thng tin trin trong vng 24 72 gi, v hi chng thng ko di 10 14 ngy nu khng iu tr. Chn on thng b b l trong nhng ngy u, do tnh trng thu rt v kch ng c th b nhm l phn ng nng ca tnh trng lon thn. Nam thng gp nhiu hn n, ngi tr thng gp nhiu hn ngi gi. T l t vong c th n 20 30% hoc cao hn nu dng loi thuc chch trc . Thng gp do cc thuc c tim lc cao.

Nu nghi ng c hi chng ny, nn ngng ngay DRA v x l nh sau: tr liu nng , lm mt thn nhit, theo di sinh hiu, cn bng nc v in gii, lng nc tiu. Thuc chng parkinson c dng lm gin tnh trng cng c. Dantrolene (thuc dn c xng) dng liu 0.8 2.5mg/kg mi 6 gi, ng tim truyn, tng liu ti a 10mg/ngy, c th iu tr c. Khi bnh nhn c th ung, dng dantrolene 100 200mg/ngy. Bromocriptine (20 30mg/ngy chia lm 4 ln) hoc amantadine c th kt hp iu tr. iu tr tip tc khong 5 10 ngy. Cng nn tip tc iu tr lon thn bng cch i sang cc thuc DRA tim lc thp hoc thuc SDR, d cc thuc ny, k c clozapine cng c th gy ra hi chng c tnh.

Ngng ng kinh: thuc DRA c th lm gim ngng ng kinh. Chlorpromazine, thioridazine v cc thuc tim lc thp khc c cho l gy ra ng kinh nhiu hn thuc c tim lc cao. Molindone l thuc t gy ng kinh nht trong s cc thuc DRA. Nguy c cao b co git l nhng bnh nhn c ng kinh hoc c tn thng no.

An thn: do phong ta th th histamine H1, nn DRA thng gy an thn. Chlorpromazine l thuc DRA gy an thn nhiu nht. Nn cho ton b liu thuc c ngy vo bui ti trc khi ng hn ch tc dng ph an thn ny, sau , bnh nhn s dung np dn tc dng ph ny.

Tc dng anticholinergic trung ng: triu chng anticholinergic trung ng gm: kch ng d di, mt nh hng thi gian, con ngi, ni chn, o gic, co git, st cao v dn ng t. Sng s v hn m c th xy ra. iu tr anticholinergic trung ng: ngng ngay thuc gy hi chng ny, theo di st v y khoa, v dng physostigmine 2mg truyn tnh mch chm, lp li sau 1 gi nu cn. Nu dng qu nhiu physostigmine s gy nguy him vi triu chng ng c: tng tit nc bt, tot m hi. Atropine c th i khng li tc dng ng c physostigmine.

Tc dng ph tim: DRA lm gim co bp tim, hy emzyme gy co bp trong t bo c tim, tng tc lu hnh catecholamine v ko di thi gian dn truyn nh tht, ko di thi gian tr ca t bo c tim. Thuc DRA tim lc thp gy ng c tim nhiu hn thuc tim lc cao Chlorpromazine gy ko di khong QT v PR, gy vi sng T v suy gim khong ST. Thioridazine v mesoridazine c bit cn gy ko di nng n khong QT, c nguy c gy xon nh. Nhng thuc ny ch c dng khi nhng thuc khc khng c hiu qu.

t t: c nhiu bo co cho thy c nhiu trng hp t t do tim mch khi dng DRA, c th do lon nhp tim. Nhng nguyn nhn khc c th gy t t l: co git, ngt, st c tnh, sc tim, hi chng c tnh.

H huyt p t th: h huyt p t th thng xut hin khi dng thuc c tim lc thp, c bit l chlorpromazine, thioridazine, chlorprothixene. Khi tim bp thuc c tim lc thp, nn theo di huyt p (khi nm v ng) trc v sau khi dng liu u tin v trong nhng ngy u iu tr.

H huyt p t th do phong ta h adrenergic v thng ch xut hin trong nhng ngy u. Sau , thng bnh nhn s dung np vi tc dng ph ny. Do , ch nn dng liu khi u thp i vi nhng thuc ny. Chng mt, t ng d khng thng gp nhng c th gy chn thng cho bnh nhn. Nn thng bo cho bnh nhn bit v tc dng ph ny, v hng dn h ng ln t t sau khi nm hoc da lng. Bnh nhn nn trnh dng caffein, ru; v nu khng phi ang iu tr h p, nn cho bnh nhn n nhiu mui. Mang bt tt cht c th hu ch.

H huyt p c th c iu tr bng cch cho bnh nhn nm di, chn gc cao hn u, p hai chn nh i xe p. Dng nhng thuc tng th tch tun hon hay tng huyt p, nh norepinephrine, c th c ch nh trong nhng trng hp nng. Ngoi h huyt p do thuc phong ta -adrenergic, thuc cn phong ta tnh kch thch -adrenergic ca epinephrine, nhng li khng kch thch h -adrenergic. Do , dng epinephrine lm tr nng tnh trng h huyt p nn b chng ch nh dng trong h huyt p do thuc chng lon thn. Trong trng hp h huyt p ny, nhng thuc kch thch duy nht -adrenergic nh metaraminol, norepinephrine l nhng thuc c la chn dng iu tr.

Tc dng ph huyt hc: gim bch cu tm thi khong 3500 cng thng gp nhng khng nng. Gim bch cu ht l mt tc dng ph nguy him e da tnh mng, gp 1/10.000 bnh nhn iu tr bng DRA. Gim tiu cu hoc ban xut huyt khng do gim tiu cu, thiu mu tn huyt, gim ton th cc dng t bo mu cng xut hin nhng him. Mc d ch nh m cng thc mu khng phi thng quy, nhng nu bnh nhn b au hng v st, cn phi thc hin ngay cng thc mu kim tra nhng tc dng ph v huyt hc. Nu cc ch s v mu thp, nn ngng ngay DRA v nn chuyn bnh nhn n chuyn khoa huyt hc. T l t vong do bin chng ny cao, khong 30%.

Tc dng ph anticholinergic ngoi bin: tc dng ph ny c cc biu hin: kh ming, mi, nhn m, to bn, b tiu, gin ng t thng gp, c bit l vi thuc c tim lc thp nh chlorpromazine, thioridazine, mesoridazine. Mt s bnh nhn c th b nn, bun nn.

To bn c th iu tr bng cc cht x thng dng, nhng nu to bn nng c th do lit rut. Cn gim liu DRA hoc thay i thuc khc t tc dng ph anticholinergic. Pilocarpine c th dng iu tr lit rut mc d tc dng ph ny c cho l ch thong qua. Bethanechol (Urecholine) (liu 20 40mg/ngy) c th dng iu tr b tiu.

Tng cn c lin quan n tng tn sut t vong, mc bnh v tnh trng khng p ng vi thuc. DRA tim lc thp gy tng cn ng k nhng khng nhiu nh SDA nh olanzapine, clozapine. Molindone v loxapine t gy tng cn nht.

Tc dng ph ni tit: phong ta th th dopamine ti rnh c phu s gy ra tng tit prolactine, lm v to, tit sa, mt kinh, c cht khoi cm n v gy bt lc nam. Thuc SDA, ngoi tr risperidone, khng lin quan n tng prolactine v l thuc chn la iu tr khi bnh nhn mc phi tc dng ph do tng prolactine.

Tc dng ph tnh dc: c nam v n khi dng DRA u b gim khoi cm, gim ham mun tnh dc. Khong 50% bnh nhn nam dng thuc chng lon thn cho bit b ri lon phng tinh v cng cng. Sildenafil (Viagra), vardenafil (Livitra) hay tadalafil (Cialis) thng c dng iu tr ri lon cc khoi do thuc chng lon thn, nhng hin nay cha c nghin cu no v kt hp gia cc thuc ny v DRA. c bit, thioridazine gy ra gim ham mun tnh dc v phng tinh ngc nam. Chng cng cng v au khi khoi cm cng c c ghi nhn, c th do tc ng i vn th th -adrenergic.

Tc dng ph v da v mt: vim da d ng v nhy cm vi nh sng c th gp, c bit l vi nhng thuc tim lc thp. Ni mn nga, ni ban sn, m xut huyt v mn nc c th xut hin sm trong nhng tun u, v hi phc dn. Phn ng nhy cm vi nh sng ging nh l tnh trng rm nng nng cng xut hin nhng bnh nhn dng chlorpromazine. Nhng bnh nhn ny nn c cnh bo v tc dng ph , v khng phi nng qu 30 60 pht, v phi dng thuc chng nng. Dng chlorpromazine lu di c th xut hin mng da i mu xanh xm nhng vng phi nng. Thay i da thng bt u bng mu nu hoc nu vng v tin trin thnh cc mu: xm en, xanh kim loi, mu ta. Nhng mng i mu ny hi ph dn khi bnh nhn c i sang dng thuc khc.

Nhim sc t vng mc bt hi phc c lin quan n s dng thioridazine vi liu trn 1000mg/ngy. Nhng triu chng sm ca tc dng ph ny thnh thong c th gy l ln v m do gp kh khn v th gic vo bui ti. Nhim sc t c th vn tin trin sau khi ngng dng thioridazine, v cui cng l gy m. V l do ny m ch khuyn dng thioridazine vi liu ti a 800mg/ngy.

Bnh nhn dng chlorpromazine c th b nhim sc t lnh tnh mt, c trng bng nhng ht trm tch nu trng mt trc thy tinh th v mt sau gic mc, ch pht hin khi khm bng rch thy tinh th. Trm tch c th tin trin thnh ht trng v vng nu, thng thnh hnh sao. Thng kt mc i mu thnh mu nu. Khng gy nguy hi cho vng mc v th gic vn khng bao gi b suy gim. Bnh l ny thng hi phc dn khi ngng chlorpromazine.

Vng da: tng men gan trong qu trnh iu tr bng DRA thng thong qua v khng ng k v mt lm sng. Khi ln u tin dng chlorpromazine, vng da do thuyn tc hoc do mt trong gan c th gp. Thng xut hin trong thng u tin khi iu tr v c d bo trc bng tnh trng au bng trn, bun nn, nn. Sau thng c st, ban , tng bch cu i toan, bilirunin niu, tng bilirunin huyt thanh, tng phosphatase kim, tng men gan. Hin nay nhng trng hp ny cc k him gp nhng nu xut hin vng da, nn ngng ngay thuc.

Tim lc v tc dng ph ca DRA

Tn thucPhn loi ha hcLiu ung tng ng (mg)Tc dng ph

3. 4. 5. An thnT ngNgoi thp

PimozideDiphenylbutylpiperidine1.5+++++

FluphenazinePhenothiazine2+++++

HaloperidolButyrophenone2+++++

ThiothixeneThioxanthene4+++++

TrifluoperazinePhenothiazine5++++++

PerphenazinePhenthiazine8+++++/+++

MolindoneDidydroindolone10++++

LoxapineDibenzoxazepine10+++/++++/+++

ProchlorperazinePhenothiazine15++++++

AcetophenazinePhenothiazine20+++++/+++

TriflupromazinePhenothiazine25+++++/+++++

MesoridazinePhenothiazine50++++++

ChlorpromazinePhenothiazine100++++++++

ChlorprothixeneThioxanthene100+++++++/++

ThioridazinePhenothiazine100+++++++

2.2. Thuc chng lon thn khng in hnh:

Cc thuc i vn serotonine dopamine (SDA serotonine dopamine antagonist) cn c gi l thuc chng lon thn th h 2, hoc khng in hnh. Bao gm: risperidone, olanzapine, quetiapine, clozapine, ziprasidone. Thuc phong ta th th serotonine type 5-HT2 v th th D2 lm c s cho vic iu tr bnh. SDA cng tc ng chuyn bit hn ln h dopamine mesolimbic nhiu hn th vn, lin quan n vic phn ly nhanh chng khi th th D2.

Tt c cc thuc SDA c cng c tnh sau: (1) phong ta t th th D2 hn so vi DRA; (2) t c nguy c mc phi hi chng ngoi thp hn so vi DRA, nht l ri lon vn ng mun; (3) c hiu qu r rt trong iu tr tm thn phn lit v (4) c hiu qu r rt trong iu tr cn hng cm. Cc thuc SDA u c cu trc phn t khc nhau, c i lc th th khc nhau. Tng tc gia th th vi hiu lc tr liu cng khng r.

Aripiprazole li c mt cc tc ng mi hn: i vn tng phn ln th th dopamine. y l mt tin b xa hn so vi thuc chng lon thn th h th 2 trong vic iu tr lon thn.

Mc d t nhng cc thuc SDA vn c tc dng ph ngoi thp, thuc SDA cn gy tng cn ng k, v lm tng nguy c mc phi bnh tiu ng Theo FDA ca Hoa K, tt c cc thuc SDA u phi gn nhn cnh bo cn c theo di st xao v nguy c gy bt thng ng huyt.

Trong s nhng thuc SDA, clozapine c c tnh ring bit. y khng c xem l thuc chn la hng u v cc tc dng ph v cn phi kim tra huyt hc mi tun. Mc d thuc ny c hiu qu cao trong iu tr hng cm, trm cm, nhng vn khng c FDA xp vo ch nh iu tr cc tnh trng bnh l . Olanzapine c ch nh l thuc iu tr cc giai on hng cm cp, mn tnh trong ri lon lng cc I, nhng li ch dng cho nhng trng hp tht bi tr liu vi nhng can thip khc (thuc).

2.2.1. Ch nh tr liu:

Mc d c chng minh l c hiu qu iu tr cn hng cm, nhng cc thuc ny thng c t nh tr liu thm vo vi trm cm khng tr, PTSD (posttraumatic stress disorder), ri lon hnh vi trong sa st tm thn. Nhng thuc SDA cn c xem l thuc chn la hng u, ngoi tr clozapine do thuc ny gy ra tc dng ph huyt hc nn cn theo di huyt hc mi tun

Tm thn phn lit v ri lon cm xc phn lit: cc SDA c hiu qu trong iu tr cc chng lon thn cp v mn, nh tm thn phn lit v ri lon cm xc phn lit, c ngi trng thnh v tr v thnh nin. Cc thuc SDA c hiu qu, thm ch cn tt hn, nh cc thuc chng lon thn in hnh (DRA) trong iu tr cc triu chng dng tnh ca tm thn phn lit v c hiu qu cao hn r rt so vi DRA trong iu tr triu chng m tnh. BN dng thuc SDA t b ti pht hn, t phi nhp vin hn, t phi cn cp cu tm thn, t phi t vn in thoi v tm thn, v s ngy iu tr ngn hn so vi dng DRA.

V clozapine c nhng tc dng ph gy nguy him n tnh mng nn ni gn nh ch dng bnh nhn tm thn phn lit khng vi tt c cc thuc chng lon thn khc. Nhng ch nh khc ca clozapine bao gm: ri lon vn ng mun nng, nhng bnh nhn c ngng d b triu chng ngoi thp. Nhng bnh nhn dung np tt vi clozapine c th s dng lu di. Tc dng ca clozapine c th tng ln do risperidone, aripiprazole do cc thuc ny lm tng nng ca clozapine v thnh thong c th gy ci thin v lm sng mt cch ngon mc.

Ri lon kh sc: tt c cc thuc SDA c FDA chng thc cho iu tr cn hng cm. Olanzapine cng c chng minh l iu tr duy tr trong ri lon lng cc. Tuy nhin, ni chung, thuc chng lon thn in hnh v benzodiazepine c hiu qu lm m du cn hng cm nhanh hn cc thuc SDA. Cc thuc SDA cn c hiu qu triu chng trm cm trong tm thn phn lit, tng tc dng chng trm cm trong iu tr cn trm cm. Do , kt hp thuc SDA v thuc chng trm cm thng dng iu tr trm cm khng tr. Kt hp fluoxetine v olanzapine l kt hp c FDA khuyn dng.

Cc ch nh khc: c khong 10% bnh nhn tm thn phn lit c hnh vi gy hn v bo lc. Thuc SDA cng c hiu qu iu tr tnh trng gy hn. Cc ch nh khc cn bao gm: hi chng suy gim min dch mc phi (AIDS), ri lon kiu t k, ri lon Tourette, bnh Huntington, hi chng Lesch-Nyhan. Risperidone v olanzapine cn c dng kim sot tnh trng gy hn v t gy thng tch tr em. Nhng thuc ny cn c ch nh cng vi thuc kch thch giao cm, nh methylphenidate hay dextroamphetamine iu tr chng tng ng gim ch tr em (ADHD), l nhng bnh nhn thng c kt hp c ri lon ng x, ri lon chng i (opposition-defiant disorder). Cc thuc SDA, c bit l olanzapine, clozapine, quetiapine, cn c ch cho nhng bnh nhn b ri lon vn ng mun. Thuc c ngn chn nhng vn ng bt thng trong ri lon vn ng mun. Thuc cn iu tr trm cm lon thn, lon thn th pht sau chn thng u, sa st tm thn, lon thn do thuc.

iu tr bng SDA cn lm gim nguy c t st, ng c nc bnh nhn tm thn phn lit. Bnh nhn OCD khng tr c th p ng vi SDA, nhng cng c mt s bnh nhn c triu chng cp cu ca OCD khi iu tr bng SDA. Mt s bnh nhn ri lon nhn cch ranh gii c th ci thin khi iu tr bng SDA.

2.2.2. Tc dng ph: cc thuc SDA c cng ph tc dng ph, nhng khc nhau mc thng xuyn v mc nng ca tc dng ph. Tc dng ph thng gp c th xem bng Tc dng ph SDA. Cc tc dng ph chuyn bit, thng gp ca mi SDA c nhn mnh trong gii thiu tng thuc.

2.2.3. Risperidone: l mt thuc nhm benzisoxazole. Risperidone c chuyn ha rt nhiu gan thnh 9 hydroxyrisperidone, mt chuyn ha cht c hot ng lon thn tng ng risperidone. Nng huyt tng ca risperidone t nh sau 1 gi v ca cht chuyn ha u tin l sau 3 gi (sau khi ung). Risperidone hot ng sinh hc n 70%. Thi gian bn hy kt hp ca risperidone v 9 hydroxyrisperidone l khong 20 gi, nn c hiu qu ch bng liu duy nht trong ngy. L mt cht i vn ca th th 5-HT2A v th th dopamine D2, th th 1 2 adrenergic v th th histamine H1. Thuc cng c i lc thp vi th th adrenergic v th th muscarinic cholinergic. Mc d thuc c tim lc i vn th th D2 nh haloperidol nhng thuc t gy tc dng ph ngoi thp nh haloperidol.

Tc dng ph ca risperidone: ty thuc vo liu lng v c khuynh hng xut hin nhiu khi dng liu thp hn liu khi u cn thit. Tng cn, bun nn v nn, gy lo u, gy nght mi, ri lon cng, ri lon cc khoi, v gy sm da l cc tc dng ph thng gp ca risperidone. Nhng l do thng gy ngng risperidone li l tc dng ph ngoi thp, chong vng, tng ng, bun ng, bun nn. Tng r rt prolactin c th xut hin v gy v to, tit sa. Tng cn li thng gp tr em hn ngi trng thnh.

Liu lng: liu khi u thng l 1 2mg/m., v sau c th tng n 4mg mi ngy. Khi kho st bng PET (positron emission tomography) cho thy: vi liu 1 4mg/ngy s gy phong ta th th D2 cn cho tc dng tr liu. Vi liu cao hn 6mg/ngy th s gy ra nguy c b tc dng ph, nht l tc dng ph ngoi thp. Khng c tng quan gia nng huyt tng v hiu qu iu tr. Risperidone l dng thuc SDA c dng tc dng chm, c tim bp su mi 2 tun. Liu lng tim bp c th thay i 25 50 75mg. Nn dng risperidone liu ung cng vi liu tc dng chm trong 3 tun u tin trc khi ngng liu ung. VN, risperidone c trnh by di dng vin nn: 1mg, 2mg (Risperdal, Respidon, Resdep, Risperidone, Repadon )

Nhng thuc c ch men CYP 2D6 nh paroxetine, fluoxetine c th c ch cc chuyn ha cht hot ng ca risperidone. Risperidone l cht c ch yu men CYP 2D6 nn t gy nh hng ln cc thuc khc. Kt hp risperidone v cc thuc SSRI c th gy tng ng k prolactine, gy tit sa, v to.

2.2.4. Olanzapine: gn 85% olanzapine c hp thu qua ng tiu ha v c n 40% liu b bt hot khi chuyn ha u tin gan. Nng nh t c sau 5 gi v thi gian bn hy l 31 gi, do ch nn dng 1 ln/ngy. Cng vi tc ng i vn 5-HT2A v D2, olanzapine cn i vn th th D1, D4, 1, 5-HT1A v th th muscarinic M1 M5, H1.

Tc dng ph ca olanzapine: khc vi clozapine, olanzapine ch gy tng cn nhiu v thng xuyn hn cc thuc chng lon thn khng in hnh khc, v n nh li sau khong 10 thng. Tc dng ny khng lin quan n liu lng v khng tin trin tip theo thi gian. Cc d kin lm sng cho thy nh im ca tc dng ph ny l khong 9 thng, sau c th tng tip nhng chm hn. Bun ng, kh ming, chong vng, to bn, kh tiu, tng ngon ming, bn chn khng yn, run, c th do s dng olanzapine. Mt s bnh nhn (khong 2%) c th phi ngng olanzapine v tng men gan. Tc dng ph ngoi thp c th lin quan vi liu, tc: liu cng cao th cng c th b hi chng ngoi thp. Chnh nhng tc dng ph ny m cn theo di ng huyt v men gan trong qu trnh iu tr bng olanzapine. FDA (t chc thuc v thc phm ca M) khuyn co nguy c b sc bnh nhn sa st tm thn khi iu tr bng olanzapine hay nhng thuc SDA khc nhng vi t l thp; vi tnh trng tng cn, c th ci thin bng luyn tp th lc.

Liu lng olanzapine: VN, olanzapine c trnh by di dng vin nn: 5mg, 10mg (Zyprexa, Oleanz rapitab, Ozapine, Olanzapine ). Liu khi u ca olanzapine iu tr lon thn thng l 5 10mg; iu tr hng cm cp thng l liu 10 15mg, dng 1 ln trong ngy. Vi liu 10mg tim bp/tnh mch, c th dng iu tr cn kch ng ca tm thn phn lit, ri lon lng cc.

Vi liu khi u 5 10mg/ngy, sau 1 tun, c th tng liu n 10mg/ngy. Liu s dng trong lm sng thng l 5 20mg/ngy nhng nu cn thit c th tng n 30 40mg/ngy vi trng hp khng tr. Tuy nhin vi liu cao s c nguy c b tc dng ph ngoi thp v nhng tc dng ph khc.

Tng tc thuc ca olanzapine: fluvoxamine v cimetidine lm tng nng olanzapine; carbamazepine, phenytoin lm gim nng ca olanzapine. Ru ethanol lm tng hp thu olanzapine n hn 25%, dn n tnh trng an thn, bun ng tng. Olanzapine t gy nh hng n chuyn ha ca cc thuc khc.

2.2.5. Quetiapine: l mt cht thuc nhm dibenzothiazepine, c cu trc gn ging clozapine, nhng khc bit r rt vi clozapine v tc ng sinh hc. Thuc c hp thu nhanh chng qua ng tiu ha, t nng nh sau khong 1 2 gi. Thi gian bn hy khong 7 gi, v nng ti u nht l sau 1 2 ngy. Cng vi kh nng i vn vi D2 v 5-HT2, quetiapine cn phong ta th th 5-HT6, D1, H1, 1, 2. Thuc li khng phong ta th th muscarinic, hay th th benzodiazepine. Tnh i vn th th ca quetiapine thng thp hn so vi cc thuc chng lon thn khc, v thuc thng khng gy ra hi chng ngoi thp.

Tc dng ph ca quetiapine: an thn, h huyt p t th, chong vng l nhng tc dng ph thng gp nht ca quetiapine, nhng thng thong qua v c th kim sot dn khi tng dn liu t t. Quetiapine l thuc SDA t gy hi chng ngoi thp nht, bt k liu lng. Do , y l thuc c ch nht iu tr bnh nhn b Parkinson c triu chng lon thn khi dng thuc ng vn dopamine. Tng prolactine him gp khi dng quetiapine, v thng b nh v thong qua nu c. Thuc c th gy tng cn nh mt s ngi, nhng mt s khc li b tng cn r rt. Tng nh nhp tim, to bn, tng nh men gan cng c th xut hin. C th c lin quan n tnh trng c thy tinh th trong nhng nghin cu trn ng vt, nhng li khng ghi nhn thy trong lm sng. Tuy nhin, li ghi nhn thy c nhng bt thng trn thy tinh th trong giai on u iu tr.

Liu lng ca quetiapine: trong tm thn phn lit, thng dng vi liu 400mg; trong giai on hng cm v ri lon lng cc, thng dng vi liu 800mg v 300mg. Tuy vy, vn c nhng bnh nhn cn n liu 1200 1600mg/ngy. Mc d c thi gian bn hy ngn, cng ch nn dng quetiapine 1 ln/ngy. Liu que6tiapine 25 300mg vo bui ti cn gip gy ng trong mt ng.

Tng tc thuc ca quetiapine: vn cn ang nghin cu. Phenytoin lm tng thanh thi ca quetiapine gp 5 ln.

2.2.6. Ziprasidone: thuc nhm benzothiazolyl piperazine. t nng nh sau 2 6 gi. Sau t 1 3 ngy s dng th c t c nng iu tr. Thi gian bn hy l 5 10 gi, nn cn dng 2 ln/ngy. Hot tnh sinh hc ca ziprasidone tng gp 2 nu dng chung vi thc n. Nng nh ca ziprasidone dng ng tim bp t c sau 1 gi.

Ziprasidone cng nh cc thuc SDA khc, phong ta th th D2 v 5-HT2A, v cng i vn th th 5-HT1D, 5-HT2C, D3, D4, 1, H1. Thuc cn c i lc thp vi th th D, M v 2. Ziprasidone cn ng vn th th serotonine 5-HT1A, c ch ti hp thu serotonine, c ch ti hp thu norepinephrine. Do , c nhng bo co lm sng v tc dng ging nh chng trm cm ca ziprasidone nhng bnh nhn khng phi tm thn phn lit.

Tc dng ph ca ziprasidone: bun ng, au u, chong vng, bun nn, m sng l nhng tc dng ph thng gp khi dng ziprasidone. Thuc hu nh khng c tc dng ph ng k bn ngoi h thn kinh trung ng, hu nh khng gy tng cn v khng gy ta8g prolactine. Thuc c lin quan n tnh trng ko di khong QTC nn mt s nh lm sng khng chn ziprasidone l thuc chn la hng u. Ko di khong QTC n 1.4 milisecond gp khong 4.7% bnh nhn dng ziprasidone liu 40 120mg/ngy, nn chng ch nh dng ziprasidone phi hp vi nhng thuc ko di khong QTC, nh dofetilide, sotalol, quinidine, thuc chng lon nhp nhm Ia, III, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacine, gatifloxacine, moxifloxacine, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol, tacrolimus. Ziprasidone nn trnh dng bnh nhn b hi chng QT ko di bm sinh, bnh nhn c tin s lon nhp tim.

Liu lng ca ziprasidone: nn bt u bng liu 40mg/ngy, chia lm 2 ln. Thuc thng c hiu qu liu 80 160mg/ngy (cng chia 2 ln/ngy). Tuy nhin, trong lm sng, nn dng liu cao 240mg/ngy. Liu tim bp nn dng khong 10 20mg, mi 2 gi vi liu 10mg, v mi 4 gi vi liu 20mg. Tng liu tim bp khng nn vt qu 40mg.

Tng tc thuc ch yu vi tc dng ph ko di khong QTC. Ngoi ra, ziprasidone t tng tc thuc ng k khc trong lm sng.

2.2.7. Clozapine: thuc nhm dibenzodiazepine. c hp thu nhanh v t nng nh trong khong 2 gi. t c nng iu tr, cn t nht 1 tun vi liu dng 2 ln/ngy. Thi gian bn hy l 12 gi. Clozapine c 2 chuyn ha cht chnh, trong c N-dimethyl clozapine c th c tc ng ha dc. Clozapine l mt cht i vn th th 5-HT2A, D1, D3, D4, v (c bit l th th 1). Thuc c tim lc i vn tng i thp vi th th D2. Trn hnh nh PET cho thy 10mg haloperidol phong ta 80% th th D2 th vn, th clozapine vi liu tng ng ch phong ta 40 50%. S khc bit ny chc chn l l do cho thy clozapine khng gy ra tc ng ngoi thp.

Nhng ch nh c bit ca clozapine: ngoi hiu qu iu tr c bit cho cc bnh nhn khng tr, clozapine cn dng iu tr ri lon vn ng mun nng. Thuc cn khng ch triu chng ri lon vn ng, nhng cc bt thng vn ng s tr li nu ngng clozapine. Trong mt s him trng hp, clozapine c th gy ri lon vn ng mun. Clozapine cn dng iu tr triu chng lon thn nhng bnh nhn khng dung np vi triu chng ngoi thp do cc thuc khc, hng cm khng tr, trm cm lon thn nng, bnh Parkinson lnh tnh, bnh Huntington, bnh nhn t st trong tm thn phn lit, cm xc phn lit. Nhng bnh l khng tr khc cho thy c p ng vi clozapine, bao gm: ri lon pht trin lan ta, t k thi nin thiu, OCD (dng n c clozapine hoc kt hp vi SSRI). Tuy nhin, cng c mt s trng hp him b triu chng OCD khi dng clozapine.

Tc dng ph ca clozapine: thng gp nht l bun ng, chong vng, ngt, nhp nhanh, h huyt p, thay i ECG, bun nn, nn. Nhng tc dng ph thng gp khc l: mt mi, tng cn, triu chng tiu ha khc (thng gp nht l to bn), triu chng anticholinergic, cm gic yu c. Tng tit nc bt, chy nc bt nhiu l tc dng ph xut hin sm trong qu trnh iu tr, nht l vo ban m. Tc dng ph ny do suy gim kh nng nut nc bt. C nhiu bo co cho rng clonidine, amtriptyline c th lm gim chng tng tit nc bt, nhng cch hiu qu nht li l t khn chn 2 bn mp khi ng.

Nguy c b co git khong 4% vi liu trn 600mg/ngy. Gim bch cu, gim bch cu ht, st thng gp 1% bnh nhn. Trong nm u tin iu tr, c khong 0.73% BN b gim bch cu khng ht. n nm th 2, nguy c ny l 0.07%. Gim bch cu trung tnh gp khong 2.32% trong nm th nht, v 0.69% nm th hai. Chng ch nh dng clozapine khi m bch cu di 3500 t bo/mm3, bnh l ty xng trc y, tin s b gim bch cu ht do clozapine, dng loi thuc c tc dng c ch ty xng nh carbamazepine.

Trong 6 thng u iu tr bng clozapine, m bch cu mi tun l ch nh bt buc theo di gim bch cu. Nu bch cu vn bnh thng, vic kim tra c th gim mi 2 tun. Nu bch cu gim di 3000 t bo/mm3, hoc nu bch cu ht gim di 1500 t bo/mm3, phi ngng ngay clozapine. Khi , cn khm v c kin ca chuyn khoa huyt hc. Nhng bnh nhn b gim bch cu ht th khng nn s dng li clozapine.

Vim c tim cng l mt nguy c nng khi dng clozapine.

Liu lng ca clozapine: clozapine c trnh by di dng vin nn 25mg v 100mg. Liu khi u thng l 25mg dng t 1 2 ln/ngy, mc d c th khi u bng liu thp hn l 12.5mg x 2 ln/ngy Sau , c th tng liu t t (25mg mi 2 3 ngy) n 300mg/ngy chia lm 2 3 ln/ngy. Liu ti a c th dng l 900mg/ngy. C th phi o nng clozapine trong mu nu bnh nhn khng p ng tr liu. Nng trong mu tt nht ca clozapine l 350mg/mL, s c p ng tt nht.

Tng tc thuc ca clozapine: khng nn dng chung clozapine vi nhng thuc c th gy gim bch cu ht, suy ty xng, nh carbamazepine, phenytoin, propylthiouracil, sulfonamides, captopril. Khi kt hp lithium vi clozapine, c th c nguy c b co git, l ln, ri lon vn ng, do khng nn kt hp nhng bnh nhn tng b hi chng c tnh do thuc chng lon thn. Clomipramine c th lm tng nguy c co git do lm gim ngng co git v lm tng nng ca clozapine huyt tng. Risperidone v fluoxetine, paroxetine, fluvoxamine lm tng nng ca clozapine huyt thanh. Kt hp clozapine paroxetine c th gy thc y tnh trng gim bch cu do clozapine.

So snh tc dng ph ca SDA v DRA

DRAClozapineRisperidoneOlanzapineQuetiapineZiprasidone

HC ngoi thpn ++00n +00

Lon vn ng mun+++0(+)???

Co gitn ++++0+00

An thn+ n ++++++++++

HC c tnh++++??

H huyt p t th+ n +++n +++++00

QTCn ++0n +00 n +0 n +++

Tng men gan0 n ++0 n +0 n +0 n +0 n +0 n +

Anticholinergicn ++++++0+00

Gim BC ht0+++0000

Tng prolactine++ n +++0+ n ++000

Gim phng tinhn +00000

Tng cnn ++++++++++0

Nght min +n +n +n +0 n +0

2.2.8. Hng dn lm sng:

Tt c cc SDA (ngoi tr clozapine) u dng iu tr giai on lon thn u tin, trong khi clozapine ch dnh cho bnh nhn khng tr vi tt c cc thuc chng lon thn khc. Nu bnh nhn khng p ng vi thuc SDA u tin, nn th dng cc thuc SDA khc. Chn la thuc nn da vo tnh trng lm sng v tin s p ng vi thuc. Thuc SDA thng cn 4 6 tun t c hiu qu hon ton v c th cn n 8 tun nh gi thuc SDA c th t c hiu qu iu tr hon ton hay khng. Do , ci thin u tin trn lm sng l tnh trng an thn (bun ng). Da trn cch nh gi ny, olanzapine v quetiapine l thuc a thch iu tr ban u tnh trng kch ng, bo lc, lo u cao . Tuy vy, vn chp nhn iu tr kt hp SDA vi thuc DRA hoc benzodiazepine trong vi tun u iu tr. Lorazepam c th dng liu 1 2mg ung hoc tim bp iu tr kch ng. Khi c hiu qu, nn gim liu dn lorazepam. Vi bnh nhn khng tr, c th cn n 6 thng nh gi ci thin lm sng khi dng SDA.

Vic s dng SDA nn bt u bng liu thp, tng dn liu t liu iu tr. Vic tng dn liu l cn thit nh gi nhng tc dng ph c th c. Nu ngng thuc trn 36 gi, nn dng tr li bng liu ban u (v tng dn). Khi quyt nh ngng dng olanzapine hoc clozapine, nn gim liu t t (nu c th) trnh triu chng cholinergic di ngc, nh tot m hi, bng, tiu chy, tng ng.

Khi mun dng SDA, nn gii thch cho bnh nhn v thn nhn v nhng nguy c v li ch ca SDA. Khi dng clozapine, nn lp bng tha thun vi bnh nhn.

Khi tm hiu bnh s, cn tm hiu cc yu t: bnh l huyt hc, ng kinh, bnh tim mch, bnh l gan thn v lm dng cht. Nu c bnh l gan thn, cn khi u dng liu thp. Khm lm sng cn kim tra huyt p lc nm ngh v lc ng sng lc tnh trng h huyt t th. Cc xt nghim cn thc hin gm: ECG, cng thc mu, chc nng agn, thn. Nn theo di ng huyt, lipid mu v cn nng theo chu k.

Mc d vic i t DRA sang SDA c th t ngt nhng cng nn gim dn DRA khi bt u th nghim dn bng SDA. Clozapine v olanzapine c tc dng ph anticholinergic, v khi chuyn t 1 trong 2 thuc ny bng mt thuc khc hn, cn ch n triu chng cholinergic di ngc. Chuyn i t risperidone sang olanzapine cn thc hin t vic gim dn risperidone trong 3 tun, v cng lc vi dng olanzapine 10mg/ngy. Risperidone, quetiapine, ziprasidone khng c tc dng ph anticholinergic, nn khi ngng t ngt thuc DRA, clozapine, olanzapine sang 1 trong cc thuc trn c th gy xut hin tnh trng di ngc cholinergic: tit nhiu nc bt, bun nn, nn, tiu chy. C th gim nh tnh trng di ngc ny bng cch tng nhanh risperidone, quetiapine, ziprasidone kt hp vi mt thuc anticholinergic (v sau gim dn thuc anticholinergic ny). Bt k vic bt u dng hoc ngng dng mt thuc SDA no cng nn thc hin t t.

Khi BN b mt bch cu ht khi dng clozapine, nn i sang olanzapine mc d dng olanzapine khi ang b mt bch cu ht do clozapine c th lm ko di thi gian hi phc t khong 3 4 ngy n khong 11 12 ngy. cn thn nn i tnh trng mt bch cu ht n nh hon ton ri mi s dng olanzapine.

S dng SDA thai ph cha c nghin cu, nhng nn bit rng risperidone gy tng prolactin (c th tng gp 3 4 ln so vi bnh thng). V bi v thuc SDA c th c tit qua sa nn khng c dng cho ph n ang cho con b.

2.3. Tc dng ph ngoi thp do thuc chng lon thn:2.3.1. Lch s:

T khi phat hien ra thuoc CLT a co nhng ghi nhan ve tac dung phu ngoai thap do thuoc. Nhng bao cao au tien ve hoi chng parkinson do Chlorpromazine c cong bo nam 1953. Steck (1954) mo ta nhng trieu chng cua tac dung phu nay. Delay va Denicker (1955) khi nghien cu ve chlorpromazine va reserpine, a ra nh ngha thuoc an than kinh phai co nam ac iem, trong o co tac dung phu ngoai thap. Loan van ong muon xuat hien trong y van vao khoang cuoi nhng nam 50 cua the ky XX. au tien, Schoenecker (1957) mo ta nhng c ong bat thng vung mieng keo dai sau khi giam lieu thuoc hoac ngng thuoc an than kinh. Sigwald (1959) bao cao nhng c ong khong t y cua li, moi, cac c vung mat xuat hien sau nhieu nam ieu tr vi thuoc an than kinh. Uhrbrand va Faurbye (1960) mo ta nhng c ong vung mieng mat, cung nhng c ong bat thng cua than the va chan. Khi ngng thuoc an than kinh, 50% cac trng hp nay thuyen giam hoac mat i, trong khi nhng trng hp con lai van keo dai hoac gia tang hn na. Faurbye va cs (1964) goi tac dung phu ngoai thap nay la loan van ong muon. Cac nghien cu dch te hoc au tien cuoi nam 1960 cho thay t le loan van ong muon thay oi t 0.5%-65%. Ban au ngi ta cho rang nguyen nhan do ton thng thc the nao hoac do ECT, nhng sau o gia thuyet nay b bac bo va nguyen nhan c xac nh la tac dung phu cua thuoc CLT. Ngi ta nhan thay benh nhan ln tuoi va phu n th de mac loan van ong muon hn.

2.3.2. Loan trng lc c cap:

Xuat hien trong vong t vai gi hay vai ngay au (1 4 ngay) khi dung thuoc chong loan than.

Khi dung thuoc chong loan than chung vi lithium, co the lam tang nhay cam vi phan ng loan trng lc c cap.

Thng gap nhat la tnh trang cang en mc khong kiem soat c c co va mat; hoac co that, van veo au hoac lng. Co the anh hng en c van nhan lam xuat hien cn xoay nhan cau lam mat nhn ngc len va b khoa v tr o. Neu b thanh quan se gay kho th.

Vi nhng BN lan au tien b tnh trang nay se lam cho ho co cam giac nang ne hn, lam mat long tin vao BS ieu tr.

Co the ieu tr nhanh chong tnh trang nay bang cac thuoc khang cholinergic nh: benztropine, biperiden (Akineton), diphenhydramine (Parsidol), trihexyphenidyl (Artane). Thuoc cung co tac dung phong nga tac dung phu nay trong vai gi sau. Mac du rang tac dung phu nay cung co the nhanh chong bien mat trc khi s dung thuoc. Thuoc co the c ch nh trong vai ngay ke tiep sau khi loan trng lc c cap xuat hien.

Tieu chuan chan oan loan trng lc c cap theo DSM IV: (8)

A. Mot (hay nhieu hn) cac dau hieu hay trieu chng sau xuat hien lien quan en viec dung thuoc an than kinh

T the bat thng cua au va co so vi c the (nh veo co).

Co that cac c ham (cng ham, nhan mat, ha mieng to).

Suy giam kha nang nuot (kho nuot), suy giam kha nang noi, suy giam kha nang th (co that vung hau thc quan, roi loan phat am).

Li noi khong ro rang, noi lap do bi cng li hay ph ai li (noi kho, li to).

The li, roi loan chc nang li.

Mat liec len, xuong, hay sang ben (oculogyric crisis).

T the bat thng cua chi xa hay than.

B. Cac dau hieu hay trieu chng trong tieu chuan A xuat hien trong vong 7 ngay t khi bat au hay khi tang nhanh lieu thuoc an than kinh hay khi giam lieu thuoc ieu tr (hay phong nga) cac trieu chng ngoai thap cap (nh thuoc anticholinergic).

C. Cac trieu chng trong tieu chuan A khong giai thch thch ang vi mot roi loan tam than (nh cac trieu chng cang trng lc cua tam than phan liet). Cac trieu chng nay do bi mot roi loan tam than khi: cac trieu chng co trc khi dung thuoc an than kinh hay khong phu hp vi hnh thc can thiep dc ly (nh la khong cai thien sau khi giam lieu thuoc an than kinh hay sau khi dung thuoc anticholinergic).

D. Cac trieu chng trong tieu chuan A khong do bi cac chat khong phai thuoc an than kinh hay cac benh ly than kinh hay noi khoa tong quat khac. Cac trieu chng nay do bi benh ly noi khoa tong quat khi: cac trieu chc xuat hien trc khi dung thuoc an than kinh hay co s hien dien cac dau hieu than kinh khu tru ma khong giai thch c hay cac trieu chng tien trien trong khi khong thay oi thuoc.

2.3.3. Trang thai bon chon khong yen:

c phat hien va mo ta sm, ch sau loan trng lc c cap. Benh nhan co cam giac bt rt, bon chon, khong the ngoi yen, can phai i lui i ti e giam bt s kho chu. Trang thai bon chon khong yen cung la mot trong cac roi loan ngoai thap do thuoc chong loan than.

Co tac gia con e ngh rang: trang thai bon chon khong yen gom ca roi loan van ong va roi loan ve tam than (Stahl, 1985). Do o, tnh trang nay co the b cho mot trieu chng loan than, hoac lo au, hoac tram cam. Co trng hp, BN tr nen kch ong, bc tc v khong the kiem soat c cam giac ve tnh trang nay.

Thng xuat hien sau khi dung thuoc mot thi gian ngan. Vi haloperidol lieu 5mg, co en 40% BN co tnh trang nay; vi lieu 10mg, co en 75% co tnh trang nay. Nh vay, khi tang lieu thuoc se lam tnh trang nay cang nang hn; va khi giam lieu, tnh trang nay se c cai thien.

ay la loai tac dung phu hay gap nhat khi dung thuoc CLT co ien, thng gay ra s khong tuan thu ieu tr nhieu nhat so vi cac tac dung phu ngoai thap khac, va do o lam tang nguy c tai phat benh tam than.

Trc ay, nhieu tac gia e ngh s dung thuoc khang cholinergic e ieu tr nhng khong hieu qua, ngoai tr trng hp co ket hp vi cac trieu chng ngoai thap khac, nh: cng c.

Thuoc e ngh la cac benzodiazepine nh: diazepam (Valium, Seduxen 5mg, 10mg), lorazepam (Ativan, Temesta 0.5mg, 1mg, 2mg).

Tuy nhien, thuoc chon la hang au lai la thuoc c che beta (beta bloquants), nhat la propranolol (co the tang lieu en 120mg/ngay). Cac thuoc beta-bloquants tan trong dau thng at hieu qua cao hn cac beta-bloquants tan trong nc.

Tieu chuan chan oan trang thai bon chon khong yen theo DSM IV(8):

A. Xuat hien cac than phien chu quan ve tnh trang khong yen sau khi s dung thuoc an than kinh. t nhat mot trong cac trieu chng sau c ghi nhan

C ong bon chon, ung a 2 chan.

Nhun nhay 2 chan khi ng.

i ti lui e giam bon chon.

Khong the ngoi hay ng yen trong vai phut

B. Khi au trieu chng cua tieu chuan A va B xuat hien trong vong 4 tuan sau khi bat au hoac tang lieu an than kinh hoac giam lieu thuoc ieu tr (hoac phong nga) cac trieu chng ngoai thap cap (nh la thuoc anticholinergic)

C. Trieu chng tieu chuan A khong c giai thch thch ang bi mot roi loan tam than (nh tam than phan liet, cai nghien chat, kch ong do cn tram cam hoac do cn hng cam, gia tang hanh vi trong roi loan giam sut chu y/ gia tang hanh vi). Cac trieu chng nay do bi mot roi loan tam than khi: cac trieu chng xuat hien trc khi dung thuoc, khong thay gia tang tnh trang khong yen lien quan vi tang lieu thuoc an than kinh, khong thay giam tnh trang nay lien quan vi can thiep dc ly (nh: khong cai thien khi giam lieu thuoc an than kinh hoac khi ieu tr vi cac thuoc c e ngh ieu tr tnh trang ng ngoi khong yen).

D. Cac trieu chng trong tieu chuan A khong phai do cac thuoc khong phai an than kinh hoac cac tnh trang benh ly tong quat khac. Cac trieu chng nay do bi benh ly noi khoa tong quat khi cac trieu chng xuat hien trc khi s dung an than kinh hoac cac trieu chng ngay cang nang mac du khong thay oi che o thuoc.

2.3.4. Hoi chng Parkinson:

Hoi chng nay mang nhieu ac iem ien hnh cua benh Parkinson nguyen phat: giam dien ta bang net mat (mat na), dau banh xe rang ca, giam van ong, chay nc dai, viet ch nho, run kieu ve thuoc, run khi ngh, cng c toan than. Hoi chng nay thng xuat hien t t sau khi cho thuoc chong loan than.

ieu tr cung bang cac thuoc khang cholinergic, hoac cac thuoc ong van dopamine nh amantadine (Symmetrel), bromocriptine (Parlodel).

Ngoai ra con gap tnh trang mat van ong (akinesia): ac trng bi tnh trang giam tnh t phat nh: van ong khong t chu, noi khong t chu, lanh am, kho bat au cac hoat ong trong sinh hoat. Cung xuat hien sau vai tuan ieu tr bang thuoc CLT. Tuy nhien, tnh trang akinesia con co the bieu hien nh trieu chng am tnh trong tam than phan liet. ieu tr cung bang cac thuoc khang cholinergic, va cung co the lam cai thien cac trieu chng am tnh nay.

Hoi chng tho (rabbit syndrome): la nhng c ong nhanh, mn (nho) moi nh c ong nhai cua tho. Co the lan lon vi loan van ong muon mieng li. Co the gap khoang 4% BN dung thuoc CLT. ieu tr nhanh chong va de dang bang thuoc khang cholinergic.

Co the ieu tr phong nga loan trng lc c cap, hoi chng parkinson, hoi chng tho, mat van ong, bang cac thuoc khang cholinergic cung luc vi thuoc CLT.

Tieu chuan chan oan hoi chng Parkinson theo DSM IV: (8)

A. Mot (hay nhieu hn) dau hieu hay trieu chng sau xuat hien lien quan en viec dung thuoc chong loan than.

Run kieu Parkinson (nh: run khi ngh ngi, nhp nhang, ro ret, vi tan so 3-6 chu ky/giay, xay ra chi, au, mieng hay li ).

Cng c kieu Parkinson (nh: co cng kieu rang ca hay co cng, co cng kieu ong ch keo dai).

Mat van ong (nh: giam s bieu lo net mat mot cach t nhien, t the, li noi, van ong c the)

B. Cac trieu chng tieu chuan A xuat hien trong vong vai tuan khi bat au dung hay tang lieu thuoc chong loan than, hay giam cac thuoc ieu tr (hay phong nga) cac trieu chng ngoai thap (nh la thuoc anticholinergic)

C. Cac trieu chng trong tieu chuan A khong c giai thch thch ang bi mot roi loan tam than (nh : cac trieu chng am tnh hay cang trng lc cua tam than phan liet, cham chap tam than van ong trong giai oan tram cam chu yeu). Bang c ma cac trieu chng c giai thch thch ang bi mot roi loan tam than co the bao gom theo sau: Cac trieu chng co trc khi dung thuoc an than kinh hay khong phu hp vi hnh thc can thiep dc ly (nh la khong cai thien sau khi giam lieu thuoc an than kinh hay sau khi dung thuoc anticholinergic).

D. Cac trieu chng trong tieu chuan A khong do bi cac chat khong phai thuoc an than kinh hay cac benh ly than kinh hay noi khoa tong quat khac (nh la benh Parkinson hay benh Wilson). Cac trieu chng do bi benh ly noi khoa tong quat khi: cac trieu chng xuat hien trc khi dung thuoc an than kinh hay co s hien dien cac dau hieu than kinh khu tru ma khong giai thch c hay cac trieu chng tien trien mac du khong thay oi che o thuoc ).

2.3.5. Loan van ong muon (tardive dyskinesia TD):

Thng gap benh nhan dung thuoc CLT lau dai, nhat la thuoc CLT co ien. Bieu hien cua roi loan nay la cac c ong bat thng cua mieng, mat, li va c ong mua giat, mua vn cua tay, chan, c the. Khong giong nh cac tac dung phu ke tren, benh nhan b LVM thng khong y thc c rang ho co nhng c ong bat thng. LVM ap ng kem vi ieu tr.

La nhng c ong khong chu y mat, than mnh, hoac chi. Gom: trang thai bon chon khong yen muon, loan trng lc c muon (thng c co, c vai), tics muon.

Thng co lien quan en viec dung keo dai cac thuoc phong toa thu the dopamine, ma thng gap nhat la thuoc CLT, nhng cung co the gap BN dung thuoc chong tram cam amoxapine, thuoc chong non nh metoclopramine, prochlorperazine

C che e ngh: cac thu the sau synap tang nhay cam vi dopamine sau mot thi gian dung thuoc phong toa thu the dopamine. Co nhng c che c e ngh khac nh: tang hoat ong noradrenaline; hoac ieu tr bang thuoc chong loan than lam sinh ra cac goc t do lam ton thng cac cong catecholamine; hoac lien quan en he GABA; hoac suy thoai nao toan bo.

Tan suat thay oi tuy theo nhom dan c c nghien cu, tuoi ... Tuy nhien, co the xac nh trong khoang 15 20% BN dung thuoc CLT keo dai.

Yeu to nguy c: nguy c b TD tang theo tuoi cua BN. Phu n thng co nguy c cao hn nam. Tang theo lieu thuoc CLT c s dung, thi gian s dung va tien s b tac dung phu ngoai thap sm trong qua trnh ieu tr. TD con xuat hien cao nhng BN co ton thng nao, cac benh ve cam xuc (hng cam, tram cam )

ieu tr: thng vi nhng bieu hien nhe, BN thng khong nhan biet c. Nhng trng hp nang anh hng en an uong, ngh ngi th can ieu tr.

Ngan nga xuat hien TD la quan trong. Do o can anh gia lieu lng thuoc CLT toi thieu thch hp oi vi tng giai oan benh, nen can phai co chien lc giam lieu thuoc CLT. Khi giam lieu thuoc CLT, TD cung co the giam dan t t. Cac trieu chng TD cung co the bien mat tam thi khi tang lieu thuoc CLT, nhng cung co the nang hn khi tang lieu thuoc CLT.

oi vi BN co TD ma khong the ngng thuoc CLT, thuoc CLT c e ngh la clozapine. Thuoc nay co the lam cai thien cac trieu chng TD (gan 50% trng hp, nhat la cac trng hp loan trng lc c muon nang).

Thuoc khang cholinergic co the lam xau hn trieu chng TD.

Cac thuoc khac c e ngh nh: reserpine (1 6mg/ngay), tetrabenazine (50 200mg/ngay), oxypertine - cac thuoc nay lam suy giam cac catecholamine. Cac thuoc oi van noradrenergic nh propranolol, clonidine; cac thuoc he GABAergic nh benzodiazepine, baclofen, valproate, gamma vinyl GABA; thuoc ong van dopamine dung lieu thap nh levodopa, amantadine; cac thuoc phong toa kenh calci nh verapamil, diltiazem cung c s dung. Rieng vitamine E c ghi nhan lam cai thien trieu chng, do co ac tnh chong oxi hoa nen bao ve te bao than kinh oi vi cac goc t do; lieu s dung co the t 400 1200 UI/ngay.

Tieu chuan chan oan roi loan van ong muon theo DSM IV: (8)

A. Nhng c ong bat thng cua li, ham, than, chi xuat hien lien quan vi viec dung thuoc chong loan than

B. Nhng c ong bat thng hien dien toi thieu 4 tuan va bieu hien bat c cac dang sau:

Nhng c ong mua giat

Nhng c ong mua vn

Nhng c ong eu an.

C. Nhng dau hieu hay trieu chng trong tieu chuan A va B xuat hien trong thi gian dung thuoc an than kinh hay trong vong 4 tuan ngng hay giam thuoc uong (hay trong 8 tuan giam hay ngng thuoc dang tac dung keo dai)

D. Co thi gian dung thuoc an than kinh toi thieu 3 thang (1 thang neu hn 60 tuoi).

E. Cac trieu chng khong do cac benh ly noi khoa hay than kinh (nh la: benh Huntington, mua vn Syndenham, roi loan van ong t phat, cng giap, benh Wilson) rang gia khong phu hp, dung cac thuoc khac gay roi loan van ong cap co the hoi phuc (nh la: L-dopa, bromocriptine). Co bang c cac trieu chng do cac nguyen nhan nay: cac trieu chng xuat hien trc hay bieu hien cac dau than kinh nh v khong giai thch c. Cac trieu chng khong c ly giai thch hp bi cac roi loan van ong cap lien quan thuoc an than kinh (nh la: loan trng lc c cap, tnh trang ng ngoi khong yen cap).

2.3.6. Hoi chng ac tnh do thuoc CLT:

Hiem gap, nhng co the gay nguy hiem en tnh mang BN. Bieu hien: tnh trang cng c nang ne hn, thay oi tnh trang tam than (sang, lo au d doi, s anh sang, trang thai khong noi, cang trng lc), sot cao, tang bach cau (thng tren 15.000 BC/mm3), nhp tim nhanh, huyet ap dao ong bat thng, th nhanh, toat mo hoi nhieu. CPK (creatinine phosphokinase) tang cao do huy c (thng tang t 100 1000 lan) va dan en tieu myoglobine.

C che e ngh la do tang hoat ong he than kinh giao cam.

Thng xuat hien nhng BN mi lan au s dung trong 1 thang au, BN tre, khi tang lieu thuoc CLT, khi dung thuoc CLT ng chnh (bap, TM). Tuy nhien, co the xuat hien bat k giai oan nao khi s dung thuoc CLT. Lithium co the lam tang nguy c b HC ac tnh.

ieu tr HC ac tnh: (1) ngng ngay lap tc tat ca cac thuoc ang s dung, (2) dung cac thuoc nh: amantadine, benzodiazepine, thuoc khang cholinergic, ECT (choang ien).

Bromocriptine, mot thuoc ong van dopamine hoat ong trung ng, c ghi nhan co hieu qua. Thuoc lam giam nhanh tnh trang cng c, rieng CPK, huyet ap dao ong, tang than nhiet co the on nh dan trong vai ngay. Lieu s dung thng 1.25 2.5mg x 2 lan/ngay, co the tang en 30mg/ngay.

Tieu chuan chan oan hoi chng ac tnh do thuoc chong loan than theo DSM IV: (8)

A. Xuat hien co cng c nghiem trong va than nhiet tang lien quan en viec dung thuoc an than kinh

B. Hai (hay nhieu hn) cac trieu chng sau:

Toat mo hoi.

Kho nuot.

Run.

Tieu tieu khong t chu.

Thay oi y thc t lu lan en hon me.

Khong noi.

Nhp tim nhanh.

Tang huyet ap hay huyet ap dao ong.

Bang chng can lam sang cua ton thng c (nh la CPK tang).

C. Cac trieu chng trong tieu chuan A va B khong do bi chat khac (nh la: Phencyclidine) hay benh ly than kinh hay benh ly noi khoa khac (nh la viem nao do virus).

2.3.7. Cac trieu chng trong tieu chuan A va B khong c giai thch thch ang bi mot benh tam than (nh : roi loan kh sac co bieu hien cang trng lc)

2.3.8. C ch ca tc dng ph ngoi thp do thuc CLT:

C che benh sinh cua tac dung phu ngoai thap cha ro rang. Bnh thng co s can bang gia hoat ong he dopaminergic va he cholinergic trong nao. Thuoc CLT c che s dan truyen he dopaminergic, lam mat s can bang nay gay ra tac dung phu ngoai thap. Mot gia thuyet cho rang s c che dan truyen trong he thong dopaminergic do thuoc CLT la nguyen nhan cua parkinson.

Cac nghien cu gan ay nhan manh vai tro cua thu the D1 va D2 va thu the Serotonin ( 5-HT). Mot th nghiem lam sang cho thay, ieu tr vi Haloperidol lau dai se lam giam chat dan truyen than kinh cua he dopaminergic va lam tang thu the D2 hau synape. Ngc lai ieu tr vi Clozapine lau dai lai lam tang nhe chat dan truyen than kinh cua he dopaminergic va khong thay oi thu the D2 hau synape. ieu o giai thch c s xuat hien cua cac tac dung phu ngoai thap khi ieu tr bang thuoc CLT co ien, va khong co chung khi ieu tr bang Clozapine.Gia thuyet cho rang loan van ong muon co the do c che sieu nhay cam, co s gia tang so lng cac thu the D2 hau synape e bu tr s c che dan truyen dopamine lau dai cua thuoc CLT.

Ngoai ra, he -adrenergic cung co lien quan en tac dung phu ngoai thap, ac biet la vi HC ng ngoi khong yen, parkinson, loan van ong muon. C che gay ra HC ng ngoi khong yen co the la do s mat can bang gia he noradrenergic va he dopaminergic do tac dung cua thuoc CLT.

BANG TOM TAT CAC THUOC IEU TR TAC DUNG PHU NGOAI THAP:

Ten thuocTen thng maiLieu dungCh nh

Anticholinergic

Benztropine

Biperiden

Trihexphenidyl

Antihistaminergic

Diphenhydramine

Dopamine agonists

Amantadine

-blockers

Propranolol

UC thu the (Clonidine

Benzodiazepines

Clonazepam

LorazepamCogentin

Akineton

Artane

Benadryl

Symmetrel

Inderal

Catapress

Klonopin

Ativan1-4 mg ( 2lan /ngay

2-6 mg ( 3lan /ngay

2-5 mg( 3lan /ngay

25 mg( 3lan /ngay

100-200mg ( 2lan /ngay

20-40mg ( 3 lan /ngay.

0.1mg (3 lan/ngay.

1 mg( 2 lan /ngay

1 mg( 2 lan /ngayLoan trng lc c cap, Parkinson.

Loan trng lc c cap, parkinson, HC ng ngoi khong yen.

Parkinson .

ng ngoi khong yen, Parkinson

Trang thai bon chon khong yen

Loan trng lc c cap, trang thai bon chon khong yen.

3. THUC CHNG TRM CM SSRIs

Thuc c ch ti hp thu chn lc serotonine (serotonine selective reuptake inhibitor SSRI) u tin c pht hin nm 1987 l fluoxetine lm thay i thi v iu tr ho dc vi trm cm. L do u tin l do tc dng ph ca fluoxetine thng c dung np tt hn nhng thuc iu tr trc y, nh thuc chng trm cm ba vng (TCA) v thuc c ch MAO (MAOI) v tnh n gin trong liu dng fluoxetine.

Sau , nhng thuc SSRI khc c pht hin, c cng c tnh c bn ca fluoxetine. T 1990, danh sch cc ch nh iu tr c chng thc cho nhng thuc xp trong nhm ny m rng thm, khng ch l trm cm, nh: ri lon m nh cng ch (OCD), ri lon hong lon, ri lon lo u lan to, ri lon lon cm trc k kinh, ri lon lo u x hi v ri lon n ung. Tt c cc thuc SSRI c hiu qu tng ng iu tr cc ri lon ny.

SSRIs dng cho ngi trng thnh v tr em

CitalopramEscitalopramFuoxetineFluvoxamineParoxetineSertraline

Trm cm nngNgi trng thnhNgi trng Ngi trng thnh v tr emNgi trng thnhNgi trng thnh

Ri lon lo u lan toNgi trng thnhNgi trng thnh

OCDNgi trng thnh v tr emNgi trng thnh v tr emNgi trng thnhNgi trng thnh v tr em

Ri lon hong lonNgi trng thnhNgi trng thnhNgi trng thnh

Ri lon lo u x hiNgi trng thnhNgi trng thnh

Chng n ung v lon tmNgi trng thnh

Ri lon lon kh sc trc k kinhNgi trng thnhNgi trng thnhNgi trng thnh

3.1. Ha hc:

Cc thuc SSRI c cu trc ho hc khc bit nhau, nhng escitalopram l ngoi l, l dng ng phn ca citalopram. Tnh a dng v phn t gii thch c ti sao c c nhn p ng v dung np vi cc thuc SSRI khc nhau.

3.1.1. Dc ng hc:

S khc bit quan trng nht gia cc SSRI l thi gian bn hu trong huyt tng c thay i rng. Fluoxetine c thi gian bn hu di nht 4 6 ngy; cc chuyn ho cht hot ng ca thuc c thi gian bn hu 7 9 ngy. Thi gian bn hu ca sertraline khong 26 gi, v thuc c mt t chuyn ho cht hot ng c thi gian bn hu 3 5 ngy. Thi gian bn hu ca thuc cn li (khng c chuyn ho cht hot ng no ng k) l: citalopram 35 gi, escitalopram l 27 32 gi, paroxetine l 21 gi, fluvoxamine l 15 gi. V c bn, SSRI hp thu tt bng ng ung, t nng nh sau khong 3 8 gi. S hp thu sertraline thay i nh nu c thc n.

T l gn kt vi protein ca sertraline, fluoxetine, paroxetine cao nht; escitalopram gn kt t nht.

Tt c cc SSRI c chuyn ho gan do men cytocrome P450 (CYP). Nhng do cc SSRI c ch s tr liu rng nn him khi nhng thuc khc gy tng vn nng ca cc SSRI. Tng tc thuc quan trng nht vi SSRI l lm c ch chuyn ho SSRI nu dng ng thi. Cc SSRI u c kh nng gy c ch chuyn ho ca kh nhiu thuc.

Fluvoxamine l thuc gp nhiu kh khn nht lin quan n tng tc thuc. Fuvoxamine nh hng r rt n vi men CYP. V d v tng tc quan trng l gia fluvoxamine v theophylline do tng tc qua men CYP 1A2; fluvoxamine v clozapine qua c ch men CYP 1A2; fluvoxamine vi clonazepam v alprazolam do c ch men CYP 3A4. Fluoxetine v paroxetine c tc ng ng k n men CYP 2D6, gy nh hng n hiu qu ca cc cht ging opiate, nh: codein, hydrocodone, do phong to s chuyn i cc thuc ny thnh dng hot ng. Do , dng ng thi fluoxetine, paroxetine vi mt thuc opiate lm nh hng n hiu qu gy m ca thuc opiate. Sertraline, citalopram, escitalopram hu nh t gy cc bin chng iu tr do tng tc thuc.

Kh nng c ch men cytocrom P450 (CYP) ca cc thuc chng trm cm thng dng

Xp loi tng iCYP 1A2CYP 2CCYP 2D6CYP 3A

CaoFluvoxamineFluoxetineBupropionFluvoxamine

4. FluvoxamineFluoxetineNefazodone

5. ParoxetineTCAs

Trung bnhTCAs hng th 3SertralineTCAs hng th 2Fluoxetine

6. FluoxetineCitalopramSertraline

7. Escitalopram

8. Sertraline

Thp (ti thiu)BupropionParoxetineFluvoxamineCitalopram

9. MirtazapineVenlafaxineMirtazapineEscitalopram

10. NefazodoneNefazodoneMirtazapine

11. ParoxetineVenlafaxineParoxetine

12. SertralineVenlafaxine

13. Venlafaxine

3.1.2. Dc lc hc:

Cc thuc SSRI c cho l c hiu qu tr liu thng qua c ch ti hp thu 5-HT. Thuc cng t nh hng n ti hp thu norepinephrine hay dopamine. Thng thng tc ng lm sng thch hp, s bo ho cht vn chuyn 5-HT u t c ngay t liu khi u. V nguyn tc, liu cao cng khng lm tng hiu qu iu tr chng trm cm nhng c th lm tng nguy c b tc dng ph.

Citalopram v escitalopram l cht c ch chn lc nht n s ti hp thu serotonine, v t gy c ch ti hp thu norepinephrine hay dopamine, v t c i lc vi th th histamine H1, GABA, hay benzodiazepine. Cc SSRI khc c c tnh tng t, ngoi tr fluoxetine c ch ti hp thu norepinephrine v gn kt vi th th 5-HT2C, sertraline c ch ti hp thu norepinephrine, dopamine, paroxetine c hiu qu khng cholinergic ng k khi dng liu cao, v gn kt vi men tng hp nitric oxide. Tng tc dc lc hc xut hin tim n bn di hiu qu chng trm cm khi kt hp s dng fluoxetine v olanzapine, l khi dng chung gy tng tp trung norepinephrine no. S dng ng thi SSRI v thuc nhm triptane (sumatriptan, naratriptan, rizatriptan, zolmitriptan) c th gy tng tc dc lc hc nng n, gy ra hi chng serotonine. Tuy nhin, nhiu ngi, vic dng thuc nhm triptan vi liu thp SSRI phng nga cn au u nhng khng c tc dng ph. Phn ng tng t c th xut hin khi dng SSRI vi tramadol (Ultram).

3.2. Ch nh tr liu:

3.2.1. Trm cm:

Ngoi tr fluvoxamine cha c FDA chp nhn, cc thuc SSRI khc u c chp nhn iu tr trm cm. Mt s nghin cu cho thy cc thuc chng trm cm c tc ng ln serotonine hoc/v norepinephrine, nh MAOI, TCA, venlafaxine, mirtazapine t hiu qu hi phc bnh cao hn so vi SSRI trong cc nghin cu i u (so snh). SSRI c chn l thuc u tay trong iu tr ch v s dng n gin, an ton v ph hot ng rng.

So snh trc tip, n c th mt thuc SSRI khng bc l bt c u im no so vi thuc SSRI khc. Tuy nhin, tnh a dng r rng l do kh nng p ng ca bnh nhn vi cc SSRI khc nhau. V d: hn 50% p ng km vi mt thuc SSRI c th p ng tt vi mt thuc SSRI khc. Do , trc khi thay i bng mt thuc chng trm cm khng phi SSRI, nn th tt c cc thuc SSRI khc khi bnh nhn khng p ng vi thuc SSRI s dng u tin. Mt s bc s lm sng c gng chn mt thuc SSRI c bit cho nhng bnh nhn chuyn bit da trn danh sch tc dng ph ca ring tng thuc. V d: fluoxetine l mt thuc SSRI c tc ng kch thch, mt s bc s s tha nhn rng chn s dng fluoxetine s c hiu qu tt hn vi bnh nhn b mt ch, hn l dng SSRI c tc dng an thn. Tuy nhin s khc bit ny thng thay i tu theo bnh nhn.

3.2.2. T st:

Nhng nm cui thp nin 80 th k XX, mt s bo co c pht hnh rng ri ngh v mi lin h gia vic dng fluoxetine v hnh vi kch ng, k c t st, nhng nhiu xem xt sau khng xc nhn mi lin h ny. Mi y nht, cc nghin cu iu tr bng SSRI cho trm cm tr em v tr v thnh nin pht hin tnh trng tng nh tng hoc xung ng t st. Nhng trn thc t, vn khng r rng v nguyn nhn v tc ng gia vic dng SSRI v tng nguy c t st. Tuy nhin, mt s bnh nhn tr nn lo u, bi ri mt cch c bit khi bt u dng SSRI. S xut hin cc triu chng ny c hnh dung l c th gi ra hoc lm trm trng hn tng t st. Do , tt c bnh nhn trm cm nn c theo di st sut thi gian c nguy c cao c tng/hnh vi t st, nhng ngy u, tun u khi s dng SSRI. iu quan trng phi nh l cc SSRI l thuc chng trm cm c hiu qu u tin l ngn nga t st, rt ngn v phng nga giai on trm cm.

3.2.3. Trm cm trong thai k v sau sanh:

T l ti pht trm cm nng trong thai k khi bnh nhn ngng thuc hoc th ngng thuc, hoc gim liu thuc l rt cao. T l ny thay i t 68 100% bnh nhn. Do , nhiu ph n cn tip tc dng thuc trong sut thai k v sau sanh. nh hng ca tnh trng trm cm ngi m ln qu trnh pht trin ca tr vn cha r rng. Khng c tnh trng tng nguy c gy qui thai bm sinh khi phi s dng SSRI trong thai k. Do , nguy c ti pht trm cm thai ph ngng SSRI cao gp nhiu ln so vi nguy c ca thai vi tc ng ca SSRI. C mt s bng chng ngh rng c tnh trng tng nguy c phi chm sc nhi c bit sau sanh nhng thai ph dng SSRI. Tuy nhin cng tn ti bng chng tng t khi ngng iu tr paroxetine. Khng mi lin h no gia vic s dng SSRI v bin chng s sinh (neonatal) ng k. Cc nghin cu theo di tr trong nhng nm hc u tin cng khng pht hin bin chng quanh giai on chu sinh (perinatal), bt thng bo thai, gim im IQ, chm ni/ngn ng, hay nhng ri lon hnh vi chuyn bit no c th do s dng fluoxetine trong thai k.

Trm cm sau sanh (c hay khng c lon thn) nh hng mt t n cc b m. Mt s bc s lm sng bt u ch nh dng SSRI nu c tnh trng bun sau sanh (postpartum blues) ko di vi tun sau sanh, hoc nu thai ph bt u trm bun trong thai k. C th ch nh trc SSRI trong thai k nu thai ph c nguy c mc phi trng thi bun sau sanh v c th gip bo v tr s sinh, nht l nhng thai ph c th c suy ngh nguy him sau khi sinh. Cc thuc SSRI tit qua sa m nhng huyt tng ca nhng tr c nui bng sa ca b m ang s dng SSRI c nng SSRI rt thp. Tuy nhin, trong mt s trng hp, nng thuc trong mu tr ny cao hn trung bnh. Do , cn ch n vic thng tin v nguy c tim tng cho nhng bnh nhn ang c iu tr.

3.2.4. Trm cm ngi gi v ngi c bnh c th:

Cc thuc SSRI an ton v dung np tt vi ngi gi v ngi c bnh thc th. Nh cch phn loi, thuc SSRI c t hoc khng gy c cho tim, tc dng ph khng cholinergic, khng histamine hoc tc dng ph inotropic adrenergic. Ring paroxetine c hot tnh khng cholinergic, nn c th gy to bn, lm suy gim nhn thc. Cc SSRI c th gy suy gim nhn thc rt nh, ko di thi gian tun hon mu, gim natri mu v iu ny c th nh hng n sc kho nhng bnh nhn iu tr bng SSRI. Cc SSRI cn c hiu qu n trm cm sau t qu v lm gim kch tnh tnh trng hay khc lc.

3.2.5. Trm cm tr em:

Cc nghin cu v SSRI tr em v tr v thnh nin thng khng tm c hiu qu ca SSRI. Ch c fluoxetine c FDA chp nhn l thuc chng trm cm dnh cho la tui ny. Trn thc t, tr em cng b trm cm v can thip bng ho tr liu cng cn thit cho nhiu trng hp bnh, nn cc bc s lm sng cng phi ch nh thuc SSRI cho nhng trng hp ny. Cc nghin cu ngh rng thuc SSRI c th lm tng ngh hoc hnh vi t st, ngh hoc hnh vi bo lc tr em/tr v thnh nin trm cm. V vy, khi iu tr trm cm bnh nhn ny, cn thit theo di st tc dng v hnh vi khng mong mun ny.

3.2.6. Ri lon lo u:

Ri lon m nh cng ch (OCD): fluvoxamine, paroxetine, sertraline v fluoxetine nn ch nh cho nhng bnh nhn trn 18 tui. Fluvoxamine v sertraline c chp nhn l thuc iu tr OCD tr em/tr v thnh nin (6 17 tui). Khong 50% bnh nhn OCD c triu chng OCD t thi nin thiu/tui v thnh nin, hn s bnh nhn ny p ng tt vi thuc. p ng tr liu c th rt kch tnh. Nhng s liu lu nm cho thy kiu bnh l OCD l dng bnh c tnh di truyn v ko di sut i p ng tt nht vi iu tr duy tr bng thuc v tr liu nhn thc hnh vi, ngay t khi khi pht bnh t thi nin thiu cho n cui i.

Liu thuc SSRI cho bnh l OCD cn duy tr cao hn trong iu tr trm cm. Mc d p ng vi thuc c th xut hin trong vi tun u tin iu tr nhng cng cn nhiu thng iu tr mi t hiu qu tr liu ti a. Nhng bnh nhn khng p ng vi thuc SSRI c th s p ng tt hn vi phi hp bng risperidone. Bn cnh vic phi theo di tc dng ph ngoi thp do risperidone, cn theo di tc dng ph do tng prolactine trong nhng trng hp phi hp tr liu. Trn lm sng, tnh trng tng nng prolactine c th biu hin bng tnh trng v to, hoc chng tit sa (c nam v n) v chng mt kinh.

Hin nay, mt s ri lon khc cng c xem l bin th ca OCD. l cc bnh l vi cc triu chng c trng l hnh vi t ct c th nhng khng c t st, v d: chng nh (lng) tc, xm lng my, xung ng xm vng da d bn, xung ng ct (c th). Cc bnh nhn c hnh vi ny c th p ng vi thuc SSRI. Nhng bnh l bin th khc gm c: xung ng nh bc, xung ng mua sm, chng nghi bnh, ri lon s bin dng c th.

Ri lon hong lon: Paroxetine v sertraline c ch nh s dng iu tr ri lon hong lon, c hay khng km theo chng m s khong rng. Nhng thuc ny c hiu qu chm hn so vi alprazolam (Xanax) hay clonazepam (Rivotril), nhng c hiu qu lu di tt hn so vi benzodiazepine trong iu tr ri lon hong lon c km trm cm. Citalopram, fluvoxamine, fluoxetine cng c th lm gim triu chng cn trm cm nguyn pht hoc th pht. Do fluoxetine c kh nng gy ra cc triu chng lo u, bnh nhn b cn hong lon phi c ch nh bt u s dng liu thp (5mg/ngy) v tng dn liu chm chp. Dng benzodiazepine liu thp c th c s dng nhm kim sot tc dng ph lo u ca fluoxetine.

Ri lon lo u x hi: thuc SSRI c hiu qu iu tr m s x hi. Thuc lm gim c triu chng bnh v tnh trng mt nng lc (do bnh gy ra). T l p ng vi thuc SSRI tng ng vi MAOI phenelzine (Nardil), trc y l mt thuc iu tr tiu chun. Thuc SSRI an ton hn so vi MAOI hoc benzodiazepine.

Ri lon stress sau sang chn (PTSD): ho dc tr liu vi PTSD nhm vo cc triu chng c bit ca 3 nhm: ti tri nghim, n trnh v tng gi nh. Trong iu tr lu di, thuc SSRI c ph tr liu cc triu chng c trng ca PTSD rng hn so vi TCA v MAOI. Tng liu benzodiazepine c ch i vi cn cp tnh. Thuc SSRI gy ci thin r rt c triu chng xm ln v triu chng n trnh.

Ri lon lo u lan to: Thuc SSRI c ch iu tr cc m s chuyn bit, ri lon lo u lan to v ri lon lo u chia ly. Vic nh gi mang tnh c nhn v k lng l cc tip cn u tin, ch c bit v vic pht hin loi bnh l p ng tt vi tr liu bng thuc. Km theo , tr liu nhn thc hnh vi hay tr liu tm l khc cng nn kt hp t hiu qu cao hn.

Chng n ung v tm l v cc ri lon n ung khc: fluoxetine c ch nh iu tr cho chng n ung v , nhng php tr liu tt nht cho bnh l ny vn l tm l tr liu. Liu fluoxetine nn l 60mg/ngy th tt hn liu 20mg/ngy. Trong mt s nghin cu kim sot tt, fluoxetine vi liu 60mg/ngy tt hn nhiu so vi gi dc nhm lm gim tnh trng n ung khng ngng v gim nn. Mt s chuyn gia ngh rng ch nn tr liu nhn thc hnh vi n thun (m khng km iu tr ho dc); v nu khng c p ng sau 3 6 tun th mi kt hp vi fluoxetine. Thi gian thch hp iu tr bng fluoxetine v tm l tr liu khng c gii hn.

Fluvoxamine khng hiu qu ng k iu tr chng n ung v trong nghin cu m i, c so snh vi gi dc.

Chng chn n tm thn: fluoxetine c dng iu tr bnh nhn chn n tm thn ni tr nhm kim sot ri lon kh sc kt hp v triu chng m nh cng ch. C t nht 2 nghin cu cn thn, mt nghin cu trong 7 thng, 1 nghin cu trong 24 thng nhng u khng pht hin fluoxetine c hiu qu ln kt qu ton b v ln vic duy tr cn trng. Vic iu tr c hiu qu chng chn n tm thn l php tr liu nhn thc hnh vi, tr liu ni tm, tr liu ng nng tm thn, tr liu gia nh kt hp vi thuc SSRI.

Chng bo ph: fluoxetine kt hp vi chin lc v hnh vi cho thy c hiu qu gim cn tt nht. C t l ng k bnh nhn dng SSRI, k c fluoxetine, gim cn trong giai on u, nhng sau c th tng cn tr li. Tuy vy, cng cn bit rng, tt c cc thuc SSRI u c th gy tng cn.

Ri lon lon cm trc k kinh nguyt: ri lon lon cm trc k kinh nguyt c trng bi kh sc suy sp v thay i hnh vi vo tun trc khi c kinh, thay i r rt so vi lc bnh thng. Sertraline, paroxetine, fluoxetine, v fluvoxamine c tc dng lm gim triu chng ri lon cm trc k kinh. Nghin cu th nghim c so snh s dng fluoxetine, sertraline trong c chu k, hoc ch trong giai on hong th (2 tun gia lc rng trng v khi c kinh nguyt) cho thy u c hiu qu nh nhau.

Mt nghin cu quan st khng r rng cho thy fluoxetine lm thay i thi gian chu k kinh nguyt, nhiu hn 4 ngy, ko di hn hoc thu ngn li. Tc ng ca SSRI ln thi gian chu k kinh hu nh cha c bit r, v i hi phi theo di cn thn khi dng SSRI ph n trong tui sinh .

3.2.7. Nhng ch nh khng chnh thng:

Xut tinh sm: hiu qu chng co tht ca SSRI c li dng iu tr cho nam gii b chng xut tinh sm. Thuc SSRI cho php ko di thi gian giao hp v ci thin s tho mn tnh dc cho nhng cp v chng m ngi chng b xut tinh sm. Fluoxetine v sertraline c ch cho vic s dng nhm mc ch ny.

Paraphilias (tnh dc i try): thuc SSRI gim hnh vi m nh cng ch nhng bnh nhn b paraphilias. SSRI lm gim thi gian trung bnh trong ngy cho hnh vi tho mn, thi thc tnh dc khng thch hp. Nhng bng chng cho thy, thuc c tc ng tt ln m nh tnh dc hn l hnh vi ph by.

Chng t k: hnh vi m nh cng ch, tnh trng km giao tip x hi, tnh trng hung hng c trng cho chng t k p ng vi nhng thuc tc ng ln h serotonine nh SSRI v clomipramine. Sertraline, fluovoxamine cho thy gip ci thin tnh hung hng, hnh vi t gy thng tch, hnh vi lp li, mt s mc v tnh trng tr hon v ngn ng, v him hn l tc ng n tnh thiu lin h x hi ngi trng thnh c ri lon kiu t k. Fluoxetine cng c hiu qu n chng t k tr em, tr v thnh nin, v ngi trng thnh.

3.3. Thn trng v tc dng ph:

Tc dng ph ca SSRI thng c xem xt tu theo cch khi pht, thi gian ko di v mc nng. V d: bun nn v tnh trng bn chn lo u thng l tc dng ph xut hin sm, nh, v t gii hn theo thi gian.

3.3.1. Ri lon chc nng tnh dc: tt c cc thuc SSRI u gy ri lon chc nng tnh dc v l tc dng ph thng gp nht ca SSRI khi s dng lu di. Tn sut mi mc ca tc dng ph ny khong 50 80%. Than phin thng nht l gim cc khoi, c ch tnh trng cc khoi, gim ham mun tnh dc. Mt s nghin cu ngh rng ri lon chc nng tnh dc c lin quan n liu s dng, nhng mi lin quan ny cng khng r rng lm. Khng ging nh hu ht cc tc dng ph khc do SSRI, c ch tnh dc him khi hi phc sau vi tun u iu tr, nhng thng ko di cng vi thi gian s dng thuc. mt s trng hp, tnh trng ny c th ci thin theo thi gian.

Chin lc chng li ri lon tnh dc do SSRI c cp n rt nhiu nhng khng chin lc no chng mnh c hiu qu. Mt s nghin cu ngh gim liu SSRI v thm bupropion vo. Cc nghin cu cng m t nhng thnh cng trong iu tr ri lon tnh dc do SSRI bng sildenafil (Viagra), c hiu qu iu tr ri lon chc nng cng. Cui cng th bnh nhn cng phi i sang thuc chng trm cm khc khng nh hng n chc nng tnh dc, nh: mirtazapine, bupropion.3.3.2. Tc dng ph v d dy rut: tc dng ph ny rt thng gp, c lin quan n tc dng ln th th serotonin 5HT3. Than phin thng nht l: bun nn, tiu chy, chn n, nn, y hi, kh tiu. Sertraline v fluvoxamine thng gy ra tc dng ph ny nht. Paroxetine phng thch chm so vi paroxetine phng thch ngay lp tc, cng t gy tc dng ph d dy rut hn. Tuy nhin, vi paroxetine, do tc ng khng cholinergic, nn thng gy to bn. Bun nn v tiu lng thng lin quan vi liu s dng v thng ch thong qua, hi phc trong vi tun. Tuy nhin, tnh trng y hi v tiu chy vn tn ti, c bit l khi s dng sertraline. Chn n lc khi u iu tr cng thng xut hin v thng gp khi s dng fluoxetine. Chn n v gim cn do SSRI thng bt u khi dng thuc v gp nhiu nht khong 20 tun; sau , cn trng thng tr v mc bnh thng. C n khong 1/3 bnh nhn b tng cn, thnh thong tng n 9kg. Tc dng ph ny do tc ng n qu trnh chuyn ho, hoc lm tng ngon ming, hoc do c 2. Tnh trng ny thng din ra t t v thng khng p ng vi ch n king hoc luyn tp th dc. Paroxetine thng gy tng cn hn so vi cc SSRI khc, nht l ph n tr.

3.3.3. au u: tn sut mi mc ca tnh trng au u khi s dng SSRI khong 18 20%, ch cao hn 1% so vi gi dc. Fluoxetine l thuc d gy au u nht so vi cc SSRI khc. Tuy nhin, tt c cc thuc SSRI u c hiu qu iu tr phng nga cn au u migrain v au u cng c nhiu BN.

3.3.4. Tc dng ph ln h TKTW:

Lo u: Fluoxetine c th gy ra lo u, nht l nhng tun u iu tr. Tuy nhin, tc dng u tin ny s gim hon ton sau vi tun. Tnh trng lo u c th c gim hn nu iu tr bng paroxetine, escitalopram, nht l nu mong mun c tc dng an thn, bun ng.

Mt ng v an thn: tc ng chnh ca SSRI ln gic ng l gip ci thin gic ng nn SSRI iu tr c trm cm v lo u. Tuy nhin, c n bnh nhn dng SSRI gp vn v gic ng hoc ng qu mc, hoc cm thy mt mi. Fluoxetine l thuc thng gy mt ng nht trong s cc SSRI, nn n thng ch dng vo bui sng. Sertraline, fluvoxamine cng gy mt ng tng ng vi gy tnh trng ng nhiu; citalopram, v nht l paroxetine cng thng gy ng nhiu. Escitalopram gy cn tr gic ng nhiu hn so vi citalopram (t ng hn). Mt s bnh nhn li dng tc dng ph ca SSRI ng nn dng bui ti trc khi ng, trong khi s khc li dng thuc vo ban ngy gip gim ng. Mt ng do SSRI c th iu tr bng benzodiazepine, trazodone (nhng phi gii thch tc dng ph gy cng cng dng vt ca trazodone), hoc nhng thuc gy ng khc. Ring tnh trng ng nhiu do SSRI th cn phi i sang thuc SSRI khc, hoc i bupropion.

Tc ng khc ln gic ng: c nhiu BN dng SSRI than phin cm gic ng nh ang thc, hoc thy c mng. Mt s khc li m t tnh trng nghin rng khi ng, tnh trng chn khng yn, git c lc ng, tot m hi lc ng.

Tnh trng cn mn cm xc: cn mn cm xc l tnh trng thng thy khi s dng SSRI ko di. Cc BN m t tnh trng khng c kh nng khc, hay phn ng vi mt tnh hung cm xc no , cm thy v cm, th , khng vi thay i cm xc. Tc dng ph ny thng lm cho BN ngng iu tr ngay c khi thuc gip thot khi trng thi trm cm, lo u.

Gy ngp: cc quan st lm sng tch cc nhn thy BN dng SSRI c biu hin tng ngp. Tc dng ph ny khng phi do thuc gy mt mi, hay do gic ng m km, m l do SSRI tc ng ln vng h i.

Co git: co git chim khong 0.1 0.2% BN iu tr bng SSRI. T l ny tng t nh cc thuc chng trm cm khc v khng khc bit so vi gi dc. Co git thng xut hin khi dng liu cao (VD: fluoxetine liu 100mg/ngy hoc cao hn).

Triu chng ngoi thp: SSRI him khi gy tnh trng bn chn khng yn, run, tng trng lc c kiu bnh xe rng ca, lon trng lc c cp (vo c, trn