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S lc ve benh lao.

Hau het cac bo phan trong c the eu co the b lao : Lao xng, lao hach, lao
mang nao, lao phoi........... trong o lao phoi chiem ty le cao nhat (70%).

La mot trong t chng nan y thng gay t vog trc kia do khong co thuoc cha

Hien nay vi s tien bo cua hoa tr lieu cung vi s ho tr cua cac phng tien
chan oan va tr lieu hien ai benh lao co the ieu tr mot cach de dang benh
nhan co the khoi han sau thi gian ieu tr
Cac thuoc chong lao hien nay co t nhng rat hieu qua neu ieu tri ung cach

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1 3

S lc ve benh lao.
S lc ve benh lao.
Theo thong ke cua to chc y te the gii OMS (1993)
a mot benh xa hoi gay ra bi Mycobacterium tuberculosis do Robert Koch
tm ra nam 1882 do o con goi la vi trung Koch hay BK

316trie
trie
1,9u ung
tng
ng
i iche
ima
nhie
tcvlao
mlao
lao

Viet nam theo thong ke cua hoi ngh chong lao 1994 th moi nam co them 45000-
50000 ca lao mi. Cac tnh thanh pha Nam tnh hnh benh lao rat nang:Ty le phat
trien lao mi hang nam la 100 ca/100.000 ngi dan, thanh pho Ho Ch Minh : 125
ca/100.000 ngi dan.
Robert Koch - Nobel 1905
1 2 1 4
1843 1910

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S lc ve benh lao.
S lc ve benh lao.
Nguyen nhan cua tnh trang gia tang benh lao

Benh lao thng tap trung nhng nc ngheo la nhng nc cac ieu kien kinh HIV lam giam kha nang mien dch cua c the dan ti lam nang hn benh lao, cu
te thap, cac phng tien phong cha benh kem. Cac thuoc chong lao tuy re tien the tang so benh lao trong so ngi nhiem lao hay rut ngan thi gian chuyen t
nhng mot ca ieu tr lao thng dai (6-8 thang) do o oi hoi mot so lng thuoc nhiem lao sang benh lao
ln ma khong phai bat c mot quoc gia nao, mot gia nh hay ca nhan nao cung
co the cung de dang ap ng. Do o benh lao khong phai ch la mot hien tng y
hoc thuan tuy ma con la van e kinh te xa hoi.

Tr lao Tran a chong lao


HIV
nc ngheo
Macclao
Ma lao

Nhie
Macmlao
lao
NHiem lao Tran a chong lao
nc giau He mien dch

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5 7

S lc ve benh lao. S LC VE VI KHUAN LAO

s e khang thuoc la van e ang bao ong. Th du : tai My trong nhng nam
1982-1986 ty le e khang Rifampicin la 0,5% en 1991 la 3%. e khang INH 1982-
1986 la 3% en 1991 la 7%.

Hnh the Mycobacterium tuberculosis

1 6 1 8

6 8

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IEU TR LAO THEO QUAN NIEM CU
Cau tao mang mycobacterium tubeculosis
Phat hien benh

Khong phan biet oc ngi mac l


va nhiem lao cung nh lan vi mot
benh khac

Th mau

thng ch dung phat hien lao phoi

1 9 1 11
Acid mycolic

9 11

IEU TR LAO THEO QUAN NIEM CU


IEU TR LAO THEO QUAN NIEM CU
Phong benh
Phong va phat hien benh
ch co tac dung tren tre em
Ton kem
Khong can thiet

Khao sat tai Madrat ( An o )


1 nam
1ngi mac lao lay 10 ngi
1 nam Chung BCG
1 ngi mac lao

Cach li

1 10 Lon Charles Albert Calmette 1 Camille Guerin 12


1863- 1933
(1872-1961)

10 12

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AC IEM TRC KHUAN LAO
IEU TR LAO THEO QUAN NIEM CU
Sinh san cham
Hoa tr lieu lao cu
20gi / lan va thuoc ch co tac dung vao luc nay . ieu nay rat quan trong v ch
can uong thuoc 1 lan /l ngay va phai dung trong nhieu ngay.

Trc kia do khong hieu biet ay u ve BK nen cac


phac o ieu tr thng la
n thuoc
Lien tuc
dai ngay.
ieu nay dan en s ton kem, ty le tai phat cao, e 20 gi
khang thuoc ln.

Sau khi tiep xuc vi thuoc mot so BK b tieu diet so con lai trang thai ngu. luc
nay thuoc kem tac dung do o nen dung thuoc cach quang (2-3 lan tuan)
1 13 1 15

13 15

AC IEM TRC KHUAN LAO


AC IEM TRC KHUAN LAO e khang thuoc

Hieu kh tuyet oi Ty le ot bien e khang thuoc kha cao. Trong 106 trc khuan co:
40 khang streptomycin
Trc khuan lao rat can oxy e phat trien. Khi thieu oxy BK se ngng 5 khang INH
phat trien va trang thai ngu. Dang nay khong nhay cam vi thuoc 0,1 khang Rifampicin

Viet nam ty le benh nhan e khang thuoc


Streptomycin 35%
O2 INH 19,5%
Rifampicin 4,5%
Ethambutol 2,6%

Luon luon phai phoi hp cac thuoc chong lao ( t nhat la 3 loai )

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AC IEM TRC KHUAN LAO
CAC PHAC O TR LIEU LAO
Chu trnh phat trien vi khuan lao
Muc ch
pH acid
Thieu oxy - Tieu diet nhanh nguon lay nhiem
Vi khuan phat trien cham - Ngan nga s chon loc ot bien khang thuoc
- Tieu diet het cac vi trung trong cac sang thng tranh tai phat
pH trung tnh
Nhiea
u oxy
i thc bao Cac giai oan cua phac o ieu tr lao
Vi khuan phat trien nhanh - Giai oan tan cong
pH trung tnh - Giai oan cung co chong tai phat
Ba au Thieu oxy
Hang lao
Vi khuan phat trien cham

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17 19

AC IEM TRC KHUAN LAO CAC PHAC O TR LIEU LAO

ten thuoc dang trc khuan lao nhay cam


12 thang : 3 S,H/ 6S2,H2 / 3 H
9 thang : 3 S,H,Z/ 6S,H
streptomycin ( trc khuan trong hang lao)
8 thang : 2R, S,H,Z/ 6H,E hay 2R,S,H,Z/ 6H,T
INH ( trc khuan trong hang lao va ai thc bao)
6 thang : 2R,H,Z/ 4R,H ( dung cho tre em )
Pyrazinamid ( trc khuan trong ai thc bao)
Trong o : S streptomicin
Rifampycin tac dung tren ca 3 dang nhng kem tren 2
H isoniazid
ethambutol km khuan
R rifampicin
PAS km khuan
Z Pyrazimamid
E Ethambutol

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CHNG TRNH DOT ISONIAZID
1946 Domagk thay thisemicarbazon cua aldehyd benzoic co tac dung khang lao.
Ong e ngh thay the aldehyd benzoic bang aldehyd nicotinic va aldehyd
isonicotinic cho thay co tac dung manh hn nhieu

CHNG TRNH DOT CH N NH C N H2 CH N NH C N H2

S S
thiosemicarbazon N
( Directly observer treatment) H2 N NH C NH 2 +
S
N N C HO
C 6 H 5 SO 2 Cl
N a2 C O 3

C NH N H2 C NH NH SO 2 C 6H5
O O
1 21 1 23
Isoniazid

21 23

ISONIAZID
ISONIAZID
ieu che
C O N HN H2
C H3 CO O H CO C 2 H5 C O N HN H2

K MnO 4 C 2 H5 O H NH2 NH2


N
ten khac: INH, isonicotinic hydrazid, nidrazid, nesteben, nikozid, rimifon N N H 2 SO 4 N N
C6H7ON3 p.t. l 137,14 - picolin
OH Cl
Mayer va Maly a tong hp INH t 1912 nhng khong biet tac dung dc ly N H3 PO Cl3 H2
HO OCCH2 COOH
1945 Chorin a thay rang vitamin PP ( amid cua acid nicotinic ) co tac dung HO OCCH2
N CO O H N COOH N COO H
OH
khang lao yeu.
OH Cl
acid citric
CO N H2

N
1 22 1 24

22 24

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ISONIAZID ISONIAZID
Tnh chat .
Ly tnh Tnh kh:
Bot ket tinh trang hay hi co anh vang hoac tinh the khong mau, Nhom hydrazid co tnh kh manh co the tham gia va nhieu phan ng kh:
khong mui , v luc au hi ngot sau hi ang . De tan trong nc, kho
tan trong ether va cloroform. C O N HN H 2 CO OH

Hoa tnh Ag(N H 3 )2


+4 NO3 + H2 O + Ag + NH3 + N H4 N O 3 + N2
Nhan pyridin kha ben vng : Khi ot INH vi N2CO3 khan se giai phong N
Pyridin cho mui ac biet N
OH - OH
CONHNH2 C O C
C O N HN H 2 N N H2 C O
N N H2
CuSO4 ++
N a 2 CO 3 Cu + + N2 +
H2O Cu2 O
N N N
N 2
Tua o
N N Xabh ngoc
INH co the kh thuoc th Fehling giai phong Cu2O

1 25 1 27

25 27

ISONIAZID ISONIAZID
Phan ng vi PDAB
Phan ng the
CO N HN H2 CO O H

CO N HN H2 CO N HN H2 H2 O
+ N H2N H2
N N
Br2
CH 3
N Br N Br C H3 N CH N
NH 2 NH 2 + HOC N CH 3
Phan ng kieu alkaloid C H3
CH
Do trong nhan cha d vong co N bac ba nen INH mang tnh chat giong nh N CH N
alcaloid va cung cho nhng phan ng vi thuoc th chung cua alcaloid, th du : + CH3 CH 3
Vi thuoc th Dragendoc cho tua nau. N CH N
CH3
Tnh kiem
N trong nhan co tnh kiem nen co the tao tua vi nhieu kim loai nang (Fe, Cu, Zn,Al) CH3
N CH N
CH3
1 26 1 28
Kation quinoid

26 28

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ISONIAZID ISONIAZID
Tac ong dc lc
Phan ng vi vanilin
Isoniazid thng dung dang uong nhng cung dung tiem bap.

CONHNH2 C HO Nong o cc ai trong huyet tng at c sau 12 gi uong thuoc. Thc an


CO N HN =C H
co the lam giam s hap thu.

+ Isoniazid khuech tan ti tat ca cac mo va dch cua c the. tap trung mot cach
O CH 3 N O CH 3
N ang ke nao, phoi, khuech tan tot vao ba au. Isoniazid i qua nhau thai va
OH OH
sa.
Vanilin ftivazid

Isoniazid acetyl hoa gan va mat hoat tnh, S acetyl hoa tuy thuoc vao tng
ngi khong phu thuoc vao gii tnh tuoi tac va co tnh di truyen. Thi gian ban
huy la 14 gi phu thuoc vao toc o acetyl hoa
Ngi ta chia ra 2 nhom ngi:
Nhom ngi acetyl hoa cham : thi gian ban huy > 3gi
Nhom ngi acetyl hoa nhanh : thi gian ban huy < 70 phut

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29 31

ISONIAZID ISONIAZID
Kiem nghiem

nh tnh : Dung cac phan ng tren Tac dung khang khuan

Th tinh khiet: Cl-, SO42- , tro sulfat, As INH la chuyen biet tr lao tuy rang no cung co tac dung tren mot so chung vi
khuan khac.
nh lng: Thuy phan INH bang acid hay kiem giai phong hydrazin. nh
lng hydrazin bang phng phap iod: INH la thuoc khang khuan hay diet khuan phu thuoc nong o thuoc, the lao, va
s tiep nhan cua c the.

CO N HN H2 CO O H INH la thuoc au tien dung cho ieu tr M. tuberculosis. nong o toi thieu co tac
dung: 0,025- 0,05 g/ml
H2 O INH co hieu qua va t oc hn cac thuoc khang lao khac nh aminosalicylic
+ N H2N H2
N acid, capreomycin, cycloserine, ethionamid.
N

N H2N H2 + I2 N2 + 4HI
2 N a2 S 2 O 3 + I2 2NaI + N a2S 4O 6
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ISONIAZID ISONIAZID
C che tac ong Tac dung phu

Isoniazid c che nhieu enzym.Trong te bao mycobacteria, isoniazid can tr gan: phat ban , vang da

tong hp acid mycolic, pha v s tong hp te bao vi khuan. Tuy nhien c che than kinh : viem day than kinh van ong va cam giac, co giat
cha ro rang O Co the oc tnh lien quan en s thieu hut vitamin B6 khi dung INH

C
CHO N H2 N HCO
HO CH2 O H
CO N HN H2 Chuyen hoa
Katalase c che hydratcarbon ><
Acid H3C N N
O mycolic
Peroxydase
C - Chuyen hoa Ch nh. Tr cac the lao trong s phoi hp vi cac thuoc chong lao khac.
N INH lam sang thng mau lien seo va kch thch an ngon cm
Acid beo
Dang dung . Vien :50mg,100mg, 300mg
Xiro: 10mg/ml
Dung dch tiem:100mg/ml
Lieu dung . 10mg/kg/ngay
1 33 1 35

33 35

PYRAZINAMID
ISONIAZID
N CO N H2
S e khang

Khi s dung mot mnh se xuat hien nhng BK e khang. ty le BK ot bien


khang thuoc la 10-6 Khong co s e khang cheo gia INH va cac thuoc chong N
lao khac tr ethionamid, chat co cau truc lien quan ti INH. ten khac : PZA, Pezetamid;Pyrafat; Pirilegravene ; Piraldina; Tebrazid
C che e khang C 5H 5N 3O p.t.l 123,11
Mat kha nang hoat hoa INH cua cac enzym Ten khoa hoc: Pyrazincarboxamid
ieu che
enzym
INH
NH 2 O CH N aHSO 3 N N CO OH
+ KMnO 4
O CH
Tang them lp lipid tren mang vi khuan
NH 2 N N CO OH
210oC/ 3-4mmHg N COOH N CO O CH3 N C O N H2
C H 3O H N H3

1 34 N 1 N N 36

34 36

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PYRAZINAMID PYRAZINAMID

Tnh chat Tac ong dc lc


Bot ket tinh trang hay gan nh trang khong mui hay gan nh khong mui. t tan Pyrazinamid (PZA) c dung chuyen biet e tr lao. PZA la thuoc hang au
trong nc , cloroform, alcol va rat t tan trong ether. khi them vao phac o cung vi isoniazid, ethambutol, rifampicin,
streptomycin trong ieu tr lao nhay cam hay e khang.
Kiem nghiem C che tac ong
nh tnh .Pho IR. UV ( max 268 nm )
un soi vi NaOH cho mui amoniac
Nhiet o nong chay: 188oC 191oC.
Phan ng vi FeSO4 N CO N H2 pyrazinamidase COOH
OH O - N
N CON H2 N C FeSO 4 N C Giam pH
NH NH ++ N
Fe N
N N N 2
N CO OH
NaOH
+ N H3 + Fe(O H)2
N 1 37 1 39

37 39

PYRAZINAMID PYRAZINAMID

Th tinh khiet Tac dung phu .


Mau sac va o trong cua dung dch Chu yeu gan nen khong dung cho ngi yeu gan. Ngoai ra co the gay c
Gii han acid kiem che thai tr acid uric, au khp, sot, buon non, non
Tap chat lien quan : Sac ky lp mong
Kim loai nang
Ch nh.
nh lng Chuyen tr lao trong giai oan au thng vi vai tro chong tai phat trong

bang phng phap moi trng khan cac phac o. Ch dung trong s phoi hp vi thuoc chong lao khac. B e
khang nhanh chong.
Thuy phan che pham vi NaOH giai phong NH3. Hng NH3 vao
H2SO4 0,05M va nh lng H2SO4 0,05M d bang NaOH 0,1M.
Dang dung. vien 500mg

Lieu dung. 20-35mg/kg/24 gi

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38 40

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ETHAMBUTOL ETHAMBUTOL
CH2 OH H Kiem nghiem

C 2 H5 C NH CH2 CH2 NH C C 2 H5 nh tnh: Pho IR va cac phan ng tren.


2 HCl
nh lng: nh lng moi trng khan: chuan o bang HClO4
H
CH2 OH 0,1N trong moi trng acid acetic bang va thuy ngan acetat ch
en khac : myambutol
th tm tinh the.
C10H24N2O2 2HCl p.t.l 277,23
Ten khoa hoc. 2,2-(1,2-Ethanediyldiimino)bis-1-butanol

ieu che

CH3CH2
2
CH NH2 + Cl C H2 C H2 Cl Ethambutol
HOCH2

1 41 1 43

41 43

ETHAMBUTOL
ETHAMBUTOL Tac ong dc lc
Ethambutol c dung ieu tr nhiem mycobacteria: M. tuberculosis; M. bovis;
Tnh chat. M. marinum; M. kansasii, M. avium, M. fortuitum, M. intracellulare. No thng
dung phoi hp vi isoniazid, pyrazinamid. No co tac dung ca tren chung a e
Bot ket tinh trang , hau nh khong mui. Tan trong cloroform, methylen khang INH
clorid; kem tan hn trong benzen; hi tan trong nc. Dang muoi HCl de tan
trong nc
C che tac ong
Nhiet o nong chay. 87.5-88.8oC .
Ethambutol c che Arabinosyl transferase, ket qua la c che tong hp
[] D 25 +13.7o (c = 2 trong nc). Lipoarabinomanan
Phan ng vi CuSO4 trong NaOH cho mau xanh H H O

HO O O P O
H OH
NH CH2 CH 2 NH CH 2 CH 3 H OH
CH3 CH2 OH H
Cu C
C H D arabinofurnosyl -1-monophosphoryldecaprenol
H CH 2 O H
CH 2 O H
Arabinosyl transferase ethambutol
Phan ng cua HCl

1 42
Arabiofuranose + galactose
1
Lipoarabinomanan
44

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C che tac ong cua ethambutol RIFAMPICIN
Ethambutol C H3
OH
H 3C C H3 N
O
H3C CH OH O HN H
OH 3
C H 3C H 3 N
C H 3C O O
CH N
C H3O O
OH
O CH
3 O

ten khac : Rifadin, rimactane, rifampin

C43H58N4O12 p.t.l. 822,95

Ten khoa hoc.3-[[(4-Methyl-1-piperazinyl)imino]methyl]rifamycin


5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-hepta methyl-8-[N-
(4-methyl-1-piperazinyl)formimidoyl]-2,7-(epoxy penta
deca[1,11,13]trienimino)naphtho[2,1- b ]furan-1,11(2 H) -dion 21-acetat
1 45 1 47

45 47

RIFAMPICIN
ieu che
ETHAMBUTOL OH OH
H3 C C H3 H3C C H3
O O
tac dung phu H3C CH
OH 3
OH O HN H H3C CH
OH 3
OH O HN H
C H C H3 C H C H3
co the gay au au, au khp, au bung. Phan ng phu quan trong nhat la tren C H3C O O
3
HN (C 2 H 5 )2 C H3 C O O
3

than kinh th giac dan en khong phan biet c mau xanh, o. Khong than C H3 O O C H3O O
C H 2 N (C 2 H
HCHO
trong ( ngng thuoc ) co the dan ti mu. Khong nen dung cho tre em. OH OH
O CH acid ascobic
3 O O CH
3 O
Dang dung. vien 100, 400mg Rifamycin
Lieu dung . 15mg/kg/ngay OH
H3C C H3
O
H3C CH OH O HN H
OH 3
H2 N N N CH3
C H 3 ( C H 2 )4 O N O C H C H3
3
C H3 C O O
C HO
Rifampicin
C H3O O
acid ascobic
OH
H2 O
O CH
3 O

1 46 1 48

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RIFAMPICIN
RIFAMPICIN
Tnh chat.
Tac dung phu
bot ket tinh mau o gach en o nau de tan trong cloroform, methanol, DMSO Rifampicin co the gay viem gan
hi tan trong aceton, ethanol, ether, tetraclorid. va nc. Rat ben trong DMSO, Rifampicin co the lam cac dch nh nc tieu , nc bot, nc mat co mau o
kha ben trong nc. Rifampicin cung oc vi tuy song.
Phan huy 183-188oC. tr lao cho phu n co thai can theo doi e phong nhng nguy c co the xay ra.
Rifampicin i vao sa me nhng anh hng tren tre s sinh cha thay.
UV max (pH 7.38): 237 , 255 , 334 , 475 nm

Tng tac thuoc .


Kiem nghiem.
Rifampicin co tac ong tren he thong enzym cytocrome P-450 gan va do o co the
nh tnh. IR, UV (max 237, 254, 334, 475 nm )
Tron 25mg che pham vi 25ml nc thanh hon dch . Loc va them vao dch loc lam giam nong o va hieu lc cua nhng thuoc sau:

1ml dung dch amonipersulfat 10% trong dung dch em photphat pH=7 Mau cua Chloramphenicol, corticosteroid, cyclosporin, diazepam cac chat nay. Rifampicin
dung dch chuyen t vang cam ti o tm. tang chuyen hoa AZT gan trong ieu tr HIV.
nh lng : bang phng phap o pho UV bc song 475nm

1 49 1 51

49 51

Tac ong dc lc.


RIFAMPICIN
Rifampicin c coi la thuoc tot nhat hien nay tuy nhien no cung khong bao
Ch nh.
gi dung mot mnh v s e khang phat trien nhanh chong.
C che tac ong: Rifampincin c che ADRP ( DNA dependent RNA Benh lao cac the, cac benh nhiem khuan nang, d phong viem mang nao, tr
polymerase) dan ti c che tong hp RNA vi khuan phong
Rifampicin Dang dung. Vien nang 150, 300mg
Hon dch uong 2%
ADRP Bot pha tiem 600mg /lo
ADN Lieu dung.
Tr lao:Ngi ln : 600mg ngay uong 1 lan cach xa ba
Tre em : Uong hon dch tuy theo tuoi:
0-1 thang tuoi 10mg/kg/1lan / ngay
1-7 tuoi: 100mg/5kg/ 1lan / ngay
Tren 7 tuoi: Uong nh ngi ln
Dang tiem c pha trong dung moi i kem va pha trong dung dch glucose 5%
RNA tiem tnh mach cham. Lieu nh lieu uong
D phong viem mang nao: 600mgx2 lan / ngay
Tr cui: Ngi ln : 600mg lan x 1 lan / thang. Dung t nhat trong 2 nam
1 50
Tre em : 10mg /kg/ 1 lan / than
1
g. Dung t nhat trong 2 nam 52

50 52

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