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CHNG 1: MT S KIN THC CHUNG V HA DC

1.1. Ha dc qu kh, hin ti v tng lai:
1.1.1. M u:
- Hi ngh IUPAC 1970 nh ngha v ho dc: HO DC L NGNH
KHOA HC CHUYN V PHT HIN, SO SNH, PHT TRIN V LM
SNG T C CH TC DNG CA CC HP CHT C HOT TNH
SINH HC S DNG TRONG PHNG NGA, IU TR BNH
- HO DC l mn khoa hc nghin cu v tt c cc mt ca cc hp cht ho
hc, cc vt liu s dng trong phng nga v iu tr bnh.
- Cc mt: Ho hc (iu ch cht), sinh hc (pht hin tc dng), dc hc (dc
l, dc liu, c tnh, liu dng, tc dng ph,), y hc (tc dng tr bnh, so
snh tc dng, nghin cu c ch tc dng, nghin cu s dng trong iu tr
bnh).
- HO DC bao trm cc ngnh c lin quan: Ho hc, vt l, sinh ho, ho l,
dc lc, y hc, vi sinh vt. Cc ngnh ny c s kt hp cht ch.
- Yu cu i vi mt nh ho dc: am hiu cc ngnh khoa hc c lin quan n
thuc.


- i tng hc mn ho dc:
+ Y, bc s (dc l: au ci g?, dc lc: mnh hay yu?)
+ Dc s (ho dc)
+ K s, c nhn (ho dc v k thut tng hp)
- Ngi hc ho dc phi hc:
+ Hc nhm thuc tc dng ln cc bnh
+ Hc v bnh (Khi nim, nhm thuc tr bnh )
+ Phi bit phng php iu ch n (SX nguyn liu)
CNG NGHIP DC
CNG NGHIP HO
DC
CNG NGHIP BO CH
CN SN XUT NGUYN
LIU
CN SN XUT THUC THNH
PHM
K S CN HO DC
o to cc trng HKT,
H TNG HP (SP)
DC S
o to ti cc trng H
Dc
i hc Y Dc
-2-
+ Phi bit liu tc dng ca thuc khong no
+ i vi k s: phi bit cng ngh, thit b SX thuc cn i vi c nhn th
khng i hi su
- Tn thuc gm tn khoa hc (IUPAC), tn ring v tn bit dc (do 1 cng ty
hoc 1 nc no sn xut ra 1 ch phm s dng).
- Cc mn cn hc trc:
+ Ho v c, hu c (95% hp cht hu c c trong thuc)
+ Cc qu trnh c bn tng hp hu c v tng hp ho dc
- Cc mn cn hc cho ho dc:
+ QTCB TH hu c v TH ho dc (1,2,3)
+ Cc hp cht c hot tnh sinh hc.
+ Ho dc v k thut bo ch.
+ C ch. + X cu trc. + PT ho l. + Ho hc bi thuc.
- Mc tiu hc tp cc hc phn Ho dc v KTTH 1, 2, 3
+ Hiu bit c bn trong nghin cu, sn xut 1 hp cht lm thuc, hiu bit c
bn v thuc.
+ Cc yu t nh hng n tc dng sinh hc ca 1 hp cht trong vic nghin
cu, tm kim thuc mi.
+ S phn ca thuc trong c th.
+ V 1 s loi bnh ch yu hin hu vi loi ngi v thuc tr bnh, phng
php tng hp, iu ch mt s nhm thuc ch yu, thuc thit yu s dng trong
phng nga v iu tr bnh.
1.1.2. i nt v lch s pht trin ca ha dc:
- T 4000-5000 nm trc s dng thc vt tr bnh theo kinh nghim.
- Th k th 4 trc CN: Hippokrates (Hy Lp) a mui vo s dng tr bnh.
- Th k th X v XI ngi Ba T a opi vo cha ho, a Canhkina vo tr
st rt.
- Th k XVII, Canhkina vo Chu u, 1805: Serturner phn lp ra morphin, 1820
phn lp c quinin.
- Th k XVIII dng cy a hong (foxglobe) iu tr bnh tim.
- Wohler 1828 tng hp ra cacbamit m u tng hp hu c.
- Mt lot cc thuc ra i:
1.1.3. Tm tt v tnh hnh pht trin v hin trng ca ngnh dc v ha dc
Vit Nam
1. T thi hng c n th k th XVIII (kinh nghim, truyn ming)
- T ngn xa
- i Hng Vng (200 nm trc cng nguyn)
- Hn 1000 nm phong kin Trung Quc
2. Th k th XIII v XIX (c sch v ghi li)
- Chu Vn An (1292-1370): vit nhiu thuc t cy c
- Tu Tnh (Nguyn B Tnh): Nam Dc thn diu: 580 v thuc
- L Hu Trc (Hi Thng Ln ng): 1720-1791: pht hin thm 300 v
thuc nam, tng hp thm 2854 phng thuc dn tc.
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3. Thi Php thuc
- Thuc Ty xm nhp
- o to dc s i hc Vit Nam c t nm 1930.
4. Sau cch mng thng tm
- T lc cnh sinh l chnh, khng c thuc ngoi
- Tm kim c nhiu bi thuc, nhiu xng sn xut th s ra i, cc
xng qun dc: CaCl2, cafein, morphine, du long no, NaCl tim, bt
b,
5. Ho bnh lp li
- H Ni, Hi Phng c 40 hiu thuc t, ton min Bc c khong 1000 i
l thuc Ty.
- 1958: hnh thnh nn cng nghip sn xut dc phm.
- 1961: thnh lp 1 s nh my, x nghip: XN Ho dc-Thu tinh, cc XN
dc TW-1,2,3.
- 1964: i hc Dc tch khi i hc Y-Dc H Ni, Vin kim nghim,
Vin Dc liu c thnh lp
6. Thi k chin tranh ph hoi min Bc
- Cc XN dc phm phn tn, hnh thnh cc XN a phng, mi tnh c 1
XN
- Nhim v ngnh dc lc : phc v chin tranh
- c th ca ngnh: phn phi thuc vin tr.
7. Thi k sau chin tranh chng M n nm 1990 (1975-1990)
- Khi phc cc XN TW v pht trin cc XN a phng: XN-1, XN-2,
XN-3,XN-5, XN-21, XN-22, XN-23,
- 61 tnh thnh u c XN. Bo ch cc loi thuc n gin t nguyn liu
nhp ngoi.
- Cc nguyn liu c th sn xut: + Cc thuc v c: Al(OH)3, BaSO4,
MgSO4, NaCl,
+ Cc tinh du (chm, khuynh dip, du bc h, qu, du s,)
+ Chit xut mt s hot cht t dc liu (morphine, tetrahidropalmatine,
palmatine, berberine, phytine, rutine, Camphor,)
+ Mt s thuc hu c n gin: etanol, ete m, cloroform, paracetamol,)
8. Trong thi k m ca 1990 n nm 2003
- Kinh t th trng nh hng x hi ch ngha
- n nm 2002 ton quc c hn 35.000 quy bn l trong c khong
4.400 quy thuc doanh nghip nh nc, 120 doanh nghip nh nc, 400
cng ty t nhn, 28 c s u t nc ngoi.
- S n v tham gia SX nguyn liu: XN Ho dc, vin dc liu, cng ty
dc liu TWI,
- S hot cht nhp khu 384, SX nguyn liu trong nc cha chim n
5% trong c berberin, tetrahidropalmatine, mt s ng dc,
- Nm 2002 SX 6184 bit dc (t 384 hot cht), nhp thnh phm 4743
mt hng (t 864 hot cht).
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9. Thi k 2004 n 2010, d nh
- C quan qun l ngnh CN Ho dc thay i B Y t B Cng Nghip.
- 2004 n nay: SX ho dc chuyn cho B Cng thng.
- 2005: thnh lp chng trnh trng im quc gia v pht trin Ho dc.
- Mc tiu u t ca B Cng Nghip:
+ Xy dng nh my SX khng sinh -lactam (pha Bc, 80 triu USD).
+ Xy dng nh my ho dc v c v t dc thng thng ti Vit Tr (5
triu USD).
+ Xy dng nh my lin doanh SX ho dc ti H Ni (20 triu USD).
+ Xy dng nh my lin doanh SX t dc (min Trung, 10 triu USD).
+ Xy dng nh my chit xut dc liu min Bc (10 triu USD).
1.1.4. Cc vn v tnh hnh nghin cu ha dc trn th gii hin nay:
- Cch y khong 60-70 nm, bnh vim no, bnh tim, bnh phi, cc bnh
nhim khun v phng cu cha nhng sau khi tm ra cc sunfamit, sau
l cc khng sinh nm th t l ngi cht c khng ch.
- Hin c khong 3000 hot cht 10.000 bit dc nhng thc t vn
cha p ng c cho cha bnh. V hin tn ti 30.000 loi bnh nhng
thuc ch tr c khong 1/3 trong cc loi bnh .
- Cc thuc khng virus, thuc tr AIDS, thuc ung th, thuc thn kinh TW,
huyt p (c bit l huyt p thp), cc thuc v min dch, v da l mt p
lc cho vic iu tr bnh, gn y l bnh SARS.
1.1.5. iu ch thuc:
Hng sn xut thuc:
- Hin ti 75-80% thuc cha bnh sn xut theo phng php ho hc c in.
- Cu hi t ra l trong tng lai s iu ch ra thuc cha bnh bng
phng php no? Cng ngh sinh hc hay vn dng phng php ho
hc?
i a s cc nh khoa hc ln nh sn xut vn cho rng trong tng lai,
phng php ho hc chim u th.
1.1.6. Nhng thch thc trong iu tr bnh , ch ph ngy mt tng:
- Nhng thnh tu trong sn xut thuc cha bnh l iu khng th chi ci.
- Cc tranh ci ch yu v tc dng ph ca thuc c bit l sau s kin xy
ra cch y hn 40 nm v bit dc Contergan: thuc an thn gy ng
(gy khuyt tt ung khi c thai) trc lc a thuc vo s dng cn
phi kim tra, th nghim cht ch, nghim ngt kinh ph cho nghin
cu v pht trin tng d rng t l cht do thuc thp so vi cc tai nn
khc.
- Chi ph NC v PT thuc mi 150-200 triu USD. Thi gian 4-11 nm
chi ph NC v PT tng.
- Mu thun thi gian ko di, chi ph tng nhng thi gian lu hnh thuc
th ngn li so vi nhu cu thuc mi, tt hn ngy cng tng.
- Mi thi k khc nhau, nhu cu tiu th loi thuc mt khc nhau.

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1.2. Cc yu t ha l v cu trc ha hc nh hng n tc dng sinh hc
1.2.1. Lin quan cu trc ha hc v tc dng sinh hc:
Trc ht t cy c lm thuc phn lp ra cc hp cht c hot tnh tc dng
tm mi lin h gia cu trc ho hc v tc dng sinh hc b khung c tc
dng hoc nhm chc c tc dng tm kim thuc mi c tc dng hon thin
hn da trn vic thay i b khung hoc thay i nhm chc (thay i ho tan,
mi v, gim c tnh).
Mi quan h cu trc tc dng ch mang tnh tng i nn cho n nay vn
cha th p dng c mt cch chc chn. Hin nay c a my tnh vo vic
tnh ton, thit k thuc mi nhng vn ang trong thi k m mm, th nghim.
1.2.2. Lin quan tnh cht vt l v hot tnh sinh hc:
- u th k XX ngi ta nhn thy c lin quan gia tnh cht vt l ca cc
hp cht vi tc dng sinh hc ca chng.
- Tnh cht vt l ng vai tr ht sc quan trng trong vic hp thu, gn kt, phn
b, thi tr thuc.
- Theo Ehrlich: thuc tc dng ti cc t bo bng cc phn ng ho hc, bng cc
lin kt ho hc (VanderWalls, lin kt lng cc - lng cc, lng cc ion,
lin kt hidro, lin kt ion, lin kt ng ho tr). Lin kt c th thun nghch, cn
bng. Cc thuc khc nhau gn kt vo 1 loi th th cng khc nhau.
V d: nalorphine gn kt vo th th gim au mnh hn morphine rt nhiu nn
cho nng hp thu c ging nhau trn th th gim au th cn mt lng
morphine gp 40 ln so vi nalorphine.
1.2.3. Vai tr ca ng cu in t v ng cu in t sinh hc trong nghin cu
thuc:
- Li ch: ng cu in t (isosteric), ng cu in t sinh hc (bio-isosteric)
gip ch cho vic nghin cu tm ra nhng thuc mi c tc dng nh cht ch vn
(cht c tc dng chnh) hoc tc dng i khng.
- ng cu in t, ng cu in t sinh hc l g? L vic thay th mt nguyn
t hoc mt nhm nguyn t ca mt cht ban u no bng mt nguyn t
hoc mt nhm nguyn t c cu hnh khng gian v cu trc in t tng t nh
th to ra hp cht c tc dng vt l, ho hc, sinh hc tng t hoc c tc dng
i khng vi cht u.
- Khi nim ng cu in t c Lang muir a ra nm 1919. Thuyt cu to
phn t l hnh thc mi tip cn vi ng cu in t. Vi cc nh Ho dc,
ng cu in t l phng tin quan trng nghin cu tm cc thuc mi.
- Phng php mi iu ch mt cht c ng cu in t sinh hc sinh hc l
to ra cc hp cht c cc nhm th tng ng nhau, c cu trc ging nhau, c
tnh cht vt l, ho hc ging nh nhau tc dng sinh hc tng ng.
1.3. Khi nim v dc l hc:
1.3.1. i nt v dc l hc
- Dc l hc: l mn khoa hc nghin cu v thuc v tc dng n cc h sinh
hc.
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- Thuc: l cht c tc dng iu tr, d phng, chn on bnh dng cho ngi
hoc ng vt
- Dc l hc thc nghim: trn ng vt
- Dc l hc lm sng: trn ngi
* Dc l hc:
- Dc lc hc: nghin cu tc ng ca thuc trn c th sng. Tc dng chnh,
tc dng ph.
- Dc ng hc: nghin cu tc ng ca c th n thuc. S phn ca thuc
trong c th.
- Dc l thi khc: nh hng ca nhp sinh hc trong ngy, trong nm.
- Dc l di truyn: tnh cm th ca tng c th, gia nh chng tc do tnh di
truyn.
- Dc l cnh gic: nghin cu, nh gi 1 cch c h thng cc c hi lin
quan n vic dng thuc ca cng ng.
Trong phm vi chng trnh chng ta ch nghin cu v Dc lc hc v
Dc ng hc c khi nim c bn v s phn ca thuc trong c th.
- Vn chuyn thuc vo c th
- Hp thu
- Phn b
- Chuyn ho, tc dng
- Thi tr
Nhm nh hng kt hp cng tc nghin cu tm kim thuc mi cng nh iu
ch cc hp cht lm thuc, nhng hp cht c hot tnh sinh hc.
1.3.2. S phn ca thuc trong c th

1.3.2.1. Hp thu ca thuc







3 yu t nh hng n hp thu
1.3.2.1.1. Cu to v c trng ca mng sinh hc
- Cu to: Mng sinh hc c cu to bng lp lipit vi hai hng phn t, c cu
trc mm, th lng c qunh, c cc anbumin vn chuyn c qua mng.
- c trng ca mng: C kh nng nhanh chng thay i cu trc, cc phn t
anbumin nh ang bi c trong mng, cu trc khng gian bin i ti mc l
trong mng to thnh nhng rnh cc phn t c kch thc nh, cc cht ho
tan, cc ion c th i qua c. Th th hoc enzym c th bm c vo.
1.3.2.1.2. Tnh cht ho l ca phn t thuc v tc dng pH ti s hp thu
- S vn chuyn ca thuc qua mng ph thuc vo:
Thuc Mu
T bo
Ni tc dng
Hp thu
Phn phi
Mng sinh hc
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+ Cu to lipit ca mng.
+ H s phn b lipit-nc.
- Mc ion ho nh hng n h s phn b lipit-nc. Mc ion ho c
biu th bng hng s phn ly Kd. Mi lin h gia Kd v pH c Henderson
Hasselbach tnh nh sau:
+ Vi trng hp axit:

+ Vi trng hp baz:




Trong pKd = -log Kd; Kd l hng s phn ly.
1.3.2.1.3. C ch vn chuyn ca thuc qua mng sinh hc
a. Khuych tn th ng: Thuc khuych tn qua mng nh chnh lch nng ,
thuc chuyn t nng cao n nng thp qua mng lipit, t bn ngoi vo
bn trong.
b. Lc
- chnh lch p sut gia hai pha ca mng sinh hc to ra qu trnh lc. p
lc lc l do huyt p.
- ng knh l xp khong 7A
0
, vi ng knh ny cc phn t c trng lng
<100 n v mi i qua c, cc phn t c phn t lng > 100 n v th i
qua cc khe h m khng qua c mng t bo.
- Kt qu lc ph thuc vo ng knh ng dn, vo bc thang thu tnh, vo s
in ho hoc s thm thu qua mng.
c. Vn chuyn tch cc
- Vn chuyn xy ra khng da vo chnh lch nng m cn ti nng lng.
Hnh thc vn chuyn ny c hnh thnh trong vic vn chuyn cc cht ni
sinh (cc phn t ng, cc axit amin, cc nucleic tin cht) v ch c hiu cho
loi vn chuyn cc loi cht ny.
- Ch cc cht thuc c cu trc ging nh cc hp cht ni sinh mi tham gia
c vo qu trnh vn chuyn tch cc.
- Thnh phn trong vn chuyn loi ny l cht mang c i lc cao vi thuc, to
phc vi thuc, dn dt thuc t bn ny mng sang bn kia mng, sau li nh
thuc ra v quay tr li lm tip tc nhim v.
- c trng ca vn chuyn tch cc l gn kt chn lc thng qua cht mang, vn
chuyn mt chiu, c tnh bo ho, c tnh cnh tranh v c ch (c cu trc gn
ging nhau c th tranh chp vi nhau).
- Nng lng cho qu trnh vn chuyn ny do ATP cung cp.
d. Khuych tn thun li
- c tnh c trng ca khuych tn thun li gn ging nh qu trnh vn
chuyn tch cc (thng qua cht mang, gn kt chn lc c hiu, c tnh bo ho),
pKd = pH + log
axit ko phan ly
axit ion hoa
pKd = pH + log
bazo ion hoa
bazo ko phan ly
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duy ch khc l vn chuyn theo hng gradient nng v khng c nhu cu
nng lng.
- Cht mang l cc anbumin. Hiu sut vn chuyn ny ln hn khuych tn th
ng.
e. Vn chuyn cp ion: Cc phn t c ion ho cao (cc amoni bc 4) c h s
phn b lipit-nc thp, c mc hp thu qua d dy nh, khng vn chuyn
theo c ch a,b,c,d k trn. Cc phn t th ny to ra phc-cp ion vi cht nhy
ca knh dinh dng. Nh vy m vn chuyn c qua mng bng khuych tn
th ng.
1.3.2.2. Cc v tr hp thu ca thuc
Thuc c a vo c th qua nhiu v tr hp thu khc nhau. Sau y l
cc v tr ch yu:
1.3.2.2.1. Hp thu qua khoang ming:
khoang ming PH~6. Cc hp cht baz yu cha kp phn ly.
- Ung
- Nim mc li ( t di li, dung dch) nitroglyxerin, polinitrat iu tr gin
mch vnh).
1.3.2.2.2. Hp thu thuc t d dy:
Mng li cung cp mu di do ca b mt d dy l iu kin thun li
cho s hp thu thuc. Dch v d dy c pH t 1-2.
- cc thuc c tnh baz cao ( pKa 4-11) kh hp th qua d dy do h s phn b
lipoit- nc gim.
- co bp ca d dy nh hng n tc thi tr ca thuc ( lc i co bp
ln nht).
- Cc thuc c tnh axit s hp th tt qua d dydo thuc t b ion ha, h s phn
b lipoit- nc cao.
1.3.2.2.3. Hp thu thuc qua rut:
- Thuc hp thu c qua c rut non ln rut gi. Nim mc rut non c b mt
ln, trn nim mc tua ta nhung mao. Tng din tch nhung mao kh ln ( 40m
2
)
- H thng rut c pH =5-6, l mi trng thch hp cho cc thuc c tnh kim.
Rut non hp thu tt hn nhiu so vi ru gi.
- Trc trng l ni hp thu thuc tt nht ca rut gi v l ni c s dng
t thuc n, nhng thuc c mi v kh ung hoc nhng trng hp khng
ung c ( hn m, tc rut, co tht thc qun) th t trc trng l tt nht, nht
l t em v ngi gi.
- t trc trng, thuc vn qua gan, thuc di chuyn nhanh t hu mn vo tc
trng, tan ri thm vo mu qua tnh mch trc trng.
1.3.2.2.4. Hp thu thuc qua phi:
- Phi c b mt ln (50-100m
2
) c mng mng, lu lng cung cp mu ln, l
ni thun li cho hp thu thuc.
- Cc thuc dng kh, dng xt c th p dng hp thu qua phi.
- H s phn b gia mu- khng kh chi phi ti hp thu ca thuc qua phi.
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- Vic vn chuyn thuc qua phi theo nguyn tc khuych tn th ng v
khuych tn thun li, cc tiu phn th rn vn chuyn theo nguyn l thc bo.
1.3.2.2.5. Hp thu thuc qua da:
- B mt ca da thch hp cho vic hp thu thuc d rng trong lp sng ca da c
mt hng ro c nhim v ngn chn s xm nhp cc cht l vo c th.
- Cc t bo biu b ca da cha nc v lipoit thp hn ca nim mc dn n
xm nhp qua da b gim.
- Cc thuc c h s phn b lipoit nc ln th hp thu qua da tt, c bit khi
trn lp da c ph mt lp chng hay bay hi dn n lng nc cha lp
sng tng 40-50%, dn n da b trng ln, dn n nng thuc c tnh thn
du tng ln hng trm ln so vi bnh thng.
- Thi gian li gn y cc ch phm thuc hp thu qua da tng ( thuc dnh tn
bng, bng dn). u im m bo nng n nh, ko di thi gian, an ton.
1.3.2.2.6. Hp thu thuc ngoi ng tiu ha:
- Hnh thc ph bin nht l tim bp, tim di da. m bo cho vic hp thu
thuc nhanh nhng hnh thc tim vo c nhanh hn.
Nhc im: gy au lc tim, c th b nhim trng, gy p x, co ko c, thuc
c tnh kim cao gy hoi m.
- Tim ven: thuc i thng trc tip vo mu, thuc c tc dng ngay lp tc.
Nhc im: gy nhim trng, qu liu.
Cc hnh thc a thuc vo c th ( bng 1.7)
Bng 1.7. cc kh nng a thuc vo c th
V tr a thuc vo Phng thc a thuc
vo
Cc dng thuc thch hp
1. Nim mc ca h thng
tiu ha
Ung

Ngm
t di li
t trc trng
Dung dch, hn hp, vin
nhng
Vin
Vin
Vin t
2. Cc loi nim mc
khc
Mi
Cung phi, nim mc
kh qun
Mng mt

m o

ng tiu tin
Xt, thuc git, bt ht
Xt, thuc git, bt ht

Dung dch, nh git,
thuc m
Thuc au, bi trn, dung
dch
Dung dch

3. Da Mt da Thuc m bi, bng dn,
hn hp lc
4. Ngoi h thng tiu
ha
( thuc tim)
Qua da
Di da
Vo bp c



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Tnh mch
Tim vo ven
( intrathecal)
Trong mng bng
Vo mng phi
Vo mng khp
Vo ty xng
Vo mng tim

Dung dch tit trng l
ph hp
5. Cy ghp di da Di da Vin cy ghp, cc vi tinh
th.

1.3.2.3. Cc quy lut phn phi thuc:
Nhiu yu t nh hng n phn phi thuc trong c th:
- V pha c th: tnh cht mng t bo, ni tip nhn, pH.
- V pha thuc: phn t lng, tan trong nc- du, tnh axit hay baz,
ion ha, i lc thuc- receptor.
1.3.2.3.1. Kt hp thuc vi protein huyt tng:
Thuc vo mu thnh hai dng l kt hp v t do.
- Kt hp vi huyt tng ( gn vi anbumin, globulin), c loi gn mnh
( sunfamit chm), gn yu ( bacbital), khng gn c ( cc phn t nh, rt
tan trong nc, glucoz)
- ngha ca gn thuc vo protein huyt tng
+ dng kt hp cha c tc dng.
+ Tng kho d tr thuc, sau nh dn.
+ Hai thuc c i lc gn kt cng mt ni dn n cnh tranh, dn n tng
tc dng, ch lc kt hp thuc.
+ Liu u tin ca thuc gn mnh vo protein, phi dng liu tn cng ( cao),
sau l liu duy tr.
1.3.2.3.2. Th th ( receptor):
- Thuc ch gn c hiu vo mt ch ( receptor) v pht huy hot tnh ca n
(cht ch vn) hoc km hm hot tnh nhng thuc khc (cht i khng).
- Phn bit khi nim receptor th th v acceptor (cht chp nhn)
- C nhiu cch gn thuc vo receptor: lin kt hidro, lin kt ion, lin kt
lng cc- lng cc, lin kt cng ha tr.
- Mt cht thuc gn vo receptor theo nhiu kiu lin kt, mt cht cng gn
c vo nhiu receptor nh adrenalin c c tc dng v u nhau,
histamin ln c receptor H
1
, H
2
.
- C hai loi to phc vi receptor
+ Cht ch vn (agonist) dn n hot tnh (hiu lc).
+ Cht i khng (antagonist)
1.3.2.3.3. Hng ro thn kinh trung ng:
- No v dch no ty (DNT) c bo v bi mt h hng ro. Nhng hng
ro ny ngn cn khng cho nhiu thuc thm vo no.
-11-
- No v dch quanh no l mt h c 3 khoang: huyt tng, dch no ty,
no; ngn cch nhau bi ba hng ro.
+ Hng ro mu- no ngn cch mu vi no.
+ Hng ro mu- dch no ty ngn cch mu vi dch no ty.
+ Hng ro dch no ty- no ngn cch dch no ty vi no.
1.3.2.3.4. Phn phi qua rau thai:
Rau thai l rau mu- m. Nhng mao m nhng tong h mu, nhung mao
ny c bao bc bi hp bo, lp hp bo ny cng vi trung m ca nhung
mao m v ni bo ca mao mch rn s ngn cch mu m (cha trong h
mu) vi mu thai (cha trong mao mch rn). Hng ro rau thai chnh l c ba
lp trn, b dy thay i t 0,025mm- 0,002mm tong sut thi k c thai. B
mt hp thu ca rau~50m
2
.
- Lu lng mu tun hon rt cao 500ml/pht.
- Cc thuc u lipoit qua rau thai d, cc thuc d ion ha u nc ( axit
mnh, baz mnh) vo rau thai chm, cc cht c phn t lng < 500 d vt
qua rau thai.
- C nhiu thuc cm dng cho ngi m khi c thai.
- C mt s thuc cn dng thn trng khi c thai.
1.3.2.3.5. Di chuyn vo m:
C nhng thuc c di chuyn vo m. Vai tr ca m y l:
- Kt thc tc dng ca thuc.
- Ko di tc dng ca thuc.
- D phng ng c ca thuc (lm ni thu ht thuc, gim nng ni
khc).
1.3.2.3.6. Tch ly thuc:
Sau khi phn b, thuc c th b tch t li mt ch c bit (v lin kt bn vi
th th bng lin kt cng ha tr) nh thuc c ch , thuc dit cn
trng loi photpho hu c, cc thuc asen, ch gn vo cc hp cht cha nhm
SH.
1.3.2.4. Chuyn ha thuc
- C thuc ung vo c th ri thi ra nguyn vn nh saccharin, mt s khng
sinh aminoglycozit.
- C thuc vo b trung ha bi dch v nh NaHCO
3
.
- Nhiu thuc sau khi hp th phi c chuyn ha ri mi thi tr. Cc cht
chuyn ha thng c tnh phn cc cao, t tan trong lipit hn cht m, d thi
hn. Do thuc chuyn ha thng th mt tc dng, mt c tnh.
- C mt s thuc phi qua chuyn ha c tc dng, mi c c tnh (v d
vitamin D
3
cha c hot tnh, nhng 1,25-dihidroxi-calcipherol c hot tnh).
- Cc cht khi chuyn ha th cht chuyn ha cng c tc dng nh cht m,
v d cloral hidrat tricloetanol (thuc ng), phenyl-
butazonoxyphenylbutazon (chng vim)
- Cc c quan gi vai tr quan trng trong chuyn ha:
+ Gan, thn, rut, c, lch, no, phi.
-12-
+ Cc loi enzim ng vai tr trong chuyn ha thuc: esterase, oxidase,
hidroxylase.
1.3.2.4.1. Nhng phn ng ging ha:
Bao gm cc phn ng oxi ha, kh ha hoc thy phn (gi chung l phn
ng pha I)
a/ Phn ng oxi ha:
oxi ha thuc qua enzim li ni bo khng ht ca t bo gan. Cc yu t c
hot tnh enzim oxi ha thuc gi l microsom.
1.3.2.4. Chuyn ha ca thuc:
- Chuyn ha ca thuc l g? V sao thuc phi chuyn ha?
- Nhng nhn t v cc v tr c vai tr trong chuyn ha thuc?
- Kt qu ca qu tnh chuyn ha thuc?
Mt s cht phi chuyn ha mi c tc dng
Cht ban u cha c
hot tnh
Cht chuyn ha c hot
tnh
Tc dng
- methyl- DOPA
DOPA
Cyclophosphamide
Vitamin D
3


Carbon tetraclorina
Parathion
- methyl- noradrenaline
Dopamine
Aldophosphamide
1,25 (OH)
2
calciferol

CCl
3
, Cl
Paraoxon
Cha cao huyt p
Chng Parkinson
Chng ung th
Lm tng hp thu canci
rut
Gy hoi t gan
Dit cn trng

Mt s cht khi chuyn ha cht chuyn ha vn c tc dng:
Cht ban u c tc dng Cht chuyn ha vn cn
c tc dng
Tc dng
Imipramine
Phenylbutazone
Cloral hidrat
Demethylimipramine
Oxyphenylbutazone
Triclorethanol
Chng tm cm
Chng vim
Thuc ng
Bng 1.8. Cc loi phn ng ging ha pha I
1. cc phn ng oxi ha (ph thuc P-450)
- Oxi ha nhn thm
- To epoxit
- Oxi ha kh amin
- Dechalogen ha
- Oxi ha mch thng
- N-, O-, S- deankyl ha
- S-, O- oxi ha
- Oxi ha ancol
2. Oxi ha c xc tc ca cc enzim khc
- Ancol dehidrogenase - Xantinoxidase
- Aromatase
- Andehidoxidase
- Aminoxidase
3. Phn ng kh
- Kh azo. - Kh nitro
-13-
- Kh epoxit - Kh cc hp cht d vng
4. Thy phn
- Thy phn este.
- Thy phn azit
- Thy phn amit.

5. Hidrat ha
6.ng phn ha.
7.Cc phn ng lin hp
- ng vng - M vng
- N- cacboxyl ha - Dime ha
- Chuyn ti amit - Decacboxyl ha
1.3.2.4.1. Nhng phn ng chuyn ha ( ging ha pha I).
1.3.2.4.1.1. Phn ng oxi ha thng qua enzim li ni bo ( microsoma
oxidations)
Hnh thc chuyn ha sinh hc ca thuc ph bin nht l oxi ha, cn chuyn
ha bng kh ha th t c ngha hn.
- Enzim microsoma l enzim oxi ha nhiu chc nng ( mixed function
oxidase)
- Monooxigluose
- iu kin c th oxi ha l phi c O
2
v NADPH ( nicotinadenin-
dinucleotit-phosphat).
- Microsoma-hidroxylase.
Cc loi phn ng oxi ha thng qua enzim microsoma:
a. Hidroxyl ha nhn thm:
CH
3
NHCOCH
2
NH(CH
3
)
2
CH
3
CH
3
NHCOCH
2
NH(CH
3
)
2
CH
3
OH
lidocaine
m-hidroxi-lidocaine
acetanilide
paracetamol

b. Hidroxyl ha mch thng

HN
HN
O
O
O
C
2
H
5
CH(CH
3
)(CH
2
)
2
CH
3
HN
HN
O
O
O
C
2
H
5
CH(CH
3
)CH(OH)CH
3
Pentabarbital


-14-
c. To epoxi
O
Benzpiren
Benzpirenepoxi

d. N-deankyl ha
N
N
Cl
CH
3
O
N
H
N
Cl
O
+ HCHO
diazepame
nordiazepame

e. O-deankyl ha
O H
3
OC
OH
N
CH
3
O HO
OH
N
CH
3
+ HCHO
codeine morphine
phenaxetin paracetamol + CH
3
CHO

f. S-deankyl ha
-15-
N
N
N
H
N
SCH
3
N
N
N
H
N
SH
+ HCHO
S-metyltiopurin
nor-S-metyltiopurin

g. Oxi-dezamin ha
CH
2
CH(CH
3
)NH
2
CH
2
COCH
3 + NH
3
amphetamine
phenylaxeton

h. N-oxit ha
N
H
3
C
N
H
3
C
O
3-metyl-piridin-N-oxi

i. S-oxit ha
N
S
(CH
2
)
3
N(CH
3
)
2
N
S
(CH
2
)
3
N(CH
3
)
2
O
Cl
Chlorpromazine Chlorpromazine-S-oxid

j. Dehalogen ha
F
3
C CH Br
Cl
F
3
CCH
2
-OH F
3
C-COOH
halothan
axit triflo axetic

k. Oxi ha etanol
CH
3
CH
2
OH
CH
3
CHO

1.3.2.4.1.2. Cc phn ng oxi ha khng phi qua li ni bo (N
0
microsoma
oxidations)
Cc loi oxi ha khng thng qua li ni bo gm cc loi enzim sau:
a. Dehidro ha ancol bng enzim ancol-dehidrogenase.
-16-
CH
3
CH
2
OH
CH
3
CHO
NADH + H
NAD

b. Oxi ha andehit bng enzim andehit-oxidase.
CH
3
CHO
NADH + H
CH
3
COOH
H
2
O
NAD

c. Oxi ha amin bng aminoxidase (monoaminoxidase, diaminoxidase)
HO CH
2
CH
2
NH
2
O
2
+ H
2
O
HO CH
2
CHO + NH
3
+ H
2
O
2

d. Thm ha
CO S CoA
H
2
O
FAD
FADH
2
O
2
CO S CoA

1.3.2.4.1.3. cc ging ha trn c s kh ha:
Cc loi ging ha tn c s kh ha:
a. Kh ha azo bng enzim aroreductase.
NH
2
NO
2
N N SO
2
NH
2
prontosil
NH
2
H
2
N N N SO
2
NH
2
+
H
2
N
NH
2
NH
2
sulfanilamide
(co hoat tinh)
triaminobenzen

b. Kh ha nitro bng enzim nitroreductase.
O
2
N CHOH CH (CH
2
)OH
NH - COCHCl
2
H
2
N CHOH CH (CH
2
)OH
NH - COCHCl
2

c. Kh ha xeton bng xetoreductase.
COCH
3 CH(OH)CH
3
axetophenon 1-phenyletanol

1.3.2.4.1.4. Ging ha bng phn ng thy phn.
-17-
Cc loi enzim thy phn:
a. Thy phn este bng enzim esterase.
H
2
N COO(CH
2
)
2
N(C
2
H
5
)
2
+H
2
O
H
2
N COOH + HO(CH
2
)
2
N(C
2
H
5
)
2
procaine axit p-aminobanzoic

b. Thy phn amit bng enzim amidase.
H
2
N CONH(CH
2
)
2
N(C
2
H
5
)
2
H
2
O
procainamide
H
2
N COOH
axit p-aminobanzoic
+ H
2
N(CH
2
)
2
N(C
2
H
5
)
2

c. Thy phn hidrazit
N CONHNH
2
H
2
O
N COOH + H
2
N - NH
2
isonicotin hidrazide
axit isonicotinic

1.3.2.4.2. Cc phn ng chuyn ha thuc pha II
Bng 1.9. cc phn ng chuyn ha thuc pha II

Phn ng Enzim Nhm phn ng
To glucuronid UDP glucuronid
transferase
-OH,-COOH,-NH
2
,-SH
Sunfo ha Sunfo tranferase -OH,-NH
2
,-SO
2
NH
2

Metyl ha Metyl tranferase -OH,-NH
2

Acyl ha Acyl tranferase -OH,-NH
2
,-SO
2
NH
2
Aminoaxit-hp Glutation S- tranferase -COOH
Glutation-hp Epoxit
Axit bo- hp -OH
Ngng t Cc nhm chc khc

1.3.2.4.2.1. Vi axit axetic:
NH
2
SO
2
NHR
+ CH
3
COOH
H
3
COCHN SO
2
NHR

1.3.2.4.2.2. Vi axit sunfuric:
C
6
H
5
OH + H
2
SO
4
C
6
H
5
OSO
3
H

1.3.2.4.2.3. Vi axit mercapturic:
-18-
C
6
H
5
CH
2
Cl CH - COOH
OCHN
H
2
C
CH
3
HS
+
CH - COOH
OCHN
H
2
C
CH
3
C
6
H
5
H
2
CS
(N-acetyl-cystein) acid benzyl mercapturic

1.3.2.4.2.4. Vi glycocol (glycin):
C
6
H
4
COOH
OH
+
H
2
NCH
2
COOH C
6
H
4
CONHCH
2
COOH
OH
Acid salicylic
acid salicyluric


1.3.2.4.2.5. Metyl ha:
HO
HO
CH(OH)CH
2
NH
2
COMT
HO
H
3
CO
CH(OH)CH
2
NH
2
Nor-adrenaline
Nor-metanephrine

1.3.2.4.2.6. Vi axit glucuronic:
Nhiu thuc lin hp axit glucuronic hot ha cho glucuronid nh xc tc
ca UDP- glucuronyl-transferase. (UDP: uridin-diphosphat).
Dng glucuronyl va c to thnh c tnh axit, ion ha c cc pH sinh
l, rt tan trong nc, cho nn c thi nhanh qua nc tiu hoc qua mt.
Nh vy, phn ng glycuro- hp r rng l qu trnh gii c thuc.
O
COOH
O
COOH
COOC
6
H
5
O
COOH
NHC
6
H
5
eter glucuronic
este glucuronic
DX N-glucuronid

1.3.2.5. Thi tr thuc khi c th
Thuc chm dt tc dng khi b thi tr khi c th. Thuc vo c th bn
cnh tc dng cha bnh n cn b chuyn ha mt hot tnh, mt phn khc
tch tr li mt s b phn ca c th (trong m, trong xng, trong gan,
-19-
trong phi). mt phn na th thi ra nguyn vn. Nh vy thuc mt tc
dng bng ba hnh thc: thi ra, phn b li, chuyn ha.
Cc c quan quan trng trong thi tr thuc l: thn, mt, h thng tiu ha,
tip theo na l phi, nc bt, tuyn m hi, tuyn sa.
1.3.2.5.1. Thi tr thuc qua thn:
Phn ln cc thuc tan trong nc c tr thi qua thn. Sau khi ung 5-15
pht thuc c mt nc tiu, sau 80-90 pht c nng cao nht nc
tiu, khong 80% lng thuc s thi ra trong 24 gi.
Thi thuc qua thn theo ba c ch:
- Lc qua mao mch cu thn
- Thi qua t bo ca biu m ng thn (theo vn chuyn tch cc). C hai
loi h thng vn chuyn tch cc tc l hai loi carrier ng ln gn h
vn chuyn anion hu c (cc axit) v h vn chuyn cation hu c (cc
baz)
- Ti hp thu qua t bo biu m ng thn.
+ pH nc tiu c lin quan n hp thu v thi thuc.
+ Thiu nng thn ngn cn thi t, lm tng c tnh ca thuc.
1.3.2.5.2. Thi tr thuc qua b my tiu ha.
- Tit qua nc bt ( mi ngy 1 ngi tit trung bnh 2 lt nc bt)
- Tit vo d dy (mt s thuc c tnh baz)
- Tit qua mt (cc thuc axit cacboxylic M= 300-400)
- Thi tr qua rut, chu k gan- rut. c bit ca phn ng chuyn ha
rut l ging ha.
1.3.2.5.3. Thi tr thuc qua mt.
Hng ngy c khong 1 lt dch mt tit vo rut, t trng. Do m c ca
dch mt m gy nn p sut thm thu, tc dng ht do thm thu ny lm
tng nhanh dng chuyn ng ca cc hp cht khc (trong c thuc).
Ngc li vi hng chuyn ng ny hot tnh ti hp thu ca cc loi ion
Na
+
, K
+
, Cl
-
, cng c xy ra ngay trong cc ng dn mt.
1.3.2.5.4. Thi tr thuc qua phi:
- Cc cht kh, cc cht d bay hi (thuc m) cng nh ru c th thi ra
ngoi qua phi.
- Mt s thuc, mc du dng theo ng khc (ung, t hu mn, tim
bp) nhng vn vo phi v tc ng trn h hp. Cc thuc ny cng c th
thi tr qua phi.
1.3.2.5.5. Thi tr thuc qua cc tuyn dch ca c th.
- qua tuyn m hi bi tit
- qua tuyn nc bt
- qua tuyn sa (chnh v th m gy ng c cho tr con khi m cho con b
ung thuc).
1.3.3. Cc cch tc dng ca thuc.
1.3.3.1. Cc kiu tc dng.
-20-
- Thuc tc dng ti ch: a vo u tc dng ti (thuc t, thuc st,
khun bi), thuc bc nim mc (nhm hidroxyt).
- Thuc tc dng ton thn: a vo theo mu n s chy, lan u vo ton c
th, c th trc tip hoc gin tip.
1.3.3.1.2. Tc dng chnh v ph.
- Tc dng chnh l tc dng cha bnh
- Tc dng ph l tc dng khc vi tc dng chnh, tc dng ngoi mong
mun.
V d: aspirin tc dng chnh l cha thp khp, tc dng ph l gy tn
thng nim mc d dy.
Trong iu tr c gng tm cch gi tc dng chnh v gim tc dng ph (v d
s dng thuc t hu mn i vi cc thuc c tc dng ph kch ng nim
mc, c mi v kh chu).
1.3.3.1.3. Tc dng hi phc v khng hi phc.
- Tc dng hi phc: v d thuc gy t (procaine) ch c ch dy thn kinh
cm gic nht thi, homatropine lm gin ng t trong vi gi, sau c th
tr li trng thi bnh thng.
- Tc dng khng phc hi: v d Tetracyclin to phc Chelat bn vi Ca
2+

xng, rng tr em duy tr rt lu khng th tr li trng thi c.
1.3.3.1.4. Tc dng chn lc.
Thuc c th tc dng ti nhiu c quan khc nhau nhng gi l chn lc v tc
dng xut hin c hiu v sm nht vi 1 c quan no ( v d codeine c
ch c bit hnh no).
1.3.3.1.5. Tc dng i khng.
- i khng c cnh tranh.
Cht ch vn (agonist) v cht i khng (antagonist) cnh tranh vi nhau
cng mt ni ca receptor.
V d: cht ch vn- cht i khng:
Axteylcholine-piperazine (receptor N c giun)
Histamine-phenergane (receptor H
1
)
Histamine-cimetidine (receptor H
2
)
- i khng khng cnh tranh
cht i khng c th tc ng ln receptor v tr khc vi cht ch vn, cht
i khng lm cho receptor bin dng, qua receptor s gim i lc vi cht
ch vn nn nu c tng liu th cht ch vn cng khng t c hiu lc ti
a. (V d cc khng hicctamin receptor H
1
).
- i khng chc phn (functional antagonism)
Hai cht l ch vn, receptor khc hn nhau nhng tc dng i khng li
biu hin ten cng mt c quan. V d Histamine (tn receptor H
1
) lm co c
tn kh qun (cht ch vn kch thch), adrenaline (trn receptor ) lm co c
ta, gy gin ng t ( ch vn tng nhp tim, co tht ng mch).
- i khng ha hc (chemical antagonism).
-21-
C hai loi tng tc thuc, khc nhau ni v cch thc m cc cht tng
tc vi nhau:
+ Tc dng tng h (interference, interation) xy ra trong mi trng in vivo
do tng tc sinh hc gia cc thuc c cc protein (acceptor, receptor, enzim)
tham gia.
+ tng tc tng k (incompatibility) l tng tc in vivo, hoc gia hai dng
bo ch hoc gia nhng hot cht trong lc chng hp thu trong c th, tng
k l tng tc thun ty ha l, khng cn c s tham gia ca t chc sng
(nh protein). Tng k l i khng ha hc (cc thuc axit khng trn ln
cc thuc baz, thuc l protein khi gp mui kim loi s kt ta hoc mt tc
dng)
- i khng do nh hng ti dc ng hc.
+ Cn tr hp thuc qua ng tiu ha.
+ Cm ng enzim chuyn ha thuc gan.
Thuc gy cm ng Cytocrom P
450
khin nhiu thuc khc chuyn ha mnh
qua gan (tng thanh thi) v lm mt tc dng.
+ Cn tr hp thu qua ng thn.
1.3.3.1.6. Tc dng hip ng.
Thuc A c tc dng l m, thuc B c tc dng l n, lc A kt hp vi B
xy ra 2 trng hp:
Tc dng = m+ n l hip ng cng (additive effect).
Tc dng > m+ n l hip ng vt mc (synegism).
C khi A khng c tc dng ging B nhng A vn lm tng tc dng ca B th
ni A lm tng tim lc (potentiation) ca B.
Tc dng hip ng c 2 loi sau:
- Hip ng do nh hng ti dc ng hc.
+ nh hng ti hp thu
+ y nhau ra khi protein- huyt tng.
+ ngn cn chuyn ha
+ gim thi tr
- Hip ng cng receptor
Khi dng cc khng sinh cng nhm vi nhauth hip ng nh mt php
cng:
- Hip ng trc tip nhng khc receptor.
Hai thuc A v B tc dng ln receptor khc nhau nhng cng c tc dng
dc l ging nhau.
V d: phi hp thuc h huyt p vi thuc li tiu cha cao huyt p cng
l hip ng trc tip. Aspirin dng cng dn xut coumarin ( nh warfarine)
lm tng tc dng chng ng mu: aspirin chng kt dnh tiu cu cn
Warfarin c ch tng hp cc yu t ng mu.
- Hip ng gin tip.
Thuc A c tc dng ph, lm hn ch hot tnh ti a ca n. Dng thuc B
loi tc dng ph ca A. Ta ni B l hip ng gin tip ca A. V d: dng
-22-
metylatropin trc khi tim noradrenalin s ct c phn x vegus lm chm
nhp tim vn sn c noradrenalin, v l ko di c s tng huyt p do
noradrenalin to ra.
- Hip ng vt mc.
Axit folic l coenzim gip to nn cc baz purin, thymin, v cc axit amin cn
cho tng hp AND, ARN v protein l nhng nguyn liu cn cho vi khun
pht trin. Sunfamit cng vi trimethoprim c ch hai loi enzim khc nhau
hai khu khc nhau nhng trong mt qu trnh tng hp axit tetrahidrofolic.
Hai loi thuc dng chung s c tc dng hip ng vt mc. l
nguyn tc to nn thuc khng khun hoc chng st rt c hiu lc cao nh
Bactrim (sunfamethoxazole + trimethoprime), Fansidar (sulfadoxine +
pyrimethamine).
- Tc dng canh tranh 2 pha.
Tc dng cnh tranh 2 pha cn gi l tc dng hip ng i khng
(synergism-antagonism). Lc u l hip ng, sau l i khng. Cht gi l
i khng thc ra l cht ch vn tng phn (partial agonist), cn gi l cht
ch vn i khng (agonist- antagonist).
V d: ngi ta dng nalorphine i khng vi cc opiat ( v d cha suy h
hp bng morphine, pethidine gy nn). Vi receptor thuc phin narlophine
c i lc mnh hn cc opiat, nhng hiu lc yu hn nhiu. Vi liu php
thch hp lc ban u narlophine cng l cht ch vn receptor, pht huy
hot tnh morphinic (pha I, pha hip ng) nhng v sau narlophine li y
opiat ra khi receptor (pha II, pha i khng).
- o ngc tc dng:
L hin tng c mt s thuc (ru etylic, barbiturat) lc u gy hng phn
do chng c ch u tin trn loi t chc li c ch ca nhiu thn kinh trung
ng ( c ch ci c ch thnh hng phn), v sau th tc dng c ch ny li
lan ta c trn loi t chc li hot ha gy ng, gy m. Adrenaline va
lm co mch ( hot ha ) v gin mch (hot ha ), khi dng adrenaline
cng thuc c ch nh ergotamine), hot tnh ca adrenaline tri ln, lm
gin mch v h huyt p.
1.3.3.2. c ch tc dng ca thuc.
Thuc vo c th biu hin tc dng di nhiu dng khc nhau.
1.3.3.2.1. Tc dng c l do thay i sinh ha.
- c ch enzim (acetazolamit c ch anhydrase cacbonic).
- hot ha (vitamin B
6
l ng yu t hot ha Dopa- decacboxylase ngoi
bin) lm gim lng levodopa cn qua hng ro mu no (v vy lm
gim tc dng cha bnh parkinson ca levodopa).
- nhng thay i khc.
Nhiu thuc c nh hng ti nng cht trung gian ha hc trong c th v
d thuc ng lm tng nng GABA v glycocol trong no.
1.3.3.2.2. Tc dng c l do nh hng n vn chuyn qua mng sinh hc.
-23-
- Thay i trao i ion ( phenultoine lm tng hot tnh Na
+
, K
+
gy tng
xut Na
+
ra ngoi t bo, gi K
+
).
- Thay i trao i nhng cht khc (liu nh salysilay km hm ti hp thu
thuc probenecide qua ng thn cho nn lm gim tc dng cha gout ca
probebecide).
1.3.3.2.3. C ch to chelat.
Trong y hc gii c thng dng cc cht ta chelat, hay cn hi l cht
ni phc, cht cng cua c cc nhm phn cc nh OH, -SH, -NH
2
hoc
cc cht ion ha nh -O
-
, - COO
-
khi vo c th n to phc nn s khng
thm qua hng ro sinh hc d thi, gim c tnh (gii c th dng EDTA,
canxi dinatri, Pb
2+
s y Ca
2+
ra khi phc vo chim kh, v phc EDTA
ch ra ngoi theo nc tiu.
1.3.3.2.4. Tc dng dc l khng cn s tham gia ca receptor.
- Thuc tc dng do tnh l ha khng c hiu, thuc ty mui cha cc ion
kh hp thu qua nim mc rut nh Mg
2+
, sunfat, photpho,citrat v l chng
lm cho nc thnh rut chuyn vo lng rut, th tch dch lng rut tng
ln v kch thch nhu ng rut.
Than hot hp ph c cc hi, cc ancaloit, toxin nn dng cha i lng,
nh c thc n hoc gim y hi trong chng kh tiu.
- Thuc tc dng do tnh baz hoc tnh axit.
+ Thuc tung ha axit nh MgCO
3
MgO, Ca(CO
3
)
2
, Al(OH)
3
.
+ Thuc trung ha axit ha nc tiu nh NH
4
Cl; CaCl
2
dng tng thi
baz (ancaloit, amphetamin).
+ Thuc kim ha nc tiu nh NaHCO
3
.
- Thuc m hi (nh ete) cng c c ch gy m thun ty vt l
1.3.4. Nhng yu t quyt nh tc dng ca thuc
1.3.4.1. Yu t l, ha tnh
1.2.4.1.1. Tan trong nc
Thuc phi tan trong nc th mi hp thu, phn b, di chuyn trong nhng
khoang ca c th, mi c th pht huy c tc dng v c tnh.
V d: Ba(CO
3
)
2
, BaCl
2
tan trong nc c
BaSO
4
khng tan trong nc khng c dng lm thuc cn quang
1.3.4.1.2. Tan trong lipoit
tan trong lipoit l c s cho vic tip nhn, hp thu, phn b nhng thuc
c phn t lng ln trong c th theo cch khuch tn th ng. tan trong
nc nghch bin vi tnh tan trong lipoit. Thng dng thuc c t l nghch
ng gia hai tan ny.
1.3.4.2. Lin quan gia cu trc v tc dng
1.3.4.2.1. nhm c hot tnh.
Trong cu trc ha hc ca thuc c nhng nhm quyt nh tc dng.
+ thuc st rt loi aminoquinonlin (dit th v tnh) v 8 aminoquinolin
(lm ung giao t)
+ Isoniazide (cha lao,), iproniazide (chng trm cm).
-24-
N CONH - NH
2
isoniazide
N CONH - NH - CH(CH
3
)
3
iproniazide

+ Procaine v procainamide c tc dng gim tm thu nh nhau.
H
2
N COO(CH
2
)
2
N(C
2
H
5
)
2
procaine
H
2
N CON(CH
2
)
2
N(C
2
H
5
)
2
procainamide

1.3.4.2.2. Thay i nhm th.
Thay i nhm th cng c th thay i s phn ca thuc trong c th. V
d t
1/2
ca tolbutamide v chlorpropamite.
R SO
2
NHCONH - C
4
H
9
(n)
R=CH
3
: tolbutamide t
1
/
2
= 4 - 8h
R=Cl : chlorpropamide t
1
/
2
= 35h

1.3.4.2.3. ng phn quang hc.
Cc ng phan (+) v (-); D v L tc dng khc nhau kh r. V d:

Thuc Hot tnh tng i Tng quan cng
tc dng (-)/(+)
gin ph qun
ng phn (-) ng phn (+)
Noradrenaline 1 0,014 71
Adrenaline 58 1,3 45
Isoprenaline 270 0,33 820

1.3.4.2.4. ng phn hnh hc.
Gia ng phn cis v trans tc dng dc l khng ging nhau. V d
dietylstiboestrol ng phn trans c hot tnh oestrogen mnh hn ng phn
cis rt nhiu.
-25-
HO C
C
C
2
H
5
C
2
H
5
OH
trans-dietylstilboestrol
HO
C
C
C
2
H
5
HO
C
2
H
5
cis-dietylstilboestrol

1.3.4.3. Dng thuc.
Dng thuc, cch thc bo ch, dng tinh th, iu kin bo qun nh hng
su sc n hot tnh sinh hc ca thuc.
a/ tn nh:
thuc cng mn, b mt tip xc gia cc ht vi dung mi cng tng, tc
ha tan cng ln, th hp thu cng nhanh hot tnh cng cao.
b/ dng tinh th:
thuc rn c th dng v nh hnh hoc tinh th, dng v nh hnh d tan
hn dng tinh th.
C th c nhiu dng tinh th khc nhau. Nhng tinh th khc nhau ca cng
mt thuc, cch sp xp cc phn t khng ging nhau, nn l tnh khng
ging nhau, tan cng bin ng theo dng tinh th. V d: choramphenicol
c hai dng tinh th v 1 mt dng v hnh ( t tn l A, B, C), v nng
dng C trong mu ngi cao gp 10 ln.
c/ trng thi solvat:
nhiu thuc hai dng khan v ngm nc l tnh ca thuc s thay i ( tnh
tan) theo thuc ngm nc v khan. Dng khan d tan, tip thu sinh hc d hn
dng ngm nc. Thay i qui trnh sn xut c th thay i tnh tan ca thuc,
t nh hng ti tip thu sinh hc.
d/ nh hng ca t dc:
t dc khng ch l cht n cho thm vo, m c nh hng su xa n
hiu lc ca chnh thuc, lm thay i s khuych tn, ha tan v ton b
tip thu sinh hc ca thuc.
1.3.4.4. nh hng ca ngi bnh
c im ca ngi bnh nh hng ln n hp thu v tc dng ca thuc.
a. V tui tc:
- Tr em: tr em khng phi l ngi ln thu nh v chng do cc b phn c
th cha pht trin bnh thng nn khi dng thuc cn phi lu . Chia ra 3
-26-
la tui: s sinh, ang b, tr ln tui t 2-10 tui. c bit phi ch tr em
s sinh nht l tr thiu thng. S khc bit ny cn phi ch cc khu:
+ Hp thu thuc
+ Phn phi thuc
+ Hng ro thn kinh trung ng
+ Chuyn ha
+ Thi tr qua thn (cc chc nng ca thn cn yu)
- Ngi cao tui: ngi gi mt s ch tiu sinh l thay i nn tc dng ca
thuc, ca c tnh cng thay i nn t l tai bin dng thuc ngi gi tng
ln 3-4 ln so vi ngi trng thnh.
b, V gii tnh:
n gii vo nhng thi k c kinh nguyt, c thai, cho con b cn phi
ch :
- Thi k kinh nguyt: Khng cm hn nhng phi thn trng nn ngh thuc
vo lc c kinh.
- Thi k c thai: c th c nhiu thay i nn dng thuc phi ht sc thn
trng. C nhiu loi thuc cm khng c dng, nhng thuc cn phi cn
thn.
- Thi k cho con b: Thuc s i qua sa.
c, Cn nng: Hai ngi c cn nng khc nhau ch yu l khc nhau m v
tht cn lc ph ng tng th gn nh nhau. Nn ch cc thuc c tch ly
m hoc thuc tan trong lipoit.
d, Quen thuc
L trng thi ca c th chu c nhng liu thuc ng k gy c cho
ngi, cn vi liu ng l c hot tnh sinh hc th vi c th ngi quen
thuc p ng yu hn hn so vi c th ngi bnh thng. C 3 loi quen
thuc sau y thng hay nhn thy:
- Quen thuc t nhin: C nhng c th c kh nng p ng khc hn: c
ngi ch dng 2,6g natrisalicylat c triu chng ng c (nn, tai, nhc
u) nhng c ngi dng n 31g mi c triu chng . C s quen thuc
1 s c th v h thuc:
+ Thuc gn mnh vo protein-huyt tng
+ Tng chuyn ha
+ Tng thi tr
+ Gim hp thu thuc
Tm li thay i dc ng hc
- Quen thuc xy ra dn dn
+ Dng lu ngy c th gim nhy cm ti khi thuc mt hiu lc
+ Dng nhiu ln s gy cm ng nhng enzim chuyn ha chnh n, thuc
lm gim tc dng. l quen thuc do cm ng enzim
- Quen thuc do c ch kim tra ngc
Phn bit quen thuc trng din v nghin thuc
+ Quen thuc: khng c nhiu ri lon sinh l
-27-
+ Nghin thuc: c nhiu ri lon sinh l, tm thn.
e, Dc l di truyn
Mt s ngi (trong mt gia nh, mt dn tc thiu mt loi enzim hoc
mt s yu t chuyn ha no do di truyn) d b ng c thuc
- Ri lon pha dc ng hc (do thiu enzim)
- Thay i tc dng dc l ca thuc
- Xut hin tc dng mi
f, Dinh dng
- nh hng ca thc n ti ng hc, tc dng v c tnh ca thuc: thc n
lm thay i pH ca d dy (lc i pH=1,7-1,8), khi no pH>=3 (ty ch
n), thuc hp thu ph thuc pH.
- nh hng ca nc ung ti ng hc, tc dng v c tnh ca thuc:
+ Nc
+ Sa
+ Cafe, nc ch
+ Ru
g, Thi im dng thuc
- Ung lc no, lc i
- Ung thuc gia ba n
- Ung sng, ti, m
h, D ng thuc
Nhiu thuc v ha cht l d nguyn, c bn cht khng nguyn, gy di
ng do hnh thnh c khng th d ng trong c th, kt hp c hiu vi
khng th .
i, Trng thi bnh l
- C mt s bnh l cm dng mt s thuc hoc dng th phi ht sc thn
trng: C thai, suy tim-suy mch vnh, suy h hp, cao huyt p, suy gan, vim
lot ng tiu ha, ng kinh, nghin ru, suy thn, i tho ng.
1.4. Tin trnh nghin cu a mt thuc mi vo s dng
a mt thuc mi vo s dng trong iu tr phi tri qua nhiu giai
on nghin cu, kt hp nhiu ngnh khoa hc (ha hc, vt l, sinh hc, dc
hc, y hc,), thi gian thc hin cng di (5-7 nm), kinh ph tn km (hng
chc n hng trm triu USD), hng nghn cht mi c c mt cht (5-10
nghn cht).
Tin trnh nghin cu bao gm:
1.4.1. Nghin cu v mt ha hc, iu ch ra hot cht
- Trn c s lin quan cu trc v tc dng sinh hc iu ch ra cc cht
- Xc nh c tnh vt l, ha hc
- Tinh ch t tiu chun dc dng
- Ngun nguyn liu iu ch:
+ T tho dc, thc vt (kinin t canhkina)
-28-
+ T ng vt (tuyn thng thn adrenalin tr tim) v cortison (chng
vim), t tuyn yn no hormon ACTH (chng vim), t du gan c
Vitamin A + D)
+ T ha cht: i t du kh tng hp ra 85-90% hot cht lm thuc
1.4.2. Nghin cu th tc dng sinh hc (hot tnh)
- Th trong ng nghim (in vitro)
- Th trn ng vt thc nghim (in vivo)
+ Th tc dng
+ Th c tnh (cp, trng din)
+ Th v s phn thuc
+ Th xc nh liu dng
- Th tin lm sng
Ch : S khc nhau gia ng vt v ngi.
1.4.3. Th c tnh
- c tnh trong thuc l g?
- c tnh cp
- c tnh trng din, mn tnh
1.4.4. Th tc dng dc lc
- Th tc dng dc l xem cht c tc dng g?
- So snh tc dng vi mt thuc bit
- Th nghim xc nh liu c tc dng? Nng tc dng?
1.4.5. Nghin cu c ch tc dng ca hot cht thuc
- Nghin cu xem thuc c tc dng trong c th nh th no?
- Tc dng chi phi ca thuc ti cc phn ng enzim nh th no?
- V tr tc dng ca thuc? Thuc tc dng u?
+ Thuc c tr (liu nh)
+ Thuc khng c tr (liu ln)
1.4.6. Nghin cu hp thu, phn b chuyn ha v thi tr ca thuc trong c th
- Cch a thuc vo c th
- Nghin cu s phn thuc trong c th (t hp thu, phn b, chuyn ha, thi
tr)
1.4.7. Nghin cu xc nh liu dng ca thuc
Cc khi nim v liu:
- Liu ti thiu c tc dng (dosis effective minimum) DE
- Liu c tc dng iu tr (dosis curative) DC

- Liu ti a c th cn chu ng c (dosis toleration) DT
- Liu c (dosis toxica) Dt
- Liu gy cht 50% (dosis letalis 50%) DL
50

- Liu cht (dosis letalis) DL

- Ch s iu tr = DC/DT, gii hn tc dng DC-DT
1.4.8. Nghin cu dng bo ch
- Dng bo ch l g?
-29-
- Dng bo ch c nh hng g ti tc dng?
- C nhng dng bo ch g?
1.4.9. Nghin cu iu tr bnh ca thuc trn lm sng
- Nghin cu tin lm sng lm g?
- Nghin cu lm sng l g?
- Ti sao phi nghin cu tin lm sng?
1.4.10. Hon thin cc th tc xin cp php lu hnh thuc
Ni dung xin cp giy php lu hnh gm nhng g?
+ Bn quyn s hu
+ Cc phng php kim tra
+ Cc kt qu th nghim tc dng sinh hc dc lc, dc l, c tnh, tc dng
ph, liu dng, c ch tc dng, chuyn ha,
+ Dng bo ch v phiu nh gi cht lng
+ Kt qu th nghim tin lm sng
1.4.11. Th lm sng
Th thuc trn ngi, theo di tc dng cha bnh ca n.



























-30-
CHNG 2: CC THUC TC DNG LN H THN KINH TRUNG
NG
2.1. I CNG V H THN KINH TRUNG NG V HOT NG CA
N.
- c im ca cc ng vt bc cao: c h thn kinh pht trin.
+ H thn kinh iu hnh mi hot ng, m bo s cn bng i vi mi trng.
+ H thn kinh iu tit cc phn x, iu hnh mi hot ng ca c th.
+ V tr ca h thn kinh trung ng: nm no (i no, hnh no, tiu no v
ty sng).
+ S phn vng theo nhim v ca h thn kinh trung ng.
- Chu k hot ng ca thn kinh:
+ Tip nhn kch thch (thn kinh ngoi bin).
+ Chuyn tn hiu v thn kinh trung ng.
+ X l thng tin, pht ra phn x mi ph hp, phn x c th c thc v v
thc (v thc).











2.2. CC THUC C CH H THN KINH
- Thuc c ch thn kinh trung ng l g? (lm t lit m). M l t lit c
phc hi.
- T lit theo thc t: i no, trung hnh no, tiu no, ty sng, hnh no.
+ T lit i no mt tri gic.
+ T lit trung ng hnh no v tiu no lm nh ch s cn bng v iu ha
nhit.
+ T lit ty sng ngng phn x.
+ T lit hnh no ngng hot ng ca cc chc nng s sng nh h hp,
ngng tim.
- Cc thuc c ch thn kinh trung ng gm 8 nhm sau :
+ Thuc gy t.
+ Thuc gy m.
+ Thuc gy ng.
+ Cc thuc cha ng kinh.
+ Cc thuc gim au.
+ Cc thuc an thn.
T bo hch thn kinh cm th
T bo hch thn kinh vn ng
T chc c ch v qu o ca n
Qy o truyn dn trung chuyn
ng dn ni cc hch cm th
1. Ngn dy thn kinh cm th
2. ng dn cm th
3. ng dn vn ng
4. Ngn dy thn kinh vn ng
-31-
+ Cc thuc gan c.
+Cc thuc cha bnh Parkinson.
2.2.1. CC THUC GY T
2.2.1.1. I CNG:
a, nh ngha: l thuc lm mt cm gic mt vng c th ti ch dng thuc m
cc chc phn hot ng khng b nh hng.
b, Tiu chun ca mt thuc gy t tt: gy t c, phc hi li sau khi dng
thuc, thi gian va cho mc ch gy t.
c, Lin quan cu trc v tc dng:
i b phn cc thuc t c cu trc ging lidocaine.
Theo Logren (1948) gm 3 phn: thn m, thn nc, chui trung gian
(xem bng 2.1).
d, Tc dng dc l:
Tc dng ti ch, tc dng trn cc si thn kinh trung ng, thn kinh thc
vt. C cc loi gy t sau:
+ Gy t b mt ( bi v thm thuc ti ch).
+ Gy t thm nhim (tim di da).
+ Gy t dn truyn (tim vo cnh ng dn truyn ca thn kinh ).
- Tc dng ton thn (khi thuc i vo vng tun hon).
Bng 2.1. Cu trc cc hp cht c tc dng gy t.
-32-




Cng thc
Loi nhm
nc
Tn
Phn thn m
Chui trung gian Phn thn nc




este Cocaine (2-1)
thuc u tin
pht hin v s
dng



Este Procaine (2-2)







anilit Lidocaine (2-4)






uretan Diperodone (2-
5)






Xeton Dyclonine (2-
6)




ete Pranocaine (2-
7)













-33-
2.2.1.2. CC LOI THUC GY T THNG DNG.


N CH
3
C
6
H
5
COO
N H
2
COOCH
2
CH
2
N(C
2
H
5
)
2






* Phng php tng hp procaine (2-2) (phi thuc): c 3 con ng tng hp:

CH
3
O
2
N
2-8
COOH O
2
N
2-9
COOC
2
H
5
O
2
N
2-14
COCl O
2
N
2-10
A
COOH
N H
2
COOC
2
H
5
N H
2 COOCH
2
CH
2
Cl O
2
N
2-11
2-13
2-15
COOCH
2
CH
2
N(C
2
H
5
)
2
O
2
N
COOCH
2
CH
2
N(C
2
H
5
)
2
N H
2
2-12
procaine
(Novocain, Ethocaine, Syncaine)
C
B


cocaine Procaine
(novocain)
lidocaine
-34-


* Tng hp lidocaine (2-16)
NH
2
CH
3
NH
2
CH
3
+ ClCOCH
2
Cl
CH
3
NH-COCH
2
Cl
CH
3
NH(CH
5
)
2
CH
3
NH-COCH
2
N(C
2
H
5
)
2
CH
3

* Mt s hp cht gy t khc

CH
3
NH CO
N
H


2.2.2. CC THUC M.
2.2.2.1. I CNG.
a, nh ngha: thuc lm cho con ngi v ng vt mt ht tnh cm v mi cm
gic. Vi liu iu tr, thuc khng nh hng ti h h hp, tun hon v c th
phc hi sau khi dng thuc.
b, iu kin ca mt thuc m tt: mnh, khi mo ngn, khng chy n nu
dng kh.
2.2.2.2. CC THUC M DNG THEO NG H HP.
Bng 2-2: Cc thuc m dng theo ng h hp.
N=N=O
Dinitrogen oxit
CH
2
=CH
2

Etylen C H
2
CH
2
CH
2

C
2
H
5
OC
2
H
5

Dietyl ete (ETE M)
CHCl
3
Cloroform
CCl
2
=CHCl
Tricloetylen
CF
3
-CHClBr
Halothane
(Fluothane)
CH
2
=CH-O-CH=CH
2
Divinyl ete
(Vinydon)
CF
3
-CH
2
-O-CH=CH
2
Fluroxen
(Fluromar)
CHCl
2
-CF
3
-O-CH
3

Methoxyfluraen
(Metofane)
CHClF-CF
2
O-CHF
2

Enflurane
(Ethrane)
CHF
2
-CHCl-O-CHF
2

Isoflurane
(Forane)

2.2.2.3. CC THUC GY M THEO NG TNH MCH.
- C hi mi n vi cc nh phu thut khi H.Wesse (1932) tm ra hexobarbital
(thuc ng, tim).
- u im: Lm m nhanh, phng tin gy m n gin (tim).
-35-
- Nhc im: Tc dng gim au, mm c km, thi gian gy m ngn.
a, Cc thuc gy m nhm barbiturat: hexobarbital (2-19), thialbarbital (2-20),
thiopental (2-21).
- Tng hp hexobarbital (2-19)

O +
C H
2
CN
COOC
2
H
5
C
CN
COOC
2
H
5
C
CN
COOC
2
H
5
H
2-22
2-23
1. CH
3
ONa
2. CH
3
Br
C
NC
H
5
C
2
OOC
C H
3
CH
3
NH-CONH
2
C N
H
C
N
H
CH
3
O
O
O
2-19
2-24 1. NH
2
- CO - NH
2
2. H
2
O/H
+
H
3
C

- Tng hp thialbarbital (2-20) v thiopental (2-21)
COOC
2
H
5
COOC
2
H
5
R
1
R
2
+ C
N H
2
N H
2
S
N
H
C
C C
N
H
C
R
1
R
2
O
O
S


2-21 R
1
= CH
2
-CH=CH, R
2
= thialbarbital
2-22 R
1
= C
2
H
5
, R
2
= CH(CH
3
)CH
2
CH
3
inactin
2-23 R
1
= C
2
H
5
, R
2
= thiopantal


b, Cc thuc m nhm benzodiazepin: tnh cht an thn
Gm c flunitrazepam (2-23) v midazolam (2-24).

N
N
O
2
N
CH
3
O
F

N
N
C l
N
F
C H
3
N




flunitrazepam (2-23)
midazolam (2-24)

-36-
Tng hp flunitrazepam (2-23)
NH
2
O
2
N
+
COCl
F
NH
O
2
N
CO
F
O
F
2-25
C
2
H
5
OH
H
2
SO
4
NH
2
O
2
N
O
F
2-26
NH
2
CH
2
COOC
2
H
5
O
2
N
NH
O
N
F
1. NaOCH
3
2. (CH
3
)
2
SO
4
O
2
N
N
O
N
F
CH
3
2-27
2-23










Tng hp midazola (2-24)
-37-
2-30
N
N
Cl
F
NXCH
3
2-32
N
H
N
Cl
F
NO
2
N
H
N
Cl
CH
2
F
N H
2
CH
2
NO
2
2-31
N
N
Cl
CH
2
F
C H
3
N
CH
3
-C(OC
2
H
5
)
3 -H
2
/MnO
2
N
N
Cl
CH
F
C H
3
N
2-24


Trong hp cht khi u 2-28 c iu ch theo s phn ng sau
-38-
Cl
NH
2
O
F
H
2
NOH
Cl
NH
2
NOH
F
ClCH
2
COCl
NaOH
Cl
NH-COCH
2
Cl
NOH
F
HCl
Cl
F
N
N
CH
2
Cl
O
H
2
NCH
3
Cl
F
N
H
N
NHCH
3
O
Cl
F
N
N
NHCH
3
2-33
2-34
2-35 2-36
2-37
2-38

c, Cc thuc m nhm steroit:
- Tnh a dng sinh hc ca cc hp cht khung steroit.
- Lch s pht hin ra thuc m loi steroit.
Ti vin nghin cu dc l Monstreal J.Selye (1941) c 1 tr l cho
hay l ton b s chut th nghim b cht do iu tr progesteron. T pht hin
ny, nm 1955 hng dc phm Pfizer pht minh ra thuc ng loi steroit tim
tnh mch u tin l natri hydroxydion (2-38) v sau l cc cht alfadolone
axetat (2-39), alfaxalone (2-40), minaloxone (2-41).
-39-

Bit dc Althesin l bit dc ca hng dc phm Glaxo (hn hp
alfaxalone v alfaxalone-axetat t l 3:1).
d, Cc thuc m khc:
Gm cc thuc m c cu trc b khung khc nhau. l: Dolitrone (2-
42), propanidid (2-43), etonidate (2-44), ketamine (2-45), phencyclidine (2-46).
S
N H
O
O
C
2
H
5
2-42
H
3
CH
2
CH
2
COOCH
2
C
OCH
3
(H
5
C
2
)
2
NOCH
2
CO
2-43
N N C H
CH
3
COOC
2
H
5
2-44

Cl
O
NHCH
3
2-45
N
2-46

-40-
Tng hp etomidate (2-44)
CH
CH
3
NH
2
+ ClCH
2
CN
N(C
2
H
5
)
2
CH
CH
3
NHCH
2
CN
HCOOH/NEt
3
CH
CH
3
N CH
2
CN
CHO
C
2
H
5
OOCH
NaOCH
3
CH
CH
3
N CH
CHO
CHO
CN
2-47
2-48 2-49
NaSCN
NaOCH
3
CH
CH
3
N
C NH
2
S
CH
3
NC
2-50
CH
CH
3
N
C N
SH
H
2
NOC
2-51
H
2
SO
4
-HNO
3
CH
CH
3
N
CH N
H
2
NOC
2-52
CH
CH
3
N
CH N
H
5
C
2
OOC
2-44

Tng hp ketamine (2-45)
Cl
CN
+
BrMg
Cl
C
NH
H
2
O
Cl
C
O
Cl
C
O
Br
CH
3
NH
2
/H
2
O
Cl
C
N
O H
CH
3
Cl
C
N
+
O H
CH
3
H
Br
2
Cl
C
N H
CH
3
O H
C H
2
Cl
NHCH
3
+
2-53
2-54
2-55
2-56
2-57
2-45







-41-

Tng hp phecyclidine (2-46)

O
KCN
CN
OK
piperidin.HCl
CN
N
N
+
MgBr
N
2-58
2-59
2-46


2.2.3. CC THUC GY NG
2.2.3.1. I CNG
- nh ngha: l thuc c ch thn kinh trung ng to gic ng sinh l.
An thn ng m cht
C ch chung ca thuc ng: c ch cc chc phn ca h li m
vai tr dn dt v chn lc nhng thng tin t ngoi bin vo v no. Thuc
ng cn lm tng tch ly axit -aminobutyric (GABA) (cht c ch tin
synap no) v glyxin (cng l cht c ch).
2.2.3.2. NHM THUC NG (AN THN)
Gm cc nhm sau: ancol, andehit, dn xut uretan, cc amit, dn
xut barbituric, nhm dioxopiperidin, nhm diazepam v cc nhm khc.
2.2.3.2.1. Cc loi thuc ng loi ancol.
- Thuc ng u tin c pht hin l ancol etylic. Nng trong mu
0,08%: sng khoi; 0,2%: i ng lo o, say; 0,3%: say hon ton, long
chong, phn x ri lon: 0,4%: hon ton mt tri gic; 0,5%: lit trung tm
h hp, ngng tim.
- Cc ancol khc:









-42-
C C CH
2
OH
CH
3
CH
3
C H C C CH
OH
CH
2
CH C H Cl
CH
3
Cl C C
Cl
Cl
CH
3
OH
CH
3
2-60
2-61
2-62


Cl C C
O H
CH
3
CH
3
OH
CH
3
C C
O H
H
CH
3
OH
CH
3
2-63
2-64



2-65

2.2.3.2.2. Cc thuc ng nhm andehit.
Thuc ng andehit u tin l tricloro-axetandehit (cloral
hidrat).J.V.Liebig iu ch 1832, O.Liebreich (1869) a vo iu tr.
Trong c th cloral hidrat nhanh chng chuyn ha thnh hp cht c tc
dng l tricloetanol.

2-70 2-71

Ngoi ra cn c:
O
CH
O
Cl
3
C
(CH
2
OH)
2
Cl
3
C C H
CH
3
O CH
CH
3
C(CH
3
)
2
OH
Cl
3
C C H
OH
NH CHO


CH
3
CHO
O
O
O
CH
3
C H
3
C H
3
2-72




2.2.3.2.3. Cc thuc ng nhm uretan, ureit.
C nhiu cht a vo lm thuc, hin ang s dng cc cht nh sau:
Meparfynol
Ethchlorvynol
Chlorbutanol
phenaglycodol
centalum
Polyetylenglycol
Penthricloral
Cholorhexado
l
Cloralformam
it
Paraaldehit
-43-
- iu ch bromisoval uretan (2-76)
(CH
3
)
2
CHCHBrCONHCONH
2
(C
2
H
5
)
2
CBrCONHCONH
2

2-76 2-77
Bromisoval carbomal
(bromural, Albroman) (bromadal, Adalin)

(C
2
H
5
)
2
CBrCONHCONHCOCH
3

2-78 2-79
Acetylcarbomal apronalide
(abasin, sedamyl) (sedormid, isodormid)

*iu ch Bromisoval uretan (2-76)

Bromisoval

* iu ch carbomal (2-77)

(C
2
H
5
)
2
C(COOC
2
H
5
)
2
NaOH/C
2
H
5
OH
lm nng
(C
2
H
5
)
2
C(COONa)
2
H
2
O/H
+
(C
2
H
5
)
2
C(COOH)
2
(C
2
H
5
)
2
CHCOOH
180
0
SOCl2
(C
2
H
5
)
2
CHCOCl
Br
2
(C
2
H
5
)
2
CBrCOHlg
(C
2
H
5
)
2
CBrCONHCONH
2
CO(NH
2
)
2
lm nng

2.2.3.2.4. Cc thuc ng c dn xut amit.
Trong nhm ny c isovaleryl dietylamide (2-81) v propanidid (2-43)
(CH
3
)
2
CHCH
2
CON(C
2
H
5
)


2-81
isovaleryl dietylamide propanidid

(Valyl, Xalyl) (Epontol, Sombrevin)

*Tng hp propanidid (2-43)

-44-

2.2.3.2.5. Cc thuc ng dn xut axit bacbituric.
Bayer (1863) iu ch ra axit bacbituric.
F.Fischer (1903) iu ch v a vo s dng 5,5 dietyl bacbituric
(veronal).
* ngha vic tm ra veronal vi nghin cu ha dc: iu ch ra 1200
dn xut trong c 60 cht c dng lm thuc.
* Lin quan cu trc v tc dng
C
NH
C
NH C
H
2
C
O
O
O
1
2
3
4
5
6
2-82
C NH
C
NH C
C
O
O
O
R
1
R
2
2-83

+ Axit bacbituric khng c tc dng.
+ Thay 1H C
5
bng R
1
tc dng gy ng km.
+ Thay 2H C
5
bng R
1
,R
2
tc dng gy ng tng nhng R
1
,R
2
>6C, R
1
+R
2

<8C th tc dng gim.
+ R
1
hoc R
2
lin kt kp tc dng gy ng tng.
+ R
1
v R
2
l mch nhnh hoc mch vng tc dng tng nhng thi gian
tc dng ngn.
axit bacbituric bacbiturat
-45-
+ Thay 1H C
5
bng phenyl xut hin tc dng chng co git, tc dng ko
di, nhng thay c 2H mt tc dng gy ng.
Phn loi cc bacbiturat:
- Loi tc dng cc ngn (0,5-1h)
- Loi tc dng ngn (1-3h)
- Loi tc dng trung bnh (4-8h)
- Loi tc dng bn (8-12h): tan nhiu trong nc.
Bng 2.3. Cc thuc ng loi bacbiturat


Tn chung R
1
R
2
R
3
R
4
Bit dc
1. Loi tc dng bn
Phenobarbital (2-84) etyl phenyl H H Gardenal
barbital (2-85) etyl Etyl H H Veronal
butobarbital (2-86) etyl n-butyl H H Soneryl
aprobarbital (2-87) allyl allyl H H Alonal
2. Loi tc dng trung bnh
amobarbital (2-89) etyl isoamyl H H Amyltal
heptabarbital (2-90) etyl 1-cycloheptenyl H H Medomin
pentobarbital (2-91) etyl 1-metyl butyl H H Nembutal
cyclobarbital (2-92) etyl 1-cyclohexenyl H H Phanodorm
3. Loi tc dng ngn
secobarbital (2-93) allyl 1-metylbutyl H H Imesonal
Hexobarbital (2-94) metyl 1-cyclohexenyl CH
3
H Evipan
-46-
4. Loi tc dng cc ngn
thiopental (2-95) etyl 1-metylbutyl H H Trapanal
thiobarbital (2-96) allyl 2-cyclohexenyl H H Kemithal
* Tc dng dc l:
- Tc dng trn thn kinh: c ch thn kinh trung ng. Ty loi
barbiturat, ty liu lng, cch dng (ung hay tim) hoc ty trng thi ngi
bnh m s c tc dng an thn, gy ng hoc gy m. Barbiturat lm du c
phn ng tm thn gy nn do nhng cn au, c th phi hp tt vi loi thuc
h st gim au.
Vi liu gy m, barbiturat c ch ty sng lm gim phn x a suynap
v n suynap. Liu cao lm gim p lc dch no ty.
- Trn b my h hp: c ch trc tip trung tm h hp hnh no nn
lm gim bin v tn s cc nhp th. Liu cao hy hoi trung tm ny, lm
gim p ng vi CO
2
.
- Trn b my tun hon: Liu gy m lm gim lu lng tim v h
huyt p, liu c c ch c tim.
*Tc dng ph: Gy nghin (quen thuc), iu ny trc ht biu
hin qua vic tng liu dng, nhng nu s dng lin tc th hnh thnh nn s l
thuc vo thuc.
*Phng php chung tng hp cc barbiturat.
- Tng hp cc nguyn liu trung gian.
COOR
CH
2
COOR
R
1
X/RONa
COOR
CHR
1
COOR
R
2
X/RONa
COOR
C
COOR
R
1
R
2
2-97
2-98 2-99
COOR
CH
2
CN
R
1
X/RONa
COOR
CHR
1
CN
R
2
X/RONa
COOR
C
CN
R
1
R
2
2-101 2-102
2-100

- Tng hp barbiturat t diankyl 2,2 diankylmalonat.
-47-
COOR
C
COOR
R
1
R
2
2-99
HN=C(NH
2
)
2
C NH
C
NH C
C
O
NH
O
R
1
R
2
C NH
C
NH C
C
O
O
O
R
1
R
2
C NH
C
NH C
C
O
NH
O
R
1
R
2
N
C
H
N
C
=
(
N
H
C
H
2 )
2-103
2-83
2-104
H
2
O/H
+
, nng

- Tng hp barbiturat t ankyl diankyl xianoaxetat
-48-
COOR
C
CN
R
1
R
2
2-102
C NH
C
NH C
C
O
O
NH
R
1
R
2
2-105
C NH
C
NH C
C
O
NH
NH
R
1
R
2
C N
C
NH C
C
O
NH
NH
R
1
R
2
CN
NH=C(NH
2
)
2
2-107 2-106
C NH
C
NH C
C
O
O
O
R
1
R
2
H
2
O/H
+
/
H
2
O/H
+
/
H
2
O/H
+
/
2-83

*iu ch barbital (2-85) (veronal): c nhiu phng php i qua cc
hp cht trung gian khc nhau. Sau y l s tng hp cc phng php .




-49-
Phng php ca Wacker i t nguyn liu trung gian ca cng nghip
axetylen.


*iu ch phenobarbital (2-84) (Gardenal, sevenal)

*iu ch mui natri ca phenobarbital.
-50-

*iu ch hexobarbital(2-94)


2.2.3.2.6. Cc thuc ng dn xut ca dioxopiperidin
- Cc dn xut 2,4- dioxopiperidin
-51-
N
H
C
2
H
5
C
2
H
5
O
O
2-116

N
H
C
2
H
5
C
2
H
5
O
O
2-117


- Cc dn xut 2,6- dioxopiperidin

(H
3
C)
2
C NH
2-127
O
O


* Dn xut glutarimit: bemegride (2-126)
Bemegride l cht c tc dng i khng cnh tranh vi cc Cc dn xut
barbiturat v th c s dng lm cht gii c thuc ng rt tt.
Pyrithyldio
n
methyprylo
n
dihyprilon
bemegride glutethimide (redimyl) aminoglutethimide
-52-
C
O
C
2
H
5
H
3
C
CH
2
NC
CONH
2
C
C
2
H
5
H
3
C
C
NC CONH
2
C O
NH
2
NC
C
2
H
5
C
N
H
3
C
CONH
2
C
C
N
H
C
CH
NH
O
H
3
C
CONH
2
NC
C
2
H
5
2-135
C
C
N
H
C
NH
O
H
3
C
NC
C
2
H
5
C
C
N
H
C
O
O
H
3
C
C
2
H
5
2-126

- Thalidomide (2-137) v rc ri ng nh ca n.


+ Nm 1957 cng ty dc phm Chemie Grumenthal (c) cng b sng
ch c quyn.
+ Thuc t c: liu dng 100mg nhng ung 14g vn khng vic g.
+ 1961: pht hin ra vic pht trin chn tay khng bnh thng i vi tr
s sinh khi ngi m dng thuc ny trong thi k c thai.
+ Khp Chu u trong 5 nm 10 vn tr em sinh ra thiu tay chn, 20% s
s sinh b.
2.2.3.2.7. Cc thuc nhm benzodiazepin
- u im ca loi thuc ng diazepin: To gic ng n nhanh, lm gim
s ln thc gic ngi b mt ng. Dng cha mt ng do u t, lo
lng hoc kh i vo gic ng.
-53-
- Lch s pht minh:
Nm 1957 Leo Sternbach nh ha hc ngi M chuyn cho mt
nh dc l ca hng Hoffman La Roche l Lowell Randal mt hp cht
iu ch t 2-138 vi gi thit hp cht ny c cu trc 2-139

Sau vi hm th nghim L.Randal thng bo cho Sternbach mt tin
hp dn rng hp cht k trn c tc dng an thn ging nh meprobamate
(2-443),(l thuc an thn th yu) nhng li tt hn nhiu. Sau khi pht
hin dc l ny cu trc ha hc ca cht k trn c xc nh li th cu
trc khng phi l hp cht 2-139 m l chlordiazepoxide (2-140). K t
nhm hp cht 1,4-benzodiazepin c bc ra l i. Nm 1960
Librium bit dc ca 2-140 c tung ra th trng, nhiu nghn hp cht
c tng hp a vo th tc dng, hin c trn 50 cht ang c s
dng lm thuc.
- Cc gt hi ca Roche trong nhm hp cht ny:
+ 1960: Librium.
+ 1963: Valium.
+ 1970-1976: Mogadon, Rohupnol, Dormicum.
Nm 1987 hng Roche tm ra cht tc dng i khng vi cht
diazepin l mefenorex (Anexate) (C
6
H
5
CH
2
CH(CH
3
)NH(CH
2
)
3
Cl) iu
tr ng c (gii c) cc thuc h diazepin.
- Cc hng c uy tn trong nghin cu cc dn xut diazepin.
+ Upjohn: cht 3 vng triazolo-1,4-benzodiazepin (triazolam(1-170)).
+ Hoeschts: a dn xut 1,5-benzodiazepin (clobazam(2-177)).
+ Wyeth: nghin cu chuyn ha diazepam v phn lp c oxazepam-
cht chuyn ha c hot tnh.
+ Sankyo: tng hp ra cc hp cht 3 vng oxazolo-1,4-benzodiazepin.
(oxazolam (2-165)).
+ EGYT iu ch dn xut 2,3-benzidiazepin (tofisopam, 2-175).
*Phn loi cc diazepam: chia thnh 6 nhm:
I. Cc dn xut 7-cloro-1,4-benzodiazepin.
II. Cc dn xut 7-bromo-1,4-benzodiazepin.
III. Cc dn xut 7-nitro-1,4-benzodiazepin.
IV. Cc dn xut axazolo-1,4-benzodiazepin.
V. Cc dn xut triazolo-1,4-benzodiazepin.
-54-
VI. Cc dn xut c cu trc c bit.
Cl N
N
O
2-144
OH
H
CH
3
Cl N
N
O
2-141
CH
3
Cl N
H
N
O
2-143
OH
H
Cl N
H
N
O
Cl O
NH
2
2-142

Bng 2-4. Bng lit k mt s dn xut 1,4-benzodiazepin quan trng
nht


2H-1,4-benzodiazepin-2-on


I. Cc dn xut ca 7-cloro-1,4-benzodiazepin (X=Cl)
-55-
Tn cht v bit dc R
1
R
2
R
3
Nm
iu
ch
Diazepam (2-141) (Valium,
Seduxen)
CH
3
H H 1961
Nordazepam (2-142) (Calmday,
Madar)
H H H 1961
Oxazepam (2-143)(Adumbran,
Serax)
H OH H 1962
Temazepam (2-144)(Cerepax,
Levanxol)
CH
3
OH H 1962
Fludiazepam (2-145)(Erispan) CH
3
H F 1962
Medazepam (2-146)(Nobrium,
Rudotel)
CH
3
H H 1963
Lormetazepam (2-
147)(Loramet,Noctamid)
CH
3
OH Cl 1963
Lorazepam (2-148)(Ativan, Tolid) H OH Cl 1964
Flurazepam (2-149)(Dalmane,
Dalmadorm)
(CH
2
)
2
N(C
2
H
5
)
2
H F 1964
Prazepam (2-150)(Centrax,
Verstran)
H H 1965
Flutoprazepam (2-151)(Restas)

H F 1967
Clorazepate (2-152)( Belseren,
Tranxene)
H COOK H 1968
Halazepam (2-153)(Paxipam) CH
2
CF
3
H H 1969
Ethyloflazepate(2-154)(Vietan) H COOC
2
H
5
F 1970
Quazepam (2-155)(
Centrax,Dormalin)
CH
2
CF
3
H F 1971
Camazepam (2-156)(Albego) CH
3
OCON(CH
3
)
2
H 1972
Doxefazepam(2-157)(Doxaus) (CH
2
)
2
OH OH F 1974
Ghi ch: C=O v tr C
2
c thay bng *CH-OH,**CH
2
,***C=S.
Cc cht c s dng lm thuc ng:
Diazepam,Temazepam,Lormetazepam,Flurazepam,Quazepam,Doxefazepam
II. Cc dn xut ca 7-bromo-1,4-benzodiazepin (X=Br)
Tn cht v bit dc R
1
R
2
R
3
Nm
iu
ch
Bromazepam(2-158)(Lexomil,Lexotani) H H N** 1962
Metaclazepam (2-159)(Talis)* CH
3
H Cl 1974
Ghi ch : C=O v tr C
2
c thay bng CH-CH
2
-O-CH
3
III. Cc dn xut 7-nitro-1,4-benzodiazepin(X=NO
2
), **N trong nhn
-56-
Tn cht v bit dc R
1
R
2
R
3
Nm
iu
ch
Nitrazepam (2-160) (Eunoctin, Mogadon) H H H 1963
Nimetazepam (2-161)(Elimin,Hypnon) CH
3
H H 1963
Clonazepam (2-162)(Clonopin,Rivotril) H H Cl 1963
Flunitrazepam (2-23)(Rohypnol,Roipnol) CH
3
H F 1963
Ghi ch: Clonazepam s dng lm thuc chng ng kinh, cn ba th khc ch l
thuc ng.
IV. Cc dn xut axazolo-1,4-benzodiazepin

Tn cht v bit dc R
1
R
2
R
3
R
4
R
5
Nm
iu
ch
Mexazolam(2-163)(Melex) H CH
3
H Cl Cl 1967
Cloxazolam(2-164)(Enadel,Sepazon) H H H Cl Cl 1969
Oxazolam(2-165)(Sevenal,Tranquit) H H CH
3
H Cl 1969
Flutazolam(2-166)(Coreminal) CH
2
OH H H F Cl 1969
Haloxazolam(2-167)(Somelin) H H H F Br 1971
Ghi ch: haloxazolam c s dng nh l thuc ng
V. Cc dn xut triazolo-1,4-benzodiazepin



Tt Tn cht v bit dc R
1
R
2
Nm iu ch
1 Estazolam(2-168)(Eurodin,Juloam) H H 1970
2 Alprazolam(2-169)(Xanax) CH
3
H 1970
3 Triazolam(2-170)(Halcion) CH
3
Cl 1970
4 Midazolam(2-24)(Dormic,Hypnovel) CH
3
F 1976
-57-
Ghi ch: Trong midazolam th N* thay bng CH
2,
cc cht c s dng lm thuc
ng l estazolam va midazolam.

Bng 2-5. Cc benzodiazepin c cu trc c bit

I. Cu trc 1,4-benzodiazepin








II. Cc hp cht cu trc 1,5 v 2,3- benzodiazepin.

N
N
O
CH
3
2-177
Cl
O
N
N
CH
3
C
2
H
5
2-178
H
3
CO
OCH
3
OCH
3
H
3
CO


Ngoi cc benzodiazepin tng hp nh lit k trong bng 2-4 v
2-5 trn th trong t nhin cng tn ti mt s hp cht l dn xut 1,4-
2-171
lopazolam
2-172
ketazola
m
clotiazepam
-58-
benzodiazepin (m ch yu l do Streptomyces sn sinh ra), sau y l 3 hp cht
trong s :




Cc benzodiazepam cng c thi gian bn phn hy cng khc nhau (bng
2-6)
Bng 2-6. Thi gian bn phn hy ca mt s benzodiazepam.
TT Tn hp cht Thi gian bn phn hy(h)
1 Flurazepam(2-149) 74
2 Nordazepam(2-142) 62
3 Diazepam(2-141) 43*
4 Nitrazepam(2-160) 26
5 Clonazepam(2-162) 23
6 Flunitrazepam(2-23) 15*
7 Lorazepam(2-148) 14
8 Temazepam(2-144) 13
9 Alprazolam(2-169) 10,6
10 Chlordiazepoxide(2-140) 10*
11 Oxazepam(2-143) 7,6
12 Triazopam(2-170) 2,3
13 Clorazepate (2-152) 2*
14 Prazepam (2-150) 1,3*
* Cht chuyn ha to thnh ca n cng c hot tnh do c th ko di
thm tc dng.
* Chuyn ha ca cc benzodiazepam trong c th - (flunitrazepam)
-59-
O
2
N
F
2-123
N
N
O
CH
3
H
2
N
F
N
N
O
CH
3
HN
F
N
N
O
H
Ac
O
2
N
F
N
N
O
H
O
2
N
F
N
N
O
CH
3
OH
H
2
N
F
N
N
O
H
f lunitrazepam

-60-
Cl
Cl
2-170
N
N
triazolam
N
N
H
3
C
Cl
Cl
N
N
N
N
H
3
C
OH
Cl
Cl
O
N
N
N
H
3
C
CH
2
OH
thuy phn
Cl
Cl
N
N
N
N
HOH
2
C
OH
-
OH
-
OH
-
Cl
Cl
N
N
N
N
HOH
2
C
thuy phn
OH
Cl
Cl
O
N
N
N
HOH
2
C
CH
2
OH

-61-
Cl
N
N
O
H
OH
thuy phn
Cl
O
CH
2
OH
C
N
O H
(NH
2
)
2
CO
Cl
O
CH
2
NHCONH
2
C
N
O H
2-143
oxazeam
+ H
2
nhn thom
Cl
N
N
O
H
OH
OH
Cl
N
N
O
H
OH
OCH
3
Cl
N
N
NHCH
3
O
Cl
N
N
NH
2
O
Cl
N
H
N
O
2-140
chlordiazepoxide
Cl
N
NH
2
CH
2
COOH
O
Cl
O
NH
2

* Lin quan gia cu trc v tc dng
B khung c bn l 5-phenyl-1,4-benzodiazepin.

-62-
-Nu thay 1,4-benzodiazepin bng 1,5-benzodiazepin hoc vng A benzo
bng thieno pyrazolo cht to thnh vn c hot tnh.
-Ph C
5
lm tng hot tnh.
-Cc H 1,2,3 c th thay i, gn vng triazolo hay imidasolo vo v tr
1,2 cht to thnh vn c hot tnh.
- v tr 7 nhm ht in t tng tc dng, nhm y in t gim tc dng.
-Vng B lun lun vng 7 cnh v cha 2 nguyn t N.
-Vng C lun l benzen, cc nhm th C
2
ht in t tng hot tnh.
Nu thay vng C bng oxo v tr 5 v CH
3
vo v tr 4 th flumazenil (2-
176) to thnh c tc dng khng li benzodiazepin.
*Tc dng dc l:
Trn thn kinh trung ng: an thn, gim ho, gim hung hn, lm d ng,
chng co git, lm gin c.
Tc dng ngoi bin: gin mch vnh, phong ta thn kinh c.
*C ch tc dng:
Lm tng hot tnh GABA- cht dn truyn thn kinh c ch no.
Benzodiazepin i lc trn th th c hiu mnh hn protein ni sinh nn
n y protein ni sinh ra v chim c receptor do GABA mi gn
c vo receptor.
*Tc dng khng mong mun:
- Khi nng trong mu cao hn liu an thn th t ti liu gy ng. Cc
triu chng c th gp: u oi, ng tc khng chnh xc, l ln, ming kh
ng, gim tr nh.
- c tnh trn thn kinh gim theo tui
- V tm thn i khi gy tc dng ngc: c mng, bn chn, lo lng, nhp
tim nhanh, v m hi.
*Ch khi dng thuc:
- Trnh dng cho ngi b tm thn trm cm hoc c khuynh hng t t.
- Thn trng khi dng cho ngi b bnh ng h hp, nhc c, ph n
c thai v cho con b.
- Cc triu chng nhc u, chng mt, chong vng c th ko di n
ngy hm sau nht l vi thuc c tc dng ko di v th cn lu i vi
nhng ngi li xe hoc ngi vn hnh my.
- Cn gim liu cho ngi c tui hoc b suy nhc.
*Tng hp diazepam (2-141):(Valium, Seduxen,Sedapam).








-63-
a. L.H. Sternbach v E. Reeder (1961)
Cl
N
N
O
O
Cl
N
H
N
O
Cl
O
NH
2
2-182
H
2
N-OH
Cl
N
NH
2
OH
2-183
1. CH
2
Cl
2. NaOH
H
2
O
2
2-184
CH
3
2-141


b. C. Stanley (1964)

c. A.G. Archer (1964)

d. i t 6-cloro-2,4-diphenyl-quinazolin
-64-



* Tng hp Flumazenil (2-176)

* Tng hp triazolam(2-170) (Clorazolam, Halcion):
-65-

* Tng hp chlordiazepoxide (2-140) (Librium, Libritabs, Zetran):
N
N
CH
2
Cl
Cl
NH
2
+ 2
CoCl
ZnCl
2
Cl
N
N
C
6
H
5
OH
Cl
Cl
NH
2
H
(+)
O NH
2
OH
Cl
NH
2
NOH ClCH
2
COCl
Cl
NHCOCH
2
Cl
NOH
HCl
Cl
O
N
N
NHCH
3
Cl
O
2-140
chlordiazepoxide
NH
2
CH
3
2-194

-66-
* Tng hp cloxazolam (2-164)(Enadel, Sepazol) v oxazolam (2-165)
(Oxazolazepam,Serenal, Tranquit)
Cl
O
NH
2-195, X= Cl
Cl
O
CH
2
NH(CH
2
)
2
OH
N
S
H
O
CH
2
Br
X
2-196, X= H
NH
2
(CH
2
)
2
OH
Cl
AcOH
N
H
N
O
Cl
O
Cl
2-164
cloxazolam
NH
2
CH
2
CH CH
3
OH
O
HN
O
Cl
HN
CH
3
OH
AcOH
N
H
N
O
Cl
O
CH
3
oxazolam

* Tng hp brotizolam (2-173) (Lendrom, Lendromin)
-67-

2.2.3.2.8. Cc thuc ng thuc nhm cu trc khc:
- Cu trc 3H-quinazolinon















-68-


- Tng hp 2-203, 2-204 v 2-205

- Cu trc khc:

2.2.4. CC THUC CHA NG KINH (ANTIEPILEPTIC)
2.2.4.1. I CNG
ng kinh: L hot ng qu kch thch ca thn kinh tm thn dn
n co git.
nh ngha thuc cha ng kinh: L thuc c kh nng loi tr
hoc lm gim tn s mc trm trng ca cc cn ng kinh hoc cc
triu chng tm thn km theo bnh ng kinh. Thuc chng ng kinh
khng ng ngha vi thuc chng co git.
C ch sinh ng kinh: c nhiu nguyn nhn, nhng nguyn nhn
chnh l c 1 s t bo thn kinh nht nh no phng in ng thi.
-69-
Cch tc dng ca thuc ng kinh: lm gim phng in hoc
tng ngng chu ng kch thch.
* Yu cu mt thuc cha ng kinh tt:
+ t tc dng ph v ng gy quen thuc hoc gy nghin.
+ Thuc c tc dng c hiu l chng co git, ng lm mt tri gic.
+Thuc phi hp thu theo ng ung, c thi gian tc dng di.
* Cc loi ng kinh:
+ Cn ng kinh th ln (Grand mal): ng kinh ton thn lm mt thc
hon ton thng ko di 1 vi pht (thuc : phenyltoine, phenobactital).
+ Cn ng kinh th nh (Petit mal): mt thc thong qua, c hoc khng
km nhng c ng bt thng ca mt, u, chn tay (thuc: ethosuximide,
trimethadione).
+ Cn ng kinh th tm thn vn ng (Psychomotor epiepsia) hay l cn
ri lon tm thn, tc phong, xc cm, c nhng tc ng khng iu ha c
(carbamazepine)
Cc thuc ng kinh a tr: c tc dng ti nhiu th ng
kinh.(clonazepam, acetazolamide, progabide).
2.2.4.2. CC NHM CHA NG KINH
Phn theo nhm cu trc ha hc gm c 6 nhm sau:
2.2.4.2.1. Cc dn xut ca barbituric
Cc dn xut barbiturat c cp trong phn 2.2.3.2.5 (thuc
ng), nu C
5
thay 1 H bng nhm phenyl th dn xut c tc dng chng
co git s dng chng ng kinh, gm cc thuc sau:
C
NH
NH
O
O
O
C
2
H
5
2-84
phenobarbital
(Sevenal, Luminal)
C
NH
N
O
O
O
C
2
H
5
CH
3
2-211
mephobarbital
(Prominal, Mebaral)
C
NH
NH
O
O
C
2
H
5
2-212
primidone
(Sertan, Mylepsin)

2.2.4.2.2. Cc dn xut ca hidantoin
Vic tm ra diphenylhidantoine l mt cuc cch mng trong iu tr
bnh ng kinh (khng gy cho bnh nhn bun ng, khng ri lon nhp
tim).
T nm 1908-1976 tng hp ra 800 dn xut ca hidantoin . Sau
y l mt vi dn xut quan trng ang c s dng (bng 2-7).
Bng 2-7. Mt vi dn xut ca hidantoin quan trng nht.
-70-
N
N
H
O
O
R
3
R
2
R
1
1
2
5
3 4

Tn cht v bit dc R
1
R
2
R
3
Thi gian iu
ch (s dng )
Liu dng
1 ngy (g)
Phenytoin (2-213)
(Dihydan,Dilatin,Zentropil)
C
6
H
5
C
6
H
5
H 1908 (1938) 0,2-0,6
mephenytoin (2-214)
(Insulton,Mesantoin,Sacerno)
C
2
H
5
C
6
H
5
CH
3
1934 (1939) 0,2-0,6
Ethotoin (2-215) (Peganone) H C
6
H
5
C
2
H
5
1988 (1957) 2-3
Nhng im quan trng lin quan gia cu trc v tc dng:

N
N
H
O
O
R
1
2
5
3
4


- c tc dng ng kinh ti thiu phi c 1 nhm phenyl C
5
.
- Tc dng mnh nht nu 2H C
5
thay bng 2 nhm phenyl.
- Mt tc dng nu hai nhm phenyl bng 2 nhm benzyl.
- Trn phn phenyl nu c cha nhm th lm gim hoc lm mt tc dng.
- M vng imidazolidin th hp cht mt tc dng.
* Tng hp phenyltoin(2-213): benzandehit benzoin benzyl

CHO
KCN
C
O
CH
OH
benzoin
cc HNO
3
C
O
C
O
ure/C
2
H
5
OH/OH
C O
C
6
H
5
O
(-)
C
6
H
5
NHCONH
2
C
C
6
H
5
C
6
H
5
NHCONH
2
COO
(-)
chuyn vi
benzilic
HN
(C
6
H
5
)
2
C
C
N
(-)
O
O
Me
(+)
H
(+)
/H
2
O
2-213
phenytoin

-71-
* Tng hp mephenyltoine (2-214),(2-215): tng hp theo phng php
ca Buchrer-Bergs


2.2.4.2.3. Cc dn xut ca oxalidon
Nit v tr s 1 trong hidantoin thay bng oxi cc hp cht nhm ny c
tc dng chng ng kinh th nh (petit mal). Cc hp cht trong bng (2-8) sau
y ang c dng:
Bng 2-8. Mt s oxazolidon c tc dng chng ng kinh


Tn cht v bit dc R
1
R
2
R
3
Nm
iu
ch
Liu
dng 1
ngy (g)
Trimetadione(2-
216)(Absentol, Trimedal,
Tridione, Ptimal)
CH
3
CH
3
CH
3
1944 0,8-1
Paramethadione (2-
217)(Paradione)
CH
3
C
2
H
5
CH
3
1951 0,4-0,6
Dimethadione (2-
218)(Eupractone)
CH
3
CH
3
H 1888 0,9-2,4
Ethadion(2-219)
(Dimedion,Epinyl, Petidion)
CH
3
CH
3
C
2
H
5
1949
Aloxidone (2-220) (Malidone,
Malazol)
H CH
3
CH
2
CH=CH
2
1949
-72-

* iu ch Trimetadione(2-216): M.A.Spielman(1951)



* iu ch 2-216,2-217,2-218,2-219,2-220
C
R
1
R
2
C
R
1
R
2
CN
O
C
R
1
R
2
CN
OH
C
R
1
R
2
C
O
NH
KSCN
O
HCN
(KCN)
HS=CN S=C=NH
S
NH
2
NH
S
H
(+)
/H
2
O
C
R
1
R
2
C
O
NH
O
S
Br
2
/dd NaBr
hoac nuoc bro
C
R
1
R
2
C
O
NH
O
O
2-216
2-217
2-218
2-219
2-220


2.2.4.2.4. Cc dn xut ca succinimit
Cc hp cht nhm ny c iu ch ra trn c s ca hai nhm hidantoin
v oxazolidon (thay NH hay O v tr 1 bng CH
2
- . Cc hp cht trong bng 2-9
sau y c a vo s dng:

Bng 2-9. Mt s dn xut succinit lm thuc chng ng kinh

Tn cht v bit dc R
1
R
2
R
3
Thi
gian
iu
ch(s
dng )
Liu
dng
1
ngy
(g)
Ethasuximide (2-222)(Ethymal,
Pemal,Zarcntin)
CH
3
C
2
H
5
H 1927 0,5-
1,5
-73-
mesuximide (2-223)(Celontin,
Petinutin)
CH
3
C
6
H
5
CH
3
1951 0,6-
1,2
phensuximide (2-
224)(Liphene,Milontin,Succitimal)
H C
6
H
5
CH
3
1951 2-4
Morsuximide (2-225)
(Morfolep,Perlepsin)
CH
3
C
6
H
5


1962 0,5-2

*iu ch Ethasuximide (2-222)


* iu ch mesuximide (2-223) v phensuximide (2-224)
2.2.4.2.5. Cc dn xut axyl-cacbamit

Barbiturat, hidantoin l amit vng ca cacbamit, liu amit khng vng ca
cacbamit c tc dng hay khng ? M.A.Spielman nghin cu v tr li cu hi
ny ( iu ch ra trn 50 hp cht, cc cht trong bng 2-10 sau y tr thnh
thuc )

Bng 2-10. S liu mt s dn xut axyl-cacbamit quan trng nht

C
6
H
5
CH CONHCONH
2
R

Tn cht R Nm iu
ch
Liu dng 1
ngy (g)
Phenacemide(2-230) (Epiclase,
Neophedan, Phenurone)
H 1933 0,5-2
-74-
Ethyphenacemide(2-
231)(Pheneturide,Benuride,Trinuride)
C
2
H
5
1912 0,6-1
Chlorphenacemide(2-
231)(Comitiadon)
Cl 1956 0,5-1

Cc thuc loi ny ch yu iu tr cc cn ng kinh th tm thn vn
ng.
Tng hp Phenacemide(2-230) v ethyphenacemide(2-231) theo
M.A.Spielman

2.2.4.2.6. Cc thuc ng kinh nhm khc
Gm cc hp cht cha b khung n c nh sau:




-75-
- Valproic acid (2-233) tr c cc loi ng kinh, c bit l th nh khng
c cn co git.
- Beclamide (2-234) tr ng kinh th ln v ngng cc cn ng kinh th
tm thn vn ng (nay t dng)
- Acetazolamide (2-236) tr ng kinh a tr, li tiu, glocom.
- Cacbamazepine(2-240) iu tr bnh ng kinh th tm thn vn ng v
au thn kinh.
- Progabide(2-241): c tc dng trn mi loi thn kinh
*Tng hp progabide (2-241)

2.2.5. CC THUC GIM AU
2.2.5.1. I CNG
-au l g?
-Cc tc dng gy au.
-Chu k x l ca h thn kinh trung ng khi c th b kch thch.
-Cc phng thc lm gim au ca thuc:
+Lm t lit cm gic ca cc chi (ti ch)
+Lm gim kh nng dn truyn ca thn kinh trung ng.
+Lm gim nhy cm ca thn kinh trung ng nng cao mc (ngng)
chu au.
Thuc gim au u tin l nha thuc phin (opium) ,m hot cht chnh
l morphine
Cc nguyn nhn gy au ca c th:
+au do co hp mch mu (thiu oxi) (cht gin mch)
+au do co c h thng tiu ha (thuc gin mch)
+au do c th gii phng ra oligopeptit l hoc prostaglatin E
1
,E
2
.
Phn loi cc nhm thuc gim au:
+Gim au mnh(gy nghin)
-76-
+Gim au h nhit.
+Gam au chng vim.
2.2.5.2. CC THUC GIM AU MNH
2.2.5.2.1. Morphine v cc dn xut
- u im v nhc im ca Morphine
- Nguyn liu sn xut Morphine
- Thnh phn ca nha thuc phin ch yu l ancaloit, lng ancaloit ton
phn 20-25%, c 25-30 ancaloit.
Cu trc ancaloit thuc phin chia thnh hai nhm
1
2
3
4
5
6
7
8 9
10
11
12
13
14
phenantren






-77-


Hnh 2.2. Cu trc khng gian ca morphine v enkafeline
Morphine l ancaloit chnh ca nha thuc phin
- c im cu trc ca morphine
- Vn morphine v morphinic trong c th, cu trc morphine v
enkafeline
- Th th opiat
Lin quan n cu trc v tc dng gim au cc dn xut ca morphine:
- Khi ankyl ha nhm OH phenilic (codeine, ethomorphine) th tc dng gy
ng, chng co git, gim thng, tnh nghin gim c l OH phenolic gy
nn tnh nghin.
- Khi axyl ha (heroine) tc dng gim au tng nhng c tnh v tc dng
gy nghin cng tng.
- Khi hydro ha ni i, oxi ha OH ancol thnh oxo (dihidromorphine) tc
dng gim au tng nhng c tnh cng tng.
- Vch kp v cc nhm OH trong phn t morphine quyt nh tc dng
gim au v gy nghin ca morphine.
- Nhm metyl trn N ca morphine cng nh hng n tc dng gim au,
gaay nghin ca morphine.
- Thay metyl bng allyl (nalorphine) to ra hp cht va c tc dng ch vn
v tc dng i khng morphine.
- Sn phm oxi ha v th allyl trn N (naloxone) c tc dng i khng
hon ton c s dng lm cht chng nghin v gii c morphine.
-78-

Bng 2-11. Cc dn xut th ti O ca morphine.

Tn cht v bit dc R
1
R
2
Liu dng 1
ln (mg)
Morphine(2-244) H H 10
Codeine (2-
245)(Tussipan)
CH
3
H 120
Ethomorphine (2-
251)(Dionin, Cosylan)
C
2
H
5
H 20
Benzylmorphine(2-
252)
C
6
H
5
CH
2
H -
Phocodine (2-
253)(Codylin,Pectolin)

H 5
diacetylmorphine(2-
254)
OCCH
3
OCCH
3
4
Thebacone (2-255) CH
3
OCCH
3

Bng 2-12. Cc dn xut dihidro-morphinon

Tn cht v bit dc R
1
R
2
R
3
Liu
dng 1
ln
(mg)
hidromorphone(2256)
(Dimorphone,Dilandid,Novolaudon)
H H H 1,5
Hidrocodone (2-257) (Bekadid,
Dicodid, Hycodan)
CH
3
H H 5
Oxomorphone(2-258) H OH H
Oxycodone(2-259) (Percodan,
Eucodale)
CH
3
OH H 10
Metopone(2-260) H H CH
3
3,5

Bng 2-13. Mt s dn xut th trn N ca morphine
-79-

Tn cht v bit dc R
1
R
2
R
3
Morphine(2-244) H H CH
3
Normorphine(2-
262)(Desmetylmorphine)
H H H
Norcodeine(2-263)(N-
demetylcodeine)
CH
3
H H
N-allyl norcodeine(2-264) CH
3
H CH
2
CH=CH
2
Nalorphine(2-
265)(Nalline,Norfin,Anarcon)
H H CH
2
CH=CH
2

Nalorphine dinicotinate(2-
266)(Nimelan)
C
5
H
4
NCO C
5
H
4
NCO CH
2
CH=CH
2


Bng 2-14. Mt s dn xut c tc dng i khng ca morphine

Tn cht v bit dc R
1
R
2
Naloxone(2-267)(Narcon
Narcan, Narlone)
O CH
2
-CH=CH
2
Naltrexone(2-268) O

Nalbuphine(2-269) OH

Cc phng php chng chit cc ancaloit thuc phin chnh:
1. Phng php Robertson-Gregory:
a. Chit nc 25
0
C cc ancaloit dng mui meconat v sunfat.
b. Dch mui meconat + CaCl
2
Ca-meconat+ ancoloit.HCl.
C dch ancoloit.HCl kt tinh mui gregory : morphin.HCl
+codein.HCl

c. Nc ci ca b c pha long v thm amoniac ta to ra l hn
hp thebaine + papaverin + narcotine.
d. Nc ci ca c, cha ch yu narceine.
-80-
e. X l mui gregory: ha tan trong 10 phn nc, dng amoniac kim
ha tan (pH=8) morphine ta, nc ci dng dung dch NaOH kim
codeine kt ta.
f. X l hn hp thebaine, papaverine v narcotine thu t c.






































Thuc phin + nc
NARCOTINE
2-247
B

Dung dch + CaCl
2


Kt ta
(canxi sunfat v meconat, nha)
Dung dch clohidrat
alkaloid
(canxi sunfat v
Bc hi
t
0
<50
0
C, chn khng
(canxi sunfat v meconat,
Nc ci

Kt tinh

Ha tan vo H
2
O + NH
4
OH long

+ NH
4
OH

Kt ta

MORPHINE
2-244
+ KOH

CODEINE
2-245
Kt ta gm Thebaine,
Papaverine v
Narcotine (t)
Dung dch cha
+ KOH
Phn khng tan
NARCOTINE
2-247
Phn dung dch trung
ha bng
AcOH + (AcO)
2
Pb
Kt ta hp cht ch
PAPAVERINE
2-248
Dung dch

THERBAINE
2-246
Tinh th mui Gregory clohidrat
morphine v clohidrat codeine
-81-
Hnh 2-4. S tm tt phng php chit tch cc ancaloit chnh ca
thuc phin theo Robertson-Gregory
Phng php Canhepskaia Kliatskin
Nguyn tc: thuc phin chit nhiu ln bng nc nng, sau bc hi dung dch
ny n m c, dng amoniac ta ancaloit baz tch ring cc ancaloit ny
nh vo ha tan v bn vng khc nhau ca mui ancaloit .
S chit xem hnh 2-5




































NARCEINE
2-249

Dch lc (cn-nc-amoniac)
Papaverin, Therbain, Codeine
Thuc phin + nc nng
CODEINE
2-247
Bc hi c c dch lc
Dch lc
Morphine dng mui
AcOH + benzen
Ta
Morphine + Narcotine

+ NH
4
OH 25% + etanol

Axit axetic

Kt ta

NARCOTINE
2-247
+ NH
4
OH

MORPHINE
2-244
Dung dch nc
Thebaine, Codein
(dng mui)
Dung dch cha
KOH

Dch lc
Dung dch benzen
Papaverin
Ct loi benzen
PAPAVERINE
2-248
Ta

THERBAINE
2-246
+ NH
4
OH

-82-
Hnh 2.5. S chit cc alkaloid chnh ca thuc phin theo Canhepskaia
Kliatskin
Phng php chit morphine:
- Theo Robertson-Gregory (hn hp mui HCl ca morphine v codeine)
- Theo Thiboumery Mohr (da OH phenol).
- Bn tng hp mt s dn xut ca morphine

- Ankyl ha, axyl ha
- Hidro ha, oxi ha


- Thay nhm metyl
-83-
O
RO
OH
N CH
3
p.u. Braun
Thuy phn
2-245, R= CH
3
2-244, R= H
O
RO
OH
N CN
2-272, R= H
2-273, R=C H
3
O
RO
OH
N CH
3
2-262, R= H normorphine
2-263, R= CH
3
norcodeine
BrCN
O
RO
OH
N CH
3
BrCH
2
-CH=CH
2
2-265, R= H naorphine
2-264, R= CH
3
N-allylnorcodeine

- Thay nhm metyl trn N bng cc nhm allyl (nalorphine). Xut hin tc
dng i khng lm cht gii c.
*Tng hp cht c tc dng i khng opiat: naloxone (2-267)
- Bn tng hp oxymorphone

- N-demetyl ha v N-allyl ha.
-84-

*Tng hp naltrexone(2-268) v nalbuphine(2-269)

*Bn tng hp metopon (2-260): cht c tc dng gim au mnh, dng c theo
ng ung tt.
-85-
O
H
3
CO OCH
3
N
2-260
metopon
2-246
2-286
2-285, R=CH
3
2-288, R= Ac
O
H
3
CO
N CH
3
OR
CH
3
1
2
3
4
5
O
H
3
CO
N CH
3
OR
H
3
C
OH
H
3
CO
N CH
3
O
H
3
C
2-287
OH H
3
CO
N CH
3
O
CH
3
2-289
Br
Br
O
H
3
CO
N CH
3
O
X
CH
3
2-290, X=Br
2-291, X= H
O
HO
N CH
3
O
CH
3


*Sn xut codein(2-245) t morphine.

2.2.5.2.2. Cc dn xut thebaine
T thebaine nhiu dn xut c tc dng gim au c iu ch trong ng
quan tm l oripavine (2-292), etorphin(2-293), diprenorphine(2-294),
buprenorphine(2-295)
Etorphine l cht ch vn hon ton, trn chut tc dng gim au mnh gp
morphine 1700 ln thuc ng cho ng vt ln cn diprenorphine (2-294) c
tc dng i khng morphine hn nalorphine 100 ln.
Buprenorphine (2-295) c hot tnh gp morphine 12000 ln l cht c coi l
gim au mnh nht.
-86-

Buprenorphine (2-295) c hot tnh gp morphine 12000 ln, l cht c coi l
gim au mnh nht.

-87-

2.2.5.2.2. Cc thuc tng hp trn c s n gin b khung ca morphine
Mc ch: tm kim hp cht c tc dng gim au nh morphine nhng khng
gy nghin v khng c ch h hp, c cu trc n gin hn.
S gt o b khung dn n tm ra 4 nhm hp cht sau:
- Cc hp cht thuc b khung morphinan(I)
- Cc hp cht thuc b khung benzomorphan(II)
- Cc hp cht cha khung phenyl- piperidin(III)
- Cc hp cht cha khung phenyl propyl amin(IV)
-88-
O
HO OH
N
morphine
CH
3
N
C O
N
morphinan (I)
phenyl-piperridin (III)
O
N N
benzomorphan (II) phenyl-propylamin (IV)
A
B
C
D
E
A
B
C
E
A
E

Hnh 2.6. Cc b khung c bn trn c s gt o khung morphine
2.2.5.2.3.1. Cc dn xut ca morphinan(I)
Cc hp cht c cu trc ging morphine nhng t hn morphine 1 vng do A.
Grewe tng hp ra vo nm 1948.
Bng 2-15. Mt s dn xut ca morphan c s dng lm thuc gim au v
i khng morphine
R
1
N R
3
R
2
A
B
C

Tn cht,bit dc R
1
R
2
R
3
Tc dng gim
au
-89-
(morphine=1)
Morphinan (2-305) H H H 0
N-metyl morphinan(2-
306)
H H CH
3
0,2
Racemorphan(2-
307)(Dromoran,Cetarin)
OH H CH
3
>1
Levorphanol(l-
isome)(2-
308)(Levodromoran)
OH H CH
3
6
Levallorphan(2-
309)(Lorphan)
OH H CH
2
-
CH=CH
2
15
Cyclorphan(2-310) OH H


Butorphanol (2-
311)(Stadol, Torate)
OH OH

10
*dng racemic
*tng hp N-methyl morphinan(2-306)

*Tng hp racemorphan (2-307) v levorphanol(2-308):
Tch ng phn L ta khi raxemic bng to mui vi L-tactarat c
levorphanol (2-308) . Levorphanol c hot lc gim au mnh hn morphine 6-8
ln. Hp cht 2-323 l dextromorphan c tc dng ngn chn cn ho lm thuc
tr ho.
-90-

*Tng hp levallorphan (2-309) v cc hp cht c tc dng i khng morphine.

2.2.5.2.3.2. Cc dn xut benzomorphan(II)
L cc hp cht c cu trc morphinan thiu vng C c iu ch ra t nhng
nm 1947-1955. Cc thuc trong nhm ny gm cc cht trong bng 2-16
Bng 2-16. Mt s dn xut benzomorphan c s dng trong iu tr
-91-
N R
HO
CH
3
CH
3

Tn cht, bit dc R Nm
iu
ch
Tc dng gim au
(morphin=1)
Metazocine(2-331), benzomorphan CH
3
1957 0,7
Phenazocine(2-332)(Prinadol,Narphen) CH
2
CH
2
C
6
H
5
1959 3
Pentazocine (2-333)(Talwin, Fortral) CH
2
CH=C(CH
3
)
2
1962 0,3
Cyclazocine(2-334)

1962 40
*Tng hp phenarocine(2-332), pentazocine(2-333), cyclazocine(2-334)

2.2.5.2.3.3. Cc dn xut ca phenyl-piperidin (III)
B khung c bn gm cc phn sau:
- C mt vng thm (a)
- Vng thm .
- C cha mt N bc ba nm cch cacbon bc bn mt khong cch khong
hai nguyn t cacbon (c).
-92-
C
N
III
(a)
(b)
(c)


Bng 2-17. Mt s dn xut ca phenylpiperidin v cc cht c cu trc
tng t

I. Dn xut
pethidine




1956 0,2


1959 0,2


1960
II. Dn xut ging vi pethidine


1939
III. Cc prodin (este nghch o)


R= H

1950


1957


IV. Cc hp cht vng c s cnh 5 hoc 7


1954
-93-


1956
V. Cc hp cht c nito xen gia mch


1964

*Tng hp cc thuc gim au nhm phenylpiperidin
a, pethidine, meperidine(2-341):(Dolatin)

b, ketobemidone(2-345) v bemidone(2-375)
Bn cnh nhng dn xut trn c s normeperidine cn iu ch ra nhng
dn xut c cha nhm th trong nhn thm. Cc nhm th v tr m c tc
dng mnh hn. Ketomidone c tc dng gim au ngang morphine nhng
c tnh v tc dng gy nghin thp hn nhiu.
-94-
ketomidone
CH
2
CN
(ClCH
2
CH
2
)
2
NCH
3
2-357
2-372
H
3
CO
+ (ClCH
2
CH
2
)
2
NCH
3
H
3
CO
NC
N CH
3
C
2
H
5
MgBr
2-374
H
3
CO
C
2
H
5
OC
N CH
3
2-345
HO
C
2
H
5
OC
N CH
3
2-372
HBr
HO
HOOC
N CH
3
HO
C
2
H
5
OOC
N CH
3
2-375
bemidone

c, Alphaprodine(2-346)

L meperidine ngc
-95-

d, Fentanyl(2-350): tc dng gim au mnh hn morphine 80 ln.

2.2.5.2.3.4. Cc dn xut ca phenyl-propylamin (IV)
Cc dn xut hin ang dng lm thuc gim au bng 2-18
Bng 2-18. Mt s dn xut c tc dng gim au cha b khung
phenylpropyl amin




-96-
Tn cht, bit dc Cu trc Nm iu
ch ra
Tc dng
gim au
(morphin=1)



R
1
R
2
R
3

Methadone(2-395)(Amidon,
Depridol,Poliamidon)
C
6
H
5
COC
2
H
5

1941 2
Phenadoxone(2-
396)(heptalgin,
Heptalin,Supralgin)
C
6
H
5
COC
2
H
5


1948 2
Dipipanone(2-397)(Fenidon,
Pamedone,Pipadone)
C
6
H
5
COC
2
H
5


1950 2
Isomethadone(2-398)
(isoadonone, Liden)
C
6
H
5
COC
2
H
5


1948 1
Imepheptanol(2-
399)(methadol, Pangerin)
C
6
H
5


1949 1,5
Dextromoramide(2-
400)(Dimorlin,Jetrium,
Palfium)
C
6
H
5


1956 2,5
Piritramide(2-
401)(Dipidolor, piridolan)
C
6
H
5
CN

1961 1
Diphenoxylate(2-371)
Diarsed,Lomotil,Reasec
C
6
H
5
CN

1959 0
D-propoxyphene (2-
403)(Darvon, Develin,
Propox)
C
6
H
5
CH
2
OCOC
2
H
5



1953 0,2
Henoperidine (2-
344)(Operidine, Lealgin)
H OH

1960 0,2
Metofoline (2-
405)(Versidyne)

1960 0,1
Tramadol (2-406)(Cripsin)

1965 0,2

*Tng hp methadone(2-395)
-97-
Methadone c E.M.Schultz (ngi c ) tng hp ra vo nm 1947 theo
s phn ng sau:

2-409
CHCN +
CH
CH
3
Cl
CH
2
N
CH
3
CH
3
2-407
CH
H
3
C
CH
2
N
H
3
C
CH
3
Cl
(-)
C NC CH
CH
3
CH
2
N(CH
3
)
2
C NC CH
CH
3
CHN(CH
3
)
2 +
CH
3
2-408
2-410
C C
2
H
5
CO CH
CH
3
CH
2
N(CH
3
)
2
1. C
2
H
5
MgBr
2. H
2
O/H
(+)
1. C
2
H
5
MgBr
2. H
2
O/H
(+)
C C
2
H
5
CO CH
2
CHN(CH
3
)
2
CH
3
2-398
isomethadone
2-395
methadone

Trong hp cht trung gian 2-410 c iu ch theo phng php c bit sau:


*Tng hp dn xut methadone: dimepheptanol (2-399), acetyl
methadone(2-413)

*Tng hp dextromoramide(2-400)

-98-
*Tng hp D-propoxyphene(2-403)
L thuc gim au loi trung bnh, c s dng kh rng ri.
ng phn L khng c tc dng gim au nhng l cht c tc dng gim
ho nn c s dng lm thuc ho vi cc bit dc Novrad, Letusin,
Contratus.


*Tng hp trmdol(2-406) v nexeridine(2-437)

2.2.5.2.3.4. Cc thuc c tc dng gim au mnh khc:
Cc thuc gim au c b khung khc nhau nhng c c tnh gn kt vo
th th morphine ging nhau, c chung chui cu trc Ar-N-C-C (gn
ging nh phenylpropylamin)
Bng 2-19. Mt s hp cht c tc dng gim au, c cu trc khc nhau
Tn v bit dc Cu trc N
m
iu
ch
Tc dng
gim au
(morphin=1
)
Phenampromide(2-438)

195
9
0,1
Diampromide(2-439)

195
9
1
Propiram(2-
420)(Algeril)

196
3
0,1
-99-
Fentanyl(2-
350)(Leptanal,
pentanyl)

196
4
80
Etonitazene(2-
441)(Opioid)

195
7
1000
Thiambutene(2-
442)(Grapori,Themalon
)

195
0
1

Kt lun: Tng hp cc thuc gim au mnh hn morphine hng nghn ln
(etorphine(2-293)); etonitazene(2-441) )nhng cng vn cn tc dng gy
nghin.
2.2.5.3. CC THUC I KHNG VI OPIAT
Thuc i khng l g?
Bng 2-20. Cc thuc cai thuc phin
Tn v bit dc Hot tnh morphinic Hot tnh khng
morphine
Nalorphine(2-265) s1 1
Naloxone(2-267) 0 10-30
Natrexone(2-268)
Levalorphane(2-309) 0,8 3
Cyclazocine(2-334) 4 4,5
Cyprenorphine 10 35

2.2.6. CC THUC TM THN
2.2.6.1. I CNG V THUC TM THN
- nh ngha thuc tm thn.
- Phn nhm cc thuc tm thn (c an thn v kch thn).
*Nhm 1: Thuc an thn : lm gim hot ng tm thn.
+Thuc gim tnh to (barbiturat)
+Thuc an thn th yu (lm gim s xc cm benzodiazepin,
meprobamat).
+An thn ch yu (c ch hot bt, gy trng thi th , lnh m
phenothiazine).
*Nhm 2: Thuc chng trm cm: kch thch tm thn hot ng tng ln
+Thuc hng thn(lm mt tnh trng u su : Tricyclic v IMAO)
-100-
+Thuc tng tnh to (amphetamine)
+Thuc kch thch tm thn(cafeine).
*Nhm 3: Thuc iu ha hot ng tm thn.
*Nhm 4: Cc cht gy lon thn (gy ri lon hot ng tm thn, gy o
gic):ma ty(axit lysergic).
- Cc vng tc dng ca tng loi thuc no
2.2.6.2. CC THUC AN THN TH YU (AN THN)
- c im chung
- Cc thuc an thn c in
+ Cc loi tho mc
+Ru
+Opinen (nha thuc phin)} hu qu nghin ru v ma ty.
+Cc ha cht n gin: cloral hidrat, paraandehit.
+Cc thuc an thn hin i: cacbamat, benzodiazepin thuc an thn
pht trin mnh c v s lng, chng loi cng nh s bng pht minh
sng ch.
V d trong nm 1986: trong s 50 mt hng c sc tiu th ln th c 3 mt
hng ca benzodiazepin
+Valium(diazepam): 279 triu USD/nm
+Xanax(alpraropam): 245 triu USD/nm
+Ativan (lorazepam): 220 triu USD/nm
V bng sng ch (1772/8480): bng 2.21
Bng 2-21. Bng ng k phn b pht minh sng ch v dc phm nm
1985 trn ton th gii.
Loi thuc S lng bng pht minh sng ch
1. Thuc thn kinh
2. Thuc h h hp
3. Thuc v trao i cht
4. Thuc dit vi trng
5. Thuc khng sinh
6. Thuc tun hon
7. Cc ch phm mu
8. Thuc d dy rut
9. Cc vitamin
10. Cc thuc chng k sinh
trng
1772
1482
1409
867
805
724
591
525
202
103
Tng cng 8480 patent = 23patent/ngy

2.2.6.2.1.Cc dn xut carbamat
Bng 2-22. Mt vi carbamat lm thuc an thn th yu
Tn v bit dc Cu to Nm iu
ch
Liu dng
1 ngy (g)
-101-
Meprobamate(2-
443)(Andaxin,
Miltown,Atraxin,Panediol)

1951 0,4-1,6
tybamate(2-444)(Benvil,
Solacin)

1960 0,2-1
pheprobamate(2-
445)(Extacol, Gamaquil)

1960 0,4-1,2
Emylcamate(2-
446)(Muncital, Striatran)

1961 0,6-0,8
Methylpentinolcarbamate(2-
447)(Oblivon-
C,Trusono,Pentin-C)
1955 0,3-0,6

*Tng hp Meprobamate(2-443) v tybamate(2-444)


2.2.6.2.2. Cc dn xut ca diazepin:
(xem mc 2.2.3.2.7 trang 202 cc thuc ng)
2.2.6.2.3. Cc thuc ng an thn khng histamin:
Gm cc dn xut ca diphenyl metan. Cc thuc trong nhm ny gm c cc cht
trong bng 2-23.
Bng 2-23. Mt s thuc an thn l dn xut ca diphenylmetan
Tn v bit dc Cu trc Nm iu
ch
Liu dng 1
ngy (g)
Benactyzine (2-
457)(Phobex, Suavitil)

1938 3-6
-102-
Hidroxyzine (2-
458)(Atarax, Vistaril)
C
6
H
5
CH N N(CH
2
)
2
O(CH
2
)
2
OH
Cl

1956 50-100
Azacyclonol (2-
459)(Ataractan,
Frenquel)

1957 60-300
Captodiamine(2-
460)(Covatix, Suvren)

1958 150-450

*Tng hp Benactyzine (2-457) v Hidroxyzine (2-458).

HN NCOOCH
CO CH
OH
OH
(C
6
H
5
)
2
C COOH
OH
(C
6
H
5
)
2
C COOCH
2
CH
2
N(C
2
H
5
)
2
2-461
2-462
2-457
benactizine
C
6
H
5
CH N Cl NH +
O
H
2
CH
2
C
HOH
2
CH
2
C
Cl
C
6
H
5
CH N Cl N CH
2
CH
2
O(CH
2
)
2
OH
C
6
H
5
CH N Cl N CH
2
CH
3
C
6
H
5
CH N Cl N CH
2
C(CH
3
)
3
C
6
H
5
CH Cl X +
C
6
H
5
CH N X NR
2-466, X= Cl, R= COOH
2-463, X=Cl, R= H
2-463
2-458
hydroxyzine
2-464
meclizine
2-465
buclizine

2.2.6.2.4. Cc thuc an thn th yu thuc cc nhm cu trc khc:

-103-

*iu ch benoctamine(2-476) v buspirone(2-477)

COOH
COX
2-480 X= OH
2-481 X= Cl
2-485 X= NHCH
3
CH
2
NHCH
3
2-476
benoctamine
N
N
Cl
N
N
N
N R
O
O
O
2-486
N
N (CH
2
)
4
N
N
N
O
O
2-477
buspirone (1970)
(Bespar, Buspar)
NH
O
O
2-488
N
O
O
R
2-489 R= (CH
2
)
4
Cl
2-490 R= (CH
2
)
4
NH(CH
2
)
2
NH
2
2-483 R= H
2-484 R= (CH
2
)
3
CN
2-485 R= (CH
2
)
4
NH
2
N(CH
2
)
4
NHCH
2
CH
2
NH
O
O
N
N
2-491


2.2.6.3. CC THUC AN THN TH YU
- nh ngha.
- Cc c im c bn ca thuc an thn ch yu.
- Phn chia theo ha hc c 5 loi
2.2.6.3.1. Cc ancaloit cy ba gc (nay t dng v c nhiu thuc tt hn).

-104-

Cc tai bin khi dng reserpine thi gian lu:
- c ch tm thn qu mc, mt kh nng t duy.
- Hi chng ngoi b thp mnh.
- Ri lon ni tit: chy sa, mt tnh dc, lit dng.
- Du hiu cng ph giao cm, lot d dy..
2.2.6.3.2. Cc thuc an thn nhm phenolthiazin
Lch s pht minh tm ra thuc an thn nhm phenolthiazin
+ Otto Unvedorben: thu c anilin khi phn hy indigo tng nhm l tt
c thuc nhum t nhin u i t anilin.
+Cng ngh thuc nhum i t anilin:
- 1856 W.H.Perkin tm ra thuc nhum mu tm mauvein(2-496) bng
cch oxi ha anilin vi kali bicromat.
- 1876 H. Caro pht minh ra xanh metylen (2-497) cht nhum mu
cc dy thn kinh.

-105-



Nm 1945 Halpern a nhm hp cht phenolthiazin vo th nghim c tc
dng dit giun sn, khng histamin (rt hp dn lc ny!)
Charpentier (Rhone- Poulence) iu ch ra promethazine (2-498), fenethazine (2-
499), chlorpromazine (2-500).

Bng 2-24. Mt s thuc lit thn thuc nhm phenothiazin.



-106-
Tn, bit dc R
1
R
2
N
m
i
u
ch
Liu
dng
(mg/ng
y)
I. Cc dn xut ca amino-ankyl
Promazine (2-
501)(Sparin,
Verophene)
H CH
2
CH
2
(CH
3
)
2
195
0
300-
1000
Chlorpromazine(2
-500) (Hibernal,
Thorazine)
Cl CH
2
CH
2
(CH
3
)
2
195
2
300-800
methopromazine
(2-
502)(Mopazine,
Tentone)
OCH
3
CH
2
CH
2
(CH
3
)
2
195
2
50-500
acetylpromazine
(2-503)( Notensil,
Soprintin)
COCH
3
CH
2
CH
2
N(CH
3
)
2
195
7
150-200
triflupromazine
(2-504)(Nivoman,
Vesprin)
CF
3
CH
2
CH
2
N(CH
3
)
2
195
7
100-150
levopromazine (2-
505)(Neurcil,
Tisercin)
OCH
3
CH(CH
3
)
2
CH
2
N(CH
3
)
2
195
7
50-100
II. Cc dn xut ca piperidin-ankyl
Thioridazine(2-
506)(Mellaril,
Melleril)
SCH
3
N
H
3
C
H
2
C

195
8
200-600
Mesoridazine(2-
507)(Lidanil,Sere
ntil)
SOCH
3
N
H
3
C
H
2
C

196
3
75-300
pipamazine(2-
508)(Mometine,
Nausidol)
Cl


196
0
20-30
Pericyazine (2-
509)(Neuleptil,
Neulactil)
CN

196
0

III. Cc dn xut ca piperazinyl - ankyl
-107-
Perazine (2-
510)(Taxilan,
Teusilan)
H

195
7
50-100
Prochlorperazine(
2-511)(Nipodal,
Compazin)
Cl

195
7
15-40
Trifluoperazine
(2-512)(Stelazine,
Terfluzine)
CF
3


195
9
6-20
Thioproperazine(2
-513)(Majeptil,
Vontil)
SO
2
N(CH
3
)
2

195
9
20-60
Butaperazine(2-
514)(Magalectil,
Randolectil)
CO(CH
2
)
2
C
H
3

196
1
30-50
Perphenazine(2-
515)(Fentazin,
Trifalon)
Cl

195
6
8-32
Metofenazate(2-
516)(Frenolon)
Cl

196
2
50-80
Fluphenazine(2-
517)(Dapotum,
Prolixin)
CF
3


196
0
1-20
Acetophenazine(2
-518)(phentoxate,
Tindal)
COCH
3

196
1
60-120
Pipotiazine(2-
519)(piportil, RP
19552)
SO
2
N(CH
3
)
2


197
0
10-20

*c im cu trc :
- khong cch N ca nhn vi N mch nhnh l 3C (khc vi anti-histamin
ch c 2C)
- N mch nhnh phi bc 3
- Gam 1 nhm ankyl mch nhnh th gim tc dng.
- V tr C c nhm th ht in t (Cl, OCH
3
) tng tc dng an thn
-108-
- Khung phenolthiazin tan trong m, mch nhnh tan trong nc, t l tan
trong m/ nc c vai tr quan trng.
CHLORPROMAZINE
a, Tc dng dc l:
- Trn h thn kinh trung ng.
- Trn h thn kinh thc vt.
- Trn h ni tit .
- C tc dng khng histamin nhng yu.
b, Tng tc thuc:
- Lm tng tc dng ca thuc ng.
- C tc dng i khng vi cc thuc kch thch thn kinh tm thn
(amphetamine)
- Khng c tc dng hip ng tng mc.
c, C ch tc dng:
d, Dc ng hc
e, Tc dng khng mong mun
f, p dng lm sng (c tc dng a dng c dng nhiu khoa: tm
thn, khoa sn, gy me, khoa ni, da liu)
g, Chuyn ha:
Chlorpromazine trong c th tm thy 12 loi cht chuyn ha
*Cc phng php chung tng hp cc dn xut ca phenothiazin

-109-
N
S
R
1
S
R
COOH
Cl
+
H
2
N
R
+ K
2
CO
3
N
H
COOH
R
- CO
2
N
H
R
N R
R
1
R
1
-Cl
NaNH
2
H
SH
NH
2
+
S + I
hoac
SCl
2
Cl
R
Cl
O
2
N
NaOH
NH
2 O
2
N
Cl
R
S
NH O
2
N
Cl
R
N
H
S
R
COCH
3
N
S
COCl
R
R
1
OH
N
S
COOR
1
R
B
COCl
2
- CO
2
SH
Br
R
Cl
O
2
N
+
S
Br O
2
N
Cl
R
+ Na
2
S
S
Br H
2
N
R
G
S
Br HN
R
R
1
+ K
2
CO
3
A S + I hoac SCl
2
F
N
S
X Cl
R
C
l
X
Br
E
amin bc 2
D
R
1
Cl, NaH
ClCOOR
1
C

Hnh 2.7. Cc phng php chung tng hp cc dn xut ca phenothiazin


*Tng hp Chlorpromazine(2-500) v methopromazine (2-502)
Hai hp cht ny tng i ging nhau.

-110-

*Tng hp Thioridazine(2-506)


*Tng hp Mesoridazine(2-507)

-111-
N
S
COCH
3
SCH
3
N
H
SCH
3
N
H
S
SCH
3
SCH
3
+
N
H
S
COOH
Cu/t
0
Cl
NH
2
nung nng
COOH
nung nng
- CO
2
N
H
SCH
3
nung nng
S + I
2
SCH
3
2-532
2-533
2-531
N
H
S
SCH
3
2-531
CH
3
OCl 1. R-COOH (oxh)
2. deaxetyl ha
N CH
2
CH
2
Cl
2-530
NaNH
2
CH
3
N
S
SCH
3
H
2
C N
N
H
3
C
H
2
C
2-507
mesoridazine

II. Mch nhnh cha vng piperazin
*Tng hp pepazine

-112-


*Tng hp cc dn xut phenazin


2.2.6.3.3. Cc dn xut ca thioxanthen:
Cu hi t ra liu thay phenolthiazin bng thioxanthen th tc dng an thn c
cn khng? . C
10
=C c tc dng mnh hn C
10
-C., cis c tc dng mnh hn trans

Bng 2-25. Mt s thuc lit thn nhm thioxanthen

Tn cht, bit
dc
R
1
R
2
Nm iu
ch
Liu dng
ngy
(mg)
I. Dn xut amino-ankyl
-113-
Prothixene (2-
543)(Prothixenum)
H N(CH
3
)
2
1960
Chlorprothixene(2-
544) (Taractan,
Truxal)
Cl N(CH
3
)
2
1960 50-400
II. Dn xut piperazinyl-ankyl
Thiothixene (2-
545)(Navane,
Orbinamon)
SO
2
N(CH
3
)
2

1964 6-30
Clopenthixol (2-
546)(Ciatyl,
Sordinol)
Cl

1962 5-50
Flupentixol(2-
547)(Fluanxol,
Siplarol)
CF
3

1963 3-6

*Tng hp prothixene (2-543) v chlorprothixene(2-544)


*Tng hp clopenthixol (2-546) v flupentixol (2-547)

-114-



C th iu ch theo cch khc:



*Tng hp thiothixene(2-545)

-115-
+
S
SO
2
N(CH
3
)
2
H
2
CH
2
CN NCH
3
S
Y
2-545
thiothixene
2-555, X= SO
2
Cl
2-556, X= SO
2
N( CH
3
)
2
Br
COOH
S
2-557, X= SO
2
N( CH
3
)
2
C
6
H
5
SH/Cu/
SO
2
N(CH
3
)
2
2-558 Y=O
2-559, X= H
2
,
NaBH
4
COOH
HSO
3
Cl
X
Br
COOH
X
HN(CH
3
)
2
cc. H
2
SO
4
hoac SOCl
2
1. Bu Li
2. CH
3
COOCH
3
S
C
SO
2
N(CH
3
)
2
O
CH
3
2-560
NH
2
-NH
2
/NaOH
p.u Mannich
CH
2
O/N metyl piperidin
O
S
SO
2
N(CH
3
)
2
C
H
H
2
CH
2
CN NCH
3
HO
POCl
3
/piridin
- H
2
O
1. Br-MgCH
2
CH
2
Cl
2. HN N-CH
3
3. Ac
2
O/
(-H
2
O)

2.2.6.3.4. Cc thuc an thn dn xut butirophenon
Cc thuc nhm ny thuc nhm lit thn. C ch tc dng ca chng gn ging
vi cc thuc nhm phenolthiazin, cc hp cht ny cng ngn cn cc th th D
2

v cn c tc dng gim au, chng tit cholin, chng nn. Cc cht s dng xem
bng 2-26.
Bng 2-26. Mt s thuc lit thn nhm butirophenon

Tn cht, bit dc R Nm iu ch Liu dng ngy
(mg)
I. Nhm dn xut phenylpiperidin
Haloperidol (2-
563)(Haldol,
serenase)

1959 5-15
-116-
Methylperidol (2-
564) (Morperone,
Luvatren)


1959 5-15
Anisoperidone(2-
565)

1961 40-100
Aceperone(2-
566)(Acetabutone)

1961
Trifluperidol(2-
567)(Trisedyl,
Triperidol)


1962 1-2
Paraperidide(2-
568)(Amiperone)

1962 5-40
Haloperidide(2-569)
N
CO
N
Cl

1962 5-30
Methylperidide (2-
570)(Meperidide)

1962 5-40
Fluropipamide
(Dipiperon,Propitan)

1962 20-60
II. Dn xut piperidyl- imidazolin
-117-
Spiroperidol (2-
571)(Spiperone,
Spiropitan)
N
N
C
6
H
5
NH
O


1964 0,5-3
Benperidol(2-
572)(glianimon,
Frenactyl)
N
N NH
O
H

1963 0,5-1,5
Droperidol (2-
573)(Inapsine,
Dridol)
N
N NH
O

1964 5-20
III. Cc dn xut ca piperazin
Butrropipazone (2-
574)

1961 100-400
Fluanisone(2-
575)(Haloanisone,
Sedalande)
N
N
H
3
CO

1961 5-60

*c dng vo neuroleptanalgezia
HALOPERIDOL l thuc tiu biu ca nhm butirophenol ny:
- L thuc an thn kinh a nng, chng thao cung.
- Cu trc ha hc haloperidol gn ging vi GABA l cht trung gian ha
hc ca cc qu trnh c ch thn kinh trung ng.
- Tc dng an thn mnh l do c ch receptor dopaminegic trung ng.
a, Tc dng dc l: c ch phn x, c ch kch thch tm thn vn ng,
c ch thao cung, c ch hoang tng.
b, Chuyn ha : chuyn ha ch yu qua gan do qu trnh kh ankyl-oxi
ha.
c, Ch nh :
- Cc trng thi thao cung, hoang tng, lon tm thn cp v mn, phn
lp.
- Chng nn.
-118-
d, cn thn trng: khng dng chung vi thuc cng h dopaminergic
(levodopa)
e, Tc dng khng mong mun: ng g, ri lon ni tit.
f, Liu lng.
*Tng hp haloperidol (2-563) v trifluperidol (2-567)



Trong qu trnh 2-580 a-e xy ra nh sau:


-119-
Y
X
CH
2
H
3
C
Y
X
H
3
C
NH
CH
3
OH +
NH
4
ClH HOCH
2
NH
2
HOCH
2
NHCH
2
OH HOCH
2
NHCH
2
+
HOCH
2
NHCH
2
+
HO
(+)
-H
(+)
Y
X
H
3
C
H
N
O
2-577 a-e
B
z
: C
6
H
5
CH
2
-
Y
X
H
3
C
H
2
C
NH
(+)
/ H
+
- H
2
O
Y
X
H
2
C
H
N
H
2
C
(+)
Y
X
H
N
/ H
+
H
(+)
2-578 a-e
2-576 a-e
B
z
: NH
2
-
1. CH2=CH- CN
2. CH2=CH- CN
3. EtOH/H
+
N
Bz-N
OEt
O
COOEt
Dickman
N O Bz
1. H
2
O/H
+
MgX
Y
X 2.
2-580 a-e

* Tng hp haloperidol (2-563)




*Tng hp aceperone (2-566): i t phenylaxetonitrin i qua thuc gim
au loi morphin l normeperidine (2-360)
-120-

*Tng hp paraperidide (2-568), haloperidide(2-570)

-121-

*Tng hp droperidol (2-574) v benperidol (2-572)

-122-

*Tng hp fluanisone(2-575) v butropipazone (2-574)


2.2.6.3.5. Cc thuc lit thn c cu trc khc
a, Cc dn xut ca diphenyl-butyl piperidin:

-123-
p-FC
6
H
4
OC(H
2
C)
3
N
OH
Cl
2-563: haloperidol
(Haldol, Serenase)
(p-FC
6
H
4
)
2
HC(H
2
C)
3
N
CH
HN
N
O
H
2-606:f luspirilane
(Imar, redeptin)
liu dng 2-6 mg/tun
(p-FC
6
H
4
)
2
HC(H
2
C)
3
N
R
1
R
2
2-607: pimozide (1965), R
1
= H, R
2
=
( Opiran, Orap)
2-608: penf luridol (1973), R1= OH, R2=
(Semap)
N
N
H
O
Cl
CF
3

*Tng hp fluspirilene (2-606)


*Tng hp pimozide(2-607)



*Tng hp penfluridol (2-608)


-124-

b, Cc dn xut ca benzamit
Bng 2.27. Cc thuc an thn nhm benzamit

Tn hp cht (bit
dc)
R
1
R
2
R
3
Nm
iu
ch
Liu
dng
ngy
(mg)
Metoclopamide(2-
613)(Maxolon,
Reliveran)
NH
2
Cl CH
2
N(C
2
H
5
)
2
1962 10
Sulpiride(2-
614)(dogmatil,
Mirbanil)
H SO
2
NH
2

1964 300-
800
Sultopride(2-
615)(Barnetil,
Topral)
H SO
2
C
2
H
5

1968 400-
600
Tiapride(2-
616)(Tiaprizal,
Doparid)
H SO
2
CH
3
CH
2
N(C
2
H
5
)
2
1970 100-
200
Trong sulpiride(2-614) l i din cho nhm ny.
Tc dng:
Sulpiride l thuc an thn c tc dng lng cc (bipolar)
Ch nh
Cnh bo
Tc dng ph
*Tng hp sulpiride (2-614)


-125-
2.2.7. CC THUC GIN C
2.2.7.1. I CNG V HOT NG CA C
2.2.7.2. CC THUC C TC DNG GIN C.
a, Dn xut ca propandiol v etylendiol

2-617 phenylglyceryl ether
(Autodyne)
OCH
2
CH CH
2
OH
OH
OCH
2
CH CH
2
OCONH
2
OH
CH
3
2-619 me phenesin carbamate
(Tolseram)
CH CH
2
OCONH
2
OH
2-621 styranmate
(Linaxar, Sinaxar)
2-618 me phenesin
(Atesin, Myodetensin)
OCH
2
CH CH
2
OH
OH
CH
3
2-620 chlorphenesin carbamate
(Maolate)
OCH
2
CH CH
2
OCOCH
2
OH
Cl
CH CH
2
NH
OH
N
2-622 phenylramidol
(Elan, Miodar)
CH
3
CH
2
CH
2
C
CH
2
OCONH
2
CH
2
OCONH
CH
3
CH(CH
3
)
2
2-623 carisopidol (Carisoma, Flexal, Soma)

*Tng hp mephenesin(2-618) v mephenesin carbamat (2-619)


*Tng hp phenyramidol (2-622)
-126-


*Tng hp carisoprodol(2-623)S


b, Dn xut ca benzoxazol


c, Dn xut ca GABA v hidrazon

HC
2-627
dantrolen
(Dantamacrin, Dantrium)
2-626
baclof en
(Baclon, Liosenal)
Cl
CH
2
COOH H
2
C H
2
N
O
2
N
O
CH=N NH N
O


*Tng hp baclofen (2-626):
-127-

*Tng hp dantrolen(2-627)

2-633, X= H
2-634, X= N
(+)
Cl
(-)
O
2
N NX
O
O
2
N
CHO
2-635
CH
2
COOC
2
H
5
NH H
2
N
NH
N
O
H
2
N
O
O
O
2
N
CH N
NH
N
O
O
2-627
dantrolen
2-638
CH
2
COOC
2
H
5
N
H
2
N
O
NH
2
N
H
O
H
2
N
O
O
O
2
N
CHO
2-635
2-637
2-638

2.2.8. CAC THUC CHA BNH PARKINSON
2.2.8.1. I CNG V BNH PARKINSON
Do hu qu thng tnt thoi ha mt s nhn xm kim tra cc hot ng
bn t ng v t ng no cng nh x cng mch mu no nh
hng ti h vn ng gy nn cc triu chng nh lm mt cc ng tc
cn s tham gia ca mun, to ra cc ng tc t ng, gy run tng
trng lc c gy nn t th cng nhc, nguyn nhn l do gim st hm
lng dopamine

-128-
CH
2
CH
COOH
NH
2
L
phenylalamin
(Phe)
Phehidroxilasa
CH
2
CH
COOH
NH
2
L
phenylalamin
(Phe)
Tyhidroxilasa
OH
CH
2
CH
COOH
NH
2
3,4-dihiroxi-phenylalamin
(DOPA)
OH
OH
Dopamin
- hidroxilase
CH
2
CH
COOH
NH
2
OH
OH
dopamine
(DA)
DOPA
- decarboxilasea
CH
CH
2
NH
2
OH
OH
OH
noradrenaline
(NA)
PEA-N-metyl
transf erase
CH
CH
2
NHCH
3
OH
OCH
3
OH
CH
COOH
OH
OH
OH
CH
CH
2
NHCH
3
OH
OH
OH
metanef rin
adrenaline
epinef rin
MAO
(A)
CH
CH
2
OH
OH
OCH
3
OH
MAO
COMT
COMT
CH
COOH
OH
OCH
3
OH
3-metoxi-4-hidroxi-
phenylglicol
MHPG
axit
3-metoxi-4-hidroxi-
mandulic
(VMA)
axit
3,4-dihidroxi-
mandulic
(VMA)

Hnh 2.10. Cc bc sinh tng hp v phn hy adrenaline
2.2.8.2. CC THUC CHA BNH PARKINSON
Trong bnh parkinson c s gim st hm lng dopamine dn n hu qu
l lm tng trng lc c ca h ph giao cm trung ng, nn trong iu
tr s dng cc thuc cng h dopaminergic v loi thuc hy ph giao
cm trung ng.
2.8.2.8.1. Cc thuc cha bnh parkinson loi cng h doparminergic
a, Cng h doparminergic : Levodopa (L-dopa)(2-639)
b, Phi hp L-dopa vi cc cht c tc dng phong ta dopa-
decacboxylase: benserazide (2-640) , carbidopa(2-641).
c, Cc cht c tc dng lm gii phng dopamine nh amantidine (2-642),
memantine(2-643), tolperizone (2-644)

-129-




a, Levodopa (L-dopa)(2-639)
- Tc dng dc l
*Tng hp : c nhiu con ng tng hp, sau y l ba cch trong s :
1. Tng hp L-dopa i t vanillin v hydantion


2. Tng hp L-dopa t vanillin v glyxin
-130-



3. Tng hp L-dopa t 3-(3,4-metylen dioxiphenyl)-1-alanin

b, Cc ch phm phi hp levodopa v thuc phong ta dopa-decacboxylase l
beserazide (2-640) v carbidopa (2-641)
S phi hp ny lm gim s kh carboxyl ca levodopa ngoi bin, lm
tng lng levodopa xm nhp vo no.
c, Cc cht lm tng kh nng gii phng dopamine
Cc thuc nhm ny gm c : amantadine(2-642), memantine (2-643) v
tolperisone (2-644).
Cc thuc ny lm gii phng dopamine t cc ngn dy thn kinh h
dopaminergic c ngoi bin v c trung ng, nng dopamine trong cc
nhn xm trung ng tng cao.
*Tng hp amantadine (2-642): i t adamantan(2-645)





2-645, R=H
2-646, R=Br
2-647, R=Cl

2-642, R=H
2-648, R=COCH
3
amantadine
-131-
d, Cc thuc cng h dopaminergic khc
Cn k n apmorphine (2-649), bromocriptrine (2-540)








Apmorphine bromocriptrine




2.2.8.2.2. Cc thuc hy ph giao cm trung ng
a, Cc thuc hy ph giao cm l hp cht thin nhin
b, Cc thuc hy ph giao cm loi tng hp
Bng 2-28. Mt vi s liu v cc loi thuc hy ph giao cm tng hp
Tn hp cht (bit
dc)
Cng thc cu to Nm
iu
ch
Liu dng
ngy (mg)
I. Dn xut ca phenylpropanolpiperidin
Pridinol (2-
653)(Parks,Ridinol)



1949 10-20
Trihexyphenidyl(2-
654)(Artane, Parkan)



1949 1-20
Cycrimine (2-
655)(Pagitane)

1950 1-20
Biperiden(2-
656)(Akineton,
Dekinet)

1957 1-10
II. Dn xut ca diphenylmetan
Etanautiene(2-
657)(Antiparkin,
Rigidyl)
1946 10-100




-132-



Benztropine(2-658)
(Cobrentin, Cogentin)



1952 1-4
Orphenadrine(2-
659)(Myophane,
Parekin)

1955 25-200
III. Dn xut phentiazin v tioxanten
Diethazine(2-660)
(Antipar, Diparcol)

1947 50-200
Ethopropazine(2-
661)(Parkisol,
Parsitan)

1952 60-150
Methixene(2-
662)(Tremaril,
Tremoquil)

1958 5-20
- Cc cht ny va c tc dng khng histamin bn cnh tc dng c
ch axetylcholin.


-133-






Cl-
CH CH N(C H ) /Na

Cc thuc hy ph giao cm quan trng ang s dng
Bao gm: pridinol(2-653), trihexylphenidyl(2-654), orphenadrine(2-659),
diethazine(2-660).
a, Nhm I: phenylpropanolpiperidin
*Tng hp pridinol(2-653)
CH
2
=CHCOOC
2
H
5
+


pridinol
*Tng hp Trihexyphenidyl(2-654) v Cycrimine (2-655)







2-667 Trihexyphenidy
2-655 R=
Cycrimine
b, Nhm II: diphenylmetan ete ca diaminoetylen
*Tng hp Orphenadrine(2-659)









c, Nhm III: phentiazin
*Tng hp Diethazine(2-660)











Xilen
-134-
2.3. CC THUC KCH THCH H THN KINH TRUNG NG
- nh ngha: kch thch thn kinh l tng cng hot ng ca cc t bo
gy ra s tng nhanh cc qu trnh khuych tn trong t bo hnh thnh nn cc
phn ng bt thng chng li s tng nhanh .
S kch thch h thn kinh trung ng c sinh ra di hai dng:
- Kch thch tm thn
- Kch thch thn kinh vn ng co c, mc cao l gy nn s co git
(ng kinh
- C hai kh nng sinh ra s co git l:
- Co git do s kch thch s cp cc trung tm vn ng ca no (ng kinh
v no)
- Co git do kch thch t bo hch v cc qu o ca dy thn kinh cm th.
- Cc cht sng khoi u tin t cy c:
- Ch
- C ph
Coffein
Do Runge phn lp 1819
Medicus xc nh vo 1875
Emil Fischer tng hp 1895
- Phn nhm cc thuc kch thch thn kinh trung ng:
- Thuc hi sc
- Thuc kch thn
- Thuc chng trm cm
- Thuc gy lon tm thn
2.3.1. THUC HI SC
- nh ngha
Nhng thuc c tc dng kch thch trung tm h hp v vn mch c
gi l thuc hi sc. Cng cc loi thuc ny khi s dng liu cao s gy
nn s co git do cc thuc hi sc ch c s dng trong nhng
trng hp khi m c th b ng c hoc b nhim trng, dn n s e
da lm t lit cc trung tm quan trng ca c th.
- Cc thuc hi sc
- Ngun gc t thc vt
+ Coffein (2-672), campho(2-675), picrotoximin(2-676) (Barth v Kretschy
phn lp ra nm 1880), cu trc ha hc c Conroy v Craven xc nh
vo nhng nm 1951-1960), strychnine(2-677)
-135-

- Cc cht tng hp khc :
+ nikethamide(2-678), pentetrazol(2-679), etamivan(2-680), doxapram(2-
681), bemegride(2-126)


- Pentetrazol(2-679) tc dng kch thch cc trung tm h hp v tun hon
hnh no.
*S dng :
- Tr tim mch v h hp trong trng hp ng c thuc ng.
- Gy co git iu tr bnh tm thn phn lit hay ri lon tm thn.
*Tng hp pentetrazol
-136-
75
0
C
3%NH
3
/
A




- Doxapram (2-681)
*Tc dng : kch thch h hp, tc dng trc tip n trung khu h hp
(kch thch s thng gi ph nang, tng th tch khng kh lun chuyn,
ci thin cc trao i kh).
*Tng hp doxapram(2-681)













doxapram
- Bemegride (2-126): tc dng kch thch trc tip cc trung khu h hp v
tun hon trn hnh no, lm tng nhp tim, tng huyt p, tng bin h
hp.
*Tng hp: xem phn 2.2.3.2.6. thuc ng nhm dn xut dioxopiperazin
2.3.2.CC THUC KCH THN
Lch s pht hin ra:
- D (-)treo-ephedrine(2-688)(Miura,1887)
- D(-)adrenaline(2-689)(Aldrich,Takemine,1901)
- D-(+)amphetamine(2-690)(Edelesno 1867,1927)




2-688
D -(-)ephedrine
(o:R; |:S)
2-689
D-(-)adrenaline
(o:R)1 - epinefrine
2-690
D-(+)amphetamine
Dexedrin,
Dextroamphetamin
-137-


Bng 2-30. Cc sn phm chuyn ha ca amphetamine

Bng 2-29. Mt vi s liu ca mt s hp cht c tc dng kch thn nhm
dn xut ca amphetamine
Tn(bit
dc)
Cng thc
cu to
Nm -ch Liu dng
ngy(mg)
I. Cc phenyl-etylamin
Amphetamine(2-
690)(Aktedron,
Benzedrine)

1887 5-30
metamphetamine(2-
691)(Fetamin, Pervitin)




1929 5-15

Fenproporex(2-
692)(Gacilin, Solvolip)




1966 10-20
Mefenorex(2-
693)(Doracil, Pondinil)



1966 40-80
Phentermine(2- 1946 20-40


-138-


694)(Duromine,Ionamine)


Phenpentermine(2-
695)(Liprodne,
Modatrop)



1964 10-20
Chlorphentermine(2-
696)(Desopimon, Pre-
State)



1954 50-75
Chlortermine(2-
697)(Voranil)





1965 25-50
Norpseudoephedrine(2-
698)(Adiposetten, Thinz)






1927 30
Dimepropion(2-
699)(Medulor)




1928 50-100
Diethylpropion(2-
700)(Tenuate, Tepanil)





1928 50-75
Benzphetamine(2-
701)(Didrex, Inapetyl)



1957 50-150
Clobenzorex(2-
702)(Dinintel, Rexigen)



1966 30-60
Furfenorex(2-
703)(Frugal, Frugalan)

1965 80-120








-139-


Fenfluramine(2-
704)(Ponderax,
Pondimin)


1963 60-120
II. Cc piperidin
Methylphenidate(2-
705)(Centedrin, Ritalin)

1944 10-60
Pipradrol(2-706)(Detaril,
Meratran)

1948 3-6
Levophacetoperane(2-
707)(Lidpran)

1960 15-45
III. Cc morfolin
Phenmetrazine(2-
708)(Gracidin, Preludin)
N
H
O
CH
3


1958 25-75
Phendimetrazine(2-
709)(Dietrol, Plegine)

1956 70-100

-140-
Fenbutrazate(2-
710)(Cafilon, Filon)

1962 50-100
IV. Cc oxazolin
Aminorex(2-
711)(Apiquel, Minocil)

1963 5-10
Clominorex(2-712)


Fluminorex(2-713)


Pemoline(2-
714)(Cylert,Tradon)

1913 20-60
V. Cc cu trc khc
Mazindol(2-
715)(Sanorex, Teronac)
N
N
HO
Cl

1969 1-3
Fluoxetine (2-
716)(Prozac)

1974 40-80
*Loi tr fenfluramine ra th cc hp cht nhm ny va c tc dng gy
chn n va c tc dng an thn.
**Cht ny do tc dng ph nn b loi ra khi th trng do hai dn
xut tng t ca n cng vy.
***Cht ny cng c s dng nh l thuc chng trm cm

- Tng hp phentermine(2-694)
-141-

- iu ch chlorphentermine(2-696)

2-720

- Tng hp phenmetrazine(2-708) v phendimetrazine(2-709)


Ngi ta cng c th tng hp phenmetrazine i t 2bromo-1-oxo-1-
phenyl-propan theo s phn ng sau.

2-696
chlorphentermine

-142-


2.3.3.THUC CHNG TRM CM (PSYCHOENERGETICUM)
- L thuc tm thn c tc dng hng thn (thymolepticum) hoc thuc dng
iu tr bnh trm cm ni (endogen depression).
- Cc dng bnh trm cm:
- Cc l thuyt v nguyn nhn trm cm
Cc l thuyt v nguyn nhn trm cm do thiu ht:
+ noradrenalin (NA)
+serotonine
+dopamine(DA)
+gim phenyletylamin(tin catecholamone)
Qu trnh tng hp adrenaline v cc cht lin quan trong c th.


-143-
CH
2
HC - NH
2
COOH
CH
2
HC - NH
2
COOH
OH
CH
2
HC - NH
2
COOH
OH
OH
CH
2
CH
2
NH
2
CH
2
CH
2
NH
2
CH
2
CH
2
NH
2
OH
OH
OH
CH
2
COOH
HC - OH
CH
2
NH
2
HC - OH
CH
2
NH
2
OH
HC - OH
CH
2
NH
2
OH
OH
HO
CH-CH
2
NHCH
3
OH
OH
phenyl alanin
tirosin
DOPA
axit phenyl axeticphenyl - etylamin
tiramin
dopamine(DA)
phenyl etanol amin
octopamin
noradrenaline
adrenaline(A)





Hnh 2-11. Qu trnh tng hp adrenaline v cc cht lin quan trong c th.

-144-

CC THUC KCH THN
C hai nhm chnh sau:
- Nhm cc thuc c ch monoaminooxidase(IMAO)
- Nhm cc hp cht chng trm cm loi ba vng v nhng cu trc khc.
2.3.3.1. Cc thuc c ch Monoaminooxidase (IMAO)
- Lch s pht hin ra cc thuc chng trm cm loi IMAO
Bc s Selikoff (bnh vin Sea View trn o Staten Island thuc thnh ph New
York)
+ Dng INH (isonicotinic-hidrazit) iu tr bnh lao ci thin tm thn
+Zeller pht hin rng INH ngn cn hot ng ca enzim monoaminooxidase
(MAO) cc dn xut INH
Bng 2.3.1. S liu v mt s cht c ch MAO
Tn cht Cu to Nm iu ch Liu
dng
mg/ngy
I. Cc dn xut hidrazin
Iproniazid(2-
728)(Euphozid,Marsilid)

195
3
100
Nialamide(2-
729)(Espril,Niamid, Nuredal)

195
9
100
Isocarboxazid(2-
730)(Marplan)

195
9
30
Phenelzine(2-731)(Kalgan,
Nardil, Stinerval)

193
2
30
Pheniprazine(2-732)(Catrol,
Catron, Cavodil)

195
8
6
Mebanazine(2-733)(Actomol)

195
8
40
Phenoxypropazine(2-
734)(Drazine)

196
3
15
II. Cc amin
Tranylcypromine(2-
735)(Parnate,Parnitene,Tylciprin
e)

194
8
30
-145-
Etryptamine(2-736)(Monase)

196
0
45
Pargyline(2-737)(Eudatin,
Eutonyl,Supirdyl)

196
2
25
Clorgiline(2-738)

196
2
20
L-deprenylselegiline(2-
739)(Eldepryl,Jumex)

196
4
15
*Cc cht ny b nh ch s dng
- Tc dng ph ca IMAO:
- Tc dng h huyt p
- Tc dng chng au tht ngc
- Ko di tc dng ca barbiturat
- Cc c tnh ca IMAO
- Cc c tnh gy nn do kch thch thn kinh trung ng:
+ Run, mt ng, v m hi, kch thch thao cung, l ln, o gic, tng phn
x, co git.
+ Tt huyt p khi ng.
+ Vim gan nhim c, tn thng nng t bo gan, thng khng lin
quan n liu lng v thi gian dng thuc.
- c tnh do tng tc thuc vi thc n
+ Khi MAO b c ch th nhiu amin ni sinh v ngoi sinh khng b kh
amin oxi ha s gy ra cc triu chng bt thng.
+ Cn tng huyt p kch pht: (do cc amin a vo theo thc n)
+ To cn nhc u khi dng cc ung c ru
Cc thuc IMAO s dng b hn ch.
- Thuc phong ta IMAO c hai loi:
- Loi phong ta MAO-A: lm gim ging ha NA, 5-HT
- Loi phong ta MAO-B: lm gim ging ha phenyl etylamin
S dng thuc phong ta MAO-A th tc dng c tnh chn lc, t tc
dng ph.
*Thuc phong ta MAO-A: 2-742 v 2-743

-146-
*Thuc phong ta MAO-B: 2-741
Tng hp mt s hp cht IMAO:
*Tng hp iproniazid (2-728) v nialamide(2-729)


*Tng hp tranulcypromine(2-735)

*Tng hp etryptamine(2-736)


-147-


*Tng hp moclobemide(2-743)


2.3.3.2. Cc thuc chng trm cm loi cc hp cht ba vng v nhng cu trc
khc
- L loi s dng ph bin nht trong iu tr bnh trm cm hin nay.
- Pht hin ra nhm ny t vic s dng phentiazine lm thuc an thn
imipramine (2-756)
Bng 2-32. Cc thuc chng trm cm quan trng nht thuc nhm cu trc ba
vng 6-7-6
Tn Cng thc cu to N
m
iu
ch
Liu
dng
mg/ng
y
I. Cc dn xut dibenzozepin
Imipramine(2-756)(Antideprin,
Melipramin, Tofranil)

195
1
150
Clomipramine(2-757)
(Hydiphen,Anafranil)

196
1
20-30
Trimipramine (2-758)(Sapilent,
Stangyl, Surmontil)

196
1
150
-148-
Desipramine(2-759)(Irene,
Norpramin,Pertofran)

196
2
75
Opipramol (2-760)(Dinsidon,
Insidon, Nisidana)

196
1
100
II. Cc dn xut dibenzosuberon
Amitryptyline(2-761)(Elavil,
Saroten, Teperin)

196
0
100
Nortryptyline(2-
762)(Allegron,Aventyl,Nortrilen)

196
2
40
Butryptyline (2-
763)(Centrolyse,Evadene,
Evadyne)

196
2
100
Noxiptiline (2-764)(Agedal,
Nogdal)

196
5
100
-149-
Amineptine (2-765)(Survector,
Manecon)
NH - (CH
2
)
6
COOH

197
0
200
Protryptyline(2-766)(Concordin,
Maximed, Vivactil)

196
2
30
III. Cc cht c cu trc khc
Doxepin (2-
767)(Curatin,Novoxapin,Sinequan
)

196
2
120
Dothiepin (2-
768)(Altapin,Depresym,Prothiade
n)

196
2
100
Dibenzepin (2-769)(Ansiopax,
Deprex, Noveril)

196
3
100
Amoxapine (2-
770)(endin,Demolox)
O
N
N
NH
Cl

196
7
250
-150-
Iprindole (2-771)(Galatur,
Prondol,Tertran)

196
3
90

Bng 2-33. Cc thuc chng trm cm quan trng nht thuc nhm cu trc ba
vng 6-6-6 v bn vng lin hp
Tn Cng thc cu
to
Nm iu ch Liu dng
mg/ngy
I. Cc cht ba vng
Dimethacrine(2-
772)(Istonil,Linostil)
N
CH
3
H
3
C
(CH
2
)
3
-N
CH
3
CH
3

1963 150
Melitracen(2-
773)(Dixeran,Trausabun)

1963 75
Danitracen (2-774)
OH H
N
CH
3

1965 3
II. Cc cht bn vng
Mianserin (2-
775)(Athymil,Bolvidon,
Tolvin)

1967 50
-151-
Maprotiline (2-
776)(Ludiomil)

1969 100

Bng 2-34. Cc thuc chng trm cm thuc nhm cc cht c cu trc khc nhau
Tn Cng thc cu to Nm
iu
ch
Liu
dng
mg/ngy
Tofenacin (2-777)
(Elamol, Tofacine)

1963 200
Zimelidine (2-778)
(Normud, Zelmid)

1972 200
Fluoxetine (2-779)
(Prozac)

1974 50
Nomifensine (2-
780) (Alival,
Hostalival,Merital)

1969 150
Trazodone (2-781)
( Desyrel,
Molipaxin,
Tombran)

1968 150
Caroxazone (2-
782) (Timostenil)

1968 450
-152-
Thozalinone (2-
783) (Stimsen)

1962 100
Viloxazine (2-784)
(Vivalan)

1969 200
Bupropion (2-785)
(Wellbutrin)

1971 300

2.3.3.2.1. C ch tc dng ca cc hp cht loi ba vng
Ngn cn ti thu hi cc amin sinh hc cht chuyn ti nron gii phng ra i
vo cc ht tin sinap
- c ch s thu hi serotonine chng c tm trng bun ru tht vng,
mun t st.
- c ch s thu hi noradrenaline (NA), lm tng nng tnh hot ng.
- Khng cholinergic trung ng v ngoi bin.
Tc dng chng trm cm ch xut hin sau 10-20 ngy dng thuc. Du hiu
sm ca chng trm cm l tr li n ngon ming.
2.3.3.2.2. Nhng tc dng dc l khc ca nhm cc cht ba vng:
- Trn thn kinh trung ng: c tc dng tng t nh chlorpromazine
- Trn thn kinh thc vt: tng tc dng ca adrenaline v noradrenaline, i
khng tc dng vi cc thuc cng giao cm, c tc dng hy ph giao
cm, lm gin ng t v nhu ng rut; c tc dng khng histamin
- Trn h tim mch: liu cao c ch c tim, gim cung lng tim v h huyt
p. C tc dng chng lon nhp tim, liu cao gy block nh tht.
2.3.3.2.3. Cu trc mt s thuc chng trm cm loi ba vng v nhng cu
trc khc
- Dn xut dibenzodiazepin (I)
- Dn xut dibenzosuberon (II)
- Cc cht c cu trc khc (IIIa,IIIb)
N
C
-C
-C
-N

I II
C
-C
-C
-N

-153-


X= O,S,N
IIIa IIIb X=C,N
Cc hp cht c th xem trong bng 2-32
2.3.3.2.4. Tng hp mt s thuc chng trm cm
- Tng hp imipramine (2-756)

* iu ch hp cht 2-789


-154-
- Tng hp desipramine (2-759)

- Tng hp amitriptyline (2-761) [156]

- Tng hp doxepin (2-767)


- Tng hp miaserin (2-775)
-155-

- Tng hp maprotiline (2-776)

- Tng hp fluoxetine (2-779) v nisoxetine (2-817)
-156-


- iu ch trazodone (2-781)




2.3.4. CC CHT GY RI LON TM THN
nh ngha: cc cht c kh nng gy ra trn ngi bnh thng mt s triu
chng ca bnh lon tm thn v cc o gic c gi l cc cht lon thn
(lon tm thn).
2.3.4.1. Ngun gc ca cc cht lon tm thn:
- a s l c ngun gc t thc vt v phn nhiu l cc hp cht ancaloit.
Bng 2-35. Mt s cht c tc dng lon thn bit
Tn Cng thc cu to Nm
iu
ch
Liu
dng
mg/ngy
-157-
Ergotamine (2-829)
N
H
N
CH3
OC-NH
N
O
H
3
C
O
OH
N
H
CH2C6H5
O
H


Lysergide (2-830)
(LSD-25,Delysid)
N
H
N
CH3
C
O
N
C2H5
C
2
H
5

1938 0,05-0,1
Ibogain (2-381)
(Ibagin)

1901 300-400
Harmin (2-832)

1841 300-400
Harmalin (2-833)


1941 300-400
Psilocibine (2-834)

1958 4-8
Bufotenin (2-835)

1934 15-20
i..v
-158-
Imethyltryptamine
(2-836) (DMT)

1955 50-100
i.v.
Diethyltryptamin (2-
837) (DET)

1957 50-100
Adrenochrome (2-
838)

1937 20-50
i.v.
Adrenolutin (2-839)

1949 50-70
Mescalin (2-840)

1896 300-500
Myristicine (2-841)

1909 400-600
Axit ibotennic (2-
842)

1964 70-100
Muscimol (2-843)

1964 10-15
Tetrahidrokannabinol
(2-844) (THC)

1964 20-30
-159-
Phencylidine (2-46)
CH N

1960 10-20
i.v.
2.3.4.2. Tc dng dc l:
Cc cht lon thn u gy cc ri lon tm thn nh: o nh (o th, o thnh),
cm gic xon vn, mt nh hng v khng gian v thi gian, vi n tng
thi gian tri qua nhanh chng, cn sng gp. n tng nh ang bp bnh
bay bng trong v tr, hnh nh c th mo m vi tnh cm gii th nhn cch,
phn i nhn cch, lo u, hi hp.
2.3.4.3. C ch tc dng:
Lm thay i s sn xut, s gii phng cc amin sinh hc (serotonine,
catecholamine, encephaline) hoc thay i tnh cm th ca cc receptor c
hiu vi cc amin ny ti cc vng khc nhau trn h thn kinh trung ng.



























-160-
TI LIU THAM KHO

1. Phan nh Chu, Ha dc v k thut tng hp 1, NXB Khoa hc v
k thut.
2. Ha dc - dc l, sch o to dc s trung hc, NXB Y hc.
3. Trnh Thanh oan, Nguyn ng Quang, Hong Trng Ym, Ha hu
c, NXB Gio dc, 1992.
4. Hong Tch Huyn, Dc l hc, NXB Y hc, 1999.
5. ng Nh Ti, C s ha hc lp th, NXB Gio dc H Ni, 1998.
6. Nguyn Minh Tho, Tng hp hu c, NXB i hc Quc gia H Ni.
7. Wolf. M. E. Burger

s Medicinal Chemistry. John and Sons, New York,

1981.
8. Gareth T.: Medicinal Chemistry. John Wiley and Sone, 2000.
























-161-
MC LC

CHNG 1: M S KIN THC CHUNG V HA DC ............................ 1
1.1. Ha dc qu kh, hin ti v tng lai ........................................................ 1
1.2. Cc yu t ha l v cu trc ha hc nh hng n tc dng sinh hc ........ 5
1.3. Khi nim v dc l hc ................................................................................... 5
1.4. Tin trnh nghin cu a mt thuc mi vo s dng ................................... 27
CHNG 2: CC THUC TC DNG LN H THN KINH TRUNG NG
2.1. i cng v h thn kinh trung ng v hot ng ca n ........................... 30
2.2. Cc thuc c ch h thn kinh trung ng........................................................ 30
2.2.1. Cc thuc gy t .............................................................................................. 31
2.2.2. Cc thuc m ................................................................................................... 34
2.2.3. Cc thuc gy ng ........................................................................................... 41
2.2.4. Cc thuc cha ng kinh ............................................................................... 68
2.2.5. Cc thuc gim au ......................................................................................... 75
2.2.6. Cc thuc tm thn .......................................................................................... 99
2.2.7. Cc thuc gin c ........................................................................................... 125
2.2.8. Cc thuc cha bnh Parkinson.................................................................... 127
2.3. Cc thuc kch thch h thn kinh trung ng ................................................. 134
2.3.1. Thuc hi sc ................................................................................................. 134
2.3.2. Thuc kch thn .............................................................................................. 136
2.3.3. Thuc chng trm cm ................................................................................... 142
2.3.4. Cc cht gy ri lon tm thn ...................................................................... 156
Ti liu tham kho .................................................................................................... 160