CHNG 3.

THUC TC DNG TI H THN KINH THC VT

3.1. Cu to v hot ng ca h thn kinh thc vt
Phn ca h thn kinh phc v cho s bo tn, sinh sn v sinh trng ca c th c gi l
h thn kinh thc vt. H thn kinh thc vt trc tip iu khin hot ng ca cc c quan
tim, mch mu, tiu ha, h hp, bi tit v sinh sn. Hot ng ca cc b phn nu trn c
lin quan n cc hot ng ngoi mun, n c vai tr iu ha gi cho c th gi c
s n nh trong khi mi trng sng lun lun thay i. Do tnh c lp t nhiu khng ph
thuc mt cch tuyt i vo h thn kinh trung ng ca n nn h thn kinh thc vt cn
c gi l h thn kinh t ng.
H thn kinh thc vt c c phn trung ng v phn ngoi bin
H thn kinh thc vt hnh thnh t nhng trung tm trong no vo ty sng i ti cc tng
(gan, thn, lch ) mch mu v c trn. Trc lc ti cc c quan thu nhn, cc si ny
u dng li ti hch sinap. V vy, c si trc hch (hay tin hch) v c si sau hch (hay
hu hch). Khc vi cc b phn do h thn kinh trung ng iu kin, cc c quan do h
thn kinh thc vt chi phi vn c th hot ng khi ct t nhng si thn kinh dn n
chng.
H thn kinh thc vt c chia thnh hai h: h giao cm v h ph giao cm. Hai h ny
khc nhau c v gii phu v v chc phn sinh l, chng chi phi ln nhau.
V mt gii phu, hai h ny c c im khc nhau:
V im xut pht:
H giao cm xut pht t nhng t bo thn kinh sng bn ca ty sng t t sng c th
by n t sng lng th ba (C7-L3).
H ph giao cm xut pht t no, hnh no v ty cng. no gia v hnh no, cc si
ph giao cm i cng vi cc dy thn kinh trung ng: dy III i vo mt, dy VII vo cc
tuyt nc bt, dy X vo cc tng trong ngc v trong bng. ty cng, xut pht t t
sng cng th II n th IV (S2-S4) chi phi cc c quan trong h chu.
V hch:
H giao cm: c ba nhm hch:
Nhm chui hch ct sng nm hai bn ct sng.

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Nhm hch trc ct sng gm hch tng, hch mc treo v hch h v u nm trong
bng.
Nhm hch tn cng gm nhng hch nm cnh trc trng v bng quang.
H ph giao cm:
Cc hch nm ngay cnh hay trong thnh c quan.
V si thn kinh:
H giao cm: mt si tin hch thng tip ni vi khong 20 si hu hch cho nn khi kch
thch giao cm th nh hng thng lan rng.
H ph giao cm: mt si tin hch thng ch tip ni vi mt si hu hch cho nn xung
tc thn kinh thng khng lan xa hn so vi xung tc giao cm. Tuy nhin i vi dy X
th m ni Auerbach v Meissner (c gi l hch) th mt si tin hch c tip ni
vi khong 8000 si hu hch.
V hch nm ngay cnh cc c quan nn cc si hu hch ph giao cm thng rt ngn.

V mt chc phn sinh l: Chc phn sinh l ca hai h giao cm v ph giao cm trn cc
c quan ni chung l i khng nhau.

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Khi ta kch thch cc dy thn kinh (trung ng v thc vt) th u mt ca cc dy s
tit ra nhng cht ha hc lm trung gian cho s dn truyn gia cc dy tin hch vi hu
hch, hoc gia dy thn kinh vi cc c quan thu nhn. Cht ha hc lm trung gian cho s
dn truyn gi l cht dn truyn thn kinh hay cht trung gian ha hc.
H thng thn kinh ca ngi c hng chc t nron. S thng tin gia cc nron cng
da vo cc cht dn truyn thn kinh. Cc thuc nh hng n chc phn thn kinh
thng l thng qua cc cht dn truyn thn kinh . Cht dn truyn thn kinh hch giao
cm, ph giao cm v hu hch ph giao cm u l acetylcholin, cn hu hch giao cm
l noradrenalin, adrenalin v dopamin (gi chung l catecholamin). Cc cht dn truyn thn
kinh tc ng n mng sau xinap lm thay i tnh thm ca mng vi ion Na +, K+ hoc
Cl- do gy ra hin tng bin cc (kh cc hoc u cc ha). Ion Ca++ ng vai tr quan
trng trong s gii phng cht dn truyn thn kinh.
Hnh 3.1. Sinap v cht trung gian ha hc
Cc cht dn truyn thn kinh c tng hp ngay ti t bo thn kinh, sau c lu tr
di th phc hp trong cc ht c bit nm ngn dy thn kinh trnh b ph hu.
Di tc dng ca nhng lung xung tc thn kinh, t cc ht d tr , cht dn truyn
thn kinh c gii phng ra di dng t do, c hot tnh tc ng ti cc receptor. Sau
chng c thu hi li vo chnh cc ngn dy thn kinh va gii phng ra, hoc b ph
hu rt nhanh bi cc enzym c bit. Acetylcholin b cholinesterase thu phn, cn
noradrenalin v adrenalin th b oxy ha v kh amin bi catechol - oxy- methyl- transferase
(COMT) v mono - amin- oxydase (MAO).
Mt s iu c bit ng ghi nh trong h thn kinh thc vt l:
Dy giao cm i ti tu thng thn khng qua mt hch no c. tu thng thn, dy ny
tit ra acetylcholin kch thch tuyn tit ra adrenelin. V vy, thng thn c coi nh
mt hch giao cm khng l.
Cc ngn dy hu hch giao cm chi phi tuyn m hi ng l phi tit noradrenalin, nhng
li tit ra acetylcholin.
Cc dy thn kinh vn ng i n cc c xng (thuc h thn kinh trung ng) cng gii
phng ra acetylcholin.

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Trong no, cc xung tc gia cc nron cng nh acetylcholin. Ngoi ra cn c nhng cht
trung gian ha hc khc nh serotonin, catecholamin, acid - gama- amino- butyic (GABA)...
H thng thn kinh thc vt trong no:
Khng th tch ri hot ng ca h thn kinh trung ng vi h thn kinh thc vt. Gia 2
h lun lun c mi lin quan cht ch vi nhau m bo tnh thng nht ca c th.
Nhng mi lin quan v ang c tm thy vng di i, h vin (systema
limbicus), hi hi m (hyppocampus), l nhng ni c cc trung tm iu ha thn nhit,
chuyn ha nc, ng, m, iu ha huyt p, ni tit, hnh vi...
Trong h thn kinh trung ng cng thy cc cht dn truyn thn kinh v cc receptor
nh ca h thng thn kinh thc vt ngoi bin.
3.2. Phn loi cc thuc h thn kinh thc vt
C hai cch phn loi:
Phn loi theo phng din gii phu v sinh l
Thuc cng giao cm (sympathicomimetic): nhng thuc c tc dng ging nh tc dng
kch thch giao cm.
Thuc cng ph giao cm (para - sympathicomimetic): nhng thuc c tc dng ging nh
kch thch ph giao cm.
Thuc hu giao cm (sympathicolytic): thuc c tc dng km hm tc dng ca giao cm.
+Thuc hy ph giao cm (parasympathicolytic): thuc c tc dng km hm tc dng ph
giao cm.
Phn loi theo phng din dc l:
Nh chng ta thy, hot ng ca thn kinh l nh nhng cht trung gian ha hc, cho
nn cch phn loi v gi tn theo gii phu v sinh l khng ni ln c y v chnh
xc tc dng ca thuc.
V vy, mt cch hp l hn c, ng v phng din dc l, ta chia h thn kinh thc vt
thnh 2 h. Cc thuc tc dng trn h thn kinh thc vt cng mang tnh c hiu, tc dng
chn lc trn cc receptor ring i vi chng.
H phn ng vi acetylcholin, gi l h cholinergic (gm cc hch giao cm, ph giao cm;
hu hch ph giao cm; bn vn ng c vn; mt s vng trn thn kinh trung ng).
H phn ng vi adrenalin, gi l h adrenergic (ch gm hu hch giao cm).

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Cc receptor ca h cholinergic cn c chia lm 2 loi:
Loi nhn cc dy hu hch (v d tim, cc c trn v tuyn ngoi tit) cn b kch thch bi
muscarin v b ngng hm bi atropin, nn c gi l h cm th vi muscarin (hay h M).
Loi nhn dy tin hch cn b kch thch bi nicotin, nn cn c gi l h cm th vi
nicotin (hay h N), h ny phc tp, bao gm cc hch giao cm v ph giao cm, tu
thng thn, xoang ng mch cnh (b ngng hm bi hexametoni) v bn vn ng c vn
thuc h thn kinh trung ng (b ngng hm bi d - tubocurarin).
Cng trn nhng c s tng t, cc receptor ca h adrenergic c chia lm 2 loi: alpha (
) v beta ().
Cc thuc kch thch c th tc ng theo nhng c ch:
. Tng cng tng hp cht dn truyn thn kinh
. Phong to enzym phn hu cht dn truyn thn kinh
. Ngn cn thu hi cht dn truyn thn kinh v ngn dy thn kinh.
. Kch thch trc tip cc receptor
Mi lin h ca h thng thn kinh ngoi bin c th thy trong s sau:

5
3.3. Cc thuc tc dng trn h thn kinh thc vt.
Ty thuc thuc tc dng ti h cholinergic hoc adrenergic m chia thnh hai nhm chnh
sau:
3.3.1 Cc thuc tc dng ln h cholinergic
Cc thuc thuc nhm ny cn c phn ra theo c tnh tip nhn chng ca receptor.
Loi receptor b kch thch bi muscarine (h muscarinic M) hay bi nicotine (h
nicotinic N).
3.3.1.1. Cc thuc tc dng ln h muscarinic (h M)
Ty thuc vo tc dng kch thch hay km hm ca thuc ln h M m ta c thuc cng h
M hay ngng hm h M.
1. Cc thuc cng h M (cng h ph giao cm)
Cc thuc ny c tc dng kch thch cc t bo thn kinh h M ging nh cht trung gian
ha hc acetylcholine hoc c tc dng lm tng hot ha acetylcholine trong t bo, ngn
cn vic thy phn ca acetylcholine bng vic lm t lit cc emzim cholinesterase, kt qu
trc tip lm cho nng acetylcholine tng ln v duy tr ko di.
Cc thuc cng h M thng c s dng bao gm cc nhm hp cht sau: Acetylcholine
(3-1) v cc dn xut: bentanechol (3-2), cacbachol (3-3), metacholine (3-4), oxaproponium
(3-5), muscarine (3-6), pilocarpine (3-7), furtretonium-propionat (3-8), oxotreponium (3-9).

6
 OO H
CH3COOCH2CH2N(CH3)3 H2N C C CH2N(CH3)3

3-1: acetylcholine CH3

3-2: betanechol
H2NCOOCH2CH2N(CH3)3
OO H
H3C C C CH2N(CH3)3
3-3: cacbachol
O CH3

CH CH2N(CH3)3 3-4: metacholine

O
HO

3-5: oxaproponium
CH CH2N(CH3)3
C2H5 CH3 H3C
O

H2
N 3-6: muscarine
O C

N
CH3OCH2CH2N(CH3)3
O
3-8: furtretonium-propionat
3-7: pilocarpine (Pilocapinum)

Acetylcholine l mt cht trung gian ha hc quan trng trong c th ngi v ng vt,

c tng hp t choline v acetyl coenzim A vi xc tc enzim choline-acetyltranferase, n
c si sau hch ph giao cm tit ra t cc ngn cc si tit cholin (thn kinh vn ng,
xng c, si trc hch ph giao cm v ph giao cm). Sau khi tng hp, acetylcholine
c lu tr trong cc nang ng knh khong 300-600A0 ngn dy cholinergic di
dng phc hp khng hot tnh. Di nh hng ca xung thn kinh v ca ion Ca2+,
acetylcholine c gii phng ra dng t do, lc n ng vai tr mt cht trung gian ha
hc, tc dng ln cc receptor cholinergic mng sau sinap, ri b thy phn mt hot tnh
rt nhanh di tc dng ca enzim cholinesterase thnh cholin v axit axetic.
Qu trinh tng hp acetylcholine c th b c ch bi hemi-cholin, cn c t ca vi khun
batulinus c ch vic gii phings acetylcholine ra dng t do.
Tc dng dc l ca acetylcholine:
Vi liu thp (10mg/kg tnh mch cho ch), ch yu l tc dng trn hu hch ph giao cm
(h muscarinic): lm chm nhp tim, gim mch, h huyt p, tng nhu ng rut, co tht

7
ph qun, gy cn hen, co tht ng t, tng tit dch nc bt v m hi. Atropne lm mt
hon ton nhng tc dng ny.
Vi liu cao acetylcholine kch thch cc hch thc vt ty thng thn (h N), lm tng
nhp tim, co mch tng huyt p v kch thch h hp.
p dng lm sng:
V acetylcholine b ph hy rt nhanh trong c th nn t c dng trong lm sng. Ch
dng lm gin mch trong bnh tm ti u chi (bnh Raynaud) hoc cc biu hin hoi
t.
Tim di da hoc tim bp 0,05 0,1g, mi ngy 2-3 ln.
Tng hp:
Acetylcholine c tng hp bng vic acetyl ha dimetylamino-etanol bng acetyl clorua
hoc anhidric acetic sau cho este thu c to mui vi metyl clorua c
acetylcholine clorid.
CH3COCl + HOCH2CH2N(CH3)2 CH3COOCH2CH2N(CH3)2

CH3Cl
CH3COOCH2CH2N(CH3)3Cl
Acetylcholine chloride

Betanechol (3-2), cacbachol (3-3) l dn xut cacbamat, c thi gian tc dng ko di hn do

cc thuc ny khng b enzim cholinesterase phn hy.
Bentanechol tc dng chn lc trn ng tiu ha v tit niu, dng iu tr chng bng,
y hi v b i sau khi m (ung 5-30mg, 3-4 ln mt ngy). Cn cacbachol dng cha
bnh tng nhn p, nh dung dch 0,5-1%.
Cacbachol cn c dng lm chm nhp tim trong cc cn nhp nhanh kch pht, ri lon
tun hon ngoi bin (vim ng mch, bnh Raynaud), to bn, trng bng, b i sau m.
Ung 0,5-2mg/ngy. Tim di da 0,5-1,0mg/ngy.
Tng hp:
H2 H H2 H
(H3C)2N C C OH + CO(Cl)2 (H3C)2N C C OCOCl

R R

NH3 H2 H CH3Cl H2 H
(H3C)2N C C OCONH2 (H3C)3N C C OCONH2
Cl
R R

8
R = CH3: bentanechol; R = H: cacbachol
2. Cc thuc ngng hm h muscarinic (h M) hay cn gi l cc cht hy ph giao cm
(parasympatholiticum)
Tc dng hy ph giao cm c c l do ngn cn tc dng ca acetylcholine gii phng ra
mt cch sinh l trong cc u dy thc vt th cm. Cc cht c tc dng kiu ny gm
c:
Cc hp cht ancaloit nhn tropan: bao gm atropine (3-9), scopolamine (3-10).
Cc hp cht tng hp c b khung tropan gm homatropine (3-11)
Cc hp cht tng hp khng c b khung tropan l propanthelin bromide (3-12),
methantheline bromide (3-13)
CH3 CH3

N N
OH OH
O
CH2 CH2

O O
O C C O C C
H H

3-9: atropine 3-10: scopolamine

CH3

N
CH(CH3)2

OH O COOCCH2CH2 N CH(CH3 )2 Br

O
O C C CH3
H

3-11: homatropine
CH3
3-12: propantheline bromide
COOCH2CH2 N(C2 H5)2Br

O
3-13: methantheline bromide

Atropine (3-9) l ancaloit ca l cy Atropa belladona, c c dc, thin nin t.

c bng A.

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 0,7 nm

O CH3
O CH3
H2
H3C C H2C C N acetylcholine

CH3

O CH2
O CH3
H2
H3C C H2C C N carbamoylcholine
CH3

O CH2 H
O
pilocarpine
C N
N
H2
C2H5 CH C C

HO CH2 O H2 C CH CH2
O

HC C CH H3C N atropine

H2 C CH CH2

Atropine l nhng cht i khng tranh chp vi acetylcholine receptor ca h muscarinic.

C s i khng tranh chp ny c l c gii thch thng qua s ging nhau v cu trc
ca chng, khong cch t lin kt este v nito trong cc hp cht ny gn bng nhau (gn
bng 0,7nm), nh vy c kh nng chng u gn kt vo th th cholinergic.
Cc tropein gn kt vo th th lm ngn cn s gn kt ca acetylcholine. Nh vy, lm
cho tc dng cholin khng c sinh ra. i lc ca atropine ti receptor mnh hn ca
acetylcholine do dng atropine to ra tc dng i khng vi tc dng ca
acetylcholine. Ch vi liu cao v tim vo ng mch th mi thy tc dng ny trn hch
v bn vn ng c vn.
V vy tc dng thng thy l:
Trn mt: lm gin ng t v mt kh nng iu tit do ch nhn c xa. Do thuc lm
c mi gin ra nn cc ng thng dch nhn cu b p li, lm tng nhn p. V vy, khng
c dng atropin cho nhng ngi b tng nhn p.
Lm ngng tit nc bt lng, gim tit m hi, dch v, dch rut.

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Lm gim nhu ng rut khi rut b tng nhu ng v co tht.
Lm gin c trn, gy h huyt p.
- c ch tc dng ca acetylcholine trong h thn kinh trung ng.
p dng lm sng:
Lm thuc nh mt atropin sunfat 0,5-1% dng trong soi y mt hoc iu tr vim mng
mt, vim gic mc.
Do tc dng lm gin c trn nn c dng ct cn hen, cn au ti mt, cn au thn,
au d dy.
Tim trc khi gy m trnh tit nhiu m di, trnh ngng tim.
iu tr ng c do mn c loi muscarin v ng c cc thuc phong ta enzim
cholisnestase.
Chng ch nh: bnh tng nhn p, b i do ph i tuyn tin lit.
iu ch atropin: chit xut t r cy Atropa belladona.
Scopolamine (3-10): l ancaloit ca cy Scopolia carniolica.
Tc dng gn ging atropine. Thi gian tc dng ngn hn. Trn thn kinh trung ng
atropine kch thch cn scopolamine th c ch cho nn dng cha bnh Parkinson, cc cn
co git ca bnh lit rung, phi hp vi thuc khng histamin chng nn khi say tu xe,
say sng. Ung hoc tim di da 0,25-0,5mg. Liu ti a mi ln 0,5 mg, 1,5mg/ngy.
Vin Aeron cha 0,1mg scopolamin camphonat v 0,4mg hyoscyamine camphonat dng
chng say sng, say tu xe.
Ung 1 vin trc lc khi hnh 30 pht.
Sn xut scopolamine :
R hot ht dc liu (Datura innoxia, Scopolia carniola...) c xay nh, ngm trong t du
ha tch du, sp. Sau ngm t bt ny vi 60-70% trng lng dung dch natri
cacbonat 10%, sy kh trong hai gi. K , chit vi ete nng trong h thng thit b kn
theo phng php ca chemnitius (mt m khong 500kg dc liu). Chit i chit li 4-5
ln. Lc thu ly dch chit, ct thu hi ete, cn c ha tan trong dung dch axit acetic 5%,
lc loi cht khng tan sau chit 3 ln vi ete. Pha nc mui cha axetat ca ancaloit
c kim ha vi dung dch natri cacbonat bo ha sau chit 3 ln vi ete. Dch ete em

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ct thu hi ete. Cn thu c c mu vng l baz scopolamin. Ha tan cn trong etanol v
to mui brom hidrit (kt tinh bng vic ha long vi aceton).
Homatropin (3-11) :
c bng A. L cht c tng hp t tropanol v axit mandelic vi s c mt ca kh HCl
(este ha). Kt qu thu c homatropin hidroclorua. Thng s dng di dng mui
hidrobromua.
Homatropin c tc dng gin ng t thi gian ngn hn atropine. Dng soi y mt, dung
dch 0,5-1%.
Propantheline bromide (3-12) l hp cht tng hp khng cha b khung tropan.
O

COOH

O O O
3-15 3-16
3-14

COOCH2CH2N[CH(CH3)2]2Br COOCH2CH2N[CH(CH3)2]2 COOH

CH3Br

O O O
propantheline bromide 3-18 3-17
3-12

3.3.1.2. Cc thuc tc dng ln h nicotinic (h N)

Cc thuc tc dng trn h N cng c loi thuc cng hoc hm h N.
1. Cc thuc kch thch h nicotinic (cng h N)
Cc thuc ny t c dng trong iu tr nhng li quan trong v mt dc l v c dng
nghin cu cc thuc tc dng trn hch. Thuc kch thch hch c chia lm hai nhm,
nhm th nht l kch thch trn cc recept nicotinic (h N) ca hch b hexametoni c ch.
Cn nhm th 2 l cc thuc kch thch cc recept muscarinic (h M ca hch, khng b
hexametoni c ch m b atropine c ch.
Cc thuc kch thch h N gm c nicotine (3-19), lobeline (3-20), tetramethylanmonium
bromide (3-21, TMA), 1,1-dimethyl-4-phenyl-piperazinium iodide (3-22, DMPP).

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 CH3
N H2 H2
CH3 H
OC C N C C OH
N
C6H5 C6H5

3-19: Nicotin 3-20:lobelin

CH3
H3C CH3

N Br N N I
H3C CH3 CH3
3-22: DMPP
3-21: tetrametylamonium bromide

Nicotin (3-19) : thuc c bng A

Nicotin c trong thuc l, thuc lo (0,5-8%). Khi ht thuc l, nicotin c gii phng ra
di dng baz t do. Liu gy cht khong 69 mg (ht mt iu thuc l hp thu khong 1-
3 mg nicotin). Trn hch thc vt, liu h gy kch thch, liu cao lm t lit hch do gy
bin cc v sau l tranh chp vi acetylcholine.
Tc dng :
Trn tim mch gy tc dng 3 pha : h huyt tm thi, tng huyt p mnh ri cui cng l
h huyt p ko di.
Trn h hp : kch thch lm tng bin v tn s.
Gin ng t, tng tit dch, tng nhu ng rut.
Nguyn nhn ca nhng tc dng l do :
Lc u nicotin kch thch hch ph giao cm v trung tm c ch tim hnh no nn lm
tim p chm, h huyt p nhng sau nicotin kch thch hch giao cm, trung tm vn
hch v cc c trn lm cho tim p mnh, tng huyt p, gin ng t v tng nhu ng
rut. ng thi kch thch ty thng thn (ni c coi l hch giao cm khng l) lm tit
adrenalin, qua cc recept nhn cm ha hc xoang cnh, kch thch phn x ln trung tm
h hp, cui cng l giai on lit sau khi b kch thch qu mc lm h huyt p ko di.
Nicotin khng dng trong iu tr, ch dng trong cc phng th nghim hoc git su b.
Nicotin gy nghin nhng khi cai thuc th khng gy bin chng nh cai thuc phin.
Ht thuc l c hi n tim, mch, nim mc ng h hp, phi v trong khi thuc c
CO2, nit baz, cc axit bay hi l nhng cht kch thch nim mc, ngoi ra cn c cc cht
nha (c cha 3,4-benzpyren, c th l mt trong cc nguyn nhn gy ung th).
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Sn xut nicotin : nicotin c chit xut t thuc l, l thuc lo (thng th ly phn ph
thi ca thuc l trong nh my sn xut thuc l). Nicotin trong thuc l di dng mui
nn trc lc chit phi gii phng ra dng baz bng vic x l vi nc vi. Tip bng
cch ct ko hi nc hoc chit vi dung mi hu c chit xut ly nicotin.
Lobelin (3-20) : l ancaloit ca cy Lobelia inflata.
Lobeline tc dng km nicotin rt nhiu. c bit kch thch xoang cnh v cung phn x
lm tng h hp, mt khc cn lm gin ph qun, d th, nht l trong trng hp ph qun
b co tht (do lm gii phng adrenalin t ty thng thn). Ch dng khi trung tm h hp
cn kch thch phn x c (nh khi ng c oxit cacbon hoc morphine). Nu phn x
mt (ng c thuc m) th khng tc dng, khi phi dng corazol, niketamide.
Tim di da mi ln 10mg, tim tnh mch mi ln 3mg. Mi ngy tim 2-4 ln. ng 1ml
cha 0,01g lobeline hidroclorua.
Lobeline c sn xut bng cch chit xut t l cy Lobelia inflata.
Tetrametyl amoni bromide (3-21) v 1,1-dimetyl-4-phenyl-piperazini iodide (DMPP).
Hai hp cht ny c tc dng ging nicotin (hp cht DMPP c hot lc mnh hn nicotin
gp 3 ln) kch thch c hch giao cm, ph giao cm nn tc dng phc tp, khng c s
dng trong iu tr.
2. Cc thuc ngng hm h nicotinic (h N)
Cc thuc ngng hm h N c chia ra lm 3 loi: loi lm ngng hm hch thc vt, nh
hng ti hot ng ca c trn, lm ngng hm trn bn vn ng c vn v loi lm gin
c vn do c ch trung ng.
Cc thuc lm ngng hm h nicotinic ca hch
Cc thuc ny cn gi l thuc phong ta hch hay thuc lit hch v lm ngn cn lung
xung tc thn kinh t s tin hch ti si hu hch. C ch chung l tranh chp vi
acetylcholin ti recept mng sau sinap ca hch.
Tuy trong cc c quan ca c th thng nhn s chi phi ca c hai h giao cm v ph
giao cm song bao gi cng c mt s chim u th. V vy, tc dng ca cc thuc lit
hch trn tng c quan ph thuc vo tnh u th y ca tng h.
Trong lm sng, cc thuc lit hch thng c dng lm h huyt p trong cc cn
tng huyt p, h huyt p iu khin trong m x v i khi iu tr ph phi cp.

14
Cc thuc lm ngng hm h nicotinic ca hch gm c: cc mui bc 4 l tetraetylamoni
bromide (3-23), hecxametoni (3-24), azamethonium bromide (3-25), pentolonium tartarate
(3-26) v mt s amin bc hai, bc ba nh mecanylamine (3-27), pempidine (3-28).

C2H5 C2H5 (H3C)3N (CH2)6N(CH3)3 2Br

N Br
3-24: hexametonium bromide
C2H5 C2H5
CH3
3-23: tetraetylamonium bromide
CH3 CH3

H3C N (CH2)2N (CH2)2N(CH3)2 2Br CH3

C2H5 CH3 C2H5 HN CH3

3-25: azamethonium bromide 3-27: mecamylamine

COO
CH3
HC OH H3C CH3
N (CH2)5N 2 N
HC OH
CH3 H 3C H3C CH3
COOH

3-26: pentolonium tartarate 3-28: pempidine

iu ch Mecamylamine:
CH3 CH3
CH3

CH3 CH3
HCN + H2SO4 CH3 LiAlH4
PU Ritter CH3 CH3
CH2
HN CH3
NHCHO *
Cc thuc lm ngng hm h nicotinic ca c vn.
Thuc lm ngng hm h nicotinic ca c vn gm c curae v ch phm ca n m hot
tnh sinh hc ca curae l d-tubocurarine chloride. Cc cura l thuc c bng B.
Cc cura ny c tc dng u tin trn h nicotinic ca cc c xng (c vn) lm ngn cn
lung xc tc thn kinh ti c bn vn ng nn lm gin c. Di tc dng ca cc thuc
cura cc c khng b lit cng lc m ln lt b lit theo th t sau: cc c mi (gy sp mi),

15
c mt, c c, c chi trn, c chi di, c bng, cc c lin sn v cui cng l c honh
lm bnh nhn ngng h hp v cht.
V tc dng ngn nn nu c h hp nhn to kp thi th chc phn cc c s c phc
hi theo th t ngc li.
Ngoi ra, cc cura cng c tc dng c ch trc tip trung tm h hp hnh no v lm
gin mch gy h huyt p hoc co tht kh qun do gii phng histamin.
Hu ht cc thuc u cha nhm chc mui amin bc bn nn rt kh thm vo thn kinh
trung ng, khng hp thu qua thnh rut.
Cc cura theo c ch tc dng c th chia lm hai loi:
Loi tranh chp vi acetylcholine bn vn ng lm cho bn vn ng khng kh cc
c gi l loi kh cc (antidepolarisant) hoc loi ging cura (curarimimetic). Gii c
thuc ny bng cc thuc phong ta cholinesterase (physostignin, prostignin).
Cc thuc ny gm c d-tubocurarine (3-29) v gallamine triethiodide (3-30).

H3C CH3 OCH3 OCH2CH2N(C2H5)3

O
N
OH OCH2CH2N(C2H5)3

H
3I
H 2Cl

O N
OCH2CH2N(C2H5)3
H3C H

3-29 3-30
d-tubocurarine chloride gallamine thietthiodide

d-tubocurarine (3-29) l loi ancaloit ly t cc loi cy Chondodendron tementosum

Strychnos m th dn Nam M dng tm tn c. Tc dng ko di vi gi.
Gallamine (3-30) l thuc tng hp, c thm tc dng ging atropine nn tim p chm,
khng gii phng histamine v km c hn d-tubocurarine 10 n 20 ln. Tc dng pht
trin chm trn cc nhm c khc nhau, thi gian lm gin c bng n lit c honh kh di
nn gii hn an ton rng hn.
Loi tc ng nh acetylcholine:
Cc thuc ny lm bn vn ng kh cc qu mnh, cc tc ng ging acetylcholine nn
c gi l loi ging acetycholin (acetylcholinomimetic). Cc thuc phong ta

16
cholinesterase lm tng c tnh ca loi thuc ny. Khng c thuc gii c, tuy d-
tubocurarine c tc dng i khng.
Cc thuc loi ny gm c decamethonium bromide (3-31) v succunylcholine iodide (3-
32).

H2C COOCH2CH2N(CH3)3
2I
(H3C)3N (CH2)10
N(C)3 2Br H2C COOCH2CH2N(CH3)3

3-31 3-32
decamethonium bromide succinylcholine iodide

Decamethonium bromide (3-31) gy git c v au c, c th gy tai bin ngng th ko

di nn ngy nay c xu hng dng succinylcholin thay th
Sucinylcholin iodide tc dng rt ngn, khong 5-10 pht do thuc chuyn ha nhanh trong
c th. Liu cao c th gy tc ng trn tim v tun hon ging acetylcholine.
Cc thuc lm gin c vn do c ch trung ng:
Cc thuc nhm ny c tc dng c ch chn lc trn cc nron trung gian kim tra trng
lc ca c no hoc ty sng, do lm gim trng lc ca c vn v gy gin c. Khc
vi cc loi thuc curare l ngay c vi liu c cng khng nh hng n truyn thn kinh
c.
Cc thuc ny c ch nh trong trng hp co tht do thp khp hoc thn kinh, vim a
khp, thoi ha khp, vim thn kinh ta, ng kinh, chong in hoc trong iu tr chnh
hnh.
Cc thuc ny mt phn cp trong phn thuc c tc dng gin c nh mephenesine
(2-618), mephenesine carbamate (2-619), ngoi ra cn c thm methocarbamol (3-33).
OCH3

OH

OCH2CH CH2OCONH2

3-35
methocarbamol

Tng hp mephenesine (2-618), mephenesine carbamate (2-619), methocarbamol (3-33)

c thc hin theo dy phn ng sau:

17
 R
R
OH

+ OH
ClH2C C CH2OH
H
OCH2CH CH2OH
OH

1) COCl2
OH
2) NH4OH
OCH2CH CH2OCONH2

R = CH3 2-619
R = OCH3 3-33

3.3.1.3. Cc thuc phong ta cholinesterase

Cholinesterase l enzim thy phn lm mt tc dng ca acetylcholine (thy phn
acetylcholin thnh cholin v axit acetic).
Cc thuc phong ta cholinesterase lm mt hot tnh ca enzim nn lm bn vng
acetylcholine ni sinh gy cc triu chng cng h cholinergic ngoi bin v trung ng.
Cc thuc phong ta cholinesterase c chia thnh hai loi: loi phong ta c hi phc
(c s dng trong iu tr) v loi phong ta khng hi phc hoc rt kh hi phc (dng
lm thuc dit cn trng hoc cht c chin tranh).
1. Cc thuc phong ta cholinesterase c hi phc
Cc thuc ny kt hp vi cholinesterase hoc ch mt v tr anion ( N+) nh
edrophonium hoc c hai v tr tc dng ca enzim ( c N+ ln CO ca cacboxyl).
Trong nhm ny cc thuc thng hay s dng gm c physostigmine (3-34), neostigmine
(3-35), edrophonium bromide (3-36), galanthanmine (3-37).

18
 CH3 CH3 N(CH2)3BrH

N H N

OCON(CH3)2
H3CNHCOO
CH3
3-35
3-34 neostigmine bromide
physostigmine
OH

N(CH3)2Br
O
C2H5
H3CO

OH N

CH3
3-36 3-37
edrophonium bromide galanthamine

Physostigmine (3-34) l ancaloit ca ht cy Physostigma venenosum. c bng A. V

trong phn t c cha N amin bc ba nn d hp thu v thm uc c vo thn kinh trung
ng.
Thuc c s dng cha tng nhn p hoc dng kch thch nhu ng rut (tim di
da).
Khi ng c dng atropine liu cao.
Neostigmine (3-35): l thuc tng hp, c bng A.
V trong phn t c mui amin bc 4 nn khng thm c vo thn kinh trung ng, c i
lc mnh hn vi acetylcholinesterase. Tc dng nhanh, t tc dng trn mt, tim v huyt
p. Ngoi tc dng phong ta cholinesterase, neostigmine cn kch thch trc tip c vn, tc
dng ny khng b atropine i khng.
Ch nh:
Ch nh tt trong bnh nhc c bm sinh v thiu ht acetylcholine bn vn ng c vn,
cn dng trong cc trng hp teo c, lit c.

19
Lit rut, b i sau khi m.
Nh mt cha tng nhn p.
Cha ng c cc thuc cura loi tranh chp vi acetylcholin.
Edrophonium chloride (3-36) l thuc tng hp c tc dng gn ging vi neostigmine.
Galanthamine (3-37): l ancaloit ca cy Galanthus woronowi v galanthus nivalis. c
bng A nhng ng c tng hp hn physostigmin.
Ch nh ging nh neostigmin.
2. Cc thuc phong ta cholinesterase khng phc hi hoc kh phc hi
Cc cht nhm ny u l dn xut ca photpho hu c, cc cht ny lin kt vi
cholinesterase v tr cacbonyl ca este, cc enzim b photphoryl ha rt bn, kh b thy
phn phc hi tr li nn i hi c tng hp phi tng hp li cholinesterase mi.
Cc cht phong ta cholinesterase loi photpho hu c c cng thc chung l:
R1 O

R2 X

Trong R1, R2 l cc ancoxy

X c th l halogen, xianua, thioxianat, ancoxy, thiol, pyrophotphat.
Trong s cc hp cht loi ny c isoflurophate (3-38) v echo thiophate (3-39) c dng
l thuc nh mt cha tng nhn p cn cc dn xut khc ch yu c dng lm thuc tr
su (TEPP, parathion) hoc s dng lm hi c chin tranh (tabun, sarin, soman).
(H3C)2CHO O C2H5O O
P P
(H3C)2CHO F C2H5O SCH2CH2N(CH3)3I

3-38 3-39
isiflurophate echothiophate iodide

C th gii phng c cc enzim b cc thuc photpho hu c phong ta bng mt s tc

nhn nucleophin nh hydroxyl amin (NH2OH), axit hydroxamic (R-CONH-OH) v oxim
(R-CH=N-OH). Cht thng hay c s dng l mui clorua hay bromua ca pralidoxime
(3-40).

20
 CH3

HC N OH
N

X=Cl, I, CH3SO3

3.3.2. Cc thuc tc dng trn h adrenegic

H adrenegic l h hu hch giao cm, gii phng cht trung gian ha hc gi chung l
catecholamin. Cc catecholamin gm c adrenaline (c sn xut ch yu ty thng
thn), noradrenaline (c to ra cc u mt cc si giao cm) v dopamine ( mt s
vng trn thn kinh trung ng).
3.3.2.1. Chuyn ha ca catecholamin
Cc catecholamine c sn xut ch yu cc t bo a chrom ca tuyn tu thng thn v
cc si hu hch ca h thng thn kinh giao cm. Dopamine tc ng nh mt cht dn
truyn thn kinh (neurotransmitter) h thng thn kinh trung ng, c sn xut trong
thn cc t bo thn kinh vng ca thn no. Cc catecholamine c sinh tng hp t L-
tyrosine v L-phenylalanine theo con ng sau:
Tyrosine L-DOPA Dopamine Noradrenaline Adrenaline
Cc phn ng trn c xc tc bi cc enzyme sau: (1) tyrosine hydroxylase, (2) L-amino
acid decarrboxylase, (3) dopamine--hydroxylase v (4) phenylethanolamine-N-
methyltransferase.
Cc catecholamine trong c th c thoi ho thnh metaadrenaline v metanoradrenaline
cui cng thnh vanillylmandelic acid (VMA) nh xc tc ca cc enzyme catechol-O-
methyltransferase (COMT) v monoaminooxidase (MAO) c bi xut ra nc tiu.
Vai tr chnh ca catecholamines l gip c th thch ng vi stress cp tnh v mn tnh.
Adrenaline ch yu nh hng n cc c tim v chuyn ha, trong khi noradrenaline hot
ng nh mt cht gy co mch (vasoconstrictor) cc ng mch ngoi vi. Cc
catecholamine c tc dng lm tng nhp tim, huyt p, nhp th, trng lc c v tng cm
gic tr tu. Chng cng lm gim khi lng mu n da v lm tng lng mu n cc c
quan ni tng chnh nh no, tim v thn.

21
 OH OH OH L-tyrozin

OH OH
DOPA-
decarboxilasea dopaminhidroxilase
Phehidroxilaza Tyhidroxilaza

CH2 CH2 CH2 CH2

H C NH2 H C NH2 H C NH2 H C NH2

COOH COOH COOH H

dopamine (DA)
L-Phenylalanin 3,4-dihidroxi-phenylalanin (DOPA)

OH
OH

COMT
MAO
HC OH

COOH
OH OH OH OH
axit 3,4-dihidroxi-
OH OH -mandulic OCH3 OCH3

PEA-N-metyltransferase

HC OH HC OH HC OH HC OH

CH2 CH2 CH2 COOH

COMT
NH2 NH OH
Noradrenaline (NA) OH 3-metoxi-4-hidroxi
3-metoxi-4-hidroxi- mandulic
MAO OCH3 phenylglicol (VMA)
CH3
adrenaline (A) MHPG
epinefrin

HC OH

CH2

HN CH3

metanefrin

3.3.2.2. Thuc cng h adrenegic (kch thch h adrenegic)

L nhng thuc c tc dng ging adrenalin v noradrenalin , kch thch hu hch giao cm
nn cn gi l thuc cng giao cm. Theo c ch tc dng c th chia cc thuc ny lm
hai loi:
Loi tc dng trc tip trn cc receptor adrenergic sau xinap nh adrenalin, noradrenalin,
isoproterenol, phenylephrin
Loi tc dng gin tip do kch thch cc receptor trc xinap, lm gii phng
catecholamin ni sinh nh tyramin (khng dng trong iu tr), ephedrin, amphetamin v
22
phenyl - ethyl- amin. Khi dng reserpin lm cn d tr catecholamin th tc dng ca cc
thuc s gim i. Trong nhm ny, mt s thuc c tc dng kch thch thn kinh trung
ng theo c ch cha hon ton bit r (nh ephedrin, amphetamin), reserpin khng nh
hng n tc dng ny; hoc c ch mono - amin- oxydase (MAOI), lm vng bn
catecholamin.
Cn theo v tr tc dng trn cc loi receptor th phn thnh bn loi sau: loi tc dng c
trn receptor v , loi tc dng trn receptor , tc dng trn receptor , thuc cng
giao cm gin tip.
1. Thuc cng receptor v
L cc thuc tc dng trc tip trn c cc receptor ln . Trong nhm ny gm c cc
cht sau y: Adrenalin (3-41), Noradrenalin (arterenol)
(3-42), dopamine (3-43).
C ba hp cht ny u l dn xut ca dihidroxiphenyl-etanolamin.
Tng hp: Do trong phn t c 1 C bt i nn c hai ng phn quang hc. ng phn
quay phi (D-) c tc dng km hn ng phn quay tri (L-) 20 ln. Trong c th, L-
adrenaline c sinh ra phn ty ca tuyn thng thn.
HO HO HO
OH OH
H2
HO CH CH2 NHCH3 HO CH CH2NH2 HO C CH2NH2

3-41 3-42
epinephrine, adrenaline norepinephrine, noradrenaline 3-43
dopamine

Epinephrine, adrenaline (3-41)

HO HO

HO H + ClOC CH2Cl HO COCH2Cl

3-44 3-45
HO HO

CH3NH2 NaBH3
HO COCH2NHCH3 HO CH CH2NHCH3

3-46 HO
3-41
adrenaline

c bng A.

23
L hormon ca tu thng thn, ly ng vt hoc tng hp. Cht t nhin l ng phn t
tuyn c tc dng mnh nht.
Adrenalin tc dng c trn v receptor.
Trn tim mch: Adrenalin lm tim p nhanh, mnh (tc dng ) nn lm tng huyt p ti
a, tng p lc t ngt cung ng mch ch v xoang ng mch cnh. Mt khc,
adrenalin gy co mch mt s vng (mch da, mch tng - receptor ) nhng li gy gin
mch mt s vng khc (mch c vn, mch phi - receptor ...) do huyt p ti thiu
khng thay i hoc c khi gim nh, huyt p trung bnh khng tng hoc ch tng nh
trong thi gian ngn. V l adrenalin khng c dng lm thuc tng huyt p.
Tc dng lm gin v tng lu lng mch vnh ca adrenalin cng khng c dng trong
iu tr co tht mch vnh v tc dng ny li km theo lm tng cng nng v chuyn ha
ca c tim.
Di tc dng ca adrenalin, mch mu mt s vng co li s y mu ra nhng khu vc t
chu nh hng hn, gy gin mch th ng nhng ni (nh mch no, mch phi) do
d gy cc bin chng t mch no, hoc ph phi cp.
Trn ph qun:
t tc dng trn ngi bnh thng. Trn ngi b co tht ph qun do hen th adrenalin lm
gin rt mnh, km theo l co mch nim mc ph qun, lm gim ph cho nn nh hng
rt tt ti tnh trng bnh. Son g adrenalin b mt tc dng rt nhanh vi nhng ln dng sau,
v vy khng nn dng ct cn hen.
Trn chuyn ha:
Adrenalin lm tng hu glycogen gan, lm tng glucose mu, lm tng acid bo t do trong
mu, tng chuyn ha c bn, tng s dng oxy ca m.
p dng iu tr:
Chng chy mu bn ngoi (p ti ch dung dch adrenalin hydroclorid 1% lm co
mch).
Tng thi gian gy t ca thuc t v adrenalin lm co mch ti ch nn lm chm hp thu
thuc t.
Khi tim b ngng t ngt, tim adrenalin trc tip vo tim hoc truyn mu c adrenalin
vo ng mch hi tnh.

24
 Sc ngt: dng adrenalin tng huyt p tm thi bng cch tim tnh mch theo phng
php trng bm tim.
Liu trung bnh: tim di da 0,1- 0,5 ml dung dch 0,1% adrenalin hydroclorid. Liu ti a:
mi ln 1 ml; 24 gi : 5 ml ng 1 ml = 0,001g adrenalin hydroclorid
Noradrenalin (3-42):
c bng A.
L cht dn truyn thn kinh ca cc si hu hch giao cm. Tc dng mnh trn cc
receptor , rt yu trn , cho nn:
Rt t nh hng n nhp tim, v vy khng gy phn x cng dy ph v.
Lm co mch mnh nn lm tng huyt p ti thiu v huyt p trung bnh (mnh hn
adrenalin 1,5 ln).
Tc dng trn ph qun rt yu, v c trn ph qun c nhiu receptor 2.
Tc dng trn dinh dng v chuyn ho u km adrenalin. Trn nhiu c quan, tc dng
ca NA trn receptor km hn adrenalin mt cht. Nhng do t l cng tc dng gia
v khc nhau nn tc dng chng khc nhau r rt.
Trn thn kinh trung ng, noradrenalin c nhiu vng di i. Vai tr sinh l cha hon
ton bit r. Cc cht lm gim d tr catecholamin no nh reserpin, methyldopa u
gy tc dng an thn. Tri li, nhng thuc c ch MAO, lm tng catecholamin th u c
tc dng kch thn.
iu ha thn nhit ph thuc vo s cn bng gia NA, serotonin v acetylcholin phn
trc ca vng di i.
C th cn tham gia vo c ch gim au: thuc lm gim lng catechola min tim vo no
tht c ch c tc dng gim au ca morphin.
Ch nh: nng huyt p trong mt s tnh trng sc: sc nhim c, nhim khun, sc do d
ng...
Ch truyn nh git tnh mch t 1 - 4 mg pha long trong 250 - 500 ml dung dch glucose
ng trng. Khng c tim bp hoc di da v lm co mch ko di, d gy hoi t ti
ni tim.
ng 1 ml = 0,001g
Dopamin:

25
Dopamin l cht tin thn ca noradrenalin v l cht trung gian ha hc ca h
dopaminergic. C rt t ngn dy giao cm. Trong no, tp trung cc nhn xm trung
ng v b en vn.
Trn h tim mch, tc dng ph thuc vo liu:
Liu thp 1- 2 g/ kg/ pht c gi l liu thn, tc dng ch yu trn receptor
dopaminergic D1, lm gin mch thn, mch tng v mch vnh. Ch nh tt trong sc do
suy tim hoc do gim th tch mu (cn phc hi th tch mu km theo).
Ti thn, liu thn ca dopamin lm tng nc tiu, tng thi Na +, K+, Cl-, Ca++, tng
sn xut prostaglandin E 2 nn lm gin mch thn gip thn chu ng c thiu oxy.
Liu trung bnh > 2 - 10 g/ kg/ pht, tc dng trn receptor 1, lm tng bin v tn s
tim. Sc cn ngoi bin ni chung khng thay i.
Liu cao trn 10 g/ kg/ pht tc dng trn receptor 1, gy co mch tng huyt p. Trong
lm sng, tu thuc vo tng loi sc m chn liu.
Dopamin khng qua c hng ro mu no.
Ch nh: cc loi sc, km theo v niu.
ng 200 mg trong 5 ml. Truyn chm tnh mch 2 - 5 g/ kg/ pht. Tng gim s git theo
hiu qu mong mun.
Chng ch nh: cc bnh mch vnh.
2. Thuc cng receptor
Trn c s v hnh thi hc, cc receptor c chia thnh hai loi tin sinap v hu sinap.
Cc receptor hu sinap c gi l 1: kch thch 1 co ko c trn, h HA.
Cc receptor tin sinap c gi l 2: kch thch 2 ngn cn gii phng noradrenalin ni
sinh lm h HA v cng lm h nhn p.
Cc cht ch vn chn lc trn receptor 1 bao gm cc hp cht sau: metaraminol (3-47),
phenylephrine (3-48), heptaminol (3-49), amidephrine (3-50), methoxamine (3-51).

26
 CH3
OH NH2 OH CH3
H2
C C CH3 C C NH CH3 H3C C (CH2)C3 NH2
H H H H

CH3
HO 3-47 HO 3-48
metaraminol phenylephrine 3-49
heptaminol
CH3
OH
H2
C C NH CH3 CH C NH2
H H

OH
HO 3-50 HO 3-51
amidephrine methoxamine

Tr heptaminol cn li u l dn xut ca phenyl etyl amine. Trong , metaraminol,

phenylephrine tc dng u tin trn receptor 1, heptaminol cng receptor 1 v l cht
c s dng ph bin hn c.
Metaraminol (Aramin)
Tc dng u tin trn receptor 1, lm co mch mnh v lu hn adrenalin, c th cn do
kch thch gii phng noradrenalin, khng gy gin mch th pht. Lm tng lc co bp ca
c tim, t lm thay i nhp tim, khng kch thch thn kinh trung ng, khng nh hng
n chuyn ha. V mt gc phenol trn vng benzen nn vng bn hn adrenalin.
Dng nng huyt p trong cc trng hp h huyt p t ngt (chn thng, nhim khun,
sc).
Tim tnh mch 0,5- 5,0 mg trong trng hp cp cu. Truyn chm tnh mch dung dch 10
mg trong 1 ml. C th tim di da hoc tim bp. ng 1 ml= 0,01g metaraminol bitartrat.
Phenylephrin (neosynephrin)
Tc dng u tin trn receptor 1. Tc dng co m ch tng huyt p ko di, nhng khng
mnh bng NA. Khng nh hng n nhp tim, khng kch thch thn kinh trung ng,
khng lm tng glucose huyt.
Ch nh: nh noradrenalin
Tim bp 5- 10 mg. Truyn chm vo tnh mch 10 - 15 mg trong 1000 mL dung dch
glucose ng trng. Cn dng chng xung huyt v gin ng t trong mt s ch phm
chuyn khoa.
Tng hp pheylephrine (3-48):

27
 O
C
OH OH N
CHO C CH2COR C C
H H H2

C6H5H2CO C6H5H2CO C6H5H2CO

3-53 R = OC2H5 3-55
3-52
3-54 R = NHNH2

O O OH
O O H2
C C
C C NHCH3
CH CH H
NH N
C C
C6H5H2CO H2 C6H5H2CO H2 CH3 C6H5H2CO
3-48
3-56 3-57 phenylephrine
Vic tng hp xut pht t 3-benzyloxi-benzadehyt (3-52) bng phn ng Reformatski vi
etyl brom-km axetat thu c este 3-53, sau x l hp cht ny vi hidrazin nhn c
hidrazi 3-54. Tip bng phn ng chuyn v Curtius to ra hp cht trung gian isocianat
3-55 (x l hp cht 3-54 vi axit nitro). Hp cht 3-55 t thc hin cng ni phn t gia
nhm hydroxyl vi nhm C=O ca isocianat to thnh hp cht vng oxazolidon 3-56 sau
N-metyl ha hp cht ny bng metyl iodua trong s hin din ca natri amidua thu c
hp cht 3-57. Cui cng x l hp cht 3-57 vi ait mnh ng thi va tch loi c nhm
benzyl ln cacbonat vng thu c phenylephrine 3-48.
Cc cht ch vn chn lc trn th th 2 c bit n gm: guanabenz (3-58),
moxonidine (3-59).
Cl Cl
H
NH N N

C N N C H3C N C
H H
NH2 N N
H
Cl OCH3
3-58 3-59
guanabenz moxonidine

Cc cht ch vn c trn th th 1 v 2 c tc dng nh noradrenalin, adrenalin, -metyl-

noradrenalin gm c clonidine (3-60), aplonidine (3-61), tramazoline (3-62), guanfacine (3-
63), 2,3,6-tricloro-clonidine (364).

28
 HO
HO

H H
HO CH C N R2

R1
3-41, R1 = H, R2 = CH3 : adrenaline
3-42, R1 = H, R2 = H : noradrenaline
R1 = CH3, R2 = H : - metyl-noradrenaline
Cl Cl
H H
N N

N C H2N N C

N N
H H
Cl Cl
3-60 3-61
clonidine aplonidine
Cl Cl Cl
H H
N NH N

N C CH2CONH NH2 N C

N N
H H
Cl Cl
3-62
tramazoline 3-63 3-64
guanfacine 2,3,6-tricloroclonidin
Trong cc hp cht trn clonidine l quan trng hn c.
Clonidin (dicloro - 2, 6 phenyl- amino- imidazolin) c tc dng cng receptor 2 trc
xinap trung ng v thuc qua c hng ro mu- no. Tc dng cng 2 sau xinap
ngoi bin ch thong qua nn gy tng huyt p ngn. Sau , do tc dng cng 2 trung
ng chim u th, clonidin lm gim gii phng NA t cc nron giao cm hnh no, gy
gim nhp tim, gim trng lc giao cm, gim lu lng mu no, tng, thn v mch
vnh, a n h huyt p.
Clonidin lm cn bi tit nc bt, dch v, m hi, lm gim hot tnh ca renin huyt
tng, gim li niu. ng thi c tc dng an thn, gim au v gy mt mi. Mt s t c
gi cho rng clonidin gn vo receptor imidazolin thn kinh trung ng, l loi receptor
mi ang c nghin cu.

29
Tc dng khng mong mun: ng g, kh ming.
Ch nh: tng huyt p th va v nng (xin xem bi Thuc cha tng huyt p).
Chng ch nh: trng thi trm cm.
Khng dng cng vi guanetidin hoc thuc lit hch v c th gy cn tng huyt p.
Liu lng: vin 0,15 mg. Ung liu tng dn ti 6 vin mt ngy, tc dng xut hin chm.
Dng cng vi thuc li niu, tc dng h huyt p s tng.
Tng hp clonidine (3-60) v cc dn xut c cu trc tng t arylimino-imidazolidine nh
moxolidine (3-59), aplonidine (3-61), tramazoline (3-62), 2,3,6-tricloronidine (3-64).
N

H HCOOH or HCOOH/Ac2O Ar NH2 + X

Ar N CHO
B 3-65
3-67 N
H
3-66
X = Cl, OCH3, SCH3
B

A
Cl
H2N CH2
Ar N C + B
3-68 H2N CH2 H
Cl N
3-69
NaOCH3 Ar N C
C or NaSCH3
N
C H
Y aryl-imino-imidazolidin
H2N CH2
Ar N C +
Y H2N CH2
3-70

Y = OCH3, SCH3

NH NH
H2N CH2
H
Ar N C + Ar N C
H2N CH2 H2
Y HN C CH2NH2
3-71 3-72
Y = Cl, OCH3, SCH3 Bt
u t dn xut aryl-amin 3-65, cho hp cht ny phn ng vi imidazolidin cha nhm tch
loi 3-66 theo con ng A hoc trc phn ng vi axit focmic hoc anhydric hn tp
ca axit acetic v axit focmic c dn xut N-formyl 3-6, sau cho hp cht mi to
thnh tc dng vi hn hp sunfinyl iclorua v sunfinyl diclorua thu c aryl-imino-
30
cacbonic axit diclorua 3-68, cui cng cho hp cht 3-68 ng vng vi etylen diamin 3-69
(con ng B) hoc trc cho hp cht 3-68 tc dng vi natri metylat hoc natri
thiometylat to ra di-este ca aryl imino-cacbonat hoc aryl-imino thiometylat 3-70, ri
sau ngng t ng vng vi etylen diamin-cacbonat hoc aryl-imino thiometylat 3-70, ri
sau ngng t ng vng vi etylendiamin 3-69 (con ng C0 nhn cc hp cht
mong mun loi aryl-imino-imidazolidin 3-59, 3-60, 3-61, 3-62, 3-64.
Tng hp guanabenz (3-58):
Cl Cl

NH NH
H
CHO + H2N N C C N NH C
H
NH2 NH2
3-58
Cl Cl guanabenz

3. Thuc cng receptor

Cc th th c chia ra thnh hai loi 1 v 2.
Cc th th 1 gm c tim v c trn rut.
Cc th th 2 gm cc c trn khc trong c cc th th ph qun, c t cung, c
mao mch.
C 4 tc dng dc l chnh:
Tc dng gin ph qun, dng cha hen: loi cng 2.
Tc dng gin mch: loi cng 2
Tc dng kch thch 1 lm tng tn s, tng lc co bp ca c tim, tng tc dn truyn
trong c tim, tng ti mu cho c tim.
Trn t cung c cha, thuc cng 2 lm gim co bp c dng chng da xy thai.
Trong cc cht tc dng chn lc trn th th 1 th ng ch nht l cc dn xut ca
dopamine (3-73), cng nh nhng nm gn y, ngi ta tm ra mt s cht c tc dng
chn lc trn th th 1 2 thuc dn xut aryloxi propanolamin nh xamoterol (3-74),
cicloprolol (3-75).

31
 HO

HO CH2CH2NH CH(CH3)CH2CH2 OH

3-73
dobutamine

OH

O
HO OCH2 CH CH2NH CH2CH2NH C N O

3-74
xamoterol
OH

CH2O CH2CH2 O OCH2CH CH2NH CH(CH3)2

3-75
cicloprolol

Trong s nhiu cht cng th th chn lc loi 2 th ng ch l cc dn xut ca

isoprenoline (3-76).

32
 HO HOH2C
HO HO

HO CHCH2NH CH(CH3)2 HO CHCH2NH C(CH3)3

3-76 3-77
isoprenaline, isoproterenol salbutarol

H3CO2SHN H2NOCHN
HO HO

HO CHCH2NH CH(CH3)2 HO CHCH2NH C(CH3)3

3-78 3-79
seterenol carbuterol
HO
HO HO

HO CHCH2NH CH(CH3)2 HO CHCNH2 CH(CH3)2

C2H5

N 3-81
3-80
quinterenol isoetarine

HO HO
HO HO

HO CH CH CHCH2NH CH(CH3)2

3-82 HN 3-83
rimiterol metaproterol
HO

HO HO
HO HO CH3

CHCH2NH C(CH3)3 CHCH2NH CH C OH

H2
3-84 3-85
terbutaline fenoterol
HO HO

33
 HO OH

HO
OCH3
HO CHCHNH CH2CH2 OH
H2
CH3 C OCH3
3-86
ritodrine NH

3-87 OCH3
OH tretoquinol

HO CHCH2NH CH(CH3)CH2
O

HO 3-88
O
protokylol

Cc cht t 3-76 n 3-82 c gi l cng th th 2 nhm I (mnh). Cc cht t 3-83 n

3-88 c gi l cng th th 2 nhm II (yu hn).
Isoprenaline (3-76) c chn lm cht chun v tc dng cng th th 2, c tc dng
gin ph qun, gin c trn, lm gin co cng thnh mch, lm h huyt p.
Lin quan n cu trc v tc dng:
hp cht c tc dng cng 2 th trong phn t cn phi hi t :
Trong hp cht c cha mt nhn thm, trong nhn thm c cha nhm hydroxyl v tr
para hoc meta.
C nhm OH ancol (ng phn L c hot tnh cao hn ng phn D)
Trong phn t c cha nhm amino v trn amino c nhm th iso-propyl hoc tert-butyl
th s tng tc dng.
Nu trn nhm amino c nhm th trc tip ni vi CH2 th hiu lc tc dng b gim v
lc ny hot tnh chn lc / s tng theo hng u tin i vi th th .
Do , cc hp cht cng 1, 2 u l dn xut ca hydroxiphenyl etanolamin hocj
hidroxiphenyl-etylamin.
Tc dng dc l: cc thuc ny c 4 tc dng dc l chnh sau y
Tc dng gin ph qun, dng cha hen: loi cng 2.
Tc dng gin mch: loi cng 2
Tc dng kch thch receptor 1 lm tng tn s, tng lc co bp ca c tim, tng tc
dn truyn trong co tim, tng ti mu cholinesterase c tim.

34
 Trn t cung c thai thuc cng 2 lm gim co bp, c dng trong trng hp c s
e da sy thai.
Tng hp cc thuc nhm cng 1
Dobutamine (3-73): Cng thc gn ging dopamin: tc dng u tin trn 1 receptor. Tc
dng phc tp do dobutamin raxemic c 2 ng phn; ng phn ( -) dobutamin c tc dng
cng 1 mnh, gy tng huyt p; trong khi ng phn (+) dobutamin li c tc dng i
lp hy 1. C hai ng phn u c tc dng cng , nhng ng phn (+) 10 ln mnh
hn ng phn ( -). Tc dng ca dobutamin raxemic l tng hp ca c hai ng phn.
Trn tim, do dobutamin lm tng co bp mnh v t lm tng nhp, v vy khng lm tng
nhu cu s dng oxy ca c tim. Tc dng km isoproterenol. t tc dng trn mch nhng
lm gin mch vnh. Tc dng li niu ch yu l do tng lu lng tim.
Dng trong hoc sau phu thut tim, bnh v c tim, suy tim km nhi mu c tim.
V thi gian bn thi ch khong 2 pht nn ch dng bng ng truyn chm tnh mch.
Ch phm: Dobutamin hydroclorid (Dobutrex) l 20 mL cha 250 mg dobutamin. Khi dng,
ha long trong 50 ml dung dch dextrose 5%, truyn tnh mch vi liu 2,5 - 10 g/ kg/
pht. Nu nhp tim tng nhanh, gim tc truyn.
Tng hp:

Raney-Ni/H2 H2
H3CO C CHCOCH3 H3CO C CH2COCH3
H

HO
HO
CH3
HO CH2CH2NH2
1. H2
HO C CH2NHCH CH2CH2 OCH3
2. H2/XT
HO
CH3

HBr H2
HO C CH2NHCH CH2CH2 OH

3-73
dobutamine

Xamoterol (3-74)

35
 H2
epiclorohidrin C6H5H2CO O C CH CH2
C6H5H2CO OH

O
3-89 3-90

NH2CH2CH2NH2
O N COCl O N C NHC2H4NH2

O
3-92

OH

HO OCH2CH CH2NHC2H4NH C N O

3-74 O
xamoterol *
Cicloprolol (3-75):

CH3SO3CH2CH2OCH2
C6H5H2CO OH RO OC2H4OCH2
3-93

3-89 3-94, R = CH2C6H5

3-95, R = H
O
H2
Cl C C CH2 H2 H2
H H
C OCH2CH2O O C C CH2
HO
3-96 O
OH
H2 N CH(CH3)2 H2 H2
C OCH2CH2O O C CH CH2NH CH(CH3)2

3-75
cicloprolol *
Phng php chung tng hp cc dn xut aryl-etanolamin (isoprenaline (3-76), salbutamol
(3-77), soterenol (3-78), cabuterol (3-79), quinterol (3-80), isoetarine (3-81), metaproterenol
(3-83), terbutaline (3-84), fenoterol (3-85), ritodrine (3-86), protokylol (3-88)).

36
 O O
SeO2
Ar C CH2R1 Ar C C O
F 1. R2NH2
3-97 3-103
R1 2. H2/XT
Br2 E,F
DMSO
E
O O OH

H R 2
NH2 H H
H2/XT H H
Ar C C Br Ar C C N R2 Ar C C N R2
A A H
1 3-99
3-98 R R1 R1
B
O
R2NHCH2C6H5 B
H H2/XT
Ar C C N R2

3-100 R1 CH2C6H5
NaBH4 C D R2NH2
R2NH2

OH
O
C H KOH/EtOH
Ar C C Br Ar C CH
H H
3-101 R1 3-102 R1
Cch khc i t dn xut clorua axit 3-104:
Cu(CN)2 H2/XT H R1R2CO/H2XT H
Ar C Cl Ar C CN Ar C CH2NH2 Ar C CH2NR1R2

O O OH OH
3-104 3-105 3-106 *
Tng hp Rimiterol (3-82):

37
 H3CO
H3CO
p-ximen OH
H3C CHO + KMnO4
O
H3CO C
N COOH H
N
3-107

HO
H3CO
O
O
HO C
cc HBr
H3CO C
3-109 N
N
3-108
HO
PtO2/H2 OH

HO C
H
HN
3-82
rimiterol

Tng hp Tretoquinol:
H3CO
HO
O

+ H3CO C C COONa
H H
NH2
HO
3-110 H3CO 3-111

AcOH/HCl
pH = 2,3/115h

HO

OCH3
NH
HO

H2C OCH3

3-87
tretoquinol OCH3

4. Thuc cng giao cm gin tip

38
L thuc va c tc dng gin tip lm gii phng catecholamin ra khi ni d tr, va c
tc dng trc tip trn receptor.
Thuc c tc dng nh th trong nhm ny l ephedrin (3-112) v l cht hay c s dng
nht.
OH

H
CH C NH CH3

CH3
3-112
ephedrine

Ephedrin (ephedrinum)
c, bng B.
Ephedrin l alcaloid ca cy ma hong (Ephedra equisetina v Ephedra vulgaris).
Hin nay tng hp c. Trong y hc, dng loi t tuyn v raxemic.
L thuc va c tc dng gin tip lm gii phng catecholamin ra khi ni d tr, va c
tc dng trc tip trn receptor.
Trn tim mch, so vi noradrenalin, tc dng chm v yu hn 100 ln, nhng ko di hn
ti 10 ln. Lm tng huyt p do co mch v kch thch trc tip trn tim. Dng nhiu ln
lin nhau, tc dng tng p s gim dn.
Thng dng chng h huyt p v kch thch h hp trong khi gy t tu sng, trong
nhim c ru, morphin, barbiturat.
Kch thch trung tm h hp hnh no v lm gin ph qun nn dng ct cn hen, tc
dng tt trn tr em.
Trn thn kinh trung ng, vi liu cao, kch thch lm mt ng, bn chn, run, tng h hp.
Ephedrin d dng hp thu theo mi ng. Vng bn vi MAO. C huyn ha gan, khong
40% thi tr nguyn cht qua nc tiu.
Dng di th mui clohydrat hoc sulfat d ha tan. Ung 10- 60 mg / ngy. Liu ti a
24h l 150 mg.
Tim di da, bp tht hoc tnh mch 10 - 20 mg/ ngy
Nh nim mc (mt, mi) dung dch 0, 5- 3%

39
ng 1 ml = 0,01g ephedrin clohydrat
Vin 0,01g ephedrin clohydrat
Pseudoephedrin l ng phn lp th ca ephedrin, t gy tim nhanh, tng huyt p v kch
thch thn kinh trung ng hn ephedrin. Thng c dng trong cc ch phm nh mi
chng xung huyt nim mc.
Tng hp ephedrine (3-112): c th s dng cc phng php chung tng hp cc dn
xut aryl-etanol-amin m t trong phn thuc cng receptor vi cht khi u la
propiophenon.
3.3.2.3. Thuc hy h adrenergic (adrenergic blocking agents)
L nhng thuc lm mt tc dng ca adrenalin v noradrenalin. Cc thuc ny thng c
dng iu tr chng tng huyt p, bnh Raynaud, lon nhp tim, hi chng cng tuyn
gip (tim nhp nhanh, li mt, gin ng t, tng h hp; chnh l nhng du hiu cng
giao cm).
Cc thuc c chia thnh hai nhm:
Thuc hy giao cm (sympatholytic): l nhng thuc phong to nron adrenergic trc
xinap, lm gim gii phng catecholamin, khng c tc dng trn receptor sau xinap, khi ct
cc dy hu hch giao cm th thuc mt tc dng. Do thiu cht dn truyn thn kinh ni
sinh, tnh cm th ca cc recept or sau xinap vi catecholamin ngoi lai s tng ln.
Thuc hu adrenalin (adrenolytic) l nhng thuc phong to ngay chnh cc receptor
adrenergic sau xinap, cho nn khi ct t cc si hu hch giao cm, tc dng ca thuc
khng thay i. Catecholamin c ni sinh ngoi lai u b mt tc dng.
1.Thuc hu giao cm
Cc thuc hy giao cm thy thuc vo vic thuc tc dng vo khu no m c th phn
thnh bn nhm sau:
a. c ch tng hp catecholamin

40
 HO
NH2
H2
HO C C COOH

CH3
3-113
-metyldopa

Thuc hay c dng l methyl dopa (3-113) phong ta dopa decarboxylase, lm dopa
khng chuyn thnh dopamin v 5 - hydroxytryptophan khng chuyn thnh 5 -
hydroxytryptamin (5 HT - serotonin). Do s lng catecholamin v serotonin c ngoi
bin v thn kinh trung ng u gim. Mt khc cn ngn cn kh nng gn catecholamin
vo cc ht lu tr.
Ngoi ra, trong c th methyldopa cn c th chuyn thnh methyl noradrenalin, tc
dng nh mt cht trung gian ha hc gi chim ch ca noradrenalin (xem bi Thuc cha
tng huyt p)
Tc dng ph: m mng, c ch tm thn, chng mt, nhc u, kh ming, ph.
Khng dng khi c ri lon tun hon no v mch vnh, cc trng thi trm cm, ri lon
gan, thn.
Liu lng: ung vin 250 mg. C th dng ti 8 vin/ ngy. Ch phm: Dopegyt vin 0,25
g methyl dopa.
Carbidopa v bemerazid, c ch dopa decarboxylase ngo i bin. c dng phi hp vi
l - dopa iu tr bnh Parkinson.
Tng hp methyldopa:
H3COC H3 COC
NH2
H2 H2
H3COC C C CH3 H3COC C C CN

O CH3
3-114 3-115

HO
NH2
H2
HO C C COOH

CH3
3-113
-metyldopa

b. Ngn cn gii phng catecholamin

41
Thuc s dng: bretylium tosylate (3-116).
CH3
H2
C N C2H5 SO3

CH3
Br 3-116
bretylium tosylate

C ch cha tht r. c ch gii phng catecholamin, nhng khng nh hng n tc dng

ca adrenalin v noradrenalin ngoi lai. C th l bretylium lm cho mng cc ht lu tr
gim tnh thm vi ion Ca ++ m lm cho catecholamin khng c gii phng ra.
C tc dng gy t ti ch.
V c nhiu tc dng ph (nh xung huyt nim mc mi, kh th, a lng, h huyt p,
nhc c) cho nn cn t c s dng lm sng.
c. Lm gim d tr catecholamin trong cc ht
Thuc c tc dng kiu ny gm: reserpine (2-493), guanethidine (3-118).

N CH2CH2NH C NH2

N
NH
H3CO
N H
H H 3-118
OCH3 guanethidine
H

H3COOC O C OCH3

OCH3 O
OCH3
2-493
reserpine

* Reserpin:
Lm gii phng t t catecholamin t cc ht lu tr ra ngoi bo tng MAO ph hu,
do lng catecholamin gim c trn thn kinh trung ng (gy an thn), c ngoi bin
(lm h huyt p). Reserpin cn cn tr qu trnh gn catecholamin (c ni sinh ln ngoi
sinh) vo cc ht lu tr.
Guanetidin (Ismelin)
Chim ch noradrenalin trong cc ht lu tr v tr thnh cht trung gian ha hc gi. Khc
reserpin l lc u guanetidin gy tng nh huyt p do lm gii phng nhanh noradrenalin

42
ra dng t do, mt khc guanetidin khng thm c vo thn kinh trung ng nn khng c
tc dng an thn.
Tc dng ti a xut hin sau 2 - 3 ngy v mt i 6 - 10 ngy sau khi ngng thuc.
Khng dng cho ngi bnh c lot d dy, suy mch vnh, suy thn. Khng dng cng vi
clonidin.
Liu lng: lc u ung 10 mg/ ngy, sau tng dn ti 50 - 75mg/ ngy
Ch phm: vin 10 v 20 mg.
Tng hp guanethidine:
CH2NH2 O N OH
O

1. HCN HNO2 NH2OH

OH
2. LiAlH4

CV
Beckman
O

NCH2CH2NH2 NCH2CN NH NH

3-121 3-120 3-119

NCH2CH2NH C NH2

NH

3-118
guanethidine

d. Thay th catecholamin bng cc cht trung gian ho hc gi.

Mt s cht khng c tc dng dc l, nhng chim ch ca catecholamin v cng c
gii phng ra di xc tc kch thch dy giao cm nh mt cht trung gian ha hc, c
gi l cht trung gian ha hc gi. Cc thuc loi ny gm c:
methyldopa to thnh methyl noradrenalin.
Thuc c ch MAO: tyramin chuyn thnh octopamin.
Guanetidin (3-118)
2. Cc thuc hu adrenalin
Cc thuc phong ta tc dng trn receptor tng i c hiu hn thuc kch thch, ngha l
nhiu thuc kch thch c tc dng c trn hai loi receptor v , cn thuc phong to

43
thng ch tc dng trn mt loi receptor m thi. Do thuc loi ny c chia thnh hai
nhm: thuc hu v thuc hu adrenergic.
a. Thuc hu - adrenergic
V phong to cc receptor nn lm gim tc dng tng huyt p ca noradrenalin, lm o
ngc tc dng tng p ca adrenalin. Khng c ch tc dng gin mch v tng nhp tim
ca cc thuc cng giao cm v u l tc dng trn cc receptor . Hin tng o ngc
tc dng tng p ca adrenalin c gii thch l cc mao mch c c hai loi receptor v
, adrenalin tc dng trn c hai loi receptor , nhng bnh thng, tc dng chim u
th nn adrenalin lm tng huyt p. Khi dng thuc phong to , adrenalin ch cn gy
c tc dng kch thch trn cc receptor nn lm gin mch, h huyt p.
Cc thuc hy - adrenergic cn c phn thnh cc nhm:
Thuc tc dng chn lc trn receptor 1
Thuc tc dng trn c 1 v 2
Nhm thuc ny c ch nh trong cc cn tng huyt p, chn on u tu thng thn,
iu tr bnh Raynaud. Hin ang nghin cu thuc hu 1A iu tr ph i lnh tnh
tuyn tin lit. Nhc im chung l d gy h huyt p khi ng, nhp tim nhanh, xung
huyt nim mc mi, co ng t, bun nn, nn v tiu chy do tng nhu ng d dy - rut.
Cc thuc ch khc nhau v cng tiu chy v thi gian tc dng.
Thuc tc dng i khng trn 2: thuc chng trm cm.
Cc thuc c tc dng hy chn lc trn 1 ang c s dng gm prazosin (3-122),
doxazosin (3-123), trimazosin (3-124), tiadazosin (3-125), labetalol (3-126), ketanserin (3-
127) v urapidil (3-128).

44
 O O
H3CO N N C
N O
O

N H3CO N N N
O
H3CO
NH2 N
3-122 H3CO
prazosin 3-123
NH2 doxazosin

O
H3CO N N C OCH2 C(CH3)2
N

OH
N
H3CO
H3CO
NH2 3-124
CH3
trimazosin
O HO CH CH2NHCH
N N
OH CH2CH2
3-126
O SCH3 labetalol
H3CO N N N

N 3-125
H3CO tidazosin
O
NH2
CH2CH2 N CO F
N

N O 3-127
H ketanserin
CH3

N O
H
N N CH2CH2CH2 N

NH
OCH3 3-128
urapidil
O

Prazosin (Minipress): cht in hnh phong to 1.

Dng iu tr tng huyt p, ung 1 20 mg mt ngy.
Cc thuc hy - adrenegic tc dng va c trn receptor 1 ln trn receptor 2
Cc cht ny c tc dng lm tng trng lc, h huyt p.
Gm cc cht phentolamine (3-147), tolazolin (3-148) v phenoxy benzamine93-149).

45
 CH3

N N CH CH2O
H2 H2
N C C C N
H2
N N CH2CH2Cl
H H
3-148 3-149
3-147 tolazolin phenoxybenamine
phentolamine

Cc cht c tc dng i khng chn lc trn 2

Gm cc cht yohimbine (3-153) v rauwolscine (3-154) l ng phn cu trc ca
corynanthine (3-155), imiloxan (3-156), idazoxan (3-157).

H
N N OH

N C OH N H
H H H O H H
H C
O
3-153 3-154 O
yohimbine rauwolscine O
CH3

CH3
O
OCH3
H O N
C H2
C
N
O N
3-156
OH C2H5
N imiloxan
H H H
O N
H2
3-155 C
corynanthine
O N
3-157 H
idazoxan

b. Thuc hu adrenergic
Cn gi l thuc phong to ( blocking agent) c tc dng c ch tranh chp vi
isoproterenol cc receptor. Cht u tin c tm ra l dicloisoproterenol (Powell v
Slater, 1958). c dng nhiu trong lm sng.
Tc dng dc l: c 4 tc dng dc l chnh vi mc khc nhau gia cc thuc:
Kh nng hu giao cm : l tnh cht chung duy nht ca tt c cc thuc hu :

46
 Trn tim: lm gim nhp tim (20 - 30%), gim lc co bp ca c tim, gim lu lng tim,
gim cng nng v gim s dng oxy ca c tim, gim tc dn truyn ca t chc nt.
Ch yu l do hu 1.
Trn kh qun: lm co, d gy hen. Ch yu l do hu 2, gy tc dng khng mong mun.
Trn thn: lm gim tit renin, h huyt p trn ngi c HA cao.
Trn chuyn ha: c ch hu glycogen v hu lipid
Tc dng lm n nh mng: ging quinidin, lm gim tnh thm ca mng t bo vi s
trao i ion nn c tc dng chng lon nhp tim.
C hot tnh ni ti kch thch receptor : mt s thuc phong to khi gn vo cc
receptor li c tc dng kch thch mt phn. Hiu qu thc t t quan trng, nhng c th
hn ch tc dng lm gim nhp tim, gim co bp c tim, gim co kh qun ca chnh n.
Tnh chn lc: nhiu thuc phong to i lp vi tt c cc tc dng cng giao cm ca
(1: tim v 2: mch, kh qun). Nhng mt s thuc li ch phong to c mt trong hai
loi receptor (1 hoc 2), v th phn bit thnh cc loi phong to chn lc trn giao cm :
Loi tc dng chn lc trn 1 hay loi chn lc trn tim (cardioselectifs), nh practolol,
acebutalol, atenolol. Thng dng metoprolol (Lopressor) v atenolol (T enormin). Li ch
ca loi thuc ny l: Do rt km tc dng trn 2 ca kh qun nn hn ch c tai bin co
tht kh qun. Km tc dng trn 2 ca thnh mch s c li cho iu tr cao huyt p (gim
co mch ngoi bin). Do rt km tc dng trn 2 ca thnh mch vnh nn khng bc l tc
dng cng - adrenergic (tc dng co mch vnh ca CA tun hon trong mu). Bnh
thng, do c tc dng th tc dng ca b lu m. Khi b phong to th tc dng ca
s c bc l ra. Do khng nh hng n cc receptor trong hu glycogen nn khng lm
nng thm tnh trng h ng huyt. Loi c tc dng chn lc trn 2, ng u l
Butoxamin, t c ngha trong lm sng.
Ch nh chnh:
Cn au tht ngc, ch yu do lm gim s dng oxy ca c tim. Trong nhi mu c tim,
tim tnh mch ngay t gi u s lm gim lan rng nhi mu v ci thin c tin
lng bnh.
Lon nhp tim: nhp nhanh xoang, nhp nhanh trn tht, tim cng gip, cung ng nh do
nhim c digital.

47
 Tng huyt p: do lm gim lu lng tim, gim sc cn ngoi bin, gim tit renin v
gim gii phng noradrenalin (xin xem thm bi Thuc cha tng huyt p)
- Mt s ch nh khc; cng gip, migren, glocom gc m (do lm gim sn xut thu
dch), run tay khng r nguyn nhn.
Chng ch nh:
Suy tim l chng ch nh chnh v n c ch c ch b tr ca tim.
Bloc nh - tht v thuc c tc dng lm gim dn truyn ni ti trong c tim.
Hen ph qun. Loi c tc dng chn lc trn receptor 1 dng cho ngi hen t nguy him
hn, nhng vi liu cao, trong iu tr tng huyt p th cng b mt tnh chn lc.
Khng dng cng vi insulin v cc sulfamid h ng huyt v c th gy h ng huyt
t ngt.
C thai: khng chng ch nh tuyt i, nhng gp tr mi b chm nhp tim, h
ng huyt, suy h hp, thai chm pht trin.
Cc tc dng khng mong mun c chia lm hai loi:
Loi tai bin l hu qu ca s phong to receptor .
Tim: suy tim do lm yu co bp ca c tim, chm nhp tim, nh tht phn ly.
Mch: hi chng Raynaud, tm lnh u chi, i khp khing, (thng gp vi propranolol,
do b phong to th s cng). Cc thuc chn lc trn 1 v c hot tnh kch thch ni
ti th t tai bin ny hn.
Phi: cc thuc c tc dng hu 2 > 1 s gy co kh qun, kh th. Khng dng cho
ngi hen.
Thn kinh trung ng: mt mi, mt ng, hay ng m, o nh, trm cm, thng gp hn
vi cc thuc d tan trong m v d thm vo t bo thn kinh (propranolol, metoprolol), loi
t tan trong m (atenolol, nadolol) t tai bin hn.
Chuyn ho: lm h ng huyt (cn thn trng vi ngi b i tho ng), tng
triglycerid trong mu.
Loi tai bin khng lin quan n tc dng phong to .
Hi chng mt - da- tai: xut hin ring hoc phi hp vi cc tn thng ca mt (vim
gic mc, vim cng mc), da (sn nga lng bn tay, bn chn, dy da), tai (ic v vim
tai nng). gp vi practolol, iu tr trong 1 - 2 nm.

48
 Vim phc mc x cng: au cng bng phc mc c nhng mng dy do t chc x . Sau
khi ngng thuc hoc iu tr bng corticoid s khi. Gp sau khi iu tr ko di trn 30
thng.
Trn thc nghim, gp ung th tuyn c, ung th v, lymphosarcom. Do cn theo
di trn ngi khi dng liu cao ko di.
Tng tc thuc:
Cc thuc gy cm ng cc enzym chuyn ha gan nh phenytoin, rifampin,
phenobarbital, ht thuc l, s lm tng chuyn ha, gim tc dng ca thuc hu .
Cc mui nhm, cholestyramin lm gim hp thu.
Cc thuc hu c tc dng hip ng vi thuc chn knh calci, cc thuc h huyt p.
Indomethacin v cc thuc chng vim phi steroid lm gim tc dng h huyt p ca cc
thuc hu .

49
CHNG 4. THUC TC DNG TI TIM
4.1. Cu to, hot ng ca h tim mch
H tim mch (bao gm tim v h tun hon) l mng li phn phi mu n khp cc ni
trong c th. Bng mi nht p ca tim, mu i n tng ni trn c th thc hin qu
trnh trao i kh (cung cp oxy cho t bo v ly li cacbonic) v trao i cht (cung cp
cht dinh dng cho t bo v thu gom cht thi t t bo). C khong 7.571 lt mu chy
sut chiu di 96.500km qua li cc mch mu mi ngy.
Tim l c quan chnh trong h tun hon, tim nhn thng tin nhu cu t cc b phn trong c
th v iu chnh nhp p nhm p ng lng mu cn thit. Khi ng hoc khi ngh ngi,
tim vn p nhng ch cung cp mt lng oxy va cho nhu cu c th.
Cc mch mu dn mu c nhiu kh oxy t tm tht tri n nui cc c quan gi l ng
mch. Tnh mch c chc nng thu hi mu cha nhiu kh cacbonic t cc b phn vo
tm nh. Thnh tnh mch v ng mch u c cu to 3 lp nhng thnh tnh mch khng
c nhiu c nh ng mch m n c nhiu van ri rc sut chiu di ngn chn tnh
trng mu chy ngc tr li.
Mt h thng cc mch mu li ti to thnh mt mng li ni cc tiu ng mch v tiu
tnh mch gi l h thng mao mch. Tuy nh nhng mng li mao mch l ni rt quan
trng din ra qu trnh trao i kh v trao i cht vi t bo.
Chc nng ca h tun hon: Nu h tun hon khng hot ng, chng ta khng th no
sng st. Nhng thng s v nhp tim, huyt p c gi l cc du hiu sinh tn cho s
sng. H tun hon lm vic rt cht ch vi cc h thng khc trong c th. N cung cp
oxy v dng cht cho c th, ng thi n vn chuyn cc cht thi t c th n cc c
quan tng ng thi ra ngoi. Ngoi ra, h tun hon cn phn phi cc cht cn thit nh
ni tit t, vitamin, khong cht v cc cht dn truyn thn kinh cho mi hot ng c bn
ca t bo.
Mt s bnh l thng gp.
Cc bnh l tim mch l nhng bnh l thng gp v c t l t vong rt cao. ng ngh
rng bnh l tim mch ch xy ra ngi ln tui, di y l mt s bnh l tim mch
thng thy tui tr:

50
 Bnh tim bm sinh: y l cc d tt bt thng trong tim v h mch mu ln ngay khi
sinh ra. Tim bm sinh hnh thnh t khi cn trong bng m. Tim bm sinh gy ra nhng
hu qu nghim trng, c th t vong hoc nh hn l chm pht trin th cht.
Ri lon nhp tim: y l tnh trng tim p bt thng, c th do bm sinh hoc do mc
phi sau ny. Trong ri lon nhp tim, nhp p bt thng, khng u, nhanh qu hoc
chm qu u c th xy ra. Hu qu l nh hng xu n qu trnh lu thng ca mu c
th gy ra cc hu qu nghim trng.
Bnh tim to: y l hu qu sau mt thi gian di bnh l ca cc bung tim, sau lm
hy hoi t bo c tim, cui cng l tnh trng suy yu ca c tim. Nhiu trng hp phi
thay tim.
Cc bnh l mch vnh: bnh thng pht trin do tnh trng x va ng mch. S tch
t cht bo, cht Calci trong cc t bo cht gy ra cc cc mu ng trong lng mch mu
gy ra tnh trng lp tc dng chy ca mch mu. Hu qu sau cng ca bnh l mch vnh
l nhi mu c tim, c th dn n t vong.
Bnh tng m mu: Qu nhiu Cholesteron trong mu gy ra cc yu t nguy c nghim
trng cho cc bnh l tim mch. Tr bo ph rt nhiu kh nng b bnh l tim mch v chc
chn lng Cholesteron mu cao.
Cao huyt p: L hu qu ca mt s bnh l mc phi, khi y gi l triu chng cao huyt
p. Bnh cao huyt p l hu qu ca li sng qu nhiu cng thng, ht thuc l, ch n
nhiu mui, nhiu m, t vn ng. Tr em thng b co huyt p triu chng do hu qu
ca cc bnh l c sn tim, thn.
Bnh thp tim: hay cn gi l vim tim dng thp. Tnh trng thng xy ra sau mt vim
nhim vng hng. Loi nhim trng ny gy ra vn mn tnh tim, thng xy ra
tui t 5 - 15. Nu iu tr vim hng ng cch c th ngn nga c chng bnh ny.
4.2. Cc thuc tc dng ti tim
Cc thuc iu tr bnh tim l nhng thuc trong chng mc nht nh c tc dng gip cho
tim phn no tr v trng thi bnh thng ca n. Cc thuc tc dng ln tim c phn
thnh ba loi chnh nh sau:
Thuc cha cn au tht ngc.
Thuc chng lon nhp tim.

51
Thuc tr tim.
4.2.1. Thuc cha cn au tht ngc
Nguyn nhn ca cn au tht ngc l do c tim b thiu oxy t ngt v mt thng bng
gia s tng nhu cu oxy ca c tim v s cung cp khng oxy ca mch vnh.
C tim ch chim 0,5% trng lng c th, nhng khi ngh ngi cng lu gi 5% lu lng
tim. C tim ly 80- 90% oxy ca dng mu qua c tim. Khi c gng, khi xc ng hoc
dng catecholamin, tim phi lm vic tng, nhu cu oxy ch c tho mn bng tng lng
mu cung cp cho tim.
T lu, chng cn au tht ngc, vn dng thuc lm gin mch vnh. Tuy nhin, nhiu
thuc ngoi tc dng lm gin mch vnh, li ng thi lm gin mch ton thn, v vy mt
khi lng mu ng l cn cung cp cho tim th li chy ra cc vng khc. Mt khc, p lc
tnh mch gim, i hi tim phi lm vic nhiu hn, v v vy li cng tng s dng oxy
ca tim. Khi mt phn mch vnh b tc, vng di ch tc b thiu mu, chuyn ho lm
vo tnh trng k kh, lm tng to thnh acid lactic, adenosin, kali l nhng cht gy gin
mch mnh ti ch. Nu cho thuc gin mch, s cung cp mu s tng ln vng lnh,
khng c li g cho vng b thiu mu, tri li, s ti mu cho vng b thiu mu li cn b
gim i. Hin tng ny c gi l ly trm ca mch vnh (vol coronarien). Trong
cn au tht ngc m nguyn nhn l do thiu mu t ngt ca c tim th vic cn trc ht
l lm gim nhu cu oxy ca c tim, v hn na l loi tr tt c nhng tc ng i hi tim
phi lm vic nhiu ln v chuyn ho tng ln.
V vy, cc thuc chng cn au tht ngc tt cn t c nhng yu cu sau:
a) Tng cung cp oxy, ti mu cho c tim.
Bng cch dng thuc hoc dng dng c can thip lm gin mch vnh (dng ng t
vo mch vnh).
Gim p sut ca tm trng hoc gii quyt bng phu thut
b) Gim s dng oxy bng cch gim cng nng tim (tnh trng co bp ca c tim, nhp
tim).
Lm gim tn s ca tim.
Lm gim p sut ng mch (thn trng).
Lm gim nh lc co bp ca tim (nhng trng hp tim yu th khng s dng c).

52
 Lm gim hiu lc ca tim (gim lu lng mu tnh mch hoc lm tng th tch trn
pht).
c) Lm gim cn au. Tuy nhin cn thy rng v tr ca vng thiu mu c tim khng
hon ton c lin quan n s c mt hoc mc ca cm gic au, ngha l c th thiu
mu c tim m khng c au.
Cc thuc iu tr (theo c ch tc dng) c chia thnh bn loi:
Loi iu tr cn au, gin mch: cc este nitrat v nitrit hu c. Loi thuc ny c.
Nhm c ch knh canxi: c tc dng lm gim mch, gim cng nng, nhp p ca tim,
gim s co bp ca tim.
Nhm thuc phong to recptor adrenergic: c tc dng iu tr, cng c, gim cng
nng ca tim, tit kim s dng oxi ca tim, c ch trao i cht.
Nhng nhm khc: c tc dng tng cng dng chy ca mch vnh.
4.2.1.1. Cc este hu c nitrat, nitrit
Cc nitrat hu c l cc este polyol ca acid nitric, cn cc nitrit hu c l cc este ca acid
nit. Este nitrat (C -O-NO2) v este nitrit (C -O-NO) c c trng bi chui C -O-N,
trong khi cc hp cht nitro l C -NO2. Nh vy, nitroglycerin l tn gi khng ng ca
glyceryl trinitrat v khng phi l hp cht nitro, nhng do dng quen v qu ph bin nn
khng sa c.
Cc thuc nhm ny hoc l dung dch bay hi (amylnitrit 4-1), hoc l dung dch bay hi
nh (nitroglycerin 4-2), hoc l th rn (isosorbid dinitrat). Tt c cc hot cht trong nhm
ny u gii phng nitric oxid (NO) ti m ch c trn thnh mch.
Cc loi thng dng lm sng l:
Tn Cng thc cu to Thi gian tc dng
Amyl nitrit (4-1) (CH3)2CH CH2CH2 ONO 3-5 pht
Nitroglycerine (4-2) H2C CH CH2 10-30 pht
8-12 gi
O2NO ONO2 ONO2
24 gi

53
 O
Isosorbit dinitrate (4-3) 2-4 gi
ONO2
12 gi
H
H2C C C CH C CH2
H H

ONO2

Pentaerytrol (4-4) H2 H2C ONO2 4-5 gi

O2NO C
C 12 gi
O2NO CH2 C ONO2
H2

Nicorandil (4-5) O H
C N CH2CH2 ONO2

* Tc dng dc l:
Nitrat lm gin mi loi c trn do bt k nguyn nhn gy tng trng lc no. Khng tc
dng trc tip trn c tim v c vn.
Trn mch, nitrat lm gin mch da v mt (gy mt) lm gin mch ton thn. Tnh
mch gim, lm gim dng mu chy v tim (gim tin gnh). ng mch gin, lm gim
sc cn ngoi bin (gim hu gnh). Mc d nhp tim c th nhanh mt cht do phn x gin
mch, nhng th tch tm thu gim, cng nng tim gim nn vn gim s dng oxy ca c
tim.
Trn c trn khc, nitrat lm gin ph qun, ng tiu ho, ng mt, ng tit niu sinh
dc.
Dc ng hc
Cc nitrat hu c chu nh hng rt mnh ca enzim gan glutathion - organic nitrat
reductase, thuc b kh nitrat tng bc v mt hot tnh.
Nitroglycerin t di li, t nng ti a sau 4 pht, t/2 = 1 -3 pht. Cht chuyn ho
dinitrat c hot tnh gin mch km 10 ln v t/2 khong 40 pht.
Isosorbid dinitrat t di li c pic huyt tng sau 6 pht v t/2 = 45 pht. Cc cht
chuyn ho ban u l isosorbid - 2 - mononitrat v isosorbid - 5 - mononitrat vn cn tc
dng v c t/2 l t 2 - 5 gi.
c tnh.

54
c tnh cp tnh lin quan n tc dng gin mch: tt huyt p th ng, nhp tim nhanh,
au nhi u. Cc ch phm nitrat vn c th dng cho ngi c tng nhn p, tuy nhin
khng dng c cho ngi c tng p lc ni s.
Lin quan gia cu trc v tc dng ca cc nitrat nitrit.
Trong phn t thng cha 2-4 nhm nitrat mi c tc dng.
Trong phn t nu cn c nhm hydroxyl t do th lm gim tc dng.
Cc cht c tnh thn du c tc dng tt hn cc cht c tnh thn nc.
Cc hp cht nitrat v c c tc dng km hn cc nitrat ca cc ancol mch thng.
Cc phng php chung iu ch: to este ca axit nitrit v nitr.

NaNO2/H
R ONO

N2O3
R OH R ONO

ONCl/piridin
R ONO

HNO3
R OH R ONO2

Nicorandil (4-5) c u im hn so vi nitroglycerin (4-2) l thi gian tc dng di hn, t

tc dng ph hn. C ch tc dng ca n cng c im khc l n tng cng hot ng
ca knh kali, chnh v th gy nn s gin mch.
iu ch nicorandil (4-5):
COCl CO NH CH2CH2 ONO2

H2N(CH2)2ONO2
+ HCl
N N
nicotin 4-5
nicorandil

4.2.1.2. Thuc chn dng calci

Thuc chn dng calci cn gi l thuc c ch calci, thuc i khng vi calci, thuc chn
knh chm calci.

55
Trong hiu th hot ng ca tim, Ca2+ c vai tr trong giai on 2 (giai on cao nguyn)
v c bit l trong kh cc ca nt dn nhp (pacemaker), nt xoang v nt nh tht. Calci
vo t bo theo knh chm. Trong c tim, Ca 2+ gn vo troponin, lm mt hiu qu c ch
ca troponin trn b co tht, do actin v myosin c th tng tc vi nhau gy ra co c
tim. V th, cc thuc chn knh calci lm gim lc co bp ca c tim lm chm nhp tim v
gim dn truyn nh tht.
C ch tc dng chng cn au tht ngc:
Cc thuc chn knh calci do lm gim lc co bp ca c tim nn lm gim nhu cu oxy
ca c tim (c ch chnh).
Trn thnh mch, cc thuc lm gin mao ng mch, lm gim sc cn ngoi bin, gim
huyt p v gim p lc trong tm tht, gim nhu cu oxy.
i khng vi co tht mch vnh. Tc dng tt trong iu tr cc cn au tht ngc cha
n nh.
Tc dng phn phi li mu trong c tim, c li cho vng di ni mc, l vng rt nhy
cm vi thiu mu.
Ch nh
D phng cc cn co tht mch vnh
Cn au tht ngc do co tht mch vnh (Prinzmetal) l ch nh tt nht.
Cn au tht ngc do co tht ngc khng n nh: tc dng tng t vi thuc chn .
C th dng phi hp vi cc dn xut nitro
Tc dng khng mong mun: Cc tc dng khng mong mun thng lin quan n tc
dng gin mch nh nhc u, cn bc ho, tt huyt p th ng. Nng hn l cc du hiu
c ch trn tim: tim nhp chm, nh tht phn ly, suy tim sung huyt, ngng tim.
Cc thuc hay s dng:
Bng 4.2: So snh cng tc dng trn tim v mch ca mt s thuc
Cht C tim T chc dn truyn C thnh mch
Nifediprime (4-6) ++ + ++++
Verapamil (4-12) +++ +++ +++
Diltiazem (4-13) ++ ++ ++

56
Qua bng trn cho thy nifedipin v cc thuc cng nhm (xem Thuc cha tng huyt
p) lm gin mch vnh mnh, t nh hng n hot ng ca c tim. Verapamil c ch
hot ng ca c tim mnh nht, dng tt cho iu tr lon nhp tim.
Cc thuc i khng vi calci c tc dng n t bo ca c tim v t bo c trn thnh
mch da vo cu to ha hc c phn thnh 5 nhm:
Nhm I: dn xut ca 1,4 dihidropiridin (nifedipine) (4-6).
Nhm II: dn xut ca verapamil (4-12).
Nhm III: dn xut ca diltiazem (4-13).
Ba nhm ny td ch yu n knh calci ca c tim.
Nhm IV: dn xut ca diphenyl-ankyl-amin (cinnarizin (4-14), fendiline (4-16). Loi ny
tc dng yu hn, chn lc thp hn ba nhm trn.
Nhm V: Nhm cu trc khc.
Bng 4-3. Cc thuc chn dng calci quan trng ang s dng.
Tn (bit dc) Nm iu ch S dng
R1

R2OOC COOR5

H3C N R4

1. Cc dn xut 1,4 dihidropiridin R3

Nifedipine (4-6) 1968 Mch vnh cp v mn, au tht ngc, tng trng
lc
Nitrendipine (4-7) 1972 au tht ngc, cc dng khc nhau ca tng trng
lc
Nisoldipine (4-8) 1979 au tht ngc, trng lc c dng tnh, khng
nh hng n tn s tim
Nimodipine (4-9) 1981 au tht ngc v gin mao mch no
Darodipine (4-10) 1987 au tht ngc
Nicardipine (4-11) 1974 au tht ngc, huyt p cao
II. Dn xut amin bc ba ca diarakyl
Verapamil (4-12) 1966 au tht ngc, lon nhp tim, cao huyt p do ng

57
 mui mng m
III. Dn xut benzo-thiazepin
Diltiazem (4-13) 1971 au tht ngc, c tc dng khng ng k ti lc
co c m tnh
IV. Dn xut ca diphenyl-ankyl-amin
Cinnarizine (4-14) 1959 Ri lon tun hon no v ngoi vi
Flunarizine (4-15) 1970 Ging nh cinnarizine, cc bnh v tai trong
Fendiline (4-16) 1962 Tng cng tun hon mch vnh, nhi mu c tim
Prenylamine (4-17) 1961 au tht ngc
V. Cc cu trc khc
Perhexiline (4-18) 1966 au tht ngc
Gallopamil (4-19) 1966 au tht ngc, lon nhp tim, cao huyt p
Tiopamil (4-20) Ging nh gallopamil
Pepridil (4-21) 1973 au tht ngc, lon nhp tim
Ipriflavone (4-22) 1971 au tht ngc
Mt s dn xut quan trng ca 1,4-dihidropindin
R1

R2OOC COOR5

H3C N R4

Cng thc chung R3

Tn R1 R2 R3 R4 R5
Nifedipine CH
2-NO2C6H4 CH3 H CH3
(4-6) 3

Nitrendipine CH
3-NO2C6H4 CH3 H C2H5
(4-7) 3

Nisoldipine CH
2-NO2C6H4 CH3 H CH2CH(CH3)2
(4-8) 3

Nimodipine CH(CH3 CH
2-NO2C6H4 H (CH2)2OCH3
(4-9) )2 3

58
 N
Darodipine CH
C2H5 H C2H5
(4-10) N 3

CH
felodipine 2,3-Cl2C6H3 CH3 H C2H5
3

CH
FR 7534 3-NO2C6H4 C2H5 H 2O C2H5
H
CH(CH3
Nilvadipnie 3-NO2C6H4 H CN
)2
N
CH(CH3 CH
isradipine H CH3
N )2 3

(H2C)2 N O CH
flordipine 2-CF3C6H4 C2H5 C2H5
3

CH (H2C)2 N N C6H
PO 219 3-NO2C6H4 CH3 H
3

Lin quan n cu trc v tc dng

Cc dn xut 1,4-dihidropiridin:
- Thng mt tc dng khi H trn N ca piridin thay bng mt nhm th khc. (tr trng
hp ca flordipine).
- Cc nhm cacboxylat v tr C3 v C5 thay bng cc nhm ng in cu in t sinh hc
khc (CN, SOR, NO2, SO2R) th u dn n cc hp cht c tc dng yu hn.
- Cc hp cht c u th v tc dng khi R2 = R5
- Nhm phenyl C4 c th thay bng nhm d vng nhng ch c mt s nhm c tc dng.
- Trong nhm phenyl C4 c th thay bng nhm NO2 hoc CF3 v tr 2 hoc 3 mi c nh
hng tt.

59
- v tr C2 c mch nhnh ancoxi th thng lm cho hp cht c thi gian tc dng ko
di hn.
- Cc ng phn quan hc c tc dng sinh ha v dc hc khc nhau.
Cc cht thng t ca verapamil (4-12):
CN CH3

H3 C (CH2)3 N (CH2)2 OCH3

CO
CH(CH3)2
H3CO OCH3

Cc dn xut v cht tng t ca verapamil mun c tc dng dc l th cn thit phi c

mt ng thi c hai vng thm v cha nhm isopropyl cnh nhm phenyl.
Tc dng ca cc ng phn khng gian ca verpamil khng ging nhau: ng phn S (-) c
tc dng chn dng canxi mnh hn ng phn R.
Nhm amino trn mch nhnh b to mui bc bn th hp cht mt tc dng.
Cc cht tng t ca diltiazem (4-13)
OCH3

OCOCH3

N
O
(CH2)2

N(C2H5)2

Diltiazem v mt ha hc l dn xut nhm benzo- (1,5) tiazepin

cho hp cht c tc dng th trn nguyn t N phi c nhm th (nhm th tt nht l
(C2H5)2N(CH2)2.
Vng thm gn vi tiazepin phi l vng benzen gn theo kiu ngng t v trong nhn
benzen khng c cha bt k nhm th no.
Nhm axetoxi v 4-metoxiphenyl th ng phn cis v ng phn (+) c tc dng tt hn.
V tr nhm axetoxi thay bng nhm axyl khc vn c th c tc dng.
Cc hp cht l dn xut ca diphenyl-ankylamin (bit dc stugeron)

60
Cu trc chung ca cc hp cht ny l nht thit phi c nhm iphenylmetyl v trong nhn
benzen nu c nhm th th phi l nhm c hiu ng khng gian b.

H
C
C C N N R R' = R'' = H
H H2
cinnazine (4-14)

R'
H
C
C C N N R R' = R'' = F
H H2
R = CH
flumarizine (4-15)

R"'
CH NH (CH2)2 R
R' = R'' = H
CH3
fendiline (4-16)

H2 R' = R'' = H
C CH NH (CH2)2 R

CH3
prenylamine (4-17)

Cc thuc chn dng canxi thuc nhm cu trc khc:

61
 C6H11 H
H2 N O C N O (CH2)N(C
2 2H5)2
CH C

C6H11

perhexiline (4-18) Cl gallopamil (4-19)

H3CO

Cl

OCH3 O
O2S SO2 CH3
C6H5
H3CO
(CH2)3 N (CH2)2 OCH3

O
H3CO tiopamil (4-20) (H3C)2CHO
ipriflavone (4-22)
H2 H2 H
C6H5 C N C C C OCH2CH(CH3)2
H2
C6H5 N

bepridil (4-21)

Tng hp cc thuc chn knh canxi:

Nhm I: cc dn xut 1,4-dihidropiridin:
Cc dn xut 1,4-dihidropiridin thng c iu ch theo phng php tng hp piridin
ca Hantzsch hoc theo mt dng ci tin ca phng php. Phng php ny l phng
php u tin nhng l phng php tt nht v kinh t, hiu sut 70-75%.
T etyl axetoaxetat, axetandehyt vi s c mt ca amoniac hp cht 3,5 etoxi-cacbonyl-
2,4,6-trimetyl 1,4-dihidropiridin (4-23) c to thnh.
CH3
C2H5 OCO CH3 OCOC2H5
C2H5OOC COOC2H5

+ CHO +
-3H2O
H3C O NH3 O CH3 N
H3C H CH3

4-23

Nu thay axetandehyt bng cc andehyt khc nhau v etyl axetoaxxetat bng dn xut khc
th thu c mt lot cc dn xut 1,4-dihidropiridin (4-24) khc.

62
 R
R2OCO R OCOR4
R2OOC COOR4

+ CHO +
-3H2O
R1 O NH3 O R3 N
R1 H R3

4-24

NO2

Vi R l v R1 = R2 = R3 = R4 = CH3 th thu c infedipin, l thuc quan trng

nht trong nhm ny.
Hp cht 1,4-dihidropiridin cng c th c tng hp t 4-25 v 4-26
X X

COOR4

R2OCO + R2OOC COOR4

H2N CH3
4-26 N
H3 C O amin croton este H3C H CH3

4-25 4-27
benzilidin axetoaxetat

Nhm II: Verafamil (4-12)

Mt trong nhng phng php tng hp verapamil l xut pht t 3,4-dimetoxiphenyl-
axetonitrin (4-28) qua hai con ng khc nhau to hai sn phm trung gian l 4-29 v 4-30.
Cho hai hp cht ny tc dng vi nhau thu c verapamil (4-12).
CN
NaOC2H5
H3CO CH2CN H3CO CH

(H3C)2HC Br CH(CH3)2
H3CO H3CO

Cl(CH2)3OH

CN CN
SOCl2
H3CO C (CH2)3Cl H3CO C (CH2)3OH

CH(CH3)2 CH(CH3)2
H3CO H3CO
4-29

63
 Pd/H2
H3CO CH2CN H3CO CH2CH2NH2

A
H3CO H3CO
4-28
C6H5CHO

H2 CH2CH2N
H3CO CH2CH2NH C C6H5 NaBH4H3CO C
H
C6H5

H3CO
H3CO
CH3I

H2
I H3CO CH2CH2N C C6H5
H2
H3CO CH2CH2NH C C6H5
H2O/H CH3
CH3 H3CO 4-30
H3CO

CN CH3

H3CO C (CH2)3 N (CH2)2 OCH3

4-29 + 4-30
CH(CH3)2
H3CO OCH3
4-12
verapamil

* Nhm III Diltiazem (4-13)

Diltiazem c tng hp bt u t vic m vng epoxit hp cht 4-31 vi anion ca
2-nitrothiophenol cho hp cht 4-32, phn lp ng phn bng cinchonidin sau kh thnh
amin 4-33, tip tc ng vng thnh hp cht lactam 4-34. Cht ny c ankyl ha vi 2-
cloroetyldimetylamin, s dng natri dimetylsunfinyl nh mt bazo. Tip theo l axetyl
ha vi anhidric axetic c ng phn d-ditiazem (4-13)
iu ch 4-31

64
 H
H3CO CHO + (CH3CO)2O H3CO C C COOCOCH3
H
O
C
OOH PBA
PBA: or m-Cl PBA

O O
H2O/H
H3CO C CH COOH H3CO C CH COOCOCH3
H H

CH3OH/H2SO4

H3CO C CH COOCH3
H

4-31

65
 OCH3

OCH3
S
SH

+ to
CH OH
O
NO2
NO2 COOCH3
H3COOC
4-32

1) To mui
vi L lysin
Tch ly ng phn +
2) Kh ha H2/Pd
OCH3

OCH3
S
H

S CH OH

H NH2
COOCH3
OH 4-33
N
H
4-34 O

1) Cl(CH2)2N(CH3)2
2) (CH3CO)2O

OCH3

OCOCH3

H
N
H2 O
H2C C N(CH3)2

diltiazem DP cis

Nhm IV: cc dn xut ca diphenyl-ankylamin

Cinnarizine (4-14) l dn xut ca benzhidrylamin. iu ch cinnarizine ngi ta
cholinesterase benzhidryl clorua (4-35) tc dng vi N-etoxicarbonyl piperazin (4-36) sau
thy phn loi nhm etoxicarbonyl i ti hp cht diphenyl metyl piperazin 4-37 sau
axyl ha hp cht ny vi cinnametyl clorua c amit tng ng 4-38, kh ha hp cht
ny bng LiAlH4 thu c cinnarizine (4-14)

66
CHCl3 + C6H6

CH Cl + HN N COOC2H5 CH N N COOC2H5

4-35 4-36
H2O/H

C6H5 C CHCOCl
H CH N NH
CH N N COCH C
H cinnametyl clorua

4-37
4-38

LiAlH4 C6H5CH=CHCHO: cinnadehyt

CH N N CH2CH C
H

4-14
cinnarizine

Prenylamine (4-17): benzadehyt v malonitrin este tng hp xianoeste 4-39. Tip theo a
nhm phenyl vo bng cch cng phenyl magie bromua vo ni i ca 4-39 thu c 4-40.
Sau thy phn v decacboxyl ha thu c 4-41, kh ha nhm nitrin thnh amin 4-42,
cui cng ankyl ha amin ci 2-cloro-1-phenyl-propan thu c prenylamin. Hoc em 4-42
phn ng vi phenylaxeton ri kh ha vi H2/Pd.

67
 CN CN
H
CHO H2C C

COOC2H5 COOC2H5
4-39

Ph-MgBr

CN
H2 1) H2O H
C6H5 CH C CN C6H5 CH C
2) - CO2 COOC2H5
C6H5 4-41 C6H5
4-40

LiAlH4

H2 H2 H2
H2 H2 ClCH(CH3)CH2C6H5 C H CH C C NH CH C C6H5
6 5
C6H5 CH C C NH2

C6H5 CH3
C6H5
1) Phenyl xeton 4-17
4-42
2) H2/Pd

1) BrMgCH2CN H2 H2
C6H5 CH C C NH2
2) H2O/H
3) -H2O C6H5
4) H2/Pd
4-42
C6H5 C C6H5

CN
1) CNCH2COOEt H
C6H5 CH C
2) H2/Pd
COOC2H5
C6H5
4-40

Nhm V: cc cu trc khc Tng hp bepridil (4-21):

H2 H2 1) SOCl2 H2 H2
HO C C CH2O C CH(CH3)2 C6H5H2C N C C CH2O C CH(CH3)2
H H
2) Benzylanilin
4-43 C6H5
4-21

68
 Cl2/3000C H2 H2O2 H2
H3C C CH2 Cl C C CH2 Cl C CH CH2
H H
O

HOCH2CH(CH3)2

H2 H2 N H2 H2
H (H3C)2HC C O C CH CH2
(H3C)2HC C O C CH CH2

O
4-43 N OH

1) 2) ClCH2CH(CH3)2
N
H
O
H2
OH C C CH2
H

4.2.1.3. Cc thuc cha au tht ngc loi hy - adrenegic

C ch: tc dng chng au tht ngc lin quan n vic c ch - receptor ca tim, khng
lin quan n tc dng n nh mng v gy t ti ch, lm gim cng nng ca tim, tit
kim s dng oxi cho c tim, c ch qu trnh trao i cht ca c tim.
Khng dng cho ngi c suy tht tri, v c th gy try tim mch t ngt. Khng nn
ngng thuc t ngt v c th gy hin tng bt li lm nhi mu c tim, t t.
Cc thuc s dng:
OH OH OH

O iPr O iPr O iPr

N N N
H COCHH3 H

CH2COCH3 HN COCH2CH2CH3 NH COCH3

4-44 4-45 4-46
atenolol acebutolol practolol

69
 OH OH OH

O iPr O O iPr
iPr
N N N
H H H
O
CH
2

4-47 4-48
H
propranolol H2C C CH2 oxprenolol
4-49
alprenolol

Tng hp practolol: c hai phng php

Phng php 1:
Vic tng hp cc hp cht dn xut ete ca 1-aminoprophan -2,3-diol tng i ging
nhau, u c chung giai on to ete gia nhm phenolat v ankyl-halogenua. Ngoi ra, mi
hp cht khc nhau th c thm nhng bc phn ng khc nhau a nhng nhm th
vo nhn benzen.

70
 H2C OH H2C OSO2 CH3

HC OH + ClSO2 CH3 HC OH

H2C OH H2C OH

axetyl ha

H2C O NHCOCH3
H2C OSO2 CH3

HC O p-CH3NHC6H4ONa
C CH3 HC O
C CH3
H2C O
H2C O
CH3
CH3

deaxetyl

H2C O NHCOCH3 H2C O NHCOCH3

1) p-CH3C6H4SO2Cl/piridin HC
HC OH
2) NaOH O
H2C OH H2C
iPr-NH2

(H3C)2HC N O NHCOCH3
H

HO
4-46
practolol

Vic tng hp cc hp cht 4-44, 4-45, 4-47, 4-48 u c th tin hnh theo phng php
tng t.
Phng php 2: khng cholinesterase glyxerin phn ng trc tip vi ArONa v phn ng
khng xy ra hoc xy ra rt chm.

O
OH
O

NaOH RNH2
H2C OH
+
O H2 H2 H
Cl Ar O C C C N R
H

71
 O Cl O
O
OH
NaOH, t0

iPr-NH2 H CH3
N
O CH
CH3
OH

propranolol

4.2.1.4. Cc thuc c tc dng chng au tht ngc khc

Thuc t tho mc: khelline v visnadine
Thuc tng hp: carbocromum, amiodarone, dipyridamole

72
 OCH3 O

O O
O

H3C

O CH3 OCOCH3
O H3C
OCOCH C2H5
OCH3
CH3 visnadine
khelline
CH3
O (CH2)3CH3 I

O(CH2)2N(C2H5)2

C2H5OCO H2CO O O
amiodarone
carbochromum I

N N(CH2CH2OH)2
N

N
(HOH2CH2C)2N N

N
dipyridamole

Tng hp dipyridamol:

N N
X
5 N Cl N N(CH2CH2OH)2
4 X
3 N N N
N 6 HN(CH2CH2OH)2
Piridin N
N
2 9 (HOH2CH2C)2N N
N Cl N
7
X N 8
1 N N
4-49 X = OHX 4-51
4-50 X = Cl

dipyridamole

4.2.2. Cc thuc cha lon nhp tim

73
4.2.2.1. i cng v hot ng ca tim
Sut c cuc i tn ti ca mt qu tim, n thc hin bm mt khi lng 160.000m3 mu
(trung bnh 4.900 cm3/pht). thc hin c chc nng ny, cn thit tim phi p u
n.
Khi s co bp, phi hp ca cc c tim khng ng u s gy ra lon nhp tim. Lon nhp
tim c hai loi: p nhanh hoc p chm hn. Do lon nhp tim, lu lng mu/1 pht b
bin i, do cng sut ca tim cng thay i. Nng hn th tim c th ngng hot ng v
c th gy cht bt thnh lnh.
C tim c kh nng pht ra cc xung tc t ng theo chu k do c kh cc t pht trong
thi k tm trng sau l ti kh cc. Kh cc v ti kh cc l kt qu ca s trao i
cc ion Na+, K+, Ca2+ qua mng t bo.
4.2.2.2. C ch hnh thnh s lon nhp v cc thuc chng lon nhp
1. Lon nhp
Lon nhp tim l s ri lon hot ng in sinh hc ca tim v ba mt: s to thnh xung
ng, dn truyn xung ng, s phi hp gia to thnh v dn truyn xung ng.
Ri lon nhp tim c nhiu loi, gp tt c cc khoa lm sng v ngay c nhng ngi
bnh thng, mt ngi bnh cng mt lc c th gp nhiu loi ri lon nhp tim khc
nhau, mt khc t ri lon nhp tim ny c th chuyn thnh cc ri lon nhp tim khc.
Ngay c cc thuc iu tr ri lon nhp tim cng c th gy ri lon nhp tim. Nu phn tch
k lng tng trng hp c loi lon nhp tim cn thit phi iu tr, nhng cng c khi c
nhng ri lon nhp tim khng cn phi iu tr, nhng vn ny cc thy thuc cn phi
nm vng p ng yu cu thc tin trong lm sng.
Cc nguyn nhn gy ri lon nhp tim:
Ri lon nhp tim chc nng: xut hin nhng ngi bnh thng c ri lon tm l; lao
ng gng sc; lin quan n n ung; ht thuc l; ung ch, ru, c ph...
Ri lon nhp tim thc th do tn thng thc th ti tim nh: thiu mu c tim, nhi mu
c tim, vim c tim, cc bnh van tim, cc bnh tim bm sinh...
Ri lon nhp tim do bnh ca cc c quan khc, v d: cng chc nng tuyn gip, bnh
vim phi-ph qun cp hay mn tnh, thiu mu, ri lon thng bng kim-toan v in
gii, do thuc ...

74
Biu hin lm sng ca ri lon nhp: Lm sng ca ri lon nhp tim cng phc tp v ph
thuc vo tng th bnh, tng loi v bnh gy ra ri lon nhp. Mt s ri lon nhp tim
lun phi cp cu v c t l t vong cao do ri lon huyt ng nng n. V d: nhp nhanh
tht, rung tht, blc nh-tht cp III, yu nt xoang...
Phn loi ri lon nhp tim: Da vo c ch bnh sinh ca ri lon nhp tim, ngi ta chia
thnh 3 nhm:
Ri lon qu trnh to thnh xung ng: nhp xoang nhanh hoc chm, ngoi tm thu, cung
ng v rung...
Ri lon qu trnh dn truyn xung ng: blc xoang nh, blc nh-tht, blc trong tht...
Kt hp gia ri lon to thnh xung ng v dn truyn xung ng: phn ly nh- tht, hi
chng qu kch thch dn truyn sm...
2. Cc thuc cha lon nhp tim
Thuc c tc dng iu ha tim v chng suy tim. C 4 nhm I, II, III, IV.
Cu to ca cc thuc cha lon nhp tim
OH

O NHCH(CH3)2

R2

R1 = CH2CONH2; R2 = H: atemolol
R1 = NHCOiPr; R2 = COCH3: Acetantolol

R1

Nhm IA:

75
 H
C CH2

HO
H N
HO

N OH
H3CO

N H
H
CH3
C2H5
N
4-52 4-53
quinidine aJmaline

CONH2
H2 H2 H H2
C C CH2 N(CH(CH3)2)2 O C C C NH C3H7
H2 H2 O
N C6H5 C C C OH
C6H5
4-54
disipyramide
4-55
propafenone

CONHCH2

HN
H2N CONHCH2CH2N(C2H5)2
F3CH2CO OCH2CF3

4-56 4-57
procainamide flecainide

Nhm IB:
CH3
N CH2CH2CH2N(C2H5)2

NHCOCH2N(C2H5)2 C6H5

4-59
aprindine
4-58 CH3
lidocaine CH3
H O
N

(C2H5)2C OCH2 CH NH2

NH
C CH3
O
4-60 4-61 CH3
phenytoin mexiletine
CH3

C6H5H2CCON N CH(CH3)2
H
NH C C NH2
C6H5 O
4-62
CH3
lorcainide
4-63 CH3
tocainide

Nhm III:

76
 O (CH2)3CH3
OH
I
H2
H3CO2SHN C C NHCH(CH3)2
H

C OCH2CH2N(C2H5)2
O 4-64
sotalol

4-47 I
aminodarone

Tng hp mt s hp cht c tc dng cha lon nhp.

Disopyramide:
H2
C CN Br H
N N C CN

+ NaNH2
C6H5

ClCH2CH2N[CH(CH3)2]2

NaNH2
CONH2

CN
[(H3C)2HC]2NH2CH2C C N
H2O/H [(H3C)2HC]2NH2CH2C C N
C6H5

C6H5
4-54
disopyramide

Flecainide
OCH2CF3 OCH2CF3
N CH2NH2 N
CO2CH2CF3 CONHCH2

t0

OCH2CF3 OCH2CF3
H2/Pd

OCH2CF3 H
N
CONHCH2

4-57
flecainide
OCH2CF3

Aprindine (4-59)

77
 PhNH2/NaBH4
H
O N

(C2H5)2N(CH2)3Cl

C6H5

(CH2)3N(C2H5)2

4-59
aprindine

Lorcainide (4-62)

NH2
N N COOC2H5

+ O N COOC2H5

Cl 1) NaBH4
Cl
2) C6H5CH2COCl

N N COOC2H5
N N COOC2H5

COCH2C6H5 1) H2O/H COCH2C6H5

Cl 4-62
lorcainide 2) (H3C)2HC I Cl

Sotalol (4-64)

78
 NH2 NHSO2CH3 NHSO2CH3

Cl C CH3

O
+ H3C SO2Cl
AlCl3

NHSO2CH3

OC CH3

A
Cl2/AS
CH3
H2N CH
CH3
H2 H CH3
A C C N CH A C CH2Cl
CH3
O O

CH3
CH3
Benzyl H2/Roney
H2N CH Benzyl CH Benzyl
NH
C6H5CH2Cl
CH3 CH3 +
CH3
H2 H
A C C N CH
CH3
O

CH3
H2
A C C N CH
CH3
O Benzyl

4.2.3. Cc thuc tr tim

4.2.3.1. i cng
Nhim v ca tim: cung cp mu cho tt c cc b phn ca c th v p ng y nhu
cu v dinh dng.
Suy tim l tnh trng bnh l do c tim hot ng khng hiu qu. Cc chuyn gia tim
mch v tim nh cc my bm. B suy tim l chc nng ca tim khng hon thnh, khng
a mu nui c th nh bnh thng. Khi , s thiu ht ny li bt tim bm mu
nhiu hn. Hu qu l mu tch t li trong cc mch mu ngoi vi ca phi v lm cho
ngi bnh thng b kh th. Suy tim bn T (ph phi) so vi suy tim bn P (tng p
lc tnh mch cnh, gan to huyt, ph ngoi bin).

79
 C hai loai suy tim:
Cp tnh: t ngt, gy sc.
Mn tnh:
Khi bn cm thy mau mt hn c bit khi i li hay lm mt vic m trc y bn cm
thy bnh thng.
Bn khng th nm u thp ng d trc y bn ng rt tt vi t th y. C khi bn
c nhng cn kh th vo lc na m v mun ngi dy th.
Bn c th ph chn (ph v n lm vng cng chn, bn chn), c th km tnh mch
c dn r rt.
Nhng nguyn nhn no thng gp trong suy tim?
Suy tim thng c nguyn nhn gy ra nh huyt p cao khng iu tr, bnh c tim thiu
mu, nhi mu c tim, bnh van tim (hp, h van 2 l, hp h van ng mch ch), bnh tim
bm sinh khng iu chnh bng phu thut (thng lin tht, thng lin nh, t chng fallot,
hp van ng mch phi, cn ng ng mch), vim c tim, cng gip khng iu tr,
suy thn mn, lon nhp tim ko di
Cc cp suy tim: theo hi tim New york c 4 cp .
Cp 1: tim cn cha gim cng sut
Cp 2: Vi ti trng ln mi lm gim cng sut
Cp 3: vi ti trng nh lm gim cng sut
Cp 4: trong trng thi ngh b gim cng sut.
C my cch thc c dng iu tr suy tim?
1. S dng thuc : l phng thc bt buc cho cc bnh nhn nh trnh by trn v cc
thuc ny gip ci thin triu chng, tng kh nng gng sc, gim nhp vin v ko di
cuc sng.
2. Cy my to nhp-kh rung: l phng php p dng cho ngi c lon nhp v ngi c
nguy c t t cao. Khi c lon nhp, my s phng ra dng in xo i lon nhp gip
bnh nhn khng b t t.
3. Ti ng b tim: l phng php t in cc vo bung tim phi v xoang vnh tim gip
tim kch thch ng b, c tc dng gim triu chng, ci thin chc nng tim v gim t l
t vong.

80
4. Phu thut:
Phu thut iu tr nguyn nhn nh phu thut thay van tim nu bnh van tim, phu thut
iu chnh tim bm sinh, phu thut bt cu ng mch vnh cho bnh tim thiu mu v nhi
mu c tim, phu thut bc c tim cho bnh c tim ph i
Phu thut ghp tim l bin php cui cng cho bnh nhn suy tim giai on cui.
Thuc tr tim l nhng thuc c tc dng lm tng lc co bp ca c tim, dng trong cc
trng hp suy tim. Cc thuc c chia lm 2 nhm:
Thuc loi glycosid c ch nh trong suy tim mn.
Thuc khng phi glycosid dng trong suy tim cp tnh.
4.2.3.2. Cc glycosid tr tim
Cc thuc loi ny u c 3 c im chung:
Tt c u c ng un gc t thc vt: cc loi Digitalis, Strophantus
Cu trc ho hc gn ging nhau: u c nhn steroid ni vi vng lacton khng bo ha
C17, gi l aglycon hoc genin, c tc dng chng suy tim. V tr C3 ni vi mt hoc nhiu
phn t ng (ose), khng c tc dng dc l nhng nh hng n dc ng hc ca
thuc.
Hin ch cn digoxin v digitoxin c dng lm sng. Digitoxin khc digoxin l khng
c OH C12 v th t tan trong nc hn.
Cc thuc tc dng trn tim theo cng mt c ch. y l tc dng ch yu: digitalis lm
tm thu ngn v mnh, tm trng di ra, nhp tim chm li. Nh , tim c ngh nhiu
hn, mu t nh vo tht thi k tm trng c nhiu hn, cung lng tim tng v nhu
cu oxy gim. Do bnh nhn kh th v nhp h hp tr li bnh thng. Digitalis cn
lm gim dn truyn ni ti v tng tnh tr ca c tim nn nu tim b lon nhp, thuc c th
lm u nhp tr li.
Ngoi ra cn c cc tc dng khc:
Trn thn: digitalis lm tng thi nc v mui nn lm gim ph do suy tim.
C ch ca tc dng ny l: mt mt, digitalis lm tng cung lng tim, nn nc qua cu
thn cng tng; mt khc, thuc c ch ATPase mng t bo ng thn lm gim ti hp thu
natri v nc.
Trn c trn: vi liu c co tht kh qun v t cung (c th gy xy thai).

81
 Trn m thn kinh: digitalis kch thch trc tip trung tm nn sn no tht 4 v do phn
x t xoang cnh, quai ng mch ch.
p dng lm sng
Ch nh:
Gin tm tht.
Nhp nhanh v lon.
Suy tim do tn thng van.
Chng ch nh:
Nhp chm.
Nhp nhanh tm tht, rung tht.
Vim c tim cp (bch hu, thng hn...)
Nghn nh tht.
Khng dng cng vi cc thuc sau, c th gy cht t ngt hoc tng c ca digitalis:
calci (nht l khi tim tnh mch), quinidin, thuc kch thch adrenergic, reserpin.
Mt s loi glucozit c tc dng cha suy tim:
Scilaren (4-65):
O

4-65 R1 = OH, R2 = H, R = scilabioz

12 H3C scilaren
17
4-66 R1 = H, R2 = H, R = H
11 13 scilarenin
H3C R2 16 4-67 R1 = -OAc, R2 = OH, R = -glucose
9 14
scilliroside
2 1
10 8 15
H OH
3 5
6 7
RO 4

R1

Scilaren c trong cy hnh bin.

82
 Bufodienolit gm bufalin, bufogenin, bufotalin v bufotoxin c trong da cc.
O

4-68 R1 = H, R = H
bufalin
4-69 R1 = OH, R = H
12 H3C
17 bufogenin
11 4-70 R1 = -OAc, R = H
13 bufotalin
H3C H R1
9 14 4-71 bufotoxin
R1 = -OAc, R =
2 1
10 8 15
CHO(CH2)6CONHCH (CH2)3NH C NH
H OH
3 5
6 7 COOH NH2
RO 4
H

Adonitoxin (4-73): c trong cy c phc th

83
 O

12 H3C
17
11
13
OHC 9 H R1
14
2 1 4-72 R1 = H, R2 = OH
10 8 15
H OH
convallatoxin
3 5 4-73 R1 = OH, R = H
6 7 adonitoxin
OH O
4
R2

CH3

OH HO
O
O

12 H3C
17
11
13
H3C 9 H R1
14
2 1 4-74 R1 = OAc, R = -L-arabino
10 8 15 hexopiranosyl
H OH oleandrin
3 5
6 7 4-75 R1 = H, R = -L-gluco-piranosyl
RO 4 nerifolin
R2

Cu trc ca glucozit tr tim: cis trans cis, ca axit mt: trans trans trans, ca
hocmon: cis trans trans.

84
 O
O

O
O

12 H3C
12 H3C 17
17 11
11 13
13 OHC H
OHC H 9 14
9 14
2 1
2 1 10 8 15
10 8 15
H OH
H OH 3 5
3 5 6
6 7
7 4
HO
RO 4
HO
HO
4-77
4-76 R = -glucose ramnoz strophanthidin
hellebrin 4-
76 c chit tch trong cy Hellebunomiger cn 4-77 c chit t ht cy sng tru.

85
 O

12 H3C
17
11
HO 13
HO 9 HO 14
2 1
10 8 15
H OH
3 5
6 7 OH O
RO 4
HO
CH3
R=
4-78
ouabain
4-79 R = H OH OH
ouabagenin

R2
12 H3C
17
11
13
H3C 9 H 14 R1

2 1
10 8 15
H OH
3 5
6 7
RO 4
H

86
tt tn tn R R1 R2
CH3
1 4-80 digitalin OH H
O
CH2OH OCH3

O O

OH
OH
HO

2 4-81 Diginatigenin H OH OH
3 4-82 digitoxigenin H H H
4 4-83 digitoxigenin H H OH
5 4-84 digitoxin CH3 H H
O

HO

OH
3

6 4-85 gitoxin CH3 OH H

O

HO

OH
3

7 4-86 gitoxigenin H OH H

87
Thnh phn ng:
O
CH3 CH2OH
H3C
O O O
HO HO HO O
O HO
OH HO OH
RO digitoxoz (R = H)
axetyldigitoxoz (R = Ac) ramnosit glucosit

iu ch glucosit A (4-87) v glucosit B (4-48) t digitalis purpurea: Thng thng,

glucozit A v B c chit t cy D-purpurea nhng rt kh do b enzim phn hy thnh
digitoxin v gitoxin.

H3C

H3C

enzim
H OH digitoxin (4-84
-glucoz
O
H
zoxotigid glycozit A (4-87)

digitoxoz

digitoxoz

glucoz

88
 O

H3C

H3C H OH

enzim
H OH gitoxin (4-85)
-glucoz
O
H
zoxotigid glycozit B (4-87)

digitoxoz

digitoxoz

glucoz

Digitalis lanata: cha 3 genin glycozit, cc hp cht ny c gi l lanatosit (digilanit ) A

(4-89), B (4-90) v C (4-91) c chit t D lanato.

89
 O O
O
O O
O
HO
H3C
H3C
H3C

H3C H OH H3C
H3C

H OH OH
H OH

O O
O H
H H
zoxotigid
zoxotigid zoxotigid
digitoxoz
digitoxoz digitoxoz
acetyl digitoxoz
acetyl digitoxoz acetyl digitoxoz
glucoz
glucoz glucoz
lanatosit B (4-90) lanatosit C (4-91)
lanatosit A (4-89)

deaxetyl ha - glucoz - tridigitoxoz

lanatosit A glycozit A digitoxin digitoxigenin
dd Ca(OH)2 4-87 enzim 4-84 enzim 4-82

deaxetyl ha - glucoz - tridigitoxoz

lanatosit B glycozit B gitoxin gitoxigenin
dd Ca(OH)2 4-88 enzim 4-85 enzim 4-86

deaxetyl ha - glucoz - tridigitoxin

lanatosit A lanatosit A digitoxin digoxigenin
dd Ca(OH)2 4-89 enzim 4-84 enzim 4-83

Minh ha cu trc ca lanatosit A (4-89):

O
O
CH2OH CH3
CH3 CH3 H
HO O
O O CH3 C D
O O CH3 B OH
HO H
O O A H
OCOCH3
OH O
OH

4.2.3.2. Cc thuc tr tim khng phi loi digitalis

V sao phi nghin cu tm cc thuc tr tim khng phi l digitalis?
Do glycosit tr tim c c tnh cao, vng iu tr hp.
tch ly trong c th cao.
Do glycosit tr tim ch iu tr c bnh tim mn tnh, khng dng c cho ngi b
bnh tim cp tnh.
Do cc thuc tng hp cn t c cc tiu ch sau:
Chi phi mt cch hiu qu cc triu chng lm sng ca bnh suy tim.
Thuc c th dng theo ng ung.

90
 c tnh thp hn, t tch ly trong c th hn.
Khng th hin tc dng ph khi phi dng thuc trong thi gian di.
Ko di c cuc sng ca ngi bnh.
Nh chng ta cp, qu trnh co bp ca c tim c quan h mt thit vi ion canxi. T
vai tr ni bt ca ion canxi suy ra rng mt thuc tr tim hoc trc tip hoc gin tip lm
tng nng canxi trong t bo v lm tng cng nhy cm ca cc yu t co bp ca
c tim.
Phn nhm cc hot cht c tc dng tr tim loi khng phi glycosit:
Nhm tc dng trc tip ti cAMP trong t bo
Cc cht tc dng ch vn ti cc th th c trn mng t bo (cc thuc cng -
adrenergic).
Cc cht ch vn trn th th histamin, glucagon, PGE2, tiroxine.
Cc cht hot ha enzim adenylat-cyclase.
Cc cht hot ha enzim protein-kinase.
Cc cht phong ta enzim phosphodiesterase.
Nhm tc dng gin tip ti cAMP trong t bo
Cc cht tc dng ch vn ti knh canxi.
Cc cht lm tng nhy cm ca cc yu t co bp ca tim.
Cc cht c tc dng ch vn ti knh natri.
Cc loi thuc c tc dng co bp dng tnh cc im tn cng khc
1. Cc loi thuc tc dng trc tip ti cAMP
a) Cc cht tc dng ch vn ti adrenergic receptor
Tc dng chnh ca chng l kch thch th th 1 ca tim nhng ngoi ra thng thng n
cn c tc dng ti cc th th 1, thm ch n cng cn c th tc dng ti cc th th khc.
Cc thuc tr tim s dng v th nghim trn lm sng: c 3 nhm cu trc.
Nhm I: phenyl etyl amin

91
 H
N R''

R'

Phng php iu ch chung:

CH2Cl CH2CN CH2CH2NH2
HCHO + HCl NaCN khu ha
clo metyl ha
HO
HO HO HO

OH
OH OH OH

RX

CH2CH2NHR

HO

OH
dopamin

tt Tn thuc R R R
1 Dopamine (4-92) OH OH H

H H2
C C
2 Dobutamine (4-93) OH OH C
H2
OH

CH3

3 Dopexamine (4-94) OH OH (CH2)6N

H
(CH2)2

4 Ibopamine (4-95) OCOCH(CH3)2 OCOCH(CH3)2 CH3

* Nhm II: phenyl etanol amin
OH

H
N R''

R'

tt Tn gi R R R

92
 1 isoproterenol OH OH CH(CH3)2

Butopamine CH
H2 H2
C OH
C
2 OH H
(4-96) CH3

OCH3

Denopamine
3 OH H H2 H2
(4-97) C C OCH3

Cc phng php iu ch chung:

C CH3 C CH2Cl
AlCl3 Cl2/AS
+ Cl C CH3
O O
O
R R R

R' R' R'

NaCN

H H2
C C C NH2 C CH2CN
H2 NaBH4
OH O

R R

R' R'

Nhm III: phenoxi pronanol amin

OH

H
O N R''

R'

tt Tn gi R R R
Prenalterol
1 OH H CH(CH3)2
(4-98)

xamoterol
(H2C)2 NH C N O
2 OH H
(4-99)
O

Tng hp mt s cht i din ca nhm tc dng trn adrenergic receptor:

Dobutamin (4-93):

93
 hidro ha H2 H2
H3 CO C C COCH3 H3 CO C C COCH3
H H

OCH3
OH
H2 H2
CH3
1) H2N C C OCH3
H2 H2
HO C C C NHCH2 CH2 OH
2) Khu ha H
3) HBr
4-93
dobutamine

Butopamine (4-96)

H2 H2
AcO C C COCH3 AcO C C CH CH3
H2 H2

NH2

OH
DCC HOOC C OAc
H

H2 H
AcO C C CH NH CO C OAc
H2

CH3 OH

H2 H
HO C C CH NH CO C OH
H2

CH3 OH

4-96
butopamine

Cc nhc im chnh ca cc thuc tr tim tc dng ch vn ti 1:

Cng lm tng cng s tiu th oxi ca c tim.
Thng cc loi thuc ny khng c hiu qu ng ung.
C khuynh hng lon nhp tim.
Do cc nhc im ny m phm v s dng ca cc loi thuc trn ch yu b gii hn ti
cc trng hp bnh cp tnh.
b) Cc thuc tc dng ch vn trn th th H2 (H2-receptor agonists)
Tc dng ca cc cht tr tim lin h mt thit vi vic tng cAMP.
Thuc phi c s chn lc v th th H2 c c loi th th ca tim v c c loi th th
histamin (H1 v H2).

94
 Tc dng ch vn trn th th H2 i khng vi H1 (v i khng vi H1 gy nn vic gin
mch vnh).
Thuc loi ny c impromidine (4-100) v 4-101.
H
(CH2)3NH C N (CH2)2S CH2 CH3

NH
HN N N NH
4-100
impromidine
H H
(CH2)3NH C N (CH2)3 N N

NH
HN N
4-101

c) Cc cht hot ha enzim adenylat-cyclase

2. Cc thuc tc dng gin tip ti cAMP
Cc thuc tr tim tc dng gin tip ti cAMP gm ba loi:
Cc cht c tc dng ch vn ti knh canxi.
Cc cht lm tng cng nhy cm ca cc yu t co bp theo hng ion canxi.
Cc cht c tc dng ch vn ti knh natri.
a) Cc cht tc dng ch vn ti knh canxi
O
CH3
H3C
N
N

N
O N

CH3
4-105
caffeine
b) Cc cht lm tng cng nhy cm ca cc yu t co bp theo hng ion canxi

95
 CH3

NH
H
N

S CH3 4-116 O
O
X HN N
N
Y
H
H3CO O N N

4-114, X = CH, Y = N
sulmazole
4-115, X = N, Y = CH 4-117
isomazole

c) Cc cht c tc dng ch vn ti knh natri

OH
H2 H2
O C C C N N CH(c6H5)2
H

CN

N 4-118
H
DPI-201-206
iu ch DPI-201-206
OH
O
H2 H2
OH OCH2CH CH2 O C C C N N CH(c6H5)2
H
O
HN N CH(C6H5)2
ClH2CHC CH2
CN CN CN
N N N 4-118
H H H DPI-201-206

3) Cc hp cht c tc dng co bp dng tnh cc im tn cng khc

Sau khi pht hin ra tc dng co bp dng tnh (tr tim) ca taurine (4-119), ngi ta
kim tra tc dng ca cc hp cht c cu trc tng t (4-120, 4-121), kt qu cho thy cc
cht ny cng c tc dng tng t taurine.
SO3H
H
H2N CH2CH2SO3H H2N C CH2SO3H

4-119 COOH
taurine NH2
4-120 4-121

96
C ch tc dng ca taurine (v ca cc hp cht tng t) l tng nng ion canxi trong
t bo.
Tc dng co bp dng tnh v tc dng gin mch ca berberine (4-123) cng c khng
nh. Tc dng ny c th l do kt qu tc dng ti h thng cAMP.
O

H3CO

OCH3
4-123
berberine

Cht ny chit trong cy vng ng.

97
CHNG 5. CC THUC IU CHNH HUYT P
Huyt p l g?
Huyt p l s o v lc tc ng ca mu ln thnh ng mch. Huyt p ph thuc vo lc
bm mu ca tim, th tch mu c bm, kch thc cng nh n hi ca thnh ng
mch.
Huyt p lin tc thay i ty theo hot ng, nhit , ch n, cm xc, t th, v s
dng thuc.

Huyt p bao gm 2 thng s:

S trn (huyt p tm thu): L tr s huyt p cao nht khi tim co bp
S di (huyt p tm trng): L tr s huyt p thp nht khi tim ngh ngi.
Huyt p bnh thng l bao nhiu? ngi ln, huyt p tm thu di 120mmHg v
huyt p tm trng di 80mmHg.
Cc tnh trng lm nh hng n huyt p?
Tr s huyt p c th b nh hng khi bnh nhn c mt trong cc yu t sau y:
Bnh l tim mch
Bnh l thn kinh
Cc ri lon v thn v ng tit niu
Tin sn git ph n mang thai
Cc yu t v tm l nh stress, gin d, s hi...

98
Cao huyt p o chong trng (Bnh nhn cm thy lo lng khi c thm khm)
Khi no th chn on l cao huyt p?
Khi huyt p tm thu t 140 mmHg tr ln hoc huyt p tm trng t 90 mmHg tr ln
th chn on l cao huyt p.
Gi tr nm gia huyt p bnh thng v cao huyt p (Huyt p tm thu t 120-139 mmHg
hoc huyt p tm trng t 80-89 mmHg) th c gi l tin cao huyt p.
Du hiu sm ca tng huyt p:
a s nhng ngi b tng huyt p giai on u u khng c biu hin g. Mt s
ngi c th c nhng du hiu sm sau:
au u, au git git hai bn thi dng, trn, hai h mt, lan dc nh u xung gy,
au tng cn hoc lin tc.
Chong vng, gim kh nng tp trung, ri lon tr nh v mt ng, mt nng bng.
Hi hp nh trng ngc.
Gim th lc, du hiu rui bay.
Chy mu mi...
Nguyn nhn ca tng huyt p:
a s cc trng hp tng huyt p ngi ln l khng c cn nguyn hay cn gi l tng
huyt p nguyn pht, chim ti trn 95% s ngi b tng huyt p. S cn li c th c
cn nguyn (tng huyt p th pht), tc l c nguyn nhn do b mc cc bnh l v thn,
bnh ni tit, bnh l tim mch...
C nhiu yu t c th dn n tng huyt p nh:
- Ht thuc l.
- Tha cn.
- Bo ph.
- n mn - n nhiu m ng vt.
- Cng thng thn kinh.
- Ung nhiu bia ru.
- Tin s gia nh c ngi b tng huyt p, tui t 40 tr ln....
Nhng bin chng v hu qu thng gp ca tng huyt p:

99
Tng huyt p rt nguy him bi cc bin chng ca n c th gy t vong hoc li
nhng di chng nng n (tai bin mch mu no, suy tim, suy thn...) nh hng n cht
lng cuc sng ca ngi bnh v l gnh nng cho gia nh, x hi.
Tng huyt p c th dn n:
- Cc bnh tim mch: Nhi mu c tim, suy tim, ph phi cp...
- Cc bnh v no: t qu, xut huyt no, nhn no...
- Cc bnh v thn: i ra mu, i ra protin, suy thn...
- Cc bnh v mt: Gim th lc hoc m la...
Cch phng chng tng huyt p: Mi ngi c th phng b tng huyt p bng cch:
- Thc hin li sng lnh mnh:
Hng ngy luyn tp th dc th thao, i b 30-45 pht.
Hn ch ung ru bia.
Khng ht thuc l.
Hn ch n ung cc cht bo, c bit l m ng vt.
Hn ch n mn.
Hn ch thc n c ng, giu nng lng.
C ch lm vic, ngh ngi hp l.
Thng xuyn kim tra huyt p. Mi ngi cn nh s o huyt p nh nh s tui ca
mnh.
Duy tr cn nng hp l, khng tha cn (BMI 18,5 - 23).
Khi no th chn on l h huyt p?
H huyt p (huyt p thp) c chn on khi huyt p tm thu di 90 mmHg hoc gim
25 mmHg so vi bnh thng.
Huyt p thp thc cht khng phi l mt bnh, m l mt triu chng gp trong mt s
bnh nhng cng c th gp ngi bnh thng.
Huyt p thp thng l do ri lon chc nng ca v no ca trung khu thn kinh vn
mch.
Nguyn nhn hay gp:
Do cu to c th: C nhng ngi thng xuyn c huyt p thp nhng khng tr ngi
g trong sinh hot, loi ny khng c triu chng g tr trng hp b ngt.

100
- Do cc bnh tim mch.
Tnh trng sc do bt c nguyn nhn g v d nh mt mu v chn thng, nn lim tc,
a chy nhiu lm mt nc...
Suy tuyn thng thn...
Cc bnh nhim khun ko di hoc nhim khun cp tnh
Cc bnh gy suy mn cho c th.
C ba loi huyt p thp sau:
H huyt p kch pht: Ngi bnh trong tnh trng sc do cc nguyn nhn k trn,
chn tay thng lnh, thn nhit h, tim p yu, huyt p t nhin xung thp thm ch
khng o c.
H huyt p ko di: ngi bnh lun cm thy mt mi, d ngt, nht l khi lao ng chn
tay, tinh thn khng minh mn. Thng gp trong cc bnh suy tim, hp vanng mch ch,
suy tuyn thngthn, lao, x gan...
H huyt p t th ng: Ngi mc chng ny thng ang nm m ng dy t ngt
th huyt p h xung thp lm cho ngi bnh lim i, c khi ngt, dng thi tim p nhanh.
Tt c cc triu chng qua i nu bnh nhn li nm xung. Ngi ta cho rng, do t mu
cc tng, chi di, ng thi c ri lon thn kinh giao cm lm mt kh nng co mch nn
huyt p h khi ngi bnh ng. C th gp nhng bnh ny nhngngi ct on thn
kinh giao cm tht lng, nnhng ngi gin tnh mch chi di qu mc, ngi c thai,
ngi thiu mu, nhc c...
5.1. Cc yu t quyt nh ti huyt p c th ngi
V c quan ca c th: tim, thn
V h thn kinh: B phn iu phi vn mch huyt p (TKTW).
H thn kinh thc vt
B phn nhn cm p
V mch: ng mch ch
ng mch ch vng
Cc mao mch vng ngoi vi: cc ng dn mu t tim ra: ng mch, tnh mch.
V mu: nht ca mu: long, c. Khi mu long hng cu trong mu gim,
nht ca mu gim. Khi mu c, ngc li

101
V cc cht trung gian:
Cc cht chuyn ti, nron thn kinh, adrenergic, cc th th
Cc cht trung gian ha hc: A, NA, D
H cc enzim, renin angiotensin
Hocmon chng bi tr nc tiu
Thng bng mui v dch th
Huyt p tng c chia thnh hai loi:
Tng huyt p th pht: khi huyt p tng ch l mt triu chng ca nhng tn thng
mt trong cc c quan nh: thn, ni tit, tim, mch, no iu tr nguyn nhn, huyt p
s tr li bnh thng.
Tng huyt p nguyn pht: khi nguyn nhn cha r, lc c gi l bnh tng huyt p.
iu tr kh.
Tt c cc thuc cha bnh cao huyt p u l thuc cha triu chng ch khng cha c
nguyn nhn.
C ch ca bnh tng huyt p: C ch bnh sinh ca tng huyt p rt phc tp, nhn chung
huyt p ph thuc vo 2 yu t chnh: - Cung lng tim
Sc cn ngoi vi
Tng huyt p xy ra khi c tng cung lng tim hoc tng sc cn ngoi vi, hoc tng c
hai yu t . Cc nghin cu c bn cho ti nay u cho thy hai yu t ny ph thuc vo
hng lot cc yu t khc: H TKTW, h TKTV, ty, thng thn, hocmon, cc ion Natri v
Canxi cng vi h Remin Angiotensin trong vic iu ha huyt p.
Cc nhm thuc cha tng huyt p:
Nhm tc dng ln trung ng: tc dng ln hnh no, ty, c quan iu ha huyt p.
Nhm tc dng thng qua h TKTV: tc dng ln receptor , ca tim, thn,mch mu.
Nhm tc dng lm gin mch: tc dng ln adrenalin 1, 2.
Nhm c ch h rennin angiotensin: iu ha rennin, gi li cc ion tng HA sau
o thi h HA.
H cc cht c tc dng ti cc v tr khc: gy gin mch
5.2. Thuc cha tng HA l nhng cht tc dng ln TKTW

102
Nhm thuc tc ng ln h thn kinh trung ng: Gm c Reserpin, Methyldopa,
Clonidin... C ch ca thuc l hot ha mt s t bo thn kinh gy h huyt p. Hin nay t
dng do tc dng ph gy trm cm, khi ngng thuc t ngt s lm tng vt huyt p.
Hai th th tip nhn adrenalin l th th , :
- c 1 v 2. 1 c tc dng co mch cn 2 l ch th tin sinap iu ha HA.
- c 1 v 2. 1 ch th tim cn 2 l ch th mch.
Cc cht ch vn trn : c tc dng h HA ln 1, 2 hay c 1 v 2.
v

N
clonidine (5-1)
CHCH2NHCH3 R N

X guanfacine (5-4)
OH NH2
xylazine (5-8)
phenylephrine R = CH2 = CHCH2, X = S
talipexole
OCH3
R = CH2CH3, X = O
Guanabenz (5-3)
H H2 OH
CH C C NH2 Br N
H
N N CH CHNHR2
OH CH3
N
R1
H
OCH3 N HO

methoxamine OH
brimonidine
R1 = R2 = H
Noradrenaline
N(CH3)2
R1 = H, R2 = CH3
N adrenaline

OCH2 R1 = CH3, R2 = H
HO -metyl-noradrenaline
cirazoline N
H HO

Loi tc dng trn c 1 v 2 c hu sinap c tc dng iu ha lu lng tim, hin

ang c s dng nhiu
Cc cht i khng :

103
 v

parazosine (5-35) phentolamine (5-32)

labetalol (5-45) N tolazoline (5-31)
H3CO
O
phenoxybenzamine (5-34)
O CH2NH(CH2)2O N
H
O
H3CO indazoxane (5-32)
O

N
N
COOCH3
N
N
H H3COOC
johimbine
H OH
OH
corynanthine
N OH

H COOCH3

rauwolscine
* Cc th th tin xinap phn ln thuc loi th th 2.
Cc th th hu xinap th thuc loi va l th th 1 va c th th 2. Cc th th ny
trong cc c quan khc nhau th c vai tr khc nhau:
- 2: tin sinap iu ha HA
- 1, 2: hu sinap trong c trn thnh mch iu ha trng lc (1 co mch nhanh, khng
ph thuc vo ion canxi; 2 ch co mch khi c dng ion canxi vn chuyn vo t bo).
Cc hot cht c tc dng h HA tn cng ti TKTW quan trng nht v hin ang c s
dng nhiu nht trong iu tr.
Bng 5.1. Cc hot cht quan trng h HA thuc loi tn cng vo TKTW
tn S dng, cc tc dng ph
Clonidine Trc ht l dng cho cc trng hp tng trng lc mc trm trng
(5-1) loi nh v trung bnh, i khi dng iu tr nhc na u, gim nhn p.
Tc dng ph l an thn v trm cm, c ch bi tit, gy tng glucoz-mu,
ng g, tm ti. Cc cht chng trm cm c th chn ng c tc dng h

104
 HA. Dng thuc t ngt c th gy nn s tng HA mt cch t ngt
Liu lng: ngy u ung 1 vin 0,1 mg, liu duy tr 2-4 vin.
Methyldopa S dng trong cc trng hp tng trng lc mc trm trng loi nh v
(5-2) trung bnh cn tng trng lc mc trm trng loi nng th kt hp vi
cc thuc khc (v d guanethidine). Tc dng ph: an thn gy nn s tn
hi cho gan, i khi gy nn bt lc.
Guanabenz Dng trong tng trng lc mc trm trng loi nh v trung bnh. Tc
(5-3) dng ph: kh ming, an thn.
Guanfacine Dng trong tng trng lc tt c cc dng, trong trng lc mc trm
(5-4) trng nng th dng kt hp.

Cng thc cu to cc cht h HA tn cng vo TKTW

105
 Cl
CH3
H
N
H2
HO C C COOH
N

N NH2
H
Cl HO
5-2
5-1 methyldopa
clonidine
Cl
Cl

NH
CH2CO NH C NH2
C N NH C
H
NH2 NH
Cl 5-4
Cl guanfacine
5-3
guanabenz
N
H2 H
C N

N N
H
X2 N
5-5 H
X1
5-6, X1 = 2-Cl, X2 = 4-CH3
CH3
HN 5-7, X1 = 2 - CH3, X2 = 5 - F

N
S OH

CH3 5-8 HO CH CH NH2

Cl
CH3

N HO 5-10
H
-methyl-noradrenaline
O C

N
CH3 H
Cl 5-9

Lin quan n cu trc v tc dng:

Clonidine:
Trong clonidine thay phenyl bng d vng nn tc dng km hn
Thay d vng 5 cnh bng d vng khc khng c tc dng tt hn.
Methydopa: R = OH v X = H

106
 H2C X
H2
HO C C COOH

NH2
R
R = OCH3, OCH2CH3, CH2OH
X = OH, F

Tc dng ca cc hp cht ny khng at ti cng tc dng nh methyldopa.

Tng hp mt s hp cht:
Clonidine (5-1)
Cl Cl

N N
H
NH2 + H3CS N

N N
H H
Cl 5-12 Cl
5-11 5-1
clonidine

X1
axyl ha X1 Cl
1) HCOOH/Ac2O
NH2 N C
2) SOCl2/SO2Cl2
X2 X2 Cl
cloro ha
H2 H2
H2N C C NH2

X1 N
H
N

X2 N
H

Methyldopa (5-2):

107
 vanilin
CH3
H2
H3CO CH2COCH3 C C CN
H3CO

KCN/NH4Cl 1) tch dng phn

NH2
pu stracker 2) Thuy phn H2O/HCl
HO HO
3) HBr (-CH3)
5-13

H3C
H2
HO C C COOH

H2N

HO
5-2
methyldopa - P L

H3CO CHO
H3CO CH2Br H3CO CH2CN
H2/Pd NaCN
HBr
HO
HO HO

CH3MgBr

H2
C C CH3 H2
H3CO
H3CO C C CH3

O H2O/H NMgBr

HO
HO

Tng hp Guanabenz (5-3):

108
 Cl Cl

H H
CHO + H2N N C NH2 C N N C NH2
H

NH NH
Cl Cl

CH3 CH3
CH3 CH3

Cl Cl Cl Cl

HNO3 Cl2/Fe [H]

NO2 NH2
NO2

HNO2/HCl

CHO CH3 CH3

Cl Cl Cl Cl
Cl Cl
HPO3/t0
KMnO4
N2 + HCl +

N2Cl N2Cl

Tng hp guanfacine (5-4):

CH3
Cl Cl
H2N C NH2

NH CH2CONH C NH2
CH2COOCH3
NH
Cl
5-4
Cl
guanfacine

5.3. Thuc h HA tc dng thng qua h thn kinh thc vt

Cc thuc h HA tc dng thng qua h thn kinh thc vt ty theo v tr v tnh cht tc
dng ca chng c th phn thnh nm nhm nh sau:
5.3.1. Cc cht i khng - adrenoceptor
Th th c th th 1 (tim) v 2 (phi, h mch).
Cc thuc i khng c tc dng cha au tht ngc, chng lon nhp cn tc dng h HA
mi c pht hin ra sau ny v c ch nh ch yu.

109
S to ra tc dng h HA ca chng c vai tr ca nhiu yu t:
- c ch s iu chnh HA trung ng.
- Gim cng sut ca tim (do s c ch ca th th ).
- Ngn chn s gii phng rennin bng vic phong ta cc th th (-receptor) c trong
thn.
- Chi phi ti th th cm p (baroreceptor)
- Gim trng lc giao cm (c kh nng l tc dng thng qua tin sinap)
- Tng cng s nhy cm ca h thng mch, ngc vi cc cht gin mch ni sinh.
Cch s dng ca cc cht phong ta : cc cht phong ta ngoi vic s dng iu tr
bnh au tht ngc, chng lon nhp v cc bnh cao huyt p trn cc loi ng vt cn
c s dng iu tr cc loi bnh khc nh nhc na u, u tuyn thng thn, ri lon
pht trin tim, rung tim.
Cc thuc quan trng thng c s dng trong iu tr c tng kt li trong bng 5.2,
cng thc cu to trong bng 5.3.
Bng 5.2. Nhng c trng dc l v s dng ca cc cht phong b -receptor quan trng
Tn Hiu lc T1/2 S dng
Ly propranolol = 1 trong huyt
tng
a) cc cht phong b khng chn lc ( 1 + 2)
Aprenolol (5-15) 0,3 6 Triu chng ri lon tun hon
tim, au tht ngc, tng trng
lc.
Bunolol (5-16) 50 2-3
Nadolol (5-17) 0,5 14-18 Tng trng lc (ngy mt ln),
au tht ngc.
Oxprenolol (5-18) 0,5-1 1-2 Ri lon tun hon ngun gc thn
kinh giao cm, lon nhp do dng
qu liu digitalis tr tim
Penbutolol (5-19) 5-10 26

110
Pindolol (5-20) 5-10 3-4 Tng trng lc, bnh mch vnh
sau nhi mu c tim, lon nhp
Propranolol (5-21) 1 3-5 Tng trng lc, au tht ngc,
rung tim, nhc na u
Sotalol (5-22) 0,3 5-12 Tng trng lc, tng vn ng
au tht ngc, nhp tim nhanh
Timolol (5-23) 5-10 4 Tng trng lc (thin u thng)
ngn chn ngng tim v ti nhi
mu c tim.
Cloranolol (5-24) 5-10 4 Tng trng lc, lon nhp.
b) Cc cht phong b chn lc ( 1)
Acebutolol (5-25) 0,3 3 Tng trng lc, tng vn ng,
triu chng tim.
Atenolol (5-26) 1 6-8 Tng trng lc, khng gy nn
gim glucose huyt, nhp tim
nhanh, ri lon nhp.
Celiprolol (5-27) 1 4-5 Tng trng lc, au tht ngc
(gin ph qun).
Metoprolol (5-28) 0,5-2 3-4 Tng trng lc, au tht ngc,
sau nhi mu c tim.
Practolol (5-29) 0,3 5-10 Cc bnh mch vnh
Tolamolol (5-30) 0,3-1 3-6 b nh ch s dng v gy m
mt.
Cu trc chung:
OH
H2
Ar O C C CH2NH R
H

Lin quan n cu trc v tc dng: v mt ha hc, cc cht phong ta (chn

hay c ch ) c bn ng nht hn cht phong ta . Cc cht hin dng trong iu tr i
b phn l cu trc ca 1-amino-3-(aryloxi)-2-propanol.

111
Ar OCH2CH CH2NHR Ar CHCH2 NHR

OH OH
aryloxi-propanol amin aryl etanol amin

Ar: aryl hoc d vng thm

R: iso-propyl hoc tert-butyl
H
H
HO O HO C2
C2 C3H2 C4 RHN
C1 H R
RHN C H R
C5
H
H

II
I
H
R
H
HO HO C2 O R
O C C C
C2 C3H2 N RHN H2
R
C1 H
RHN C H
O
H
H
III IV
R = ankyl R = aryl, ankyl

Hnh 5.4. S so snh cu hnh cc nhm hp cht khc nhau c tc dng phong ta
receptor.
Cu trc III v IV cng tng t nh cu trc I v II. Do cc cht phong ta khng cn
thit phi c aryl m c th l mch thng nhng thc t cha tm c cht no c tc dng
ny.
Cu hnh S c tc dng mnh hn cu hnh R.
Tng hp cc cht I:
* Vi cc dn xut phenol

112
 O
H2
OH O C CH CH2
O
H2
Cl C CH CH2
X X
[OH]
R NH2

H2 H
O C C CH2NHR

OH
X

* Vi cc dn xut d vng thm th xut pht t halogenua aryl:

R CN HO R CN

1) Na/DMF
+ O NR'
2) H2O/H
N N O
Cl H Ph NHR'

OH
DMF: dimetyl formamide.
* Tng hp cc ng phn lp th:

113
 HO N R'
H
HO

O
C C6H5
H
H OH CH3
H
R S
TsO
+ + TsO
N CH3
O NR'
O

(B)
(A) Ph

1) Na/DMF

2) H2O/H
H
H CH3
O O
OH

OH N CH3
O

1) TsCl/piridin (ho?t ha) X Ph

1) TsCl/piridin
2) NaOMe (t?o oxit)
2) NaOMe
3) R'NH2
3) R'NH2
2R - I 2S-I

* Tng hp cc dn xut aryl-(etanol-amin) II:

114
 H H2 HR
O C C N
C CH3
1) Br2 R2 OH
R2 2) Kh? ha (NaBH4)
3) RNH2
R1 II
R1
2) RNH2

1) NaBH4

H2 O
R2 + Cl2 C C Cl

R1

5.3.2. Cc cht c tc dng i khng -adrenoceptor

Cc cht c tc dng i khng -receptor quan trng nht v mt iu tr.
Bng 5.3. Mt s cht i khng -receptor quan trng trong iu tr
Tn Cng thc cu to S dng
Tolazodine (5-31) N Cc bnh v mch
H2
C
ngoi vi
N
H

Phentolamine (5-32) iu tr u t bo crom

N
(u tuyn thng thn)
HO H2
N C trc phu thut
N
H

H3C

Phenoxybenzamine H2
Cc bnh v mch
(H3C)HC C O
(5-34) Cl
H2
C
H2
C N
ngoi vi, trng hp
H2 C b t cng (tng c
bp giao cm)

115
Prazosin (5-35) Tng trng lc nh
N N CO
N v trung bnh
O

NH2

Lin quan n cu trc v tc dng:

a) Cc cht tng t phenoxybenzamine (5-34)
hp cht c tc dng phong ta th cu trc ca chng cn phi c cc yu cu
sau:
- Ti thiu phi cha mt nhm halogeno - etyl
- Cn phi cha nito l amin bc ba hoc mui bc 4 ca n
- Cn phi c mt ca nhn thm.
b) Cc cht tng t prazosin (5-35)
Trong hng trm cht l dn xut quinazolin ngi ta chn lc c prazosin.
Trong qu tnh chn lc , ngi ta rt ra c nhng kt lun quan trng lin quan n
cu trc v tc dng nh sau:
- Thng thng cc hp cht cha nhm ng cu in t sinh hc v tr th hai
ca piperazin u c hot tnh.
- Cc nhm metoxi trong nhn thm c thay th bng ankoxi khc hoc hidroxi
th hp cht iu ch ra c tc dng b gim i mt cch ng k.
- Trong s cc dn xut ca prazoxin th trimazosin (5-36), tiodazosin (5-37) v
doxazosin (5-38) c tc dng i khng trn -receptor chn lc hn prazosin.
- Phn cu trc amidin ca prazosin thay bng sunfoximin cng nhn c hp cht
c tc dng tng t.

116
 1
H3CO 2 N N CO
N
O

N3
H3CO 5 4
NH2

O
H3CO N N N C OCH2 C(CH3)2

OH
N
H3CO N N N CO
H3CO O SCH3
NH2
N
5-36 H3CO
5-37
trimazosin NH2 tiodazosin

O O
H3CO N N N C

O N N N CO
N
H3CO O
5-38
NH2 doxxazosin N
S
5-39
O CH3

Tng hp:
* Tolazoline (5-31):
CH2 Cl CH2CN

NH N
CH3OH/H H2 NH2(CH2)2NH2 H2
NaCN C C
HCl kh
OCH3 N
H
5-41 5-32
5-40 tolazolin
phenyl axetonitrin
CH3

* Phentolamine (5-32):

117
 N
H2
Cl C N
HO H2
N N C
H
N
HO H
N H
5-32
phentolamine
H3C

H3C CH2O/HCN
HO NH2(CH2)2NH2
N CH2CN

H3C

* Phenoxybenzamine (5-34):
OH OCH2CH CH3 OCH2CH NH CH2CH2OH
ClCH2CH(OH)CH3 1) SOCl2
OH CH3
NaOH/t0
5-42 2) NH2(CH2)2OH

1) PhCH2 Cl

2) SOCl2

H2C CH2Cl
H
OCH2 C N
H2C
H3C

5-34
phenoxybenzamine

* Prazosin (5-35)

118
 R 1) HNO3 R NO2
(CH3)2SO4/OH 2) Oxi ha
vanilin
or CH3I/OH 3) Amit ha
R CHO R CONH2

1) Kh? ha

2) (NH2)2CO or COCl2
R Cl H
N 1) POCl3 R O
N

2) NH3 (1:1)
N
NH
R
R

NH2
1) Piperazin 5-44 O

HN NH

2) Axyl ha

O
R N N C
N
O

N
R
5-35
NH2 prazosin

5.3.3. Cc cht i khng c trn v -adrenoceptor

t vn : Cc cht c ch khng chn lc trn -receptor ngoi bin c mt tc
dng ph kh chu l lm nhp tim nhanh. Vi vic s dng ng thi cc cht c tc
dng c ch c th chi phi mt cch c hiu qu ti tn s ca tim, c th duy tr c
gi tr sinh l bnh thng. Trn c s hiu bit ny, ngi ta c gng iu ch ra nhng hp
cht m trong phn t ca n mang tnh cht phong ta c ln ( lm nhanh cn lm
chm, hai yu t ny b tr cho nhau.
Labetalol c c tc dng phong ta c ln .
Cc thuc ang s dng:
* Labetalol:

119
 H2 H
HO CH C N CH CH2CH2

OH CH3
H2NOC 5-45
labetalol

Trong labetalol c hai nguyn t C* nn c 4 ng phn quan hc i quang nhau, s dng

thuc dng hn hp ca 4 ng phn. Labetalol c tc dng phong ta c ln c
dng iu tr tng trng lc u t bo.
O

H3C
N

O N
HN (CH2)3N N

CH3
5-46
urapidil H3CO

Urapidil phong ta 1 v 1, c tc dng ti TKTW, kch thch nh 2-receptor.

Tng hp mt s hp cht:

COOH CONH2 H3COC CONH2

NH4OH CH3COCl
FeCl3
OH OH OH

Br2/AS

BrH2COC CONH2
H2 H 1) Kh? ha
HO CH C N CH CH2CH2
2)H2N CH (CH2)2Ph
OH CH3 OH
H2NOC 5-45 CH3
labetalol

120
 N

N N

usotrophin - hecxametylen tetraamin

Cc cch hnh thnh lin kt C-N:

C Cl H2N

C N
Kh? ha
NH2 O C

Cch khc iu ch 5-45:

H2 NaOEt H Ki?m -axit long
H3C C C COOEt H3C C C COOEt
PhCH2Br H2
H3C C C CH2Ph
O O CH2Ph

BrH2COC CONH2 H2 N H2COC CONH2

usotrophin

OH OH 5-45

H2 H
HO CH C N CH CH2CH2

OH CH3
H2NOC 5-45
labetalol

5.3.4. Cc cht phong ta thn kinh adrenegic

Cc thuc thuc nhm tc dng ny gm cc hp cht c tc dng h HA trn c s ngn
chn s gii phng noradrenaline t cc tin hch thn kinh giao cm.
Cc thuc c tc dng phong ta thn kinh adrenegic:

121
 CH3 Br
CH3
H2
O CH2CH2 N(CH3)3X C N C2H5 O3S C6H4CH3

CH3
5-47
CH3 xiclo polin 5-48
bretylinm tosylate

N CH2CH2 NH C NH2 N C NH2

5-49 O NH
guanethidine
5-50
dipriroquin
Cl
H2 H
O C N C NH2
H
OCH2CH2NH N C NH2
NH

5-51 NH 5-52
O
guancolin guanxan
Cl

H2 H NH
C N C NH2
O

NH
CH2NH C NH2
5-53
O guanadrol 5-54
guanozidine NH

H
N OCH3

N H OCO OCH3
H3CO H
H

H3COOC OCH3 OCH3

5-55
reserpine

* Tng hp guanethidine (5-49):

122
 O
H2SO4
O + H2NOH NOH
CV NH

RCOOOH Lactam

O
LiAlH4
Lacton

CH2CH2NH C NH2 NH
CH2CH2NH2
H3CS
N N
NH NH2 1) ClCH2CN
5-49 2) Kh? ha NH
guanethidine

* Tng hp bretylinm tosylate 5-48:

CH3 CH2Cl Br
H2
Br Br C N CH3

Cl2/AS (CH3)2NH CH3 C2H5 Cl

C2H5 Cl
C2H5 OHl Br
Br
H2
H2 C N CH3
C N CH3
H3C SO2Cl
NaHCO3
CH3
CH3

Br
CH3
H2
C N C2H5 O3S C6H4CH3

CH3
5-48
bretylinm tosylate
5.3.5. Cc hp cht phong b hch
Cc thuc c tc dng ny gm cc cht ngn cn tc dng ca acetylcholine trn t bo thn
kinh hu hch.

123
Cc hp cht c tc dng h HA trn c s ngn cn hch gm c trimethaphan (5-56),
mecamylamine (5-57), pempidine (5-58).

H2
C CH3 CH3
N
H3C CH3
CH3 N
CH3
S N CH3
H3C
H2C HN CH3

5-57 5-58
5-56 mecamylamine pempidine
trimethaphan
* Trimethaphan (5-56) l sn phm trung gian ca qu trnh tng hp biotin, c
iu ch ra vo nhng nm ca thp k nm mi. N cng c s dng xa l cc
trng hp nguy kch tng trng lc v tng phn x t ng.
* Mecamylamine (5-57) c iu ch ra vo nm 1955, i t campho vi phn ng
Ritter thu c dn xut N-formyl, sau kh amit vi LiAlH4 thu c amin 5-57.
CH3 CH3 CH3

CH3 HCN/H2SO4 CH3 LiAlH4 CH3

PW Rilter CH3 CH3

CH2
HN CHO HN CH3
5-57
mecamylamine

124
 CH3
CH3
O C
CH3
H2
CH3 CH3 C
HCl H2N CH3
O C OH
O C
OH
CH3 CH3
H2 C
O C CH3
CH3 CH3
CH3
CH3
H3C CH3 CH3
N
Kh?
O N CH3
H3C CH3
CH3

5-58 CH3
pempidine
5.4. Cc thuc gin mch
Ngy nay, cc thuc gin mch ng vait tr quan trng trong vic iu tr cc dng khc
nhau ca bnh tng trng lc, thiu nng tim (suy tim) cng nh nhiu bnh v tim mch.
Theo ngha m rng, thuc gin mch ngoi cc cht tc dng gin mch trc tip th cng
cn lit k vo y cc cht i khng canxi, cc cht phong b -adrenoceptor tin sinap,
cc cht ch vn trn 2- adrenoceptor v cc cht i khng ca h renin-angiotensin.
Cc hot cht quan trng nht v mt iu tr gin mch c tng kt bng sau
Bng 5.4. Mt s thuc gin mch quan trng ang c s dng ph bin trong iu tr
Tn Cng thc Phm vi s dng
HN NH2
Hydralazine (5- Dng iu tr tng trng lc di hn
59) (thng phi hp vi thuc phong ta .
N

N
Tng trng lc phi s cp.

Dihydralazine (5- HN NH2 Ging nh trn

60)
N

HN NH2

125
Minoxidil (5-61) N NH2 Tng trng lc trung bnh v trm trng,
N
bnh thn km theo tng trng lc.
N
Tc dng ph: mc tc, mc ru. Sau ny
O

H2N
dng lm thuc mc tc cho ngi hi.
N CH3
Diazoxide (5-62) Tng trng lc nguy kch, tng insulin
huyt
NH
Cl S
O O

Odium Na2[Fe(CN)5NO] Tng trng lc nguy kch, gim chy

nitropussid (5-63) mu ti mc ti thiu khi phu thut.
B tr trong trng hp thiu nng tim
cp tnh
Cc dn xut ca piridazin 5-66, 5-67, 5-68 c tc dng h huyt p mnh hn hydralazine
cn budralazine (5-64) v endralazine (5-65) th c nhiu u im hn v t gy tc dng lm
nhanh nhp tim. Ring 5-69 th ngi ta tht rng tc dng h HA mnh hn v t c tnh
hn hydralazine.

126
 CH3
HN N C
H
C6H5OC N NH2
C C(CH3)2
H N
N
N
N N
5-65
endralazine
HN NH2
HN N C CH3
5-64
budralazine
CH2COOCH(CH3)2
N
HN NHR
N

N 5-66: R = H, X = N(CH2)2OH

5-67: R = H, X = N(CH3)CH2CH(CH3)OH N
N
5-68: R = COOC2H5, X = N(CH3)CH2CH(CH3)OH
5-69
X O
* Tng hp hydralazine (5-59): c tc dng trc tip lm gim c tim, thnh mch. C
th l di kch thch cc paraceptor -drenegic lm tng nhp tim do c ch phn x.
O Cl

COOH
NH NH
hydrazin.H2O POCl3

N N
CHO
HN NH2
hydrazin.H2O

NH

127
 O Cl

COOH
NH NH
hydrazin.H2O POCl3

NH N
COOH

O hydrazin.H2O Cl
HN NH2

NH

HN NH2

O Cl

COOH
NH NH
hydrazin.H2O POCl3

NH N
COOH

O Cl

hydrazin.H2O
CH3
HN N C
HN NH2
C C(CH3)2
H
N CH3
NH
O C CH3
N
HC C N

CH3
HN NH2
HN NH2
5-64
budralazine

Cc dn xut ca minoxidil (5-61):

R =
R N N NH2
N N NH2

N O
O

O NH2
5-61
minoxidil NH2 O
S

128
5-61 ngoi tc dng gin mch th thuc ny cn c tc dng gy mc lng (bt li cho ph
n) nn cn c dng trong iu tr hi u.
Tng hp minoxidil (5-61):
O HO Cl

C OC2H5 H2N N N
POCl3
H2C NH2 NH2
C NH

C N N N
H2N

H2N H2N

1) mCPBA

2) piperidin

NH2

H2N O
meta-Chloroperoxybenzoic acid 5-61
minoxidil

Diazoxide (5-62) c tc dng lm gin c trn thnh mch theo c ch cha r, c th l do

tng tc vi Ca2+.
Tng hp diazoxide:
Cch 1:

129
 NO2
NO2
HNO3
PhCH2SH
HO
Cl Cl Cl Cl
Cl SCH2Ph

1) Cl2/H2O, H

2) NH3
O O
NH2 NO2
S
NH CH C(OC H ) kh? ha
3 2 5 3

N CH3 Cl SO2NH2 SO2NH2

Cl Cl
5-62
diazoxide
Cch 2:
NH2 NHAc NHAc

Cl
O O 1) HSO3Cl
NH2
S
NH CH C(OC H )
3 2 5 3 2) NH4OH

N CH3 Cl SO2NH2
Cl
5-62
diazoxide

130
 NHAc NHAc NHAc
NH2
Cl Cl

Cl2/Fe

NO2 NO2

H2 O

NH2

Cl Cl Cl Cl
Cl Cl Cl
Cl

Diazo ha [H] Diazo ha

HPO3, t0 HPO3, t0

NO2 NO2
NH2

Cc cht c tc dng h huyt p loi gin mch xut hin thi gian sau ny phi k n
pinacidil (5-73) v levcromakalin (5-74).
O CH3

CH3

H
NH C NH C C(CH3)3 NC OH

N CN CH3 N O

5-73
pinacidil
5-74
levcromakalim
Tng hp pinacidil (5-73):

131
 NH2 HN C NHR N C NR

S
-H2S
COCl2 H2N CN

N N N
H2N CN

DCC H
NH C NH C C(CH3)3

H N CN CH3
R: C C(CH3)3
5-73
CH3
pinacidil

5.5. Cc cht c ch h Renin- angiotensin

5.5.1. Vai tr ca h renin-angiotensin
H renin-angiotensin (vit tt ting Anh l RAS) hay cn gi l H renin-angiotensin-
aldosterone (vit tt ting Anh l RAAS) l mt h thng cc hormon lm nhim v iu ha
cn bng huyt p v (dch ngoi bo) trong c th ngi.
Khi th tch mu trong c th ngi h thp khin huyt p gim, thn s bi tit mt men c
tn l renin. Renin l enzyme protease xc tc chuyn angiotensinogen thnh angiotensin I,
sau men chuyn ACE (angiotensin converting enzym) bin angiotensin I thnh
angiotensin II.
Angiotensin I l 1 decapeptid (chui 10 peptid), angiotensin II l octapeptid (chui 8 acid
amin) v angiotensin III l heptapeptid (chui 7 acid amin). Heptapeptid gip tng tit
aldosterone l mt khong-cocticoit (mineralocorticoid) iu ha chuyn ha natri (sodium)
v kali (potassium). iu s dn ti vic tng lng nc trong c th, phc hi huyt p.
Nu h renin-angiotensin-aldosterone lun tnh trng hot ng th huyt p s ln qu
cao. Ngi ta bo ch ra nhiu loi thuc tc ng ln cc bc khc nhau trong h ny
lm gim huyt p. Nhng thuc thuc loi trn l mt trong nhng phng php c
dng iu tr chng cao huyt p trong cc bnh suy thn, suy tim, v cc bin chng ca
bnh tiu ng.
H thng ny c th c hot ha khi c s gim thiu th tch mu hay st gim huyt p
(nh trong xut huyt).

132
1) Nu lu lng nc qua cc t bo cn tiu cu nm trong phc hp cn tiu cu thn
gim xung, sau cc t bo cn tiu cu gii phng enzyme renin.
2) Renin s tc ng ln mt protein trong huyt tng l angiotensinogen vn ang dang
bt hot bng cch ct mt on zymogen, chuyn n thnh angiotensin I.
3) Angiotensin I sau c chuyn i thnh angiotensin II bi enzyme chuyn i
angiotensin (vit tt ting Anh l ACE)[4] c tm thy ch yu mao mch phi.
4) Angiotensin II l cht c tc dng sinh hc cao ca h renin-angiotensin, s gn ln cc
th th nm trn mng t bo ni m mao mch, lm cho cc t bo ny co tht v mch mu
quanh chng dn n s gii phng aldosterone t vng cung thng thn v. Angiotensin
II hot ng nh l hormon ni tit, t tit, cn tit, v kch thch t ni bo.
Tng hp sinh hc ca angiotensin theo 2 ng khc nhau: ng c in bit t lu gm
renin v men chuyn ACE, v mt ng khc mi bit sau ny gm nhng enzym khc,
men chymase gi vai tr nh men chuyn v nhng enzym khc bin trc tip
angiotensinogen thnh engiotensin II.
Angiotensinogen l 1 glycoprotein trng lng phn t t 50 000 n 100 000, do gan tng
hp v phng thch trong huyt tng v gn vo glbulin. iu s dn ti vic tng lng
nc trong c th, phc hi huyt p.
Cc cht c ch h renin-angiotensin c chia thnh hai nhm:
- Cht i khng angiotensin II
- Cht c ch enzin chuyn ha ACE
5.5.2. Cc cht i khng angiotensin II
Cht tiu biu nht l saralasin (5-75) mt cht i khng angiotensin II l mt
angiotensin II tng t. Cng thc phn t C42H65N13O10, phn t lng 912,06 c iu
ch nm 1972, l mt octapeptid, cc axit amin ni nhau theo th t:
Sar Arg Val Tyr Val His Pro Ala

133
 Khc vi cc octapeptit khc, saralasin c tc dng i khng th th t cu trc ca
cc axit amin phi l Alanin v tr th nht v Sarcosin v tr th 8, s c mt ca
sarcosin trong phn t khng ch lm chm s phn hy h cn lm tng hot tnh th th
ca hp cht.
Losartan l mt cht i khng angiotensin II receptor loi thuc s dng ch yu iu
tr huyt p cao (tng huyt p) . Losartan l cc cht i khng th th angiotensin II u
tin c bn trn th trng.

5.5.3. Cc thuc c ch enzim chuyn ha angiotensin

C ch ca thuc l c ch mt enzym c tn l men chuyn angiotensin (angiotensin
converting enzym, vit tt ACE) bng cch gn ion km (Zn) ca men chuyn vo cc gc
ca c ch men chuyn. Nh men chuyn angiotensin xc tc m cht sinh hc angiotensin I
bin thnh angiotensin II v chnh cht ny gy co tht mch lm THA. Nu men chuyn
ACE b thuc c ch (lm cho khng hot ng) s khng sinh ra angiotensin II, gy ra hin
tng gin mch v lm h huyt p. Thuc hu hiu trong 60% trng hp khi dng n

134
c (tc khng kt hp vi thuc khc). L thuc c chn khi bnh nhn b km hen
suyn (chng ch nh vi chn beta), i tho ng (li tiu, chn beta).
Nhiu cng trnh nghin cu chng minh c tc dng c li ca nhm thuc c ch men
chuyn angiotensin (ABCD trial; CAPPP; FACET): gim nhi mu c tim 63%, gim t
vong do mi nguyn nhn 62%. Thuc cn c u im khng gy ri lon m mu, ng
mu, acid uric khi dng ko di.
Gm c captopril, enalapril, benazepril, lisinopril, perindopril, quinepril, tradola-pril...
Lin quan n cu trc v tc dng: L dn xut ca L-proline + amino propanoic
Proline (vit tt l Pro hay P) l mt - amino acid, cc ng phn L ph bin hn S.

H
H3CH2COOC H3C H
H3C H
C
H2CH2C N CO
HSH2C CO H
COOH
COOH N
N
5-77
enalapril H
H

5-76
capropril NH2

(H2C)3 H O COOH
H3CH2COOC H H
H C
HOOC H2C H H2CH2C N
H N
C
H2CH2C N CO N
H 5-79
COOH cilazapril
N
5-78
lisinopril H

135
 HH C
H3CH2COOC 3 H
H C C
HOOC H3C H
H3CH2CH2C N
C C H CO
H
H2CH2C N CO
H
N COOH
COOH
N
5-80
enalaprilat H H

H
5-81
H3CH2COOC H3C H perindopril
C C
H2CH2C N CO
H
COOH
N

H
H3C H
H
H2C
C
5-82 H3CCOSH2C CO C
quinapril
CONH COOH
N

H
HH C
H3CH2COOC 3 H
5-83
C C alacepril
H3C N OH
H CO
COCH2CH2 SH
N COOH
N COOH
H
H
H
5-85 S
pentopril 5-84
fentlapril

Tc dng bt li l ho khan dai dng 10- 20% v 1% b ph mch (l tc dng ph khin

nhiu ngi bnh b thuc khng tip tc dng). Nguyn do l v men chuyn ACE khng
ch xc tc bin angiotensin I thnh angiotensin II gy THA m cn c vai tr trong s phn
hy mt cht sinh hc khc c tn l bradykinin. Nu c ch men ACE, bradykinin khng
c phn hy mc cn thit s tha v gy nhiu tc dng, trong c ho khan. Thay v
c ch men ACE, hng nghin cu mi l tm ra cc thuc c tc dng ngn khng cho
angiotensin II gn vo th th ca n (angiotensin II receptors, type 1) nm mch mu,
tim, thn do s lm h huyt p.

136
Tng hp captopril 5-76:

137
CHNG 6. THUC TC DNG TI CC C QUAN TO MU V TI MU
6.1. Vai tr sinh hc ca mu
Mu l mt t chc di ng c to thnh t thnh phn hu hnh l cc t bo (hng cu,
bch cu, tiu cu) v huyt tng.
Chc nng chnh ca ca mu l cung cp cc cht nui dng v cu to cc t chc cng
nh loi b cc cht thi trong qu trnh chuyn ha ca c th nh kh carbonic v acid
lactic.
Mu cng l phng tin vn chuyn cc ca cc t bo (c t bo c chc nng bo v c
th ln t bo bnh l) v cc cht khc nhau (cc amino acid, lipid, hormone) gia cc t
chc v c quan trong c th. Cc ri lon v thnh phn cu to ca mu hay nh hng
n s tun hon bnh thng ca n c th dn n ri lon chc nng ca nhiu c quan
khc nhau.
Thnh phn cu to ca mu:
Thnh phn hu hnh chim n 40% th tch mu ton b. Huyt tng chim 60% th tch
cn li ca mu.
Cc thnh phn hu hnh gm:
Hng cu: chim khong 96%. ng vt c v, hng cu trng thnh mt nhn v
cc bo quan. Hng cu cha haemoglobin v c nhim v chnh l vn chuyn v phn
phi xy.
Bch cu: chim khong 3% l mt phn quan trng ca h min dch c nhim v
tiu dit cc tc nhn gy nhim trng v pht ng p ng min dch ca c th.
Tiu cu: chim khong 1%, chu trch nhim trong qu trnh ng mu. Tiu cu
tham gia rt sm vo vic hnh thnh nt tiu cu, bc khi u ca qu trnh hnh thnh
cc mu ng trong chn thng mch mu nh.
Huyt tng l dung dch cha n 96% nc, 4% l cc protein huyt tng v rt nhiu
cht khc vi mt lng nh, i khi ch dng vt. Cc thnh phn chnh ca huyt tng
gm:
Albumin
Cc yu t ng mu
Cc globulin min dch (immunoglobulin) hay khng th (antibody)

138
 Cc hormone
Cc protein khc
Cc cht in gii (ch yu l Natri v Clo, ngoi ra cn c can xi, kali, phosphate.
Cc cht thi khc ca c th.
Trong c th, di tc ng ca c tim, h thn kinh thc vt v cc hormone, mu lu
thng khng theo quy lut ca lc trng trng. V d no l c quan nm cao nht nhng
li nhn lng mu rt ln (nu tnh theo khi lng t chc no) so vi bn chn, c bit
l trong lc lao ng tr c.
Chc nng ca mu
H hp: Huyt sc t ly oxi t phi em cung cp cho t bo v vn chuyn kh CO2
t t bo ra phi thi ra ngoi.
Dinh dng: Mu vn chuyn cc cht dinh dng: Axt amin, axit bo, glucose t
nhng mao rut non n cc t bo v cc t chc trong c th.
Bi tit: Mu em cn b ca qu trnh chuyn ha n cc c quan bi tit.
iu ha hot ng ca c th: Mu cha cc hormon do cc tuyn ni tit tit ra c
tc dng iu ha trao i cht v cc hot ng khc.
iu ha thn nhit: Mu cha nhiu nc c t l nhit cao, c tc dng iu ha
nhit cc c quan trong c th.
Bo v c th: Trong mu c nhiu loi bch cu c kh nng thc bo, tiu dit vi
khun. Mu cha khng th v khng c t c tc dng bo v c th.
6.2. Cc cht c tc dng ti qu trnh to mu
Qu trnh to mu hay b thiu mu cng l qu trnh to hng cu hoc thiu hng
cu. Trong qu trnh ny th mui st, vitamin B12 v axit folic l nhng cht ng vai tr
sinh hc rt quan trng l nhng yu t khng th thiu trong qu trnh to mu.
6.2.1. Cc mui st
i sng ca ngi v ng vt khng th thiu c st v st gi hai chc nng v cng
quan trng i vi c th sng:
- S h hp ca t bo (ng vai tr l cht xc tc trong cc qu trnh oxi ha).
- Lm cm mu cho cc t bo hng cu, to ra hemoglobon (hnh thnh mng t bo ty
xng).

139
C th phn chia cc hp cht ca st thnh hai nhm:
- St II (ferro): cc hp cht mui ferro c pH trung tnh, khng lm kt ta anbumin, do
khng nh hng n mng nhy c th, c hp thu qua d dy v rut v cc hp cht
ferro thng c th ha tan c trong lipoit.
- St III (ferri): dung dch nc ca hp cht ferri phn ly mnh do trong mt chng mc
no c tnh axit lm kt ta anbumin, tn cng vo mng nhy ca d dy gy ra au n
v ri lon tiu ha. Nng m c c th c tnh n mn mnh v n kt ta anbumin
di dng ferrianbuminat. Tc dng ny ca hp cht ferri c s dng lm gim chy
mu b mt.
Ferrihem: st hng cu huyt t.
- St c vn chuyn i nh cc anbumin.
- Hemoglobin l cht quan trng trong vn chuyn st (mt phn t cha 4 nguyn t st)
ngoi ra cn c cc anbumin khc ferritin, hemosiderin v tranferrin.
- Mc tiu th st hng ngy ngi bnh thng l 30-40mg.
Khi c th tha st, gan gim sn xut apoferritin lm cho apoferritin trong mu v mt gim
v cng lm gim hp thu st. Trong trng hp n qu nhiu st, st vo mu nhiu dn n
lng ng hemosiderin trong cc t bo vng - ni m, gy c hi cho t bo ny.

140
 St t thc n Fe2+ hoc Fe3+

D dy Fe3+ HCl Fe3+

D tr v vn chuyn
T trng 2+
Fe + anbumin ferritin
(hp thu 1mg
Fe/ngy

Thi ra ngoi

mu Fe3+ + apotransferrin transferrin

3 mg Fe/ngy

Bo tng

Ty xng
To hng cu
25 mg/ngy Gan
Thi ra ngoi

Cc t bo hng
cu tun hon

H thng ni m
25 mg/ngy

Cc mui st hay dng: ferrosunfat.7H2O (cha 20% st), ferrofumarat (19% st),
ferolactat, ferrihydroxit + dextran (tim).
6.2.2. Vitamin B12
1. i cng
Vitamin B12 dng n thun c th ng ngha vi cyanocobalamin, dng dc cht thng
dng nht trn thc t ca vitamin B12. Vitamin B12 tham gia phn ng tng hp

141
thymidylate, mt thnh phn trong phn t ADN, cung cp nguyn liu tng hp ADN,
gp phn vo qu trnh phn chia t bo v trng thnh t bo trong c th.
Vitamin B12 thuc nhm vitamin ha tan trong nc - Vitamin B12 c cng thc cu to rt
phc tp, Vitamin B12 cng l cht kh phn tch nht trong thc phm dinh dng bi v
lng vitamin B12 hin din trong hp cht qu thp, nn i hi phi c nhng phng
php c ng v loi b nhng tp cht khng cn thit, trc khi vitamin B12 c phn
tch. Thiu ht vitamin B12 gy ra thiu mu c tnh, xo trn h thn kinh
Vitamin B12 c phn lp u tin t gan vo nm 1948 do hai nhm nghin cu ca
Folker v Smith, cng trong nm ny E.L.Rickes cng pht hin ra chng Steptomyces cng
sn sinh ra Vitamin B12, y l yu t m ra kh nng a vo sn xut quy m cng ngh
sau ny.
Cu trc ca Vitamin B12 c tm thy vo nm 1955.
Trng lng phn t: 1355.36
Cng thc ha hc: C63H88CoN14O14P
Tn theo h thng IUPAC: -(5,6-dimethylbenzimidazolyl)cobamidcyanide
Tn theo h thng CAS: Cyanocobalamin
Phn t cha nguyn t coban, khi thy phn n cho mt nucleotit trong baz l 5,6-
dimetyl-benzimidazol, ng ribose v mt phn t H3PO4, mt nhm ciano, h vng ln
cha nguyn t coban trung tm c tn l corin. Cng thc cu to ca Vitamin B12:
Corin: - 8 nhm CH3
- 4 nhm propionyl amit
- 8 axetyl amit

142
 corin

ng ribosse

Vitamin B12 do vi khun tng hp t thin nhin, sau mi i vo chu trnh thc n ca
cc ng vt, ch yu t cc ng vt n c. ng vt v thc vt khng t tng hp c
vitamin B12. Trong thc phm ca chng ta, vitamin B12 c trong thc n ngun gc ng
vt nh tht (nht l ni tng, c bit l gan), trng, sa. Cc thc n thc vt nh rau, tri
nu khng "dnh" vi khun th khng c vitamin B12.
Vitamin B12 trong thc n u dng phc hp vi protein. Trong ch bin, vitamin B12
kh bn vng vi nhit , tr khi trong mi trng kim v nhit qu 1000C. Tht luc
1700C trong 45 pht mt 30% B12. Sa nu si 2-5 pht mt 30% B12. Khi c s hin din

143
ca vitamin C, B12 tr nn t bn vng vi nhit hn v c th b ph hy nhng lng
ng k.
S hp thu vitamin B12 cn c yu t ni ti (mt protein do t bo thnh ca nim mc d
dy tit ra) v enzyme phn hy protein ca ty. Vitamin B12 c hp thu bi on cui
rut non.
D tr vitamin B12 trong c th ch yu nm gan. ngi bnh thng, tng s vitamin
B12 d tr khong 1-10mg. Trong khi nhu cu ti thiu hng ngy ca B12 ch bng
0,1mcg. Do khi c th khng c cung cp vitamin B12 trong thi gian di (khong 5
nm tr ln) lng B12 trong c th mi cn kit v tnh trng thiu vitamin B12 mi xy
ra.
Vai tr ca vitamin B12:
Vitamine B12 l ng yu t ca hai loi phn ng men thit yu:
- ng phn ha
- Vn chuyn nhm methyl (transmethyl ha).
Hai loi phn ng ny c nhng vai tr quan trng lin quan n nhng vn sau.
- To mu: Trong ty xng, vitamine B12 can d vo cng mt lc qu trnh trng thnh
v s nhn ln ca hng cu. Trng hp thiu vitamine B12, suy nhiu dng t bo dn n
tng kch thc ca cc t bo c sinh ra. iu ny lm cho hng cu khng l, c gi
l t bo ln.
- Tnh ton vn ca h thn kinh: Thiu vitamine B12 a n thoi bin dy thn kinh
ngoi bin, ty sng v i khi no. iu ny bt u bi tn thng v bo v ca cc u
tn cng dy thn kinh.
- Tnh hiu qu ca h min dch, v c bit tit ra khng th.
- Qu trnh nhn i ca ADN trong t bo.
- Tng hp methionin.
Nhn chung, vitamine B12 rt cn thit cho qu trnh nhn ln ca t bo.
Thiu B12 nh hng mt cch c bit n tt c cc m m trong qu trnh nhn i
xy ra nhanh chng hn mu, nim mc rut non, ni mc t cung.
Vitamine B12 tham gia vo chc nng ca h thng thn kinh (tr nh, kh nng hc) v
qu trnh pht trin hi ha tr em.

144
Tc hi ca vic thiu vitamin B12:
Biu hin thiu vitamin B12: Thiu vitamin B12 gy thiu mu, cc triu chng thn kinh v
nhng triu chng khc.
Thiu mu do thiu vitamin B12 l thiu mu nguyn bo khng l. Loi thiu mu ny c
nhng c trng v hnh th t bo mu thy trn xt nghim. Trn thc t, hu ht cc
trng hp thiu mu nguyn bo khng l l do thiu vitamin B12 hoc acid folic. Ngi
bnh xanh xao, yu, d mt, n mt ngon, hi hp nh trng ngc, au u, kh th, ngt
xu.
Cc biu hin v thn kinh th hin i xng trn c th v ko di nhiu thng, gm:
- D cm, tc c nhng cm gic t rn, nht nht nh kin b.
- Gim cm nhn v cm gic rung.
- Gim cm gic v th a n chng tht iu, i ng xiu vo.
- Kh nng tr c gim st. Thm ch c th hoang tng.
Nhng triu chng khc:
- L li, au li.
- To bn.
- H huyt p th ng.
Khi c iu tr, cc triu chng thn kinh ci thin chm nht.
Cc nguyn nhn dn n thiu vitamin B12:
Trong thc t, thiu vitamin B12 rt him gp. Hu ht thiu vitamin B12 ngi l do km
hp thu B12, do thiu yu t ni ti hay gim hoc mt chc nng hp thu c hiu ca on
cui rut non.
Nhng ngi d b thiu vitamin B12 gm:
- Nhng ngi n chay trng, hon ton khng n tht c, trng, sa trong nhiu nm.
- Ngi c bnh d dy, c bit l b vim teo nim mc d dy.
- Ngi ct b mt phn hay ton b d dy.
- Ngi c bnh rut non, phn rut bnh bao gm c phn cui rut non nh bnh Celiac,
bnh Sprue, bnh vim rut vng, ct on rut hoc ni tt rut.
- Ngi ung viatmin C nhiu.
- Ngi nghin ru mn tnh, thiu tt c cc vitamine nhm B.

145
- Ngi ln tui.
- Nhng ngi c iu tr lu bng cc thuc tc ng n chuyn ha vitamine B12 nh
Metformin (glucophage, ghicinan) mt thuc iu tr tiu ng. Thuc chng lot d dy
nh: cimetidine hay ranitidine. Colchicin c dng cha bnh gout.
Neomycin. Thuc nga thai lm gim lng vitamine B12.
Ch nh v cch thc dng ty theo triu chng v nguyn nhn.
- Thiu cung cp c iu chnh d dng bng cch b sung bng ng n ung.
- Thiu bi bnh ca chuyn ha, cng c th cha lnh bng ng n ung.
- Thiu do km hp thu, i hi phi dng ng tim.
Ch nh dng B12 rt nhiu, kt qu t cc quan st lm sng, ngi ta s dng thng
xuyn vitamine B12, n c hay kt hp, vi B1 v B6:
- h tr chng au do bnh thn kinh, au thn kinh ta, au thn kinh c, cnh tay, bnh
thn kinh gy au, vim dy thn kinh th gic.
- hot ha chuyn ha chung, chng mt mi (liu cao).
- Bnh x cng ri rc.
- Kh c cyanure.
- Thuc nh mt trong vim k mc l vt thng gic mc.
- Nhng nhu cu s dng thng gp l b sung thm nga tnh bin i ca hot ng
tr tu nhng ngi ln tui, ging nh B9.
Dng Vitamine B12 thng xuyn hay dng liu cao hn khuyn co ca bc s c
nguy him khng?
ngi, khng ng c do qu liu. Tuy nhin, vi ngi trng thnh nhn ko di liu
cao vitamine B12, c nghin cu cho rng c s xut hin khng th chng B12. Cng phi
tnh n rng liu cao c nguy c pht trin u c tnh, v hot ng ca vitamine ln qu
trnh pht trin ca u.
C mt vi phn ng min dch d ng (biu hin da) sau khi tim nh: nga, ni m ay,
da, trng c, nc tiu c mu , au ch tim. Mt vi ngi cng d ng vi vitamine
B12 bng ng tiu ha.
6.2.3. Axit folic B9

146
Axt folic (hay Vitamin M v Folacin), v Folat (dng anion) l cc dng ha tan trong nc
ca vitamin B9, cn thit cho dinh dng hng ngy ca c th ngi phc v cc qu
trnh to mi t bo. Nhu cu v cht ny tng cao ph n mang thai v tr s sinh. Cht
ny c mt t nhin trong thc n v cng c th thu t thuc ung b tr.
H
H2N N N

H
N N
N

H
O N COOH

O COOH
6-2
axit folic
Danh php IUPAC:
N-[4(2-Amino-4-hydroxy-pteridin-6-ylmethylamino)- benzoyl]-L(+)-glutamic acid.
Tn khc: Axt pteroyl-L-glutamic, Vitamin B9, Vitamin M, Folacin
Cng thc phn t: C19H19N7O6
c trng ca axit folic l tham gia trong cc phn ng chuyn ti nhm metyl trong qu
tnh trao i cht, tham gia vo qu trnh sinh tng hp axit thymonucleic- mt cht quan
trong trong pht trin thnh t bo. Trong qu trnh tng hp axit thymonucleic trong c th
t uracil va c vai tr xc tc ca axit folic va c c vai tr ca xc tc vitamin B12:

147
 O O O

CH3 CH3
HN HN HN
axit folic Vitamin B12

OH
O N O N O N
H H O
uracil thimine

CH3
OH
HN
thymidine

O PO3H2
O N
O

OH
axit thymonucleic
C axit folic ln vitamin B12 u l cht xc tc sinh hc cc k quan trng, khi thiu chng
s gy nn nhng ri quan nghim trng trong i sng ca t bo.
Cc nguyn nhn gy thiu ht axit folic:
Acid folic c nhiu trong t nhin.
1. Trong rau xanh (mu xanh cng m cng tt nh rau dn, c ci, bng ci), trong
nm, u lima, bnh m bng bt m nguyn cht, bp, u H Lan, u nnh, c rt, c
chua, chui, cam, chanh, bi, gan, thn, trng, u, sa Tt c nhng ph n mun mang
thai nn n thm nhng thc phm ny hng thng trc khi c thai.
2. Trong thuc vin liu 400 microgram, ung ngy 1 vin t 3 thng trc khi c thai n
khi sinh.
3. Trong dng axit folic ung, 1 bch khong 1 ly y cha lng axit folic cn dng
hng ngy. Dng ny thch hp cho nhng ngi khng mun dng thuc vin.
Mt ch nh l axit folic rt d b hy hoi qua nhit v nh sng. Nguyn nhn gy
tht thot thnh phn axit folic trong ngun thc phm xanh l: Ngm, ra qu k; luc rau

148
ci qu lu. iu gy ra s thiu ht ngun d tr axit folic trong c th, cho d bn c
mt ch dinh dng hon ton hp l.
Nguyn nhn thiu acid folic:
+ Trong khu phn n thiu acid folic
+ Qu trnh tng hp acid folic b ri lan
+ Nhu cu tng ph n mang thai v tr em ang b
+ Nghin ru
+ Mt s cht gy c ch men dihidrofolatreductase nh methotrexat, trimethoprim
cng gy nn s thiu ht axit folic.
Hu qu ca thiu acid folic:
+ Thiu mu nguyn hng cu khng l tr em, c biu hin: gim bch cu, tiu cu,
+ Tiu chy do thiu acid folic v m ng vt, bnh hay gp vng nhit i : Bnh gy
thiu mu v ri lan hp thu m. C bu hin: vim li, vim ming, thiu mu hng cu
khng l, thiu dch v, tiu chy phn m
+ D tt ng thn kinh: thai nhi s thiu mt phn no, ch i t sng, nt t sng, c khi
thai v s dn n tnh trng cht trc hay ngay sau khi sinh.
+ Khu phn n ph n mang thai thiu acid folic: thiu mu hng cu to, bong nhau thai
Nga thiu acid folic:
+ Chm sc thai sn v ch dinh dng cho ph n mang thai cho con b. Phu n mang
thai s dng cht m, rau xanh, tri cy, sa c b sung cc dng cht, acid folic
nga thiu mu, d tt ng thn kinh thai nhi.
+ Khu phn n cho tr cc cht dinh dng, cn i v hp l. Trong khu phn n lun
rau xanh v tri cy cung cp cc vitamin C, nhm B v acid folic, sa c b sung cc
dng cht, acid folic, nga thiu mu
+ Theo di sc khe thng xuyn mi thng cho tr di 2 tui v mi 3 thng cho tr trn
2 tui. S dng v thc hin chm biu tng trng cn nng v chiu cao cho tr nh
mi thng.
Dng axit folic qu liu
Mc d axit folic rt cn thit cho c th, tuy nhin nu dng qu nhiu, axit folic c th gy
tc hi khng nh cho sc khe. N gy tng sinh t bo. S tng sinh nhanh chng s dn

149
n thoi ha ty sng bn cp. i vi nhng ngi c khi u, axit folic cng gy tng sinh
t bo, lm cho khi u pht trin nhanh hn.
Tha axit folic cn c th gy ra chng nga, ni ban, m ay v ri lon tiu ha. Trn thc
t, c th rt nhiu ngi (c bit l tr em) gp cc phn ng ny nhng khng bit
nguyn nhn l do tha axit folic.
Tuy nhin, cch gii c cht ny li rt n gin. Axit folic l mt sinh t tan c trong
nc, ch cn ung tht nhiu nc lng axit d tha c thi ra ngoi c th qua
ng tiu.
Ch nh:
- Thiu mu hng cu to. nhng bnh nhn ny khi iu tr cn kim tra du hiu
tn thng thn kinh do thiu ht vitamin B12 v axit folic khng iu tr c tn thng
thn kinh do thiu vitamin B12 gy ra.
- Phng v iu tr s thiu ht axit folic do mt s thuc c ch
dihidrofolatreductase nh methotrexat, trimethoprim v thuc hn ch hp thu v d tr axit
folic (thuc trnh thai).
- Axit folic lm gim tc dng ca mt s thuc chng ng kinh nn thn trng khi
dng phi hp.
- Ngoi ra, thuc cn c dng trong cc trng hp gim bch cu, mt bch cu
ht, i ra porphyrin.
6.2.4. Erythropoietin
Erythropoietin (EPO) l cht kch thch chnh yu ca qu trnh to hng cu p ng vi
tnh trng thiu xy. Thiu vng hormon ny, tnh trng thiu xy khng lm tng hoc lm
tng khng ng k hot ng to hng cu. Bnh thng, tnh trng thiu xy s lm tng
ng k s sn xut erythropoietin, ko theo l s tng sn xut hng cu cho n khi tnh
trng thiu xy c gii quyt.
ngi bnh thng, 90% lng erythropoietin trong c th c sn xut thn (phn cn
li ch yu c sn xut gan).
Erythropoietin do thn sn xut dng cha hot ng gi l erythogenin. Nh kt hp vi
mt globulin (do gan sn xut) erythogenin chuyn thnh erythropoietin hot ng.
Vai tr:

150
- Kch thch to t bo tin nguyn hng cu t t bo gc.
- Kch thch tng hp hemoglobin
- Kch thch vn chuyn hng cu li t ty xng ra mu ngoi vi.
Ch phm: Epoetinalpha (Epogen, Eprex) Dung dch tim-2000IU-4000iu v 10.000 iu.
Tim tnh mch hoc di da.
Nhm Dc l: Thuc tc dng i vi mu
Thnh phn: Erythropoietin ngi ti t hp
Ch nh:
- iu tr thiu mu lin quan n bnh nhn suy thn mn bao gm bnh nhn lc mu v
bnh nhn khng lc mu.
- Thiu mu bnh nhn HIV.
- Thiu mu bnh nhn ung th do s dng ho tr liu.
- Gim s truyn mu bnh nhn phu thut.
- Thiu mu tr sinh non.
Chng ch nh:
Khng dng thuc cho cc bnh nhn:
- Cao huyt p ng mch khng kim sot.
- C tin s mn cm vi human albumin.
- C tin s mn cm vi cc ch phm c ngun gc t t bo ng vt c v.
- Tng tc vi thnh phn ca thuc.
Tc dng ph:
au u, au khp, mt mi, bun nn, tiu chy.
Ch phng:
Thn trng vi bnh nhn c tai bin co git.
6.2.5. Cc kim loi v vitamin khc c tc dng chng thiu mu
* ng: nghin cu trn sc vt thc nghim, thiu ng km theo gim hp thu st ng
tiu ha v gim gii phng st t h thng lin vng ni m, kt qu lm gim tng hp
hemoglobin v cytochromoxydase gy thiu mu.
ng sunfat dng ung 0,1mg/kg th trng hoc 1-2mg trong 24h.

151
* Coban clorid: ung 200-300mg trong 24h. Trong c th, ion coban kch thch gii phng
Erythropoietin lm tng s lng hng cu.
* Vitamin B6: tng sinh hng cu nhng bnh nhn thiu mu do ri lon tng hp
hemoglobin v s tch t st trong cc t bo tin hng cu nhng khng tc dng nhng
trng hp thiu mu do cloramophenicol v ch.
* Riboflavin: ung vitamin B2 lm tng sinh s hng cu v huyt sc t trong mu.
6.3. Cc dch thay th huyt tng
Khi th tch huyt tng b gim do mt nc v mui n thun (tiu chy, nn nhiu) th
ch cn truyn nc v in gii l . Nhng nu do mt nhiu mu hoc huyt tng nh
trong sc xut huyt, bng nng, th phi truyn mu, huyt tng hoc cc dch thay th c
p lc keo cao.
Cc sn phm thin nhin (mu, huyt tng ca ngi) l tt nht, nhng t v c nhiu
nguy c (phn ng min dch, lan truyn vim gan siu vi khun B hoc C, lan truyn
AIDS).
V vy, cc dch thay th huyt tng c nghin cu v s dng. Cc dch ny cn phi
c by tnh cht sau:
- Tn ti trong tun hon lu, ngha l c p lc keo tng t vi huyt tng, c trng
lng phn t tng ong vi albumin huyt tng ( ~ 40.000).
- Khng c tc dng dc l khc.
- Khng c tc dng khng nguyn, khng c ch nhit t.
- Khng c tng tc hoc phn ng cho vi nhm mu.
- Gi n nh lu khi bo qun hoc thay i ca nhit mi trng.
- D kh khun
- nht thch hp vi s tim truyn.
Di y l mt s dch truyn t tiu chun hin ang c dng:
- Gelatin bin tnh.
- Cc loi dung dch polime: polivinyl pyrolydon, dextran.
6.3.1. Cc ch phm ca mu ngi
Mu ngi c phn theo nhm mu v x l vi cc tc nhn bo qun
(thng dng dung dch mang tnh axit gia citrat + dexotroz). Mu ti ca ngi khng

152
cha cc i t bo, giu abumin c lm lnh su (-200C). Ngay trc lc s dng c
hm nng ln 370C.
u im: cc tnh cht ca mu, cht dinh dng nhng c nhc im l
mu d b nhim bnh v kh bo qun.
6.3.2. Gelatin c bin tnh
c sn xut t colagen ca xng, thu phn cho ti khi t c cc phn t protein c
trng lng phn t khong 3.000. C nhiu dng:
- Plasmion: cha 30g gelatin lng trong 1 lt, c thm thnh phn cc ion Na +, K+, Mg++
v Cl- tng t nh huyt tng, khng c Ca++. Cht m l lactat. ng trong l 500 mL.
- Plasmagel: cha 30g gelatin lng trong 1 lt dung dch mui ng trng, thm 27 mEq
Ca++ (cho nn khng c dng cho bnh nhn ang c iu tr bng digitalis). Khng
c cht m. ng trong l 500 mL.
- Plasmagel khng mui, c ng (Plasmagel dsod glucos): cha 25 g gelatin trong 1 lt
dung dch glucose ng trng, khng c mui, Ca ++ v cht m (trnh b tha mui).
ng trong l 500 mL.
+ u im ca gelatin lng l d bo qun, khng cn xc nh nhm mu trc khi truyn.
+ Nhc im:
- Khng gi c lu trong c th, khong 75% b thi tr qua nc tiu trong 24h.
- Vn cn phn ng khng nguyn: d ng biu hin da, him gp phn ng tim mch.
- C ri lon ng mu: gim protrombin, fibrinogen, tiu cu, ko di thi gian chy mu.
- Gy protein- niu gi. Nu dng Plasmagel, ch c th lm tng calci huyt.
- Phi hm nng trc khi dng v rt qunh khi gp lnh.
6.3.3. Cc polime
Cc polime c s dng lm dung dch thay th huyt tng c dextran v
polyvinyl pyrolidone.
1. Polyvinyl pyrrolidone
Polyvinyl - pyrrolidone (PVP) l cht tng hp, c trng lng phn t khong 40.000.
ng trong l 500 mL

153
 H2
CH C n

- u im: tng i d bo qun, gi thnh va phi.

- Nhc im: cn phn ng khng nguyn, gy protein - niu gi v nht l b gi lu trong
h lin vng ni mc.
2. Dextran
L cht trng phn c trng lng phn t rt cao, c to ra t glucose di tc ng ca
vi khun Leuconostoc mesenteroides.
Phn hai loi:
* Loi c trong lng phn t cao. Khong 80.000. ng trong l 250 v 500 mL. Thi tr
qua chuyn ha.
- u im: d bo qun, gi khng t lm.
- Nhc im:
+ To phc hp fibrinogen- dextran, gn vo hng cu, lm tng dnh tiu cu, v vy c th
gy ri lon ng mu.
+ Rt t c, nhng c th gy phn ng qu mn ngay t ln truyn u tin v mn
cm vi dextran t nhin gp trong mt s thc n.
* Loi c trng lng phn t thp: Khong 40.000. ng trong l 250 v 500 mL
(Rheomacrodex). Thi tr bng chuyn ha v qua thn.
- u im: lm d dng tun hon ca hng cu trong mao mch.
- Nhc im: gi thnh cn cao v gy ri lon ng mu. Ch l sau khi truyn, c th
lm sai lc vic xc nh nhm mu v glucose mu.
Ngoi ra cn c cc dung dch in gii. Cc loi hay dng.
* Dung dch ng trng
* Dung dch nc mui sinh l (NaCl 0, 9%)
- u: R, ph bin.

154
- Nhc: d gy toan mu do lng Cl- cao. Truyn nhiu v nhanh d gy nc ngoi
bo v ph phi cp.
* Ringer lactat (dung dch Hartman)
- Vo c th, lactat chuyn thnh bicarbonat (do gan) v kim ha mu (chnh c toan
nh).
- C thm K+ v Ca2+.
- Truyn 1 lt s tng c 200- 300 mL th tch tun hon, v vy cn truyn 1 lng gp 3
ln th tch b mt. Nhng khng c gi lu trong mu nn cn truyn lin tc.
* Dung dch u trng
- Cc loi dung dch: NaCl 1,2- 1,8- 3,6- 7,2- 10 v 20%. Trn th trng c sn loi 10-
20%, ng 10- 20 mL. Khi dng, pha vi glucose 5% t nng mong mun.
c im:
- ASTT qu cao, d gy ph.
- Lm gim kt tp tiu cu, tng nguy c chy mu.
- Lm gin mch ni tng: thn, tim. Tng co bp tim
- Lm gim ph no, gim tng p lc ni s tt hn so vi dung dch keo
6.4. Cc thuc tc dng n ng mu
6.4.1. i cng
ng mu l phn ng bo v, gi cho c th khi b mt mu khi b thng. Hin
tng ng mu ch xy ra ni mch mu b tn thng. Mu chy trong mch khng b
ng l do b mt bn trong thnh mch mu trn nhn, tiu cu khng b v, v do
khng c tromboplastin ni sinh tham gia qu trnh ng mu, ng thi cc t bo lt thnh
mch mu c kh nng tit ra cht chng ng mu t nhin.
Bn cht ca qu trnh ng mu l mt lot nhng phn ng ho hc, m kt qu ca
phn ng ny l cht hot ho cho phn ng sau, cui cng hnh thnh si t huyt. Cc si
t huyt an xen vo nhau thnh tm li, gi ly cc t bo mu, to thnh cc mu nh bt
kn vt thng.
6.4.2. C ch ng mu

155
 ng mu l mt qu trnh l ho phc tp gm nhiu phn ng lin tip vi s tham
gia ca 13 yu t. Theo quy c quc t, cc yu t ng mu c nh s La M t I n
XIII , nh bng sau:
Cc Tn gi v vai tr
yu t
I Fibrinozen, l mt loi globulin, do gan tng hp a vo mu
II Protrombin, l 1 protein huyt tng do gan sinh ra. S tng hp protrombin lin
quan cht ch n s hp th vitamin K. Nu ri lon hp th vitamin K ng
tiu ha s dn n gim protrombin.
III Tromboplastin - enzim to ra khi tiu cu b v, hoc m b tn thng
IV Ion Ca++ c trong huyt tng, c tc dng hot ha protrombin
V Proaccelerin, mt loi globulin, do gan sinh ra, lm tng tc ng mu
VI Dng hot ho ca yu t V
VII Proconvectin, yu t xc tin to Trombin
VIII Yu t chng chy mu A, c trong huyt tng, c vai tr quan trng trong s
to thnh tromboplastin ni sinh. Nu thiu yu t ny, mu vn ng nhng cc
mu mm, d di ng.
IX Yu t chng chy mu B, cng l 1 protein huyt tng, cn cho s to thnh
tromboplastin.
X Yu t stuart, c trong huyt tng, do gan sinh ra tng i bn vng c tc
dng trong s to thnh tromboplastin v chuyn protrombin thnh trombin.
XI Protromboplastin - c sn trong huyt tng, c vai tr tp trung tiu cu
XII Yu t hageman, c trong huyt tng, c tc dng hot ho s ng mu
XIII Yu t n nh fibin, c sn trong huyt tng, c tc dng cng c si fibrin
thm vng chc.
ng mu l mt qu trnh phc tp v th chia thnh 3 giai on chnh:
+ Giai on 1. Hnh thnh v gii phng Tromboplastin ni sinh v ngoi sinh hot
ng (hay trombokinaza), vi s tham gia ca cc yu t IV, V, VII, VIII, IX, X, XI, XII.

156
 Khi t chc b tn thng, tiu cu chm vo mp vt thng, b v ra, gii phng
Tromboplastin cha hot ng (l Tromboplastin ni sinh)
Mt khc, cc m b vt thng cng gii phng ra Tromboplastin (gi l
Tromboplastin ngoi sinh)
Cc tromboplastin ny di tc dng ca cc ion Ca 2+ v protein trong huyt tng,
c bin i thnh trombokinaza (l dng Tromboplastin hot ng)
+ Giai on 2. Hot ho protrombin thnh trombin
Nh s tham gia ca yu t V, tromboplastin dng hot ho. Di tc dng ca
tromboplastin hot ng v cc yu t V, VIII, IX, XII, vitamin K, protrombin do gan tit ra
dng cha hot ng, c bin i thnh trombin hot ng (yu t V c hot ha
thnh accelerin, tc dng vi tromboplastin thnh protrombinaza. Enzim ny bin
protrombin thnh trombin dng hot ng)
+ Giai on 3. To thnh si fibrin
Di tc dng ca trombin v cc yu t IV, XIII, cht fibrinozen dng ho tan lin
kt li vi nhau thnh cc si mnh fibrin (si t huyt). Cc si t huyt an xen vo nhau
thnh mng li, qun ly cc t bo mu thnh cc mu, bt kin l vt thng. Sau khi hnh
thnh mt thi gian, cc mu s co li v trn mt cc mu ng s c dch trong, mu vng
nht, l huyt thanh. Huyt thanh l huyt tng b ly i fibrinogen cng vi mt s yu
t ng mu khc.

6.4.3. Cc thuc lm ng mu
C hai loi: ng mu ton thn v ng mu ti ch
6.4.3.1. Thuc lm ng mu ton thn
1. Nhm vitamin K
Vitamin K l mt ci tn tp hp m bn thn n bao gm cc dn xut ca
naphtoquinon c tc dng lm gim kh nng chy mu. Trong s th vitamin K1 (2-
metyl-3-phityl-1,4-naphtoquinon) l c ngha hn c.
Vitamin K s dng trong lm ng mu c ba dng:
- Vitamin K1 (phytomenadionen (6-5), phylloquinon) c ngun gc thc vt.
- Vitamin K2 (menaquinon (6-6)) do vi khun gram m ng rut tng hp.

157
 - Vitamin K3 (menadion (6-7)) c ngun gc tng hp.
Vitamin K tan trong lipid, nhng ring vitamin K3 dng mui natribisulfit hoc
mui tetra natri tan trong nc vo c th b chuyn ha thnh vitamin K3.
CH3
O CH3 CH3 CH3

CH3

6-5
CH3 phytomenadione
O
CH3
O CH3 CH3 CH3

CH3

6-6
CH3 menaquinone
O

CH3

O
6-7
menadione

Vai tr sinh l: Vitamin K gip cho gan tng hp cc yu t ng mu nh

prothrombin (II), VII, IX v X.
Du hiu ca s thiu ht: Nhu cu hng ngy khong 1g/kg. Khi thiu ht s xut
hin bm mu di da, chy mu ng tiu ha, rng ming, i ra mu, chy mu trong
s.
Dc ng hc: Vitamin K tan trong du, khi hp thu cn c mt ca acid mt. Loi
tan trong du thng qua h bch huyt vo mu, cn dng tan trong nc hp thu i trc tip
vo mu. Vitamin K1 c hp thu nh vn chuyn tch cc cn K2, K3 c hp thu nh

158
khuych tn th ng. Sau hp thu vitamin K1 tp trung nhiu gan v b chuyn ha nhanh
thnh cht c cc thi ra ngoi theo phn v nc tiu.
c tnh: Mc d c phm vi iu tr rng, nhng c th gp thiu mu tan mu v
cht do vng da tan mu tr di 30 thng tui dng vitamin K3. Vitamin K3 cn gy kch
ng da, ng h hp, gy i albumin, gy nn v c th gy tan mu ngi thiu G6PD.
* Tng hp vitamin K:
Vitamin K1 (phylloquinone (6-5)) ngoi vic chit xut t cc loi rau xanh th vo
nhng nm 1939, ngi ta cng tng hp n t 2-metyl-naphtoquinon:
O CH3
CH3 CH3 CH3

CH3
+ Br

CH3 phytol bromua

O
6-7 Zn/AlCl3
menadione
CH3
O CH3 CH3 CH3

CH3

6-5
CH3 phytomenadione
O

159
 O
O
CH2

[O] HC
1000C/CH3COOH
+
HC
CH3 CH3 CH2 CH3
NH2 O
O
toluy quinon O

O2 /CH3COOH

CH3

O
6-7
menadione

Quy m cng nghip:

O

CrO3/CH3COOH

CH3 CH3

2. Cc thuc lm ng mu khc
- Calci clorid CaCl2: Ca +2 cn hot ha cc yu t VIII, IX v X chuyn
prothrombin sang thrombin.
- Coagulen: L tinh cht mu ton phn, c bit c tinh cht ca tiu cu. Dng
trong ngoi khoa ngi bnh a chy mu v trong nhng trng thi chy mu (ban chy
mu, i ngoi ra mu v.v...).
- Carbazochrom (Adrenoxyl): Lm tng sc khng mao mch, gim tnh thm thnh
mch, nn lm gim thi gian chy mu. Tc dng sau khi tim 6 - 24 gi (tim bp 1,5 - 4,5
mg mi ngy hoc ung 10 - 30 mg mi ngy). Cha chy mu do gin mao mch hoc
phng chy mu sau phu thut to hnh, tai mi hng, ct b tuyn tin lit.

160
 - Ethamsylat v dobesilat calci: Lm tng sc khng mao mch, gim tnh thm
thnh mch. Dng phng chy mu cp trong phu thut to hnh, tai mi hng, ct b tuyn
tin lit, rong kinh.
- Vitamin P (flavonoid, rutosid rutin v dn xut):
+ Rutosid v dn xut ngun gc thc vt c hot tnh vitamin P u gim tnh thm
thnh mch v lm tng sc khng mao mch do c ch s t oxy ha ca drenalin, v c
ch COMT gan, do ko di tc dng ca hormon ny. Hot tnh vitamin P biu hin r
trn s tng hp mucopolysacharid v glycoprotein ca m lin kt.
6.4.3.2. Thuc lm ng mu ti ch
1. Enzym lm ng mu
C hai loi enzim:
- Thrombokinase (prothrombinase): L tinh cht ca ph tng ngi v ng vt,
thng ly no v phi. Tinh cht ny cha thrombokinase v c nhng yu t ng mu
khc. Tc dng khng chc chn bng thrombin. Dng khi chy mu t, ti ch, thng
xuyn (chy mu cam, rng ming) v c trong trng hp chy mu nhiu (phi hp vi
bng cht).
- Thrombin: Chuyn fibrinogen thnh fibrin n phn, ri thnh fibrin polymer
khng tan trong huyt tng. Ch dng ti ch, tuyt i khng tim tnh mch (v mu ang
chy s gy ng mu nguy him). Ung cha chy mu d dy.
2. Nhng loi khc khng phi enzim
- Cc keo cao phn t gip tng nhanh ng mu: Pectin, albumin v.v...
- Gelatin, fibrin dng xp tng din tip xc, qua hy tiu cu nhiu hn, mu
ng nhanh hn.
- Mui kim loi nng: Lm bin cht albumin, lm kt ta fibrinogen v cc protein
khc ca mu. Hay dng dung dch FeCl3 10% bi ti ch hoc tm bng FeCl3 p ln vt
thng.
- Thuc lm sn: Lm co mao mch nh, nn chng ng. Thng dng tanin, mui
Al, Pb, Zn hoc KMnO4 pha long.
6.5. Cc thuc chng ng mu

161
 Cc mu ng l kt qu ca mt lot cc hin tng xy ra trong qu trnh cm
mu vi 3 giai on chnh l: co mch, kt tp tiu cu, ng mu. Cc mu ng c hnh
thnh trong c th do nhiu nguyn nhn khc nhau gy ra cc cn au tht ngc, nhi mu
c tim, t qu, thuyn tc khi tnh mch... v u li hu qu nng n cho bnh nhn,
thm ch c th gy t vong. Do vy, vic s dng thuc chng ng mu trong d phng v
iu tr cc bnh do nguyn nhn huyt khi ng vai tr rt quan trng.
C 3 nhm thuc chng ng mu chnh c s dng trn lm sng vi bn cht
v c ch tc dng khc nhau.
6.5.1. Heparin v cc ch phm tng t
c gi l Heparin v cht ny u tin c pht hin thy nhiu gan ng vt.
Ngoi gan ra, heparin cn c tm thy thn, phi, hch bch huyt, nim mc rut. Sau
ny c tm thy dng bo ca cc m lin kt ca c gan, phi, thn, tim, hch bch
huyt. Dng bo thng tp trung gn mch mu khi c ng mu mch, heparin s
c ngay ti ch.
Hin nay heparin c chit xut t nim mc rut ln hoc phi tru, b hoc bn
tng hp.
Heparin l mt polisacharid (glucozaminoglican). Mt n v cu trc c tc dng
sinh hc ca heparin l tetrasacharid c to thnh t hai isacharid l D-glucosamin-axit
L-iduronic (6-13) v D-glucosamin-axit D-glucoronic (6-14). Mi mt mch cha 8-15 n
v ny. Heparin c tnh axit mnh.
OSO3Na

H2C

O O
NaOOC OH

O
H HO NH
O

O OSO3Na SO3Na
n

L - iduronic D-glucosamin v
mui sunfonat

162
 NaOOC
O
O
H
OSO3Na
HO
OH H2C
O
O
D-glucoronic HO

HN
O
SO3Na m

D-glucosamin
Trong thc t iu tr hin nay c 2 loi heparin: heparin thng (trng lng phn
t trung bnh 12.000 - 15.000) v heparin trng lng phn t thp (trng lng trung bnh
5.000).
C ch v tc dng chng ng mu: Heparin c tc dng chng ng mu nhanh
c bn trong v ngoi c th. Tc dng ca heparin ty thuc vo chiu di chui
polysaccharid, tc l ph thuc vo trng lng phn t heparin. Tc ng chnh ca thuc
l chng thrombine. Thuc tng cng tc ng ca ng yu t protein, antithrombine,
trung ha thrombine v nh vy n chng li s chuyn dng fibrinogen thnh fibrin. Tc
dng ny xy ra tc th. Cng ca n ph thuc vo t l gia s lng heparin lu
hnh v nng thrombine hnh thnh. nng huyt tng cao(trn 30 microgam/ml)
heparin ngng chn hon ton s chuyn dng ni trn. nng huyt tng thp hn (2-
10 microgam/ml) n lm chm i s hnh thnh fibrin v to iu kin thun li cho qu
trnh t bo v sinh l chng li s ng mu ni mch v hnh thnh huyt khi. Heparin b
bt hot trong trng hp c th nhim toan.
ng dng lm sng: Heparin c dng d phng v iu tr cc bnh do huyt
khi: d phng huyt khi tnh mch su; iu tr thuyn tc do huyt khi; d phng thnh
lp cc mu ng trong chy thn nhn to; kt hp trong iu tr hi chng mch vnh cp.
Heparin trng lng phn t thp: Mc d heparin thng l mt thuc c s dng t
lu v c u im l gi thnh r. Nhng hin nay, n dn c thay th bng cc heparin

163
trng lng phn t thp (enoxaparin, nadroparin) trong mt s trng hp do nhng u
im ni bt ca chng. Enoxaparin tin dng hn do c th tim di da, trong khi heparin
thng phi tim tnh mch; thi gian bn thi ca enoxaparin di hn heparin thng 2 - 3
ln nn ch cn dng 1 ln/ngy. Enoxaparin tc dng chn lc ln yu t xa nn tc dng n
nh, c th dng liu c nh theo cn nng; cn heparin thng phi iu chnh liu theo
tc dng chng ng. Hn na, hiu qu ca enoxaparin bng hoc hn heparin thng, m
tc dng ph nh chy mu hay gim tiu cu cng t gp hn.
6.5.1.2. Cc heparinoit
Heparinoids l glycosaminoglycans l dn xut ca heparin, c ngun gc t nhin
cng nh bn tng hp hoc tng hp ton phn m tc dng ca chng tng t nh
heparin.
6.5.1.3. Hirudin
Hirudin l macropeptide c 65 acid amin, trng lng phn t 7000 - 9000 c
cha trong tuyn n bo trong thc qun ca a, vt, c tc dng chng ng mu do
ngn cn tc dng ca thrombin thng qua s to phc vi thrombin lm cho fibrinogen
khng chuyn thnh fibrin.
Trong mt s trng hp, hirudin c li th hn cc thuc chng ng mu, lm tan
huyt khi thng c s dng. Chng hn nh heparin, hirudin khng can thip vo cc
hot ng sinh hc ca cc protein huyt thanh cng nh hot ng m khng cn s c mt
ca antithrombin III.
6.5.2. Nhm thuc c ch s tng hp ca cc yu t ng mu gan (khng vitamin K)
y l nhng thuc chng hnh thnh cc mu ng dng theo ng ung v c
th iu tr lu di cho ngi bnh. Tc dng ca chng ko di hn ca heparin nhng xut
hin mun. Hn na th k trc, ngi ta chng minh cc cht gy chy mu cho cc
loi ng vt n c c trong cy c ngt, k t bng con ng tng hp iu ch ra
nhiu dn xut c tc dng chng ng mu. C hai nhm cu trc chnh
- Cc dn xut ca coumarine:4-hidroxicumarin (I), bishidroxycumarin
- Cc dn cht ca indanedione

164
 O O O
O O O O

R''

R
O
OH OH R' OH

* C ch tc dng: Do dn xut coumarin v indandion c cu trc gn ging

vitamin K, nn c ch cnh tranh enzym epoxid -reductase lm cn tr s kh vitamin K -
epoxid thnh vitamin K (yu t cn thit cho qu trnh to cc tin yu t ng mu).
V c kh nng lm gim t l thrombin v lm chm s hnh thnh thrombine, to
thun li cho tc dng antithrombine sinh l nn cc AVK c tc dng phng nga s hnh
thnh huyt khi.
Hiu qu iu tr khng c ngay tc th. tc ng trn t l prothrombine, thi
gian gn cn thit l 5 ngy, 36 gi i vi yu t X, 24h i vi yu t IX, 4 gi i vi
yu t VII. iu tr lu di l cn thit c c mt s gim ng n nh.
* Tc dng ph:
- Dng liu cao, ko di gy ri lon thm phn mao mch, xut huyt, rt nguy
him bnh nhn lot d dy t trng, chn thng, cao huyt p.
- D ng, rng tc, vim gan, thn, tng bch cu a acid, nhng li gim hoc
mt bch cu ht.
- Nc tiu mu da cam.
- Warfarin: dit khun
* Ch nh :
+ Phng hoc cha bnh tc nghn mch nh: vim tnh mch, tc mch phi,
nhi mu c tim.
* Chng ch nh: Ph n c thai, cho con b. Thuc c th i qua rau thai, qua sa.
Nng thuc trong rau thai v tr em b m cao c th gy xut huyt cho thai nhi v tr
b m. Nu ung thuc vo 3 thng u thai k c th gy cho tr s sinh mt s d thng
mi, mt, xng; cao huyt p, vim ty cp; lot d dy - t trng tin trin; tai bin
mch mu no v tng chy mu.

165
 * Cc thuc chnh: theo thi gian tc dng c chia thnh ba loi chnh
- Loi c i lc cao vi receptor, liu dng thp nhng tc dng bn: warfalin (6-
15), dicumarol (6-16).
- Loi c tc dng trung bnh: acenocumarol (6-17), phenindione (6-18).
- Loi c tc dng nhanh: etyl biscoumacetate (6-19).
O O
O O O O

OH OH OH
CH3

6-15 6-16
warfarin dicumarol
O

O O NO2

O
OH 6-18
CH3
phenindione
6-17
acenocoumarol
O
O O
O O

OH OH
O O

6-19 CH3
etyl biscumacetate

* Tng hp mt s dn xut ca cumarin v indandion:

Tng hp wafarin (6-15) va acenocoumarol (6-17):
166
 OH

COCH3 COCH2COOC2H5

(Et)2CO2 PU Maicon
-EtOH
OH OH O O
6-20 6-21 6-22

OH CH2COCH3
H
X C C COCH3
H
CH

6-23, X = H
X 6-24, X = NO2
O O

6-15, X = H: wafarin
6-17, X = NO2: acenocoumarol

Tng hp dicoumarol (6-16)

O OH

COOCH3

-CH3OH

COOCH3 O O O O
6-25
6-26
OH OH
CH2O

O O
O O
6-16
dicoumarol
Tng hp phenidione (6-18):

167
 O HC R

COOH
A-E
O H2C R O
NaOEt
-CO2 + H2O

O 6-27 6-28 O
bazo

O HC R

bazo
R O

6-29
O O
6-18, R = H: phenindione
6-30, R = OCH3: anisindandione
6-31, R = Cl: chclorindadione

Tng hp etyl biscoumacetate:

HO

H O O
CHO
6-19
COOC2H5 -H2O
O O H

OH

6.5.3. Cc thuc chng kt dnh tiu cu

Tiu cu l cc i bo ca ty sng, l nhng t bo khng nhn, hnh a, tch
in m mnh, ng vai tr quan trng trong giai on khi u ca qu trnh ng mu.
Trn b mt mng tiu cu c cha cc yu t ng mu I, V, VII v c cc fibrinogen
receptor (Gp IIb/IIIa) c c tnh kt dnh v kt t nn khi thnh mch b tn thng cc
tiu cu dnh vo ni b tn thng v dnh vo nhau thnh tng lp to ra nt trng tiu cu
cn gi l inh cm mu Hayem. Trong qu trnh kt dnh, tiu cu cn gii phng ra
phospholipid gip thc y qu trnh to ra phc hp prothrombinase.
168
 S kt dnh tiu cu l yu t to ra mng x va ng mnh v gy nn tc
mch. Hin c mt s thuc chng kt dnh tiu cu c s dng trong lm sng
phng v iu tr huyt khi nh: thuc chng vim phi steroid (aspirin), dipyridamol,
ticlopidin, clopidogrel v thuc c ch glycoprotein IIb/IIIa.

N N(CH2CH2OH)2
N
COOH S
N
(HOH2CH2C)2N N
N
N
OCOCH3 6-34
6-32 6-33
dipyridamole
aspirin Cl ticlopidine

* Aspirin (acid acetylsalicylic): Ngoi tc dng h st, gim au, chng vim,
aspirin cn c tc dng chng ng vn tiu cu.
- Dng liu thp duy nht 10mg/kg cn nng, cch qung 48 gi, aspirin c ch
90% cyclooxygenase ca tiu cu, rt t nh hng n cyclooxygenase ca ni m mao
mch nn nh hng khng ng k s tng hp ca prostacyclin I 2. Do vy, tc dng
chng kt dnh tiu cu v ko di thi gian chy mu liu ny l ti a. Dng liu cao
aspirin khng ch c ch COX tiu cu m cn c ch COX ni m mao mch nn hiu
qu chng kt dnh tiu cu khng cao.
- Ngoi c ch COX tiu cu, aspirin cn lm n nh mng tiu cu, hn ch
s gii phng ADP v phospholipid nn gim s kt dnh tiu cu v tng thi gian chy
mu.
- Ch nh: dng aspirin trong phng v iu tr huyt khi ng - tnh mch vi
liu duy tr 75 mg/ngy..
- Chng ch nh v tc dng khng mong mun (xin xem bi thuc h st, gim
au v chng vim).
- Ht sc thn trng khi phi hp aspirin vi thuc chng kt dnh tiu cu khc v
thuc chng ng mu nh heparin, dn xut coumarin.

169
 * Dipyridamol (Persantone, Peridamol): Va c tc dng gin mch vnh, va c
tc dng chng ng vn tiu cu do :
- c ch s nhp adenosin vo tiu cu v c ch adenosin desaminase lm tng
adenosin trong mu. Adenosin tc ng ln A 2-receptor lm gim s ng vn tiu cu.
- c ch phosphodiesterase lm tng AMP v trong tiu cu.
- Ch nh: thuc c phi hp vi warfarin trong phng huyt khi bnh
nhn thay van tim nhn to.
* Ticlopidin (Ticlid): Do ticlopidin tng tc vi glycoprtein IIb/III a receptor ca
fibrinogen lm c ch s gn fibrinogen vo tiu cu hot ha, ngn cn s kt dnh tiu
cu.
6.5.4. Cc thuc lm tiu fibrin
Cc mu ng c th tan tr li nh qu trnh tiu fibrin. l qu trnh ngc vi
ng mu. Bnh thng, enzym plasmin xc tc cho s tiu fibrin trong mu th khng
hot tnh gi l plasminogen. Trong iu kin nht nh, cc cht hot ha (kinase, activator)
c gii phng ra khi t chc, hot ha plasminogen to thnh plasmin. Plasmin va to
thnh gip fibrin tr thnh cht phn hu tan c.
Cc thuc lm tng tiu fibrin c hai loi:
- Loi enzim phn hy protein.
- Loi cht hot ha plasminogen: cht hot ha mu v hot ha m.
6.5.4.1. Cc enzim thy phn protein
Mi mt loi men proteaz c ngun gc t ng vt v cc cht c t nc rn c
ngun gc enzim phn hy c fibrin (c fibrinogen) nn v mt l thuyt c th s dng
ph tan cc cc mu. Cc proteaz c ngun gc ln men cng ph hy c fibrin nhng
tt c cc enzim phn hy anbumin ny khng ch ph hy fibrin m nhng nhn t ng
mu khc cng nh nhng anbumin khc ca huyt tng cng b phn hy. V tc dng
khng c hiu ny ca chng m khng c s dng trong iu tr.
6.5.4.2. Cc cht hot ha plasminogen
Cht hot ha plasminogen l nhng cht gip gii phng cht hot ha (kinase,
activator) hot ha plasminogen hoc tng tng hp plasminogen v cui cng lm cho
fibrin tr thnh cht phn hy tan c. Thng dng ethylestrenol, phenformin,

170
nicotinamid. Dng khi c th khng t gii phng c cht hot ha, v d khi mu tnh
mch do tai bin huyt khi tnh mch, hoc phng ti pht vim tnh mch.
1. Urokinase ( Abbokinase)
L endopeptidase, gm 2 chui a peptid cha 411 acid amin, trng lng phn t
53000, c phn lp t nc tiu ngi (URO = urine = nc tiu) hoc t nui cy t bo
phi thn ngi.
Urokinase xc tc cho phn ng ct lin kt peptid ca plasminogen (plasminogen
c 791 acid amin) to thnh lys-plasminogen v chuyn thnh plasmin. Lysin cui cng ca
plasmin l v tr gn c i lc cao vi fibrin gip cho s thu phn fibrin.
2. Streptokinase ( SK, Streptase)
Gm mt chui apeptid, phn t lng 48000, c phn lp t lin cu tan mu
nhm A. Streptokinase kt hp vi plasminogen theo t l ng phn t (equimolar) to
thnh phc hp SK-plasminogen. Phc hp ny ct lin kt arginin -valin v tr 560 ca
plasminogen chuyn thnh SK-plasmin c hot tnh tiu fibrin.
Ngoi tiu fibrin, Sau khi tim tnh mch vi liu thp thi gian bn thi khong 18
pht streptokinase cn xc tc cho phn ng thu phn nucleoprotein thnh cc base purin
t do v pyrimidin nucleotid, do vy lm long cc dch ng c nh m. Nhng khi tim
liu cao hoc liu thp ko di th thi gian bn thi t 83 pht v ht hin tng kt hp
khng th khng streptokinase do bo ha. Thuc b chuyn ha v thi tr qua thn.
- Trong qu trnh dng thuc c th gp mt s tc dng khng mong mun: chy
mu, d ng hay gp vo ngy th 8, nn sau khi dng thuc 8 ngy, cn phi chuyn sang
dng thuc khc.
3. Anitreplase (Aminase)
L phc hp ca plasminogen ngi tinh khit v streptokinase ca vi khun
c acetyl ho bo v v tr hot ng ca enzym. Khi s dng, nhm acetyl c thu
phn, gii phng phc hp streptokinase - cht tin hot ho thnh phc hp, hot ho
plasminogen thnh plasmin. Thuc c tc dng trn plasminogen ca cc mu ng mn h
hn plasminogen t do nn lm tan cc huyt khi nhanh.
Ngoi c ch trn thuc cn lm gim yu t V,VIII v cht c ch tiu fibrin o-2-
antiplasmin.

171
4. Cht hot ho plasminogen m (t-PA, Alteplase)
L mt protease sn phm ca k thut ti to gen cha 527 acid amin c tc dng
trn plasminogen gn vi fibrin mnh gp vi trm ln plasminogen t do. Khi lng fibrin
thp tc dng chuyn plasminogen thnh plasmin thp. Thuc c thi gian bn thi ngn 5 -
10 pht. Trong nhi mu c tim cp tim tnh mch 15 mg sau truyn tnh mch 50 mg
trong 30 pht v trong 60 pht tip theo truyn 35 mg (tng liu truyn trong 90 pht khng
vt qu 100 mg).
5. Reteplase (r-PA, Retavase, Rapilysin)
L cht hot ho plasminogen ti t hp thuc th h th 3, tc dng ging
Alteplase nhng cng v thi gian xut hin tc dng nhanh hn. Thuc c dng
trong nhi mu c tim cp khi u tim chm tnh mch 10 n v trong 2 pht sau c
30 pht tim thm 10 n v.
6. Tenecteplase (Metalyse)
Thuc mi c tc dng tiu fibrin v ch nh nh reteplase, tim tnh mch ton b
liu 500-600 mcg/kg nhng khng vt qu 50mg.
Ch nh v chng ch nh ca cc thuc tiu fibrin
* Ch nh:
- Tc nghn ng, tnh mch
- Nhi mu c tim
- Vim m, ng mu mng phi hoc cc khp xng hay cc hch dng
streptokinase ti ch.
- Bm vo ng dn lu m trnh tc (streptokinase).
* Chng ch nh
- Sau khi phu thut cha qu 8 ngy; mi hoc sy thai cha qu 4 ngy; cao
huyt p nghim trng, qu trnh cm mu bt thng; c a d ng; mi dng streptokinase
cha qu 6 thng; mi b bnh do lin cu; c thai (thuc khng qua rau thai, nhng
phng bong rau sm); chy mu ng tiu ha nng trong vng 3 thng; tin s tai bin
mch mu no; vim mng ngoi tim cp; phu thut ng mch ch; vim ty cp; bnh
gan nng.
6.5.5. Thuc chng tiu fibrin

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 C trng thi bnh lm tiu nhanh fibrin, gy chy mu trm trng, v d khi ngi
b bnh tng plasmin trong mu. Plasmin khng nhng lm tiu fibrin, m cn kt hp vi
mt s yu t ng mu v hy hoi chng, lm c ch ng mu cng ri lon.
Nhng phn t mi sinh do fibrin b hy cng kt hp li vi fibrin cho phc
hp khng ng c na. Nhng cht phn hu ny cn lm cho tiu cu khng ngng kt
thnh cc c. Kt qu lm chy mu trm trng.
Thuc lm gim s tiu fibrin s c tc dng cm mu. Thuc chng tiu fibrin c
hai loi:
- Thuc l cc cht c ch c ngun gc t nhin (aprolinin) l cc cht c cu trc
polipeptit, c tc dng c ch protease. Do cu trc l polipeptit nn thuc ch hiu qu
ngoi ng tiu ha nn vic s dng b hn ch.
- L cc a peptit base. Aprotinin (Trasylol) l thuc c ch protease gm 58 acid
amin, c 3 cu ni disulfur, phn t lng 6500, ly t tuyn mang tai, phi, gan. iu ch
t tin, thi gian bn thi ngn:150 pht; ch tim tnh mch hoc truyn tnh mch vi liu
lng tu thuc vo ch nh. Phng chy mu khi phu thut tim m liu 2000000 n v,
chy mu do tng plasmin mu khi u 500000-1000000 n v.
Thuc to phc vi plasmin cho phc hp mi aprotinin -plasmin khng c
hot tnh plasmin. Aprotinin cn c ch c cc enzym hu protein khc na, nh trypsin,
chymotrypsin, kalikrein.
Aprotinin thi qua nc tiu di dng mt hot tnh, nn khng dng chng tiu
fibrin ng tit niu. Dng nhiu ln c th gy nhng phn ng qu mn ngi c c
a d ng.
- Cc cht c ch tng hp: trong s cc cht c ch tng hp s dng thnh cng
trong iu tr hin nay phi k ti cc thuc sau

173
 H2N H2
COOH H2N C COOH

6-35
axit -aminocaproic 6-36
H axit p-aminomethyl banzoic

H2N COOH

6-37
H axit tranexamic

* Acid - aminocaproic
C cu trc ging lysine c tc dng chng tiu fibrin nh hai nhm amin v
carboxyl cch nhau 0,7nm, c ch s hot ha ca plasminogen, km hm khng cho
plasmin tc ng ln fibrin, lm cho fibrin khng b ging ha bi plasmin na.
Thuc khng c ch c cc cht hot ha plasminogen (kinase, activator). Thuc
c th ung 24 gam chia lm 4 ln trong ngy hoc tim chm tnh mch 5 - 7,5g d
phng hoc iu tr chy mu.
* Acid tranexamic (Cyclokapron) l ng ng v c tnh cht, tc dng ging
acid - aminocaproic, c th tim tnh mch hoc ung phng chy mu sau m tuyn
tin lit, nh rng ngi b hemophilia hoc qu liu thuc tiu cc mu ng hoc ph n
b a kinh vi liu 2 - 4g/24 gi, chia lm 3 ln.
p dng iu tr ca thuc chng tiu fibrin
- Ch nh: Dng trong trng thi tiu fibri n nguyn pht, tiu fibrin cp, d phng
chy mu sau phu thut to hnh, tai mi hng, ct b tuyn tin lit v.v...
- Chng ch nh: c tnh ca Acid - aminocaproic v acid tranexamic rt t, tuy
nhin cn dng thn trng khi suy thn nng (c th g y tch lu thuc), khi c tin s hoc
c biu hin huyt khi tc tnh mch hoc ng mch.

174
 CHNG 7. THUC TC DNG TI CC C QUAN H HP
7.1. H h hp
H h hp: gm c mi, thanh qun, kh qun, ph qun v phi, c nhim v a
-xi trong khng kh vo phi v thi kh cac-b-nic ra mi trng ngoi.

Hu hng ging nh mt ng t giao nhau gia mt bn l mi & kh qun, bn

cn li l ming & thc qun. iu ny c ngha l lng khng kh ht vo c th mang
theo bi bm cha mm bnh gy ra vim nhim cho h h hp ln h tiu ha trn, m c
th l vng hu hng.
Thanh qun l on u tin ca ng dn kh vo c th. Thanh qun c cha hai
dy thanh c chc nng chnh trong vic pht ra cc m tit khc nhau trong ngn ng &
nhng m thanh khc pht ra t mi ming.
Kh qun l mt ng c cu to ch yu l sn, bt ngun t thanh qun ri chy
song song vi thc qun bn trong lng ngc. u cn li ca kh qun c chia l hai
nhnh ln dn kh vo tng phi qua v s cc nhnh dn kh c phn chia tip theo
(gi l tiu ph qun) n tng v tr trong m phi. Cc tiu ph qun dn kh n phi lm
thi phng cc ti kh bn trong phi (gi l ph nang), ni din ra qu trnh trao i kh vi
hng cu. T hai nhnh ph qun vo hai phi, s phn chia thnh cc tiu ph qun & tiu
tiu ph qun cn thit dn kh cho c 300-400 ph nang cho mi bung phi.

175
 Qu trnh trao i kh xy ra do vic tip xc gia hng cu vi khng kh giu
oxy trong ph nang. Cc hemoglobin c trong hng cu bt gi ly cc phn t oxy & nh ra
cc phn t CO2 vo ph nang. y l chc nng c bn v thit yu nht ca h h hp.
Hin nhin CO2 s b thi ra ngoi trong th th ra, cn O2 c em n cung cp
cho t bo t chy nhin liu to ra nng lng cho mi hot ng ca c th. Qu trnh
ny c tip din tng ngy, tng gi, tng pht, tng giy duy tr chc nng c bn ca
s sng.
C honh ng vai tr ch o trong qu trnh ht th. Mt khi c honh y ln
trn, to ra mt sc nn lm nh lng ngc li v c tc dng y kh ra ngoi, gi l th th
ra. Tng t, ht vo, c honh s h xung lm gia tng th tch bn trong lng ngc,
ko theo s gin n ca hai bung phi lm cho khng kh tun y vo bn trong, gi l th
ht vo. Nn th l mt ng tc c gng lm bt ng c honh v th tch lng ngc c
gi nguyn, kh s khng lu chuyn ra vo.
Nhng bnh l gp phi h h hp:
Hen suyn: Trn 20 triu ngi M mc chng bnh ny v y l nguyn nhn
chnh lm gin on vic hc hnh ca tr. Suyn lu ngy dn n tnh trng nhim trng
phi mn tnh gy ra tt nghn, co hp ng th. Tnh trng hen suyn khng ch l nhng
dng trm trng nh Bn thng thy. Nhng trng hp c xut hin kh th mi khi ht
phi cc cht gy kch thch nh khi thuc l, bi bm hoc lng xc vt cng l tnh
trng ca suyn ri.
Vim ph qun: Vim ph qun thng thy nhng ngi ht thuc hoc lm
vic trong mi trng nhiu bi bm hoc cc ha cht gy c. Khi vim ph qun, cc
nim mc ph qun tng tit dch qu mc gy ra tnh trng kch thch ho nhiu v tng khc
m di.
Cm cm: Cm cm gy ra bi 200 loi virus khc nhau & gy vim nhim
ng h hp trn (mi, hng & thanh qun). Cm cm l bnh thng thy nht gy ra
nhim trng h hp. Cc triu chng bao gm st nh, ho, au u, chy nc mi, ht hi
& au hng.
Ho: Ho l mt triu chng ch khng phi l mt bnh l. C nhiu loi ho do
nhiu nguyn nhn khc nhau gy ra. Triu chng ho c th ca mt bnh l rt nh hoc

176
thm ch ca mt bnh l trm trng nh ung th phi chng hn. Mt s bnh l gy ho
thng gp l cm cm, suyn, vim xoang, d ng, vim phi, ...
Bnh tng tit m nht: l mt bnh l c lin quan n di truyn gy ra tnh
trng bt thng cht nhy bn trong lng ng th, gy hp ng th gy ra kh th &
phi d b nhim trng hn.
Vim phi: Vim phi l tnh trng nhim khun su bn trong hai bung phi.
Vim phi c th do virus (influenza), c th do vi khun (thng thy do vi khun
Streptococcus Pneumoniae). Vim phi gy ra st, tn thng cc nhu m phi, kh th.
Thuc s dng iu tr cc b phn ca h thng h hp:
- Thuc tc dng ti nim mc mi
- Thuc lm gin ph qun
- Thuc c tc dng long m
- Thuc chng ho
- Thuc kch thch h hp, thuc hi sc h hp
- Thuc cha hen
7.2. Cc nhm thuc tc dng ti h h hp
7.2.1. Thuc tc dng ti nim mc mi
Mi nh ngi nh khng ca, v vy bi bm vi trng, virt gy bnh thng xuyn
c mt trong mi ca chng ta. Nu khng lm v sinh hng ngy, mi s d nh nh khng
c qut dn vy. Cng chnh v mi thng vi mi trng bn ngoi nn khi cha ht
vim mi t ny, sau khng gi gn k c th b tip t sau lm cho chng ta ngh vim
mi, vim xoang khng iu tr ht.
Thng th ngi ta ni vim mi, nng na vo xoang th ni vim xoang. Khi
vim mi xoang th nim mc mi b sung huyt sng n lm chy mi nght mi.
Vim mi c nhiu loi, vim mi do nhim khun, vim mi do nhim virt, vim
mi do d ng thi tit Vim mi theo thi tit gi l vim mi d ng theo ma. Khi c
th khe mnh th thi tit c thay i cng t b bnh. Nhng khi ngi khng khe li
thm c c a d ng th ch cn thay i thi tit, hay ht phi bi bm hot ht phi ha
cht cng c th s mi, ht hi
Triu chng ca vim mi:

177
 au hng thng xuyn
Khn ging
Nght mi thng xuyn m khng c cc triu chng khc.
Thng phi th bng ming (c bit lc ng) v hay gp tr em.
Ng thng hay ngy
Tr em hay b nhim trng tai gia
Thng hay b nhc u m khng c nguyn nhn khc
Ho, c bit tr em lc nm ng ban m
Mi mt cm gic v mi
Thng hay b ri lon gic ng.
Cc thuc tc dng ti nim mc mi: chia thnh 3 nhm cu trc
7.2.1.1. Cc dn xut ca -phenyl-etylamin
Mt s hp cht quan trng c tc dng ti nim mc mi
Epinephrine (7-1) HO
OH

HO C CH2NHCH3
H

Phenylephrine (7-2) HO
OH

C CH2NHCH3
H

Ephedrine (7-3) OH CH3

C CHNHCH3
H

Norephedrine (7-4) OH CH3

C CHNH2
H

178
 Mephentermine (7-5) OH CH3

C CNHCH3
H

CH3

Tng hp mt s hp cht:
* Norephedrine (7-4): t 1-phenyl-1-hydroxy-propanon-2:
OH CH3 OH CH3

H2/CH3OH/Ni
C O + NH3 CH NH2

7-4
norephedrine

* Ephedrine:
OH CH3 OH CH3

H2/CH3OH/Ni
C O + CH3NH2 CH NHCH3

7-3
ephedrine

7.2.1.2. Cc dn xut ca ankyl etylamin

Tn Cng thc
Propylhexedrine (7-6)
H2 H
C C NHCH3

CH3

Cyclopentamine (7-7)
H2 H
C C NHCH3

CH3

Tuaminoheptane (7-8) H
H3C (CH2)4C NHCH3

CH3

Tng hp mt s hp cht:
* Propylhexedrine (7-6):

179
 OH CH3 OH CH3
H2
C CHNHCH3 C CHNHCH3
H AcOH/PtO2 H

* Tuaminoheptan (7-7):
H2 H
H3C (CH2)4C O + CH3NH2 H3C (CH2)4C NHCH3
EtOH/PtO2
CH3 CH3

7.2.1.3. Cc dn xut ca imidazol

H3C N
N
H2
H2 H3C C C
C
H3C N
N H
H 7-9
7-8 xilometazoline
naphazoline

NH.HCl

CH2CN CH2C
C2H5OH/HCl OC2H5 H2NCH2CH2NH2
7-8
naphazoline
N
H2
C

N
H
7-8
naphazoline

180
 CH3 CH3

CH2O/HCl NaCN
(H3C)3C (H3C)3C CH2Cl
ZnCl2

CH3 CH3
CH3
CH3
H
N 1) C2H5OH/HCl
H2 (H3C)3C CH2CN
(H3C)3C C 2) H2NCH2CH2NH2
N
CH3
CH3
7-9
xilometazoline

7.2.2. Thuc lm gin ph qun

Trong iu tr bnh phi tc nghn mn tnh (BPTNMT) v hen ph qun, ngoi
vic trnh cc tc nhn kch thch nim mc h hp (khi thuc l, bi, d nguyn khng
kh), s dng liu php oxygen, thuc khng vim v khng sinh khi cn thit; vic iu tr
ch yu vn phi dng n thuc gin ph qun (PQ) nhm gim triu chng kh th v ci
thin chc nng h hp.
Hin nay, c ba loi thuc gin PQ chnh c s dng trong lm sng:
- Ch vn b2
- Khng-cholinergic
- Methyl-xanthin
7.2.2.1. Thuc Ch vn b2
Thuc ch vn b 2 l thuc c chn u tay trong cc bnh h hp c hin tng
co tht ph qun. Cc th th giao cm b 2 ch yu hin din trong phi v c phn b
khp h thng ng dn kh v ph nang. C ch gy gin PQ ca thuc ch vn b2 l trc
tip gn vi cc th th b 2 trn b mt t bo c trn, gy gin c. Mt khc, thuc ch vn
b2 cn c ch s phng thch cht trung gian t cc t bo vim, ci thin s thanh thi cht
tit ng h hp.
Cc thuc chnh hin dng l salbutamol, terbutalin v fenoterol. a s u l
nhng ch phm c dng dng thuc ht. Tc dng gin PQ ko di khong 4 n 6 gi

181
v c gi l thuc ch vn b 2 tc dng ngn, phn bit vi nhng thuc ch vn b2 mi
hn (salmeterol v formoterol), c tc dng gin ph qun di n 12 ting.
OH
OH
HO H
N
HO

HN
HO
HO
terbutalin
salbutamol OH

HO

HN
HO
fenoterol

OH

Salbutamol l mt thuc ch vn b 2 c tnh chn lc cao v l thuc an ton nht

thuc nhm ny. Terbutalin cng c tnh chn lc tng t i vi th th giao cm b2 v
cn c dng di dng thuc ung (tin dc bambuterol). Fenoterol c hiu lc gin PQ
mnh nh salbutamol.
Salmeterol khi pht tc dng chm hn (chng 15 pht) so vi cc thuc tc dng
ngn; do khng thch hp dng trong cn hen cp. Tc dng ko di ca n thun li
cho vic kim sot cc cn hen v m v nga kh th khi gng sc. Formoterol cng l
mt ch vn b2 chn lc, c tc dng gin PQ khi pht nhanh v ko di hn salmeterol.
Trong hen ph qun, hiu lc gin PQ ca formoterol khi dng vi liu ht 12-24 mg ngy 2
ln, t ra bng hoc ln hn hiu lc ca salbutamol, fenoterol hoc terbutalin.
Cc tc dng ph ca thuc ch vn b2 khi dng ng ung hoc tnh mch
thng xy ra hn khi dng dng ht. Tc dng ph thng thy l: nhp tim nhanh (kch
thch phn x i vi cc th th b1 tim sau khi gin khng sc ngoi bin), run, tng
ng huyt v gim kali-mu. Khi dng lu di, c th s quen dn vi nhng tc dng ph
ny. Tuy vy, tc dng ph ca ch vn b2 c th tr thnh vn quan trng i vi s

182
ng bnh nhn BPTNMT, ngay c khi dng thuc ht, v bnh ny phi cn n thuc gin
PQ liu cao nhiu hn so vi hen ph qun.
7.2.2.2. Thuc khng-cholinergic
Thn kinh i giao cm ng h hp ch yu chi phi cc ng dn kh ln
phi. Thuc khng-cholinergic c ch tc ng ca acetylcholin c tit ra u tn si
i giao cm trn c trn - l mt tc ng thng qua th th muscarinic M3 lm co c
trn - nn c tc dng gin PQ nh gim trng lc i giao cm ca c trn ng h hp.
Do vy, thuc khng-cholinergic t c tc dng trn ngi bnh thng m ch th hin tc
dng gin PQ trn nhng bnh nhn b co tht ph qun di tc ng ca kch thch i
giao cm.
Thuc khng-cholinergic c dng nhiu nht hin nay l ipratropium bromid.
Hp cht ny c hot tnh ti ch v km c hp thu qua phi v ng tiu ha, nn
thng c dng di dng ht. Mt thuc mi l oxitropium bromid, cng l mt cht i
khng th th muscarinic khng chn lc, c tc dng di hn nhng khi pht mun hn v
khng mnh bng ipratropium bromid.

Br N

OH

Thuc khng-cholinergic c xem l hu hiu trong iu tr BPTNMT hn l

trong hen ph qun. Tuy nhin, trong hen ph qun cng c mt trng lc i giao cm
nht nh, nht l ngi gi b hen km vim ph qun, nn cng c p ng vi loi thuc
ny. Thuc khng-cholinergic vn hu ch cho bnh nhn khng p ng hoc khng dung
np c cc thuc gin PQ khc dng iu tr hen. Trong hen ph qun, nhm thuc ny

183
khng hiu qu bng thuc ch vn b2 v chng ch ngn nga s co tht ph qun qua trung
gian i giao cm.
Ipratropium bromid t c hp thu nn khng thy c tnh ton thn. Nhng
nghin cu lm sng cn thy ipratropium bromid v oxitropium bromid khng nh hng
n s thanh thi cht tit phi, hoc trn th tch v qunh ca m trn bnh nhn
BPTNMT.
Tc dng ph ng lu nht l c ch tit nc bt khi dng liu cao hn liu
iu tr. i khi c th thy co tht ph qun nghch thng do s c ch th th M2 tin tip
hp trn si i giao cm (bnh thng c ch s phn tit acetylcholin).
Tiotropium bromid - mt thuc khng-cholinergic mi - c tc dng ko di, ch
cn dng ngy mt ln di dng ht, ang c nghin cu s dng trong BPTNMT. V
cu trc, y l mt hp cht ammoni ha tr c lin quan vi ipratropium bromid. Do ,
ngi ta hy vng tiotropium bromid cng hu hiu v an ton khi dng trong BPTNMT v
hen ph qun.

H2
Si S
N

O
OH

O
O
S

184
7.2.2.3. Cc dn xut xanthin

H 3N CH2
(H3C)3N CH2CH2OH
O H2N CH2
O
H3C
N H3C
N N
N

N
O N
N
O N
CH3
choline theophylinate (7-11) CH3
7-10
theophylamin
dimetyl xanthin

O O O O

OH

HO OH
O O

Cromolyn natri-Cromoglicic axit

O O
Theophyllin l thuc cng giao cm thng dng nht thuc nhm ny, c dng
ung v tim tnh mch, nhng khng c dng ht.- Nhng nghin cu gia thp nin 90 cho
thy ngoi tc dng gin PQ thuc cn c tc dng khng vim. Tuy vy, theophyllin lm
gim oxygen tun hon no, nn c th gy co git khi dng liu cao.
Nhng tc dng khc ca thuc l: li tiu, kch thch c tim v kch thch h hp.
Tc dng ph ca thuc bao gm bun nn, nhc u, nhp tim nhanh, kh ng.
Tc dng gin PQ ca theophyllin khng mnh bng tc dng ca thuc ch vn b2
v thuc khng-cholinergic. Hn na, liu gin PQ thng cao hn liu chng hen v gn
vi liu gy c tnh. C ch gy gin PQ ca theophyllin ni chung cha c hiu r.
Hin nay, theophyllin t c dng nh mt thuc gin PQ v khng an ton bng cc thuc
gin PQ mi.

185
 Cromolyn natri thng c dng nh mt iu tr b tr trong hen ph qun. C
ch tc dng ca thuc vn cha c bit r. C gi thuyt cho rng thuc ny c tc dng
n nh cc t bo vim c ch s phng thch cc cht trung gian t- nhng t bo ny,
nhng tc dng ny rt- kh chng minh trn ngi. Thuc ch c tc dng d phng co tht
ph qun, nhng khng hu ch mt khi tnh trng co tht ph qun xy ra. Trn lm
sng, cromolyn natri thng dng di dng thuc ht cho bnh nhn hen ph qun cn tr.
i vi bnh nhn BPTNMT, thuc c rt t tc dng.
Trong bnh hen ph qun v BPTNMT, iu tr bng thuc gin PQ ch l iu tr
triu chng, thng c ch nh trong cc t tr nng hoc c triu chng kh th cp do
co tht ph qun. Xu hng chung hin nay trong vic s dng thuc gin PQ l:
- t dng methylxanthin v nhng tc dng ph ton thn kh kim sot, c bit l
khi dng ng tnh mch trn bnh nhn ln tui hoc tr em;
- Cromolyn natri ch c tc dng d phng co tht ph qun, c s dng hn ch
trn bnh nhn hen nh mt iu tr b tr, ch khng phi l thuc gin PQ tht s, v hon
ton khng c tc dng trong BPTNMT;
- Thuc ch vn b2 c tc dng chn lc c dng nh thuc gin PQ u tay
trong cc bnh ng h hp, c bit trong hen ph qun, v ty yu cu iu tr (ct cn
nhanh, d phng cn hen hoc kh th v m) m chn thuc c tc dng ngn
(salbutamol, terbutalin) hoc ko di (salmeterol. formoterol), nhng khng nn dng di
hn v s b ln thuc;
- Thuc khng-cholinergic (ipratropium bromid, oxitro-pium bromid, tiotropium
bromid) c u tin s dng trong BPTNMT, c th s dng di ngy vi hiu qu cao khi
dng phi hp vi thuc ch vn b2 di dng ht;
- Cc thuc gin PQ hin ang thng dng trn lm sng u c dng dng kh
dung, nn bnh nhn cn c hng dn cch dng ng k thut t hiu qu cao nht.
Hng nghin cu hin nay v thuc gin PQ l pht trin nhng thuc mi c tc
dng ch vn chn lc hn na trn th th giao cm b2 hoc cc thuc c ch chn lc th
th i giao cm M2 v M3; nh gi kh nng dung np khi iu tr lu di vi thuc khng-
cholinergic v/hoc phi hp thuc khng-cholinergic vi ch vn b2. Nhng nghin cu
ny hin nay ch mi c thc hin trn mt s t bnh nhn. Kh nng p dng thuc gin

186
PQ mi trn lm sng cho bnh nhn hen v BPTNMT phi ch cho n khi c kt lun r
rng.
7.2.3. Thuc long m
Thuc long m l nhng thuc c tc dng lm tng bi tit cht nhn v lm du
bi tit.
7.2.3.1. Thuc lm tng bi tit cht nhn (cht nhn c)
CH3

HO C OH

CH3
H3C H

terpin hydrat

Terpin hydrat l mt cht long m, thng c s dng lm lng cht nhy

trong cc bnh vim ph qun cp tnh hoc mn tnh v bnh lin quan. N c ngun gc
cc loi du nh tinh du nha thng, hng ty v bch n.
CH3
CH3

HO C OH
H3C
H2O/H2SO4
CH3
H3C H3C H

terpin hydrat

Loi thuc ny thng c dng di dng kt hp v bng ng ung.

7.2.3.2. Thuc lm du bi tit cht nhn long
C nhiu nhm cu trc khc nhau c tc dng sinh hoc ny. Mt trong s nhm
l cc siro ca cy ipecacuana (hot cht emetine), siro ca antimony-kali-tartarat, natri
citrat, amoni clorua v kali iodua.

187
7.2.3.3. Thuc lm tan dch nhy
Thuc tc ng trn giai on gel ca nim dch bng cch ct t cu ni disulfur
ca cc glycoprotein tng ra ngoi.
H2 H H2 H2 H
HS C C COOH HOOC C S C C COOH

HN COCH3 NH2
7-13
7-12 carbocysteine
acetylcysteine
* Acetylcystein
- Dc ng hc: Sau khi ht qua ming hoc nh thuc vo kh qun, phn ln thuc tham
gia vo phn ng sulfhydryl - disulfid, s cn li c biu m phi hp thu. Sau khi ung,
acetylcystein c hp thu nhanh ng tiu ha v b gan kh acetyl thnh cystein v sau
c chuyn ha.
- Tc dng: Acetylcystein c dng lm thuc tiu cht nhy v thuc gii c
khi qu liu paracetamol. Thuc lm gim qunh ca m phi c m hoc khng bng
cch tch i cu ni disulfua trong mucoprotein v to thun li tng m ra ngoi bng
ho, dn lu t th hoc bng phng php c hc.
188
 Acetylcystein cng c dng ti ch iu tr khng c nc mt.
Acetylcystein dng bo v chng gy c cho gan do qu liu paracetamol,
bng cch duy tr hoc khi phc nng glutathion ca gan l cht cn thit lm bt
hot cht chuyn ha trung gian ca paracetamol gy c cho gan.
- Chng ch nh : Tin s hen (nguy c phn ng co tht ph qun
vi tt c cc dng thuc cha acetylcystein). Qu mn vi acetylcystein.
- Tc dng ph: Acetylcystein c gii hn an ton rng. Tuy him
gp co tht ph qun r rng trong lm sng do acetylcys-tein, nhng vn c th xy ra vi
tt c cc dng thuc cha acetylcystein. Thng gp: bun nn, nn. t gp: Bun ng,
nhc u, tai. Vim ming, chy nc mi nhiu. Pht ban, my ay. Him gp: co tht
ph qun km phn ng dng phn v ton thn. St, rt run.
- Qa liu : Qu liu acetylcystein c triu chng tng t nh triu chng ca
phn v, nhng nng hn nhiu c bit l gim huyt p. Cc triu chng khc bao gm suy
h hp, tan mu, ng mu ri rc ni mch v suy thn. T vong xy ra ngi bnh b
qu liu acetylcystein trong khi ang iu tr nhim c paracetamol. Qu liu acetylcystein
xy ra khi tim truyn qu nhanh v vi liu qu cao.
7.2.4. Thuc cha ho
C rt nhiu nguyn nhn gy ho v phn x ho l c ch t v sinh l quan trng
ca c th tng ra ngoi cc d vt phn trn ca ng h hp c th gy tc ng th
ra ngoi. Tuy nhin, nu ho qu mc th vic iu tr triu chng ho l rt cn thit.
Ch dng thuc gim ho trong trng hp ho khng c m, ho nhiu lm ngi
bnh mt mi, mt ng. Khng dng thuc lm gim ho trong trng hp ho c m (trong
bnh vim ph qun mn, gin ph qun...) v ho c coi nh c ch bo v c li, lm
sch ng th.
Cc thuc gim ho c chia lm 2 loi:
- Thuc gim ho ngoi bin
- Thuc gim ho trung ng
7.2.4. Thuc gim ho ngoi bin
C tc dng lm gim nhy cm ca cc receptor gy phn x ho ng h hp.
C th dng mt ong, glycerol (lm du ho do c tc dng bo v, bao ph cc receptor cm

189
gic hng); benzonatat, bc h cn gi l menthol (c tc dng gy t cc ngn dy thn
kinh gy phn x ho nn lm gim ho).

C4H9HN COO (CH2CH2O)9CH3

7-14
benzoatate (menthol)

Benzonatat c tc dng gim ho. N c tc dng gy t tng t benzocaine v lm

t lit cm gic dn trong phi. Benzonatat xut hin tc dng 15-20 pht sau khi ung, tc
dng ko di gi. Thuc khng lin quan n cc thuc gim au gy nghin nh codein
(thng dng gim ho).
Tc dng ph: phn ng c hi hay gp nht khi dng benzonatat l bnh thn, au
u, hoa mt, to bn, bun nn v nn.
7.2.4.2. Thuc gim ho tc dng ln trung ng
Cc thuc ny c ch trc tip trung tm ho hnh tu, ng thi c tc dng an
thn nn c ch nh c trung tm h hp. Cc thuc loi ny l cc cht c cu trc l dn
xut ca ancaloit mocphin (cc cht c tnh gy nghin) v mt s cu trc khng c tnh
gy nghin khc.
1. Cc thuc gim ho c tnh cht gy nghin
O O
H3C H3C

O H O H

H H
N CH3 N CH3

HO O
7-15 7-16
codeine hidrocodone

190
 C6H5 CH3 C6H5
H2 H2 H2
H3CH2COC C C CH N(CH3)2 H3CH2COC C C C N(CH3)2

C6H5 C6H5
7-17 7-18
methadone normethadone
C6H5 H
C6H5 N
O
H2 H2
HO C C C N(CH3)2 H C CH
CH2CH2 N
N
C6H5 C6H5
7-20
7-19 prenoxdiazine
clofenadone
C6H5 H
N
C6H5 O
NH2 O Na/C2H5OH
H2 C CH2CH2 N H C CH
CH C C
CH2CH2 N
N
C6H5 OC2H5 C6H5
N OH
7-20
prenoxdiazine
OH OH
C6H5
Zn (CH3)2NH
C O CH3COOC2H5 (C6H5)2C CH2COOC2H5 (C6H5)2C CH2CON(CH3)2

C6H5

LiAlH4

C6H5
H2 H2
HO C C C N(CH3)2

C6H5

7-19
clofenadone

7.2.4.2.2. Cc thuc gim ho khng gy nghin

Cc thuc gim ho khng gy nghin bao gm nhiu nhm cu trc ha hc khc
nhau v c c ch tc dng khc nhau. Cht gim ho khng gy nghin hay c s dng
ngoi prenoxdiazine cn c dextromethorphane (7-21) v noscapine (7-22).

191
 O

H OCH3
N
O
CH3

O
H3C H
O
H

H3C N

O
H3C O
O CH3
7-21
7-22 dextromethorphane
noscapine
Tc dng gim ho ca dextromethorphane khng mnh bng codeine nhng khng
gy nghin nn ngy cng c a dng. Thuc khng dng cho ngi suy h hp, ngi
hen v tr em di 15 tui.
Noscaphine l ancaloit khng c tc dng gim au ca thuc phin, c cu trc
isoquinolein nh papaverin, c tc dng gim ho trung ng v ngoi bin nhng cng ch
bng ca codeine. Khng c ch h hp v khng gy nghin.

7.2.4.3. Cc thuc gim ho nhm khng histamin

Mt s thuc c tc dng khng histamin H1 trung ng v ngoi bin ng thi
va c tc dng chng ho do d ng ng h hp trn, khng serotonin, khng cholingic
v an thn. Cc cht loi ny c dng lm thuc chng ho gm trimeprazine 7-23 v
clocinizine c tc dng lm kh cc cht tit, gim lng m sinh ra.
S C6H5
H2 H
Cl C N N C C C C6H5
H H

N
7-25
H2 C CH(CH3)CH2N(CH3)2 clocinizine
7-23
trimeprazine

192
 Trong trng hp khc, v d nh ho do vim ph qun, khng histamin c th gy
nguy him do lm kh cht tit khin kh khc m. Tc dng ph l gy bun ng, kh
ming, to bn, tiu kh (c th gy b tiu ngi b u x tin lit tuyn).
7.2.5. Cc thuc kch thch h hp, hi sc h hp
Kch thch h hp l cch iu tr hen ph qun (astma bronchiale) nhng kch
thch h hp cng c th gi mt vai tr quan trng trong vic bo v ngi bnh khi tc
dng ca cht c ti trung tm h hp.
Suy h hp cp l trng thi suy sp chc nng h hp hnh thnh nhanh chng,
xy ra trn mt bnh nhn khng c tin cn bnh l h hp, i hi phi iu tr ngay, nu
khng s e da sinh mnh bnh nhn.
Suy h hp c rt nhiu nguyn nhn khc nhau, nhng trong mi trng hp cn
thc hin cc yu cu thc hin cc yu cu bt buc m bo lu thng ng th v
thng kh h tr.
Suy h hp l mt trnh trng bnh l cp cu thng gp trong cc khoa hi sc
cp cu, trong v sau m, trong mt s cc bnh ni, ngoi khoa, ly, nhi ...
Kch thch c th t c bng cch tc dng trc tip hoc thng qua th th iu
hnh h hp v tun hon.
Nguyn nhn ca suy h hp:
Gm 2 hi chng ln:
1. Do tc nghn ng h hp
2. Do cc nguyn nhn t trong lng kh ph qun
* Triu chng ca suy h hp:
+ Kh th:
Khi thiu oxy km theo tng hay gim CO2 u gy kh th.
Khi kh th c th chia lm 3 mc :
- 1: kh th khi gng sc, nhp th cha thay i, cha co ko cc c h hp.
- 2: kh th lin tc, thng xuyn, co ko cc c h hp, c trn n, cnh mi
php phng, nhp th thng tng > 25 l/p, th thng su, c khi c ting rt, kh kh ...
- 3: kh th d di, nh ai chn c, gng sc m th, nhp th thng nhanh c
khi n > 40 l/p, bin c khi rt su.

193
 - C khi li th yu, chm nhp th gim < 13 l/p, bin nng, c khi th ngp c.
+ Xanh tm:
Khi kh thng km theo xanh tm c th:
- Xanh tm mi v cc u chi khi Hb > 5g/100 ml PaO2 di 85% nhng cc u
chi cn m.
- C th c tm ti c da,chn tay lnh, c shock km theo.
- C khi li ta, v m hi: trong trng hp tha CO2.
+ Ri lon tm thn kinh:
No tiu th 1/5 s oxy ton c th dn n khi thiu oxy, no chu hu qu sm
nht, nht l tnh trng thiu O2 + CO2 gim hoc tng trong mu.
- Nu nh th kch thch ht hong, kh chu.
- Nng hn: Giy da, ln ln, mt phn x.
- Rt nng: Ri lon thc, l , li b hoc bn m khi c hn m.
+ Ri lon tim mch:
- Nhp tim: thng l nhanh xoang hoc c nhp nhanh b ni, c khi rung nh
rung tht.
- HA lc u c th tng c ti a + ti thiu hoc ch tng ti a, tiu thiu bnh
thng, giai on sau th huyt p gim.
- Mch nhanh theo nhp tim, giai on sau th khng bt c.
- Ngng tim: do thiu oxy qu nng hoc PaCO2 tng qu mc, cn cp cu ngay.
7.2.5.1. Cc thuc kch thch trc tip ti trung tm h hp
Nng CO2 ca khng kh tng cng lm cho h hp tng v lm tng su ca
qu trnh h hp. Ngi ta s dng hin tng ny kch thch h hp bng vic s dng
CO2. Ngoi ra cn c cc cht khc c tc dng kch thch h hp na l pentetrazol (7-
25), atropine (7-26) thm ch c etyl ancol.

194
 CH3

N N

N
N
N CH2OH

7-25
O CO C
pentetrazol H
7-26
atropine
7.2.5.2. Cc thuc kch thch trung tm h hp thng qua th th iu ha h hp v tun
hon
Cc hp cht tc dng loi ny l gm nhiu cht c cu trc ha hc khc nhau.
Trong ng ch nht l lobeline (7-27), pimeclone (7-28), nalorphine (7-29)

C6H5
H2 H H2
C6H5 C N C

O
OH
O
N CH2
7-27
lobeline N CH2CH CH2
7-28
pimeclone

OH
HO O
7-29
nalorphine

195
 O O

H2O N
+ CH2O + HN
1000C

7.2.5.3. Cc thuc dng trong hi sc h hp

Dng cho ngi b bnh tim v bnh trm trng.

196
 O O
CH3 CH3
H3C
H3C H3C H CH3
N N
O

N N
O N O N
7-32
CH3 CH3 camphor
7-30 7-31
caffeine theophyline
O
CON(C2H5)2
N C2H5

N NH
N
N N C2H5
7-25 7-33
pentetrazol niketamide 7-34 O
begmeride
Nikethamid kch thch thn kinh trung ng u tin trn hnh ty, c bit trn
trung tm h hp v tun hon, lm tng nhp th, tng nhy cm CO2 ca trung tm h
hp, tng sc co bp c tim, tng nhp tim. iu tr cc trng hp truy mch, sc, suy tun
hon , tr s sinh b ngt th, h hp v tun hon b suy yu trong khi mc cc bnh nhim
khun nng. Chng tim b suy nhc ngi gi, ngi b suy nhc. Cp cu cho cc
trng hp b ng c carbon oxyd, cc barbituric...
Theophylline trc tip lm dn c trn ca ng ph qun v cc mch mu phi.
Ngi ta chng minh rng theophylline c hiu lc trn tnh co tht ca c honh ngi
bnh thng v v ci thin s co tht bnh nhn b bnh tc nghn ng th mn tnh.
Theophylline cng l mt cht kch thch h hp trung ng. Ch nh: Lm gim triu
chng hoc phng nga hen ph qun v tnh trng co tht ph qun cn o
ngc c ngi vim ph qun mn tnh v kh thng phi. Cn ngng th tr thiu
thng.
Long no c tc dng hng phn trung khu thn kinh, tng cng h hp v tun
hon, nht l trung khu thn kinh ang trng thi c ch th tc dng cng r. C ch tc
dng l lc chch di da thuc kch thch ti ch gy phn x hng phn.

197
7.2.6. Cc thuc cha hen
Hen suyn l bnh vim mn tnh ng dn kh (ph qun). Vim mn tnh i km
vi s qu nhy cm ca ng dn kh dn n cc cn suyn ti i ti li ca cc triu
chng kh kh, kh th, nng ngc v ho, c bit xy ra vo ban m hay sng sm. Cc
cn suyn i km vi vic lan rng ca s tc nghn ng dn kh bn trong phi m
thng l hi phc t nhin hay do iu tr.
Hen suyn l mt bnh l mn tnh trn ng dn kh phi. Cc ng dn kh
ny cng c gi l cc ph qun (ngy xa gi l cung phi). Hen suyn l mt bnh
mn tnh - bnh mn tnh c ngha l n khng bao gi mt i c.
Hen suyn l mt bnh l c hai vn ch yu xy ra su bn trong ng dn kh
ca phi.
Co tht ng dn kh Cc c quanh ng dn kh sit cht hay tht cht li vi
nhau. S co tht ny cng cn gi l co tht ph qun, v c th gy cn tr khng cho
khng kh c ht vo hay th ra ti phi.
Vim ng dn kh Nu b hen suyn ng dn kh phi lun lun b vim,
v tr nn sng nhiu hn v kch ng khi bt u c hen suyn. Bc s ca bn c th gi s
sng ny l vim. Vim c th lm gim lng khng kh m bn c th ht vo hay th ra
khi phi ca bn. Trong mt s trng hp, cc tuyn nhy trn ng dn kh tit qu
nhiu cht nhy c, v h qu l lm tt nghn ng dn kh. Lc ny bn c cm gic
ngp th d bn ang ni y khng kh.
Ty thuc vo c ch tc dng, c bn loi thuc cha hen.
1. Cc amin cng giao cm
Trc y ngi ta hay dng adrenaline, ephedrine nhng hin nay ch dng mt s
thuc chn lc cng 2 ca kh qun nh albuterol hay salbutamol (7-35) v terbutaline (7-
36).
HO

H H2 H H H2 H
HO C C N C(CH3)3 C C N C(CH3)3

OH OH
HO HO
7-35 7-36
albuterol terbutaline

198
 1) NaBH4

2) ClCOCH2Cl/AlCl3 H H2 H
HO HO C C N C(CH3)3
3) i-Pr-NH2
OH
HOOC 4) NaBH4 HO
7-35
albuterol
Bricanyl dng iu tr hen ph qun, vim ph qun mn, kh ph thng &cc
bnh phi khc c km co tht Bricanyl dng tim : Dng ct cn co tht ph qun trong cc
trng hp cp tnh hoc bn cp, lm gin c trn t cung trong cc trng hp da sanh
non.
2. Theophyline v cc dn xut
Xem phn 7.2.2.2
Cc thuc ny c tc dng lm gin ph qun ng thi kch thch trung tm h hp
hnh ty, lm tng nhp v bin thp.
3. Fenspiride
Fenspiride (7-37) l mt cht tng hp c tc dng i khng vi cc cht trung gian
ha hc ca qu trnh vim ti ng h hp gy ph n, tng xut tit v co tht ph qun.
Thuc hp thu d dng qua ng tiu ha v t nng ti a trong mu sau 6 h, tn ti
lu trong mu. Thi tr qua thn v phn.
O
O

CH2CH2 N
NH
7-37
fenspiride

199
 COOEt
COOEt
Cl OEt
OEt
C6H5(CH2)NH2 C6H5(H2C)2N

Cl C O O

Pw Dickman
NaOEt
-EtOH
COOEt
1) H2O/H
2) t0/-CO2
C6H5(H2C)2N O C6H5(H2C)2N O

HCN
OH OH
LiAlH4
C6H5(H2C)2N C6H5(H2C)2N

CN CH2NH2
(C2H5O)2CO

O
O

CH2CH2 N
NH
7-37
fenspiride
Ch nh: thuc s dng ngi b bnh hen, vim ph qun mn tnh km suy h
hp hay nhng ngi biu hin h hp d ng, s mi.
4. Cromolyn v mui ca n
Ch phm s dng trong iu tr hen l mui dinatri ca cromolyn 7-38 hay cn gi
l axit cromoglycat.

200
 COOH
HOOC O O

OH

O O O O

7-38
cromolyn
Cromolyn c tc dng c ch phosphodiesterase ca mng dng bo lm tng
AMP vng, c tc dng lm bn vng mng. Bnh thng khi tip xc vi phc hp khng
nguyn khng th mng dng bo b kh cc t ngt lm Ca 2++ thnh lnh xm nhp vo
trong t bo, gii phng ra cc cht trung gian ha hc t cc ht trong bo tng. V lm
bn vng mng, cromolyn c tc dng lm kh kh cc do c ch c s gii phng cc
trung gian ha hc ca dng bo.
Cromolyn khng c tc dng lm gin ph qun trc tip, khng c tc dng chng
vim, khng khng Histamin. N ch c tc dng d phng ch khng c tc dng iu tr
khi cn hen xut hin. Dng di dng kh dung.

201
CHNG 8. THUC H NHIT GIM AU
8.1. i cng
- Trung tm iu ha nhit:
St l trng thi tng thn nhit xy ra do im chun b nng ln cao hn bnh
thng. Khi , cc p ng tng thn nhit xut hin v a thn nhit tng ln bng im
chun mi gy nn st.
Cht gy st ngoi sinh bao gm cc sn phm ging ho, c t ca vi khun hoc
ton b vi sinh vt.
Cht gy st ni sinh l cc cytokin c tit ra t bch cu mono, i thc bo,
bch cu ht trung tnh, bch cu lympho... Cc cht gy st ni sinh thng c tit ra khi
cc t bo trn thc bo hoc nhn din cc cht gy st ngoi sinh.
Khi bt u cn st s c cc biu hin nh n lnh, co mch, run. Khi ht cn st
th gin mch, ra m hi.
- Thuc h nhit gim au: Thuc chng vim khng steroid l loi thuc c tc
dng h st, gim au, chng vim khng c cu trc steroids. L thuc gim au, nhng
khc vi cc thuc opiat, NSAIDs l thuc gim au ngoi vi v khng c tc dng gy
nghin. Nhng thuc tiu biu ca nhm ny gm c aspirin, ibuprofen, diclofenac, v
naproxen c s dng rng ri trong iu tr t lu. Paracetamol (acetaminophen) c tc
dng chng vim khng ng k, nhng li c tc dng h st v gim au rt tt, nn i
khi vn c xp trong nhm ny.
- C ch tc dng ca thuc h nhit gim au: Thuc tc dng trc tip ln c ch
gy st: Khi vi khun, nm, c t...(gi chung l cht gy st - pyrogen ngoi lai) xm nhp
vo c th s kch thch bch cu sn xut cc cht gy st ni ti. Cht ny hot ha men
cylo-oxygenase (COX), lm tng hp PG (nht l PG E1 v E2) t acid arachidonic ca vng
di i. PG s gy st do lm tng qu trnh to nhit (rung c, tng h hp, tng chuyn
ha) v gim qu trnh thi nhit (co mch da...). Thuc h st do c ch COX lm gim
tng hp PG do lm gim qu trnh gy st nn c tc dng h st. Thuc khng tc ng
ln nguyn nhn gy st nn ch c tc dng iu tr triu chng.
8.2. Phn loi cc thuc h nhit gim au

202
 Ngi ta phn loi da trn tc dng dc l hoc da trn cu trc ha hc ca
chng. C ba nhm sau:
- Nhm axit salixilix v cc dn xut ca n.
- Nhm dn xut ca anilin.
- Nhm cc dn xut ca pirazolon
8.2.1. Cc thuc h nhit nhm dn xut ca axit salixilic
COOR1

OR2 R1 = H, R2 = H
R1 = Na, R2 = H
R1 = H, R2 = COCH3
R1 = Ca, R2 = COCH3
R1 = NH2, R2 = H

Tinh th hnh kim, khng mu, n h, ng nh, khng mi, v chua v hi ngt, kh
tan trong nc. Do kch ng mnh nim mc nn khng dng ung. Dng ngoi da, dung
dch 10% cha chai chn, ht cm, nm da...
c im tc dng:
- Tc dng h st v gim au trong vng 1 - 4 gi vi liu 500 mg/ln. Khng gy
h thn nhit.
- Tc dng chng vim: ch c tc dng khi dng liu cao, trn 3g/ngy. Liu thp
ch yu l h st v gim au.
Nim mc d dy - rut sn xut ra PG, c bit l PG E 2, c tc dng lm tng to
cht nhy v c th l c kch thch phn bo thay th cc t bo b ph hu. Nh vy, vai
tr ca PGE l bo v nim mc ng tiu ha. Aspirin v cc thuc chng vim phi
steroid ni chung, vi mc khc nhau, c ch cyclooxygenase, lm gim PG , to iu
kin cho HCl v pepsin ca dch v gy tn thng cho nim mc sau khi "hng ro" bo v
b suy yu. V vy, khng c dng thuc cho nhng ngi c tin s lot d dy v phi
ung thuc sau ba n.

203
 OH ONa OC ONa
OH

O COONa
0
CO2/60-90 C
+ NaOH t0, P
P

OH

COOH
H2SO4

OCOCH3 OH OH

COOH COOH C NH2

Ac2O/Benzen NH4OH O

Or CH2=CO

Ca(OH)2 NaHCO3

OCOCH3 OH
COOCa1/2 COONa

8.2.2. Cc thuc h nhit gim au thuc dn xut ca anilin

Cc dn xut ca anilin c s dng lm thuc h st gim au bao gm
acetanilit (17-6), N-acetyl-p-amino-phenol (17-7, paracetamol) v phenaxetine (17-8).

204
 R NHCOCH3

17-6, R = H
17-7, R = OH
17-8, R = OC2H5
- Dc ng hc: Hp thu nhanh qua ng tiu ha, sinh kh dng l 80-90%, hu
nh khng gn vo protein huyt tng. Chuyn ha ln gan v mt phn nh thn, cho
cc dn xut glucuro v sulfo-hp, thi tr qua thn.
- c im tc dng: Khc vi cc dn xut trn, cc dn xut anilin ch c tc dng
h st v gim au tng t nh aspirin, khng c tc dng chng vim v thi tr acid uric,
khng kch ng tiu ha, khng nh hng n tiu cu v ng mu.
- c tnh: Vi liu iu tr hu nh khng c tc dng ph, khng gy tn thng
ng tiu ha, khng gy mt thng bng kim toan, khng gy ri lon ng mu. Tuy
nhin, khi dng liu cao (>10g) sau thi gian tim tng 24 gi, xut hin hoi t t bo gan
c th tin trin n cht sau 5-6 ngy. Nguyn nhn l paracetamol b oxy ha gan cho N-
acetyl parabenzoquinonimin. Bnh thng, chuyn ha ny b kh c ngay bng lin hp
cc glutathion ca gan. Nhng khi dng liu cao, N-acetyl parabenzo quinonimin qu tha
s gn vo protein ca t bo gan v gy hoi t t bo. Biu hin bng au h sn phi,
gan to, vng da, hn m gan, toan mu, GPT, GOT v LDH u tng. Bnh nhn thng
cht sau 6-7 ngy. Nu iu tr sm bng N-acetyl-cystein (NAC) l tin cht ca glutathion,
bnh nhn c th qua khi, nu sau 36 gi gan b tn thng th kt qu diu tr s km.
Tng hp paracetamol:

205
 OH
NH2 NHAc NHAc NHAc

NO2

(CH3CO)2O HNO3

NHAc
NO2

KOH/t0

OH OH OH OH

NO2

HNO3
Fe/H

NO2 NH2

NaOH/t0 H2SO4 d

H
Cl Cl Cl NHOH

NO2

HNO3
H2SO4

NO2

NO2

Trong phng th nghim:

5-100C
HO + NaNO2 + H2SO4 HO NO

55-600C
HO NO + Na2S + H2O HO NH2

+ Na2S2O3 + NaOH

206
HO NO

tan trong Na2S (NaOH + S bt) v c d NaOH, un si thu c dung

dch, sau lm lnh n 55-600C v cho cht phn ng vo:

HO NO HO NHOH HO NH2

Nu t0 thp hn, phn ng ch dng li -NHOH cn nu nhit cao hn th

NH2 b oxi ha thnh C=NH CO

80-900C
HO NH2 + Ac2O HO NHCOCH3

+ AcOH
Nu nhit thp th phn ng xy ra rt lu v Ac2O khng si nhng nu nhit
cao th NH2 b oxi ha. Do , tng tc phn ng lm si phn ng ln vi pht sau
nhit ta ra ca phn ng s lm phn ng xy ra nhanh hn.
8.2.3. Cc thuc h nhit gim au thuc dn xut pirazolon
R CH3

17-9, R = H
O N CH3 17-10, R = N(CH3)2
N 17-11, R = N(CH3)CH2SO3Na

C6H5

Tng hp phenazone (17-9):

207
 CH3 CH3 CH3

t0

-(H2O + C2H5OH) O N O NH
O
N N
C NH2
O OC2H5 HN C6H5 C6H5

C6H5 CH3 CH3I/OH

O N CH3 Or (CH3)2SO4
N

C6H5
17-9
phenazone

Tng hp aminophenazone 17-10:

CH3 ON CH3 H2N CH3

NaNO2/H2SO4
O N CH3 O N CH3 O N CH3
N O0C N NaHSO3
N

C6H5 C6H5 C6H5

17-9
phenazone
(H3C)2N CH3 (HOH2C)2N CH3
2HCHO
HCOOH
O N CH3 O N CH3
t0
N N

C6H5 C6H5
17-10
amino phenazone

208