Giao Trinh Duoc Lam Sang (Tap 1) PDF

TRUONG DAI HOC DUOC HA NQI DAI HQC GRONINGEN, HA LAN
universityof
groningen
DlT AN NPT-VNM-240
DLPaC LAM SANG

•
NHtTNG NGUYEN LY CO BAN VA

SU* DUNG THUOC TRONG DIEU TRI
TAP I
CAC NGUYEN LY CO BAN TRONG

DlTOC LAM SANG
(Ta"i b£n Ian this nhat)
Chu bien: GS. TS. Hoang Thj Kim Huyen

GS. TS. J.R.B.J. Brouwers
NHA XUAT BAN Y HQC

HA NQI - 2014
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CHU BIEN:
GS. TS. Hoang Thj Kim Huyen

GS. TS. J.R.B.J. Brouwcrs
M: Hi
THAM GIA BIEN SOAN:
Cac tac gia Viet Nam
TS. Nguyen Hoang Anh Truang Da hoc Dugc Ha Ngi
PGS. TS. Nguyen Thanh Binh Trirong Da hgc Dugc Ha Ngi
TS. Nguyen Tuan Dung Truang Da hgc Y Dugc TP Ho Chi Minh
ThS. Nguyen Thuy Duong Truong Da hgc Dugc Ha Noi
TS. Duong Xuan Chir Truong Da hgc Y Dirge Can Tho
ThS. Nguyen Thu Hang Truong Da hoc Du'oc Ha Noi
PGS. TS. Nguyen Dang Hoa Truong Da hgc Dirge Ha Ngi
TS. Vu Dinh Hoa Truong Da hgc Dugc Ha Ngi
GS. TS. Hoang Thi Kim Huyen Truong Da hgc Dugc Ha Ngi
ThS. Duong Thj Ly Huong Truong Da hgc Dugc Ha Ngi
TS. Nguyen Thi Lien Huong Truang Da hgc Dugc Ha Ngi Jl S •:•' •
ThS. Le Kim Khanh Trirong Da hgc Y Dugc Can Tho
PGS. TS. Nguyen Ngoc Khoi Trirong Da hgc Y Dugc TP Ho Chi Minh
TS. Phan Quynh Lan Trirong Da hoc Duoc Ha Noi
TS. Nguyen Thj Lap Truong Da hgc Dugc Ha Ngi
GS. TS. V6 Xuan Minh Truang Da hgc Dugc Ha Ngi

'
PGS. TS. Nguyen Hai Nam Truang Da hgc Dugc Ha Noi
TS. Vo Thanh Plurong Nha Truong Da hgc Y Dugc TP Ho Chi Minh
ThS. Do Thj Nguyet Que Truang Da hgc Dugc Ha Ngi

-A AC Hi,'T f-iî
ThS. Pham Thi Thuy Van Truong Da hgc Dugc Ha Ngi
TS. Dao Thi Vui Truang Da hgc Dugc Ha Ngi
TS. Tran Van Tuan Truong Da hgc Y Dugc Thai Nguyen
PGS. TS. Nguyen Manh Tuyen Truong Da hoc Duoc Ha Noi

Cac tac gia Ha Lan
GS. TS. J.R.B.J. Brouvvers Centre of Pharmacy, University of Groningen, the

Netherlands
GS. TS. M.J.Postma Centre of Pharmacy, University of Groningen, the

Netherlands
GS. TS. C. de Vries University of Bath, United Kingdom

GS. TS.H.W. Frijlink Centre of Pharmacy, University of Groningen, the
Netherlands
GS. TS. L.T.W. de Jong van den Berg Centre of Pharmacy, University of Groningen, the
Netherlands
GS. TS.JJ.de Gier Centre of Pharmacy, University of Groningen, the

Netherlands
GS.TS. Kees van Grootheest Centre of Pharmacy, University of Groningen, the

Netherlands
TS. Frank Jansman Deventer Ziekenhuizen, the Netherlands
GS. TS. A.J.M. Loonen Centre of Pharmacy, University of Groningen, the

Netherlands
TS. E.N. van Roon Medisch Centrum Leeuwarden, the Netherlands
K. Taxis Centre of Pharmacy, University of Groningen, the

Netherlands
TS. Herman J. Woerdenbag Centre of Pharmacy, University of Groningen, the

Netherlands
GS. TS. B. Wilffert Centre of Pharmacy, University of Groningen, the

Netherlands
GS. TS. J. Zaagsma Centre of Pharmacy, University of Groningen, the

Netherlands
BAN THI/ KY:

PGS. TS. Nguyen Hai Nam
ThS. Vu Thuy Duong
BIEN TAP BAN THAO
PGS. TS. Nguyen Hai Nam

LOI GIC» THIEU
Du an "Nang cao chat lugng dao tao dugc sy lam sang tai Viet Nam de dap ung
yeu cau cap thiet ve su dung thuoc an toan, hop ly, hieu qua cua cong dong" (NPT-
VNM-240), tai trg boi Chinh phu Ha Lan thong qua Chuong trinh tang cuang nang lire
the che cho giao due va dao tao sau pho thong (NUFFIC), da dugc thuc hien trong 4
nam (2007-2011) vai sir tham gia cua 6 truang dai hoc y dugc trong ca nuac g6m
truang Dai hgc Dugc Ha Ngi, truang Dai hoc Y Duoc thanh pho Ho Chi Minh, truang
Dai hgc Y Dugc Thai Nguyen, truang Dai hgc Y Thai Binh, truang Dai hgc Y Dugc
Hue va truang Dai hgc Y, Dugc Can Tha. Du an da dat dugc cac muc tieu quan trgng
nhu i) xay dung dugc chuong trinh dao tao ve dugc lam sang dap ung cac ve su dung
thuoc an toan, hieu qua, tiet kiem, gop phan tang cuang chat lugng phuc vu y te a Viet
Nam; ii) bien soan cac tai lieu ve phuong phap giang day va giao trinh ve dugc lam sang
va cac noi dung lien quan; iii) phat trien ky nang va phuong phap giang day cho dugc si
lam sang; iv) xay dung dugc ca so du lieu true tuyen ve thuoc.
Cuon sach "Duac lam sang: Nhung nguyen ly ca ban va su dung thuoc trong rfiiu
tri" do GS. TS. Hoang Thi Kim Huyen va GS. TS. J.R.B.J. Brouwers chu bien dugc
bien soan trong khuon kho hoat dong cua du an nh4m cung cap cho giang vien, sinh
vien giang day hgc tap trong lTnh vuc y - duoc nhung nguyen ly va thong tin ca ban nhat
trong dugc lam sang va trong sir dung thuoc dieu tri cac benh thuang gap tai Viet Nam.
Ban Quan ly du an xin chanh thanh cam an Chinh phu Ha Lan da ho trg kinh phi cho
viec bien soan cuon sach; xin tran trgng cam on lanh dao Bo Y te da quan tarn tao dieu
kien thuan lgi cho qua trinh to chuc bien soan va tham dinh cuon sach. Dae biet, Ban
Quan ly du an xin cam an GS. TS. Hoang Thi Kim Huyen va GS. TS. J.R.B.J. Brouwers
da danh nhieu cong sue trong to chuc bien soan cuon sach; xin cam on sir dong gop quy
bau cua tap the cac tac gia da danh nhieu thai gian tham gia bien soan cuon sach nay.
T.M. BAN QUAN LY DlT AN NPT -VNM -240

Giam doc
PGS. TS. Le Viet Hung

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LOI NOI DAU
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"Dupe lam sang - Nhung nguyen ly ca ban va su dung thuoc trong dieu tri" la cuon
sach dugc bien soan vai sir hop tac cua Viet Nam va Ha Lan trong khuon kh6 du an
NPT-VNM-240 (Du an Nuffic). Ket cau toan bo cuon sach va ten cac chuong do cac
chuong duoc viet dong boi tac gia cua 2 phia: Ha
chuong
dua ra con noi dung dugc cac tac gia Viet Nam bien soan dua tren cac dao tao
lam sang cua Anh, My hien dang sir dung; phan su dung thuoc trong dieu tri chu
cac tri theo TCYTTG va Bo Y te" Viet Nam.
duoc sy lam sang, dong thoi cung la tai lieu tham khao cho
cac can bo y te dang lam viec tai cac benh vien hoac nha thuoc.
Muc tieu co' ban ciia cuon sach la:
- Cung cap cho hgc vien nhung kien thuc ca ban ve dugc lam sang de bao dam thuc
hien dugc cong tac chain soc Dugc theo muc tieu sir dung thuoc hieu qua - an toan -
kinh te.
- Cung cap cho hgc vien nhung kien thuc lien quan den su dung thuoc trong dieu trj
de giup hgc vien hinh thanh dugc ky nang thuc hanh duoc lam sang trong tu van va
giam sat cac cong viec lien quan den thuoc.
Sach duoc chia lam 2 tan:
.1
Tap 1: Nhung nguyen ly ca ban trong duoc lam sang (12 chuang).
khoi kien thuc:
/ Nhung kien thuc lien quan den sir dung thuoc hop ly nhu: phuong phap thiet ke
thu nghiem lam sang, cac thong so duoc dong hgc, tuong tac va tuong ky, lira chgn
duang dung thuoc, su dung thuoc cho cac doi tugng dac biet.
/ Nhung kien thuc nen can cho cham soc dugc nhu: phan ung co hai cua thuoc va canh
giac dugc, dugc dich te hgc, can nhac nguy co loi ich, kinh te duoc, hoa sinh lam sang.
Tap 1 la cac kien thuc dai cuong cho nhap mon Dugc lam sang, danh cho hgc
vien dai hgc he da khoa va chuyen khoa va hgc vien sau dai hgc chua dugc hgc chuong
trinh nay o bac dai hgc.
- Tap 2: Su dung thuoc trong dieu tri (22 chuang). Phan nay bao gom:
S Nhung chuang lien quan den su dung thuoc trong dieu tri mot so benh:
* Benh nhiem trung: viem phoi, ia chay nhiem khuan, sot ret, lao, nhiem khuan
tiet nieu.
* Benh tim mach: suy tim, tang huyet ap, huyet khoi.
* Benh ngi tiet va chuyen hoa: dai thao duong, roi loan chuc nang tuyen giap.
* Benh than kinh, tarn than: dong kinh, Parkinson, tarn than phan liet, mat tri nho.
* Benh xuong khop: viem khop dang thap va thoai hoa khop, loang xuong, Gout.
* Benh da lieu.
VNhung chuong lien quan den su dung mot so nhom thuoc dac biet nhu: hoa tri
lieu ung thu, thuoc y hgc co truyen, nuoi duong nhan tao.
Tap 2 la cac kien thuc lien quan din sir dung thuoc trong dieu tri, duoc trinh bay
tren mot benh cu the nham nham giup hgc vien thuc hanh cham soc dugc theo muc tieu
va nguyen tac dieu tri da dat ra cho moi benh. Phan nay danh cho hgc vien chuyen
nganh Dugc lam sang, he sau dai hgc. Cac ngi dung nay cung rat co ich cho cac Dugc si
va Bac si trong su dung thuoc. Tuy nhien day chi la tai lieu tham khao ma khong phai la
huong dan dieu tri chinh thuc co tinh phap ly. Cac huong dan dieu trj deu phai theo cac
huong dan cua hoi chuyen khoa va website cua Bo Y te Viet Nam!
C4u true moi chuong dugc thong nhat nhu sau:
o Ten chuong
o Muc tieu
o Dat van de
o Phan noi dung chinh
o Ket luan
o Cau hoi lugng gia (kem dap an)
o Tai lieu tham khao
De nam vung kien thuc, hgc vien nen thuc hanh tren cac tinh huong lam sang va
tra loi cac cau hoi lugng gia co a cuoi moi chuong (co kem dap an).
la cuon sach lan nhaT ve Duoc lam sang tai Viet Nam cho den thoi diem hien
tu nguyen ly co ban den thuc hanh sir dung thuoc. Sach duoc viet boi tap
nuoc, phoi hap vai tap the chuyen gia giau kinh nghiem trong linh vue Dugc lam sang
tai Ha Sir ket hop nay lam tang tinh phong phu ve hinh thuc chuyen dat kien thuc;
tuy nhien day cung la kho khan de bao dam dugc tinh nhat quan cua toan bg noi dung.
Cac tac gia da co gang bien soan nhung noi dung si lam
sang co the thieT lap quy trinh cham soc dugc khong trong sach
ma co the trien khai hon
kinh nghiem con han che nen chac con nhieu thieu sot, rat mong nhan dugc sir gop
y cua cac dong nghiep Y va Dugc!
Xin tran trong cam on!
CHU BIEN
GS. TS. Hoang Thi Kim Huyen

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Tranj
Loi gioi thieu 5
Loi noi dau 7
Mot so tu viet tat 11
Chuong 1. Dugc dong hgc lam sang 13
Hoang Thi Kim Huyin, B. Wilffert

Chu'0'ng2. Dang thuoc va duong dung 37
Vo Xuan Minh, H.J. Woerdenbag, H. W. Frijlink
Chirong 3. Phuong phap thiet ke thu nghiem lam sang 68
Nguyen Hoang Anh, K. Taxis
Chuong 4. Ung dung y hgc dua tren bang chung trong thuc hanh su dung 87
thuoc
Nguyen Hoang Anh, Nguyin Dang Hoa, J.R.B.J. Brouwers

Chuo'ng 5. Phan ung co hai cua thuoc va canh giac dugc 112
Pham Thi Thuy Van, Kees van Grootheest
Chuong 6. Tuong tac thuoc 137
Nguyen Tuan Dung, E.N. van Roon
Chinmg 7. Tuong ky, tuong hgp va do on dinh cua thuoc 161
Nguyen Tuan Dung, J.R.B.J. Brouwers
Chuong 8 Dich te dugc hgc ' 187
Nguyen Thanh Blnh, C. de Vries
Chuong 9 Kinh te dugc 211
Nguyen Thanh Blnh, Maarten J Postma
Chuong 10. Sir dung thuoc cho cac d6i tugng dac biet 230
Phan Quynh Lan, C. de Vries, J.R.B.J. Brouwers, K. Taxis,
L. T W. de Jong van den Berg
Chuong 11. Hoa sinh lam sang trong thuc hanh dugc lam sang 259
Nguyin Thi Lap, J.R.B.J Brouwers
287
Chuong 12. Cham soc dugc
Hoang Thi Kim Huyin, J.J. de Gier
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MOT SO TIT VIET TAT
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AD: Alzheimer (benh mat tri nha)
ADA: Hiep hoi dai thao duong Hoa Ky (American Diabetes Association)
ADR: Phan ung co hai cua thuoc (Adverse Drug Reaction)
AHA: Hoi tim mach hgc My (American Heart Association)
ATP: Adenine Triphosphate
AUC: Dien tich duai duong cong (Area Under the Curve)
BA: Sinh kha dung (Bioavailability)
BCS: He thong phan loai sinh dugc hgc (Biopharmaceutical Classification
System)
BE: Tuong duong sinh hgc (Bioequivalence)
BMR: Nang lugng cho chuyen hoa ca ban (Basal Metabolic Rate)
BN: Benh nhan
BN: Benh nhan
CBA: Phan tich Phi ton - Lgi ich (Cost Benefit Analysis)
CCD: Chong chi dinh
CEA: Phan tich Phi ton - Hieu nghiem (Cost Effectiveness Analysis)
CI: Do thanh thai (Clearance)
CICr: Do thanh thai creatinin (Clearance Creatinine)
CMA: Phan tich giam thieu phi ton (Cost Minimizing Analysis)
COPD: Benh phoi tic nghen man tinh (Chronic Obstructive Pulmonary Diseases)
CSD: Cham soc dugc
CUA: Phan tich Phi ton - Huu dung (Cost Utility Analysis)
DES: Diethylbestrol
DHA: Dihydroartemisinin
DK: Dong kinh
DLP: Roi loan chuyen hoa Lipoprotein huySt (Dyslipoproteinaemia)
DLS: Duoc lam sane
DSLS: Duoc sy lam sang
DTD: Dai thao duong
DVT: Huyet khoi tinh mach sau (Deep Vein Thrombosis)
ESC: Hoi Tim mach hgc chau Au (European Society of Cardiology)
FDA: Co quan quan ly thuoc va thuc pham My (American Food and Drug
Administration)
FN: Am tinh gia (False Negative)
FP: Duong tinh gia (False Positive)
11
GABA: Gamma-Aminobutyric Acid
HDL: Lipoprotein ty trgng Ion (High Density Lipoprotein)
KST: Ky sinh trung
KSTSR: Ky sinh trung sot ret
KTTP: Kich thuoc tieu phan
LDL: Lipoprotein ty trgng thap (Low Density Lipoprotein)
LX: Loang xuong
MAO: Monoamin oxidase
MAOI: Chat uc che MAO
MCE: Hieu qua lam sang toi thieu (Minimal Clinical Efficacy)
MRI: Cgng huong tu
NSAID: Thuoc chong viem phi steroid (Non-Steroidal Antiinflammatory
Drugs)
NYHA: Hoi Tim New York (New York Heart Association)
OA: Thoai hoa khop (Osteoarthritis )
PE: Thuyen tawtsc phoi (Pulmonary embolism)
PNCT: Phu nu co thai
PTU: Propylthiouracil
RA: Viem khop dang thap (Rheumatoid arthritis)
RAI: Iod phong xa (Radioactive Iodine)
REE: Nang lugng tieu hao khi nghi ngoi (Resting Energy Expenditure)
SDH: Sinh duoc hoc
;AR.
Se: Do nhay (Sensitivity)
SKD: Sinh kha dung
SR: Sot ret
TCYTTG: To chuc Y te the gioi
TG: Triglycerid
THA: Tang huyet ap
TKTLT: Than kinh trung uang
TN: Am tinh that (True Negative)
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TP: Duong tinh that (True Positive)
TSH: Hormon kich thich tuyen giap (Thyroid Stimulating Hormone)
TTT: Tuong tac thuoc
p flit, i ' ji ur-p- '•i'jf'rr' rf*"jf't *nr!'-i (•
VKDT Viem khop dang thap
VLDL: Lipoprotein tytrgng rat thap (Very Low Density Lipoprotein)
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VPMQ: Viem phe quan man
WHO: T6 chuc y te the gioi (World Health Organization)
XVDM: Xa vua dong mach
12
CHlTONG 1. DUOC DONG HOC LAM SANG
Hoang Thi Kim Huyen, B. Wilffert
MUC TIEU
1. Trinh bay dupe dinh nghla, cong thuc tinh va y nghla trong dieu tri cua 4 thong so dupe
dong hoc ca ban; sinh kha dung, the tichphan bo, dp thanh thai va thai gian ban thai cua
thuoc.
2. Lietke vaphan tich duac cac yeu to co the anh huong den cac thongso dupe dong hoc khi
su dung thuoc.
3. Trinh bay dupe y nghla cua cac thong so nay trong dieu tri
4. Trinh bay duac anh hu&ng cua su suy gidm chuc nang gan den cac thong so dupe dgng
hoc va nguyen tac su dung thuoc a doi tuong nay.
5. Trinh bay dupe anh hu&ng cua su suy gidm chuc nang than den cac thong so dupe dgng
hgc va cac buac tien hanh de hiqu chinh lieu a bqnh nhansuy them.
MO DAU
Dugc dong hgc lam sang la su van dung dugc dong hgc ca ban len ca the con nguai.
Muc dich nghien cuu cua dugc dong hgc lam sang la xac dinh mot che do lieu dieu trj khoa
hgc can cu vao nong do thuoc trong mau hoac trong huyet tuong va tinh toan dua tren cac
cong thuc dugc dong hgc.
Dugc dong hgc lam sang cho biet moi lien he giua lieu lugng va tac dung. Cac yeu to
sinh ly (lira tuoi, gioi...), benh ly (chuc nang gan-than...) co the gay ra su thay doi cac
thong so dugc dgng hgc va vi vay can co che do lieu phu hgp vai tung doi tugng. Ngoai ra
dugc dong hgc lam sang la ca sa de phat trien cac thuoc moi cung nhu danh gia lai hieu
qua va an toan cua cac thuoc da luu hanh, bao dam cho chat lugng dieu tri on dinh.
ro.'jf :
1. CAC THONG SO DUOC DONG HOC CO BAN
1.1. Sinh kha dung

1.1.1. Dinh nghla va cong thuc tinh
Sinh kha dung (SKD) la thong so bieu thi ty le thuoc vao duac vong tuan hodn chung
a dang con boat tinh so vai lieu da dimg (F%), toe dp (Tmax) va cuang do (Cmax) thuoc
tham nhcip duac vao vong tuan hodn chung.
Nhu vay, khi noi den SKD ta de cap den 3 dai lugng: F% (tinh tu AUC), Tmax va
Cmax.
13
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c
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HOURS AFTER DRUG ADMINISTRATION Thai gian (h)
Hinh 1.1. Cac thong so d$c trung cho kha n3ng hap thu thuoc vao mau
AUC la dien tich duoi duong cong bieu dien sir bien thien cua nong do thuoc trong
mau theo thai gian: Cp - t, bieu thj lugng thuoc vao dugc vong tuan hoan a dang con hoat
tinh sau mot thai gian t(Hinh 1.1). Dan vj tinh AUC la mg.h.l"1 hoac ug.h.ml"1.
AUCo-oc = AUCo-t + AUCt.oc
AUC thuang dugc tinh theo quy tac hinh thang (trapezoid): day la phuong phap thuc
nghiem tinh AUC tu nong do thuoc do dugc trong mau (thuang la huyet tuong hoac huyet thanh).
*Luuy khi tinh SKD:
Mot so thuoc khi san xuat dugc dung duoi dang muoi trong khi hieu qua dieu tri lai
phu thuoc vao dang phan tu. Do do khi tinh sinh kha dung phai nhan them he so chuyen doi
(S) de co dugc tri so thuc.
Vi du:
- Acid valproic la chat dung de dieu tri dongjdnh, co biet dugc la Orfril®. Vien nang
Orfril® chua 300 mg valproat natri tuong duong 260,28 mg acid valproic. Ty le acid
valproic/valproat natri la 0,87. Nhu vay khi tinh sinh kha dung cua acid valproic tu vien
Orfril© phai nhan vai he so chuyen doi tu dang muoi (S) la 0,87. _
Ca 1.
Mot benh nhan 37 tuoi, dugc chi djnh Solu-Decortin®H50, hoat chat la prednisolon-21
hydrogen succinat natri co S = 0,75. Bac si muon biet ham lugng prednisolon trong san
pham nay la bao nhieu? (dap so: 37,4 mg prednisolon)
1.1.2. Thai gian ban hap thu - (tI/2 hap thu)
Khi dung thuoc theo duong uong, thuoc dugc di chuyen tu ong tieu hoa vao mau.
Neu thuoc uong a dang long, qua trinh hap thu dugc thuc hien ngay a phan tren cua rugt
non (ta trang, hong trang). Nong do thuoc trong mau tang len nhanh chong gay mot su tfiay
doi nong do lan. Neu thuoc dugc bao che duoi dang giai phong keo dai, sir hap thu thuoc se
xay ra trong suot chieu dai rugt non. Luc nay sir tang nong do thuoc trong mau xay ra cham
han, Cmax dat dugc thap han nhung sir tang nong do on dinh han.
Trong do thj a hinh 1.2, pha a la pha hap thu. Do doc cua duong cong a pha hap thu
la hang so toe do hap thu, dugc ggi la ka. Ta co:
14
ti/2 a= ln2/ka
vmV
Hinh 1.2. Thai gian ban hap thu
ung yeu cau giai phong het hoat chat truac khi ra khoi duong tieu hoa hay khong vi theo
quy luat thi sau 7 lan tU2 thuoc se dugc hap thu het? (xem them t]/2 bai xuat a phan sau).
Dang thuoc tac dung keo dai dugc san xuat tu nhung hoat chat co t]/2 bai xuat ngan (< 4 h)
va co the dugc hap thu ca a nhung phan cuoi cua ong tieu hoa. Uu diem la giam dugc so
lan dua thuoc trong ngay va giam dugc ty le day - dinh cua giao dong nong do.
Ca2.
Khi dung theophylin a dang dung dich, t|/2_a la 15 phut.

- Tinh ka?
Khi theophylin dugc bao che a dang tac dung keo dai, ka la 0,277h"
- Vien thuoc dugc bao che se dugc dung may lan/24h?
1.1.3. Anh hu&ng cua vong tuan hoan
dau den sinh kha dung
Thuoc sau khi dugc hap thu qua
ong tieu hoa dugc do vao tinh mach cua
gan roi qua gan truac khi dat dugc tuan
hoan chung; giai doan luu chuyen nay
ggi la "vong tuan hoan dau" (1st pass).
Nhu vay co the thay hao hut thuoc khi
hap thu tu ong tieu hoa khong chi do
can tra bai kha nang vuot qua niem mac
rugt ma con do thuoc bj pha huy bai
vong tuan hoan dau khi vuot qua gan Hinh 1.3. Vong tuan hoan dau (1st pass)
(hinh 1.3).
Nhung thuoc bj giam nong do khi qua vong tuan hoan dau la nhung thuoc bj chuyen hoa
manh qua gan (> 70%). Toe do dong mau qua gan la yeu to anh huong tdi 1st pass. Do dac
tinh nay, can phai thay doi lai lieu dung khi chuyen duong dua thuoc tu uong sang tiem va
ngugc lai neu su dung cac thuoc co 1st pass lan.
15
Ca3.
Mot benh nhan ung thu dugc giam dau bang morphin, lieu 10 mg tiem tinh mach
each 6h mot lan. Viec su dung thuoc tiem ve lau dai la khong hgp ly nen dugc chuyen
sang dang uong. Dugc biet SKD cua morphin dang uong la 30%.
Lieu morphin uong can bao nhieu?
1.1.4. Y nghla
- SKD la ca so de lua chgn che pham:
Vi du: ampicilin va amoxicilin deu co cung ph6 tac dung nhung SKD cua ampicilin
la 30-50% trong khi cua amoxicilin la 60-90%, do do amoxicilin dugc uu tien lira chgn khi
dung duong uong.
Cung tuong tu vdi lincomycin va clindamycin (30% so vai 90%).
- SKD Id ca so de lira chgn duang dua thuoc
Khi SKD tuyet doi dat tren 80%, co the coi la thuoc hap thu tuong tu tiem tinh mach.
Truang hgp nay chi tiem tinh mach khi khong uong dugc.
Vi du: cac khang sinh nhom quinolon co SKD deu > 80% va do do duong uong dugc
uu tien. v.
- Tuongduong sinh hgc:
Tuong duong sinh hgc (Bioequivalence, BE) nham so sanh thuoc generic vdi thuoc cua
hang phat minh hoac thuoc co uy tin nhat tren thj truong. Thuc te cac thuoc dang vien cua cac
hang khac nhau thudng chenh lech kha nhieu ve kha nang hap thu sau khi uong. Dieu nay co the
dan den sir chenh lech rat ldn ve hieu qua dieu trj. Chinh vi vay tuong duong sinh hgc cho biet
kha nang thay the trong dieu tri khi sir dung thuoc generic.
1.2. The tich phan b6 (Volume of Distribution, Vd)
1.2.1. Khdi niem va dinh nghla
Gia suco 2 binh chua nude khong biet the tich la bao nhieu nhung dugc bo vao moi binh
cung mot loai thuoc vdi lieu lugng la 5.000 mg. Trong binh thu 2ta bo vao binh mot lugng than
hoat. Than hap phu 99% lugng thuoc trong binh. Lay mau dinh lugng nong do, ta co nong do
thu dugc tu binh 1 la lmg/ml con d binh 2 chi co0,01 mg/ml.
Co thi hinh dung the tich phan bo qua hinh 1.4:
'
?'.;.'
•Vx\\ '
- 5.000mg 5.000mg
i. •••';'
0,01 mg/ml
:£•.;•.. :•• *n«..-:1 1mg/ml
L! /^l*
***
••>S:i?' live, i'i v-j-

B 99 <;
.' h'?jU '-M'lWt ]>{'•• ;U • • v^^___ ___—--^'

Hinh 1.4. Sa do phan bo thuoc
16
Neu coi pha nude la huyet tuong thi nong do thuoc trong pha nude tuong tu nhu khi
ta do nong do thuoc trong phan huyet tuong (Cp). The tich phan bo dugc tinh theo cong
thuc:
a •
Vd =
Cp
Nhu vay trong truang hgp vdi binh 1:
Vd = 5.000 mg/1 mg/ml = 5.000 ml = 5L
Trong truang hgp vdi binh 2:
Vd = 5.000 mg/0,01 mg/ml = 500.000 ml = 500 L
Dinh nghla:
The tich phan bo Id'mot the tich "tu&ng tuang" (an imaginary volume) hay the tich
bieu kien (apparent volume), bien thi mot khodng khodng khong gian can phai co de toan
bo luang thuoc duac dua vao ca the phan bo a nongdo bangnongdp trong huyet tuang.
Tu so lieu tinh toan co the thay the tich phan bo khong phai la the tich cua mau, cua
huyet tuong hay djch ngoai bao ma chi la the tich "tudng tugng" cho thay thuoc sau khi vao
mau se co xu hudng d lai mau hay di ra khoi mau. Trong thuc te dieu trj de theo doi hieu
qua ta thudng can cuu vao nong do thu dugc trong huyet tuong/huyet thanh nen the tich
phan bo thuc chat chi la thong so de tinh toan lai lieu dung can cu vao nong do thuoc do
dugc hoac du doan nong do thuoc can cu vao lieu da dung.
1.2.2. Cac yeu to anh hu&ng den Vd
* Su-thay doi ty le lipid vd nu&c trong ca the
Lipid va nude la nhung hop phan co d moi to chuc. Ty le nay thay doi theo lira tuoi
(bang 1.1).
Bang 1.1. Ty le le lipid va nude va nude so vdi tong trgng lugng co the
Tuoi Ty le lipid va nude so vo»i tong trong lugng co»the
Lipid Nu&c
So sinh thieu thang 1 - 2 % 85%
So sinh du thang 15% 75 % •
12 thang- < 18 tuoi 18% 60%
18-60 tuoi 12-25% 60%
Ngudi cao tuoi 35 - 45 % 53%
Tri so the tich phan bo cong bo trong cac tai lieu ve thuoc la so lieu d ngudi truong
thanh (18-60 tuoi). Nhu vay, v&i cac doi tuang dqc bietnhutre nho, nguai beophi, ngu&i
gia... khong dp dung Vdnay.
DLS...T2 17
Cac thuoc cd chi so lipid/nudc thap nhu theophylin, gentamicin... khuyech tan tot vao
cac to chuc cd nhieu nude. C) tre so sinh, nhat la tre de thieu thang, ty le nude cua co the
chiem tdi 85%, do do the tich phan bo cua nhung loai thuoc nay la rat ldn.
Vi du: Vd cua theophylin d tre so sinh la 1 L/kg trong khi do d ngudi ldn (ty le nude
cua toan ca the la 60%) thi Vd chi con 0,48 L/kg. Cung vi vay lieu lugng tinh cho tre so
sinh theo can nang cao han lieu cho ngudi ldn.
Cac thuoc me cd Vd d ngudi beo phi tang han hSn so vdi ngudi binh thudng, do do
lugng thuoc me can su dung se ldn han (nhung thai gian h6i tinh sau me dai han do thuoc
tiep tuc phan bo trd lai mau tu mo md).
* Su- mat dich ngoai bao tram trong trong mot so trang thai benh ly:
Nhung thuoc tan nhieu trong nude, dac biet nhung thuoc chi phan bd d djch noai bao
nhu cac khang sinh nhdm amonoglycosid co Vd thay doi nhanh chong khi mat djch ngoai
bao nhu bong nang, mat mau, ia chay nang... Luc nay Vd giam keo theo sir tang nong do
thuoc trong mau dan den nguy co qua lieu, ngo doc.
1.2.2. Y nghla cua tri so Vd
The tich phan bo (Vd) giup u&c dodn ndng do thuoc datduac v&i lieu khuyen cao:
Ca4.
The tich phan bo cua theophyllin la 35 L. Lieu theophylin dung theo dudng tinh
mach la 600 mg. Nong do dieu tri cua theophylin cho phep tu 8-20 mg/L.
Vdi muc lieu nay nong do udc doan cd phu hgp cho dieu tri hen khong?
Tu cong thuc:
A = CpxVd -> DxF = CpxVd
Ta cd: Cp = D x F / Vd
The tich phan bo (Vd) giup tinh lieu kh&i dau (lieu tdi - loading dose = LD):
Ca5.
Mot benh nhan dugc chi dinh dieu tri bang theophyllin theo dudng tinh mach. Dugc
biet Vd cua theophyllin la 35 L.
Tinh lieu tai (LD) can dua de dat dugc nong do theophyllin trong huyet tuong la 15
mg/L?. " :
Trong dieu tri, mot so thuoc can cd thai gian kha dai de bao hoa to chuc va dat den
trang thai can bang (Css). Muc Css la muc can cho hieu qua dieu trj. De rut ngan thai gian
cho dgi, lieu tai (loading dose, LD) dugc su dung can cu vao Vd cho sEn. LD thuc chat la
lugng thuoc can dua cho benh nhan.
A = LD = Cn x Vd
18
Luu y:
Vdi nhung thuoc cd pham vi dieu trj hep, lieu cho tung ca the thudng phai tinh lai
dua vao muc Cp mong muon can cu vao muc dich dieu tri. Trong truong hgp nay cd the su
dung bang Vd trong cac tai lieu chuyen khao. Viec.su dung Vd cho sin chi dung cho nhung
doi tugng khong cd nhung roi loan nghiem trgng anh hudng den qua trinh phan bo va bai
xuat thuoc. Truong hgp benh nhan khong su dung dugc tri so Vd cd sin thi phai tinh lai Vd
theo cac cong thuc tren vdi du lieu cd d benh nhan.
1.3. Do thanh thai (Clearance, CI)
1.3.1. Khdi niem vd dinh nghla
Thuoc sau khi tham nhap vao vong tuan hoan se lap tuc dugc cac co quan cua ca
the tim each loai tru vi do la chat la. Ty le thanh lgc thuoc qua m6i co quan phu thuoc ban
chat ciia phan tu thuoc va ty le nay giao dong tu 0% den 100%.. Thuc te thi cd mot so thuoc
da bj loai tru ngay khi tham nhap vao ong tieu hoa nhd mot so enzym cd tai thanh rugt; tuy
nhien ty le nay rat it va do do 2 cd quan thanh lgc thuoc chu yeu la gan va than.
THUdC
Oxi hoa (Cyt.P450)

Lien hop, vd. Glucuronic
Cyt.P450
San pham chuyen hoa

San pham lien hop
J Dong khong phan eye
Bai xuat qua Bai xuat qua mat

nimctieu (vao phan)
Hinh 1.5. Gan - Th$n va qua trinh loai tru thuoc ra khoi ca the
Dinh nghla:
Do thanh thai ciia thuoc (con ggi la do thanh lgc, ky hieu ClThu6c) Id the tich tu&ng
tuang (imaginary volume) hay con ggi la the tich bieu kien (apparent volume) ciia huyet
tuang hope huyet thanh duac cac ca quan cua ca the (thu&ng la gan va than) loai bo hoan
toan thuoc trong 1 dan vi th&i gian (phut hope gi&).
So dT ggi la the tich "tu&ng tuang" vi thuc te khong bao gid cd the loai bd hoan toan
(100%) thuoc ra khdi huyet thanh hoac huyet tuong ma chi la gia trj bieu kien cho thay gia
sir neu mau chay qua gan hoac than trong 1 phut (hoac 1 gid) thi cd bao nhieu ml (hoac L)
dugc lgc sach thuoc.
Clearance trong cac bang cd sin vdi m6i loai thuoc thudng la Clt0anphdn, bieu thj kha
nang loai bd thuoc ra khdi huyet thanh, huyet tuang cua tat ca cac co quan bai xuat trong ca
the nhu gan, than, phoi, da, nude bgt, tuyen tiet... Tuy nhien, chi cd 2 ca quan gan va than
la cd kha nang lgc thuoc manh nhat, con lugng thuoc dugc bai xuat qua cac ca quan con lai
rat nhd, va it cd y nghla. Vi vay:
19
Cltoan phan ûhan • Îgan ' ^1
~ Clth$n rV Clgan
Dan vi cua CI thudng la mL/ph (L.ph"1) ho§c L/h (L.h"1).
Neu cac tai lieu ghi mL.ph"1.kg"1 hay L.ph"1.kg"1 thi khi tinh CI cho benh nhan, ta phai
nhan gia trj nay vdi so can nang cua benh nhan do. Vi du: CI cua cephalexin la 4,3 mL.ph"
l.kgT nhu vay CI cua cephalexin d mot ngudi nang 70 kg se la 4,3 mL.ph" 1.kg"1 x 70kg =
301 mL.ph"1.
Ca 6.
Theophylin cd Cltoan phan = 0,65 mL.ph"1.kg"1. Dugc biet theophylin la thuoc dugc
chuyen hoa 90% d gan.
- Tinh Clgan cua theophylin?
- Neu tinh cho mot ngudi cd trgng lugng 50 kg thi Clgan la bao nhieu? Giai thich y
nghla cua trj so vua tinh dugc?
Trj so Clxhudc thuc chat cung chi la mot trj so ao, cd tinh ly thuyet vi sir tuan hoan cua mau
qua cac co quan la hoi luu, lap di lap lai lien tuc va thuc te thuoc dugc coi la lgc sach ra khdi
huyet tuong sau mot khoang thai gian 7 x t]/2 (xem" thai gian ban thai").
1.3.2. Cacyeu to anh hu&ng den dp thanh thai cua thuoc
* Anh hu&ngcua chuc nang gan - than:
Do thanh thai thuoc (ClearanceThu6c) bieu thj kha nang lgc sach thuoc ra khdi mau
(huyet tuong/huyet thanh) bdi cac co quan bai xuat, quan trgng nhat la gan va/hoac than.
Do do thong so nay phu thuoc vao chuc nang 2 co quan nay:
Cltoan phan = Cithan "•" L'lgan
Kha nang thanh lgc thuoc qua gan phu thugc he enzym chuyen hoa thuoc. Nhung yeu
to lam thay d6i hoat tinh hoac so lugng he enzym nay nhu tuoi tac, di truyen, tuang tac
thuoc, suy gan... deu anh hudng den he so thanh thai qua gan (Clgan).
1.3.3. Y nghla cua tri so Clearance (CI)
* CI va toe dp bai xuat (vel):
CI khong phai la toe do bai xuat nhung khi biet clearance, ta cd the tinh dugc toe do
bai xuat (oei): CI dugc cho sin trong cac tai lieu chuyen khao. Tu CI da biet va Cp, ta cd
dugc Oe|:
Dei (mg.h"1) = CI (L.h"1) x Cp (mg.L"1)
CI la trj so hang djnh vdi moi thuoc khi kha nang bai xuat chua bj bao hoa. Nhu vay
toe do bai xuat thay doi ty le thuan vdi nong do thuoc trong huyet tuang (Cp).
Tuy nhien neu lieu dung qua ldn va ca che thanh lgc thuoc bj bao hoa, qua trinh bai
xuat thuoc se tuan theo dgng hgc bac 0 nghla la sau mot khoang thai gian nhat djnh cd mot
lugng co djnh thuoc dugc loai bd khdi huyet tuong. Trong truong hgp nay clearance se
khong hang djnh nua ma se giao dong.
20
* Tit CI cho san v&i moi thuoc va hang so toe dp bai xuat (kel), co the tinh duac Css:
Nong do thuoc d trang thai on djnh khi thuoc dugc dung theo each truyen tTnh mach
lien tuc dugc tinh theo phuong trinh sau:
kel
Css
CI
* Tie tri so CI vd nong dp thuoc do duac trong huyet tuang, ta co the tinh duac toe dp
truyen:
De duy tri nong do thuoc hang djnh (CSs) khi dieu tri, toe do truyen (oinf) phai bang
toe do thai tru (oei), nhu vay:
Uel =l)jnf = ClxCSS
6 day:
uei la toe do bai xuat (mg/h hoac mg.ph"1)
\)inf la toe do truyen thuoc vao tTnh mach (mg.h'hoac mg.ph"1)
CI: do thanh thai cua thuoc (L.h"1 hoac mL.ph"1)
Css: nong do thuoc d trang thai can blng (mg.L"1 hoac mg.mL"1)
1.4. Thai gian ban thai {tm)
1.4.1. Khdi niem vd dinh nghla vd cong thuc tinh tj/2
Khai niem half-life dugc ggi la nua ddi, ky hieu Un dugc bieu thj theo nhieu nghTa:
- Cd the do la \m a tuc la nua ddi hap thu, nhu tren do thj hinh 1.6 la la thdi gian can
thiet de mot nua lugng thuoc da uong vao dugc vong tuan hoan. Khai niem nay da dugc de
cap den d phan 1.1.1. Sinh kha dung.
Neu thuoc dugc dua qua dudng tTnh mach hoac dudng tiem bap thi pha nay khong cd
hoac khong dang ke, nhu vay khong cd tt/2 ot.
- Sau khi thuoc dat toi da, pha thai tru bit dau. tm /3 duac tinh tu pha thdi
tru (pha J3). thai gian ban thai (Elimination Half-
life).
1 InC Cmax
Hinh 1.6. Do thi lien quan Cp-t khi dua thuoc theo dudng uong
:\
21
Dinh nghla:
tm J3 chinh Id th&i gian can thiet de ndng do thuoc trong mau gidm di mot nua hope
luang thuoc da vao duac ca the di motnua.
Djnh nghTa nay dugc dung trong dieu trj vi ta chi tinh thdi gian sau khi thuoc da vao
duoc vong tuan hoan nghTa la khi pha hap thu da ket thuc.
C(mg/I) In C
100
100-..
) -i')-]
«. 6 8 io 12 wt(rtj& u * " ° ° " " " tW

Hinh 1.7. Dudng cong bien doi nong dg thuoc theo thdi gian khi dua qua dudng tTnh mach (I.V)
* Tinh t]/2 tie hangsd toe do thai tru (kej)
Vdi mot thuoc phan bo theo md hinh dugc dgng hgc 1 ngan, qua trinh thai tru tuan
theo dugc dgng hgc bac 1 (dang don gian nhat).
t y2 = 0,693/kd
Hoat tinh enzym, dae biet la cac enzym lien hgp hoat dong kem d tre em.
Cac enzym glueoronosyltransferase ehju trach lien hgp vdi morphin, eloramphenieol
hoac bilirubin chi dat den muc do tu 3 tuoi trd len. Vi
nhung ly do tren, toe do chuyen hoa thuoc d tre dudi 1nam, dae biet la tre sosinh yeu han
hln so vdi ngudi ldn dan tdi thai gian ban thai (ti/2) keo dai hon (Bang 1.2).
1.4.2. Cac yeu to anh hu&ng
ti/2 la thong so bieu thj cho ca 2 qua trinh: phan bova bai xuat. Chinh vi vay tat ca cac
yeu to anh hudng cac qua trinh nay deu lam thay ddi t]/2.
Bang 1.2. Su khac biet t1/2 cua mot so thuoc d tre sa sinh va ngudi ldn
Un (h)
Thuoc
Tre so* sinh du thang Ngirdi ldn
Amoxicillin -4 ~1
Amikacin -6 ~2
Digoxin -80 -35
22
Acid nalidixic -6 -2
Phenobarbital -200 60-120
Phenytoin 30-60 20-40
Salicylat -10 -5
1.4.3. Y nghla ciia tri so ti/2

* Th&i gian ban thdi la thong so xdc dinh ty le thuoc duac thdi trie:
Bang 1.3. Lien quan giua t1/2 va lugng thuoc dugc thai tru
Sd lan Lugng thudc dugc thai trip
t-l/2 (%)
1 50
2 75
3 88
4 94
5 97
6 98
7 99
Bang 1.3 dugc tinh khi dua thudc mot lieu duy nhat (single dose). Theo ket qua trong
bang thudc dugc xuat hoan toan co the sau 5-7 lan ti/2 vi liic nay lugng
thudc trong mau chi con rat it so vdi thuoc ban dau. Nhu vay khoang thai gian tu 5-7
x ti/2 dugc coi la thai gian "lam sach thudc" ra khdi co the. Day la co sd de xem xet thai
gian thay the thudc trong dieu trj.
* Tie th&i gian ban thdi co the xdc dinh khodng th&i gian can thiet de nong do thuoc dat den
trang thdi can bang (Css) sau khi dua lieu lap lai:
Bang 1.4. Ty le tich luy thuoc sau khi dua lieu ISp lai
Sd lan ti/2 Lugng thudc tich luy (%)
1 50
2 75
3 88
4 94
5 97
6 98
7 99
Tu bang 1.4 cho thay sau 5 lan ti/2 khi dua thudc theo lieu lap lai, nong do thudc dat
den trang thai can bang (Css).
23
:XJGH6<! DO.'-*
sVi4t*'';.'i
'-.•?"».'v.' )ii/.b>:î
w.••'i* •; £ ••♦ ♦ * £ # * *
DDDDDDDDDD
Hinh 1.8. Dien bien nong do thuoc trong mau khi dua lieu ISp lai
Nhin vao hinh 1.8 cd the thay tu thdi diem 5 x tm trd di, lugng thudc trong mau hau
nhu khong thay ddi nua. Luc nay lugng thudc tai cac to chuc da bao hoa, lugng thuoc tham
nhap vao to chuc bang lugng thudc dugc thai tru. Ngudi ta ggi thai diem nay la thai diem
thudc dat trang thai can bang (Css). Day chinh la nong do de duy tri hieu qua dieu trj. Viec
danh gia dieu trj chi dugc thuc hien sau thai gian nay.
Vdi thudc cd X\a dai dung dieu trj nhung benh cap tinh, can tinh den kha nang phai
dua lieu tai (loading dose) vi thdi gian de thudc dat 6&n can bang qua dai la khong cd lgi.
Vi du tj/2 cua theophylin khoang 8 h, nhu truyen tTnh mach lien tuc aminophylin de
cat con hen thi den sau 20 h nong do cung chi dat dugc mot nua so vdi nong do can
cd d trang thai can bang. Tuy nhien nen nhd rang viec dua lieu tai chi giup nong do khdi
dau gan vdi nong do mong mudn han con chd sau 5 lan tj/2.
Ca7.
Mot benh nhan tang huyet ap dugc chi djnh dieu trj bang amlodipin. Dugc biet thudc
nay cd ti/2 khoang 50 h.
Tinh thdi gian can thiet de nong do thudc dat den can bang?
Cd the dung amlodipin de ha huyet ap khan cap dugc khong? Tai sao?
* Lien quan giua tm va khoang each dua thuoc:
i Co
In —
C*
T = x ti/2
0,693
Trong do: x la khoang each dua thudc. Nhu vay, khoang each dua thudc ty le thuan
vdi ti/2. Tuy nhien nhin vao cong thuc tren thi khoang each dua thudc con phu thuoc vao
Co va Ct. Cong thuc nay chi phan anh moi lien quan khoang each dua thudc vdi dae tinh
dugc dong hgc cua thudc.
* Lien quan giua TJ/2 vd CI, Vd:
. f! r.s-b'l I *m&d vl
0,693 x Vd SG fi.&K> ijni, si n»t
t-l/2
CI
24
Theo phuong trinh tren, quan he cua ti/2 vdi Vd la ty le thuan con vdi CI la ty le
nghjch. Cd the minh hoa dieu nay qua cac sd lieu vdi mot sd thudc thudng dung sau:
Bang 1.5. Lien quan CI - Vd -11/2
CI Vd ti/2
Thudc (L/h) (L) (h)
Ethosuximid 0,7 49 48,0
Flucytosin 8,0 49 4,2
Digoxin 7,0 420 40,0
Morphin 63,0 280 3,0
Haloperidol 46,0 1.400 20,0
Cloroquin 45,0 12.950 - 200,0
Nhin vao bang 1.5 ta thay:

- Cloroquin cd U/2 rat dai (200 h). Dieu nay lien quan den kha nang phan tan ldn vao
md md va mot sd to chuc khac (nhu hong cau) dan den Vd rat ldn (12.950 L).
- Ethosuximid va flucytosin cd cung the tich phan bd nhung ti/2 chenh nhau tdi 10
lan, dd la do do 10 lan. Ngugc lai flucytosin
ti/2 cung chenh nhau khoang 10 lan do the
tich phan bd cua 2 thudc chenh nhau 10 lan.
Trong mot sd truong hgp benh ly lien quan den co quan thai tru nhu gan va than,
nhieu trudng hgp CI va Vd thay ddi theo cung mot hudng, vi du cung giam dan den tm
khong thay ddi. Nhu vay neu nhin vao trudng hgp nhu vay thi tj/2 khong phai la thong sd
phan anh dung quy luat thai tru thudc. Tuy nhien trong da sd trudng hgp d nhung ddi tugng
bat thudng ve sinh ly va benh ly, sir thay ddi CI la nguyen nhan keo dai ti/2 va do do, van de
hieu chinh khoang each dua thudc la bat budc.
2. SIT THAY DOI THONG SO DtTOC DONG HOC KHI SUY GIAM CHlfC NANG
GAN-THAN
2.1. Suy giam chuc nang gan

Suy giam chuc nang gan la hau qua cua nhieu trang thai benh ly khac nhau nhu viem
gan do sieu vi khuan, do vi khuan, do rugu, xa gan... Nhung bien ddi d gan lam giam kha
nang hoat dong cua gan ve nhieu mat, trong do dang ke nhat la:
Sir thay doi kha nang chuyen hoa cac chat.
Sir rdi loan kha nang bai tiet mat.
Sir giam kha nang tao protein va cac chat cd hoat tinh sinh ly khac...
Sau day la nhung bien ddi cua cac thong sd dugc dgng hgc qua tung giai doan:
2.1.1. Sinh kha dung (F%)
Sinh kha dung cua cac thuoc bj chuyen hoa manh qua vong tuan hoan dau (1st pass)
bj thay ddi do 2 yeu to:
- Su giam sut dong mau qua gan.
- Sir giam sut kha nang chuyen hoa thudc tai gan.
25
Hai yeu to nay lam giam ty le thuoc bj pha huy khi qua vong tuan hoan dau (1st pass)
dan den su tang sinh kha dung cua nhung thuoc ehju sir khu hoat manh khi qua vong tuan
hoan dau,'vi du: propranolol, morphin, nitroglycerin... lam tang nguy ca qua lieu. Nguy ca
qua lieu tang neu gap them tuong tac thuoc dgiai doan chuyen hoa vdi mot thudc gay kirn
ham cytocrom P450.
Bang 1.6. Thay doi sinh kha dung cua mot sothuoc d benh nhan xa gan
Thuoc % tang sinh kha dung
Labetalol 91
Midazolam 100
Morphin 115
Nifedipin 78
Propranolol 67
Verapamil 60
2.1.2. The tich phan bo (Vd)

Hau qua cua viec giam tong hop protein tai gan, trong do cd albumin va globulin -
nhung hop phan lien ket thuoc, se lam tang ty le thudc ddang tu do dan den tang the tich
phan bd cua nhung thudc cd ty le lien kit vdi protein cao (Hinh 1.9). The tich nude dd.ch
ngoai bao cung tang neu cd utre tuan hoan dtTnh cua (dae biet trong xa gan), dieu
nay dan den tang the tich phan bo cua cac thuoc tan nhieu trong
Nhu vay ndi chung Vd cua nhieu thuoc se dbenh nhan suy gan. Tuy nhien anh
hudng tdi dieu trj chi xay ra d benh nhan xa gan nang.
Thi tich phan b6 (L)
O
' v <.' ••>• ,
600 '
°/o '• iv*.K><\ -J.
400 "
•ill,•
200 - To
W.i-'lV. :y
n
u -i i i !
0 0.1 0.2 0.3 .': '••^••\ !»«J?. A.\ ' ••
TW 1£ tVmAr rt Hnna tir do iO- <!i'|<,t ju i
Hinh 1.9. Lien quan giua ty l$ thuoc d dang tu do va the tich phan bo
(Thu6c su dung: proppranolol 40 mg IV, kf hi$u ° la 6d6i tuvng nhdm chung - nguoi khoe
manh, ky hi$u • la 15 ddi tuang nhdm thu -nhung b$nh nh^n suy gan man).
26
Ca8.
Phenytoin la mot thuoc cd pham vi dieu trj hep; ty le lien ket vdi protein 90%, chu
yeu lien ket vdi albumin. Nong do penytoin trong huyet thanh khoang 10-20 mg/L dlieu
dieu tri. . •
Hdi: !.r:;iJlib itm^ '-
- Nong do thuc cd tac dung dugc ly cua phenytoin la bao nhieu?

- Nhung trieu chung khi qua lieu phenytoin?
- Anh hudng cua suy giam chuc nang gan den su dung phenytoin trong trudng hgp nay?
2.1.3. Dp thanh thdi qua gan (Clearance Gan, CLh)
Cac yeu to anh hudng tdi C1H bao g6m:
- Luang thuoc chuyen qua gan sau tung dan vj thai gian, cd nghla la phu thudc vao
luu lugng mau qua gan.
-Ty le lien ket protein cua thuoc vi chi cd nhung thuoc ddang tu do mdi bj gan pha huy.
- Hoat tinh cua enzym gan (dugc do bdi clearance ngi tai).
Cac thong so nay lien he vdi nhau trong cong thuc:
CIH= Qh .(-fuCli x Qh-Eh

_)= n f
Qh + fu . Cli
Oday:
C1H: Clearance gan
fu: Ty le thuoc d dang tu do (u = unbound)
.inVI \nwCs
Cli: Clearance ndi tai
(i = intrinsic, Cli danh gia hoat tinh cua enzym gan)
QH: Luu lugng dong mau qua gan (H = hepatic)
EH: He so chiet xuat cua thuoc tai gan.
Bang 1.7. cho ta thay dugc su bien doi ciia cac thong so dugc dgng hgc phu thuoc
vao trang thai benh ly cua gan.
Bang 1.7. Anh hudng cua suy giam chuc nSng gan den cac thong so DOH
Bien doi tai gan Thong s6 DDH bj anh hudng
Qh <->, t', I ICIH ^;t;4>
Enzym gan I I CIh I (d3c bi$t vdi thuoc c6 EH < 0,3)
Albumin I I CIh t (EH<0,3tt)
va/ ho3c:
a- glycoprotein I Ivd t
Bai tiet mat I ! CIH i (vdi thuoc bai xuat nhieu qua m§t)
27
2.1.4. Th&i gian ban thai (tm)
Hinh anh chung nhat cd the thay d benh nhan suy gan la chuc nang te bao gan giam,
dan tdi:
- Giam kha nang chuyen hoa thuoc -> giam do thanh thai thudc qua gan (C1H)
- Giam kha nang san xuat va bai tiet mat -> giam do thanh thai thuoc qua mat (C1H)
- Giam san xuat protein —> tang ty le thuoc d dang tu do.
0,693 x Vd
ti/2 =
CIT iVf<(-
Tu cong thuc tren cd the thay: sir bien doi t1/2 phu thudc vao Vd va CI. Ca 2 thong sd
nay deu thay doi: trong da so trudng hgp C1H giam, Vd tang (dae biet d benh nhan suy gan
nang); do do, tm thudng tang.
Ca9.
Benh nhan nOr, cao 1,65 nang 63kg, nghien rugu. Cac xet nghiem chuc nang gan cho
thay benh nhan bj xa gan cd c6 trudng vua va vang da. Benh nhan bj viem phoi va sot,
dugc tiep nhan vao benh vien vdi trang thai suy kiet. Albumin huyet tuong giam (3,0g/L),
bilirubin tang 3,0g/dL. Xet nghiem chuc nang than cho ket qua: Clcr = 30ml/min.
Benh nhan dugc chi djnh dieu trj bang 2 khang sinh phoi hgp la clindamycin va
eentamicin do cd tien su dj ung vdi penicilin.
Yeu cau:'
- Nhan djnh ve tinh trang benh nhan nay?
- Neu nhung diem can luu y khi su dung 2 khang sinh vua neu?
- Nhung thong tin tren cd anh hudng den cac thong so dugc dong hgc nao? Giai
thich?
2.2. Suy giam chuc nang than

Sir suy giam chuc nang than anh hudng den ca 4 qua trinh hap thu, phan bd, chuyen
hoa va thai tru thuoc, trong do sir giam sutthai tru la quan trgng nhat.
2.2.1. Sinh kha dung (F%)
Do ton thuang than, tuan hoan mau bj u tre va ca the bj phu. Trang thai benh ly nay
anh hudng den sinh kha dung cua cac thuoc dung theo dudng tiem bap va tiem dudi da. Vdi
thuoc dua theo dudng uong, ton thuang chuc nang than, ngugc lai cd the lam tang sinh kha
dung cua nhung thuoc cd he so chiet xuat d gan cao, ehju su khu hoat manh d vong tuan
hoan dau (first-pass) nhu propranolol, verapamil, cac hormon... Hau qua la do bao hoa kha
nang pha huy thuoc cua gan, do nong do thuoc trong mau tang cao va do u tre tuan hoan,
trong do cd tuan hoan gan - rugt chu khong phai do tang hap thu cua thudc.
2.2.2. The tich phan bo (Vd)
Mot so ton thuang benh ly d than gay giam lugng albumin trong huyet thanh, thay
doi cau true mot so protein cua huyet tuang. Ngoai ra, mot so chat noi sinh nhu ure,
28
creatinin, cac acid beo... bj u tre cung la nguyen nhan canh tranh vdi thudc trong lien ket
vdi protein ciia huyet tuong, lam tang nong do thudc tu do.
Sir tang the tich chat long d ngoai bao cong vdi tang nong do thudc tu do dan den
tang the tich phan bd (Vd) cua nhieu thudc.
Tuy nhien, quy luat nay khong dung vdi mgi loai thudc va trong mot sd trudng hgp
suy than lai thay giam the tich phan bd.
2.2.3. Dp thanh thdi qua than (CLp)
Ton thuang than rat Su u tre cac chat
diflunisal... Cac chat chuyen hoa qua gan dugc bai xuat vao mat rdi do vao rugt, sau do mot
phan dugc thai ra ngoai theo phan, mot phan dugc enzym glucuronidase cua rugt thuy phan,
giai phdng thuoc trd lai dang tu do va tai hap thu trd lai tu rugt vao mau. Qua trinh nay anh
hudng den do thanh thai thudc qua than ma hau qua la giam C1r.
2.2.4. Th&igian ban thai fti/$
Cac thuoc bai xuat qua than tren 50% d dang con hoat tinh cd ti/2 tang ro ret khi sue
lgc cua cau than < 30ml/min. Trai lai, nhung thudc bj chuyen hoa gan nhu 100% d gan lai
cd t]/2 khong doi khi thieu nang than (hinh 1.3).
Tu ket qua nay, cd y kien cho rang trong trudng hgp suy than, nen chgn nhung thuoc
dugc chuyen hoa d gan de giam bdt doc tinh. Nhung thudc bai xuat gan nhu 100% d dang
nhu gentamicin, tetracyclin... bat buoc phai hieu chinh lai lieu d
benh nhan suy than.
3. SU* DUNG THUOC 6> BENH NHAN SUY GIAM CHlfC NANG GAN - THAN
3.1. Su dung thuoc 6* benh nhan suy gan
Cd 3 nguyen tac co ban khi su dung thudc d BN suy gan:
3.1.1. Nen chgn nhung thuoc bai xuat chiiyeu qua than hoac nhung thuoc bai xuat qua
gan dudi dang lien hffp glucuronic
Thudng thi neu ty le bai xuat > 50% qua gan dugc coi la ldn. Tuy nhien, dieu nay con tuy
thudc dgc tinh cua ban than hoat chat va chat chuyen hoa. Vi du: diazepam la mot chat chuyen
hoa qua gan nhung 2 chat chuyen hoa ciia diazepam la nordiazepam va oxazepam deu la chat
con hoat tinh va giai doan nay thuc hien qua cyt.P450 (hinh 1.10).
Diazepam —> Nordiazepam -> Oxazepam —> Lien hop glucuronic

t t X
Oxy hoa Oxy hoa Nude tieu
Hinh 1.10. Sa do chuyen hoa diazepam tai gan
3.1.2. Tranh he dan nhung thuoc
- Co ty le lien ket protein cao: viec tranh dung nhung thudc cd ty le lien ket protein cao la
do khi benh nhan bj suy giam chuc nang gan, ty le thudc d dang tu do tang cao de dan den
tac dung khong mong muon va qua lieu.
29
- B'i khir hoat manh d vong tuan hoan dau (EH > 0,7)
Nhu da neu d phan tren, nhung thuoc bj khu hoat manh (>70%) khi qua vong tuan
hoan dau (1st pass) se bj anh hudng nhieu bdi luu lugng tuan hoan quan gan va sinh kha
dung rat de bj tang neu ke don cho benh nhan suy gan.
CalO.
Ong Acd tien su nghien rugu, hien bj xa gan cd bieu hien vang da va c6 trudng
vua. Ong mic benh dai thao dudng typ 2 da 10 nam nay va hien dang sir dung
glibenclamid phoi hgp vdi metformin de dieu trj. Ong 72 tuoi, cao 1,68m, nang 83 kg.
Xet nghiem mau cho ketqua : creatinin huyet thanh 1,4 mg/dL, HbAlc 10,0
Yeu cau:
- Neu nhung diem can luu y khi sirdung 2 thuoc chong dai thao dudng tren:
+ Nguy ca cd the gap phai khi sir dung glibenclamid?
+ Binh luan ve muc lieu dung cho metformin hi£n nay la 1000 mg x 2 lan/24h?
3.2. Sir dung thuoc 6" benh nhan suy than

3.2.1. Danh gid chuc nang thpn
Clearance creatinin dugc coi la chi so tin cay danh gia chuc nang than. Vdi benh
nhan suy than man, lugng thuoc thai qua than thay doi theo do thanh thai creatinin
(Clearance creatinin - Clcr) va lieu hieu chinh cung dugc tinh lai theo muc suy giam Clcr
ciia benh nhan suy than so vdi ngudi cd chuc n£ng than binh thudng .
He so thanh thai creatinin dugc tinh theo phuong trinh ciia Cockcroft & Gault:
(140 - Tuoi) x The trgng
Clcr =
Cr/HT x 72
Ghi chu:
- Tuoi benh nhan dugc tinh theo nam, the trgng tinh theo kg.
- Cr/HT la nong do creatinin trong huyet thanh tinh theo mg/dL. Neu Cr/HT tinh
theo don vj la umol/L thi thay vi x 72, ta se x vdi 0,88.
Don vj ciia Clcr la mL/min.
- Clcr tinh theo cong thuc tren danh cho nam gidi. Clcr-nu = Clcr-nam x 0,85.
Bang 1.8. Phan loai muc dO suy th$n theo creatinin huyetthanh va Clcr
Do suy th?n Creatinin/HT umol/l Clcr (mi/phut)
Nhe 150-300 50-20
Vua 300 - 700 20-10
N$ng >700 < 10
Can luu y rang neu danh gia chuc nang than d b^nh nhan suy than nang phai tham
tich thi creatinin trong huyet thanh cd the thay doi trong qua trinh tham tich hoac giDra
30
khoang thai gian 2 lan tham tich, trong khi neu tinh theo cong thuc tren thi nong do
creatinin trong huyet thanh co dugc chi sau 1 lan lay mau ma khong phan anh dugc ca thai
gian dieu trj. Vi vay vdi nhung doi tugng phai tham tich thi muc lieu khuyen cao can cu
vao bang hudng dan rieng.
Vidu:
Theo "Drug Prescribing in Renal Failure - Dosing Guilines for Adult and Children
cua American College of Physicians (2007), ofloxacin cd muc lieu cho ngudi ldn la 200-
400 mg each 12 h/lan cho cac BN cd Clcr > 50 ml/min, 200-400 mg, each 24 h cho BN cd
Clcr tu 50-10 ml/min, 200 mg each 24 h cho BN cd Clcr tu < 10 ml/min. Vdi benh nhan
phai tham tich thi muc lieu khuyen cao nhu sau:
IHD (Intermitent Hemodialysis): 100-200 mg sau tham tich.
PD (Peritoneal Dialysis): 200 mg each 24 h
CRRT (Continuous Renal Replacement Therapy): 300 mg each 24 h
Tuy nhien, muc lieu hieu chinh cd the sai khac chut it tuy thudc nguon tai lieu.
Ngoai ra phai chu y la vdi mot so doi tugng dae biet nhu ngudi gia, ngudi bj teo ca...
muc creatinin khong ludn tuong dong vdi chuc nang than. Vi vay lieu dung tinh theo cong
thuc hieu chinh tren co so Clcr chi cd tac dung tham dd ban dau, tiep theo do phai dieu
chinh lai lieu can cu vao nong do thuoc trong mau.
Nhung trudng hgp benh nhan nim d muc can nang va chieu cao binh thudng (BMI tu
18,5 - 24,9 theo phan loai ciia WHO), cd the danh gia chuc nang than qua toe do lgc cau
than (GFR) theo cong thuc ciia MDRD (Modifiaction Diet of Renal Diseases):
GFR (mL/min/1.73 mz) = 186 x (Cr_s) , x (Tuoi) -0.203
x (0.742 neu la nu)
Trong cong thuc tren, nong do creatinin trong huyet thanh dugc tinh theo mg/dL, con
neu nong do creatinin dugc tinh theo uMol/L thi cd cong thuc sau:
.2\ _
GFR (ml/min/l,73m/) = 186 x (Cr_s / 88,4)'' 154 x (Tuoi) -0.203
x (0.742 neu la nu)
Bang 1.9. Phan loai suy than theo toe do lgc cau than (GFR)
Muc do suy than GFR (ml/phut/1,73m2)
90+
60-89
Ilia 45-59
1Mb 30-44
IV 15-29
V <15
Tuy nhien cong thuc nay khong chinh xac bang cong thuc ciia Cockcroft & Gault.
3.2.2. Cac nguyen tacco" ban de hieu chinh lieu cho benh nhan suy gidm chuc nang than
Nguyen tic hieu chinh lieu thuoc d BN suy than can cu vao:
31
- Ty le thuoc con hoat tinh thai tru quathan.
- Muc do dgc ciia thuoc tuc la moi tuong quan ciia hieu qua va doc tinh den nong do
thuoc trong mau (pham vi dieu trj rdng hay hep).
Cach hieu chinh lai lieu cd the la: giam lieu thuoc hoac tang khoang each giua cac lan
dung thuoc hoac phoi hgp ca 2 each nay.
Giam lieu cho phep nong do thuoc trong mau khong tang nhieu, tranh dugc^nguy ca
doc tinh nhung cd nguy cakhong dat lieu dieu trj mong muon. Vdi mot so loai thuoc, trudc
khi giam lieu, neu xet can thiet cd hieu qua ngay thi phai dua "lieu tai" con ggi la lieu nap
(loading dose). "Lieu tai" ciia thuoc thudng bang lieu thudng dung cho benh nhan khong
suy than.
Keo dai khoang each dua thuoc giup giu dugc nong do dieu trj nhung lai cd nguy ca
keo dai khoang thai gian nong do thuoc dudi muc dieu trj lam tang kha nang khang thuoc
hoac bung phat con benh. Do dd neu he so hieu chinh qua ldn thi phuong an phoi hop ca 2
each lam tren la hgp ly.
Cac budc tien hanh:
*Danh gid ty le suy gidm chuc nang than &BN qua heso RF:
Clcr-st.
Rf =
Clcr- bt.
Oddy:
Clcr-st la clearance creatinin d benh nhan suy than
Clcr-bt laclearance creatinin d BN cdchuc nang than binh thudng (80-120 ml/min).
* Tinh he so hieu chinh Q:
Q=l -fex(l -RF)
Oddy:
- Q la he so hieu chinh cho benh nhan cd suy giam chuc nang than.
- fe la ty le thuoc dugc bai xuat qua than d dang con hoat tinh (dugc biet tu dae tinh
dugc dgng hgc ciia thuoc d ngudi cd chuc nang than binh thudng).
- RF nhu vua neu tren la ty le suy giam ciia chuc nang than.
Theo cong thuc tren, chi hieu chinh lai lieu ciia phan thuoc thai tru d dang con hoat
tinh qua than con phan thuoc bai xuat qua gan khong tinh dugc vi khong cd mot thong sd
nao cho biet chuc nang bai xuat thuoc qua gan se giam bao nhieu trong trudng hgp chuc
nang gan bj suy giam. Day cung la ly do tai sao khi chuc nang gan bj suy giam, ngudi ta
khuyen nen chgn cac thuoc khong bj chuyen hoa qua gan ma bai xuat chu yeu qua than d
dang con hoat tinh.
*Cong thuc hieu chinh lieu &benh nhan suy than sau khi da co he so Q
Cd 3 each hieu chinh:
32
1/ Giirnguyen khoang each dua thuoc va giam lieu:
D-st = D-bth x Q
2/ Giu nguyen lieu nhung ndi rong khodng each dua thuoc:
x-st. f T_bt / Q
CJday:
-1 la khoang each dua thuoc
- D-st la lieu dung cho BN suy than
- D-bth la lieu dung cho ngudi khong suy than
3/ Viea gidm lieu, vim noi rong khoang each dua thuoc:
Nhieu trudng hgp, neu dung he sd Q de giam lieu thi lieu mdi khong bao gid dap ung
dugc nong do thudc trong huyet tuang d muc dieu trj. Neu giu nguyen lieu thi tai thai diem
ngay sau khi dua thudc, nong do lai qua cao nhung sau do do khoang each qua dai nen giai
doan thuoc cd nong do d dudi muc dieu trj cung keo dai, do do hieu qua dieu tri thap.
Nhung trudng hgp nay, ta cd the chgn mot he sd Q khac trung gian va dung ket hgp ca 2
phuong phap: viea gidm lieu viea noi rong khodng each.
Tu nguyen tac tren, cac nha san xuat thudng dua ra bang tinh san de ngudi dung tien
ap dung.
Call.
Ba H., 80 tuoi, cao 1,65m, nang 65kg. Dugc biet ba co tien sir nghien rugu. Ba
H.nhap vien do bj suy kiet va viem phoi, sot cao. Chi sd xet nghiem creatinin huyet thanh
la 2,0 mg/dL. Qua tham kham lam sang va lam xet nghiem con phat hien ba bj xa gan.
Thudc dugc ke cho BN phoi hgp Clindamycin va Gentamicin (do BN cd tien sir dj
ling penicilin).
Yeu cau:
Danh gia tinh trang chuc nang than d BN nay?

Neu nhung diem can luu y khi sir dung 2 khang sinh tren?
Tinh lieu gentamicin cho BN cho biet lieu cho BN co chuc nang than binh
thudng la 5mg/kg/24h?
KET LUAN
* •f i •'
Cac thong so giup cho thay thudc trong viec chgn lira thuoc phu hgp vdi ca the ngudi
benh va nang cao dugc kha nang sir dung thudc mot each an toan va hieu qua. Cac thong sd
nay thudng dugc cho san trong cac tai lieu chuyen khao va chi dung cho cac ddi tugng
khong co bat thudng ve 4 qua trinh ADME.
Chiic nang gan va than co anh hudng den cac thong sd dugc dgng hgc va do do can
luu y khi sir dung thuoc cho cac ddi tugng nay. Anh hudng ciia cac thay ddi ve sinh ly len
cac thong so dugc dong hgc se dugc trinh bay trong cac chuang lien quan.
DLS...T3 33
CAU HOI LlTONG GIA
Trd lai cau hoi ngan:

1. Trinh bay djnh nghTa, cong thuc tinh ciia 4 thong so dugc dgng hgc co ban: sinh kha
dung %, the tich phan bo, dd thanh thai va thai gian ban thai ciia thuoc.
2. Phan tich cac yeu to cd the anh hudng den cac thong so dugc dgng hgc tren khi sir dung
thudc.
3. Trinh bay nguyen tic su dung thuoc d benh nhan suy giam chuc nang gan
4. Trinh bay cac budc tien hanh de hieu chinh lieu d benh nhan suy than.
Chon cau trd lai dung nhat:
5. Djnh nghTa sinh kha dung:
I. La thong so bieu thj lugng thuoc vao dugc vong tuan hoan chung d dang con hoat tinh
II. La thong so bieu thj ty le thuoc vao dugc vong tuan hoan chung d dang con hoat tinh so
vdi lieu da dung F%
III. La thong so bieu thj ty le thuoc vao dugc vong tuan hoan chung d dang con hoat tinh so
vdi lieu da dung (F%), toe do (Tmax) va cudng do (Cmax) thuoc tham nhap dugc vao vong
tuan hoan chung
A. I diing D. I va II diing
B. II dung E. I, II va III dung
C. Ill dung
6. Cac yeu to anh hudng den sinh kha dung (SKD):
I. Nhung thuoc bj giam nong dd khi qua vong tuan hoan dau cd SKD dudng uong thap
han dang ke dudng tiem
II. Cac chat cam ung hoac uc che enzym cyt.P450 lam thay ddi SKD
III. Nhung chat cd EH > 0,7 cd SKD thay doi khi chuyen tu dudng tiem sang dudng uong
va ngugc lai
B. II diing E. I, II va III diing
C. Ill diing
7. Anh hudng ciia suy giam chuc nang gan den sinh kha dung (SKD):
I. Tang SKD ciia cac thudc cd Eh > 0,7
II. Tang SKD vdi cac thudc cd EH < 0,3
III. Khong anh hudng den SKD
C. Ill diing
8. Djnh nghTa the tich phan bd:
I. The tich phan bo la mot the tich "tudng tugng" bieu thj mot khoang khong gian ao can
phai cd de toan bo lugng thudc dugc dua vao co the phan bd d nong do bang nong do trong
huyet tuang
34
II. The tich phan bd la the tich ciia cac khoang trong co the
III. The tich phan bd la the tich ciia mau va djch ngoai bao
C. Ill diing
9. Cac yeu to anh hudng den the tich phan bd:
I. The tich phan bd d tre so sinh va ngudi ldn khong khac nhau
II. Cac thudc tan nhieu trong lipid cd the tich phan bd tang d ngudi cao tuoi
III. Mat nude lam giam the tich phan bo ciia cac thudc tan nhieu trong nude
C. Ill diing
10. Dinh nghTa do thanh thai (Clearance, CI):
I. Do thanh thai ciia thudc la the tich tudng tugng ciia huyet tuang hoac huyet thanh dugc
gan va than loai bd hoan toan thudc trong 1 don vj thai gian (phut hoac gid)
11. Do thanh thai ciia thuoc la the tich huyet tuong hoac huyet thanh dugc gan va than loai
bd hoan toan thudc trong 1 don vj thai gian (phut hoac gid)
III. Do thanh thai cua thuoc la the tich mau dugc gan va than loai bd hoan toan thuoc trong
1 dan vj thai gian (phut hoac gid)
A. I dung D. I va II diing
C. Ill diing
II. Cac yeu to anh hudng tdi CIh bao gom:
I. Luu lugng mau qua gan.
II. Ty le lien ket protein ciia thudc
III. Hoat tinh ciia enzym gan
C. Ill diing
12. Ve thai gian ban thai (t\n):
I. Thudc se dat den trang thai can bang sau 5 lan ti/2
II. Thuoc se dat den trang thai can bang sau 7 lan t\/2
III. Thuoc dugc thai tru gan nhu hoan toan ra khoi co the sau 7 lan U/2
C. Ill diing
13. Thai gian ban thai bj keo dai d benh nhan suy gan do:
1. Giam kha nang chuyen hoa thuoc
35
II. Giam kha nang bai xuat thudc qua mat
III. Tang the tich phan bo
B. II diing E. I, II va III dung
C. Ill diing
14. Hieu chinh lieu d benh nhan suy than:
I. Giam lieu
II. Ndi rong khoang each dua thudc
III. Phoi hgp ca 2 each tren
C. Ill diing
DAP AN CAC CAU HOI LUA CHON (Tu cau 5 den cau 14)
5. A / 6. D / 7. A / 8. A / 9. E / 10. A / 11. E / 12. E / 13. E / 14. E
TAI LIEU THAM KHAO
1. Bd Y te - Bd mdn Dugc lire (2005), Duac ly hoc, NXB Y hgc.

2. Bg Y te - Hoang Thj Kim Huyen (2011), Dugc dgng hgc - Nhung kien thuc co ban,
NXB Y hgc
3. Bertam G. Katzung et al. (2009), Basic & Clinical Pharmacology, 11th edition
Appleton&Lange/McGraw-Hill.
4. Birkett D.J (2007), Pharmacokinetic - Made Easy, McGraw-Hill.
5. Dangoumau J. (2006), Pharmacologic generale, Universite Victor Segalen-Bordeaux 2.
6. Jambhekar S.S., Breen P.J. (2009), Basic Pharmacokinetics, Pharmaceutical Press
7. Larry A. Bauer (2008), Applied Clinical Pharmacokinetics, 2nd edition, McGraw Hill.
8. Singlas E., Tuburet (1993), Abrege depharmacocinetique, C.H.U., Bicetre.
9. Walker R, Edwards C, (2007) Clinical Pharmacy and Therapeutics, 4nd ed, Churchill
Livingstone, UK.
36
CHUONG 2. DANG THUOC VA DUONG DUNG
Vd Xuan Minh, H.J. IVoerdenbag, H. W. Frijlink

MUC TIEU
/. Neu duac 3 khdi ni$m chung ve dang thuoc: thanh phan, phan loai, qua trinh sinh duac
hoc.
2. Trinh bay duacdae diem cuaduong dimg thuoc vd cac dang thuoc hay diing
1. DAI ClTONG VE DANG THUOC

1.1. Khai niem
Dang thuoc la san pham cuoi ciing (thanh pham) cua qua trinh bao che, dat cac tieu
chudn chat luang quy dinh, duac dung de dua duac chat vao ca the nhdm muc dich phong
hay chiea benh
Trong bao che hien dai, dang thudc dugc coi la cac "He dua thuoc" vao co the (Drug
Delivery Systems) hoac "He tri lieu" (Therapeutic Systems) hay "thiet bj" mang thuoc
(Devices). Ndi each khac, dang thuoc la gid mang duac chat, la san pham ciia nganh dugc
dua den ngudi benh, la cau ndi giua dugc sT - thay thuoc va ngudi benh
Dang thudc phai dugc bao che sao cho tien bao quan, van chuyen, sir dung an toan,
hieu qua va kinh te.
Vdi ciing mot dugc chat, khi bao che dudi cac dang thuoc khac nhau dung theo cac
dudng dung khac nhau co the dan den tac dung lam sang khac nhau. Thi du: magnesi sulfat
dung dudi dang bot de uong thi co tac dung nhuan trang, nhung khi tiem lai cd tac dung chong
co giat. Vi vay, viec hudng dan sir dung diing dang thuoc la het sue quan trgng. Mot che pham
thudc dugc bao che tot nhung hudng dan su dung khdng diing cung se khdng mang lai hieu
qua, tham chi cd liic con gay nguy hiem cho ngudi benh.
1.2. Thanh phan: dang thuoc thudng cd: dugc chat, ta dugc va bao bi
1.2.1. Duac chat (active ingredients): la thanh phan chinh ciia dang thuoc, quyet djnh tac
dung dugc ly ciia thudc
Cac yeu to thudc ve dugc chat lien quan true tiep den SKD ciia thuoc din dugc xem
xet khi thiet ke dang thudc la:
- Ly-hoa tinh: do on djnh hda hgc, do tan, kich thudc tieu phan,....
- Do on dinh hoa hoc: de dam bao thuoi thg ciia dang thuoc, dugc chat can cd do on
djnh hoa hgc cao. Tren thuc te, nhieu nhom dugc chat it on djnh (de bj thuy phan, oxy
hoa,...) dan den bien chat trong qua trinh bao che va su dung, nhat la khi pha dudi dang
thuoc long: vitamin, protein,...
- Do tan: dugc chat muon dugc hap thu thi phai hda tan trong moi trudng sinh hgc.
Do vay, do tan la yeu to quan trgng quyet djnh muc do hap thu. Tat ca tinh chat ciia dugc
chat lien quan den do tan nhu nhom than nude trong cau true (OH, amin,...), dang thu hinh,
trang thai ket tinh, dang muoi,... deu anh hudng true tiep den SKD ciia dang thuoc. Cac
37
dugc chat it tan trong nude (< 1% d 20°C) thudng cd van de ve SKD, tren thuc te co
khoang 40% dugc chat cd do tan han che.
- Kich thudc tieu phan (KTTP): KTTP lien quan den dien tich be mat tiep xiic ciia
dugc chat vdi moi trudng hda tan, do do anh hudng den toe do hda tan ciia dugc chat. Khi
toe do hoa tan tang se lam tang toe do hap thu, tuc la tang SKD cua thudc. Do dd, vdi dugc
chat it tan, khi nghien nhd dugc chat cd the cai thien SKD ciia dang thudc.
- Tinh chat duac dong hoc: tinh tham qua mang sinh hgc va cac thong sd dugc dgng
hgc ciia dugc chat la nhung yeu to lien quan true tiep den SKD in vivo ciia thudc. Cac yeu
to lien quan den tinh tham nhu khdi lugng phan tu, muc do ion hda, he sd phan bd D/N ciia
dugc chat la nhung tieu chi can xem xet trong thiet ke dang thudc.
Dua vao do tan va tinh tham, he thong phan loai sinh duac hoc BCS
(Biopharmaceutical Classification System) chia dugc chat thanh 4 nhdm: nhdm 1 la dugc
chat de tan, de tham; nhdm 2 la dugc chat de tan, kho tham; dugc chat nhom 3 kho tan de
tham con d nhdm 4 cac dugc chat deu khd tan va khd tham. Dang thuoc chua dugc chat
nhom 1 co thi dugc mien thu tuong duong sinh hgc, con dugc chat nhdm 4 thudng cd van
de ve SKD.
1.2.2. Ta duac (non-active ingredients):

Vai trd ciia ta dugc trong dang thudc ngay cang trd nen quan trgng. Trudc kia, ngudi
ta thudng quan niem ta dugc la nhung chat tro, phu trg cho qua trinh bao che va bao quan
dang thuoc. Ngay nay, trong bao che hien dai, vdi quan niem dang thudc la nhung he dua
thuoc vao ca the, ta dugc dugc xem la nhung gia mang thudc cd anh hudng rat ldn den md
hinh, co che, toe do giai phong dugc chat khdi dang thuoc va do do anh hudng den tuoi thg
cung nhu hieu qua dieu trj ciia thuoc, dae biet la cac polyme tong hgp. Mat khac cung phai
luon ludn canh giac vdi nhung tuang tac bat loi ciia ta dugc vdi dugc chat va ca the cd the
xay ra ma khdng phai liic nao cung du doan trudc dugc, nhat la vdi nhung polyme khong
tuang hgp sinh hgc.
1.2.3. Bao bi: do bao gdi cung dugc xem la mot thanh phan quan trgng ciia dang thuoc.
Ngoai vai trd dam bao my quan, cung cap thong tin ve che pham thudc, bao bi con tiep xiic
true tiep va thudng xuyen vdi thudc, do dd anh hudng den do on djnh ciia dugc chat va tuoi
thg ciia thuoc, nhat la vdi cac dang thudc long ddi hoi chat lugng cao nhu thudc tiem, thuoc
nho mat.
Dugc chat, ta dugc, bao bi phai dat dudi tac dgng true tiep ciia ky thudt bao che de
hinh thanh dang thudc. Vi vay, ky thuat bao che cung dugc coi la thanh phan vo hinh ciia
dang thuoc, gdp phan quan trgng vao viec dam bao chat lugng thudc
1.3. Phan loai: co nhieu each phan loai dang thudc
1.3.1. Theo the chat: chia thanh 3 loai:
1.3.1.1. Dang thuoc long

Dugc chat dugc hda tan dudi dang phan tu hay phan tan trong moi trudng long dudi
dang tieu phan, bao gom cac dang nhu dung djch (dung djch thudc nude, con thuoc, cao
thuoc, siro thuoc, elixir, potio,...), hdn dich, nhu djch,...
Dang thudc long cd the dung uong hay dung ngoai. Khi dung de uong, thudc long cd uu
diem la de nudt, nhat la vdi tre em va ngudi cao tuoi. Trong thudc long, phan ldn dugc chat da
38
dugc hda tan dudi dang phan tu nen qua trinh SDH don gian (khdng can qua budc giai phong,
hda tan), dugc hap thu va gay tac dung nhanh, thich hgp trong trudng hgp thudc can the hien
ngay dap ung lam sang sau khi dung (tim mach, ha sot giam dau,...). Tuy nhien dang thuoc
long phan lieu kem chinh xac va it on djnh han dang thudc ran (tuoi thg ngan han); the tich
cong kenh, kho van chuyen va mang theo ngudi.
1.3.1.2. Dang thuoc mem (ban ran)
Bao gom cac dang thudc co the chat mem d nhiet do thudng, trong do, dugc chat d
dang hoa tan hay phan tan dudi dang hon dich hay nhu tuong. Dang thudc mem cd the de
uong (cao mem, nang mem) hay dung ngoai (ma-kem-gel,...)
1.3.1.3. Dang thuoc ran
Bao gom cac dang bdt, pellet, vien tron, vien nen, nang ciing,...(hinh 2.2). Dang thuoc
ran cd the tich ggn nhe, de van chuyen, bao quan va sir dung han dang thuoc long, tuoi thg
thudng dai han dang thuoc long, chiem tren 60% lugng thudc luu hanh tren thi trudng.
Dugc chat trinh bay dudi dang thudc ran de che dau mui vi va kiem soat giai phong. Tuy
nhien, dang thuoc ran dung de uong thudng chua dugc chat it tan, qua trinh bao che lai co
nhieu yeu to tac dgng bat lgi den viec giai phong dugc chat (lire nen, vd bao,....) nen la
nhung dang thudc thudng co van de ve SKD va tac dung cham han dang thuoc long.
1*0
hJr
Hinh 2.1. Dang phun mu Hinh 2.2. Dang thuoc rSn
1.3.2. Theo ca che giai phong duac chat: chia thanh 2 nhdm ldn:
1.3.2.1. Giai phong ngay (IR: Immediated Release): la cac dang thudc quy udc
(Conventional Dosage Forms), truyen thong, khi bao che chua quan tarn nhieu den giai
phong dugc chat (thudng dugc chat giai phong sau khi uong trong vong 30 phut).
1.3.2.2. Giai phong bien doi (MR: Modified Release): la cac dang thuoc trong dd, nha bao
che chii dong tac dong vao toe do giai phong dugc chat de dieu tiet hoa tan va hap thu theo
nhu cau dieu trj, bao gom:
- Giai phong nhanh (Fast Release, Rapid Disintegration, Rapid Dissolution,...): la
dang bdt, hat, vien nen ra va hoa tan ngay sau khi uong (trong vong 1-2 phut) nhu vien pha
dung djch, vien siii bgt, vien ra nhanh,... Dung trong trudng hgp thudc can phat huy tac
dung ngay: ha sot giam dau, chong viem,...
- Giai phong muon (Delay Release): dugc chat dugc giai phong sau mot khoang thai
gian tiem tang (lag time) nhat dinh.
39
- Dgng bao tan a ruot (vien, nang, pellet): theo quy dinh ciia nhieu dugc dien, vd bao
phai khang moi trudng dich vj (pH 1,2) trong vong 2 gid va giai phong dugc chat d moi
trudng djch rugt (pH 6,8) trong vong 30 phut.
- Dang giai phong theo nhip (Pulsatile Release): giai phdng dugc chat sau pha tiem
tang khoang 6-9 gid de dieu tri benh tai dai trang hoac de phdng ngua con benh dien bien
theo nhjp ngay-dem (thuoc chua hen, thuoc tim mach,...).
- Giai phong keo ddi (Extened Release, Sustained Release, Prolonged Release, Slow
Release,...): dugc chat giai phdng tu tu va keo dai sau khi uong de keo dai tac dung cua
thuoc nham giam bdt so Ian dung thudc cho ngudi benh. Vdi thuoc uong thudng co 2 md
hinh: keo dai 12 gid (moi ngay uong 2 lan) va keo dai 24 gid (moi ngay uong 1 lan).
—Giai phong kiem soat (Controlled Release): cung la dang giai phdng keo dai nhung
yeu cau cao han: bao ham viec giai phdng dugc chat deu dan lien tuc trong nhieu ngay (3-7
ngay) de duy tri nong do dugc chat trong mau trong vung dieu trj nham giam tac dung
khong mong muon ciia thuoc.
- Giai phong theo chuang trinh (Programmed Release): la dang thudc co yeu cau ve
giai phong dugc chat rat cao: toe do giai phdng phai hang djnh trong nhieu ngay (tham chi
la hang nam) tuan theo chuang trinh da dugc thiet ke trudc cho dang thudc. Cac dang thuoc
nay thudng la cac he dieu trj nhu he dieu tri qua da TTS (Transdermal Therapeutic
Systems), he dat tai mat (Ocusert) hoac la cac "thiet bj" nhu thiet bj dat tu cung IUD
(Intraurine Device), thiet bj cay dudi da (Implant),...
- Giai phong tai dich (Targetted Release): la the he cac dang bao che sieu nhd , hien dai
nham dua dugc chat tdi noi bj benh (drug targeting) nhu tieu phan nano (nanoparticles) hoac
liposome,... vdi muc dich giam tac dung khong mong muon va nang cao hieu qua dieu trj.
12 34
MTC
MEC
Thdi gian
Hinh 2.3.0o thi giai phong dugc chat ciia dang thuoc: IR (1), k6o dai (2), nhSc lai (3) va kiem
soat (4)
Ghi chii:
- MTC: nong do tdi thieu gay doc /- MEC: nong do tdi thieu co hieu qua
40
1.4. Qua trinh sinh duoc hgc cua dang thuoc va cac yeu to anh huong den sinh kha dung
Qua trinh sinh dugc hgc phan anh so phan cua dgng thuoc trong co the, gom 3 budc:
giai phong, hoa tan va hap thu (ggi tat la LDA: Liberation-Dissolution- Absorption).
1.4.1. Giai phong
Dugc chat la thanh phan quyet djnh tac dung dugc ly ciia dang thudc, do do dang
muon phat huy tac dung thi phai giai phdng trd lai dugc chat. Miic do
va toe do giai phdng lien quan den budc hda tan tiep sau; con noi giai phdng lien quan den
do on dinh hoa hgc va kha nang hap thu ciia dugc chat. Qua trinh giai phdng phu thudc vao
- Dgng thuoc: dang thuoc long dugc chat da dugc hda tan hay phan tan trong dung
moi hay chat dan rat it cd van de ve giai phong. Trong khi do qua trinh giai phdng dugc
chat tu dang thuoc ran kha phuc tap, nhat la vdi vien nen, nang thudc, pellet.
- Miec do than hay so moi truanggiai phong: moi trudng giai phdng ciia dang thuoc la
djch sinh hgc nen dung dich nude va dung moi than nude de trgn lan han dung djch dau, nhu
tuang, thudc ma,... Dugc chat trong pha dau phai co thai gian de khuech tan sang pha nude.
- Tuang tac duac chat -ta duac: hay gap trong dang thuoc ran: hap phu, tao phuc it
tan,... lam cho dugc chat khong giai phong dugc khoi dang thuoc.
- Ky thuat bao che: ky thuat tao hat, lire dap vien, do day mang bao,.... trong cac dang
thuoc vien nen, nang ciing, pellet,...neu lira chgn khdng hgp ly cd the han che qua trinh giai
phong dugc chat.
Vi vay viec thiet ke dang thudc, lira chgn ta dugc va ky thuat bao che anh hudng rat
ldn den SKD cua che pham.
1.4.2. Hoa tan
Dugc chat muon hap thu qua mang thi phai hoa tan trong djch sinh hgc. Vi vay, toe do va
miic do hoa tan anh hudng true tiep den SKD ciia che pham. Hoa tan phu thudc vao each giai
phong, vao do tan ciia dugc chat, vao kich thudc tieu phan dugc chat, vao tuong tac dugc chat -
ta dugc, vao moi trudng giai phong (lugng moi trudng, pH, chat dien hoat, enzym,...).
1.4.3. Hap thu
Toe dd va muc do hap thu quyet dinh SKD ciia che pham. Hap thu phu thudc vao giai
phong, hda tan; vao kha nang tham ciia dugc chat (miic do ion hda, he so phan bo D/N);
vao vung hap thu (niem mac, tuan hoan, chat mang,...).
Qua trinh SDH ciia dang thuoc dugc danh gia bang 2 tieu chi: SKD in vitro va SKD
in vivo:
- SKD in vitro la thu nghiem hda tan (dissolution test) dugc ghi trong cac dugc dien,
danh gia giai doan giai phong-hoa tan, dae trung cho tinh chat ly - hoa ciia dugc chat.
- SKD in vivo danh gia giai doan hap thu dua tren cac thong so dugc dgng hgc (nhu
AUC, Cmax, Tmax,....) ciia do thj nong do dugc chat trong mau theo thai gian khi nghien
ciru tren dong vat hay ngudi tinh nguyen.
Dua vao qua trinh SDH ciia dang thuoc, nhiem vu ciia nha bao che hien nay la phai
chii dong tac dong vao giai phong va hoa tan nham dieu tiet hap thu, tao ra nhieu mo hinh
giai phdng khac nhau de dap ling nhu cau da dang ciia dieu trj.
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2. DlTONG DUNG VA CACH LlfA CHON DANG THUOC
2.1. Vai trd cua dudng dung
Thuoc dugc dua vao ca the bang nhieu con dudng khac nhau: uong, tiem, dung
ngoai... Theo quan diem SDH, dudng dung chinh la moi trudng SDH ciia dang thuoc, tai
do, dugc chat dugc giai phdng khdi dang thuoc, hda tan trong mdi trudng sinh hgc de phat
huy hieu qua dieu tri tai cho hoac vugt qua hang rao de dugc hap thu. Khi thiet ke dang
thuoc, yeu to dau tien nha bao che phai tinh den la dudng dung thuoc, vi mdi dudng dung la
mot hang rao hap thu rieng cd nhung dae diem ca ban lien quan den SKD ciia dugc chat.
Vi vay dudng dung lien quan true tiep den tac dung ciia dang thuoc, chi khi dung diing
dudng dung, dang thuoc mdi phat huy toi da hieu qua dieu trj theo thiet ke va giam bdt
dugc tac dung khong mong muon.
Dua theo hang rao sinh hoc, co the chia dudng dung thanh 3 nhdm: hang rao niem
mac (dudng tieu hda, dudng hd hap, mit, am dao,...), hang rao da va dudng tiem.
2.2. Dua thuoc theo duong tieu hoa
2.2.1. Dae diem dua thudc theo dudng tieu hda
Dua thuoc theo dudng tieu hoa co nhieu uu diem:
- Day la dudng dua thuoc dugc ap dung rong rai, pho bien nhat (khoang 60% thuoc
dugc dung qua dudng tieu hda), vi day la con dudng diing thuoc don gian, thuan tien (ngudi
benh co the tu dung thuoc ma khong can den nhan vien y te; phu hgp vdi thoi quen an uong
hang ngay), tuong doi an toan va hieu qua (thuoc phat huy tac dung nhanh, SKD cao,...).
Rat nhieu dang thuoc co the dung qua dudng tieu hda, ke cadang ran, mem hay long.
- Dudng tieu hoa la ca quan hap thu chinh ciia co the, tao dieu kien cho dugc chat di
vao tuan hoan gay tac dung toan than. Thai gian van chuyen thuoc trong dudng tieu hoa
dai, tao dieu kien cho dugc chat dugc giai phong va hap thu tdi da.
- Dung thuoc qua dudng tieu hda la giai phap hau nhu duy nhat de dieu trj cac benh
tai cho tren dudng tieu hoa: nhiem trung, viem, loet,...
Tuy nhien, dung thuoc qua dudng tieu hda cung cd nhieu han che anh hudng tieu cue
den SKD ciia thuoc.
- Thuoc di qua dudng tieu hoa ehju nhieu tac dong bat lgi ciia mdi trudng sinh hgc
nhu pH djch tieu hda (thay doi trong pham vi rat rong, tu djch vi den djch rugt), enzym,
thuc an, thao rong da day, chuyen hoa qua gan lan dau,...
- Mot so dugc chat co mui vj khd ehju, co kha nang kich ling niem mac dudng tieu
hda, so khac cd phan tu lugng ldn kho hap thu,...
Tren thuc te, cd nhieu dugc chat co SKD dudng uong thap: protein (hormon sinh due,
insulin, enzym,...); giam dau (morphin, naltrexon,...); khang sinh (penicilin, erythromycin,
neomycin,...), tim mach (nitroglycerin,..);...
2.2.2. Dang thuoc tai khoang mieng
2.2.2.1. Dae diem dimg thuoc tgi khoang mieng
+ Khoang mieng cd nhieu loai niem mac cd do day va muc do keratin hoa khac nhau,
mdng nhat la niem mac dudi luoi de dang cho dugc chat tham qua. Tuan hoan dudi ludi
phong phu, di qua tTnh mach co r6i do thang ve tim. Nude bgt acid nhe, khong anh hudng
nhieu den do on dinh cua duoc chat.
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+ Dung thudc tai khoang mieng co kha nang tang SKD cho cac nhdm dugc chat.
tuan
gan nhu tiem tTnh mach).
- Thudc tac dung tai cho: sat khuan, chong viem, chong nam,..: dung thuoc true tiep
tai noi tac dung.
- Thuoc khdng ben phia dudi dudng tieu hoa: thuoc bi phan huy bdi djch vj, enzym,
chuyen hda nhieu qua gan: nitroglycerin, insulin, testosteron, ...
+ Tuy nhien dung thuoc tai khoang mieng cung gap mot so kho khan nhu:
- Rat khd giu thuoc tai khoang mieng do dang thuoc lam tang tiet nude bgt gay phan
xa nudt, day thuoc xuong phia dudi dudng tieu hoa.
- Mot so dugc chat cd mui vj khdng thich hgp cho viec dung tai khoang mieng, mot so
dang thuoc gay can trd cho sinh hoat ciia ngudi benh (vien ngam, vien dat dudi luoi).
2.2.2.2. Dgng thuoc tac dung tgi cho: thuoc tac dung tai khoang mieng thudng la thuoc sat
khuan, khang nam, giam dau,...dung chua viem hoac nam niem mac mieng, ludi, hgng;
viem lgi, viem quanh rang,... Dang bao che thudng diing la:
+ Thuoc sue mieng (Gagarism): la dung dich nude dung ngoai khong phan lieu, chua
dugc chat sat khuan chong nam (clohexidin, acid boric,....) hoac ve sinh rang mieng (natri
clorid, tinh dau,...); dung trong trudng hgp viem rang mieng, viem hgng,... De han che hap
thu va tang kha n3ng bam dinh niem mac ciia dugc chat, keo dai tac dung, thudng cd them
mot ti le thich hgp (khoang 10%) dung mdi dong tan vdi nude (nhu glycerin, PEG 400,...)
vua lam tang do nhdt vua lam tang do tan dugc chat. Ngoai ra cd ta dugc dieu huong vi
thich hgp. Thuoc sue mieng khdng nen sue lau (mot phan dugc chat se bj hap thu lam giam
tac dung tai cho) va khdng dugc nuot. Hien nay tren thj trudng cac che pham siic mieng kha
phong phii.
+ Thuoc ra mieng (Collutorium): la dang thudc long sanh khong phan lieu dung tren
niem mac, cd do nhdt cao de tang kha nang bam dinh thuoc (dung mdi la glycerin, mat
ong,...) dung chua nam mieng va ludi (tua ludi). Khi dung thudng cham thuoc vao que
bong roi ra nhieu lan vao vung bj nam.
+ Thuoc cham rang: la dang thuoc long (dung mdi hay dung ethanol) chua dugc chat
gay te, sat trung, giam dau (lidocain, mentol, tinh dau huong nhu,...). Tarn thuoc vao que
bong cham cho dau (han che thudc lan ra khoang mieng).
- Vien ngam (Lozenge): la dang vien nen chua dugc chat sat trung tai khoang mieng
(metacresol, tinh dau bac ha,...). Vien ngam bao che tu cac ta dugc cd kha nang ket dinh
cao (siro cd dae, gom, gelatin,...) nen ra cham, mai mdn tu ngoai vao trong keo dai tac dung
cua thudc (thai gian ra khoang 4 gid). Khi dung nen ngam giua ma va lgi de han che hap
thu dugc chat. Nhugc diem ciia vien ngam la can trd sinh hoat an, ndi,... ciia ngudi benh.
Ngoai ra vien ngam thudng chua mot ti le dudng cao nhu manitol, sorbitol, siro
glucosse,..(de ket hgp dinh va dieu vj), nen dung than trgng vdi benh nhan kieng dudng
(vien Strepsin,...).
2.2.2.3. Dgng thuoc tac dung toan than
+ Vien dat dudi ludi (Sublingual tablet): la dang vien nen mdng (de giam cam giac
gay com dudi ludi, tang dien tich be mat tiep xiic lam cho vien de ra), chua ta dugc tan
43
dugc, ra nhanh. Thudng ap dung cho thuoc tim mach (nitroglycerin, isosorbid,...), hocmon
(testosteron,...), nham gay tac dung nhanh hoac tranh tac ddng ciia djch vj.
+ Vien ngam: dung cho cac dugc chat khdng ben phia dudi dudng tieu hda nhu
hocmon (progesteron, testosteron,...), enzym,...dugc chat dugc giai phdng tu tu nhu vien
ngam tai ch6 nhung dugc hap thu qua niem mac mieng di vao tuan hoan chung.
+ Vien ket dinh sinh hoc hoac mieng dan (patch): la nhung dang thuoc cai tien, bao
lg ap
(nifedipin, diclofenac, acyclovir,...). Khi dung dan vao giua ma va lgi, co the keo dai giai
phong dugc chat tu 3-5 ngay vdi mo hinh giai phong khong bj tac ddng bdi che do an uong
hang ngay.
+ Vien nhai (Chewable tablet): la dang vien nen dugc nhai vd d khoang mieng tao
dieu kien giai phdng nhanh dugc chat d phia dudi dudng tieu hda sau khi chieu vdi nude.
Thudng ap dung cho cac dugc chat can phat huy tac dung nhanh nhu ha nhiet giam dau,
khang djch vi. Vien nhai antacid (chua magnesi hydroxyd, nhdm hydroxyd,..) sau khi nhai
ky tao bdt nhao vdi nude bgt roi chieu vdi nude, xuong da day tao ra hon djch dong nhat
lam tang kha nang bao phu bao ve niem mac da day va han che con trao ngugc thuc quan
(SKD tang so vdi vien khong nhai). Rieng vdi vien nhai chua vi nang nham che dau mui vj
khong thich hgp ciia dugc chat, khi dung tai khoang mieng chi nhai nhe de giai phdng vi
nang (neu nhai ky se vd vd vi nang lam mat tac dung che dau mui vj.
Co quan pH trung binh THM gian luu
.. ,_ lai trung binh
Hinh 2.4. Thdi gian v|m chuyen thuoc trong dudng tieu hoa
44
Ngoai ra, d khoang mieng con cd the dung cac dang khac nhu gel (bom vao chan
rang hoac ra mieng), thuoc tiem (tiem vao chan rang gay te), phun mu, thudc xdng, hoac
cac dang thudc nha khoa khac.
Vdi cac dang thudc uong thong thudng (khdng phai la thuoc dung tai khoang mieng)
khi uong, vi thai gian thudc di qua khoang mieng rat nhanh (khoang 2 giay vdi thudc long; 10
giay vdi thuoc ran) nen khong co giai phong va hap thu dugc chat xay ra d khoang mieng.
2.2.3. Dgng thudc gay dinh thuc quan
Thuc quan la co quan trung gian van chuyen dang thudc tu khoang mieng xuong da
day. Cung nhu vdi khoang mieng, thai gian thuoc di qua thuc quan rat ngan (khoang 10 giay)
nen khong xay ra hap thu thuoc tai day. Tuy nhien, mot so dang thudc khi di qua thuc quan cd
the bi dinh thuc quan lam thay doi md hinh giai phong dugc chat va gay nguy hiem cho ngudi
benh, nhat la vdi tre em va ngudi cao tuoi (nghen, sac thuoc hoac nang han la gay ton thuang
niem mac,...). Cac dang thudc de gay dinh thuc quan la vien nen va nang thudc.
+ Nang thudc: nang thudc thudng cd ti trgng thap, vo gelatin tuang ddng sinh hgc
cao, de bam dinh niem mac, truang nd tao do nhdt cao tai cho dan den gay dinh. Nang
thuoc chiia dugc chat kich ung niem mac khi dinh lau cd the lam thiing vd nang gay nguy
hiem cho ngudi benh ( nang kali clorid gay chay mau thuc quan).
+ Vien nen: de gay dinh nhat la vien bao bao ve (vd bao la polyme than nude nhu
CMC, HPMC,...), tiep den la vien bao tan d rudt va vien tran.
Miic do gay dinh lien quan den chuc nang nudt, do nhdt niem mac thuc quan, tu the
ngudi dung thudc va lugng nude uong thuoc. Ngudi cao tuoi chuc nang nuot suy giam, dich
tiet niem mac do nhdt cao; tre em chiic nang nuot chua phat trien, khi uong dang thuoc ran de
co nguy co sac thudc, dinh thuoc. Giai phap de han che tinh trang nay la:
+ Uong thudc vdi lugng nude vua du (khoang 150-200ml) de thuoc trdi nhanh qua
thuc quan, pha loang niem djch dong thai dam bao lugng dung moi dii de hda tan dugc chat
tai da day va tang nhanh thao rong da day.
+ Khong nen uong thudc khi nam.
+ Chuyen dang thuoc ran thanh thuoc long: Hien nay nhieu dang thuoc ran khd nuot
da dugc chuyen thanh dang long khi dung (dang pha lai), chat it on dinh d
dang long (khang sinh. vitamin, enzym,...).
- Vien, bgt, com pha dung djch, hon dich: dang hoa tan, dang siii bgt hay dang phan
tan pha hon djch (dispersible tablet),..
- Bdt, com pha siro (siro khd: dry syrup): cd the la siro dung dich hay hon dich
Nhu vay vua tien dung vua tien van chuyen, bao quan, cd kha nang nang cao tuoi thg
va SKD ciia thuoc.
2.2.4. Dang thudc d da day

2.2.4.1. Dgng thudc thao rong khdi dg day
Do la tui chua nen tat ca thuoc uong tu long den ran sau khi uong deu tap trung d da day.
Cac dang thuoc quy udc, ke ca dang ran (vien, nang,...) deu giai phong dugc chat trong dich vj.
a) Cac dgng thudc long
45
+ Dung dich: dung djch nude va dung moi than nude (ethanol, glycerin, PEG,...)
nhanh chong hda vdi djch vj ngay sau khi uong. Thai gian hda trdn dong nhat phu thudc d
muc dd nhat djnh vao do nhdt ciia che pham (siro thuoc cham hon dung djch thuoc). Mgt sd
dung djch thuoc dung hon hgp dung mdi (nudc-ethanol-propylen glycol,...) dugc chat cd
the ket tiia khi mdi pha loang do thay doi dung mdi nhung sau dd tiep tuc hda tan trong djch
vj do lugng nude qua thua. Cac dugc chat la muoi acid yeu cd kha nang ket tiia lai acid yeu
khi gap pH thap ciia djch vj, tuy nhien tiia hinh thanh thudng la tiia sieu mjn theo co che
micropH nen de tan lai va dugc hap thu dudi dang khdng ion hda. Vdi dung djch dau can
cd thai gian de dugc chat phan bo tu pha dau sang pha nude.
+ Hdn dich: sau khi hda loang vdi djch vj, dugc chat trong lieu thuoc co the dugc
hda tan hoan toan hoac tung phan trong djch vj do lugng dung mdi tang len dang ke. Nhu
vay, toe do giai phdng va hap thu se cham hon dung dich nude, phu thudc vao kich thudc
tieu phan va chat lam tang dd nhdt trong h6n dich.
+ Nhu tuang: toe do hda trdn ciia nhu tuong vao djch vj phu thudc trudc het vao kieu
nhu tuong: nhu tuong D/N bj pha loang nhanh hon N/D va dugc chat nam trong pha nude
se dugc giai phdng trudc, dugc chat trong pha dau phai cd qua trinh phan bd lai sang pha
nude nhu vdi dung djch dau. Chat dien hoat va enzym cd san trong djch vj (muoi mat,
lipase,...) giup cho qua trinh hda tan dugc chat trong hon dich va nhu tuong va nhu hda pha
dau xay ra nhanh hon.
b) Cac dgng thudc ran
+ Nang thuoc: vd nang gelatin de ra va giai phdng dugc chat trong djch vj (ra trong
vong 1-5 phut). Qua trinh giai phdng hda tan dugc chat tiep theo phu thuge vao dang bao
che ddng nang (bdt, hat, pellet hay vien nen mini,...).
+ Vien nen: theo quy djnh ciia dugc dien, phan ldn vien nen phai ra trong vong 15
phut (tru vien bao va vien giai phong keo dai). Qua trinh giai phdng hda tan dugc chat tiep
theo phu thuge vao ta dugc; do tan, muc do than hay so nude ciia dugc chat va kich thudc
tieu phan dugc chat.
2.2.4.2. Thao rong dgday dua thuoc tai vung hap thu
Dang thuoc uong dugc dua den da day, giai phdng dugc chat d da day, nhung da day
lai khdng phai la ca quan hap thu do niem mac rat day va dugc phu bdi lap niem djch^bao
ve cd do nhdt cao nen dugc chat rat kho di qua (tru dugc chat cd ban chat la acid yeu d
dang khong phan ly cd phan tu lugng nhd). Mat khac djch vj lai cd pH thap (khoang 1-2 khi
ddi va 3 - 4 khi cd thuc an) va nhieu enzym, co the phan huy lam giam hoat tinh ciia nhieu
dugc chat. Cho nen, ve nguyen tac khdng nen de dang thuoc luu lai lau d da day. Tang
cudng thao rong da day vua han che dugc cac tac dgng tieu cue ciia djch vi, vua dua nhanh
thuoc tdi vung hap thu (rugt non).
Thai gian luu ciia dang thuoc trong djch vj thay doi rat nhieu (tu 10 phut den 8gid), phu
thudc vao nhieu yeu to nhu kich thudc dang bao che, thai diem dung thuoc, che do an, lugng
nude uong vdi thuoc, tinh trang hoat ddng ciia ngudi benh,... Ket qua nghien cuu cho thay:
+ Cac dgng thuoc long: dung dich, elexir, siro thuoc, potio, hon djch, nhu tuang,
nang mem,...pha loang vdi djch vj va thao rong da day tu do ngay sau khi uong (trong vong
10 phut). Trong do, cac dang thuoc co do nhdt cao nhu potio, siro, hon djch, nhu tuong thao
rong cham han dung djch ethanol, dung djch nude,...
46
+ Cac dgng thudc ran: tieu phan ran thao rong da day thuan lgi chi khi cd dudng kinh
nho hon 7 mm. Vi vay, thuoc bdt, com, nang thuoc, vien tran, vien bao bao ve,... neu bao che
hgp ly, khi vao djch vj se ra thanh tieu phan dugc chat ran va thao rong da day tuy cham han
thuoc long nhung cung tuang ddi de dang (trong vong khoang 30 phut), dae biet la khi uong
vdi lugng nude vua du. Tuy nhien, vdi dang khdng ra trong djch vj nhu vien nen va nang
thudc bao tan d rugt, bao tan d dai trang, bao kiem soatgiai phdng hoac vien nen keo dai dang
cot tra khuech tan,... thi viec thao rong trd nen kho khan va that thudng han vi kich thudc
dang thuoc ldn hon mon vj va chi dugc thao rong khi mdn vj md. Neu uong vien bao khi no,
vien roi vao hang mdn vj kem theo thuc an giau dam, nam nghieng ben trai, thi vien cd the
nam lai da day tdi 8 gid va vd bao khang djch vj se bj phan huy, cd kha nang tao ra hien tugng
don lieu. Ngugc lai, ngudi benh uong vien bao khi doi vdi nhieu nude trong khi van ddng nhe
(di lai) se lam cho vien thuoc ra nhanh khdi da day. Thay dang bao don don vj (vien nen hoac
nang thuoc bao) bang dang da don vj (vien nen hoac nang ciing chua pellet bao) khi vao da
day giai phong ra pellet bao (dudng kinh khoang 1 mm) se lam cho thuoc de dang qua mdn vj
va trai deu len niem mac rugt lam cho SKD ciia dang thuoc 6n djnh va chac chan hon (H. 2.1)
2.2.4.3. Cac dang thudc luu lai da day
Trong mot so trudng hgp, can keo dai thai gian luu tai da day ciia thuoc de cai thien
SKD nhu:
- Thuoc dieu trj viem, loet, u da day (khang sinh, antacid,...): neu thao rong nhanh thi
chua kjp phat huy tac dung .^
- Thuoc cd ciia so hap thu dau rugt non (acid folic, riboflavin, sat,...): neu di qua vung
hap thu toi uu qua nhanh thi dugc chat cd nguy ca khdng kjp giai phdng va hap thu, se lam
giam SKD ciia thuoc.
Hien nay, cac nha bao che dang nghien ciiu cac dang thuoc luu tai da day theo 3
hudng chinh: dua vao ti trgng, ket dinh sinh hgc va tu tinh ciia dang thuoc.
+ He ndi (floating systems): la nhung vien nen hoac dang khac cd ti trgng nhd hon ti
trgng ciia djch vj, noi tren be mat djch vj va do dd khdng qua dugc mdn vj. Vien noi thudng
chiia cac ta dugc cd kha nang hut nude va truong nd manh (thach, dan chat cellulose,
carbomer,...), lam giam ti trgng ciia vien va tan cham trong djch vj, keo dai giai phong dugc
chat. Mot ca che khac la vien giai phdng khi tu tu de noi tren djch vj.
+ He chim: la nhung vien, hat cd ti trgng ldn hon ti trgng djch vj. Sau khi uong, dang
thudc se chim xuong hang mon vj, khd tiep xiic dugc vdi mdn vj de ra khdi da day va giai
phong dugc chat lien tuc cho den liic ra hoac bao mdn.
+ He ket dinh sinh hoc: nguyen tic bao che va giai phong dugc chat giong nhu vien
ket dinh niem mac mieng.
+ He tie tinh: dua tac nhan tu tinh vao vien, pellet (oxyd sat tu,...) va giu dang thuoc
luu d da day bang he tu trudng ngoai ca the.
2.2.5. Dang thuoc tac dung d rupt non
Rugt la co quan hap thu chinh ciia co the do niem mac mdng, dien tich be mat tiep
xiic ldn, thai gian thuoc di qua dai, tuan hoan phong phu, nhu ddng manh,...Q phan dau rugt
non, khi pH con nam trong vung acid, sir hap thu xay ra chii yeu vdi cac dugc chat cd ban
chat acid yeu, ton tai dudi dang khdng ion hda. Cang ve cuoi dudng tieu hoa, cac dugc chat
47
base yeu cang dugc hap thu nhieu hon. Qrugt, dugc chat cd the bj phan huy bdi enzym va
sau khi hap thu di vao tTnh mach cua bj chuyen hda qua gan lan dau.
2.2.5.1. Dgng quy u&c: tren thuc te, cac dang thuoc long va cac dang thuoc ran quy udc da
ra thanh tieu phan d da day, sau khi thao rong den rudt non de trai deu len niem mac rugt.
Vdi be mat tiep xiic ldn va dugc chat da dugc hda tan hay phan tan mjn, cac dang thuoc nay
deu dugc hap thu tot d phan dau rugt non, trong do dugc chat tir cac dang thuoc long se
dugc hap thu nhanh hon cac dang thuoc ran.
Vdi dugc chat hap thu tot dau rugt non can han che su dung cac dang thuoc long vi
dang thuoc nay di qua day rat nhanh lam cho dugc chat khdng kip hap thu het, nhat la uong
khi ddi. Ngoai he luu giu tai da day nhu da neu tren, cd the dung dangjion dich, bdt hay
pellet uong lan vdi thuc an de lam cham su van chuyen thuoc qua vung hap thu tdi uu.
2.2.5.2. Dgng bao tan a rudt: co the bao tan d rugt vien nen, nang thudc, hat, hay pellet
chiia dugc chat khdng ben trong djch vj hoac dugc chat can tap trung tac dung tai rudt non.
Nhu da noi d tren, vd bao tan d rudt phai ben trong moi trudng djch vj trong vong 2 gid va
ra trong djch rugt trong vong 30 phut. Hien tai cd 2loai vd bao giai phdng dugc chat theo 2
ca che:
- Phan ly theo bac thang pH: dung nhdm polyme acid methacrylic trung hgp
(Eudragit L,S;...), bat dau phan ly tu pH khoang 4,5 dta trang cho den 6,5 ddau hong trang,
giai phong dugc chat tuong doi on dinh.
- Phan giai nha esterase: g6m cac ta dugc cd cau true este (CAP, HPMCP,...), giai
phong dugc chat phu thudc nhieu vao hoat dgng ciia enzym drudt, do do cham va khdng on
djnh bang Eudragit.
Che pham bao tan drudt can thao rong nhanh khdi da day de tranh dich vj lam hong
vo bao, vi vay nen uong trudc khi an. Hien nay co xu hudng bao pellet nhieu han bao vien
nen de tang cudng thao rong nhu da trinh bay d tren.
22 53 Dang kiim soat giai phdng: cac dang giai phdng kiem soat de uong qua trinh giai
phong hoa tan duac chat xay ra tu tu, suot chieu dai dudng tieu hoa, dugc thiet ke theo mo
hinh keo dai tac dung 12 gid (ngay dung 2lan) hoac 24 gid (dung 1lan trong ngay) de giam
so lan dung thuoc cho ngudi benh. Thu nghiem giai phdng ciia thuoc gia. phong kiem soat
thudng duoc danh gia qua 2mdi trudng: djch vj md phong (SGF: Stimulated Gastric Fluid)
pH 12trong vong 2gid dau va djch rudt md phong (SIF: Stimulated Intertinal Fluid) pH
6,8. Trong do can han che toi da giai phdng dugc chat dda day, de tap trung cho rugt non.
Thai gian van chuyen cua vien nen trong rudt non cd the keo dai tu 5-10 gid, trong do qua
hong trang tir 2-3 gid, qua hoi trang tu 3-7 gid, dam bao cho qua trinh giai phong hap thu
dugc chat xay ra tuong doi chac chan. Miic do va vung giai phdng phu thuoc vao cau true
dang thuoc. ,,-, { { ,
Vdi dang cot tro khuech tan, cot trao doi ion va mang ban tham, ta dugc tao cot va
mang bao khong tan trong dudng tieu hoa va dugc dao thai ra ngoai.
2.2.6. Dang thuoc tai dai trang
Chiic nang chinh ciia dai trang la cd dae va dao thai chat thai. Niem mac dai trang it
gap nep, moi trudng chat thai dam dae, niem djch it, co nhieu vi ca cd kha nang phan huy
thuoc,... khdng thuan lgi cho hda tan hap thu dugc chat.
Tuy nhien, dung thuoc tai dai trang cung cd nhung uu diem can khai thac nhu:
48
- Dai trang dai, thudc di chuyen cham cho nen thai gian thudc di qua dai trang rat dai
(khoang 20-30 gid), do dd thudc van cd co hoi tiep xiic vdi niem mac va dugc hap thu.
- Dugc chat hap thu d dai trang tranh dugc mot phan tac ddng bat lgi ciia phia tren
dudng tieu hoa (dich vj, enzym rudt, chuyen hda qua gan,...).
Tren thuc te rat kho dua thuoc den dai trang do dugc chat da dugc hap thu het d rugt
non, do do nghien ciiu bao che cac dang thudc tac dung tai dai trang la van de dugc quan
tain nhieu trong nhung nam gan day.
2.2.f5.1. Dgng thudc diing tgi cho
+ Thudc thut: trong bao che quy udc, ngudi ta hay thut cac dang thudc long de dieu
trj benh tai dai trang (tao bon, viem dai trang, ung nhgt dai trang). Day la giai phap hieu qua
nhung gay phien phuc cho ngudi benh.
+ Gel bam true trang: gel chua dugc chat (thudng la thuoc nhuan, tay,...) dugc ddng
trong tuyp bdp bep dugc cd gan dau bam (canuyl) bom thudc true tiep vao true trang. Ta
dugc gel tan chay va hda tan nhanh de giai phong dugc chat tai true trang.
+ Thudc dgn: la dang thuoc dat true trang, co nhieu uu diem nhu:
- Tien dung trong trudng hgp ngudi benh khd uong thudc, dae biet la vdi tre em,
ngudi bat tinh, ngudi khong hgp tac vdi thay thuoc, thudc cd mui vj kho ehju khi uong.
- Nang cao SKD cho nhdm thuoc bj chuyen hda nhieu qua gan: khi dat nong, dugc
chat giai phong tu thuoc dan se dugc hap thu qua tTnh mach true trang dudi va giua, tranh
dugc chuyen hoa qua gan.
Thuoc dan dugc bao che tir 2 nhom ta dugc cd co che giai phong dugc chat khac nhau.
- Ta dugc beo (bo cacao, md lgn,...): giai phdng dugc chat theo ca che tan chay d
than nhiet (the chat khd on djnh ve mua nong, can bao quan d dieu kien mat). Cac dugc
chat than dau, it ion hda de hda tan trong ta dugc, sau khi giai phong de hap thu qua mang,
nhung phai qua giai doan phan bo tir pha dau sang pha nude.
- Ta dugc than nude (PEG 4000, gelatin,...): khi dat se hda tan trong niem djch giai
phdng dugc chat (the chat on djnh hon ta dugc beo, it bien ddi theo thai tiet). Cac dugc
chat phan cue than nude hda tan trong ta dugc de giai phong khoi thuoc dan, tuy nhien lai
kho tham qua mang. Thuoc dan PEG hao am, khi dat hut nude tir niem mac gay rat cho tre
em, nen nhiing vao nude vai phut cho ta dugc hydrat hda trudc khi dat.
Thuoc dan thudng chua dugc chat gay tac dung toan than dugc hoa tan hay phan tan
trong ta dugc. Hien co nhieu nhom dugc chat dugc sir dung dudi dang thuoc dan (ha nhiet
giam dau, an than, hen phe quan,..).
+ Bam tham thdu: la dang thudc mdi, dat true trang thong qua sgi chi cay d hau mon
ngudi benh. Dugc chat khuech tan qua mang ban tham do chenh lech ap suat tham thau
trong va ngoai mang, keo dai giai phong dugc chat trong nhieu ngay, cd the nap lai thuoc
khi het.
+ Vien ket dinh sinh hoc: nguyen tac bao che va giai phdng dugc chat nhu vien ket
dinh sinh hgc noi chung.
DLS...T4 49
2.2.6.2. Dgng thudc dung de uong
De dua thuoc den dugc dai trang bang dudng uong, dang thuoc phai han che dugc
giai phong dugc chat khi di qua rugt non. Mot sd giai phap dua thuoc den dai trang da va
dang dugc nghien ciiu ap dung nhu:
- Giai phap thudc ve duac chat: chgn dugc chat it hda tan, hap thu trong rugt non
(doi tugng nay khdng nhieu), chgn kich thudc tieu phan dugc chat ldn (khdng nghien mjn
dugc chat), chgn thudc me (prodrug) den dai trang dudi tac dong ciia enzym hoac vi ca se
giai phong dugc chat gay tac dung (sulphasalazine, olsalazine,...)
- Giai phap bao che: bao che dang giai phong muon, tao ra thdi gian tiem tang (Tlag)
trudc khi giai phdng dugc chat nhu dang giai phdng theo nhjp (pulsatile release) tren co sd
chgn ta dugc tuang doi ben vdi djch rudt va bj phan huy bang he vi ca hoac men d dai trang
(ta dugc tao cot hoac bao kho cd ban chat la polysaccarid nhu pectin, gdm,...bi phan huy
bang glucoronidase, galactosidase,..); ta dugc bao mang cd cau noi nita (azo-polyme lien
ket cheo bj phan huy bang azoreductase,..); ta dugc bao mang phan ly theo bac thang pH
(Eudragit L,S,...),...
Tom lai dudng tieu hoa cd nhieu vung cd cau tao va dae diem sinh ly cung nhu hap
thu thuoc rat khac nhau, can thiet ke dang thudc phu hgp vdi noi tac dung ciia thuoc va
hudng dan su dung hgp ly de nang cao hieu qua dieu trj ciia dang thudc.
2.3. Dua thuoc den mat
2.3.1. Dae diem dung thudc thudc tai mat

+ Mat la ca quan tinh te ciia ca the, tiep xiic true tiep vdi ngoai mdi, de bj ton thuang
bdi cac tac dong co hgc va vi khuan. Thuoc dung tai mat chii yeu la gay tac dung tgi cho
vdi muc dich bao ve mat va dieu trj cac benh ve mat (sat khuan, chong viem, ha nhan ap,...)
va phai la nhung che pham vo khuan.
+ Do co che tir bao ve ciia mat nen phan ldn lieu thudc dua vao mat bj rua troi theo
nude mat, vi vay SKD ciia thudc nhan khoa rat thap va rat khd danh gia.
+ Cau tao ciia mat lien quan den viec dung thudc tai mat:
- He thong tiet nude mat: nude mat dugc tiet bdi tuyen le, thong qua ong le do len
niem mac mat tao thanh mang nude che chd, bao ve niem mac. Trong nude mat cd chua
protein, muoi khoang nudi dudng niem mac va cd cac enzym co kha nang phan huy vi
khu^n bao ve mat. Khi dua thuoc vao mat, thuoc dugc coi nhu mot kich thich ca hgc lam
tang tiet nude mat va chdp mat de day thuoc ra ngoai, lam giam SKD ciia thuoc, nhat la vdi
thuoc nhd mit quy udc, lieu thudc bj rua troi co the tdi tren 90%. Do do thiet ke cong thuc
thuoc nhd mat can phai tinh den cac giai phap han che rua troi, tang luu giu thudc tai mat.
- Ket mgc: la phan niem mac ndi mi mat va giac mac, cd nhieu vi mao quan nen de
tham dugc chat tan trong nude. Dugc chat sau khi tham ket mac di vao tuan hoan chung
lam giam SKD ciia thuoc dung dieu trj cac benh tai cho ve mat (ton thuang, viem niem
mac,...). Tiii ciing ket mac la noi co the luu giu thudc tai mat han che sir rua troi do chdp
mat, nhat la vdi hon dich thudc.
50
- Giac mgc: la phan niem mac che chd trong mat, cd cau tao nhieu lap ben chac,
trong dd Idp bieu md va noi md than lipid kep lap dem than nude d giua. Do vay, chi cd
cac dugc chat cd he sd phan bd D/N tuong ddi can bang mdi di qua dugc giac mac vao cac
to chuc ben trong ciia mat.
Tuyen niroc mat
Hinh 2.5. Cau tao ciia m£t
2.3.2. Cac dgng thudc tai mat

Dang thuoc nhan khoa kha phong phu, la nhung dang thudc vd khuan, can dugc bao
quan va sir dung than trgng.
+ Thuoc nhd mdt: la dang thudc long (dung djch, hon djch, nhu tuang), dung nho
tung gigt vao mat; trong do dung mdi (hoac chat dan) chii yeu la nude. Thudc nho mat
thudng dung dieu trj hoac chan doan cac benh tai cho ve mat (ton thuang, viem nhiem,..).
Thuoc nhd mat cd SKD thap do bi rua troi, do do khi thiet ke cong thuc can cd cac giai
phap tang luu giir thuoc tai mat nhu: han che kich ling (lira chgn dugc chat, he dem, chat
phu dang truong thich hgp,...); tang kha nang bam dinh ciia thudc vdi niem mac mat (dung
chat lam tang do nhdt, chat ket dinh sinh hgc,...). Dang hon djch va nhu tuong thudng da cd
chat tang dd nhdt nen bam dinh tot hon dung dich, nhat la vdi hon dich, do cac tieu phan
dugc chat ran cd the lang dgng vao tiii cung ket mac nen kho bj rua troi hon, tao ra tac dung
dai hon dang dung djch. Thuoc nhd mat nen dung nhieu lan trong ngay de bu vao lugng bj
rua troi.
+ Thuoc riea mdt: la dang dung dich nude, thudng chua cac chat sat khuan, dung de
rua troi cac tap ban d mat, ve sinh va bao ve mat. Day la dang thudc khdng phan lieu,
khong can luu giu d mat.
+ Thuoc tra mdt: la dang thuoc md mem, kem, gel,... ddng trong tuyp bdp bep dugc,
sau khi tra, thuoc dugc dan trai len niem mac mat do tan chay va hoa tan. Thudc tra mat do co
do nhdt cao, kha nang bam dinh tot nen it bj riia troi va tac dung keo dai hon thudc nho mat,
nhat la vdi ta dugc beo so nude giai phdng dugc chat theo co che tan chay. Tuy nhien, thuoc
51
tra mat cd han che la lam md thj trudng gay cam giac khd ehju cho ngudi dung trong mot
khoang thai gian nhat djnh sau khi tra, do do thudng dung vao buoi toi (ngay nhd, t6i tra).
+ He dieu tri tgi mdt (Ocusert): la dang thuoc giai phong dugc chat theo chuang trinh,
g6m mdt dTa chua dugc chat d giua va 2 ben la mang kiem soat giai phong, khi dung, cai vao
giua mi va trong m4t, khong phan giai sinh hgc. Trong lam sang hay dung che pham Ocusert
Pilo chua 5mg pilocarpin giai phdng deu dan 20 mcg/gid trong 1 tuan, tiet kiem dugc chat,
giam tac dung khdng mong muon (lam md thj trudng) so vdi dang nhd matquy udc.
Ngoai ra con dung mang nhan khoa an mon phan giai sinh hgc.
+ Thuoc tiem: thudng la dang dung djch, tiem true tiep vao nhan cau hoac day mat,
do thay thuoc chuyen khoa dam nhiem.
2.4. Dua thuoc theo dudng ho hap
2.4.1. Dgc diem dung thudc theo dudng ho hap
- Dudng ho hap la con dudng dung thuoc tu nhien cd nhieu tiem nang: niem mac cd
be mat tiep xiic ldn, thanh niem mac phe nang mong dugc chat de di qua; tuan hdan phong
phu vdi luu lugng trao ddi ldn, khdng qua gan.
- Dua thuoc theo dudng ho hap la con dudng true tiep de dieu trj benh dudng ho hap,
tranh dugc tac ddng tieu cue ciia dudng tieu hoa vdi dugc chat.
- Theo ca che bao ve ciia ca the, mdt trong nhung chiic nang quan trgng ciia dudng ho
hap la thanh thai tieu phan la. Thuoc dua vao dudng ho hap se bj thanh thai theo ca che nay,
do do, de nang cao hieu qua dua thuoc can co cac giai phap phu hgp han che thanh thai thuoc.
2.4.2. Chuc nang vd con dudng dua thudc
Dudng ho hap khdi dau bang khoang mui hgng, di qua khi phe quan roi vao phe nang
(H. 2.8); co chuc nang van chuyen, trao ddi khi de cung cap oxy cho co the va thanh thai
chat la bao ve ca the.
2.4.2.1. Van chuyin khi: thuc hien chii yeu bang dudng ho hap tren
+ Mui: la cua vao ciia khi nen khoang mui cd chuc nang lam am, lam am, lgc va
thanh thai vat la trudc khi dua vao phoi.
Niem mac mui g6m nhieu Idp phan tang, hinh vay, cd nhieu tuyen tiet, he nhung mao
va vi mao quan. Dugc chat sau khi hap thu dugc dua vao tuan hoan chung va khdng bj
chuyen hda qua gan. Tren niem mac la lap djch nhay pH tu 5,5 den 6,5; cd tac dung lam am
khdng khi va "bay" cac tieu phan la (bui, vi khuan, tieu phan dugc chat,...) roi thanh thai ra
ngoai hoac day xuong dudng tieu hda.
+ Khi-Phe quan: la he thong dan chinh, dai khoang 11-13cm, phan nhanh lien tuc,
dudng kinh giam tir 1,5-2,5cm xuong 0,1cm do do tdc do luu thong khi giam va dien tich
be mat tiep xiic tang dan. Niem mac cd nhieu tuyen tiet, nhung mao va djch nhay.
2.4.2.2. Trao doi khi: chii yeu xay ra d dudng ho hap dudi gom tieu thuy va phe nang
2
- Phoi ngudi ldn cd tren 300 trieu phe nang vdi dien tich be mat khoang 81 m ,
chiem 75% dung tich phoi, trao doi 35% lugng khi.
- He vi mao quan phe nang co tong dien tich be mat khoang 60-80m de trao doi oxy
vdi khi hit vao. Day la dieu kien thuan lgi cho hap thu dugc chat tir thudc phun mu.
52
Nhanh phe quan
u Thuy tren
Pulmonary
- Artery
Thuy dtrai Thuy durji
* Pleura
Hinh 2.6. Cau tao ciia phoi
2.4.2.3. Van chuyen vd thanh thdi tieu phan

Khi tieu phan xam nhap dudng ho hap thi tieu phan dugc coi nhu vat the la va se bj
dudng ho hap thanh thai. Sir thanh thai tieu phan xay ra theo nhieu each.
- Lgc: qua he thong long d khoang mui.
- "Bay" tieu phan do ket dinh niem djch rdi thanh thai bang phan xa hat hoi, ho,...
dieu khien bang he than kinh nhay cam d cac nhanh phe quan.
- Day ra ngoai theo khdng khi thd ra.
- Thuc bao: vdi cac tieu phan da xam nhap vao phoi se bj dai thuc bao thanh thai theo
ca che tao thanh cac nang bgc rdi thanh thai qua ddm.
2.4.3. Cac dgng thudc dung qua dudng ho hap
2.4.3.1. O khoang mui
+ Thudc nhd mui: la dang dung dich hay hon djch, dung theo gigt, nhd true tiep vao
khoang mui, chii yeu dieu trj cac benh tai cho nhu viem mui, ngat mui. Thudc nhd mui cd
kich thudc gigt ldn, bj thanh thai nhanh khdi khoang mui (trong vdng 30 phut). Mdt phan
lieu thuoc bj day ra ngoai va phan khac tran xuong khoang mieng va bi nuot xuong dudng
tieu hoa. SKD ciia thudc nhd mui phu thudc vao dang thudc, do nhdt, kich thudc tieu phan
dugc chat va tu the ngudi dung,... Dang hon djch chi'ra tieu phan dugc chat mjn va chat lam
tang do nhdt cd ti le bi thanh thai thap han dang dung djch, dae biet la hon djch chiia
liposome cd kha nang ket dinh sinh hgc cao, bam dinh niem mac tot. Khi dung thuoc nho
mui nen ngoi d tu the thoai mai, mat hai ngua giu- cho khoang mui d trang thai can bang,
53
day nhe canh mui cho thuoc dan deu se han che dugc lugng thuoc tran ra ngoai va chay
xuong mieng.
+ Thuoc xit (spray): hay dung dang dung djch, phun vao hgng hoac khoang mui bang
binh dung co bo phan dau phun (canul) thich hgp. Thuoc xjt tao ra gigt nhd han thuoc nhd
mui (dudng kinh khoang 50mcm), chii yeu djnh vi d mui (cd khoang 10% gigt < lOmcm cd
the vao phoi). Do cd kich thudc gigt nho hon, dien tich be mat tiep xiic ciia dugc chat vdi
niem mac ldn hon nen thuoc bam dinh niem mac tot hon, SKD cao hon thuoc gigt (thuoc
xjt chiia xylometazolin giam tiet sau 10 phut).
Ket qua nghien cuu gan day cho thay niem mac mui co khe hd lien bao kha ldn, cho
phep cac dugc chat cd phan tir lugng dudi lOOODa co the di qua. Do do, mdt so dugc chat
cd phan tu lugng tuong doi ldn cd the dung d khoang mui de gay tac dung toan than nham
tranh tac dong phia dudi dudng tieu hda va chuyen hda qua gan lan dau, lam tang SKD, dae
biet la vdi cac protein. Nhieu protein da dugc nghien'curu hap thu qua niem mac mui nhu:
buserelin, nafarelin, desmopressin, lypressin, insulin, hormon,...
+ Thuoc xdng hit: la cac dang thuoc chua tinh dau sat trung dudng hd hap. Dang
thuoc xong dugc chat dugc phan tan dudi dang khi cd the di sau vao phoi.
Ngoai ra co the dung dang mem nhu md, gel bam vao khoang mui, keo dai dugc tac
dung ciia thuoc. Cac dang thuoc mdi nhu liposome, vi cau ket dinh sinh hgc la nhung gia
mang thuoc co kha nang nang cao SKD cho nhieu dugc chat d khoang mui, rat cd trien
vgng phat trien dua vao ap dung lam sang.
2.4.3.2. Ophe quan vdphoi
Chii yeu dung dang phun mu (aerosol) hoac dang bgt khd.
+ Thuoc phun mu (hinh 2.7) cd the la dang dung dich hoac hon djch hay nhu tuang
mjn, dugc day ra khoi binh dung dudi dang hat nhd (10-20 mem), cd kha nang xam nhap
sau vao dudng ho hap dudi.
Thuoc phun mu dung trong binh ehju ap lire, dugc day qua vdi phun tung lieu xac
dinh nhd khi nen hay khi hoa long (hien nay hay dung khi hda long vi khi nen lien quan den
pha huy tang ozon). Dudng kinh voi phun quyet dinh kich thudc gigt phan tan va do do anh
hudng den noi tac dung ciia thuoc.
Sir dinh vj ciia dugc chat tren dudng ho hap tir thuoc phun mu xay ra theo 3 ca che.
- Dinh niem mac do va chain: cac tieu phan cd dudng kinh tren 5mcm khi chuyen
dong vdi toe do cao khong cd kha nang ddi hudng, den cho phan nhanh bi dinh niem djch
do quan tinh.
- Lang dgng do trgng lire: cac tieu phan tren 10 mem cd khdi lugng ldn, kho bi cuon
theo khi hit vao va dinh vi tai dudng hd hap tren do lang dgng trong qua trinh van chuyen
- Ket dinh do chuyen dong Brown: chuyen dong ciia khi hit vao trong dudng hd hap
la chuyen dong quan do dng dan hep dan va cd nhieu loi re. Vi vay chuyen ddng ciia tieu
phan trong khi la chuyen ddng h6n don, do dd rat de va cham nhau ket dinh thanh tieu phan
ldr hon va lang dgng tren dudng di.
+ Bdt xdng hit: la dang bgt sieu mjn dong trong mdt lg nho chuyen dung, dugc giai
phong nhd kich hoat ciia ddng tac thd vao. Khi dung, ngudi benh ngam kin mieng lg, hit
vao va ngung thd khoang 10 giay, bdt tu ddng giai phdng va di vao phe nang theo khi hit
54
vao. Do cd kich thudc tieu phan nho,
thuoc co the di sau vao phe nang va dugc Nut bam
hap thu vao tuan hoan (corticoid, khang
sinh,...).
Nhu vay, sir dinh vi tieu phan tren
dudng hd hap phu thudc vao cac yeu to:
+ Kich thudc tieu phan: tieu phan
tren lOmcm chii yeu dinh vi d dudng hd
hap tren; tieu phan 0,5 - 5mcm vao dugc
Khi nen
dudng ho hap dudi, tieu phan dudi
0,5mcm cd the tdi dugc thanh mach; tieu
phan dudi 0,1mem de bi day ra khi thd ra. 6ng nhung
+ Do am dudng hd hap: do am cao,
tieu phan de bj ket von, lang dgng va bj
thanh thai. Dung djch thuoc
+ Cach thd:
Hinh 2.7. Cau tao binh phun mu
- Thd chain: keo dai thdi gian luu,
giam chuyen ddng Brown, giam lang dgng
tieu phan, giam lugng thuoc bi thanh thai khi thd ra. Toe do thd 15 lan mdt phut, khi luu lai
trong phoi khoang 30 giay.
- Thd cham va sau: tao nen sir phan bd thuoc chii yeu d dudng hd hap dudi va dong
nhat trong phoi.
- Thd nhanh va nong lam tang phan bo thuoc d dudng hd hap tren, tang tieu phan bj
day ra.
- Thd bang mui giam ket dinh tieu phan.
- Cac benh dudng hd hap cd kha nang lam thay d6i md hinh phan bo thuoc.
Do do, lira chgn dang thudc va sir dung hgp ly cd vai trd rat qun trgng vdi SKD ciia
thuoc dung qua dudng hd hap.
2.5. Dua thuoc theo duong am dao va tir cung
Theo truyen thong, thuoc phu khoa dugc dung tai am dao va tu cung de sat trung tai
cho hoac de tranh thai. Dung thuoc theo con dudng nay cd uu diem chung la vdi thuoc can
hap thu se tranh dugc tac ddng cua dudng tieu hoa va chuyen hoa qua gan, nang cao SKD
cho mdt sd nhdm thudc (thuoc tac dung tai cho, thuoc tranh thai, protein,...). Tuy nhien khd
khan la niem mac va tuan hoan thay ddi theo chu ky kinh nguyet nen md hinh hap thu thuoc
kho on dinh khi dung thudc keo dai.
2.5.1. Dgng thudc tai dm dao
Niem mac am dao gom 5 lap, trong dd thuang bi la cac te bao hinh vay chong lap,
khe hd lien bao tuong ddi ldn, phia dudi la sgi co lien ket kha ben chat, he mach tuang doi
phong phu.
Niem djch am dao co nhieu men co vi khuan latobacillus acidophilus hoat dong phan huy
glycogen tao acid lactic duy tri pH niem dich tir 3,9 den 4,5; han che nhiem khuan.
55
2.5.1.1. Cac dgng thuoc quy udc: thudng dung de lam sach, sat khuan, chong viem, cam
mau,...
+ Dung dich de riea: chua cac dugc chat sat trung nhe, chat dien hoat nhu acid boric,
menthol, natri clord, natri lauryl sulfat,... hda tan trong nude, dung de rua. Trong thanh
phan cd the phoi hgp them cac dung mdi than nude nhu glycerin, propylen glycol,... lam
tang dd nhdt de han che tham dugc chat. Hien nay tren thj trudng co dang bgt riia hay vien
rua pha thanh dung djch khi dung.
+ Thuoc trung: la dang thuoc dat, hinh cau, hinh triing hoac hinh ludi, ta dugc va ky
thuat bao che giong thuoc dan, giai phdng dugc chat kha nhanh; gay tac dung tai cho (thudc
triing tanin, penicilin, metronidazole.) hoac toan than (thudc trung progesteron,...).
+ Vien dat phu khoa: la dang vien nen giai phdng dugc chat nhanh (cd the la vien sui
bgt), ta dugc dgn tan dugc (hay dung lactose de khong lam thay ddi pH ciia am dao). Khi
ddng goi thudng kem theo dung cu dat thich hgp.
2.5.1.2. Cac dgng thudc cdi tien
- Vien hoac gel ket dinh sinh hgc: dung trong trudng hgp can keo dai tac dung ciia
thuoc. Bao che nhu vien ket dinh cac niem mac khac.
- Vdng am dao: la dang thiet bj giai phong dugc chat theo chuong trinh chua thuoc
tranh thai (medoxyprogesteron acetat, norgestrel va levonorgestrel,...) phan tan trong PEG
dung trong khung silicon. Vdng dugc dat xung quanh cd tir cung, giai phong theo dong hgc
bac 0 hang djnh trong 3 thang.
2.5.1. Dung cu dat tie cung IUD (Intrauterine Device)
Thanh tircung khe hd niem mac ttr400-700 A0 ldn hon cac niem mac khac (gapdoi niem
mac rugt va niem mac mui), tuan hoan phong phu, tham phan tir tich dien am va cac dugc chat
cd phan tu lugng ldn, tinh tham khong bj tac ddng bdi miic do ion hoa ciia duoc chat.
Thiet bj dat tir cung la dang giai phong theo chuong trinh. Tren thj trudng cd che pham
Progestasertchua 38 mg progesteron phan tan trong dau silicon khuech tan qua khung ethylene-
vinyl acetate, giai phong mdi ngay 65 meg dugc chat, keo dai hang djnh mdt nam. Tac dung
khdng mong muon ciia IUD la khd ehju, ton thuang niem mac, rong kinh,...
2.6. Dua thuoc theo dudng da
2.6.1. Dae diem dung thuoc theo dudng da
2
- Da la hang rao bao ve vdng ngoai ciia co the, cd dien tich be mat ldn (khoang 2m ),
nhan dugc 1/3 lugng mau tu tuan hoan chung, la con dudng dua thuoc nhieu tiem nang.
- Dung thudc tren da chua benh tai cho ngoai da la hinh thuc dua thudc true tiep tdi
noi tac dung, de su dung, hieu qua cao.
- Dung thuoc qua da, dua dugc chat vao tuan hoan de chua benh toan than cd uu
diem la tranh dugc tac ddng bat lgi ciia dudng tieu hda, nang cao SKD cho cac dugc chat
cd SKD dudng uong thap, dugc chat bj chuyen hda qua gan nhieu.
- Tuy nhien, da la hang rao bao ve vdng ngoai ben chdc nhdt ciia co the, cd chuc nang
ngan can tac dong ciia ngoai mdi, cho nen viec dua thudc qua da gap nhieu kho khan. Vi
vay, nghien cuu cac bien phap tang cudng hap thu thudc qua da hien dang thu hut dugc sir
quan tarn rat ldn ciia cac nha bao che.
56
2.6.2. Cau true vd chuc nang cua da
2.6.2.1. Da: day khoang 3mm, cau tao dai ben, bao ve co the, la hang rao hap thu, gom 3
ldp (hinh 2.8)
+ Thuang bi (bieu bi)
La hang rao bao ve vdng ngoai ciia co the, han che mat nude, dien giai, dinh dudng
va ngan can tham nude, chat la, gom 2 ldp:
- Mang chat beo:
b
La san pham tiet ciia tuyen ba nhdn, trang mdt ldp mong tren be mat da (khoang
0,3mcm); lam tran, bong da, bao ve da (han che mat nude). Ldp mang nay de rua sach bang
dung mdi (ethanol,...) va xa phong, khdng anh hudng nhieu den hap thu thudc.
Tuyen ba nhdn
Tuyen mo hoi
n Mao quan
Nang long Tuyen mo hoi

ttrur.i
Hinh 2.8. Cau true da
- Lop sung: gom lap nen va lop sung.

. Ldp nen la ldp te bao tang sinh, gom cac te bao song san xuat ra cac te bao tao sung.
Te bao sung dugc tao ra phat trien dan ra phia ngoai da (mat. 12-14 ngay), tong hgp ra
keratin roi hoa sung va chet dan sau 2-3 tuan.
. Ldp sung: gom 8-16 ldp te bao chet keratin hda day ctu, chong ldp, chua 15-20%
nude, lien ket chat che theo co che "gach" va "vua", tao nen ket cau so nude. Nhieu dugc
chat bi gu lai trong idp sung (phospho hCru co 8- 120 ngay), tao thanh "kho chua".
+ Trung bi: la ldp mdng (2-3mm) gom cac sgi protein co tac dung nang do, lam ben
bieu bi va dan hoi. Trong trung bi cd mach mau nuoi bieu bi (each be mat da 150-200mcm),
than kinh, nang long, tuyen tiet va tuyen mo hoi.
+ Hg bi: la to chuc md dudi da, ngan each va dem cho da, nuoi dudng bieu bi va
trung bi, tiet ra be mat da. Ha bi chiia tuyen tiet, he mach, lympho, than kinh. Dugc chat
muon vao tuan hoan phai dugc chuyen den ha bi, tuy nhien, dugc chat than dau cd the bj
lam cham hap thu do ai luc vdi ldp md.
57
2.6.2.2. Phan phu
+ Tuyen ba nhdn: tiet ba nhdn vao nang long. Ba nhdn g6m khoang 58% triglycerid,
26% este alcol beo cao, 12% squalene, 1% cholesterol, duy tri pH khoang 5 tren be mat da.
Dugc chat than dau co the khuech tan qua da theo nang long.
+ Tuyen mo hoi: noi chan bi vdi ngoai mdi. Mo hoi cd 99% nude, ngoai ra la protein,
lipoprotein, lipid,... Tuyen m6 hoi cho dugc chat than nude di qua.
2.6.3. Con dudng hap thu thudc qua da
Dugc chat qua da lanh phai qua nhieu hang rao cau true rat khac nhau, phu thudc vao
nhieu yeu to: do tan, tinh tham, he sd khuech tan,...
+ Qua phan phu: dugc chat than nude co the di qua tuyen md hoi; dugc chat than
dau di qua nang long. Hap thu qua phan phu nhanh hon qua da, cd the tao ra lieu ban dau.
Tuy nhien d ngudi con dudng nay la khong dang ke va rat khd danh gia.
+ Qua lap sieng: la hang rao hap thu chinh ciia co the. Dugc chat phan cue than nude
cd the di qua ldp sung chi khi sung dugc hydrat hoa, truong nd tao ra cac khe hd nhat dinh.
Miic do hap thu phu thuoc vao muc do hydrat hda. Dugc chat so nude it phan cue co the di
qua khe hd lien bao chua chat ket gan lipid, tuy nhien, dugc chat than dau co the bi giu lai
lau trong Idp siing.
+ Qua trung bi: la ldp mong than nude do dd dugc chat than nude cd the hoa tan
trong djch mo va hap thu vao he vi mao quan bat dau phat trien tirtrung bi.
+ Qua hg bi: la to chuc md dudi da, do do cac dugc chat than dau cd the di qua de
dang. He thong vi mao quan trong ha bi kha phong phu, do dd dugc chat muon dugc hap
thu thi phai.den dugc ha bi.
2.6.3.1. Anh hudng cua da
+ Liea tuoi: tre em ldp sung chua phat trien (dae biet la tre dudi 9 thang tuoi), thuoc
de hap thu, de dan den ngd ddc, kich ung da. Do dd can han che dung cac thuoc kich ung,
cd nhieu tac dung khong mong muon. Ngugc lai, ngudi cao tuoi ldp sung day va khd, dugc
chat rat khd di qua, dae biet la nhung vung da day nhu cang tay; mu ban tay, ban chan,...
+ Nai dimg: hap thu thay doi nhieu theo vung da, noi da mdng chua sung hoa nhieu,
dugc chat se de hap thu hon noi khac (thai duong, nach, ben,..). Vi vay khi dung thuoc phai
luu y den vj tri dang thuoc, nhat la vdi he qua da.
+ Tinh trgng bit kin: bjt kin da bang cac giai phap nhu bang, bd, dung ta dugc beo so
nudc,....se han che sir boc hoi nude tu da, lam tang hydrat hoa da, dan den tang tham thuoc.
+ Nhiet do: cd the lam tang hap thu qua da bang each tang nhiet do da tai vung dung
thuoc. Khi nhiet do tang se lam gian mach ngoai vi, tang van mach, tang khe hd lien bao va
tang kha nang khuech tan dugc chat. Trudc khi boi thuoc cd the xoa xat, ho nong da hoac
dung cac chat lam nong nhu tinh dau.
2.6.3.2. Anh hudng cua td duac
+ Tac ddng den cau trite da:
- Cac ta duoc than nude nhu DMFA (dimetylformamid), DMSO (dimetylsulfoxid),..:
la nhung dung mdi cd kha nang hda tan rdng, lam mem da, hda tan ldp chat beo ngoai da,
hdatan Idp lipid ket dinh lam thay doi cau true da, tao dieu kien cho dugc chat tham sau.
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- Chat dien hoat: xa phong, alkyl sulphat: la nhung chat tay riia, lam sach ldp chat
beo, lam tang khe hd lien bao do do lam tang tinh tham ciia da.
+ Tac ddng den tinh trgng hydrat hda da: ta dugc hydrocarbon so nude (vaselin, dau
parafin,...) ngan can sir bay hoi nude tir trong da, lam tang hydrat hda Idp siing.
+ Tac ddng den tinh chat li-hda ciia duac chat: lam thay doi do tan, miic do ion hoa,
tinh tham, hoat do nhiet dong ciia dugc chat do dd, anh hudng tdi hap thu.
2.6.4. Dang thudc diing tren da
Dang thudc dung tren da rat phong phu, bao gom ca dang long (dung dich, hon dich,
nhu tuong), dang mem (thudc md, cao dan) va thuoc bgt. Thuoc dung tren da cd the de dieu
tri cac benh tai cho tren da (ton thuang ca
nam,...) hoac de dugc chat tham qua da di vao tuan hoan gay tac dung toan than (viem
khdp, cao huyet ap,...).
2.6.4.1. Thudc ma
+ Thudc ma mem chua ta duac sa nude hydrocarbon: cac ta dugc sg nude nhu
vaselin, parafin, dau parafin,... la nhung ta dugc bjt kin lam tang hydrat hoa ldp sung de bao
ve da, chong khd da, thudng chua cac dugc chat than dau, gay tac dung tai cho tren da (sat
trung, chong nam, gay te be mat, tieu sung,...). Tuy nhien, neu trong thanh phan thuoc md
co dugc chat hay ta dugc gay tham (metylsalicylat, mentol, tinh dau,...) thi che pham van co
kha nang gay tac dung sau dudi da (giam dau, chong thap khdp,...). Ta dugc hydrocarbon
kho riia sach, ben vung ve mat hoa hgc, dang thuoc de bao quan (dau xoa, cao xoa,...).
+ Thudc md mem chua ta duac beo: cac ta dugc beo co ngudn goc dong thuc vat nhu
md lgn, sap ong, lanolin, acid beo, dau thuc vat,... la nhung ta dugc trong thanh phan da co
san cac chat nhu hoa thien nhien (cholesterol, ester ciia acid beo,...), cd kha nang tao nhu
tuang dan thuoc tham sau. Ta dugc beo de bj oxy hda dan den di khet, khd bao quan, do do
trong dang thuoc thudng co ta dugc chong oxy hda (BHA, BHT,...). Hien nay hay dung dau
md hydrogen hoa co the chat on dinh va de bao quan. Nhdm ta dugc nay cd the ket hgp vdi
ta dugc hydrocarbon no d tren.
+ Thudc mamem chiea ta duac nhu tuang: la nhung nhu tuong hoan chinh, thudng la
dang N/D, phoi hgp dugc ca dugc chat than dau va than nude, co kha nang dan thuoc tham
qua da. Khi dung, ta dugc beo tiep xiic vdi da hda tan ldp mang nhdn tren da va tang hydrat
hda ldp sung, lam cho dugc chat co kha nang tham vao trung bi. Den trung bi, cac dugc
chat than nude hda tan trong ldp nude khuech tan ra moi trudng va bat dau dugc hap thu
con cac dugc chat than dau de dang di qua ha bi de tiep tuc di vao tuan hoan gay tac dung
toan than.
+ Kem (cream): la nhung thudc md nhu tuong hoan chinh, hien dugc dung rat rong
rai trong ca thudc va my pham (dae biet la kem my pham), the chat 6n dinh, cd kha nang
dan thuoc tham sau.
+ Gel: la dang thuoc md chiia ta dugc than nude, co kha nang truang nd hoa tan
trong nude tao gel ben va trong. Cac ta dugc hay dung nhu carbopol, dan chat celluluse,
tinh bgt, gom, thach,...Dang gel cd uu diem la the chat 6n djnh, de rua sach. Dang gel nhu
tuong (emulgel) cd kha nang dan thuoc tham sau.
59
+ Cao dan quy udc: la dang thuoc mem gom dugc chat dugc phan tan hay hda tan
vao nen dinh trai tren vai hay giay, dung dan len da. Ta dugc gay dinh da trong cao dan quy
udc hay dung nhua thong, nhua cao su hoac polyme tong hgp. Dugc chat hay g^p tinh dau,
metylsalicylat, thuoc chong viem,... dan tai cho dau, 1-2 ngay thay la cao mdt lan, chii yeu
gay tac dung tieu sung giam dau tai ch6 dau (va dap cohgc, viem khdp,...). Dugc chat tr^ng
cao dan tham kha sau do tinh dau vua la dugc chat vua la nhung chat gay tham manh.
+ He tri lieu qua da (TTS: Transdermal Therapeutic Systems): la he dan tren da nhu
cao dan quy udc, nhung thuc chat day la he giai phdng dugc chat theo chuong trinh, dua
dugc chat vugt qua hang rao da di vao tuan hoan chung gay tac dung toan than. Cd nhieu
loai he trj lieu qua da cd cau tao khac nhau: he cot (matrix) bao gom mot nen dinh chua
dugc chat khuech tan hoac hda tan trong ta dugc hoac he binh chua cd mang kiem soat giai
phong. Hien nay tren thj trudng luu hanh cac he trj lieu chua nitroglycerin, scopolamin,
estradiol,... giai phdng dugc chat deu dan keo dai tir 3-7 ngay.
2.6.4. Dgng thuoc dimg qua da
+ Thuoc tiem tac dung keo ddi: thudng la hon djch dau tiem dudi da. Dau cd dd nhdt
cao, ket hgp vdi chat lam tang do nhdt lam cho thuoc tiem khuech tan cham trong dich md.
Dong thai dugc chat lai phan tan dudi dang tieu phan va tiem dudi da la noi cd it mach
mau lam cho thuoc gan nhu "diing yen" tao thanh cac "kho chua" tac dung cd the keo dai
tdi hang nam (thuoc tiem penicillin, thuoc tiem haloperidol enantat,...).
+ He cay dudi da (Implants): la he giai phdng keo dai hoac giai phong theo chuang
trinh, dugc cay dudi da giai phong dugc chat deu dan trong nhieu ngay. Hien da ap dung
cho hocmon tranh thai, insulin,...Dugc chat dugc phan tan trong cot polyme phan giai sinh
hgc hoac khdng. Khi dung phai lam thu thuat nho de cay va lay cot ra (vdi loai khong phan
giai sinh hgc).
2.7. Dua thuoc theo dudng tiem
2.7.1. Dae diem dua thuoc theo dudng tiem
- Dudng tiem la dudng dua thuoc vao co the nhanh nhat, vugt qua mgi hang rao hap
thu nhd kirn tiem, dua thuoc thing vao tuan hoan hoac dua thang tdi dich, thich hgp trong
trudng hgp cap cuu, trong con cap tinh ciia benh, trong trudng hgp benh nhan khong uong
dugc thuoc (ngat, non mua,...), khdng hgp tac vdi thay thuoc.
- Dudng tiem la dudng dung thuoc ngoai dudng tieu hoa (parenteral), do do, tranh
dugc tac dgng bat lgi ciia dudng tieu hoa doi vdi dugc chat, lam cho thuoc dat SKD cao
nhat (tiem tTnh mach SKD 100%), thich hgp cho cac dugc chat cd SKD dudng uong thap,
cac dugc chat cd mui vj khd ehju khi uong.
- Thuoc tiem la dang thuoc cd yeu cau cao nhat ve do an toan, bat cu sai sot nao ve
bao che, sir dung thuoc tiem deu co the de lai nhung hau qua khd ludng.
-Thuoc tiem cd nhung han che nhat djnh nhu benh nhan khdng tu dung dugc thuoc
ma can co nhan vien y te, tiem dau, gia thanh cao,...
2.7.2. Cac dang thuoc tiem: dang bao che cuathuoc tiem kha phong phu:
+ Dung dich nude: la dang thuoc tiem pho bien nhat, vi nude la dung mdi an toan
nhat khi tiem vao co the. Vdi dugc chat it tan trong nude cd the diing hon hgp dung mdi
60
do tan vua han che thuy
phan dugc chat. Tuy nhien, thudc tiem hon hgp dung mdi cd do nhdt cao nen khi tiem gay
dau va giai phdng dugc chat cham hon dung dich nude. Mot sd thudc tiem loai nay sau khi
tiem cd the gay tiia dugc chat tai noi do dung moi bi pha loang vdi djch md. Cd trudng
hgp tiia la do chii y de keo dai tac dung ciia thuoc
+ Dung dich dau: it gap hon dung dich nude (thudc tiem vitamin E, thudc tiem long
nao,...). Thudc tiem dau tiem dau va giai phong dugc chat keo dai.
+ Hon dich nude: phai la hon djch mjn va khong dugc tiem tTnh mach. Thuoc tiem
do nhdt nen tiem dau (thudng tiem bap sau), tac dung keo dai
thai gian hoa tan trong djch md.
+ Hon dich dau: hay dung tiem dudi da de keo dai tac dung (nhu da trinh bay d phan
thuoc qua da).
+ Nhu tuang: thudc tiem nhu tuong thudng gap loai nhu tuong D/N de de pha loang
vdi djch mo. Nhu tuong truyen tTnh mach phai la loai D/N.
+ Thudc bdt pha tiem: la loai bdt vd khuan pha tiem hoac bdt ddng kho dong kem
ong dung moi pha tiem. Bdt ddng kho de tan trong nude.
Trong thanh phan thuoc tiem, ngoai dugc chat va dung mdi hay moi trudng phan tan
con cd them nhieu nhdm chat phu khac nhu chat chong oxy hoa, chat sat khuan chong nam,
chat dieu chinh pH, chat dang truong,... Khi tiem bap, thudc tiem cd pH qua acid, qua kiem
hay qua uu truang se gay kich ung.noi tiem hoac mot lugng chat dien hoat lam tang do tan
dugc chat vugt qua gidi han cho phep trong thuoc tiem tTnh mach cd the gay vd hong cau.
Tac dung ciia thudc tiem phu thuoc nhieu vao dudng tiem.
+ Tiem tTnh mgch: thuoc dugc dua true tiep vao tuan hoan, khdng qua giai doan hap
thu do do phat huy tac dung nhanh, SKD dat 100%. Tuy nhien tiem tTnh mach thuoc cung
bj thai tru nhanh, de gay hien tugng "dinh-day", phai dung nhieu lan trong ngay bat tien cho
ngudi benh.
Thuoc tiem truyen tTnh mach lieu ldn (tren 15 ml) phai khdng cd chat gay sot va
khong dugc cho chat phu sat khuan, cd pH va ap suat tham thau gan vdi huyet tuong (dung
djch uu truang phai truyen vdi toe dd cham). Khi pha thuoc tiem vao djch truyen phai tuan
thu chat che cac quy djnh ve phoi hgp thuoc de tranh xay ra tuong ky hda hgc hay dugc ly
gay nguy hiem cho ngudi benh.
+ Tiem dong mgch: dung trong chan doan va chua benh ddng mach, trong dua thuoc
tdi dich (thuoc tiem nano, liposome gay nghen mach dieu trj ung thu). Thuoc tiem ddng
mach la dung djch nude pha che vd khuan (khong dugc dung chat phu sat khuan).
+ Tiem trong da: do ldp da mong nen lugng thudc tiem trong da khdng dugc nhieu (
dudi 0,1ml), thudc khdng dugc hap thu, chi dung trong trudng hgp tiem vaccin hoac tham
do phan ling qua man ciia thudc, thudng tiem dang dung dich.
+ Tiem dudi da: to chuc dudi da it mao mach, day than kinh nhieu, djch md cd do
nhdt cao nen dugc chat hap thu cham, tiem dau. Dung trong trudng hgp muon keo dai tac
dung ciia thuoc.
+ Tiem bap: bap la to chuc co sau dudi da, tuan hoan phong phu, day than kinh it nen
thuoc hap thu nhanh va it gay dau khi tiem. Thuoc tiem hon djch, thuoc tiem cd do nhdt cao
(thuoc tiem dau) thudng tiem bap sau de dd dau. Vj tri tiem thuoc anh hudng den toe do va
61
miic do hap thu thuoc (thuoc tiem lidocain tiem co Delta canh tay hap thu nhieu hon co
dui,...).
+ Tiem tgi dich: dua thuoc true tiep tdi noi bj benh: tiem vao khdp, mat, tim,...
Thuoc tac dung nhanh, SKD cao do dugc chat khdng bj mat mat tren dudng van chuyen.
Tuy nhien thuoc tiem can dat yeu cau chat lugng cao (nhu vdi tiem tTnh mach) va can cd
nhan vien y te cd kinh nghiem de dam bao an toan cho ngudi benh.
2.8. Pha che thuoc dung ngay
Hien nay, nganh cong nghe dugc pham da dua ra thj trudng nhieu dang thuoc mdi vdi
md hinh giai phong khac nhau nham dap ung nhu cau da dang ciia benh tat trong lam sang.
Tuy nhien, thuc te lam sang cho thay, cung mdt biet dugc ban san tren thj trudng, khi dung
cho nhung ngudi benh khac nhau, dap ling ciia tung ca the vdi thuoc la rat khac nhau, cd
nhung trudng hgp tao ra dao dgng lien ca the rat ldn.
Dugc lam sang di vao hudng ca biet hda dieu trj, rat can cac che pham thudc thich
ung vdi ngudi benh cu the\ Muon vay ben canh sir dung cac che pham do nganh cong
nghiep dugc cung cap, can phat trien song hanh viec pha che theo dan tai khoa dugc benh
vien de dap ung nhu cau dieu trj.
Cac dang thuoc pha che dung ngay (extemporaneous preparations) nhu dung djch
thuoc, con thuoc, siro thuoc, potio, elixir, thuoc nude chanh, thuoc md, thuoc bgt,...la
nhung dang thuoc ky thuat pha che don gian, khdng ddi hdi trang thiet bj phuc tap, cd the
pha che d quy md nho dam bao chat lugng de phuc vu tot hon cho ngudi benh.
CAU HOI Ll/ONG GIA
1. Dien trong cac cau tir 1 den 12
,-n i
1. 3 thanh phan hiru hinh ciia dang thudc la:
•J: in)
A - Duoc chat B -
C-
2. Co 2 nhdm yeu to anh hudng den SKD

A- B-
3. Do hoa tan bieu thj kha nang ciia vien
4. Thuoc dan giai phong duac chat theo 2 co che
A- ' B-
5. Thuoc tiem cd do nhdt cao thudng cho them chat phu
6. Thuoc nho mat gom 3 dang
A - B -
C - Nhu tuong
7. Hai giai phap tang hydrat hda ldp sung lam tang hap thu thuoc qua da la
A- B-
8. TTS la dang thuoc giai phdng dugc chat theo
9. Kha nang hap thu thuoc qua da phu thudc nhieu vao muc do ciia da
62
10. Hai uu diem chinh ciia viec dung thuoc theo dudng hd hap la
A- B-
11. Kha nang dinh vj dugc chat ciia thuoc phun mu trong dudng hd hap phu thuoc vao 2
yeu to chinh
A- B-
12. Hai con dudng thanh thai chinh ciia thudc nho mui la:
A- B-
2. Lira chon Diing - Sai cac cau tir 13 den 30
STT Ndi dung D S
13 Cung mot dugc chat khi dung theo cac dudng dung khac nhau, cd
the tao ra dap ling lam sang khac nhau
14 SKD in vitro bieu thj miic do hap thu ciia dugc chat
15 Thuoc co SKD cao thudng la hieu qua dieu tri se cao
16 Thudc diing qua dudng tieu hoa cd SKD cao
17 Do nhdt cao tang cudng hap thu dung djch thuoc
18 Siro khd la siro pha lai
19 Siro pha lai la dang dung dich
20 Sinh kha dung ciia hon dich phu thudc vao kich thudc tieu phan
21 Nhu djch co the che dau mui vi kho ehju ciia dugc chat
22 Nhu djch dugc chat hap thu nhanh hon dung djch
23 Pellet giai phong dugc chat on djnh hon vien nen
24 Vien tac dung keo dai khdng dugc be
25 Dung thuoc dan co the nang cao SKD cho thuoc giam dau
26 Thudc tiem khong dugc cd chat gay sot
27 Thuoc tiem nhu tuong khong dugc tiem tTnh mach
28 Thuoc tiem tac dung keo dai thudng tiem tTnh mach
29 Djch truyen khong dugc cho them chat sat khuan
30 Thuoc tra mat bam dinh niem mac mat lau hon thudc nhd mat
3. Lua chon tra loi tot nhat cac cau tu* 31 den 48
31. Yeu to sinh hgc anh hudng den sinh kha dung la
A - Dugc chat B - Ta dugc
C - Dd bao goi D - Ky thuat bao che
63
D - Dudng dung thudc
32. Yeu to dugc hgc anh hudng den sinh kha dung la
A - Gidi tinh B - Do tuoi
C - Do bao goi D - Tinh trang benh ly

D - Dudng diing thudc
33. Dang thuoc hap thu nhanh nhat la
A - Dung djch thuoc B - Siro thuoc
C - Potio dung djch D - Elixir
E - Hon djch
34. Dang thuoc hap thu cham nhat la
A - Dung djch thuoc B - Siro thuoc
C - Potio dung djch D - Elixir
E - Hon djch
35. Dang thuoc cd qua trinh giai phong dugc chat don gian nhat la
A - Thuoc bdt B - Thuoc com
C - Nang ciing D - Pellet

E - Vien nen
36. Yeu to anh hudng nhieu nhat den kha nang giai phdng dugc chat tir nang thudc la
A - Hinh dang nang B - Co nang
C - Dang thuoc ddng nang D - Lugng nude uong vdi nang
E - Tu the uong nang
37. Dang thuoc co qua trinh giai phong dugc chat phuc tap nhat la
A - Thuoc bdt B - Thuoc com
C - Nang ciing D - Nang mem
E - Vien nen
38. Dangthuoc de gay dinh thuc quan nhat la:

A - Vien tran B - Vien bao bao ve
C - Vien bao tan d rudt D -Vien bao kiem soat giai phdng
V,k- rJih T€ til i. ' ••*''.v.* •
E - Nang cung
39. Vien nen cd dugc chat dugc hap thu nhanh nhat la
A - Vien ngam B - Vien nhai
C - Vien dat dudi ludi D - Vien siii bgt
64
E - Vien bao tan d rudt
40. Vien nen khdng ra trong dudng tieu hda la
C - Vien dat dudi ludi D - Vien cot khuech tan
41. Vien nen pha hon djch la
C - Vien dat dudi ludi D - Vien phan tan
42. Vien nen uong khong can dung nude la
A - Vien bao bao ve B - Vien nhai
C - Vien siii D - Vien ra trong mieng
43. Thudc tiem cd tac dung keo dai nhat la
A - Thuoc tiem dung djch nude B - Thuoc tiem dung djch dau
C - Thudc tiem hon djch nude D - Thuoc tiem hon djch dau
E - Thuoc tiem dong kho
44. Dang thuoc bam dinh niem mac mat tot nhat la
A - Dung djch nude B - Dung djch dau
C - Hon djch D - Thuoc md
E - Liposome
45. Kho khan ldn nhat khi dung thuoc qua da la
A - Thudc kho bam dinh da B - Thuoc gay ban da
C - Co che bao ve ciia da D - Nhieu DC kich ung da
E - Thuoc kho rua sach khoi da
46. Ta dugc dan thudc tham sau nhat qua da la
A - Vaselin B - Tinh bgt
C - Thach D - Dan chat cellulose
E- Ta dugc nhu tuong
47. Ta dugc bjt kin t3ng hydrat hoa da la
A - Vaselin B - Tinh bgt
C - Thach D - Dan chat cellulose
E - Ta dugc nhu tuong
48. Dang thuoc cd kha n3ng bam dinh niem mac mui tot nhat la
A - Thudc nhd mui B - Thuoc xjt
C - Thuoc hit D - Thuoc phun mu
E - Liposome
DLS..T5 65
4. Nhan xet ve thanh phan va each dung cac che pham tir 49 den 54
49. Elixir paracetamol
Paracetamol 2,4 g
Ethanol 96% 10,0 ml
Propylen glycol 10,0 ml
Con cloroform 2,0 ml
Siro don 27,5 ml
Chat mau, chat thorn vd
Glycerin vd 100 ml
50. Thudc tiem penicilin

Procain penicilin G ket tinh
(bgt sieu mjn) 600.000 UI
Nhom monostearat 2%
Dau vung vd 2 ml
51. Thudc bdt paracetomol

Paracetamol 0,10g
Acid citric khan 0,12 g
Natri hydrocarbonat 0,20 g
Natri saccarin vd
Chat tham vd
Bgt dudng vd
52. Com cephalecin (250 mg/5ml)

Cephalecin mdnhydrat 250,00 mg
Na CMC 16,55 mg
Acid citric 1,35 mg
Natri benzoat 5,00 mg
Dinatri EDTA 2,50 mg
Tween 60 6,25 mg
Aerosil 200 25,00 mg
Chat mau, chat tham vd
Bgt dudng vd (2 g)
53. Pellet diclofenac
Natri diclofenac 50,00 g
Hat tra 78,80 g
Bdt dudng 3,00 g
Tinh bdt ngd 3,00 g
PVP 3,40 g
66
HPMCP 16,50 g
Triacetin 1,65 g
Talc 8,65 g
Ethanol vd
54. Thuoc tiem vitamin A
Vitamin A (retinol palmitat)

.at) 50.000 UI
Polysorbat 80 12,00%
Clorobutanol 0,50 %
Acid citric 0,10%
BHA 0,03 %
BHT 0,03 %
NaOH vd (pH 6,5-7,1)
Nude cat pha tiem vd 2,00 ml
DAP AN
1-B: tadugc C: bao bi

2- A: sinh hgc B: dugc hgc
3- giai phdng dugc chat
4- A: tan chay B: hoa tan
5- giam dau
6- A: dung djch B: hon djch
7- A: bang kin B: boi ta duoc so nude
8- chuang trinh
9- siing hoa
10- A: dien tich BMTX ldn B: tuan hoan phong phu
11- A: KTTP phan tan B: each thd
12- A: tran ra ngoai B: chay xuong mieng
13D -14S -15D-16S- 17S -18D -19S-20D-21D-22S-23D-24S-25D-26S-27S-29D-30D-
31D-32C-33A-34E-35A-36C-37E-38E-39C-40D-41D-42D-43D-44E-45C-46E-47A-480E.
TAI LIEU THAM KHAO
1. Bo mon Bao che, Dai hgc Dugc Ha Ndi (2006)- Ky thuat bao che va sinh dugc hgc cac
dang thuoc, tap 1 va 2- NXB Y hgc
2. Bo mon Bao che, Dai hgc Dugc Ha Ndi (2006)- Sinh dugc hgc bao che- NXB y hgc
3. Alexander T Florence (2010) - An Introduction to Clinical Pharmaceutics-
Pharmaceutical Press
4. Herman J. Woerdenbag and Hendrick W. Frijiink (2010)- Biopharrmacy, Dosage forms

and Routes of Administration- Groningen University.
5. Neena Washington, Clive Washington, Clive G. Wilson (2001)- Physiological
Pharmaceutics-Barriers to Drug absorption, second edition- Taylor & Francis.
CHUONG 3. PHlTONG PHAP THIET KE THlf NGHIEM
LAM SANG
Nguyen Hoang Anh, K. Taxis

MUC TIEU
1. Trinh bay duac cac uu diem vd hgn che cua thienghiem lam sang phdn nhdm ngdu nghien
cd kiem sodt:
2. Giai thich duac dnh hudng ciia tieu chudn hea chon/logi trie bqnh nhdn, chi tieu danh gid
den vi(>c dp dung cdc ket qua ciia thu nghiem trong thuc hanh lam sang.
3. Giai thich duac tdm quan trgng ciia vi£c phdn nhdm ngdu nhien, lam mu, hea chon nhdm
chieng, chi tieu danh gid, ca mau vd cdc phep toan thong ke sie dung trong thienghiem lam
sang.
4. Ap dung duac bang kiem CONSORTde danh gid mdt thienghiem lam sang ve thudc.
MO DAU
Bang chung ve hieu qua va do an toan ciia thudc dugc cung cap chii yeu tir cac
nghien cuu lam sang trong qua trinh phat trien thudc va sau khi dua thudc ra thj trudng.
Trong sd cac nghien cuu nay, thu nghiem lam sang phan nhdm ngau nhien cd kiem soat
(randomized controlled clinical trials), ggi tat la thu nghiem lam sang, dugc coi la chuan
muc de danh gia hieu qua ciia thudc, cho phep cung cap bang chung tin cay va cd gia trj ve
thuoc. Ndi dung ciia chuang nay se cung cap cho ngudi dgc nhung khai niem co ban nhat
ve thiet ke thu nghiem lam sang, bat dau tir xay dung cau hdi nghien cuu vua mang tinh
khoa hgc, vua cd y nghTa lam sang den cac khai niem ve chi tieu danh gia, cac phuong phap
thong ke xu ly ket qua nghien cuu va udc tinh cd mau ddng thai trinh bay ve each bien giai
ket qua va danh gia chat lugng ciia thu nghiem lam sang thong qua noi kiem va ngoai kiem.
Cac loai hinh nghien cuu lam sang khac mang tinh chat quan sat va mo ta (nghien cuu
thuan tap, nghien cuu benh chung, bao cao ca) dugc de cap trong chuong 7 "Djch te dugc
hgc". Nguyen tac ap dung ket qua ciia thu nghiem lam sang trong sir dung thuoc se dugc
trinh bay trong chuang 4 "Can nhac nguy co - lgi ich trong sir dung thuoc".
1. CAC BIT6C CAN LAM TRONG THIET KE THU NGHIEM LAM SANG
1.1. Xay dung cau hoi lam sang
Mdt nghien cuu lam sang cd chat lugng can cung cap dugc cac thong tin mdi va bo
sung cho nhung du lieu hien cd ve hieu qua va do an toan ciia thuoc. Mdt mat phai dam bao
dugc tinh khoa hgc nhung mat khac nghien cuu cung phai gan lien vdi thuc hanh lam sang
va chinh sach y te dang dugc ap dung. Vi vay, viec xay dung cau hoi nghien cuu ro rang la
nen tang ciia thiet ke thu nghiem lam sang. Cau hoi nhu "Lieu phu nu sau man kinh co nen
su dung lieu phap thay the hormon?" la mdt cau hdi qua rong. Cau hdi nghien cuu nen bao
gom md ta nhom benh nhan dugc lira chgn, md ta can thiep trong thu nghiem (thuoc, phac
do) va nhom so sanh (placebo hoac thudc dang sir dung trong phac do hien tai). Chi tieu
68
danh gia (ngan can xuat hien cac bien chung ciia benh, giam ty le tu vong, cai thien chat
lugng cudc song...) cung phai dugc de cap cu the. Nhung ndi dung nay deu cd mat trong
tiep can PICO trong xay dung cau hdi lam sang:
P - Patient (benh nhan): nhdm benh nhan nao can danh gia?
I - Intervention (can thiep): thuoc hoac phac do dieu trj nao can danh gia?
C - Comparator (nhdm so sanh): thuoc hoac phac do dieu tri nao dugc lira chgn de so
sanh?
O - Outcome (chi tieu danh gia): chi tieu danh gia phu nao phu hgp vdi can thiep
trong nghien cuu?
1.2. Lira chon doi tuang tham gia trong thir nghiem lam sang
Doi tugng tham gia nghien cuu can dai dien cho quan the benh nhan muon hudng tdi
trong thuc hanh, tu do ciia nghien cuu va
thuc te lam sang. Do vay, tieu chuan lira chgn va loai tru benh nghTa
rat ro rang. Tieu chuan lira chgn benh nhan bao gom cac tieu chi dae thu ve nhan khau hgc
(tuoi, giai) va cac tieu chi lam sang (chan doan, muc do nang nhe ciia benh, cac benh mac
kem). Tieu chuan loai tru can neu ro cac trudng hgp benh lira chgn vao
thu nghiem vi ly do dao due y hgc (vi du nhom benh nhan cd nguy eo cao nhu phu nu cd
to chuc va trien khai nghien cuu (vi du khdng cd kha nang giao
tiep...). Cac tieu chuan lira chgn va loai tru nay co anh hudng den viec dam bao chat lugng
ciia nghien ciiu. Benh nhan tham gia thu nghiem lam sang dugc thong tin ve muc tieu, qui
trinh ciia nguyen tac bao
mat thong tin ca nhan trong nghien ciiu va phai xac nhan chap nhan cac dieu kien nghien
cuu tren mdt each tu nguyen bang van ban. Van ban chap thuan tham gia nghien cuu nay cd
the dugc huy bd d bat cu thai diem nao ciia nghien cuu vdi bat ky ly do nao. Nhung noi
dung nay deu phai dugc Hdi dong dao due phe duyet trong de cuang thu lam sang trudc khi
nghien ciiu dugc tien hanh.
1.3. Xac djnh cac chi tieu danh gia cua thir nghiem lam sang
Cac chi tieu danh gia (endpoints hoac outcomes variables) la yeu to can thiet de
lugng gia ket qua, cho phep danh gia hieu qua hoac do an toan ciia thudc hay phac do dieu
trj nghien cuu trong thu nghiem. Cac thu nghiem lam sang deu cd mdt tieu chi danh gia
chinh (primary endpoint) la thong so ma ngudi lam nghien cuu lira chgn de danh gia hieu
qua ciia thuoc, tra ldi cho muc tieu chinh ciia nghien cuu. Ngoai ra, con cd cac tieu chi danh
gia phu (secondary endpoints), la cac chi tieu dugc them vao ben canh chi tieu chinh nhung
khdng quyet djnh nhu chi tieu chinh. Chi tieu chinh dugc lira chgn can
la cac chi tieu thudng qui va cd y nghTa trong thuc hanh lam sang. Vi du mdt thu nghiem
lam sang danh dung ha cholesterol ciia mot dan chat statin so sanh vdi placebo thi
viec lira chgn gia trj LDL-C la chi tieu danh gia chinh la phu hgp trong khi do do ludng sir
thay d6i creatinin huyet thanh khi dieu trj bang losartan hoac captopril de danh gia sir cai
thien ciia suy tim la khdng phu hgp vi thong so nay khdng khuyen cao la tieu chi quan
trgng trong thuc hanh de theo ddi tien trien hoac sircai thien ciia suy tim.
Cac chi tieu danh gia can phai cd y nghTa Co hai
loai chi tieu danh gia chinh:
69
Chi tieu lam sang (con dugc ggi la chi tieu "cung", hard endpoints): la cac bien co
lam sang nhu tu vong, nh6i mau co tim, gay xuong... hay cac chi tieu do ludng chat lugng
cudc song ciia benh nhan. Day la cac chi tieu cd y nghTa nhat, phan anh chinh xac hieu qua
va do an toan ciia thuoc nhung thudng ddi hdi so lugng benh nhan ldn va thai gian theo ddi
lau dai khi tien hanh thu nghiem lam sang.
Chi tieu ggi y (surrogate endpoints, con dugc ggi la chi tieu "mem", soft
endpoints): la cac chi tieu dugc su dung thay the cho cac chi tieu lam sang cho phep danh
gia hieu qua va do an toan ciia thuoc thong qua cac thong so de dang lugng gia hon, do
ludng khach quan, it ehju anh hudng ciia cac yeu to nhieu hon, tien hanh thu nghiem trong
thai gian ngan hon va can it benh nhan hon. Cac chi tieu nay bao g6m cac thong sd xet
nghiem sinh ly hoac hda sinh (nhu ham lugng albumin trong nude tieu trong suy than giai
doan cuoi, mat do khoang ciia xuong thay cho gay xuong, huyet ap ddng mach thay cho ty
le xuat hien dot quj, so lugng te bao CD4 thay the cho ty le tu vong do hdi chung suy giam
mien djch mac phai AIDS) hoac cac thong so do ludng tinh trang trudc khi xuat hien trieu
chung lam sang cua mot so benh (nhu muc do hep long mach do xa vua qua sieu am mach
vanh de du doan thay cho bien co xuat hien nh6i mau co tim hoac tu vong do benh mach
vanh). mdt so trudng hgp, cac chi tieu nay con dugc ggi la cac chat chi diem sinh
hgc (biomarkers) phan anh qua trinh sinh ly benh hoac dap ung dugc ly vdi thuoc. Cac tieu
chi ggi y phai dugc tham djnh ky cang trudc khi ap dung trong nghien cuu lam sang thong
qua moi quan chat khdng nhung ve thong ke (do nhay, do dae hieu cao) ma con cd
moi lien he nhan qua tin cay vdi chi tieu lam sang (thay doi ve chi tieu ggi y keo theo thay
doi ve lgi ich lam sang).
Nong do LDL-cholest%rol (LDL-C) la vi du dien hinh cho viec su dung chi tieu ggi y
trong thu nghiem lam sang. Trong mdt thu nghiem lam sang so sanh hieu qua ciia
atorvastain va simvastatin, LDL-C dugc danh gia sau 6 tuan dieu trj. Muc do giam gia trj
nay dugc coi chi tieu danh gia ggi y vi mac du atorvastatin lam giam LDL-C manh hon
nhung khdng the ngoai suy dugc lieu atorvastatin cd hieu qua hon trong viec giam cac bien
co tim mach han simvastatin hay khdng. Dieu nay can phai dugc kiem chung trong mdt thu
nghiem lam sang khac cd thai gian theo ddi dai hon (len tdi 6 nam), vdi so lugng benh nhan
nhieu hon de tra ldi cau lira chgn statin nao cho benh nhan. Nhu vay, viec su dung chi tieu
ggi y cho phep so sanh nhanh hieu qua ciia cac thuoc va djnh hudng cho thu nghiem dai hoi
hon de khang djnh lgi ich ve mat lam sang cua thudc.
Viec su dung cac chi tieu ggi y lam co sd danh gia hieu qua, do an toan de phe duyet
cap so dang ky luu hanh tren thj trudng ciia thuoc con cd nhieu tranh cai. Vi du,
flosequinan, milrinon, ibopamin, vesnarinon va xamoterol deu lam cai thien chi tieu ggi y
la tinh trang huyet ddng ciia benh nhan suy tim nhung cac thu nghiem lam sang sau do lai
cho thay cac thuoc nay lam tang ty le tu vong. Nhu vay, vifc su dung chi tieu ggi y de
chung minh hieu qua ve mat lam sang khdng phai liic nao cung dugc dam bao. Motso vi du
ve viec su dung cac chi tieu ggi y khdng hgp ly trong cac thu nghiem lam sang dugc trinh
bay trong bang 3.1. Mat khac, do lam giam cd mau va thai gian theo ddi benh nhan can
ddc tinh ciia

mdt thuoc trong thu nghiem
ma can phoi hgp nhieu chi tieu ggi y hoac chi tieu ggi y vdi chi tieu lam sang.
70
Bang 3.1. Mdt so vi du.ve chi tieu ggi y khdng hgp ly su dung trong thu nghiem lam sang
Chi tieu ggi y Chi tieu lam sang Tai lieu tham khao cua nghien cuu
Mat do xuang Gay xuang New England Journal of Medicine
•1990;322:802-809.
Ngoai tarn thu that Tu vong do nhjp New England Journal of Medicine
1992; 324: 781-788.
So lugng te bao CD4 Ty le song sdt d benh Lancet 1994; 343: 871-881
mau ngoai vi nhan nhiem HIV
Nong do khang sinh Ty le khdi lam sang ciia Clinical Pharmacokinetics 1995; 28:
trong huyet tuang nhiem triing 143-160.
Tren thuc te, nghien cuu co the ghep mdt nhdm cac chi tieu thanh mdt chi tieu chinh
tong hop (composite endpoint). Nhdm cac chi tieu nay thudng bao g6m cac chi tieu lam sang
lien quan den ty le tu vong hoac ty le mac benh dudi tac dung dugc ly ciia can thiep bang
thuoc (vi du nhugiam xuat hien tu vong do batcu bien co nao trong cac bien co: dot qui, nhdi
mau co tim, benh mach vanh). Ngudi lam nghien cuu cungcd the lira chgn nhdm cac chi tieu
cd y nghTa lam sang cd the xuat hien trong qua trinh dieu trj nhu sau nhoi mau co tim, sir dung
thuoc de lam giam sir xuat hien ciia cac bien co bat lgi nhu: dau nguc, tai phat nhoi mau, tu
vong. Cac chi tieu tong hop nay cho phep danh gia toan dien hieu qua ciia thudc khi ma mot
trong cac chi tieu thanh phan khdng the dai dien cho tien trien ciia benh. Khi su dung chi tieu
tong hop, nghien ciiu cung phai de cap den ket qua phan tich ciia ca cac chi tieu thanh phan vi
thuoc cd the cd hieu qua tren chi tieu tong hgp nhung khdng lam thay ddi mdt sd chi tieu
thanh phan trong dd cd the cd ca chi tieu thanh phan quan trgng nhat.
2. Xtf LY THONG KE SO LIEU THU DlTOC TU* THLT NGHIEM LAM SANG
2.1. Dae diem cua so lieu nghien ciru
So lieu thu thap trong thu nghiem lam sang thudc 1 trong 4 loai bien so: bien dinh danh
(nominal), bien thu bac (ordinal), bien tham so rdi rac hoac lien tuc (metric,
discrete/continuous) (bang 3.2). Di tu bien dinh danh den bien tham so, tinhthong tin tang dan
nhung kha nang xuat hien sai so do ludng cung tang dan. Loai so lieu nghien cuu vadae diem
phan bo ciia mau so lieu se quyet dinh viec lira chgn phep toan thong ke de xu ly ket qua.
Bang 3.2.03c diem ciia cac loai so lieu trong thu nghiem lam sang
Loai bien Cac tham sd Noi dung
Dae diem Vidu
sd thdng ke md ta thong tin
Bien dinh Bao gom cac so lieu Gidi tinh, tinh Tan so, ty le Thap
danh khong c6 thu bac trang song/chet
Bien thu Bao gom cac so lieu Muc do dau Tan so, ty le, Trung binh
bac c6 thu b$c nhung trung vi
khoang each giua
chung khdng dinh
lugng dugc
Bien lien Pham vi gia tri dugc Can nSng, so Tan so, ty le, Cao
tuc ho§c phan thanh cac dieu thuoc la trung vj, trung
bien rdi rac khoang c6 the dinh hiit/ngay, huyet binh, dg lech
c6 thu bac lugng dugc ap chuan
71
2.2. Lira chon toan thong ke
ciia thu nghiem lam sang, gia thuyet HO dat ra tai thai diem trudc
sir khac biet giua hai thuoc/hai phac do dieu trj". Gia
thuyet HO nay can dugc kiem djnh (chap nhan hay bac bd) thong qua viec su dung cac phep
toan thong ke phu hop de xu ly so lieu thu dugc tu nghien cuu. Cac phep toan thong ke
dugc su dung de kiem chung lieu mdt thuoc hoac mdt phac do dieu trj nay cd hieu qua
hon/an toan hon so vdi thuoc hoac phac do dieu trj kia hay khdng, thudng la so sanh giua
thuoc thu do dieu trj hien tai.
Trong trudng hop nay, thu nghiem lam sang dugc thiet ke theo hinh thuc "vugt troi"
(superiority trial). Tuy nhien, vdi muc tieu chung minh thudc mdi cd hieu qua tuong tu
hoac khdng kem hon cac thuoc hoac phac do chuan dieu trj hien tai, thu nghiem lam sang
cd the dugc thiet ke theo hinh thuc tuong duong (equivalent trial) hoac khdng thua kem
(noninferiority trial).
Hai loai sai lam cd the mac phai trong viec kiem djnh gia thuyet HO ciia thu nghiem
lam sang. Sai lam loai I (duong tinh gia) neu nghien cuu dung thong ke phat hien sir khac
biet co y nghTa de bac bd gia thuyet HO trong khi tren thuc te khdng cd sir khac biet ve hieu
qua giua mdt each ngau nhien
va dugc dae trung bdi xac suat xuat hien loai sai lam nay hay con ggi la muc y nghTa thong
ke (a). Sai lam loai II (am tinh gia) xuat hien khi nghien cuu khdng the bac bd dugc gia
thuyet HO mac du tren thuc te cd sir khac biet ve hieu qua giua
chieu. Sai lam loai II, dugc dae mac each ngau
nhien hoac khi cd sir khac biet giua
so 1 - p dugc ggi la hieu lure ciia nghien cuu, dae trung cho kha nang bac bd chinh xac gia
HO neu nhu tren thuc te thuc sir cd sir khac biet giua thudc mdi va thudc ddi chieu.
Thong nghTa sir khac biet cd y nghTa thong ke khi
p < 0,05) con hieu lire ciia nghien cuu bang 80% la muc do thudng dugc chap nhan trong
cac thu nghiem lam sang. Co mau se dugc tinh toan de chgn dugc sd benh nhan dii de giu a
va p d muc do chap nhan nay ma khdng lam tang chi phi hoac cac khd khan khdng can thiet
trong qua trinh tuyen chgn benh nhan vao thu nghiem lam sang.
Sau khi chgn gia trj a va p, viec chgn phep toan thong ke phu thudc vao:
- Dae diem ciia sd lieu: cac bien djnh danh va thu bac can dugc kiem djnh bang cac
phep thong ke phi tham sd (non-parametric tests) nhu % hay Mann-Whitney U test trong
khi cac bien tham sd lien tuc tuan theo phan bd chuan cd the kiem djnh bang cac phep
thong ke tham so nhu Student t-test hay phan tich phuong sai ANOVA.
- Thiet ke nghien cuu: neu chi tieu danh gia dugc lap lai nhieu lan tren mot benh
nhan, cac mau nay dugc va dugc so sanh bang cac phep toan
Ngugc lai neu so sanh cac mau la cac
nhdm khac nhau trong thu nghiem thi su dung cac phep so sanh khdng cap (unpaired). Vi
du so sanh cap danh gia sir thay ddi ciia LDL-C 12 tuan sau dieu trj so vdi trudc dieu trj
simvastatin hay atorvastatin sir khac biet ve thay
ddi LDL-C d 2 nhdm benh nhan dugc dieu trj bang simvastatin va thi so
sanh khong cap. Cac phep thong ke nay phan tich ket qua theo hudng: hieu qua duong
tinh hoac am tinh so vdi nhdm chung. Vi vay, phep so sanh 2 dudi (two-tailed) thudng dugc
su dung vi xu hudng hieu qua tac ddng ciia thudc nghien cuu con chua dugc biet ro. Trong
72
mot so trudng hgp, khi tac dung ciia ro, de do ludng
chinh xac hon sir khac biet giua hai nhdm cd the sir dung phep so sanh 1 dudi (one-tailed)
nhu trudng hgp so sanh hieu qua ciia
hai thuoc nay trong cac nghien cuu da dugc chung minh cd tac dung ro ret so vdi placebo
va cac thuoc khac.
2.3. Phan tich cac chi tieu danh gia
Nhu da de cap d tren, cac chi tieu chinh va chi tieu phu ciia nghien cuu phai dugc xac
djnh ro rang trong de cuang trudc khi tien hanh thu nghiem lam sang. Khdng nen tim kiem cac
chi tieu danh gia khac khi xu ly ket qua khdng the hien dugc sir khac biet cd y nghTa thong ke
bdi vi tang so lugng chi tieu danh gia dong nghTa vdi tang nguy co mac sai lam type I.
Mot so phuong phap thong ke khac nhau cd the su dung de hieu chinh sd lugng cac
phep toan thong ke lam giam kha nang xuat hien sai lam loai I nhu hieu chinh Bonferroni
bang each chia muc y nghTa da lira chgn cho sd lugng bien sd dugc xu ly. Vi du, neu muc y
nghTa dugc lira chgn la 0,05 va cd 10 bien sd dugc dua vao tinh toan thi muc y nghTa hieu
chinh la 0,005. Tuy nhien, kha nang xuat hien sai lam p cung tang len khi sir dung hieu
chinh Bonferroni. Mdt each tiep can khac thay cho hieu chinh Bonferroni la su dung phan
tich phuong sai da bien (MANOVA).
. Tren thuc te, viec phan tich cac chi tieu danh gia thudng chi dugc bieu hien bang gia
trj p, vdi qui udc sir khac biet co y nghTa thong ke khi p < 0,05. Tuy nhien, gia trj p thudng
chi cung cap tin ve nguy co xuat hien sai lam loai I, cd nghTa la kha nang khdng cd sir
khac biet giua ma
khdng cung cap tin ve muc dd khac biet ciia hieu qua lam sang. Mdt thudc lam giam
2% nhjp tim cd the dat muc do khac biet cd y nghTa thong ke so vdi nhdm chung nhung sir
giam nay hoan toan khdng cd y nghTa lam sang. Dieu ma bac sT dieu trj quan tarn do la muc
do khac biet ve kha nang lam giam nhjp tim ciia thudc mdi so vdi thudc ddi chieu va trong
khoang nao thi muc do khac biet nay giua hai nhdm dam bao. Chinh vi vay, trong cac thu
nghiem lam sang hien nay, viec tinh toan khoang tin cay kem theo gia trj p dan dan dugc
thay the cho viec sir dung gia trj p don doc de bien giai ket qua (hinh 3.1).
2.4. Khoang tin cay
Khoang tin cay bieu dien khoang dao ddng trong do gia trj that (nhung khdng biet)
roi vao vdi xac suat da dugc djnh trudc. Thong thudng, cac nghien cuu thudng bieu dien
ket qua dudi dang khoang tin cay 95% (95% confidence interval, 95% CI). Khoang tin cay
nay se cung cap thong tin ve sir dao dong ciia chi tieu danh gia, khoang dao ddng cang rong
chung to do chinh xac kem. Nhu vay, khoang tin cay cung cap thong tin ve gia trj va xac
suat ciia chi tieu danh gia.
Mdt vi du ve khoang tin cay, ket qua tu thd nghiem lam sang so sanh hieu qua ciia
captopril vdi hydrochlorothiazid (HCTZ) ve kha nang giam huyet ap tarn truang cho thay
gia trj trung binh ciia giam huyet ap tarn truang so vdi trudc dieu trj ciia nhdm dung
captopril va nhdm dung HCTZ tuong ung la - 11,3 mmHg (95%CI: - 8,2 den - 14,4 mmHg)
va -9,9 mmHg (95% CI: - 7,5 den - 13,3 mmHg). Cac gia trj 95% CI nay khdng nhung cho
phep bien giai hieu qua giam huyet ap tarn truang ciia tung thudc ma con giup so sanh dugc
hieu qua ciia 2 thudc. Do cac khoang tin cay 95% ve do giam huyet ap tarn so vdi
thai diem trudc dieu trj ciia 2 thudc cd giao thoa vdi nhau nen cd the ket luan rang khdng
cd sir khac biet ve hieu qua giua hai thudc. Ket luan nay cung cd the tinh toan dua tren gia
73
trj 95%) CI ciia sir khac biet ve hieu qua giam huyet ap tarn truang giua 2 nhdm: trung binh
-1,4 mmHg (95%CI: - 3,9 mmHg den +1,1 mmHg). Do khoang tin cay nay chua gia trj 0
nen cd the ket luan khdng cd sir khac biet ve hieu qua giua 2 nhdm dieu trj bang captopril
va HCTZ (hinh 3.1, trudng hgp C).
n'A jC-
Khoang tin cay 95%
Hieu qua vu"dt trpi du"dc

P= 0,002 , |« \mmm "| chiing minh ro ho"n
HieuquavUdt troi
P= 0,05 L-mi _;J
dtfdc chiing minh
Hieu qua vu"dt troi khong
P=0,2 \mmJL dUdc chiing minh
I
•MMWHMHWHMI
Thuoc doi 0 Thuoc mdi tot hdn

chieu tot hdn
Khac biet ve hi£u qua gitfa hai nhdm
Hinh 3.1. Moi lien h£ giua ph6p so sanh khac bi£t vdi khoang tin c$y de danh gia giua thuoc
mdi va thuoc doi chieu
Ca 3 trudng hgp A, B va C deu cho thay thuoc mdi cd hieu qua hon thuoc doi chieu,
tuy nhien sir vugt troi chi dugc chung minh trong trung hgp A va B. Trong trudng hgp C,
hieu qua v.ugt troi khdng dugc chung minh, cd the do su khac biet qua nhd do do khdng
phat hien dugc. Trong trudng hop nay, phep so sanh tuong duong hoac khdng thua kem
giua thuoc mdi va thuoc doi chieu se phu hgp hon.
2.5. Y nghia cua ket qua khac bh|t khdng co y nghia thong ke
Ket qua khac biet khdng cd y nghTa thong ke (chap nhan gia thuyet HO, khdng cd sir
khac biet ve hieu qua giua 2 thuoc) cd y nghTa rat quan trgng. Dieu nay cd the dugc bien giai
rang khdng cd sir khac biet thuc su ve hieu qua giua thuoc mdi va thuoc so sanh hoac cd mau
qua nhd de cd the phat hien sir khac biet giua 2 nhdm. Liic nay can dua vao gia trj gidi han
tren ciia 95%CI (gia trj bieu thj lgi ich ldn nhat ma thuoc dem lai). Neu gia tri nay khdng d
muc tao ra lgi ich dugc chap nhan tren lam sang thi cd the ket luan la thuoc mdi hoan toan
cho ket qua am tinh. Trong trudng hop ngugc lai, khoang tin cay cd the bag gom lgi ich lam
sang va ggi y cho thiet ke thu nghiem lam sang tiep theo vdi cd mau ldn hon de chung minh
dugc sir khac biet giua hai nhdm dieu tri.
Trong trudng hgp thu nghiem lam sang dugc thiet ke theo kieu "khdng thua kem",
ket qua khdng khac ve hieu qua giua thuoc mdi va thuoc chieu cho phep lira chgn
thuoc mdi thay the cho thuoc doi chieu trong dieu trj neu thuoc nay cd doc tinh thap hon,
gia thanh re hon hoac tien lgi hon khi sir dung.
2.6. Y nghia thong ke va y nghTa lam sang
Sirkhac biet cd y nghTa ke khdng dong nghTa vdi viec ngoai suy y nghTa cua sir
khac biet nay trong thuc hanh lam sang. Vi du, thuoc ha huyet ap lam giam 5 mmHg
74
huyet ap tarn truong so vdi 2mmHg d nhdm dung placebo. Sir khac biet nhd nay cd y nghTa
thong ke (p = 0,04) cho phep bac bo gia thuyet HO de chung minh dugc hieu qua ha huyet
ap ciia thudc nhung hoan toan khdng cd y nghTa lam sang vdi mdt benh nhan cd huyet ap
tarn truang la 98 mmHg dugc giam ve muc 93 mmHg sau khi dieu trj bang thudc.
Cung can luu y rang khong phai bat cu thu nghiem lam sang nao vdi ket qua khac biet
khong cd y thong ke deu khdng cd y nghTa lam sang ma can tinh den hieu qua chung
ciia ciia
lanzoprazol (30 mg) vdi omeprazol (20 mg), mdi nhdm su dung lieu 1 trong 8 tuan
tren ty le lien seo trong viem thuc quan hoi luu cho thay ty le d 2 nhdm tuong ling la 87,2%
va 87% (sir thong ke giua sir khac biet ve
lam sang khdng quan sat dugc trong nghien cuu nay nhung ket qua van cd the dugc nhan djnh
la co y nghTa
Danh gia y nghTa lam sang con phu thuoc vao quan diem va ky vgng vao ket qua ciia
ngudi dgc nghien cuu. Bac sT, hang Dugc, co quan bao hiem y te va benh nhan cd each nhin
hoan toan khac nhau ve muc y nghTa lam sang ciia cac chi tieu phan tich trong thu nghiem.
Cach tiep can hay su dung nhat de bien giai ket qua ciia thu nghiem lam sang la tinh sd
benh nhan can dieu trj (numbers needed to treat, NNT) va hieu qua lam sang toi thieu
(Minimum clinical efficacy, MCE) se dugc de cap trong chuang 4.
3. IfCfC TINH CO MAU CHO THtT NGHIEM LAM SANG

Uac tinh cd mau la viec xac djnh so benh nhan can tuyen chgn vao thu nghiem lam
dam bao chat lugng va can dugc tinh toan trudc khi tien
hanh nghien cuu. Co mau phu thudc
- Sir khac biet ky vgng hoac udc tinh ve chi tieu danh gia chinh giua cac nhdm dieu
trj. Sir khac biet nay phai tao ra dugc sir khac biet cd y nghTa ve hieu qua lam sang.
- Dao dong ciia gia trj do ludng ciia chi tieu danh gia chinh (dua vao dd lech chuan
ciia gia trj nay). Gia trj nay cang dao ddng trong mdt khoang ldn cang can cd mau nhieu
hon cho nghien cuu.
- Muc y nghTa (a) va hieu lire ciia nghien cuu (1-p) lira chgn. Vdi muc y nghTa 0,05 va
hieu lure 80% thudng dugc chap nhan trong thu nghiem lam sang, cd the tinh toan dugc so
benh nhan can dugc tuyen chgn de dam bao miic y nghTa va hieu lire nay (bang 3.3).
Bang 3.3. So lugng benh nhan can thiet de dam bao muc y nghTa 5% va higu luc 80% ciia thu
nghiem lam sang
Khac biet vi hieu qua giua cac nhom dieu trj Sd lugng benh nhan can
tuyen chon
5% 2800
10% 720
15% 320
20% 180
40% 45
75
Trong thuc te thudng khdng biet ro hieu qua ciia thuoc mdi can danh gia trong thu
nghiem lam sang vi vay can su dung cac phuong phap thong ke khac nhau de udc tinh cd
mau can thiet cho cac loai bien so khac nhau. Tuy cd mau dugc tinh toan trudc khi tien
hanh nghien cuu nhung khdng tuyen dii so benh nhan can thiet ludn la van de ndi com mac
phai ciia nhieu thu nghiem lam sang. Tuy nhien, neu cac nghien cuu nay dugc thuc hien
diing phuong phap va ket qua ve cac chi tieu danh gia dugc bieu dien dudi dang 95%CI thi
chiing van cd gia trj trong phan tich gop (meta-analysis) cac thu nghiem lam sang da dugc
tien hanh vdi thuoc (xem chuong 4).
4. NOI KIEM VA NGOAI KIEM TRONG BAO DAM CHAT LlTONG CHO THLT
NGHIEM LAM SANG
Ndi kiem (internal validity) md ta muc do tra ldi cau hdi lam sang ban dau ma thu
da dat dugc. Trong cac thu nghiem lam sang phan nhdm ngau nhien cd kiem soat,
ndi kiem dugc dam bao do qua trinh phan nhdm ngau nhien benh nhan. Hudng dan
thuc hanh lam sang tot (Good clinical practice, GCP) ciia cac quoc gia, khuyen cao ciia Hdi
nghj Quoc te ve Hai hda (International for Harmonization, ICH) cung da de cap
cac nguyen tic djnh hudng dam bao chat lugng ciia thu nghiem lam sang. Mdt trong
nhung hudng dan dugc sir dung rong rai la hudng dan cua nhdm CONSORT (Consolidated
Standards of Reporting Trials), dugc xay dung vdi muc tieu chuan hda cac bao cao thu
nghiem lam sang nham nang cao chat lugng thiet ke va thuc hien cac nghien cuu nay, tang
cudng ap dung cac nguyen tac ciia Yhgc dua tren bang chung trong thuc hanh (chi tiet xem
muc 7). Tang cudng chat lugng ciia thu nghiem lam sang giup dam bao ndi kiem va la tien
de cho nggai kiem.
Ngoai kiem cho biet muc do cd the ap dung rong rai ket qua ciia thu nghiem lam sang
trong thuc hanh thudng qui. Ngoai kiem phu thuoc vao viec lira chgn cac don vj lam sang
tham gia vao nghien cuu. Thiet ke nghien cuu da trung tarn (multicentric design) vdi sir tham
gia cua nhieu nhom chuyen mdn khac nhau tu cac quoc gia trong viec danh gia hieu qua ciia
cung mot can thiep dieu trj cho phep lam tang ngoai kiem. Mdt so yeu to anh hudng den ngoai
kiem thu nghiem lam sang dugc trinh bay trong bang 3.4.
Bang 3.4. Mot so yeu to anh hudng den ngoai kiem thu nghiem lam sang
No-i tien hanh nghien cuu He thong y te va qui trinh chSm sdc benh nhan nai dien ra
nghien cuu.
Viec lua chgn cac dan vj tham gia nghien cuu c6 the lam tSng
ty le thanh cong ciia nghien cuu. __
Benh nhan dugc quan the
benh nhan chung (tuoi, gidi, muc do n§ng ciia benh, cac benh
Lira chon benh nhan va
mac kem, cac thuoc dung cac yeu to kinh te xa hoi).
dae diem benh nhan Lua chgn ca nhung benh nhan da tham gia giai doan dung thu
thuoc trudc khi phan nhdm ngau de tham dd muc dg
dung napva tuan thu tri (run-in-period).
Cac chi tieu danh gia khong cd y nghTa lam sang.
Cac chi tieu danh gia va
Cac chi tieu lam sang thudng khdng dugc danh gia trong thu
theo ddi cac chi tieu nay
nghiem nhung rat quan trgng trong thuc hanh.
76
Thdi gian dieu tri trong thu nghiem lam sang thudng qua ngln
trong khi cac dap ung ban dau vdi thuoc khong phan anh
dugc hieu qua lau dai ciia thuoc.
lech lua chgn benh nhan, viec dieu tri tai cac trung
tarn chuyen dieu kien theo doi chSt che benh nhan
Tac dung bit \<y\ thudng lam giam so lugng cac tac dung bat lgi ciia thuoc.
Rat it tac dung khong mong muon hiem g3p ciia thuoc dugc
7 &,Uh >•'
phat hien trong khuon kho thu nghiem lam sang.
5. THIET KE THLT NGHIEM LAM SANG

Thu nghiem lam sang la nghien cuu thuc nghiem, tien cuu trong do nghien cuu vien
kiem soat viec ap dung cac bien phap can thiep khac nhau (thuoc/phac do dieu trj hoac
placebo) tren hai hoac nhieu nhom benh nhan de danh gia hieu qua ciia cac can thiep nay
tren cac chi tieu lira chgn. Hon nua, benh nhan dugc phan bo vao cac nhdm trong thir
nghiem lam sang theo phan nhom ngau nhien do dd cho phep kiem soat dugc nhieu sai so
thudng gap trong cac nghien ciiu quan sat. Can luu y, do cac ly do dao due, thu nghiem lam
sang khdng giup tra ldi dugc tat ca cau hoi lam sang trong thuc te dieu trj. Cac dae diem
cua thu nghiem lam sang dugc torn tat trong bang 3.5.
Bang 3.5. D2c diem ciia thiet ke thu nghiem lam sang
Dae diem Md ta
Muc tieu Thiet lap moi quan he nhan qua giua can thiep (thuoc.phac do dieu tri) vdi cac
chi tieu danh gia
Chien luce Danh gia su khac biet tren chi tieu giua nh6m su dung thuoc nghien cuu vdi
nhom diing placebo hoac thuoc doi chieu
Phan nhom Phan nhombenh nhan su dung thuoc nghien cuu ho£c thuoc doi chieu theo
qui trinh ngau nhien
Lfu diem Phan nhom ngau nhien giup giam thieu sai so
Nhom doi chieu giiip loai tru anh hudng ciia bien thien tac dung theo thdi gian
Cho phep kiem soat tot viec luachgn benh nhan va thiet ke nghien cuu do
dugc thuc hien tien cuu
C6 the danh gia dong thdi nhieu can thigp, tren nhieu chi tieu khac nhau
C6 the thiet lap dugc moi quan he nhan qua giua viec su dung thuoc va hieu
qua/ do an toan
Tuan thii hudng dan CONSORT lam tang chat lugng ciia nghien cuu
Co the su dung phan tich gop de tong hgp cac ket qua khac nhau tu cac thu
nghiem lam sang khac nhau
Han che Khong su dung dugc de danh gia cac tac dung bat lgi ciia thuoc
Oattien, ton thdi gian va cong sue do do thudng c6 cd mau nho, tien hanh
trong thdi gian ngin, su dung cac chi tieu ggi ythay cho chi tieu lam sang
Benh nhan c6 the bo nghien cuu lam giam lgi ich ciia phan nh6m ngau nhien
Benh nhan trong nghien cuu da trung tarn c6 the khong tuang dong
Can can nhac den vai trd ciia cac hang Dugc pham la nha tai tra, ngudi muon
tan dung san pham dau ra ciia nghien cuu
77
Co 2 loai thu nghiem lam sang chinh. Thu nghiem lam sang vdi doi chung la placebo
(placebo controlled trial) nham phan biet hieu qua ciia thuoc vdi tac dung cua gia dugc de
tra ldi cau hoi lieu thuoc co hieu qua thuc su hay khong va cd nen sir dung thuoc de dieu trj
benh hay khong. Vi du simvastatin da dugc so sanh vdi placebo de xac djnh xem lieu thuoc
cd lam giam so trudng hgp tir vong d benh nhan cd tien su dau that nguc hoac nhoi mau co
tim. Tai thai diem thu nghiem lam sang nay dugc tien hanh, cac b?nh nhan nay chua dugc
sir dung mdt each thudng qui statin do dd cd the lira chgn nhdm doi chiing la placebo. Tuy
nhien, ket qua ciia thu nghiem nay du duong tinh cung chua cho phep xac djnh dugc vj tri
cua statin trong du phong thu cap d nhung benh nhan tren do chua tra ldi dugc cau hdi lieu
cac thuoc khac cd kha nang lam giam nguy co tren tot hon simvastatin hay khdng. Tren
thuc te, viec thiet ke nhdm doi chieu placebo cang trd nen khd khan do thieu su tu nguyen
sir dung placebo tir benh nhan tham gia nghien cuu. Loai thu nghiem lam sang thu hai lua
chgn nhom doi chung la thuoc doi chieu (active controlled trial), cho phep so sanh hieu qua
ciia thuoc/phac db dieu trj mdi vdi thuoc/phac do dieu trj chuan hien tai. Viec lira chgn
thuoc doi chieu phu hgp (dang bao che, lieu dung, vj tri trong phac do dieu trj) dong vai trd
quan trgng trong danh gia chat lugng ciia thu nghiem lam sang va tham djnh ket qua nghien
ciiu. Vi du trong thu nghiem COMET, carvedilol dugc chiing minh la cd hieu qua hon
metoproloi (dang giai phdng nhanh) trong viec giam ty le tir vong dbenh nhan suy tim. Tuy
nhien, ket qua cua mdt thu nghiem lam sang khac cho thay metoproloi (dang giai phong co
kiem soat) lai lam giam ty le tir vong d benh nhan suy tim tot hon placebo. Dieu nay dat ra
cau hdi lieu su vugt troi ciia carvedilol so vdi metoproloi trong nghien ciiu COMET cd con
dugc dam bao neu sudung thuoc doi chieu la metoproloi dang giai phdng cd kiem soat.
De giam thieu sai so, hai ky thuat chinh dugc ap dung trong thd nghiem lam sang la
phan nhdm.ngau nhien va lam mu. Phan nhdm ngau nhien (randomization) cho phep phan
b6 mdt each ngau nhien benh nhan vao cac nhdm dieu trj khac nhau do do cho phep tao ra
sir tuong dong ve cac yeu to tien lugng benh chinh (da biet hoac chua biet) giua cac nhom
nay. Cung vdi ky thuat lam mu, phan nhdm ngau nhien cd vai trd quan trgng trong viec loai
trucac sai so lira chgn va phan bo benh nhan trong nghien cuu, giam thieu sir khac biet giua
cac nhdm dieu trj de cho phep kk luan neu cd sir khac biet tren chi tieu danh gia thi nguyen
nhan duy nhat la sir khac biet ve thuoc/phac do dieu trj d m6i nhom tao nen. Co nhieu ky
thuat phan nhom ngau nhien khac nhau: phan nhdm don gian dua vao bang so ngau nhien,
phan nhdm theo block dam bao so lugng benh nhan tham gia dugc phan bo deu vao cac
nhom dieu trj), phan phoi theo block phan ldp (dam bao cac yeu to tien lugng quan trgng
hoac cac yeu to nguy co dugc phan bo deu giua cac nhdm dieu trj). Lam mu (blinding) giiip
han che dugc cac yeu to sai so do thien lech, sir tin tudng, che do cham sdc/theo ddi benh
nhan den ket qua nghien cuu, dae biet vdi cac nghien ciiu sir dung chi tieu danh gia chii
quan (nhu muc do dau, thang diem danh gia tram cam). Mdt mat, ky thuat nay giiip loai bd
anh hudng ciia sir lo lang hay hy vgng ciia benh nhan bang each cho benh nhan sir dung ca
thuoc nghien cuu va placebo (dummy) co hinh dang ben ngoai giong nhau de benh nhan
khong biet dugc minh sir dung thuoc gi (mu don). Mat khac, ky thuat nay con giiip loai bd
tac dong cua ngudi lam nghien ciiu (mu doi) va ngudi xu ly sd lieu (mu ba) neu nhung
ngudi nay cung khdng dugc biet ve phac do dieu trj. Nghien ciiu khdng lam mu dugc ggi la
nghien cuu nhan md (open-label). Tren thuc te, ky thuat mu ddi (double-blind) dugc coi la
78
ky thuat lam mu chuan muc va nen dugc ap dung cho tat ca cac thu nghiem lam sang.
Trong trudng hgp cd sir khac biet ve dang bao che hoac sd lan dua thuoc giua 2 nhom dieu
tri, can ap dung them ky thuat double-dummy cho benh nhan sir dung them dang bao che
tuong duong cd chua placebo de dam bao su tuong ddng giua hai nhom. Trong mdt sd
trudng hgp, vi ly do ky thuat (nhu phau thuat) hoac dao due (phac do dieu trj co nguy co
cao cho benh nhan) thi khong the sir dung ky thuat lam mu cho ngudi lam nghien cuu.
Ve mat ky thuat, co nhieu each thiet ke thir nghiem lam sang khac nhau.
Thiet ke nhom song song (parallel-groups): day la each thiet ke pho bien nhat trong
thu nghiem lam sang de khang dinh hieu qua ciia thuoc (pha 3). Benh nhan dugc phan
nhom ngau nhien vao cac nhom dieu trj bao gom thuoc nghien cuu sir dung d mdt hoac
nhieu miic lieu khac nhau song song vdi 1 hay nhieu nhdm ddi chieu (placebo, thuoc doi
chieu) (hinh 3.2). Cach thiet ke nay dae biet huu ich trong trudng hgp benh ly tien trien
trong thdi gian ngan (nhu dau nua dau, hoi chiing rugt kich thich) nhung cung dugc ap
dung trong mot so benh ly man tinh nhu Parkinson, ung thu. Uu diem ndi bat ciia thiet ke
nay la don gian, gan tuong tir nhu dieu kien sir dung thuoc trong thirc te va tranh dugc hieu
ung "carry-over".
Thiet ke cheo (cross over): trong thiet ke nay mdi benh nhan duoc phan nhom ngau
nhien vao cac nhom dieu trj sir dung thuoc nghien cuu hoac thuoc ddi chieu/placebo sau do
mot thdi gian dugc chuyen sang sir dung phac do dieu trj ciia nhdm con lai. Nhu vay, moi
benh nhan dugc sii dung ca thuoc nghien cuu va thudc ddi chieu hoac placebo va trd thanh
doi chiing cho chinh minh trong nghien cuu. Thiet ke nay loai tru dugc sir dao dgng giua
cac ca the do do giam dugc cd mau can thiet ciia nghien ciiu. Tuy nhien, han che ldn nhat
ciia thiet ke nay la hieu ung carry-over, nghTa la anh hudng ton du ciia can thiep trudc den
giai doan sau ciia nghien ciiu. De tranh hieu ling nay, giua hai lan chuyen doi can thiep can
cd mot khoang trong (wash-out period) trong do thai gian phu thudc vao benh ly va dae tinh
dugc dong hgc ciia thuoc nghien cuu. Thiet ke cheo phu hgp vdi cac benh man tinh nhu
tang huyet ap, dau that ngire on djnh vdi dae diem benh ly on djnh trong thdi gian tien hanh
nghien ciiu.
Thiet ke thua sd (factorial design) vdi 2 hoac nhieu thuoc/phac do dieu trj dugc danh
gia dong thai thong qua sir ket hgp khac nhau giua cac phac do dieu trj nay. Thiet ke thua
so don gian nhat sir dung bang 2x2 trong dd benh nhan dugc phan nhdm ngau nhien vao 1
trong 4 ket hgp ciia hai thuoc A va B: chi dung thuoc A, chi diing thuoc B, dung phoi hgp A
va B va khong diing ca A Ian B (placebo). Thiet ke thua so dugc ap dung chii yeu de sir
dung cd hieu qua mau benh nhan trong danh gia 2 thuoc/phac do dieu trj tren cung so lugng
benh nhan, tham dd tuong tac giua thuoc A va thuoc B dong thdi cho phep thiet lap moi
tuong quan lieu lugng-dap ung ciia phoi hgp thuoc A va thuoc B khi hieu qua ciia tung
thuoc rieng le da dugc chiing minh trudc do.
79
Bien co
Nhdm dieu tri udanh gia)

Khdng
:••""'
Quan the bien co
benh nhan dich

§3I!S [Ulilffc*- Bidn co
Nhdm ddi chieu

(thuoc/placebo)
udanh gia)
Khdng
;,. . ,
bien co
Hinh 3.2. Thiet ke thu nghiem lam sang vdi cac nhdm song song
Can luu y rang cd hai each chinh de phan tich du lieu cua thu nghiem lam sang. Cach
thu nhat la phan tich theo du djnh dieu trj (intention-to-treat, ITT) trong dd du lieu ciia tat
ca cac benh nhan dugc lira chgn vao nghien ciiu deu dugc dua vao phan tich ke ca trudng
hgp benh nhan khdng hoan thanh de cuang nghien cuu (tu rut khdi nghien ciiu, khdng tuan
thu phac do, tu vong...). Cach phan tich nay udc tinh chinh xac hon hieu qua ciia thuoc
nghien cuu tren quan the benh nhan chung trong do mot so benh nhan co the khdng tuan thu
diing qui trinh dieu trj. Ngugc lai, each phan tich thu hai, phan tich dua vao de cuang (per-
protocol, PP) chi phan tich nhung benh nhan da hoan thanh can thiep theo de cuang nghien
cuu. Phan tich nay cho phep danh gia chinh xac hieu qua va do an toan thuc ciia thudc
nghien cuu ma khdng bj lam nhieu bdi yeu to khong tuan thu de cuang ciia benh nhan. Mdt
vi du ve phan tich ITT va PP la thu nghiem West Scotland trial trong do phan tich ITT cho
thay pravastatin lam giam LDL-C 15,8% so vdi 26,3% vdi phan tich PP (tir gia trj ban dau
trudc dieu trj la 190 xuong tuong ung la 160 va 140 mg/dL). 6 nhdm dung placebo, gia trj
LDL-C khong thay doi nhu da du doan trudc dd. Ca ket qua phan tich ITT va PP trong
trudng hgp nay deu cd y nghTa ung dung trong thuc hanh cho thay pravastatin co kha nang
lam giam LDL-C 26% d nhung benh nhan tuan thu va sir dung diing lieu trinh dieu trj trong
khi do con so nay giam xuong 16% khi xet tong the nhdm benh nhan sir dung pravastatin.
Nhu vay can luu y rang ket qua thu dugc qua phan tich PP se bj pha loang bdi nhung benh
nhan khong tuan thu vi nhieu ly do khac nhau nhu tac dung khdng mong muon hoac dieu trj
khdng co hieu qua.
6. DANH GIA CHAT LlTONG PHl/ONG PHAP THlT NGHIEM LAM SANG
Chi nhung thu nghiem lam sang thiet ke diing phuong phap mdi cung cap nhung ket
luan cd y nghTa hieu qua ciia thuoc cd the ap dung vao thuc tien lam sang. Cach tiep can
pho bien nhat de danh gia chat lugng ciia thu nghiem lam sang la sir dung bang kiem
(checklist) ciia nhom xay dung chuan thong nhat trong bao cao thu nghiem lam sang
80
(CONSORT). Bang kiem nay sau khi ra ddi da dugc chap nhan bdi nhieu tap chi Y khoa cd
uy tin tren the gidi, gdp phan cai thien chat lugng thiet ke va bao cao thu nghiem lam sang.
Bang kiem cap nhat nam 2010 bao gom 25 muc lien quan den cac phan ciia mdt bai bao
(bao cao ket qua thu nghiem lam sang): tieu de, phan tdm tat, dat van de, phuong phap, ket
qua va ban luan (bang 3.6). Neu bai bao thieu cac thdng tin ciia cac muc dugc liet ke trong
bang kiem dong nghTa vdi cd cac sai so trong thu nghiem cd the anh hudng den ket qua
danh gia hieu qua/do an toan ciia thudc.
Bang 3.6. Bang kiem ciis nh6m CONSORT cho thu nghiem lam sang vdi thiet ke nhdm song
song (parallel-group randomized trials)
Phan ciia bai Muc Md ta

bao
Tieu d£ va torn 1a Tim kiem cgm tu "phan nhdm ngau nhien" (randomized trials)
tat trong tieu de
Tdm tat cd de cap den thiet ke nghien cuu, phuang phap, ket qua
1b
va ket luan
Dat van di
Ca sd nghien 2a Ca sd khoa hgc va giai thich tinh hgp ly ciia nghien cuu
cuu
2b Muc tieu eg the hoac gia thiet ciia nghien cuu
Phuong phap nghien cuu

Thiet ke nghien 3a Mo ta thiet ke nghien cuu (nhu thiet ke song song, thua so...), bao
cuu gom ca ty le phan bo benh nhan vao cac nh6m
3b
Cac thay doi ldn ve phuang phap sau khi thu nghiem da dugc tien
hanh (nhu tieu chuan lya chgn) va ly do thay doi
Benh nhan 4a Tieu chuan lya chgn benh nhan
4b Dan vi lam sang tham gia tuyen chon benh nhan va thu thap du
li$u
Can thiep 5 Can thiep (thuoc/phac do dieu tri) dugc thuc hien tren moi nh6m
benh nhan vdi thong tin chi tiet cho phep lap lai dugc thu nghiem,
bao gom ca thong tin ve each thuc va thdi diem cac can thiep
dugc thyc hi$n
Chi tieu danh 6a De cap day dii phuang phap do ludng cac chi tieu chinh va phu
gia bao gom ca each thuc va thdi diem do ludng cac chi tieu nay
6b
C6 thay doi gi ve chi tieu danh gia sau khi thu nghi&m da dugc tien
hanh, ly do thay doi
Cd mau 7a Cd miu dugc tinh toan nhu the nao
7b Neu cd tien hanh phan tich sa bd hoac dung nghien cuu thi can
giai thich
Phan nhdm 8a Phuang phap danh dau phan bo benh nhan vao cac nh6m
ngau nhien 8b Kieu phan bo ngau nhien bao gom ca thong tin chi tiet ve gidi hgn
phan nhdm nhu kh6i, phan Idp
Ky thuat che 9 Ky thuat su dgnq de phan bo ngau nhien benh nhan (bang so hoac
dau viec phan qua dien thoai tong dai), lam rd lieu viec danh dau phan bo nh6m
bo benh nhan c6 dugc giu bi mat cho den khi thuc hien can thiep tren benh nhan
DLS...T6 81
Then khai phan 10 Ai thuc hi£n vi$c danh dau phan nhdm ngau nhien, ai lua chgn
bo ngau nhien benh nhan, ai quyet dinh phan bo benh nhan vao cac nh6m can
thiep khac nhau
Lam mu 11a Neu ky thuat nay dugc thuc hien, nhung ai dugc lam mu sau khi
da thuc hien thiep tren b£nh nhan (nhu benh nhan, can b6 y
te, ngudi danh gia cac chi tien) va each thuc lam mu cho hg
Trong trudng hgp can thiet, mo ta muc do ddng giua cac can
11b thi^p
Phuang phap 12a Phuang phap thong ke su dgng de so sanh giua cac nh6m ve tieu
thong k£ chi chinh va cac tieu chi phu
12b
Cac phuang phap phan tich bo sung neu su dung phan tich dudi
nhdm hoac phan tich hi$u chinh
Kit qua
Sa do dien tien 13a So lugng b£nh nhan dugc phan bo ngau nhien, so benh nhan
benh. nhan (rat dugc su dung can thiep du kien, so benh nhan dugc dua vao de
nen c6) phan tich chi tieu danh gia chinh trong moi nh6m.
So benh nhan mat mat hoac bj loai tru sau khi phan nh6m nglu
13b nhien ciing vdi ly do.
Tuyen chgn 14a Thdi diem xac djnh giai doan tuyen chgn va theo ddi benh nhan
benh nhan 14b Ly do ket thuc hoac dung thu nghiem lam sang
DO lieu trudc 15 Bang trinh bay dae diem nhan khau hgc va lam .sang ciia cac
can thi$p nhdm trong thu nghifem lam sang
(baseline)
Sd b£nh nhan 16 Sd b£nh nhan dugc dua vao phan tich du lieu d moi nhdm (miu
dua vao phan so) va lieu vi6c phan tich cd dugc thuc hien theo phan tich ITT
tich du Ii0u
Cac chi tien 17a Vdi moi chi tieu chinh va phu, trinh bay ket qua d moi nh6m benh
danh gia va udc nhan, luc thong ke va do chinh xac ciia cac ket qua nay (vi du
lugng 95%CI)
17b
Vdi cac bien so nhj phan, can bieu dien ket qua tuang doi va tuyet
doi (vi dg 10/20, chu khdng chi neu ia 50%)
Phan tich phu 18 Ket qua cua cac ph6p phan tich khac bao gom phan tich dudi
trg nhdm va phan tich dugc hieu chinh, chi r6 phan tich nao la phan
tich da dugc dinh trudc, phan tich nao phat sinh trong qua trinh xu
ly ket qua
Nguy ca (bien 19 Tat ca cac bien co bat lgi hoac cac tac dung khong mong muon
co bat lgi) xuat hi£n d moi nh6m
Ban luan
Han che cua 20 Cac han che ciia nghien cuu: nguon goc ciia cac sai so hoac
nghien cuu khong chinh xac cd the mlc, nguy ca lien
82
phep phan tich va cac chi tien danh gia
Nhan rong ket 21 Kha nang nhan rgng, ap dung (ngoai kiem) cac ket qua cua nghien
qua cuu
Bien giai 22 Ban luan ve tinh thong nhat cua cac ket qua, ve can bang nguy
ca/lgi ich c6 can nhlc den cac chung hi£n c6 trong y van
Cac thong tin khac
Dang ky 23 So dang ky va ten thu nghiem lam sang
De cuang 24 Lieu c6 the xem chi tiet dugc de cuang nghien cuu
Tai trg 25 Nguon cung cap tai chinh va cac ho trg khac (nhu cung cap thuoc)
cho nghien cuu, vai trd ciia cac doi tac nay
Nguon: Schuiz KF, Atman DG, Moher D et al (2010), CONSORT 2010 statement: Updated
guidelines for reporting parallel group randomized trials, Ann. Intern. Med 152 (11), pp 1-7.
Tham khao them trang www.consort-statement.org
Ben canh bang kiem ciia nhdm CONSORT con cd mdt so nguon thdng tin khac cd
the tham khao de danh gia thiet ke, phuang phap ciia thu nghiem lam sang cung nhu kha
nang ap dung cac ket qua nay trong thuc hanh. Dau tien phai ke den cac bai xa luan ciia
Ban Bien tap (Editorial) xuat hien trong cung so bao va binh luan (Commentaries/letter to
the editor) ciia gidi chuyen mdn dugc dang tren cac so bao sau ciia tap chi da dang thir
nghiem lam sang. Mdt so trang web nhu Journal Watch (www.iwatch.org) hoac ACP
Journal Club (http://acpjc.acponline.org) dugc xay dung de cap nhat thdng tin tu cac thu
nghiem lam sang cap nhat trong y van, tdm tat va dua ra binh luan ve cac nghien cuu nay
bdi cac chuyen gia trong lTnh vuc lam sang tuong ung. Trang Medscape
(www.medscape.com) cung thudng cung cap tdm tat kem theo binh luan cac nghien cuu
mdi dugc cong cd cac chii de danh rieng cho dugc sT.
7. KET LUAN
Thu nghiem lam sang cung cap bang chiing tot nhat ve hieu qua va do an toan ciia
thudc do dd la nguon thdng tin quan trgng ve thuoc cho can bd y te trong qua trinh cham
soc benh nhan. Vdi thiet ke nghien cuu thuc nghiem, ngudi lam nghien cuu cd the kiem
soat dugc tac ddng ciia mdt can thiep de danh gia hieu qua ciia can thiep nay tren cac chi
tieu dugc lira chgn. Them vao dd, viec phan bd ngau nhien benh nhan giiip giam thieu mdt
so sai sd (quan trgng nhat la sai sd trong tuyen chgn benh nhan) dong thdi giiip can bang
cac yeu to tien lugng cd the anh hudng den hieu qua dieu tri cho cac nhdm benh nhan do do
lam giam tac ddng ciia cac yeu to nhieu. Nhung khuyen cao hien tai cung da giiip chuan hda
thiet ke va bao cao ket qua tir dd dam bao chat lugng ciia thu nghiem lam sang. Hieu dugc
nhung uu diem, han che trong phuang phap thiet ke va bien giai dugc cac ket qua tu thu
nghiem lam sang la ky nang quan trgng ciia dugc sT trong thuc hanh tu van su dung thuoc.
CAU HOI Ll/ONG GIA
Tinh huong: mdt thu nghiem lam sang phan nhdm ngau nhien cd kiem soat dugc thiet ke
de danh gia hieu qua ciia rosuvastatin trong du phdng nguyen phat lam giam cac bien co
83
tim mach bat lgi chinh d nhdm benh nhan cd LDL-C < 130 mg/dl. Tieu chi danh gia chinh
la tieu chi tong hgp bao gom sir xuat hien bien cd tim mach nghiem trgng (nhoi mau co tim
khdng gay tu vong, dot qui khdng gay tu vong, dau that nguc khdng on dinh phai nhap vien
de dieu trj, can thiep tai tudi mau mach vanh hoac tu vong do nguyen nhan benh tim mach).
Lira chgn dap an phu hgp nhat trong sd cac dap an dua ra:
1. Ly do chinh de lira chgn thu nghiem lam sang cd kiem soat la thiet ke nghien cuu trong
trudng hgp nay la:
A. Thu nghiem lam sang cd kiem soat la thiet ke phu hgp nhat de xac dinh mdi quan
he nhan qua va do ludng sir khac biet giua nhdm can thiep va nhdm chung.
B. Thu nghiem lam sang cd kiem soat dugc tien hanh hdi cuu, nhin lai nhung gi xay ra
trong qua khu de xac djnh mdi quan he nhan qua.
C. Thu nghiem lam sang cd kiem soat la each duy nhat de do ludng mdi quan he nhan
qua.
D. Thu nghiem lam sang cd kiem soat cho phep phan nhdm ngau nhien benh nh&n lam
tang hieu lire thdng ke ciia nghien cuu.
E. Thu nghiem lam sang cd kiem soat cho phep danh gia nhieu chi tieu cung liic qua
trinh thuc hien.
2. Trong thu nghiem nay, ca nghien cuu vien va benh nhan deu khdng biet lieu phap dieu
trj dang sir dung. Ky thuat lam mu su dung d day la:
- A. Khdng mu
B. Mu don
C. Mudoi
D. Muba
E. Mil khi danh gia tieu chi
3. Cac benh nhan trong thu nghiem dugc phan nhdm ngau nhien su dung rosuvastatin 20
mg mdt lan/ngay hoac dung placebo. Diem nao sau day la dae diem ciia phan nhom
ngau nhien:
A. Cd mat trong tat ca cac loai nghien cuu.
B. Cho phep m6i benh nhan cd xac su&t giong nhau dugc phan vao nhdm thu hoac
nhdm chung.
C. La ky thuat phu hop lam tang kha nang xuat hien sai sd lira chgn.
D. Dam bao rang hieu qua dieu trj khdng chiu anh hudng ciia cac yeu to nhieu.
HO ciia nghien ciiu:
A. Cd sir khac biet ve tan suat tieu chi tong hgp giua nhdm dung rosuvastatin va nhdm
chung.
B. Tieu chi tong hgp ve hieu qua va do an toan la khac nhau giua nhdm dung
rosuvastatin va nhdm chung.
C. Rosuvastatin lam giam nguy co danh gia tren tieu chi tong hop so vdi nhdm chung.
D. Khdng cd sir khac biet ve tan suat tieu chi tong hgp giua nhom dung rosuvastatin va
nhom chung.
84
E. Khdng cd sir khac biet tren tieu chi tong hgp ve hieu qua va do an toan la khac nhau
giua nhdm dung
5. Du
A. Djnh danh
. Rai rac
C. Lien tuc
D. Rdi rac cd thu bac
6. Tieu chi nao sau day sir dung trong nghien cuu dugc xep vao tieu chi ggi y:
A. Dau that nguc khdng on dinh
B. Xuat hien lan dau tien bien cd tim mach
C. Tu vong do benh tim mach
D. Nhoi mau co tim '
E. Nong do LDL-C
7. Tan suat ciia tieu chi danh gia chinh d nhdm rosuvastatin va d nhdm dung placebo
tuong ung la 1,9% va 2,8%. Thdng sd nao va each bien giai kem theo ve moi quan he
nhan qua la phu hgp:
A. Nguy co tuong doi RR = 0,56 cho thay ty le nguy co nen dugc giam di khi dieu trj
bang rosuvastatin.
B. ARR ~ 1,2% cd nghTa la 1,2% so benh nhan dugc dieu trj bang rosuvastatin se tranh
dugc bien co tim mach (theo tieu chi danh gia chinh) so vdi nhdm chung.
C. NNT = 8,3 nghTa la can dieu trj tren 8,3 benh nhan trong vdng 1 nam de du phdng
1 trudng hgp xuat hien bien cd tim mach.
D. RRR * 44% phan anh so lugng nguy co da dugc" giam bdt vdi rosuvastatin so vdi
nhom chung.
E. Khdng the do ludng moi quan he nhan qua dua tren kieu sd lieu ciia tieu chi danh
gia chinh.
8. Phat bieu nao phu hgp nhat lien quan den lieu cd sir khac bi£t lam sang giua nhdm dung
rosuvastatin va nhdm dung placebo (tieu chi danh gia chinh: 1,6% so vdi 2,8%, RR =
0,56, khoang tin cay 95% dao dong tir 0,46 den 0,69, p < 0,00001).
A. Cd sir khac biet lam sang do gia trj p va RR tinh toan dugc.
B. Khdng cd sir khac biet lam sang do nghien cuu khdng dii hieu lire phu hgp de phat
hien su khac biet giua nhom thu va nhdm chiing.
C. Khdng cd sir khac biet lam sang do ket qua khong khac biet cd y nghTa thong ke.
D. Co sir khac biet lam sang do sir khac biet dat muc cd y nghTa thong ke.
E. Khdng xac djnh dugc sir khac biet lam sang dua tren cac thdng tin tu nghien cuu
nay.
9. Phan tich dudi nhdm cho thay benh nhan dudi 65 tuoi, cd tang huyet ap va dang hut
thuoc cd sir giam ro ret bien co tim mach (tinh theo tieu chi chinh) khi dung
rosuvastatin. Phat bieu nao sau day phu hgp nhat de bien giai ket qua phan tich dudi
nhom nay:
A. Tat ca cac benh nhan dudi 65 tuoi, cd tang huyet ap va dang hut thuoc nen dugc
dieu trj bang rosuvastatin de du phdng nguyen phat.
B. Phan tich dudi nhdm giiip khac phuc han che ciia thu nghiem lam sang va la each
de danh gia hieu qua cua thudc tren mdt so nhdm benh nhan dae biet.
C. Phan tich dudi nhdm lam tang hieu lire ciia nghien cuu.
D. Xac suatde cd dugc sirkhac biet cd y nghTa thong ke giam khi phan tich dudi nhdm
do tang sd lan phan tich.
E. Can bien giai ket qua nay mdt each than trgng do phan tich nay cd the khdng du
hieu lire de phat hien sir khac biet giua nhdm thu va nhdm chiing.
TAI LIEU THAM KHAO
1. Bo Y Te (2010), Hudng dan thie nghiem tren lam sang, NXB Y hgc.
2. Nguyen Thanh Liem (2011), Phuang phap thiet ke cdc nghien cuu lam sang (tai lieu
djch), NXB Y hgc.
3. Nguyen Van Tuan (2008), Yhoc thuc chung (Evidence-based Medicine), NXB Y hgc
4. Bouvenot G and Vray M (2006), Essais cliniques: Theorie, pratique et critique,
Mesdecine-Sciences/Flammarion, 4e edition.
5. Gaebelein CJ, Gleason BL (2008), Contemporary drug information: an evidence-based
. approach, Lippincott Williams & Wilkins.
6. Guyatt G, Rennie D, Meade MO and Cook DJ (editors) (2008), Users' guides to the
medical literature: A manual for evidence-based clinical practice, Me Graw Hill
Medical/ JAMAevidence, 2nd edition.
7. Machin D and Campbell MJ (2005), Design of studiesfor medical research, John Wiley
& Sons 2005.
8. Maloine PM, Kier KL, Stanovich JE (2006), Drug information: a guide for pharmacists,
McGraw-Hill, 3rd edition.
9. Matthews JN (2006), Introduction to Randomized Controlled Clinical Trials, Chapman
nd
& Hall/CRC, 2na edition.
? '' »;,
86
CHUONG 4. ITNG DUNG Y HOC DlfA TREN BANG
CHlTNG TRONG THUG HANH SU* DUNG THUOC
Nguyen Hoang Anh, Nguyen Dang Hda, Brouwers JRBJ

MUC TIEU
Trinh bay dugc khdi ni?m EBM vasirdying thuoc duatren bdng chieng.
Li?t kedugc 4 budc vgn dung EBMtrong thu-c hanh sirdung thuoc.
Tinh dugc cdc thdng sd tie ketqua thie nghiem lam sang: ARR, ARI, NNTvd NNH.
Trinh bay dugc cdc yeu to thudc ve b^nh nhdn can can nhdc khi dp dung chieng cie trong y
van de gidi quyet tinh huong lam sang.
MO DAU
Khai niem thuc hanh dua tren bang chung (hay y hgc dua tren bang chung, Evidence-
based medicine, EBM) da co tac ddng rat ldn den nhieu lTnh cham sdc khde khac
nhau. khoa
hgc dong
nghiep. Canada) da
dieu trj. Cac
khai niem nay hoan toan cd the ap dung trong cac giai doan qua trinh su dung thuoc ciia
dugc thay doi
nhanh sang
phai
qua trong thuc
vai dung
EBM cap nhat
thdng mang
tinh bao cao ca) cung
nhu loai hinh nghien cuu can thiep (thu nghiem lam sang), cac lieu chinh dugc su
dung chuang 8 "Djch te dugc hgc" va chuong 3
"Phuang
1. DUNG
THUOC
EBM la each tiep can trong thuc hanh y khoa su dung cac ket qua tu cac nghien cuu
lien quan den qua trinh cham sdc benh nhan va cac bang chung
la mdt sang. Hieu theo each tuong tu, sir dung thuoc
dua tren bang chung (evidenced-based pharmacotherapy) la each tiep can de dua ra quyet
djnh khi dugc sT lam chiing khoa hgc va do ciia cac bangchiing nay
ho trg cho qua trinh sir dung thudc tren benh nhan (Etminan 1998).
Nguyen tac dua quyet djnh lam sang dua tren cac chung cu tot nhat da dugc chap
nhan rong rai tuy nhien van con nhieu ban khoan lien quan den thuc hanh EBM. Ban khoan
87
thie nhdt e ngai viec ap dung EBM theo edng thuc trong thuc hanh se gay can trd khi ma
khdng phai tu
cac chung cu khoa hgc. Tren thuc te, EBM tac ddng len quyet djnh lam sang thdng qua tich
hgp kien thuc tu nghien cuu nhung EBM khdng the thay the dugc kinh nghiem lam sang.
Kinh nghiem ciia can bd y te ddng vai trd then chot trong viec quyet djnh lieu cac chung cu
cd the ap dung tren benh canh lam sang cu the benh nhan va lieu cac chung cu nay cd the
dugc tich hgp trong ke hoach dieu trj cho benh nhan dugc khdng. Ban khoan thu hai lien
quan den viec su dung thu nghiem lam sang phan nhdm ngau nhien cd kiem soat
(Randomized controlled trials, RCT, xem chuang 3) la nguon chung cu duy nhat trong
tot nhat hien cd tu nghien cuu
co ban den nghien cuu lam sang de lam co sd cho viec dua ra quyet djnh lam sang. Tu quan
dd chinh xac ciia mdt
tu nghien cuu cat ngang hay de tra ldi cau hdi lien quan den tien lugng ciia benh nhan cd
the su dung ket qua tu nghien cuu thuan tap thay cho mdt thu nghiem lam sang (xem them
chuang 8). Tuy nhien, thiet ke chat che ciia thu nghiem lam sang cho phep udc lugng chinh
xac nhat hieu qua va do an toan khi lira chgn thudc hay phac do dieu trj (xem them chuong
3). Ban khoan thu ba ghi nhan han che ciia thu nghiem lam sang dugc tien hanh trong dieu
kien kiem soat chat che "ly tudng" nen khdng phan anh dugc cac tinh hudng thuc te da
dang trong thuc hanh. Them vao do, viec ngoai suy ket qua ciia thu nghiem lam sang tren 1
thuoc cho cac thuoc trong cung nhdm cd the dan den sai lam. Nhung han che nay khdng the
phu nhan dugc vai trd ciia thu ciia thuoc trong
cac phac dd dieu trj. Trong nhung nam 1970, chi dua tren cac nghien cuu quan sat ve mdi
lien quan giua xuat hien co that that sdm (premature ventricular contractions, PVCs) d benh
nhan sau nhoi mau co tim vdi kha nang dot tu ciia benh nhan, khuyen cao su dung thudc
chong loan nhjp de loai tru PVCs va giam nguy co dot tu cho benh nhan da dugc ap dung
Principles of Internal 8th edition). Tuy ket qua tu thu nghiem
do tren benh nhan cd PVCs cho thay viec sir dung thudc chong loan nhjp lai
lam tang ty le tu vong (Echt DS et al. NEJM 1991, 324, 781-788). Vi vay, cac hudng dan
dieu trj hien nay deu khdng khuyen cao su dung thudc chong loan nhjp de loai bd PVCs cho
benh nhan sau nhoi mau co tim (ACC/AHA guidelines. J Am Coll Cardiol 1999, 34, 890-
911). Mdt vi du gan day lien quan den hudng dan xu tri nhoi mau co tim nam 1996 cd
khuyen cao "lieu phap dieu trj estrogen lam giam ty le tu vong d phu ntr cd benh mach vanh
miic do trung binh va nang" dua tren ket qua ciia nghien cuu quan sat trudc do (ACC/AHA
guidelines. J Am Coll Cardiol 1996, 28, 1328-1348). Ket qua tir thu nghiem lam sang sau
do lai khdng tim thay bat cu lgi ich nao trong viec giam nguy co chung ciia nhoi mau ca
tim va nguy co dot tu khi su dung lieu phap estrogen, ngugc lai ty le xuat hien cac bien cd
mach vanh lai cao hon trong nam dau tien d nhdm phu nu diing estrogen so vdi nhdm
chung dung placebo (JAMA 1998, 280, 605-613). Sau ket qua nay, khuyen cao dieu trj da
dugc sua ddi: "dua tren cac bang chung hien cd ve khdng cd lgi ich tren tim mach, ngugc
lai lai cd kha nang lam gia tang sdm xuat hien cac bien cd tim mach nen lieu phap su dung
estrogen phoi hop vdi progesteron khdng dugc khuyen cao de du phdng thu phat benh
mach vanh" (ACC/AHA guidelines. J Am Coll Cardiol 1999, 34, 890-911). Nhu vay, neu
chi dua vao ket qua tu dan den sai lam trong thuc
hanh ma can dua tren cac ket qua tu thu nghiem lam sang thiet ke diing phuang phap de
dua ra ket luan ve hieu qua va do an toan ciia thudc hay phac do dieu trj.
Thdng tin them ve EBM (ljch su va phat trien ciia EBM, cac thuat ngu sir dung trong EBM,
hudng dan, chuong trinh dao tao ve EBM, cac phan mem, cac dudng dan ket ndi den dja chi truy
cap tdi cac nguon co du lieu EBM, hudng dan tim kiem y van ve thudc va torn tat ket qua cac
nghien cuu dua tren bangchiing) dugc md ta chi tiet tren mdt sd trangweb tren Internet. Ngudi dgc
cd the truy cap vao dja chi trangweb ciiathu vien Y khoa trudng Dai hgc Darthmouth, Hoa ky de
cd them cac thong tin tren
(nttp://www.dartmouth.edu/~biomed/resources.htmld/guides/ebm_resources.shtml#ebm info).
2. VAN DUNG Y HOC DlTA TREN BANG CHlTNG TRONG THlTC HANH SU*
DUNG THUOC
Thuc hanh EBM la qua trinh nhan dien thong tin can thiet trong qua trinh cham soc
benh nhan, tim kiem cac chiing cu tot nhat hien co giiip giai quyet van de, can nhac chung
cu trong boi canh lam sang cu the tren benh nhan va tich hgp cac chung cu nay de xay dung
ke hoach dieu trj. Bon budc ciia EBM ap dung trong thuc hanh sir dung thudc bao gom:
- Nhan dien thdng tin can thiet va chuyen cac thdng tin nay thanh dang cac cau hdi.
- Tien hanh tim kiem hieu qua cac chung cu tot nhat de tra ldi cau hdi dat ra.
- Phan tich cac chiing cu thu thap dugc dua tren tinh hgp ly va huu ich ciia thdng tin.
- Ap dung ket qua phan tich vao tinh huong cu the ciia benh nhan de hd trg tot nhat
cac quyet djnh lam sang.
2.1. Xay dung cau hoi
Thuc te lam sang ddi hdi can nhac thudng xuyen nguy co - lgi ich ciia cac thuoc/phac dd
dieu trj khac nhau. Cac cau hdi tu thuc te lam sang thudng lien quan true tiep den benh nhan:
Lieu cd nen ke don clopidogrel cho mdt benh nhan nam 65 tuoi cd dau that nguc
khdng on djnh?
Lieu cd pen su dung lieu phap thay the hormon cho mot phu nu sau man kinh?
Sidenafil cd an toan cho benh nhan dai dudng type II hay khdng?
Do do, khi tim kiem cac chung cu de tra ldi, cac cau hdi tir thuc te lam sang can dugc
sap xep lai cho chinh xac va dae hieu hon. Cau true ciia mot cau hdi tot bao gom cac ndi
dung: benh nhan hoac van de can giai quyet, can thiep (thuoc/phac do dieu trj) dang can
nhac, cac can thiep khac de ddi chieu, so sanh can nhac lira chgn va tieu chi danh gia
(outcome) can quan tarn. Cau true nay phan anh 4 yeu to dugc md ta trong nguyen tac
PICO: benh nhan (Patient, P), can thiep (Intervention, I), nhom ddi chieu (Comparison, C)
va tieu chi danh gia (Outcome, O). Ap dung nguyen tac nay vdi cac vi du tren, cac cau hdi
co the dugc cau true nhu sau:
Lieu bd sung clopidogrel vao phac do chong ket tap tieu cau su dung aspirin (can
thiep) cd giiip giam ty le tu vong hoac du phdng cac bien cd mach vanh (tieu chi danh
gia cd y nghTa lam sang) cho benh nhan dau that nguc khdng on djnh (benh nhan va
van de can giai quyet) dang sir dung aspirin don ddc (can thiep ddi chieu) khong?
Cd nen bat dau su dung lieu phap thay the hormon (can thiep so sanh vdi khong can
thiep) de du phdng cac bien co tim mach (tieu chi danh gia) cho phu nu sau man
kinh khong cd bieu hien trieu chung cd tien su gia dinh mac benh mach vanh (benh
nhan) hay khdng?
•-nit: .j-v. :;•;>!?.} ;yji -.. !s-:1 r ,
89
Cac cau hdi cd cau true chat che se giiip lam ro muc tieu tim kiem thdng tin trong y
van dong thai giiip dam bao tinh ngoai kiem ciia viec van dung EBM trong thuc hanh su
dung thuoc la ap dung cac chung cu tim dugc trong nghien cuu de giai quyet mdt phan cac
van de trong thuc te lam sang.
2.2. Tim kiem chirng cu* tir y van
Dugc sT lam sang cd 4 each lira chgn khac nhau de tim kiem cac chung cu trong y
van tra ldi cho cau hdi da dugc xay dung trong budc 1. Mdi lira chgn deu cd cac uu diem va
han che rieng.
Hdi thdng tin tir ddng nghiep, xin y kien chuyen gia:
Day la hinh thuc cung cap cau tra ldi nhanh nhat va de dang nhat cho cac cau hdi lam
sang. Tuy nhien, nen than trgng do kien thuc y hgc thay ddi rat nhanh dan den cau tra ldi
khong con dugc cap nhat va phu thudc nhieu vao kinh nghiem chuyen mdn ciia ngudi tra ldi.
Tham khao thdng tin tie cdc hudng dan dieu tri (hudng dan dieu tri xay dung
dua tren bhng chung hay dua tren kinh nghiem cua chuyen gia) hoac cdc sach
tra ciiu chan doan vd dieu try.
Cd the su dung cac hudng dan dieu trj d cac trang tra cuu true tuyen (nhu UptoDate:
www.uptodate.com: National Guidelines Clearinghouse ciia Hoa ky: www.guideline.gov:
National Institute for Health and Clinical Exellence ciia Anh: www.nice.org.uk:
Therapeutic Guidelines, e-TG ciia Australia: www.tg.org.au, hoac trang Guidelines
International Network http://www.g-i-n.net/ tap hgp cac hudng dan dieu trj ciia nhieu quoc
gia tren the gidi), cac hudng dan ciia cac Hdi chuyen mdn (nhu hudng dan ciia Trudng mdn
tim mach Hoa ky/Hdi Tim mach Hoa ky, AHA/ACA cho chan doan va dieu trj cac benh
tim mach) hay cac sach cap nhat ve chan doan va dieu trj nhu Nguyen ly Noi Khoa
Harrisson: Harrisson's Principles of Internal Medicine (Nha xuat ban McGrawHill) hay
Current Medical Diagnosis and Treatment (Nha xuat ban McGrawHill/Lange) dugc cap
nhat djnh ky.
Tham khao thdng tin tie cdc nguon die lieu dien tu luu tru thdng tin tie cdc tong
quan he thong (systematic review) vd phan tich gop (meta-analysis):
Hudng tiep can nay cho phep can bd y te trong thai gian ngan cd the tim kiem va
tong quan y van de tra ldi cau hdi lam sang hoac dua ra quyet djnh lam sang tren benh
nhan. Cac bai bao tong quan y van kinh dien (narrative review) thudng giiip viec cung cap
thdng tin chung ve chan doan, dieu trj mot benh ly hay cap nhat cac thanh tuu trong mdt
lTnh vuc y khoa cu the. Tuy nhien, cac thdng tin nay thudng dugc viet theo mot ket cau da
djnh sin ciia tac gia do do cd the cd nhung sai so trong qua trinh thu thap, phan tich va tong
hgp thdng tin. Ngugc lai, tong quan he thong sir dung each tim thdng tin va lira chgn thdng
tin mang tinh toan dien va lap lai cao de tong ket tat ca cac chung cu tot nhat ve mdt van
de. Hon nua, viec tuan thu mdt qui trinh nghiem ngat trong danh gia va phan tich thdng tin
tu cac nguon chung cu trong y van mang tinh djnh lugng (thong qua phan tich gop) hoac
mang tinh dinh tinh cho phep dua ra cau tra ldi tot nhatcho cau hdi lam sang. Tong quan he
thong cung kiem chung tinh thong nhat ciia ket qua tu cac nhieu nghien cuu (chii yeu la thu
nghiem lam sang) khac nhau va lieu co the khai quat, nhan rong cac ket qua nay de ap dung
vao thuc te dieu trj hay khdng. Mdt trong nhung nguon co sd du lieu phong phu nhat ve
tong quan he thong la thu vien Cochrane (http://www.cochrane.org) chua han 5000 tong
quan ve cac lTnh vuc y khoa khac nhau trong dd chii yeu tap trung vao lTnh vuc dieu trj. Ben
90
canh do, cd the tim kiem cac tong quan he thong va phan tich gop tu thu vien Y khoa Hoa
ky (PubMed/Medline, http://ncbi.nml.nih.govi su dung cac tu khoa tim kiem va gidi han
tim kiem cac tai lieu lien quan den Meta-Analysis va Systematic Reviews. Ngoai ra, trang
web ciia Trung tarn Tong hgp va Truyen tai Thdng tin (Centre for Reviews and
Disseminations, CRD) ciia Bd Y te Anh dat tai Dai hgc York (http://www.crd.vork.ac.uki
cung thudng xuyen cap nhat tdm tat cac tong quan he thong va phan tich gop lien quan den
hieu qua dieu trj. Trung tarn Lam sang (National Institute for Clinical Exellence, NICE)
thuoc Bo Y te Anh vdi phuang phap tuong tu thu vien Cochrane cung danh-gia va cong bo
cac hudng dan va ket qua danh gia ciia minh tren dja chi website ciia Trung tarn
(http://nice.org.uki.
Tien hanh tim kiem thong tin tren cdc ca sd die lieu tra cuu true tuyen nhu
PubMed/Medline:
Nen can nhac tim kiem thdng tin trong y van tren cac co sd du lieu tra cuu dien tu
nhu PubMed/Medline khi cau hdi lam sang lien quan den cac thuoc mdi, cac phuang phap
dieu trj mdi. Trong trudng hgp nay, ngudi tim kiem thdng tin nen tiep can den cac nguon
thdng tin so cap la cac bai bao nghien cuu goc. Cho tdi thai diem hien tai, thu vien
PubMed/Medline la thu vien dien tu ldn nhat tap hgp va luu tru cac thdng tin ve cac bai
bao dugc edng bo trong cac tap chi Y Sinh hgc. De ho trg tim kiem thdng tin mdt each hieu
qua, PubMed/Medline da xay dung cac bd lgc (filters) khac nhau giiip tim kiem cac nghien
cuu lien quan de tra ldi cac cau hdi lam sang ve benh nguyen, chan doan, tien lugng hay
dieu trj benh. Mdt sd trang web tim kiem gop (metasearch engines) da dugc xay dung cho
phep tim kiem thdng tin lien quan den 1 cau hoi lam sang tren nhieu trang web y khoa khac
nhau nhu TRIP (Turning Research Into Practice, http://www.tripdatabase.comi.
Sumsearch2 ciia Dai hgc Kansas (http://sumsearch.orgi hay Query Server
(http://queryserver.dataware.com/health.htmi.
Sau khi tap hgp dugc cac chung cu tir y van, dugc sT lam sang can xac djnh lieu cac
khuyen cao dieu trj, cac bai bao tong quan hay cac bai nghien cuu da tim kiem dugc cd
giiip cho tra ldi cau hdi lam sang dat ra d budc 1 hay khdng thdng qua danh gia thdng tin
trong y van tim kiem dugc cung nhu y nghTa lam sang (tinh huu ich trong tra ldi tinh huong
lam sang) ciia thdng tin tir tai lieu.
2.3. Phan tich danh gia cac chirng cu thu thap dugc tir y van
Phan tich va danh gia cac chirng cu thu thap dugc tu y van bao g6m ngoai kiem
(external validity) va ndi kiem (internal validity).
2.3.1. Danh gid chat luang cua chieng ciethu thap tiey van
Noi kiem danh gia chat lugng ciia nghien cuu, cho phep kiem tra xem nghien ciin cd
dugc thiet ke diing phuang phap de can bang cac yeu to nhieu cd the anh hudng den ket qua
giua nhdm dung thuoc va nhdm doi chieu. De dam bao dugc dieu nay, qua trinh thiet ke thu
nghiem phai giam thieu toi da cac sai so he thong va cac sai so ngau nhien lien quan den can
thiep y khoa. Cac sai so nay cd the dan den danh gia thap hoac danh gia qua muc hieu qua
dieu trj ciia thuoc, lam bien giai sai ketqua thuc ciia nghien cuu. Ngudi dgc cd the tham khao
them ky nang phan tich y van qua chum bai bao hudng dan ciia tap chi BMJ (BMJ Publishing
Group, How to read a paper: http://www.bmi.com/about-bmi/resources-
readers/publications/how-read-paperi. hudng dan dang trong chum bai bao ciia tap chi JAMA
91
(Users' Guide to Evidence-Based Medicine: http://www.iamaevidence.com). Cac diem chinh
can can nhac khi danh gia thdng tin tu cac loai hinh y van khac nhau theo hudng dan ciia
nhdm chuyen mdn ve Y hgc bang chiing ciia Dai hgc McMaster (Canada) dang tren tap chi
JAMA dugc tong ket trong bang 1. Vdi loai hinh nghien ciin dae thu va quan trgng nhat trong
y van ve thuoc la thu nghiem lam sang, khi danh gia chat lugng ciia thu nghiem can tra ldi it
nhat 3 cau hdi sau:
Viec diiu tri cho benh nhdn trong nghien cieu cd duac phdn nhdm ngdu nhien
khdng?
De giam thieu sai so lira chgn, tat ca cac benh nhan tham gia thu nghiem can cd xac
suat giong nhau dugc phan bo vao nhdm dung thuoc/phac do dieu trj nghien cuu hay nhdm
chung. Phan nhdm ngau nhien la bien phap tot nhat dam bao phan bo deu cac sai so da biet
hoac chua biet vao cac nhdm benh nhan ciia thu nghiem. Neu cac yeu to nhieu quan trgng
anh hudng den tien lugng ciia bfnh nhan (nhu muc do nang ciia benh, sir cd mat ciia cac
benh mac kem) neu khdng dugc phan bo ngau nhien deu vao cac nhdm dieu trj se dan tdi
udc lugng khdng chinh xac lgi ich ciia thuoc/phac do dieu tri. Hon nua, nghien cuu vien
tuyen chgn benh nhan vao nghien cuu khdng nen dugc biet doi tugng nao (nhdm thu hay
nhdm doi chieu) se dugc tuyen chgn tiep theo vi neu hg biet dugc dieu nay se khdng tranh
khdi xu hudng lira chgn benh nhan khde hon vao nhdm thu hoac ngugc lai. Mdt so phuong
phap phan nhdm ngau nhien nhu bat tham ngau nhien thdng qua 1 don vj trung tarn khdng
cd thdng tin ve benh nhan dugc lira chgn, bat tham ngau nhien qua phong bi thu dan kin cd
chua thdng tin so tham va nhdm dieu trj tuong ung... la cac phuang phap bat tham khdng
gay sai sd lira chgn.
Nghien cuu cd duac thuc hien mu ddi khdng?
De giam thieu cac sai so lien quan den qua trinh cham sdc va dieu trj benh nhan cd
the lam sai lech ket qua, bac sT dieu trj va benh nhan khdng nen dugc bietthuoc va phuang
phap dieu trj benh nhan su dung. Phuang phap mu ddi giiip tranh viec bac sT thuc hien them
cac phuang phap dieu trj hay can thiep khac chi tren mdt nhdm benh nhan. Chang han khi
bac sT dieu tj cho rang nhdm benh nhan dung thuoc doi chung se cd hieu qua thap hon thi
thudng cd xu hudng theo ddi benh nhan chat va thudng xuyen hon so vdi qui djnh trong de
cuang. Cd the thuc hien mu vdi doi tugng thu 3 la ngudi xu ly va tinh toan thong ke ket
qua nghien cuu hay bac sT tham gia danh gia cac chi tieu ciia nghien cuu de giam cac sai sd
phat hien (detection bias) cd the xay ra do sir khac biet ve danh gia cac chi tieu chinh ciia
nghien cuu.
- Nghien cuu cd thuc hien phdn tich theo dudinh dieu tri (intention-to-treat, ITT) hay
khdng?
Phan tich theo du djnh dieu trj cd nghTa la ket qua tu tat ca cac benh nhan da dugc
phan nhom ngau nhien trong nghien cuu deu dugc dua vao tinh toan va phan bo theo nhom
dieu trj ma benh nhan da dugc phan nhdm ngau nhien trudc do. Dieu nay giiip giam thieu
sai so phan bo benh nhan va dam bao viec cac yeu to nguy co va cac yeu to tien lugng van
dugc phan bo deu giua cac nhdm khi tien hanh phan tich ket qua. Vi du, viec loai tru cac
benh nhan bd tham gia nghien cuu sdm khi tinh toan ket qua cd the dan den sai sd khi so
sanh giua cac nhdm vi ly do cac benh nhan phai bd nghien cuu sdm thudng lien quan den
tien lugng benh va hieu qua dieu trj. Viec loai tru cac benh nhan nay lam cho viec tinh toan
92
ket qua chi dugc thuc hien tren nhung benh nhan cd tien lugng tot hon, do do cd the udc
tinh qua muc hieu qua ciia phuang phap dieu tri.
Bang 4.1. Bang kiem danh gia cac nghien cuu lien quan den thuc hanh su dung thuoc
Dieu tri
Noi kiem
Benh nhan cd dugc phan nh6m ngSu nhien kh6ng?

Nghien cuu cd dugc thiet ke mii ddi khong?
Tinh toan ket qua c6 dua tren phan tich ITT khong?
Viec phan nhom ngau nhien benh nhan c6 thanh cong khi ket thuc nghien cuu khong?
Mi>c do hieu qua cua thuoc/phac do dieu tri
Tac dgng ciia phuang phap dieu tri?
Do rong ciia khoang tin cay 95% ciia cac ket qua?
Cac ket qua thu dugc c6 nghTa lam sang khong? Kha nSng ap dung cac ket qua nay.
Lieu benh nhan dang xem xet trong tinh huong lam sang c6 cac d£c diem phu hgp
vdi tieu chuan lua chgn benh nhan trong nghien cuu khong?
Lgi ich ciia thuoc/phuang phap dieu tri c6 vugt troi han nguy ca khdng?
Nguy co»
Noi kiem
Cac benh nhan trong nh6m chung c6 cac d#c diem tuang dong vdi cac benh nhan
trong nh6m benh khong? (nghien cuu benh/chung)
Cac sai so da dugc giam thieu khi do ludng viec su dung thuoc (phai nhiem vdi
thuoc nghi ngd) va danh gia bien co bat lgi ciia thuoc chua?
- Thdi gian theo d6i benh nhan de phat hien bien co bat lgi d§ phii hgp chua?
C6 dam bao dugc viec su dung thuoc (phai nhiem) xay ra trudc bien co bat lgi hay
khong?
C6 moi lien quan lieu - tac dung ciia bien co bat lgi hay khdng?
Muc dg nguy ca
Moi quan he giua su dung thuoc (phai nhiem) vdi bien co bat lgi cd chac chin
khong?
Viec udc tinh nguy ca ciia thuoc chinh xac den muc do nao?
Can bao nhieu benh nhan su dung thuoc (phai nhiem vdi thuoc) de xuat hien mot
bien co bat lai?
Kha nang ap dung ket qua

Kha nang xuat hien bien co bat lgi tren benh nhan ciia tinh huong lam sang
- Viec ngung su dung thuoc nghi ngd c6 dem lai h$u qua gi cho benh nhan khdng?
Tong quan, tong quan he thong, phan tich gop
Ngi kiem
- Tong quan c6 dua ra cau hoi dugc thiet ke ch3t che kh6ng?
93
Cac tieu chi dung de lua chgn nghien cuu dua vao su dung phan tich trong tong
quan c6 hgp ly khdng?
Li$u tat ca cac nghien cuu c6 lien quan da dugc lua chgn de phan tich trong tong
quan chua?
Cac nghien cuu dugc dua vao su dung phan tich trong tong quan cd dugc danh gia
ve chat lugng nghien cuu khdng?
Viec giam thieu cac sai so lien quan den lua chgn bai nghien cuu, trich'dln du lieu va
phan tich du lieu da dugc thuc hien chua?
Lieu tat ca cac chi tieu danh gia lam sang quan trgng da dugc can nhac phan tich
trong tong quan chua?
Ket qua ciia cac nghien cuu cd dugc ket hgp de xu ly mot each hgp ly khdng?
Muc do tac dgng
Ket qua hieu qua trung binh cua cac nghien cuu qua phan tich gdp?
Ket qua chinh xac den muc do nao?
Kha nang ap dung ket qua
DSc diem ciia bgnh nhan trong tinh huong lam sang c6 giong vdi doi tugng benh
nhan trong cac nghien cuu khong?
Ligu nguy ca ciia thuoc c6 vugt troi han lgi ich khdng?
Hudng din dieu tri
Ngi kiem
Phan dieu tri benh va cac tieu chi danh gia c6 dugc de c3p ro rang khdng?
Cac chung cu su dung c6 lien quan den cac khuyen cao dua ra khdng?
Cd su dung cac phuang phap tim kiem, lua chgn va tong hgp chung cu mdt each he
thong va day du khong?
Tat ca cac ket cugc (outcomes) lam sang da dugc danh gia chua?
Hudng dan dieu tri co dam bao tinh cap nhat khong?
Hudng din dieu tri cd de c$p den cac chung cu chung minh lgi ich cua viec thuc
hanh theo khuyen cao khong?
Hudng dan dieu tri cd dugc phan bien dgc lap khong?
Muc do tac dgng .
Do manh ciia cac khuyen cao?

Tac dgng ciia cac chung cu chua chac chin tren cac tieu chi lam sang ciia benh?
Kha nang ap dung
Lieu hudng dan dieu tri c6 hudng tdi tinh huong thuc hanh? (vi du hudng dan dieu tri
cho chSm sdc benh nhan dai thao dudng tai cong dong so vdi hudng din cho ch3m
s6c benh nhan tai cac dan vi chuyen khoa Ngi tiet/Dai thao dudng)
Lieu benh nhan trong tinh huong lam sang cd nSm trong quan the dich ma cac
khuyen cao trong hudng dan dieu tri hudng tdi hay khong?
Phan tich kinh te
Noi kiem
94
Viec danh gia chi phi va lgi ich/nguy co ciia thuoc cd dugc danh gia cho tat ca cac
nh6m can thiep khdng?
Chi phi cung nhu lgi ich/nguy ca cua thuoc c6 duac danh gia chinh xac khong?
Tac dgng ciia cac yeu to chua chic chin cd dugc danh gia khdng?
Tac ddng ciia su khac biet ve nguy ca nen ban dau (baseline) tdi chi phi va lgi
ich/nguy ca ciia thuoc c6 dugc danh gia khong?
Muc do tac dgng
Nhung chi phi gia tSng (incremental costs) va lgi ich/nguy ca nao ciia thuoc da dugc
danh gia?
Chi phi gia tSng va lgi ich/nguy ca ciia thuoc c6 thay doi giua cac nhom benh nhan
kh6ng?
Phan tich do nhay c6 anh hudng nhu the nao den chi phi gia tang?
Kha nang ap dung
Lgi ich ciia thuoc cd vugt troi nguy ca va chi phi khdng?
Ket qua c6 the ap dung vdi benh nhan trong tinh huong lam sang khdng? (doi tugng
benh nhan c6 tuang tu khong, cac loai chi phi c6 tuang tu khong?)
Nguon: Guyatt G, Rennie D, Meade MO and Cook DJ (editors) (2008), Users' guides to the
medical literature: A manual for evidence-based clinical practice, Mc Graw Hill Medical/
JAMAevidence, 2nd edition. T§p hgp cac bai dSng tren User's Guide series tren tap chi JAMA tu
nam 1993 den nSm 2000.
2.3.2. Can nhac den y nghia lam sang cua chieng cu de xem xet khd nang dp dung tren
benh nhan trong tinh hudng lam sang
Sau khi tap hgp xong cac nghien cuu cd lien quan den cau hdi lam sang va xac djnh
cac nghien cuu cd thiet ke chat che nhat, cau hoi tiep theo dat ra vdi dugc sT lam sang la se
lam gi tiep trong chudi cau hdi da dat ra tu budc dau tien. Ndi each khac, lieu nhung ket
qua tir cac nghien cuu, tu cac chung cu thu thap dugc cd thay doi viec dieu trj ciia benh
nhan khong? Budc dau tien de tra ldi cau hdi mang tinh chat quyet djnh lam sang nay la
viec danh gia y nghTa lam sang ciia cac ket qua thu thap tir y van. Lieu cac tieu chi danh gia
neu trong thu nghiem lam sang cd phan anh dugc ro ret hieu qua lam sang tren benh nhan
khong? Nguyen tac POEMs (Patient-oriented Evidence that Matters) de xuat bdi Allen
Shaughnessy va edng sir nhan manh vai trd ciia cac tieu chi quan trgng cd y nghTa lam sang
can can nhac bao gom: tu vong, benh mac kem va chat lugng cudc song ciia benh nhan. Vi
du, neu mdt thudc chi lam cai thien chuc nang tarn truang that trai - mdt chi tieu danh gia
ggi y (surrogate endpoint, xem them chuang 3) thi cd y nghTa lam sang tuong duong vdi
mdt thudc lam giam ty le tir vong hay cai thien tinh trang suy tim - chi tieu danh gia chinh
(primary outcomes) tren mdt benh nhan suy tim hay khdng?
Lgi ich mdt can thiep dieu trj tren benh nhan khdng nhung phu thudc vao hieu qua
ciia can thiep ma con phu thuoc miic do vugt troi ma lgi ich ciia can thiep dem lai so vdi
nguy ca, chi phi va lgi ich ciia cac thuoc/phac dd dieu trj khac hien dang dugc su dung
trong thuc hanh. Trong bdi canh do, sd benh nhan can dieu trj (number-needed to treat,
NNT) va sd benh nhan can thiet de gay ton hai (number-needed to harm, NNH) la cac thong
sd cd y nghTa lam sang cho phep udc lugng tac dong ciia can thiep bang thuoc ke ca lgi ich
va nguy co, tu do quyet djnh xem cd nen ap dung cho benh nhan hay khdng. NNT va NNH
95
cho biet so benh nhan can dieu trj bang thuoc va thai gian dieu trj bang thudc hay phac dd
do de dat dugc mdt ket cudc lam sang cd lgi hoac bat lgi cho benh nhan. Thdng thudng, gia
trj NNT cang thap chung to thuoc/phac do dieu trj cang cd hieu qua. NNT bang 1 cd nghTa
la ket cudc lam sang cd lgi va mong dgi tu thuoc xuat hien d tat ca cac benh nhan d nhdm
thu nhung khdng dugc ghi nhan tren bat cu benh nhan nao d nhdm chiing. Hien chua cd
thong nhat ve khoang dao ddng chap nhan dugc ciia gia trj NNT nhung gia trj nay thudng
dao ddng trong khoang tu 2 den 4. Mac du vay, can luu y den mdt so ngoai le nhu trong
trudng hgp phac do bd 3 diet xoan khuan Helicobacter pylori (HP) yeu cau gia tri NNT
cang thap cang tot (« 1,1) de dam bao tranh tai phat trong vdng 1 nam trong khi do vdi cac
cac can thiep mang tinh du phdng chi tao ra hieu qua nhd tren quan the benh nhan nhu viec
su dung aspirin d giai doan sau nhoi mau co tim de du phdng tai phat trong vdng 5 tuan thi
lai chap nhan NNT d muc khoang 40 la muc cd hieu qua. Tren thuc te, gia tri NNT da dugc
sir dung de xem xet lieu cd nen sir dung mdt thuoc/phac do cho benh nhan hay khdng cung
nhu lira chgn thuoc trong mdt nhom thuoc hoac mdt nhdm dugc ly. Su dung hudng tiep can
nay, Don vj nghien cuu Dau ciia Dai hgc Oxford (Anh) da so sanh gia trj NNT can thiet de
tao ra tac dung giam dau cua mdt so thuoc giam dau thdng thudng (hinh 4.1).
Etoricoxib 120
Valdecoxib 40
Celecoxib 400
Paracetamol/codeine 1000/60
Rofecoxib 50
Ibuprofen 400
' Lumiracoxib 400
Naproxen 500/550
Diclofenac 50
Morphine 10 IM
Paracetamol 1000
Aspirin 600/650
Tramadol 100
1 2 3 4 5 6 7
Khoang tin cSy 95% cua gia trj NNT dl tao ra tac dung giam dau 50% so vol placebo
Hinh 4.1. Gia trj NNT ciia cac thuoc giam dau de tao ra it nhat 50% tac dung giam dau trong
v6ng 4-6 gid so vdi placebo trong cac trudng hgp dau d muc dg tu- trung binh den dau nSng
Ngu6n:http://www.medicine.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/Leagtab.html
Cac thdng so RR, ARR, NNT va NNH thudng dugc tinh toan trong cac thu nghiem
lam sang dugc thiet ke de tra ldi cau hdi lieu viec su dung thudc hay phac do nghien cuu cd
lam giam mot bien co bat lgi so vdi nhdm chung hay khdng. Vi du ve bien co bat lgi nhu
nhoi mau co tim, dot quj, nhap vien hoac tu vong. Do cac tieu chi danh gia nay la bien nhj
phan (cd hoac khdng) nen cd the tdm tat ket qua nghien cuu trong bang 4.2. Tu cac gia trj
ciia bang nay, co the tinh toan cac thdng so nguy co tuong doi (relative risk, RR), giam
nguy co tuong doi (relative risk reduction, RRR), giam nguy co tuyet doi (abolute risk
reduction) va NNT (bang 4.3).
xr ocio >•
96
Bang 4.2. Bieu dien ket qua dCr- lieu ciia chi tieu danh gia trong nghien cuu
Bien cd bdt lgi
Nhdm Co Khdng
Dung thuoc/phac do nghien cuu A B
Nhom chiing (control) C D
Bang 4.3. Cac thong so tinh toan tu thu nghiem lam sang (RR, RRR, ARR va NNT)
Thong sd Md ta Cong thuc tinh
Nguy ca tuang doi Ty so nguy ca xuat hien bien co d [A/(A+B)]/[C/(C+D)]
(RR) nh6m diing thuoc va nguy ca d
nh6m chung
Giam nguy ca tuang Phan tr2m giam nguy ca so vdi udc 1-RR
doi (RRR) lugng ban dau
Giam nguy ca tuyet doi Su khac bigt ve nguy ca xuat hien [C/(C+D)] - [A/(A+B)J
(ARR) bien co d nh6m chung so vdi nhdm
diing thuoc
So benh nhan can dieu So benh nhan can dugc dieu tri 1/ARR
tri (NNT) bSng thuoc de giam 1 ca benh
De hieu ro hon ve each tinh toan va y nghTa ciia cac gia trj RR, ARR, NNT va NNH,
hay cung phan tich vi du lien quan den thu nghiem lam sang tim kiem dugc khi tra ldi cau
hdi da de cap d phan trudc:
"Lieu bo sung clopidogrel vao phac dd chong kit tap tieu cdu su dung aspirin cd
giiip du phdng tie vong hoac cdc biin co mach vanh cho benh nhdn 65 tuoi dau thdt nguc
khdng on dinh dangsirdung aspirin dan doc khdng? "
Thd nghiem lam sang nay theo ddi 12562 benh nhan mac hdi chung benh mach vanh,
dugc phan nhdm ngau nhien vao 2 nhdm: nhdm dung clopidogrel ket hgp vdi aspirin va
nhdm dung aspirin don doc (NEJM 2001, 345, 494-502). Cac benh nhan dugc theo ddi
trong vdng 9 thang de ghi nhan bien co bat lgi bao g6m nhoi mau co tim, dot quj va tuvong
do benh ly tim mach. Ket qua da ghi nhan dugc 582 benh nhan cd xuat hien cac bien co bat
lgi d nhdm dung clopidogrel + aspirin (9,28%) va 719 benh nhan d nhdm chung dung
aspirin (11,47%). Nguy co tuang doi tinh dugc la 0,81. RR do ludng ty so nguy co xuat
hi|n bien co d nhom dung thuoc nghien cuu so vdi nhdm doi chirng. Gia trj RR = 1 cho
thay khdng cd sir khac biet giua nhdm dung thuoc va nhdm chirng. Gia tri RR < 1 chung to
can thiep bang thuoc nghien cuu lam giam nguy co xuat hien bien co bat lgi so vdi nhdm
chiing va ngugc lai neu RR > 1cd nghTa la can thiep bang thuoc lam tang nguy co xuat hien
bien co bat lgi so vdi nhdm chung. Cung can luu y ben canh gia trj RR, khoang tin cay 95%
ciia gia trj nay cung ddng vai trd quan trgng quyet djnh xem lieu cd sir khac biet thuc sir
giua nhdm thu va nhdm doi chung hay khdng. Trong trudng hgp nay, RR la 0,81 vdi
khoang tin cay 95% dao dgng tir 0,72 den 0,90. Khoang tin cay nay khdng chua 1 chung to
cd the khang djnh chac chan rang phac do dieu trj phoi hgp clopidogrel + aspirin lam giam
nguy co xuat hien bien cd bat lgi so vdi nhom chi dung aspirin don ddc.
DLS...T7 97
Thdng so RRR tinh dugc la 19% (1-0,81) cho thay benh nhan dugc dieu trj ket hgp
clopidogrel vdi aspirin cd nguy co xuat hien bien cd bat lgi thap hon 19% so vdi benh nhan
chi dugc dieu tri bang aspirin don ddc. Can luu y, trong mdt sd trudng hgp, RRR, gia trj do
ludng muc do hieu qua ciia can thiep cd the dugc bien giai khdng chinh xac. Vi du, do giam
nguy co tuong doi lien quan den dot quj ciia artovastatin la 48% khi so sanh vdi nhdm
chung su dung placebo. Mac du con sd nay rat an tugng ve lgi ich artovastatin dem lai cho
benh nhan cd nguy co dot qui cao tuy nhien can can nhac den nguy co tuyet ddi (absolute
risk, AR) ben canh RRR. Thuc vay, tan suat xuat hien dot quj la 1,5% (21/1428 benh nhan
dieu tri bang artovastatin) so vdi 2,8% (39/1409 benh nhan dung placebo) cho phep tinh
toan ARR la 1,3% (2,8% - 1,5%). Nhu vay, mac du giam dugc 50% nguy co tuong doi vdi
artovarstatin, so lugng benh nhan thuc sir giam dugc nguy co rat nhd (18) tren tong sd hon
2800 b$nh nhan trong thu nghiem lam sang (Lancet 2004, 364, 685-696).
Do giam nguy co tuyet doi ARR trong vi du nay la 2,19% (11,47%-9,28%) chiing to
2,19% so benh nhan dugc dieu trj bang clopidogrel + aspirin tranh dugc nguy co xuat hien
bien cd bat lgi so vdi nhdm dung aspirin don doc.
So benh nhan can dieu tri (NNT) tinh dugc la 46 (1/0,0219) cd nghTa la can dieu trj
cho 46 benh nhan dau that nguc khdng on djnh bang clopidogrel ket hgp vdi aspirin trong
vdng 9 thang thay cho dung aspirin don ddc de du phdng xuat hien nhoi mau co tim, dot quj
hay tu vong do benh ly tim mach tren 1 benh nhan.
Lien quan den do an toan, nghien cuu cung ghi nhan 2,7% sd benh nhan d nhdm dieu
trj bang aspirin don ddc cd xuat hien xuat huyet nghiem trgng trong khi con sd nay la 3,6% d
nhdm benh nhan dung clopidogrel phoi hop vdi aspirin. Nguy co tuong ddi (RR) cho xuat
huyet nghiem trgng khi dung clopidogrel + aspirin so vdi aspirin don ddc la 1,33 (3,6/2,7).
Theo qui udc, khi RR trong khoang tir 1,0 den 2,0 dugc coi la nguy co cao hon d nhdm can
thiep so vdi nhdm chiing nhung cac bien co bat lgi ciia thudc cd the cd nguyen nhan do mot
so yeu to khac ngoai thuoc/phac do su dung d nhdm can thiep. Ngugc lai, gia tri RR > 2 cho
phep khang djnh nguy co xuat hien bien cd bat lgi chii yeu lien quan den thuoc/phac do su
dung d nhdm can thiep. Tang nguy co tuyet ddi (absolute risk increase, ARI) thay the cho
ARR la 0,9%o (3,6% - 2,7%). So benh nhan can thiet de gap ton hai (NNH) tinh dugc la 111
(1/ARI) cd nghTa la can dieu tri tren 111 benh nhan bang phac do phoi hgp 2 thudc chong ket
tap tieu cau trong vdng 9 thang de xuat hien 1 trudng hop xuat huyet nghiem trgng.
Tong hop ket qua tinh toan NNT va NNH cd the ket luan tren 1000 benh nhan dugc
dieu nhu sau: thu nghiem lam sang cho thay dieu trj 1000 benh nhan dau that nguc khdng
on djnh bang clopidogrel phoi hgp vdi aspirin giiip du phdng dugc 21 trudng hgp nhoi mau
ca tim, dot quj hoac tu vong do benh ly tim mach vdi nguy co gay xuat huyet nghiem trgng
tren 9 benh nhan.
Su dung each tinh toan tuong tu vdi cac ket qua thu dugc tir cac thu nghiem lam sang
cho phep udc lugng lgi ich ciia viec su dung thudc trong nhieu benh ly tim mach thong qua
tri so NNT (bang 4.4).
Bang 4.4. Lgi ich cho benh nhan ciia mgt so phac do dieu tri benh tim mach
Ty le xuat hien bien cd (%)
Cau hdi lam sang (TLTK) Nhom chirng Nhom thu ARR NNT
Nguy ca dgt qui trong vdng 5 nSm giam dugc 2,9 1,9 1,0 100
98
bao nhieu trong d benh nhan tSng huyet ap
dieu tri bing thuoc lai tieu (JAMA 1997, 277,
739-745)
Nguy ca tu vong trong v6ng 2 nam sau nhoi .9,8 7,3 2,5 40
mau ca tim giam dugc bao nhieu tren b£nh
nhan 60 tuoi dieu tri bing thuoc chen p
(JAMA 1982, 247, 1707-1714)
Nguy ca tu vong trong vdng 5 tuan sau nhoi 12,0 9,2 2,8 36
mau ca tim giam dugc bao nhieu tren benh
nhan 60 tuoi dieu tri bSng streptokinase
(Lancet 1988, 2, 349-360)
2.4. Ap dung chirng cu* de toi iru hoa viec sir dung thuoc tren benh nhan
Viec su dung thudc tren benh nhan khdng chi phu thudc vao cac chirng cu thu thap
dugc tir y van ma con ehju sir chi phoi r&t nhieu tu quyet djnh lam sang ciia can bd y te.
Mdt sd yeu to lien quan den benh nhan can can nhac trong budc phan tich cudi cung nay
bao gom:
So sanh dgc diem cua benh nhdn vdi dgc diem benh nhdn trong mau nghien cieu (cd
ddng nhdt ve giai dogn benh khdng, cd cdc ddc diem benh hoc ban dau giong nhau
khdng)?
Viec danh gia nay giiip dam bao cd sir tuong ddng ve giai doan benh va cac yeu to
tien lugng giua quan the benh nhan trong nghien cuu vdi benh nhan trong tinh hudng lam
sang. Vi du, ket qua ve lgi ich ciia simvastatin tren benh nhan rdi loan lipid mau nam gidi
dang cd benh mach vanh khdng the ap dung cho benh nhan nu roi loan lipid mau nhung
khdng cd cac yeu to nguy co khac.
Can nhdc cdc yeu to nguy ca nen cua benh nhdn lien quan den tieu chi danh gid vd
cdc nguy ca chinh lien quan den dieu tri.
Trong trudng hgp benh nhan trong tinh hudng lam sang cd cac yeu to nguy co ban
dau cao hon nhdm benh nhan dugc sir dung thudc trong giai doan thu* nghiem lam sang cd
the danh gia vugt muc lgi ich ciia thudc nghien cuu dem lai. Ngugc lai, neu benh nhan cd
nguy co ban dau thap hon nhdm benh nhan trong nghien cuu thi nguy co lien quan den
thudc mdi cd the vugt troi hon lgi ich ma thudc dem lai (hinh 4.2). Vi du, phu nu d trudc
tuoi man kinh cd nguy co tu vong do benh tim mach thap hon so vdi nam gidi vi vay mdt
can thiep cd hieu qua du phdng tu vong do benh tim mach d nam gidi cd the dem lai lgi ich
it hon d nu gidi.
Can nhdc den cdc yeu to lien quan den he thdng cham sdc sue khde vd khd nang
tiep can dieu tri cua benh nhdn.
Cac yeu to lien quan den he thdng y te (gia thanh, kha nang tiep can thudc, kha nang
thuc hien cac theo ddi va danh gia benh nhan trong qua trinh dieu trj, cac thudc hoac phac
do dieu trj khac dang dugc su dung) cung can dugc tinh den. Vdi xu hudng benh nhan ngay
cang tham gia tich cue vao qua trinh dieu trj, can thao luan cac chung cu de cd dugc sir
chap thuan ciia benh nhan va tich hgp cac chung cu nay vao bdi canh lam sang cu the de
dam bao hieu qua dieu trj.
99
(ii) Benh nhan co nguy cff thap U'U Benh nhan co nguy co"
(i) Benh nhantrong

thu* nghiem lam sang '
6 -
Loi ich
Loi Ngir&ng nguy coVloi ich
ich
Nguy co
dieu 4 -
trj
<V.)
2 -
10 15
Nguy co* (•/•)
Hinh 4.2. Su khac biet ve lgi ich/nguy ca khi su dung thuoc d nhdm benh nhan cd nguy ca thap
va nh6m benh nhan cd nguy ca cao vdi nh6m benh nhan trong thu nghiem lam sang.
'OV
Cac tieu chi can can nhac khi ap dung chung cu trong su dung thudc cho benh nhan
va dugc cu the hda bang cac cau hdi dudi dang bang kiem kem theo dugc tdng ket trong
bang 4.5. Bang kiem tdng ket nguy co/lgi ich ciia thuoc thu thap tu y van cung dugc trinh
bay trong bang nay.
Bang 4.5. Tien chi can can nhac va bang kiem xac dinh kha nSng ap dung chung cu
trong thuc hanh su dung thuoc
Tieu chi can can nhdc
A. C6 the ap dung ket qua nghien cuu cho benh nhan trong tinh huong lam sang?
1. Cd cac yeu to tien lugnq (tuoi, gidi, chiing tgc, sinh ly benh, benh mac kem) co the
lam thay doi hieu qua dieu tri tren benh nhan khong?
2. Lieu benh nhan cd the tuan thii cac yeu cau ciia thuoc/phac do dieu tri mdi khong
(can nhac den yeu to kinh te-xa hgi, kha nang tuan thu dieu tri)?
3. Lieu bac sT cd the tuan thu cac yen cau ciia thuoc/phac do dieu tri mdi khong (kha
nang thuc hien cac test chan doan, phuang tien theo ddi, ky thuat dua thuoc, viec
thuc hien cac xet nghiem theo d6i trong qua trinh dieu trj)
B. Li£u lgi ich ciia thuoc da vugt trgi nguy ca va chi phi cho benh nhan trong tinh huong
lam sang khong (NNT va nguy ca nen trong trudng hgp khong dugc dieu tri)?
Bang kiem tong ket nguy ca lgi ich cua thuoc
Can nhac nguyen tic POEMs (cac tieu chi tu vong, benh m£c kem, chat lugng cugc
song).
Khdng chi dua vao gia trj RRR, can tinh them ARR 'tij.,11
NNT=1/ARR
<)LC
NNH = 1/ARI
100
NNT ludn di kem.vdi tieu chi lam sang va mot moc thdicjian xac djnh
Gia tri can tren va can dudi cua khoang tin c3y 95% giup danh gia y righTa lam sang
ciia ket qua nghien cuu.
Can nhSc su dung khoang tin cay khi ngoai suy ket qua tren mdt benh nhan eg the.
Xac dinh xem lieu cac ket qua nghien cuu cd ap dung dugc cho tinh huong lam sang
• Tinh toan nguy ca ciia benh nhan trong tinh huong lam sang va hieu chinh gia
tri NNT tuang ung theo nguy ca nay
• Tinh toan nguy ca ciia b§nh nhan trong tinh huong lam sang va hieu chinh gia
tri NNH tuang ung theo nguy ca nay.
• Can doi nguy ca, lgi ich, chi phi va tinh tien lgi ciia thuoc/phac do dieu tri
Bang kiem xac djnh kha nang ap dung chirng cu vao tinh huong lam sang
Hoan thanh bang kiim x6c dinh khi n§ng ip dung chung cu
Benh nhan trong tinh huong lam sang c6 tuang tu benh nhan dugc lua chgn trong
nghien cuu khong?
• Xem xet tieu chuan lua chgn/loai tru benh nhan
• Xem xet xem nghien cuu c6 theo d6i benh nhan trong khoang thdi gian thich hgp
sau khi diing thuoc de danh gia tuan thu dieu tri, hieu qua va kha nSng dung nap
thuoc nghien cuu hay khong?
• Ty le so benh nhan dugc tuyen chgn vao nghien cuu so vdi so benh nhan sang
lgc ban dau.
Dan vi nai thuc hien nghien cuu cd tuang tu benh vien ma b$nh nhan dang dieu tri
khong? (benh nhan dugc lua chgn tai cac benh vien dai hgc hay phdng kham chuyen
khoa...)
03c diem ban dau cua benh nhan trong thu nghiem lam sang cd tuang tu benh nhan
trong tinh huong lam sang?
• Muc dd benh cd tuang tu khong?
• Cac benh mac kem c6 tuang tu khong?
• Nguy ca xuat hien phan ung cd hai cd tuang tu khdng?
Can thiep (thuoc/phac do dieu tri) trong thu nghiem lam sang cd tuang tu thuc hanh
thudng qui tai benh vien? (Thdi diem dua thuoc, nhjp dua thuoc, dudng dua thuoc
cd thyc hien dugc khdng?)
Cac tieu chi danh gia c6 y nghTa lam sang khong?
• Tidu chi danh gia la tieu chi lam sang (clinical outcome) hay tieu chi ggi y
(surrogate outcome)?
• Cac tieu chi lam sang su dung trong nghien cuu cd y nghTa vdi benh nhan trong
tinh huong lam sang khong?
• Cac tieu chi lam sang c6 bao gom tieu chi danh gia ggp (composite endpoint)
khdng?
• Su khac biet co y nghTa thong ke ve ket qua cua tieu chi danh gia ggp c6 do tieu
chi lam sang c6 y nghTa tren benh nhan quyet dinh hay khong?
Cac bien phap theo ddi va dieu trj ho trg khac di kem vdi can thiep cd kha thi tai benh
vien khdng?
• Ojnh ky sau bao lau phai kham lai benh nhan?
L—
101
• Cac benh nhan trong nghien cuu c6 phai su dung cac bien phap dieu tri ho trg
khac khong?
• Nghien cuu c6 de c3p den ke hoach theo ddi dg an toan trong qua trinh su dung
thuoc cho benh nhan kh6ng? Ke hoach nay cd kha thi tai benh vien khong?
Xac dinh muc dg hieu qua cua can thiep
- Xac dinh cac tieu chi danh gia hieu qua va dg an toan lien quan
- Tinh toan cac thdng so cho cac tieu chi nay bao gom RRR, ARR, NNT vdi tieu chi
hieu qua, ARI va NNH vdi tieu chi ve do" an toan
- Xac dinh yeu to nguy ca ciia benh nhan trong tinh huong lam sang, so sanh vdi nguy
ca nen ciia benh nhan trong nghien cuu de tinh he so hieu chinh Uvi dg f = 1 neu
benh nhan trong tinh huong lam sang c6 nguy ca (d§c diem nhan khau hgc^cac benh
mlc kem) tuang tu benh nhan trong nghien cuu, f = 2 neu benh nhan c6 yeu to nguy
ca gap 2 lan hoSc f = 0,5 neu benh nhan cd yeu to nguy ca bang 50% benh nhan
trong nghien cuu).Sau dd tinh gia tri NNT va NNH hieu chinh tren benh nhan, tuang
ung bang NNT (NNH)nghiena>u/f.
-' Can nhac nguy ca/lgi ich tren benh nhan trong tinh huong lam sang dua tren gia trj
NNT va NNH hieu chinh
Nguon: Users' guides to the medical literature: Amanual for evidence-based clinical practice va
Evidenced-based Pharmacotherapy: optimal patient care = best knowledge + competent
practitioner.
3. AP DUNG Y HOC DlTA TREN BANG CHlTNG TRONG THlTC HANH SLT DUNG
THUOC: VI DU TREN TINH HUONG LAM SANG
Tinh hudng Idm sang
'Mdt benh nhan nam 40 tuoi la giao vien cap 3 dugc dua vao khoa Cap cuu ciia mdt
Benh vien Da khoa tuyen trung uong d HaNdi. Benh nhan cd dau nguc du ddi trong vdng 2
gid qua, dau lan ra canh tay. Khi dua vao khoa, con dau van tiep tuc nhung benh nhan
khdng cam thay met mdi hay khd thd. Kham lam sang: huyet ap 110/70 mmHg, nhjp tim 92
lan/phut, tieng tim binh thudng, phoi trong. Dien tarn do cho thay chenh 3 mm doan ST d
cac dao trinh II va aVF ggi y chan doan nhoi mau co tim vung thanh dudi. Dieu dudng thiet
lap mot dudng truyen tTnh mach va chuan bj chuyen benh nhan vao khoa Dieu trj tich cue
(ICU). La dugc sT lam sang cam tai khoa, ban can nh£c nguy co va lgi ich ciia viec su dung
thuoc tieu sgi huyet cho benh nhan nay de tu van cho bac sT dieu trj.
Cau hdi PICO: lieu phac do su dung thuoc tieu sgi huyet (can thiep) cd giiip giam nguy
co tu vong (tieu chi danh gia cd y nghla lam sang) cho benh nhan nam 40 tuoi vdi chan doan
nhoi mau ca tim thanh dudi cap tinh nhap vien trong vdng 2 gid dau (b?nh nhan va van de can
giai quyet) so vdi khdng dung thuoc tieu sgi huyet (can thiep doi chieu) khdng? Lgi ich ciia
thuoc tieu sgi huyet dem lai (neu cd) cd vugt troi nguy co (xuat huyet), cd can bang vdi chi
phi vacd kha thi trong dieu kien cham sdc benh nhan ciia benh vien khdng?
Tim kiem chieng cu tiey van
Trong danh muc thuoc ciia khoa Dugc benh vien va trong tu true ciia khoa Cap cuu
cd thuoc tieu sgi huyet streptokinase. Tien hanh tim kiem y van tren co sd dur lieu
PubMed/Medline su dung tu khoa "streptokinase", "myocardial infarction" va gidi han tim
kiem cac phan tich gdp (meta-analysis) va cac thu nghiem lam sang (randommized
controlled trials), ban tim dugc 1 phan tich ggp tong ket ve hieu qua nhung khdng cd thdng
102
tin ve do an toan (Ann Intern Med 1990, 113, 961-968) vi vay ban quyet djnh phan tich
them ket qua ciia 1 thu nghiem lam sang da trung tarn ISSI-2 (Lancet 1988, 8607, 349-360)
trong so cac thu nghiem lam sang da tien hanh do cd mau ldn (17.000 benh nhan), cd
phuang phap thiet ke chat che. Kit qua tir phan tich gop cho thay su dung streptokinase lam
giam ty le tir vong tir 17,4% xuong 12,8%. Lgi ich nay vugt troi hon nguy co xuat huyet
nghiem trgng can truyen mau lien quan den streptokinase (tang tu 0,2% d nhdm dung
placebo len 0,5% d nhdm dieu tri bang streptokinase). Ban cung nhan thay benh nhan chau
A chi chiem mdt ty le rat nhd trong thu nghiem lam sang va phan tich gdp.
Tinh toan gid tri NNT tren benh nhdn
Su dung 5 budc de tinh gia tri NNT tren benh nhan
- Budc 1. Uoc tinh nguy ca nen. De udc tinh nguy ca nen cho benh nhan trong tinh
huong lam sang, ban sir dung ket qua cong bo ve ty le tir vong do nhoi mau co tim d
Vien Tim mach Quoc gia (Tap chi Y hgc thuc hanh, so 2/2001, 39-41). Tren 140
benh nhan nhoi mau co tim cd the chi djnh nhung khong dung streptokinase, ty le tu
vong tai vien la 16,4%. Ty le tu vong d benh nhan dudi 60 tuoi cd nhoi mau thanh
dudi la 2%.
- Budc 2. Uoc tinh hieu qua dieu trj. Theo nghien cuu ISSI-2, su dung streptokinase
lam giam nguy co tu vong 25%.
- Budc 3. Uoc tinh nguy co sau dieu tri. Giam 25% nguy co nen ciia benh nhan (2%)
tuong ung vdi nguy co tu vong sau dieu trj bang streptokinase la 1,5%.
- Budc 4. Tinh ARR. ARR = 2% - 1,5% = 0,5%
- Budc 5. Tinh NNT hieu chinh tren benh nhan. NNT hieu chinh = 1/ARR = 100/0,5
= 200
Gidi quyet tinh hudng
Cd the khuyen cao gi ve lieu phap tieu sgi huyet cho benh nhan trong tinh huong lam
sang tren? Ve mat ly thuyet, khdng cd ly do gi de thay doi dap ung vdi lieu phap tieu sgi
huyet tren benh nhan ngudi Viet so vdi cac ket qua nghien cuu da cong bd. Van de tuan thu
dieu trj cung khdng quan trgng trong trudng hop nay do thudc dugc dua mdt lieu duy nhat
qua dudng tiem tTnh mach tai khoa Cap cuu. Phuang tien dua thuoc, ky thuat dua thuoc,
cac phuang tien cap cuu khac (truyen mau trong trudng hgp xuat huyet nghiem trgng do
thuoc) cung dugc dam bao tai benh vien.
Neu tinh toan tren ty le nguy co nen tu vong chung trong nhoi mau co tim (16,4% tren
so lieu tai Viet nam, 17,4% tren so lieu tir phan tich gdp), gia trj NNT la 36. Tuy nhien vdi
nhung benh nhan nhoi mau thanh dudi, tre hon (< 60 tuoi) khi nguy co tu vong nen giam con
2% thi lgi ich ciia streptokinase giam di ro ret vdi trj so NNT la 200. Nhu vay, lgi ich ciia
streptokinase dem lai cho benh nhan phu thudc rat ldn vao tuoi, vi tri va kich thudc vung thieu
mau. Cung can can nhac them chi phi dieu trj lien quan den lieu phap tieu sgi huyet (khoang 2
- 3 trieu dong) ma benh nhan va bao hiem y te can chi tra.
Tdm lai, dugc sT lam sang cd the tu van cho bac sT dieu trj viec su dung streptokinase
cho benh nhan dua tren nhung chirng cu tu y van cd the lam giam nhe (25%) nguy co tu
vong cho benh nhan nhung can can nhac rang nguy co tu vong rat thap tren benh nhan cung
nhu kha nang xuat huyet lien quan den streptokinase va chi phi can chi tra khoang 2-3 trieu
dong neu su dung phac do tieu sgi huyet.
103
4. U*NG DUNG Y HOC DU'A TREN BANG CHlTNG DE CAP NHAT THONG TIN
TRONG THVC HANH
Can bd y te cap nhat thdng tin trong thuc hanh su dung thudc vdi 4 muc dich chinh:
i) cap nh£t thdng tin ve cac thuoc mdi/phac do dieu tri mdi,
ii) tra ldi cac cau hdi tinh hudng lam sang,
iii)ra soat va ciing cd cac kien thuc lam sang da tich luy dugc
iv) tiep can thdng tin cua lTnh vuc chuyen mdn quan tarn.
Muc tieu ciia viec cap nhat thdng tin trong thuc hanh la tim thdng tin tot nhat trong
khoang thai gian ngan nhat va it ton edng sue nhat. Thdng tin tim kiem dugc de trd nen
huu ich can thda man 3 dieu kien:
i) cd y nghTa va lien quan den thuc hanh thudng qui
ii) chinh xac (qua phan tich va danh gia)
iii) ton it cong sue de tim kiem nhat.
Ba dieu kien nay dugc the hien trong edng thuc (1) tinh toan tinh huu ich ciia y van
(usefulness of medicine information) dugc de xuat bdi Shaughnessy va edng sir (J Fam
Pract 1994, 38, 505-513) trong do miic do lien quan lam sang (relevance) the hien chirng cu
tim kiem theo djnh hudng tra ldi cau hdi tinh hudng lam sang (nguyen tac POEMs) cd the
anh hudng den quyet djnh lam sang; do chinh xac (validity) the hien kha nang udc lugng
chinh xac muc dd tac ddng ciia can thiep; edng sue (work factor) md ta cong sue can thiet
de tim kiem va phan tich thdng tin.
Tinh hthi ich cua Lien quan lam sang x dp chinh xac
y van „
Cong sue
Sir phat trien ciia Thdng tin Y hgc ngay cang tang tao ra thach thuc ldn vdi can bo y
te trong do cd dugc sT lam sang trong viec cap nhat y van. Hien tai, co sd du lieu ciia Thu
vien Y khoa Hoa Ky (PubMed/Medline) luu giu hon 16 trieu bai bao khoa hgc ciia gan
5000 tap chi Y Sinh hgc khac nhau. Sd lugng bai bao da tang gap 2 lan chi sau 6 nam tu
nam 1995 den nam 2001. Mdi nam cd hon 10.000 thu nghiem lam sang danh gia hieu qua
ciia cac can thiep y khoa trong do cd thudc dugc thuc hien. Trong sd cac thu nghiem nay,
ket qua ciia mot sd thu nghiem se cd tac ddng den thuc hanh (thay ddi hudng dan, phac do
dieu trj) trong khi nhieu thu nghiem khac mdi chi dung d ket qua budc dau con qua sdm de
ap dung tham chi con cd cac thu nghiem lam sang cho ket qua nhieu va khdng nen ap dung
vao thuc hanh. EBM la chien luge hieu qua giiip phan loai y van, xac djnh cac chung cu tot
can ap dung trien khai trong thuc hanh cung nhu cac chiing cu khdng du tin cay lam nhieu
thdng tin cho can bd y te.
Phoi hgp kinh nghiem lam sang va cac ky nang ciia EBM giiip can bd y te giai quyet
cac cau hdi tinh huong lam sang lien quan den viec su dung thudc tren benh nhan ddng thdi
giiip can bd y te tiep tuc cap nhat thdng tin chuyen mdn. Qui trinh cap nhat thdng tin trong
thuc hanh dien ra theo cac budc tuong tu qui trinh giai quyet cac cau hdi tinh hudng lam
sang vdi cac budc:
i) xac djnh nhu cau thdng tin (lTnh vuc thuc hanh chuyen mdn).
ii) tim kiem nguon y van lien quan den lTnh vuc chuyen mdn.
104
iii) danh gia, phan tich cac chirng cu tim dugc tir y van (danh gia chat lugng ciia
thdng tin, ndi kiem va tinh huu ich, kha nang ap dung ciia thdng tin trong thuc
hanh, ngoai kiem).
iv) thong qua cac each khac nhau deap dung chiing cu mdi vao thuc hanh thudng qui.
Trong budc dau tien ciia qui trinh cap nhat y van, dugc sT lam sang can xac djnh cac
lTnh vuc lam sang quan trgng trong thuc hanh cua minh (ndi khoa, tim mach, dinh dudng,
than kinh, tarn than, tieu hda hay dugc ddng hgc...). Tiep theo, dugc sT lam sang ra soat y
van de tim kiem cac nghien cuu lam sang lien quan den lTnh vuc da lira chgn. Cac nghien
cuu nay phai hudng tdi cac tieu chi dau ra cd y nghTa trong thuc hanh, cd kha nang thay doi
hanh vi ke don nhu cac nghien cuu ve hieu qua ciia su dung thuoc tren tu vong, benh mac
kem, chat lugng cudc song, chi phi-hieu qua. Ngugc lai, cac nghien cuu chi danh gia tren
cac tieu chi ggi y (surrogate endpoints) nhu sir thay d6i cac chi so hda sinh thudng khdng
cd y nghTa nhieu trong thuc hanh va it khi ap dung dugc ket qua de thay doi thuc hanh
thudng qui. Do vay, cac nghien cuu vdi tieu chi danh gia cd y nghTa lam sang can dugc uu
tien ra soat trong qui trinh cap nhat y van. Budc thie ba la danh gia va phan tich chung cu
thu thap dugc. Khi xem xet hieu qua dieu trj, thu nghiem lam sang cd phan nhdm ngau
nhien, cd kiem soat (RCTs) dugc coi la "chuan vang" va nen dugc uu tien hon cac nghien
ciiu quan sat khi giai quyet cac cau hdi tinh huong lam sang. Can dgc nhanh phan tdm tk
(abstracts) ciia thu* nghiem lam sang de thu thap thdng tin ve thiet ke nghien cuu (xem
chuang 3) va muc dd tac ddng cua ket qua thu dugc (xem phan 2.3) trudc khi danh gia sau
han. Cuoi cung, tich hgp thong tin mdi vao thuc hanh cd can nhac den nguy co/lgi ich, chi
phi, tinh kha thi va sir chap thuan ciia benh nhan.
Nhieu edng cu tdm tat cac thdng tin y van ciia y hgc dua tren bang chung da dugc xay
dung de ho trg can bd y te trong viec cap nhat nhanh thdng tin, lam giam dang ke (98%)
khoi lugng edng viec tim kiem thong tin (bang 4.6). Ban bien tap cac cong cu nay ra soat
nhanh cac tap chi Y khoa theo lTnh vuc chuyen nganh, xac djnh cac nghien cuu cd y nghTa
lam sang cao, danh gia va phan tich cac nghien cuu nay dong thai dua ra ban luan ve chat
lugng ciia nghien cuu cung nhu kha nang ap dung cac ket qua nghien cuu trong thuc hanh.
DailylnfoPOEMs, Journal Watch, ACP Journal Club, Evidence-based Medicine ciia tap chi
BMJ la cac cong cu hieu qua nhat trong cap nhat y van nhung can phai tra phi de truy cap.
Bang 4.6. MOt so cong egtorn tatthong tin ciia Yhoc dua tren bang chirng su dgng trong cap nhgt thong tin
Cong cu Dja chi truy cap Can tra phi/Mien phi
DailylnfoPOEMs http://www.infopoems.com/eep/ Tra phi
Journal Watch Online www.iwatch.ora Tra phi
American College of www.acoic.ora/index.html Tra phi
Physician (ACP) Journal
Club
Evidence-based Medicine http://ebm.bmj.com/ Tra phi

Turning Research into www.tripdatabase.com/index.html Mien phi
Practice (TRIP) database
PubMed NCBI http://www.ncbi.nlm.nih.gov/pubmed Mien phi
Medscape www.medscape.com/home Mien phi
105
Ben canh dd, mot so cong cu mien phi cd the sir dung de cap nhat thdng tin bao gom
TRIPdatabase, thu vien PubMed/Medline, trang Medscape. Co sd du lieu TRIP Database
tap hop cac nghien cuu tu 5 tap chi Y khoa ldn: Journal of the American Medical
Association (JAMA), New England Journal of Medicine (NEJM), Archives of Internal
Medicine, the Lancet va British Medical Journal (BMJ) dong thai cap nhat cac hudng dan
dieu trj mdi va cac tong quan he thong. TRIP Database cung luu tru cac cau hoi tinh hudng
lam sang thudng gap kem theo cac cau tra ldi dugc xay dung theo tiep can EBM. Tren co
sd du lieu ciia thu vien Ykhoa Hoa ky (PubMed/Medline), ngudi su dung sau khi dang ky
tai khoan cd the cap nhat luu tru ket qua tim kiem va de nghj nhan thdng tin cap nhat cac
nghien cuu mdi lien quan den van de tim kiem qua email (hinh 4.4). Mdt edng cu khac,
trang web Medscape cung giiip cap nhat thdng tin ve cac hdi thao chuyen nganh, xay dung
mdt so bai giang dao tao lien tuc theo hudng tiep can EBM cho can bd yte thudc nhieu
chuyen nganh khac nhau. Diem han che ciia cac cong cu mien phi la nhieu cong cu chi
diem thdng tin ma khdng cung cap cac phan tich, danh gia va hudng dan ap dung chirng cu
trong thuc hanh nhu cac cong cu phai tra phi. Hon nua, can ludn can nhac 2khia canh khi
cap nhat thdng tin tu yvan la thdng tin phai dugc phan tich, danh gia cung nhu phai cd y
nghTa ung dung lam sang cao. Trong mdt so trudng hgp, khi cong cu hd trg tdng hgp thdng
tin yvan khdng dat dugc cac yeu cau tren van can thiet phai phan tich cu the tren bai bao
nghien cuu gdc. '.,-•
Ill My NCB1 —Saved Search Settings
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Your PubMed search
Search^ rosiglitazone and diabetes AND (Clinical Trial[ptVp] AND English[lang])

Name of Search: frosiglitazone anddiabe;
E-mail: anh90tk@yahoo.com
Would you like e-mail updates of new search results?
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Isearch: rosialicazone diabetes
Hinh 4.4. Su dung cong cu PubMed de c$p nh§t thdng tin y van
Hinh tren: man hinh hien thi ket qua tim kiem PubMed vdi tir khoa "rosiglitazone AND
diabetes" gidi han vdi chi tim cac thu nghiem lam sang, ngdn ngu tieng Anh. Hinh dudi:
duac sT lam sang su dung tai khoan dang nhap (dang ky miln phi) cd the luu ket qua tim
kiem va de nghj nhan cac thdng tin cap nhat lien quan den ndi dung tim kiem qua email.
KET LUAN
Sir phat trien ciia yhgc vdi so lugng thuoc mdi dua vao su dung trong dieu tri ngay
cang nhieu, sir gia tang ciia chi phi yte cung vdi mong muon xay dung phac do dieu tri hgp
106
ly la tien de cho viec sir dung bang chung khoa hgc dua tren hudng tiep can va cac nguyen
tic ciia y hgc dua tren bang chiing trong lira chgn thudc va theo ddi trong qua trinh dieu tri
tren tung benh nhan cu the. Ung dung y hgc dua tren bang chirng trong thuc hanh su dung
thudc yeu cau kha nang tim kiem, phan tich, danh gia va ap dung hieu qua cac chung cu tot
nhat tir y van vao tinh huong thuc hanh lam sang. Hudng tiep can va cac ky nang nay rat
can thiet cho dugc sT lam sang trong thuc hanh, tang sue thuyet phuc trong quyet djnh lien
quan den su dung thuoc tren benh nhan, giiip dugc sT lam sang trao ddi tot hon vdi ddng
nghiep y trong qui trinh dua ra quyet djnh lam sang. Hon nua, ke hoach cham sdc dugc dua
tren bang chiing se tao thuan lgi cho qua trinh tu van cho benh nhan ve tinh hgp ly trong ke
hoach sir dung thuoc ciia hg. Cudi cung, cac nguyen tac ciia y hgc dua tren bang chung giiip
dugc sT lam sang tu trau ddi va cap nhat lien tuc kien thuc chuyen mdn.
TINH HUONG LAM SANG
Tinh huong 1.
Mdt ddng nghiep y hdi ban ve hieu qua ciia sumatriptan dudng uong. Ddng nghiep nay cho
biet da dugc nghe trinh dugc vien gidi thieu ve hieu qua ciia thudc tuy nhien van muon so
sanh hieu qua ciia sumatriptan vdi cac thudc dieu trj dau nua dau khac trudc khi ke don cho
benh nhan.
Cau hdi:
1/ Hay thiet ke cau hdi lam sang tu tinh hudng tren.
2/ Su dung PubMed vdi tir khoa tim kiem la sumatriptan, randomized controlled trials va
migraine, ban tim kiem dugc thu nghiem lam sang so sanh hieu qua giam dau ciia
sumatriptan vdi lysin acetyl salicylat (Aspegic®) (Lancet 1995, 346, 923-926). Ket qua ve
ty le dat tac dung giam dau d cac nhdm nhu sau: 24% d nhdm dung placebo, 57% d nhom
dung lysin acetyl salicylat va 53% d nhdm dung sumatriptan. Hay tinh cac gia trj ARR,
NNT cho lysin acetyl salicylat va sumatriptan.
3/ Tu ket qua thu dugc, ban co the tu van gi ve viec lira chgn sumatriptan cho benh nhan.
Ggi y each gidi
1. Dua tren nguyen tac PICO, xac djnh ddi tugng benh nhan, can thiep thudc bac sT muon
ke don, nhdm thudc can so sanh tac dung va tieu chi danh gia hieu qua trong tinh hudng
lam sang de thiet ke cau hdi lam sang.
2. Dau tien, tinh gia trj ARR ciia lysin acetyl salicylat so vdi placebo va ciia sumatriptan so
vdi placebo. Sau dd, dua vao cac gia trj nay tinh NNT ciia 2 thuoc (NNT = 1/ARR) (Dap
an, NNT ciia lysin acetyl salicylat = 3,03, NNT ciia sumatriptan la 3,45).
3. So sanh ket qua NNT ciia 2 thuoc, tir do ket luan ve hieu qua ciia 2 thuoc. Neu gia trj
NNT ciia 2 thudc tuong tu nhau va benh nhan khong cd chong chi djnh vdi salicylat thi
uu tien sir dung lysin acetyl salicylat do gia thanh re hon. Can luu y den lieu dung ciia
lysin acetyl salicylat trong nghien cuu de dat hieu qua tuong duong sumatriptan la 900
mg (tuong duong khoang 3 vien 325 mg). Trong trudng hgp that bao dieu trj, co the can
nhac sir dung sumatriptan nhu la phuang phap dieu trj thay the (second-line).
Tinh huong 2.
Trong mdt budi di budng d khoa Co xuong khdp, mdt dong nghiep y hdi ban lieu cd nen ke
n>! uy.:.
107
don misoprostol cho mdt benh nhan 45 tuoi, khdng cd tien su loet tieu hda dang can dugc
dieu trj dai ngay bang thuoc chong viem phi steroid cho viem khdp (NSAIDs). Benh nhan
nay khdng dung bat cu thudc nao khac.
Cau hdi:
1/ Hay thiet ke cau hoi lam sang tu tinh huong tren.
2/ Su dung PubMed vdi tu khoa tim kiem la misoprostol, arthritis, nonsteroidal
antiinflammatory drugs ban tim dugc 1 thu nghiem lam sang so sanh hieu qua ciia
misoprostol vdi placebo su dung trong vdng 6 thang trong viec ngan ngua bien chiing xuat
huyet tieu hda (Ann Intern Med 1995, 123, 241-249). Cac benh nhan nay deu cd tien su loet
tieu hda trudc dd. Ket qua cho thay, 25/4404 benh nhan d nhdm dung misoprostol va
42/4439 benh nhan d nhdm dung placebo cd xuat huyet tieu hda. Hay tinh cac thdng so
ARR, NNT vdi cac ket qua tren.
3/ Trong thuc te, ty le xuat huyet tieu hda khi su dung NSAIDs d nhdm benh nhan tre,
khong co tien sir loet, khdng sir dung cac thuoc dung kem khac tuong tu benh nhan trong
tinh huong tren la 2%. Hay tinh thdng so NNT hieu chinh va tu van cho dong nghiep tai
Khoa Co xuong khdp ve chi djn misoprostol cho benh nhan.
4/ Neu benh nhan trong tinh huong lam sang la benh nhan nu 80 tuoi, cd mac kem theo suy
tim sung huyet va cd tien su loet ta trang vdi nguy co nen la 10% (thay vi 2%). Cd nen
khuyen cao su dung misoprostol cho benh nhan nay khdng?
Ggi y each gidi:
1. Dua tren nguyen tac PICO, xac djnh doi tugng benh nhan, can thiep thuoc bac sT muon
ke dan, nhdm thuoc (hay placebo) can so sanh tac dung va tieu chi danh gia hieu qua
trong tinh huong lam sang de thiet ke cau hoi lam sang.
2. Dau tien, tinh gia trj ARR ciia misoprostol so vdi placebo. Sau do, dua vao cac gia trj
nay tinh NNT ciia 2 thuoc (NNT = I/ARR). Dap anNNT = 263.
3. Tinh NNT hieu chinh theo ggi y trong bang 5 cung nhu vi du thuc hanh trong phan 3.
NNT hieu chinh trong trudng hgp nay la 125. Can nhac lgi ich misoprostol dem lai (dua
tren gia trj NNT) vdi nguy co (tac dung khdng mong muon) va chi phi (dieu trj dai ngay
trong vdng 6 thang) tir do de xuat tu v&n cho viec sir dung misoprostol cho benh nhan co
the khdng phu hgp cho benh nhan cd nguy co thap nhu benh nhan trong tinh huong lam
sang tren. Hon nua, su dung NSAID d muc lieu toi thieu cd tac dung, su dung cac
NSAID cd nguy co thap nhu ibuprofen lam giam thieu nguy co xuat hien cac bien cd bat
lgi tren tieu hda ciia nhdm thudc nay.
4. Tinh toan NNT hieu chinh tuong tu cau 3 vdi benh nhan cd nguy co cao thu dugc NNT
hieu chinh trong trudng hgp nay la 25. Nhu vay cd the dieu trj du phdng bang
misoprostol cho benh nhan cd nguy ca cao nay.
CAU HOI LlTONG GIA
Tinh huong: mot benh nhan nam 62 tuoi cd tien su dau that ngirc on djnh, loet ta trang
dang dugc dieu trj bang aspirin lieu thap, mot thuoc ha lipid mau dan chat statin, mot thudc
uc che men chuyen va nitrat (khi can). Gan day benh nhan cd bieu hien trieu chiing xuat
huyet tieu hda tren. Ket qua ndi soi cho thay am tinh vdi Helicobacter pylori (HP). Tai
benh vien, bac sT chuyen khoa tieu hda quyet djnh doi aspirin sang sir dung clopidogrel (dua
tren kinh nghiem ciia bac sT nay da tham khao ve kha nang giam nguy ca xuat huyet tieu
108
hda khi su dung clopidogrel thay cho aspirin tren benh nhan cd nguy ca tim mach cao, RR
= 0,71 (khoang tin cay 95%: 0,59 - 0,86 trong mdt tong quan he thong edng bo gan day:
Cochrane Database Syst Rev 2003; 3(1): CD001246). Dugc sT lam sang tim kiem y van ve
viec su dung clopidogrel va aspirin su dung trong du phdng bien co tim mach tap trung vao
vao thdng tin lien quan den nguy co xuat huyet tieu hda va tim dugc 1bai bao vdi ndi dung:
"Asiprin phoi hop vdi esomeprazol lam giam nguy co xuat huyet tieu hda tai phat so vdi
clopidogrel d benh nhan cd nguy co cao" (N Eng J Med 2005, 352, 238 - 244). Day la mot
thu nghiem lam sang phan nhdm ngau nhien benh nhan, cd kiem soat va doi chung placebo
thuc hien tren 320 benh nhan dugc chan doan xac djnh xuat huyet do loet qua ndi soi, cd
ket qua HP am tinh hoac da dieu trj loai tru hoan toan HP, cd su dung thudng xuyen thuoc
chong ket tap tieu cau. Cac benh nhan dugc phan nhdm ngau nhien su dung clopidogrel (75
mg/ngay) + placebo hoac aspirin (80mg/ngay) + esomeprazol (20 mg/ngay) trong vdng 12
thang. Tieu chi danh gia chinh la xuat huyet tieu hoa tai phat. Cac tieu chi danh gia phu bao
gom xuat huyet tieu hda dudi va bien co bat lgi khac. Lira chgn dap an phu hgp nhat trong
sd cac dap an dua ra:
1. Ly do chinh de lira chgn thu nghiem lam sang cd kiem soat la thiet ke nghien cuu trong
trudng hgp nay la:
A. Thu nghiem lam sang cd kiem soat la thiet ke phu hgp nhat de xac djnh moi quan
he nhan qua va do ludng sir khac biet giua nhdm can thiep va nhdm chung.
B. Thu nghiem lam sang cd kiem soat dugc tien hanh hoi cuu, nhin lai nhung gi xay ra
trong qua khu de xac djnh moi quan he nhan qua
C.Thu nghiem lam sang cd kiem soat la each duy nhat de do ludng moi quan he nhan
qua.
D.Thu nghiem lam sang cd kiem soat cho phep phan nhdm ngau nhien'benh nhan lam
tang hieu lire thong ke ciia nghien cuu.
E. Thu nghiem lam sang cd kiem soat cho phep danh gia nhieu chi tieu cung liic qua
trinh thuc hien.
2. Trong thunghiem nay, viec phan nhdm ngau nhien benh nhan giiip:
A.Cac benh nhan khong biet dugc minh dang su dung thuoc gi.
B.Giam thieu anh hudng ciia cac yeu to nhieu lien quan den benh nhan va cac yeu to
nhieu khac den tieu chi danh gia
C. Bac sT cd the biet dugc thuoc dang su dung ciia benh nhan de dieu trj cho benh nhan
dugc tot han
D.Phan benh nhan thanh nhieu nhdm tuy theo dae diem benh hgc cho cac phan tich
thdng ke tiep theo
E. Tang hieu lire thong ke ciia nghien cuu
3. Thu nghiem lam sang tren dugc thiet ke mu ddi. Mu ddi la bien phap giiip:
A. Tranh dugc hieu ung placebo
B. Tranh dugc kha nang can thiep khac nhau ciia bac sT tren benh nhan lam anh hudng
den tieu chi danh gia
C. Giam sai sd trong lira chgn benh nhan
D.Giam sai so trong phan tich so lieu.
109
E. Giam cac sai so lien quan den benh nhan, bac sT dieu trj cd the anh hudng den tieu
chi danh gia
4. Trong tong so 320 benh nhan tham gia nghien cuu, 99% benh nhan dugc theo ddi day du
den het thai gian nghien cuu. Viec theo ddi day du benh nhan giiip:
A.Quan ly tot thu nghiem lam sang
B.Bd qua nhung benh nhan khdng dugc theo ddi day dii de phan tich
C.Danh gia tinh tin cay ciia nghien cuu. Ty le benh nhan bd nghien cuu cang nhieu,
tinh tin cay ciia nghien ciin cang giam.
D.Tim hieu xem benh nhan d nghien cuu do ly do gi.
E. Danh gia tieu chi lam sang ciia nghien cuu
5. Ket qua nghien cuu cho thay ty le benh nhan hut thuoc va nghien rugu d nhdm dung
clopidogrel cao hon nhdm dung aspirin-esomeprazol, tuong ung 13% so vdi 8,2% va 8,1%)
so vdi 5%.
A.Cac con so nay khdng anh hudng gi den ket qua danh gia tren tieu chi lam sang ciia
nghien cuu.
B.Ket qua cd the thuan lgi cho nhdm aspirin-esomeprazol neu khdng thuc hien hieu
chinh sir khac biet cac yeu to nguy co nay khi phan tich.
C.Khdng nen ban tarn den cac ket qua nay vi nghien cuu da dugc thiet ke lam mu va
phan nhdm ngau nhien.
D.Day la cac yeu to nguy ca lien quan den viec su dung clopidogrel.
E. Day la cac yeu to nguy co thudng thay tren benh nhan dau that nguc.
6. Ket qua nghien cuu cho thay: 1/159 benh nhan d nhdm aspirin-esomeprazol va 13/161
benh nhan d nhdm clopidogrel cd xuat huyet tieu hda tai phat trong thai gian theo ddi. Do
giam nguy ca tuang doi (RRR) ciia nhdm dung aspirin-esomeprazol so vdi clopidogrel la:
A. 90%
B.91%
C.92%
D.93%
E. 94%
7. Gia trj NNT ciia nhdm aspirin-esomeprazol so vdi nhdm clopidogrel la:
A. 9.
B. 10.
C. 11.
D. 12.
E. 13.
8. Ket qua nghien cuu cho thay phoi hgp aspirin-esomeprazol lam giam xuat huyet tieu hda
tai phat d benh nhan cd nguy co cao so vdi clopidogrel. Hon nua, benh nhan d nhdm
dung clopidogrel cd ty le gap bien co bat lgi chung nhieu hon trong khi khdng cd sir khac
biet ve cac bien co tim mach can du phdng d 2 nhdm. Dugc sT lam sang cd the can nhac
su dung ngay phac do aspirin-esomeprazol cho benh nhan dugc khdng:
110
A. Dugc vi hieu qua bao ve xuat huyet tieu hda qua ro rang
B. Dugc vi tac dung khdng mong muon it hon han. .^ ,
C.Dugc vi ca 2 phac do cho phep dam bao hieu qua du phdng bien co tim mach nhu
nhau.
D.Dugc vi phac dd aspirin - esomeprazol dem lai lgi ich vugt troi nguy co tuy nhien
can than trgng den sir khdng ddng deu ve dae diem ban dau ciia benh nhan cd. the
dan den sai sd khi bien giai ket qua.
E. Dugc vi phac do aspirin - esomeprazol dem lai lgi ich vugt troi nguy co tuy nhien
can than trgng den sir khdng ddng deu ve dae diem ban dau ciia benh nhan cd the
dan den sai sd khi bien giai ket qua. Them vao do can can nhac den chi phi ciia 2
phac do va sir chap nhan ciia benh nhan.
DAP AN CHO CAU HOI LlTONG GIA
1. A; 2. B; 3. E; 4. C; 5. B; 6. C; 7. E; 8. E.
TAI LIEU THAM KHAO
1. Nguyen Van Tuan (2008), Yhgc thuc chieng (Evidence-basedMedicine), NXB Y hgc chi
nhanh Thanh pho Ho Chi Minh.
2. Bond CM and Watson MC (2003), Evidence based practice, In "Encyclopedia of
Clinical Pharmacy", Marcel Dekker.
3. Chiquette E and Posey LM (2011), Evidence based medicine, In Dipiro JT, Talbert RL,
Yee GC, Matzke GR, Wells BG, Posey LM (eds) "Pharmacotherapy: A
pathophysiological approach", McGraw-Hill, 8th edition.
4. Chiquette E and Posey LM (2007), Evidenced-based Pharmacotherapy: optimal patient
care = best knowledge + competent practitioner, American Pharmacists Association.
5. Etminan M, Wright JM, Carleton BC (1998), Evidence basedpharmacotherapy: Review
of basic concepts and applications in clinical practice, Ann. Pharmacother., 32, 1193-
1200.
6. Gaebelein CJ, Gleason BL (2008), Contemporary drug information: an evidence-based

approach, Lippincott Williams & Wilkins.
7. Glasziou P, Del Mar C, Salisbury J (2006), Evidence-basedpractice workbook: Bridging
the gap between healthcare research and practice, Blacwell Publishing and BMJI
Books, 2nd edition.
8. Guyatt G, Rennie D, Meade MO and Cook DJ (editors) (2008), Users" guides to the
medical literature: A manual for evidence-based clinical practice, Mc Graw Hill
Medical/ JAMAevidence, 2nd edition.
9. Maloine PM, Kier KL, Stanovich JE (2006), Drug information: a guide for pharmacists,
McGraw-Hill, 3rd edition.
10. Wiffen P (2001), Evidence Based Pharmacy, Raddiffe Medical Press.
Ill
CHlTONG 5. PHAN ifNG CO HAI CUA THUOC VA CANH
GIAC DUOC
Pham Thi Thuy Van, Kees van Grootheest

MUC TIEU
Trinh bay dugc dinh nghia va cdc eachpi

Trinh bay dugc nguyen nhdn va cdcyeu to dnh hudng ciia ADR
Trinh bay diegc d\nh nghia, muc tieuva cdc linh v\ec uu tien ciia canh giac dugc.
Trinh bay dugc uu diem, nhugc diem ciia U thong bao cao tu nguyen
MOfDAU
Hau het cac thuoc, cho du dugc ke don bdi cac thay thuoc lam sang gidi cung co the
gay ra phan ung cd hai (ADR) tren benh nhan, tham chi la nhung ADR nghiem trgng. Day
la mot nguyen nhan quan trgng dan den benh tat va tu vong, ddng thdi lam gia tang ty le
nhap vien va chi phi dieu trj cho benh nhan. Kha nang gay ADR ciia mdt thuoc (ke ca tan
suat, muc do nghiem trgng va loai ADR chiing gay ra) quyet djnh viec lira chgn thuoc do.
Nhieu ADR cd the tranh dugc, neu nhu thay thuoc ke don cd hieu biet ro ve dae tinh dugc
ly, ca che ciia ADR va cac yeu to anh hudng, dae biet la nhung yeu to tao nen tinh nhay
cam dae trung ciia ngudi benh. Thay thuoc lam sang cd trach nhiem nhan ra ADR, hudng
dan, canh bao benh nhan ve kha nang xay ra ADR va tich cue tham gia vao he thong canh
giac dugc bang each tham gia bao cao cac ADR cho co quan cd trach nhiem.
1. PHAN ITNG CO HAI CUA THUOC (ADVERSE DRUG REACTION'- ADR)

1.1. Dinh nghia
Theo To chuc Y te the gidi (WHO):
'Than ieng cd hgicua thuoc Id mot phdn ieng ddc hgi, khdng duac dinh trudc vd xuat
hien a lieu thudng diing cho ngudi de phdng benh, chan doan, chua benh hoac lam thay ddi
mdtchuc nang sinh ly ".
Djnh nghTa nay khdng bao gom nhung phan ung do dung sai thuoc, dung sai lieu,
dung lieu cao cd chii djnh hoac vd tinh. Trong djnh nghTa nay, yeu to dap ung ca the la rat
quan trgng.
Mac du dugc chap nhan rdng rai, djnh nghTa nay cd mdt sd han che nhat djnh va do
vay, nhieu tac gia cung nhu cac to chuc da dua ra cac djnh nghTa ve ADR khac nhau vdi
cac muc dich khac nhau.
Nam 1995. vdi muc dich hudng dan each phat hien, giam sat va bao cao ADR trong
cac ca sd y te, Hiep hdi dugc sy My (American Society of Health-System Pharmacists -
ASHP), da dua ra djnh nghTa ve ADR nhu sau:
ADR la bat ky dap ieng nao khdng mong dai, khdng du tinh trudc vdi mdt thudc md:
1. Can ngieng thuoc (diing de dieu tri hay chan doan),
112
2. Can thay ddi lieu trinh dieu tri,
3. Can thay ddi lieu dung (ngogi trie cdc trudng hap hieu chinh nhd ve liiu diing),
4. Can nhap vien dieu tri,
nhan chua
ma co
phat
drug
chiing
cac to
Medical
ciing
nay
nay.
-Thudng gap ADR > 1/100

-It gap 1/1000 < ADR < 1/100
-Hiem gap ADR < 1/1000
- Rat hiem gap
o.r
ADR <1/10.000
1.2.2. Phdn loai theo muc do nang cua benh do ADR gay ra
thai gian
cue.
H3
Cac each phan loai nay giiip ngudi thay thuoc can nhac trudc khi ke don mdt thudc
cd ty le ADR cao hoac cd the gay cac ton thuang tram trgng de cd bien phap theo ddi, xu tri
thich hgp.
1.2.3. Phdn loai theo typ
Vao nam 1977, cac tac gia Rawlins MD, Thompson JW lan dau tien dua ra phan loai
theo typ don gian nhat, theo do cac ADR dugc phan loai thanh 2 typ chii yeu dua vao kha
nang phu theo lieu dung va tac dung dugc ly ciia thuoc. Theo each phan loai
nay, dae trung ciia tung typ ADR nhu sau:
* Typ A (dgngphu thudc liiu- dgng "tang cuang"):
- Tien lugng dugc ve mat dugc ly.
- Thudng phu thudc lieu dung (do do cac ADR typ A thudng gap doi vdi cac thudc cd
pham vi dieu trj hep).
- La tac dung dugc ly qua muc hoac la mdt bieu hien ciia tac dung dugc ly d mdt vj
tri khac.
Sauday la mdt so vi du cho cdc ADR typ A
- La tac dung dieu trj nhung cudng do vugt qua muc can thiet nhu: chay mau khi
dung thuoc chong ddng mau, ha dudng huyet khi dung thuoc dieu tri dai thao dudng,...
- La tac dung dieu trj nhung d vj tri hoac co quan khac hoac do tinh chat khdng chgn
lgc tren cac thu the, vi du: tac dung tren he tieu hoa ciia cac chat uc che cyclooxygenase
khong chgn lgc (cac NSAID).
- La tac dung dugc ly khac ciia thuoc khdng phai la tac dung dieu trj, vi du:
cac thuoc chong tram cam 3 vdng the hien ca tac dung khang thu the muscarinic, khdng cd
vai trd trong dieu trj chong tram cam nhung thudng gay khd mieng, giam thj lire... hoac tac
dung khang androgen ciia cimetidin.
I... >• 'C'U: 'V., '.;
* Typ B (dgng khdng phu thudc lieu - dang"la"):
- Thudng khdng tien lugng dugc ve mat dugc ly.
- Khong lien quan den cac dae tinh dugc ly da biet ciia thuoc.
- Thudng cd lien quan tdi cac yeu to di truyen hoac mien djch, u budu hoac cac yeu
to gay quai thai.
Dj ling thuoc la mdt vi du dien hinh cho ADR typ B vi khdng tien lugng dugc ve mat
duac ly va khdng phu thudc lieu dung. Dj ling thuoc dugc giai thich hoan toan thdng qua co
che mien djch dj ung, khdng lien quan den cac tac dung dugc ly ciia thuoc. Bieu hien lam
sang ciia dj ling thuoc rat da dang, cac co quan bj ton thuang cd the la da, gan, than, dudng
tieu hoa hoac toan than; muc do nghiem trgng tu nhe (phat ban d da, ngua...) den rat nang,
tham chi gay hi* vong cho benh nhan nhu soc phan ve, hdi chung Lyell, Stevens - Johnson...
Tuy khdng tien lugng dugc nhung cd the han che sir xuat hien ciia dj ung thuoc neu cac nhan
vien y te cd bien phaptheo ddi chat che va phat hien sdm.
Tuy each phan loai ADR thanh 2 typ don gian va de thuc hien, nhung mdt so ADR khd
phan loai vao 1typ, do vay mdt so phan nhdm khac da dugc bo sung, bao gom:
114
- Typ C (dang phu thudc lieu dung va thdi gian dung -dang "man tinh"): la cac ADR
it gap va cd lien quan den lieu tich luy.
- Typ D (dang lien quan den thai gian- dang "xuat hien cham"): la cac ADR it gap, thudng
lien quan den lieu dung va xuat hien hoac cd bieu hien ro sau mdt thdi gian dung thudc.
- Typ E (dang xuat hien sau khi ngung thudc): la cac ADR it gap, xuat hien sau thai
gian ngan sau khi ngung thudc.
- Typ F (That bai dieu trj khdng mong muon): la cac ADR thudng gap, phu thudc lieu
dung va thudng do hau qua ciia tuong tac thudc.
Trong cac typ ADR tren, ADR typ A va Typ B la dugc phan loai dua tren co che, cac
typ khac dua tren bieu hien ciia phan ung.
1.2.4. Phan loai theo DoTS
Cach phan loai theo typ, cho du da bo sung cac typ mdi nhung van con mdt sd khd
khan khi phan loai cac ADR.
Nam 2003, tac gia Aronson va Ferner da de xuat mdt'cach phan loai mdi, ggi la he phan
loai DoTS. He phan loai nay can nhac ca cac dae tinh ciia phan ung cd hai, cac yeu to ciia
benh nhan va thudc theo 3 true: lien quan den lieu dung (dose relatedness-Do), dien bien theo
va cac yeu to nhay cam ciia ADR (susceptibility-S). He thdng phan
ling dung de phan
loai ADR
1.3. Nguyen nhan (ca che) gay ADR
Do ADR typ A va typ B dugc phan loai dua tren co che, nen cac nguyen nhan gay
ADR dugc phan tich tren hai nhdm ADR nay.
Cac ADR du d typ A hay B cung lien quan den 3 nhdm nguyen nhan:
- Lien quan den bao che (gap ca 2 typ).
- Lien quan den su thay ddi duoc ddng hoc (gap nhieu d typ A).
- Lien quan den sir thay ddi dugc lire hgc do cac yeu to ve di truyen va benh ly d benh
nhan dan den thay ddi sir nhay cam ciia co quan dich ddi vdi thudc (gap nhieu d typ B).
1.3.1. Cdc nguyen nhdn ve bao che
- Cdc nguyen nhdn ve bao che gay ADR typ A
- Ham lugng thudc: trong qua trinh san xuat va kiem soat chat lugng dugc pham cd the
cd nhung sai sot lam cho ham lugng hoat chat trong che pham cao hon ham lugng quy djnh
ghi tren nhan va viec su dung cac che pham nay cd the gay ra ADR typ A.
- Tdc dd giai phdng hoat chat: tdc do giai phdng dugc chat ciia mdt che pham phu
thudc vao ky thuat bao che nhu kich thudc tieu phan, ban chat va lugng ta dugc trong che
pham dd:
+ Tdc do giai phdng dugc chat cao cd the gay ADR tai chd, vi du: vien nen kali clorid
gay xuat huyet va loet dudng
giai phdng cham de tranh tao nong do cao tai cho.
115
+ Toe do giai phdng dugc chat cao co the gay ADR toan than, loai ADR nay thudng
gap d dang vien giai phdng keo dai do d dang bao che nay, ham lugng hoat chat thudng cao
han vien thudng va mot khi vien bi vd se tao ra mdt nong do rat cao gay ADR toan than.
- Cdc nguyen nhdn ve bao che gay ra cdc ADR typ B
- Suphdn huy cdc thanh phdn duac chat:
San pham phan huy ciia thuoc cd the cd ddc tinh cao, tham chi cd kha nang gay tu
vong cho benh nhan. Vi du: neu su dung cac che pham da bj phan huy khi bao quan trong
dieu kien nhiet do cao ciia tetracyclin cd the bj mac hdi chirng Fanconi vdi cac bieu hien:
tang bai tiet acid amin, glucose, aceton... qua dudng tiet nieu; va kem theo tang nhay cam
vdi anh sang.
- Tdc dung cua cdc ta duac cd trong thanh phdn duacpham:
Cac thanh phan ta dugc ciia thuoc cung cd the gay ra cac ADR. Cac dung moi nhu
propylen glycol hoac dau thau dau dugc su dung de hda tan mdt so hoat chatcung cd gay ra
ADR nhu ha ap hoac phan ung phan ve. Cac chat mau (nhu tatrazine), cac chat bao
quan (nhu benzoate)
- Tdc dung ciia cdc san phdm phu trong qua trinh tdng hap hda hgc dugc chat:
Vi du: hdi chirng bach cau ua eosin da xay ra khi nhieu benh nhan dung
che pham L-tryptophan dugc san xuat theo quy trinh trong do tao ra mdt lugng dang ke
cac san pham ngung tu. Hien nay hien tugng nay it gap do sir quan ly chat che ciia cac co
quan quan ly ve chat lugng thuoc.
1.3.2. Cdc nguyen nhan lien quan den thay doi duac ddng hoc
- Cdc nguyen nhdn lien quan den thay doi duac ddng hgcgay ra ADR typ A
Cd rat nhieu nguyen nhan dan den nhung thay doi ve kha nang hap thu, phan bo,
chuyen hda va thai tru thuoc. Sau day la cac nguyen nhan gay ra cac ADR typ A do sir tang
nong do thuoc trong huyet tuong va md dich.
- Hap thu: nhung khac biet ve lugng thuoc dugc hap thu vao mau lam thay doi sinh
kha dung va cd the gay ra ADR. Nhung yeu to anh hudng sinh kha dung ciia thuoc bao
gom: lieu dung, cac to ve bao che, nhu ddng dudng tieu hda, kha nang hap thu ciia niem
mac dudng tieu hda, chuyen hda vdng dau d gan va thanh rudt trudc khi thuoc vao vdng
tuan hoan chung. Toe do hap thu cac thuoc dung qua dudng uong chii yeu bj anh hudng bdi
toe do thao rong da day, do vay bj anh hudng chii yeu bdi thuc an, benh ly va cac thudc
dung kem. Mdt so ADRtyp A cd the gap do nguyen nhan nay la:
+ Anh hudng ciia thuc an: mot so loai thuc an cd the lam tang hap thu hoac lam giam
thai tru d vdng tuan hoan dau qua gan ciia mdt so thuoc va do vay lam tang sinh kha
hydrochlorothiazid, phenytoin, mdt so thuoc tay giun nhu
mebeldazol, thiabeldazol...
+ Nhu ddng dg day - rugt: giam nhu ddng rudt cd the lam tang hap thu thuoc do lam
tang thai gian thuoc luu d vi tri hap thu tot nhat, vi du: sau khi dung propanthelin, sinh kha
dung ciia digoxin tang len.
.On'} ?€tOfi3 Ob JSflOfl QfiJ dslfVlJ .J£r fflfii '\ '••''kSx>.
116
+ Chuyen hod a vdng tuan hodn dau qua gan: sir giam chuyen hda thuoc tai gan anh
hudng nhieu den cac nhdm thuoc bj chuyen hoa manh khi qua gan trudc khi vao he tuan
hoan chung nhu: chlorpromazin, cyclosporin, glycerin trinitrat, lidocain, ethinylestradiol,
morphin, propranolol... Sir thay d6i kha nang chuyen hoa ciia cac enzym gan cd the la:
•Do yeu to chiing tdc. Vi du: ngudi chau Phi thudc loai acetyl hoa cham vdi isoniazid
nen de dan den qua lieu isoniazid;
• Do tuong tac thuoc. Vi du: erythromycin, clarithromycin, so thuoc khang nam
(ketoconazol) gay uc che chuyen hda enzym gan cyt. P450 lam tang len dang kk ham hugng
terfenadine trong he tuan hoan va chinh chat nay lam cham qua trinh tai khur tim
va keo dai khoang QT tren dien tarn do va gay ra hien tugng xoan dinh.
Tuy nhien, ngoai viec gay ra cac ADR do tang nong do thuoc nhu tren, nhung thay
ddi dugc ddng d giai doan hap thu chii yeu dan den that bai dieu tri va cung can dugc
luu y trong qua trinh dieu trj. •
- Phan bo: kha nang phan bo ciia thuoc phu thudc vao ty le lien ket ciia thuoc vdi
protein huyet tuong hoac vdi protein ciia to chuc (md):
+ Ty le thudc lien ket vdi protein huyet tuang: giam dan tdi tang nong do thuoc d
dang tir do trong mau va td chuc; do chinh la nguyen nhan gay ADR typ A, tuy nhien y
nghTa lam sang ciia co che nay chua ro rang.
+ Khd nang gan thuoc vdi md: the tich phan bo ldn ciia cac thuoc nhunortriptylin (20-
50 L/kg) chi cd the giai thich la do lien ket ciia thuoc vdi md va la co che chinh gay ra mdt sd
ADR ciia thuoc. Tetracyclin tao chelat vdi cac md xuong mdi (phuc tetracyclin - calcium
orthophosphat); thai gian ban thai ciia thuoc d md xuong la vai thang trong khi d tuong
chi cd vai gid. Hien tugng nay itanh hudng d ngudi ldn nhung gay uc che suphat trien xuong
d tre nhd cung nhu mat mau va pha huy men rang. Sir tich luy d md cung gay ddc tinh
tren gan va phoi ciia amiodaron va methotrexat.
- Chuyen hod thuoc: toe do chuyen hoa giam cd the dan den tich luy thuoc va tang
nguy co ADR typ A. Toe dg chuyen hda thuoc khac biet ldn giua cac ca the do anh hudng
ciia mdi trudng hoac di truyen, tuoi tac hoac benh ly; cac qua trinh bj anh hudng la oxy hoa,
thuy phan va acetyl hoa:
+ Oxy hod a microsome:
Sir oxy hda thuoc xay ra chii yeu d gan bdi he enzym cyt. P450. Cd nhieu typ
isoenzyme cytochrome P450 d ngudi. Nhung typ nay khac nhau trong tinh dae hieu ciia cac
phan ling ma chiing xiic tac. dugc chuyen hda bang each oxy hda d microsome gan
thudng dung la cac thuoc chong tram cam 3 vdng, chong ddng kinh, cac thuoc chong
ddng mau dudng uong, benzodiazepin, phenothiazin va mdt sothuoc chong loan nhjp...
Tdc do oxy hda thuoc khac nhau rat nhieu ngay d nhung ngudi binh thudng, do vay,
d mdt so ngudi nong do gay ddc da dat sau khi dung lieu thdng thudng ciia mdt so thuoc
nhu phenytoin va nortryptilin.
O ngudi gia, toe do oxy hda thuoc giam va do vay do nhay cam vdi cac ADR typ A
tang len. Nguyen nhan chii yeu la do khoi lugng gan va luu lugng mau qua gan giam anh
hudng den su chuyen hda d gan ndi chung va do tinh ciia cac enzyme thay doi.
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+ Cdc phdn ieng thuy phdn: khac biet ve gen cd the la nguyen nhan gay khac biet ve
toe do thuy phan suxamethonium, mdt chat uc che than kinh - co d cac nhdm chiing tdc
khac nhau.
+ Acetyl hda: mdt so thuoc chuyen hda bang each acetyl hda nhu: isoniazid,
hydralazin, procainamid va nhieu sulfonamid (sulfamethoxazol, sulfapyridin). Nhung khac
biet ve toe do acetyl hda do nhung khac biet ve gen giua cac ca the, the hien dudi dang
nhung ngudi acetyl hda nhanh va nhung ngudi acetyl hda cham, dieu nay cd the anh hudng
den ADR ciia nhung loai thuoc ke tren. nhung ngudi hda nhanh chiem khoang
50% d Anh va cao nhat d nhdm ngudi Nhat ban, ngudi Eskimo va thap nhat d mot so dan
tdc d chau Phi. Nhung ngudi "acetyl hda cd nguy co bi cac ADR typ A cao hon
nhung ngudi acetyl hda nhanh, vi du: benh ly than kinh ngoai vi do isoniazid, lupus ban do
he thong khi dung hydralazin va procainamid...
- Thdi trie: nhung thay doi trong thai tru thuoc cd the la nguyen nhan quan trgng gay
nen ADR typ A. Giam thai tru lam tang tich luy thuoc va tang nguy co gay ddc tinh do tang
nong do thuoc tai mo va huyet tuong:
Gidm khd nang lgc cua cdu than: lam giam thai tru nhung thuoc thai tru qua than.
Giam kha nang lgc gap d nhung benh nhan bj benh than, ngudi gia, tre so
sinh; do vay kha nang xuat hien ADR typ A d nhung doi tugng nay cd the gap ngay d lieu
dieu trj binh thudng vdi nhung thuoc thai tru phan ldn d dang cdn hoat tinh qua than. Mdt
so nhdm thuoc hay gap ADR do nguyen nay la digoxin, cac chat uc che men chuyen
(ACEI), cac khang sinh aminoglycosid, mdt so thuoc chong loan nhjp nhdm 1
(disopyramid, flecainide) va nhieu thuoc gay ddc te bao. Cd the han che sir xuat hien cac
ADR nay bang each dieu chinh lieu dung theo chuc nang ciia benh nhan.
- Cdc nguyen nhdn lien quan den thay doi duac ddng hgcgay nen ADR typ B
Su lien ket ciia cac chat chuyen hda cd hoat tinh ciia thuoc cd the gay doc true tiep
hoac gay doc qua trung gian mien djch. Co che gay ADR cd the do sir lien ket ciia chat
chuyen hda vdi mdt protein ciia co the, phuc hgp tao thanh cd the dan tdi hoai tu te bao (tac
dung gay ddc true tiep) hoac cac chat chuyen hda tac dung nhu mdt hapten vatham gia vao
mdt phan ling mien djch.
1.3.3. Cdc nguyen nhan lien quan den thay ddi duac luc hoc
* Cdc nguyen nhdn lienquan den thay ddi dugc luc hgcgayADR typ A
Mot so ADR typ A la do tang do nhay cam ciia cac md hoac co quan dich, nguyen
nhan con chua dugc ro nhung nhieu bang chirng cho thay miic do nhay cam ciia
ciia thuoc tai co quan dich bj thay doi hoac thay doi co che
hoac benh ly.
- Lien quan den thu the ciia thudc:
Su dap ung vdi thuoc thdng qua tac dong ciia thuoc vao thu the dae hieu. Sir khac biet
giua cac cathe vh cac thu the la do 2 nguyen nhan: khac biet ve tinh nhay cam va khac biet
ve so lugng ciia cac thu the.
+ Ve tinh nhay cam
d mdt sd gia dinh, bilu hien d cho can mdt lieu ldn warfarin va vdi nong do rat cao trong
118
huyet tuong de cd dugc tac dung ddng mau trong dieu trj. Nhung ngudi nay cung dae
biet nhay cam vdi tac dung khang warfarin
la do nhung ngudi nay cd cac thu the warfarin - vitamin K bat thudng.
+ Ve sd lugng thu the: cac bang chiing tren nghiem va lam sang cho thay so lugng
thu the hieu d md cd the khac biet cd tac dung uc che tang
trudng
sau do
Phuc hgp "thu the-corticoid" d nhan lam thay doi kiem soat qua trinh
RNA va uc che tang trudng te bao. ngudi cd so lugng cac thu the glucocorticoid
trong bao it ciing it bj tac dung uc che
-
Cac tac dung cd cac he thdng kiem soat sinh ly
phuc tap va cudng
tiem mach atropin gay ra hien tugng tang nhjp tim nhung
giua
muc lai khdng cd tac dung vdi da sd
phu thudc vao can bang yeu to dugc kiem soat bdi
tinh di
* Cdc nguyen nhdn ve duac luc hgc gay nen cdc ADR typ B
hgc gay nen cac ADR typ B dugc xep vao hai nhdm:
cac bat thudng ve gen va cac phan ung mien djch tao ra cac dap ung thudng ciia co the
doi
- Cdc nguyen
Cac khac biet ve gen giua cac ca the la nguyen nhan gay ra cac dap ling bat thudng,
khac biet vdi tac dung dugc ly ciia thuoc. Sau day se gidi thieu mdt so phan ling ADR typ B
- 400 trieu ngudi tren the gidi bj thieu men G6PD

ddi tugng nay cd nguy co gap
va trong dieu kien khdng dugc bao ve
thieu mau tan mau di kem vdi giam nhanh
PAS, probenecid, quinin va
reductase la NADH diaphorase hoac NADPH diaphorase.

cau (typ I) hoac ca d cac te
bao khac (typ II, III). vdi cac tac nhan oxy hda va bj
119
methemoglobin mau nang neu su dung cac thuoc cd dae tinh nay. May man la thieu
NADPH diaphorase rat hiem gap. Tre so sinh cd nong dd NADH diaphorase thap hon nen
nhay cam vdi cac thuoc oxy hda hon tre ldn va ngudi trudng thanh.
+ Rdi logn chuyen hda porphyrin:
La mdt nhdm cac roi loan sinh tong hgp Hem do di truyen, dae trung bdi sir giam
hoat tinh ciia mdt loai enzym trong qua trinh sinh tong hop Hem. Cac roi loan nay dugc
truyen qua cac nhiem sac the trdi (gen trdi) tru mdt so rat hiem la roi loan chuyen hda
porphyrin bam sinh, thudng cd dae tinh lan. Trong con loan chuyen hda porphyrin cap
tinh, tat ca benh nhan deu cd bieu hien dau bung (thudng la nang) va cac roi loan than
kinh... tarn than nhu: benh ly than kinh van ddng, lan, lo au, ao giac va trong nude tieu cd
lugng ldn 5-aminolevulinic acid (ALA) va porphobilinogen (PBG). Con roi loan chuyen
hda porphyrin cap tinh cd the khdi phat do rugu va cac hormon steroid ndi sinh cung nhu
ngoai sinh. Cac yeu to khdi phat khac bao g6m: nhiem trung, che do an giam calo, cac thay
d6i hormon va phu nu cd thai va do mot so thudc.
Mot so thuoc gay cam ling enzym cytochrom P450 d gan, lam tang tao tien chat ciia
haem cam.
Cac thuoc nay g6m: barbiturat, sulfonamid, griseofulvin, oestrogen (bao gom ca cac thudc
tranh thai dudng uong), mdt so thuoc chong co giat va an than, cac thudc gay me,
cloroquin, clorpropamid, va tolbutamid. Tuy nhien, con cap tinh cung cd the khdi phat do
su dung cac thuoc khdng thdng qua co che kirn ham enzym cytochrom P450 nhu
erythromycin, flucloxacillin, eloramphenieol va nifedipin; co che ddi vdi cac thuoc nay van
con chua ro.
Rat khd cd the du doan trudc la thuoc co the gay ra cac bieu hien benh ly tren cac
benh nhan nhay cam hay khdng vi mdt so benh nhan cd the khdi phat con cap tinh de dga
tinh mang sau mdt lieu duy nhat ciia thuoc trong khi cac benh nhan khac lai can lieu rat ldn
mdi thay bieu hien tren lam sang.
+ Tang nhiet do ca the (than nhiet) dc tinh: tang than nhiet ac tinh la benh ly rat hiem
nhung cd kha nang gay tu vong cao. Trong benh ly nay than nhiet tang nhanh chong (it nhat
2°C/gid) ma khdng cd nguyen nhan ro rang sau khi dung cac thudc gay me hoac gian co; tai
bien nay gap vdi tan suit khoang 1/50.000 ngudi ldn va 1/15.000 tre em, trong do hon mot
nua so trudng hop xay ra d tre em dudi 15 tuoi. Tinh trang nay thudng xuat hien sau khi diing
cac thuoc gay me toan than qua dudng hd hap nhu halothan phoi hop vdi suxamethonium.
Cung vdi tang than nhiet, hoi chung nay cd dae trung la ciing he co - xuong, thd gap, nhiem
acid, tang kali mau va cac dau hieu ciia tang hoat tinh he than kinh giao cam (nhjp tim nhanh,
co mach, tang huyet ap, tang nong do glucose mau). Tinh trang nay dugc cho la do hien tugng
giai phong bat thudng ion calci ndi bao do nhung khiem khuyetdi truyenciia mang te bao. Tu
vong cd the len den 60 -70%>.
+ Vdng da ie mat do diing thudc tranh thai dudng uong: cac thudc tranh thai dudng
uong (dae biet la cac thuoc cd thay the alkyl d vj tri CI7) cd the gay ra vang da u mat. Cac
bang chung ve ty le mac tugng nay cd co sd
di truyen. Co che ciia hien tugng nay chua ro rang nhung mdt
do estrogen gay ra nhung thay ddi ve thanh phan ciia lipid mang - nguyen nhan quan trgng
gay u mat.
120
- Cdc nguyen nhdn ve mien dich
Rat nhieu phan ung cd hai xay ra che mien djch. Mdt sd thudc, vi du
nhu cac cdn la cac chat sinh mien djch
ung "that" la cac phan
- Khdng thudng ciia thudc.

- Cd vdi thudc va thai diem
xuat hien
- Mdt khi da cd dj ung, chi can cung cd the khdi phat phan ung.
- Phan ung mat di khi ngung thudc.
- Cd the dugc nhan dien cac bieu hien dae trung ciia benh la mdt dang ciia phan ung
mien djch.
•"•
dang noi ban, benh ly huyet thanh va

phu mach cho den hien co that phe quan va ha huyet ap de dga tinh mang trong soc
phan
hien cac phan ung dj ung, trong do nguy
hgc, tren co sd khac biet ve cac gen ma hda he thong khang nguyen bach cau ngudi
(human
1.4. Cac
1.4.1. Cdc
- Tuoi:
Tre so sinh va ngudi cao tuoi la nhung doi tugng cd nguy co cao:
• Ngudi cao nhung
benh nhan khac do:
- Lam dung thudc.

- Thay ddi ve dugc ddng hgc, dugc lire hgc do giam chuc nang cac co quan.
- Ngudi cao tuoi thudng mac
thudc.
-••
• Tre sa sinh: dae biet la d tre de non bdi vi mdt so

enzvm dii.
morphin, cac barbiturat, cac sulfonamid, cac dan xuat ciia vitamin K va eloramphenieol.
- Gidi tinh
Phu nu Vi du:
phu nu cd the nhay va
chloramphenicol, keo dai hien tugng nay
121
chua ro rang, cd the la do
hgc, mien djch
- Chung tdc
Nhieu phan ung ung ngay nay da dugc lam
sang to la cd cac
cac thu the va cac
nhu ddc tinh ngudi thieu hut men G6PD do di truyen khi dung
nhung thudc cd tinh oxy hda thi cd the bj
Hien biet la he enzym Cyp P450, cung
tao thanh cac kieu hinh
chuyen hoa sieu den hieu qua dieu trj cung
nhu phan
-Benh mac
Nhung
lam thay doi
Vi du:
+ Diec
chay mau tram trgng do dung cd san thieu hut ve yeu to ddng mau.
+ Cac benh nhan
thudc thai
- Tien sie di ieng hoac phdn ung vdi thudc
Nhung dj ung vdi cung cd the gap dj ung vdi mdt
thuoc nhu cac trudng hgp dj ung vdi khang sinh penicillin
cung cd the cd dj ung cheo vdi khang sinh nhdm cephalosporin.
1.4.2. Cdc
- Ddc tinh ciia thudc
+ Anh hudng ciia ky thuat bao che: kich thudc tieu phan, lugng thudc trong che
pham, tinh chat va khdi lugng ta dugc... cd the dan tdi thay ddi tdc do giai phdng hoat chat,
gay ADR typ A. Su dung mdt sd ta dugc cho cac nhom benh nhan nhay cam nhu cac benh
nhan hen, cac tre so sinh nhe can va
dung ciia thudc nhu digoxin va phenytoin
+ Anh hudng
thudc da bj phan huy thi dan den that bai dieu trj,
thudc cd the gay ddc hoac
dung moi cho cdn
pham phan huy ciia
qua man la: polypropylen
- Dieu tri nhieu thudc ddng thdi
Nguy co gap phan ung cd hai va
khi tang
122
dugc lire ciia thudc va cung cd the do cd anh hudng
ciia tinh trang da benh ly da gay ra cac ADR
- Lieu trinh dieu tri keo dai
Nhieu ADR it xuat hien khi dung thuoc len khi

dung xuat huyet tieu hda do steroid
hoac
1.5. Cac
1.5.1.
•
• Neu benh nhan dang su dung ddng can nhac de tarn ngung
can thiet. Can danh gia cd tuong tac bat lgi khdng.
• Kiem tra va hdi benh nhan ve
1.5.2.
• Hieu ciia thudc. Chi nen
• tuong tac thudc.

• Than trgng khi ke biet la cac tuong tac do
1.5.3. Nam vung

dja dj ling, cd benh ly ve gan, than
va cac benh nhan cd bat
1.5.4. Theo phdn ieng cd hai do
thudc nhung tri kip thdi
2. CANH GIAC DlTOC (PHARMACOVIGILANCE)

2.1. Sy can thiet canh giac dugc
6 nhieu quoc tat chi ciia thuoc gay ngii
thalidomid (Softenon®, so he thong dugc thanh lap de
giam sat sau khi luu hanh (post
Tai thai tin ve cac phan ung cd hai chii
yeu thu nhan dugc khi cap phep. Tuy nhien cac thdng tin
ciia mdt thuoc khdng the
ghi nhan tat ca cac ADR cd the xay ra do cac nguyen nhan sau:
- Cac thu nghiem tren ddng vat khdng dii de tien lugng sir an toan tren ngudi.
- Nhung benh nhan tham gia thu nghiem la nhung doi tugng da qua lira chgn va cd so
lugng han che, dieu kien thu nghiem thuoc cd khac biet so vdi thuc te su dung tren lam
123
sang va thdi gian thu nghiem lieu ve tinh an toan tren
nhung doi
- Tai
ngudi thi chi phat hien dugc gap va it gap. So lugng benh
nhan dieu trj mot thudc phai ldn hon 30.000 ngudi thi mdi cd kha nang phat hien cac ADR
xay ra d tan
- Tai diem luu hanh thudc, thdng tin ve cac ADR hiem gap nhung nghiem trgng,
ddc tinh trudng cd thai, tre em,
ngudi gia), cac
trgng, cho phep phat hien cac ADR khdng bien nhung ddi khi rat nghiem trgng.
2.2. Khai niem va
2.2.1. Khdi niem
Canh giac duac phat hien, danh

gid, xiely vd ngan thudc.
Gan day djnh ca ddi vdi cac san
pham cd nguon lieu, thuoc y hgc cd truyen, thudc bd, san pham mau,
dung cu y te va vaccin.
Nhu vay thuc chat canh giac mdn khoa hgc nghien cuu giam sat tinh an
toan ciia thudc, vi vay pham vi lai d ADR ma cdn bao
gdm ca cac van de:
- Thudc kem
- Cac sai sot
- Thieu cac bao cao
- Su dung thudc vdi cac chi djnh co quan quan ly phe duyet va su dung
cac thudc thieu co sd khoa hgc.
- Ngd ddc thuoc.
- Tu vong lien quan den thudc.
- Lam dung hoac dung sai thudc.
- Tuong tac bat lgi ciia thudc vdi cac thudc, thuc an, hda chat.
2.2.2. Muc tieu cua hogt ddng canh giac duac
- Phat hien sdm nhung phan ung cd hai hoac tuong tac thudc chua biet.
- Phat hien sir thay ddi tan suat ciia cac phan ung cd hai da biet.
- Xac djnh cac yeu to nguy co va co che ciia cac phan ung cd hai.
- Danh gia chi sd lgi ich/nguy co va phd bien nhung thdng tin can thiet de cai thien
viec ke don va quan ly thudc.
2.3. Mot so llnh vyc iru tien cua canh giac dirac
De thuc hien cac muc tieu hoat ddng ciia chuang trinh canh giac dugc, cac hoat ddng
sau dugc chii trgng tang cudng:
124
2.3.1. Phat hien cdc ADR
-
cong ddng nham phat
- Thuc hien cac nghien cuu ve van de an toan thuoc nhu: nghien cuu ca ddi chirng,
nghien ciiu dich
- Xac djnh san pham sinh hgc,
thuoc thu y, dugc nghe sinh hgc va cac thudc dung de tham dd,
chan doan. Viec xac djnh tinh an toan sir
hgp tac nhieu chuyen gia trong cac
cac du ("Dau hieu" la thdng tin dugc bao cao ve bien cd cd hai
lien quan den thudc. Bien cd nay, trudc do chua dugc biet hoac chua dugc de cap day
du. Thdng thudng, phai can nhieu bao cao de phat hien ra miic
do nghiem trgng
2.3.2. Danh
Viec danh gia cac ADR gia hoac
quoc te. De thuc hien
hieu" trong cac quoc
va de cd cac
2.3.3. Du phdng
De du phdng cong viec sau:
- Cung cap cac thudc hieu qua va an toan trong dieu trj cac benh thudng gap d cac
nude dang phat trien, dae biet la trong cac chuang chuang trinh chong
lao quoc chiing md rong,...).
nhan thuc ve an toan thudc va sir dung thudc hgp ly ddi vdi cac chuyen
gia y te va ddng, ke ca cac thudc y hgc co truyen va dugc
thuoc
trinh y te khac (vi du: cac hudng dan dieu trj chuan, danh muc thudc thiet yeu,...).
2.4. Vai
2.4.1.
Assurance
chinh
vu cung
125
2.4.2. Trung tam hop tdc cua WHO ve gidm sat thuoc quoc te Uppsala (WHO
Collaborating Centrefor International Drug Monitoring)
Chuc nang chinh ciia trung tam la quan ly co sd du lieu quoc te ve cac bao cao ADR
nhan dugc tu cac trung tam ADR quoc gia. Gan day, trung tam nay da md rong vai trd nhu
la mdt trung tam dao tao, tuyen truyen ve an toan thuoc thdng qua cac ban tin thu
(Newsletters), hdi nghj hang nam ciia cac trung tam ADR quoc gia, cac nhdm thao luan,
trang web,...
2.4.3. Cdc trung tam canh giac duac (trung tdm ADR) quoc gia:
Trung tam canh dugc (trung tam ADR) quoc gia cd vai trd ciia rat quan trgng
trong he thong canh giac dugc. Phoi hgp vdi cac bd phan ciia To chuc Y te the gidi, cac
trung tam canh giac dugc quoc gia da cd nhung thanh edng ldn trong cac nhiem vu:
- Thu thap va phan tich cac bao cao ve ADR.
•
- Phat hien cac "dau hieu" tu cac thong tin thu dugc.
, r t
- Dua ra cac quyetdjnh quan ly dua tren cac dau hieu da dugc ciingco.
- Canh bao thay thuoc ke don, cac nha san xuat dugc pham va edng dong biet ve cac
phan ung cd hai mdi.
Pham vi hoat ddng ciia cac trung ve
lgi ich, nguy co, hieu qua va riii ro tdi sd
trung tam quoc gia tai cac nude phat ddng
su dung du lieu ke don lien ket va he te
hgc ve phan ung cd hai ciia mdt sd thudc.
Tai Viet Nam, hai
ciia thuoc da dugc thang 3 nam 2009
cua Bo Y te. Theo den hoat ddng
thiet lap he thong hgc trong lTnh
vuc canh giac dugc dieu
tri, cac co quan quan dugc tai
Viet Nam.
2.4.4. Cdc ca quan quan

Cac co quan
va
- Thiet lap he thong giam sat phan ling.cd hai va cac sai sot trong trj lieu tai cac khoa,
phdng kham, phdng cap cuu va dieu trj.
- Tien hanh cac nghien cuu de xac djnh nhung ADR cua thuoc sau khi luu hanh.
- Giang day, dao tao va xay dung chinh sach ve an toan thudc.
2.4.6. te
tri va tich cue bao cao cho cac
to chiic, tham quyen.
2.4.7.
thuoc tu
khi bat dau nhiem
thiet lap he tin vdi cac ca
quan quan
2.5. Mot
2.5.1. Gidm sat thu System)
He pham va
nhan vien y te canh
dugc quoc
Day la he thu thap thdng tin quan trgng nhat, vj tri hang dau trong hoat
dong canh giac hay that bai hoat ddng canh giac
dugc phu thudc vao viec bao cao cac ca benh gap phan ung cd hai.
- Uu diem
• Don gian va ton it nhan phuang phap tich cue khac.
• Ton it chi phi.
• La phuang phap dugc su dung nhieu nhat trong canh giac dugc, nen cac trung tam
canh giac dugc quoc gia va nhan vien y te quen thudc vdi phuang phap nay.
• Thu thap bao cao tir mdt quan the benh nhan ldn vdi tat ca cac thuoc.
- Nhuac diem:
• DCr lieu thu thap khdng hoan chinh, bao cao thieu (under-reporting) va bao cao sai
lech (chgn lgc). 0 cac nude
cao thieu cd the dan den ket luan sai lech rang khdng cd nguy co that su, trong khi bao cao
chgn lgc cac nguy co cd the dua ra an tugng sai lam ve mdt nguy co khdng ton tai. Tuy
nhien, bao cao thieu va bao cao chgn lgc cung co the dugc nhin nhan la uu diem, bdi vi chi
nhung muon nhat dugc bao cao, do vay se de dang
phat hien ADR, do nhung ngudi bao cao da djnh vj ring do cd the la
mdt van xuat hien.
• Khong the tinh toan tan suat ciia phan ung va do vay khdng the danh gia chinh xac
co va cung khong xac djnh dugc cac yeu to nguy co.
• Cac it khi dugc bao cao.
127
Cac bao cao tu nguyen ddng mot vai trd quan trgng trong viec xac djnh sdm cac "dau
hieu" (signal) trong van de an toan thuoc khi thuoc da dugc luu hanh. Cac bao cao nay cung
cd the cung cap cac thdng tin quan trgng ve cac doi
(cho du thdng tin han che) va cac ADR nghiem trgng da biet.
- Nhieng ngudi tham gia vao
Cac can bd y te la nhung tiep cham sdc benh nhan hang ngay va cd dieu
kien tot nhat de bao cao cac nghi ngd ve
tham gia vao he thong cham sdc khde nhan dan nhu bac
dieu deu can phai bao cao cac ADR va viec lam nay trd thanh
trach nhiem hg, ngay ca khi ADR bj nghi ngd chua cd moi quan he
vdi viec
- Nhieng ADR) cdn

ciia tung
quoc gia thudng co cac hudng dan doi vdi cac
tam va theo
bd y ke ca khi
thdng tin can thiet.
nghi
- Doi vdi cac thuoc mdi dugc dua ra thj trudng, phai bao cao mgi phan ung dang ngd,
ke ca cac
chua
thuoc da dugc biet ro hoac nghien cuu day du: Bao cao tat ca cac
nghi
an,
hoac thuoc - thuc pham bo sung (keca cac san pham lam tu dugc lieu va thuoc bo).
- Bao cao cac ADRtrong nhung lTnh vuc dugc quan tam dae biet: Lam dung thudc, dung
thuoc cho phu nu cdthai va cho con bii,ve ADR lien quan den viec ngung thuoc.
- Bao cao cac phan ung xay ra do dung qua lieu hay do sai sot trong dieu trj.
- Bao cao khi thuoc khdng cd hieu qua hoac do nghi ngd cd sai sot ve san pham.
Nhu vay, nhan vipn y te can bao cao cang sdm cang tot tat ca cac nghi ngd ve ADR
dugc coi la quan trgng tren lam sang.
- Nhung thdng tin cdn bao cao ddi vdi mdt ADR
Moi quoc gia cd mdt mau bao cao do trung tam ADR quoc canh
giac dugc) phat hanh (xem phu luc). Mau bao cao ADR nay cd quoc
gia, nhung bao gid cung cd 4 phan
128
- Gidi tinh.
- Trgng lugng ca the.

+ Thdng tin ve ADR (hoac ADE) hoac cac van de ve dugc pham
- Md ta sir cd hoac van de ve san pham.
- Thai gian xay ra sir cd.
- Thai gian lam bao cao.
- Cac ket qua xet nghiem can lam sang co lien quan den sir cd (neu cd).
- Thong tin khac ciia benh nhan (ljch sir dung thudc, tien sir benh,..) cd lien quan.
- Hau qua ciia ADE tren benh nhan.
+ Thdng tin ve dugc pham bi nghi ngd.
- Ten thudc (ten quoc te va biet duoc).
- Lieu dung, sd lan dung va dudng dung.
- Ngay bat dau dieu tri.
- Ly do dung thudc.
- Ket qua sau khi ngung dung thudc hoac sau khi giam lieu.
- So 16.
- Han dung.©
- Sir cd xuat hien sau khi tai sir dung thudc dd.
- Cac thuoc khac dung kem va thai gian dieu trj cac thuoc nay.
+ Thong tin ve ngudi bao cao
- Hg va ten, dja chi va so dien thoai.
- Chuyen mdn va nghe nghiep.
Cac trung tam ADR (canh giac dugc quoc gia) cung thudng cd them cac hudng dan
cu the cho cac nhan vien y te de dien thdng tin vao mau bao cao nham nang cao chat lugng
ciia bao cao. Cac bao cao sau khi hoan thanh, can gui den trung tam ADR quoc gia hoac
den nha san xuat ciia dugc pham bj nghi ngd cang sdm cang tot.
2.5.2. Mdt sd phuang phap gidm sat tich cue
- Gidm sat su cd doan he (cohort event monitoring)
Trong nhung nam cudi 1970 va dau nhung nam 1980, mdt dang mdi ciia giam sat tich
cue dugc phat trien dNew Zealand (the Intensive Medicines Monitoring Programme) va d
Anh (Prescription Event Monitoring).
Cac he thong giam sat tich cue nay su dung dir lieu ke don de xac djnh ngudi sir
dung mot loai thuoc nhat dinh. Ngudi ke don thudc dugc hdi ve bat ky sir cd bat lgi nao xay
ra trong qua trinh sir dung thuoc dugc giam sat.
Co sd ciia giam sat sir co tich cue la cac nghien cuu doan he quan sat tien cuu khdng
can thiep. Khac biet vdi he thong bao cao tu nguyen, he thdng giam sat sir cd doan he chi
giam sat mdt so thuoc chgn lgc trong mdt khoang thai gian nhat djnh. Qua dae tinh khong
can thiep, giam sat tich cue cung cap mot he du lieu lam sang thuc khdng ke den cac tieu
chuin lua chgn va tieu chuan loai tru trong suot giai doan thu thap dir lieu. Nd khong bj anh
DLS...T9 129
hudng bdi phuang phap lua chgn va cac tieu chuan loai tru dae trung trong cac thu nghiem
lam sang, do vay loai tru dugc sai lech lira chgn. Mdt diem manh nua ve phuong phap hgc
la nd dua tren giam sat sir cd va do vay cd kha nang xac dinh cac dau hieu ddi vdi cac sir cd
ma nhung sir c6 nay khdng nhat thiet phai bj nghi ngd la ADR ciia thudc dugc nghien ciiu.
Cac chuang trinh giam sat tich cue cung cd kha nang udc tinh tan suat ciia cac sir cd cd hai,
do vay cd kha nang djnh lugng hda nguy co ciia mdt phan ung cd hai nhat djnh nao do va
xac djnh dugc cac yeu to nguy co ciia cac phan ling nay.
Tuy nhien, each tiep can nay cung cd nhung han che. Do khdng biet ty le ciia nhung
ADR khdng dugc bao cao, ket qua ciia cac nghien cuu nay thudng la ty le cac sir co dugc
bao cao chii khdng phai la ty le cac sir co mac phai tren thuc te. Dieu nay giong nhu tat ca
cac nghien cuu dua tren du lieu tu benh an, bao gdm ca cac co sd du lieu tren may tinh va
cac du lieu lien ket. Thdng thudng, khdng co nhdm chiing (nhom khdng dung thuoc nghien
cuu) trong cac nghien ciiu giam sat sir cd tich cue, va do vay khdng biet tan suat nen that sir
ddi vdi cac su co.
So vdi he thdng bao cao tu nguyen, he thdng giam sat nay can nhieu nhan lire va dieu
kien co sd vat chat hon va thudng mdi chi dugc tien hanh d cac nude phat trien. Ddi vdi
cac quoc gia dang phat trien, trong do co Viet Nam, phuang phap nay cdn chua quen thuoc
vdi cac nhan vien y te cung nhu vdi trung tam ADR quoc gia.
- Cdc nghien cuu dich te hgc khde:
Cac nghien ciiu djch te hgc vdi nhieu thiet ke khac nhau nhu cac nghien cuu doan he
(corhort studies), bao gdm ca cac nghien cuu hdi ciiu hoac tien cuu, nghien cuu benh chirng
(case-control studies), nghien cuu cat ngang thudng dugc ap dung trong canh giac dugc de
danh gia cac dau hieu/canh bao va danh gia nguy co ciia cac dau hieu nay, tir dd rut ra cac
ket luan ve nguy co ciia mot thudc.
KET LUAN
Thudc la con dao hai ludi. Ben canh nhung lgi ich to ldn trong phdng ngua va dieu trj
benh, ban than thudc cung co the gay ra nhung phan ung cd hai, nhung benh ly nghiem
trgng, tham chi gay tu vong cho ngudi dung thudc. Khi ap dung cac bien phap han che
ADR, cac can bd y te da han che dugc tan suat xuat hien cung nhu muc do nghiem trgng
ciia cac phan ung cd hai nay tren tung ngudi benh cu the. Ddng thai khi phat hien va bao
cao day du cac sir cd bat lgi ciia thudc cho cac co quan co trach nhiem, cac can bd y te da
tham gia vao he thong canh giac dugc nham han che cac ADR d tam quoc gia va quoc te.
Ben canh do, chinh nhung thong tin thu thap dugc tu cac bao cao nay lai giiip cac can bo y
te su dung thudc an toan hgp ly hon cho benh nhan. Chinh vi vay, bat ky can bg y te nao
cung can y thuc ve trach nhiem ciia minh trong he thdng hoat dong canh giac dugc nham
hudng tdi muc tieu sir dung thudc an toan hgp ly.
TINH HUONG LAM SANG
Tinh huong 1.
Mdt bac sy chuyen khoa tam than yeu cau anh/chj tu van ve trudng hgp sau:
Mdt phu nu 49 tuoi, dang dung olanzapin lOmg/ngay de dieu trj tam than phan liet. Benh
nhan bj dai thao dudng typ 2 va dang kiem soat bang che dd an. Trong vdng 6 tuan ke tu
khi bat dau dieu trj bang olanzapin, benh nhan thay kiem soat dudng huyet kem hon.
130
Dudng huyet liic ddi ciia benh nhan liic trudc khi dieu trj nam trong khoang tu 6-9 mmol/L,
nay da tang len den 12 mmol/L. Benh nhan tang 2,5kg ke tir khi dieu trj bang olanzapin.
Cau hdi:
1. Olanzapin co kha nang lam xau di tinh trang benh nhan?
2. Neu co, cd the dung thay the thudc nay bang mot thudc chong loan than nao khac?
Trd ldi:
1. Tat ca cac thuoc chdng loan than khong dien hinh deu lien quan den tang can. Olanzapin
dugc bao cao la gay ra hoac lam xau them benh ly dai thao dudng d mdt sd nghien ciiu
(loai hinh bao cao ca). Nguyen nhan chinh xac olanzapin lam giam dieu hoa dudng huyet
cdn chua ro rang, nhung tang can cd ve la mdt nguyen nhan. Dieu nay cd the dugc giai
thich la do sir ddi khang serotonin, gay giam dap ling vdi te bao beta dao tuy, dan den giam
bai tiet insulin va gay tang dudng huyet. Can them cac nghien ciiu ve tan suat cung nhu
sinh benh hgc ciia phan ling nay.
2. Olanzapin khdng co chdng chi djnh tren benh nhan dai thao dudng, nhung can giam sat
dudng huyet chat che. Trong trudng hgp nay, khi kiem soat dudng huyet xau di trong qua
trinh dieu trj, viec ngung olanzapin co the la hgp ly va can chuyen sang mdt thudc chdng
loan than khac. Risperidol va quetiapin la nhung thudc chong loan than khdng dien hinh it
lien quan den benh ly dai thao dudng tren benh nhan nay.
Tinh huong 2.
Ong C, 37 tuoi, nhap vien de dieu trj nhiem khuan huyet do tu cau khang methicillin
(MRSA) tu nhiem khuan cateter tTnh mach trung tam.
Tien sir benh tat: bj hdi chiing rugt ngan can nuoi dudng dudng tTnh mach va 1 lan trudc do
bj nhiem trung dudng truyen do MRSA, da dieu trj thanh cong vdi vancomycin.
Tuong tu nhu vdi lan nhap vien trudc, ong dugc dieu trj bang vancomycin 750mg truyen
tTnh mach trong 60 phut, 12 gid/lan. Nong do day ciia thudc dugc do sau lieu thu 5 la
5mg/L (thap) va do vay, lieu dung dugc tang len gap ddi la 1500mg, 12gid/lan vdi cung toe
do truyen. 15 phut sau khi bat dau lieu mdi, ong C bat dau bj ha huyet ap (70/100mmHg),
nhjp tim nhanh (85Ian/phut), ngua toan than va do mat, cd. Ong C dugc chan doan la phan
ling gia dj ling vdi vancomycin.
Cau hdi:
1. Nhung thong tin lam sang nao la quan trgng de phan biet phan ung ma dng C gap phai
khdng phai la phan ling di ling that?
2. Tai sao vancomycin gay ra phan ling gia dj ling tren dng C?
3. Ong C can dugc dieu trj nhu the nao?
4. Ong C cd the tiep tuc dieu trj bang vancomycin khdng? Sau nay, can du phdng phan ung
nay nhu the nao?
5. Anh chi hay thuc hien mdt bao cao ca ADR vdi trudng hgp ciia dng C
Trd ldi:
*1. Ong C bj mdt phan ung gia dj ung thudng gap ciia vancomycin la hdi chiing "ngudi do"
(red man syndrome), thudng xay ra khi dung lieu cao vancomycin vdi tdc do truyen nhanh.
Sir phan biet giua phan ung gia dj ung va dj ling la khd khan do cac bieu hien lam sang rat
giong nhau va kho phan biet. Nhung bieu hien ciia ong C (dd mat, nhjp tim nhanh, ha huyet
131
ap, ngua) la do giai phdng histamin va cd the xay ra trong mdt can phan ve. De xac djnh
chac chan nguyen nhan gay ra phan ung, can lam xet nghiem mien dich hgc xac djnh khang
the ciia thudc, nhung viec nay khong phai liic nao cung cd the tien hanh trong thuc hanh
lam sang. Trong trudng hgp nay, ong C da tung dung vancomycin trudc dd va dung nap tot
vdi 5 lieu dau tien ciia lan nhap vien nay, do vay, dudng nhu phan ling nay khong xay ra
qua trung gian mien djch (phan ling dj ung that). Hon nua, phan ling nay xay ra khi tang
lieu vancomycin cang ciing cd chan doan ciia ong C la khong phai phan ung dj ling.
2. Cd hai co che dugc cho la gay ra phan ling gia dj ung la kich thich giai phdng histamin
true tiep (tu dudng bao) va hoat hoa he thdng bd the. Vancomycin dugc cho la gay ra phan
ung gia dj ung theo co che thu nhat (tuy nhien chi tiet ve co che nay van cdn chua ro rang).
3. Budc dau tien de dieu trj cho dng C la loai tru cac nguyen nhan tiem an. Do vay can
ngung truyen vancomycin cho den khi dieu trj dugc phan ung. Do phan ung nay la do giai
phdng histamin, nen can truyen mdt thuoc khang histamin nhu diphenhydramin 50mg.
Giam sat huyet ap va nhjp tim. Can tiep tuc truyen tTnh mach neu huyet ap van tiep tuc ha
hoac khong on dinh dugc.
4. Khong can thiet phai ngung Vancomycin trong trudng hgp dng C. Phan ung nay co the
phong ngua bang each sir dung lieu thap hon va nhieu lan hon (vi du lOOOmg moi 8h) va/
hoac keo dai thai gian truyen thuoc (vi du truyen trong 2 gid). Hoac, dung mdt thudc khang
histamin trudc khi truyen Vancomycin cung cd the co hieu qua. Hon nua, nhjp tim nhanh
trong hdi chirng ngudi do khdng phu thudc vao viec dieu trj trudc vdi khang histamin va la
mdt dae diem phan biet vdi dj ung that.
CAU HOI TIT LlTONG GIA
* Phdn biet diing sai cho cdc cau tie 1 den 10:
1. Trong djnh nghTa ADR ciia WHO bao gdm ca nhung phan ung do dung sai thudc, dung
sai lieu, ngo ddc do dung qua lieu.
2. Bien cd bat lgi ciia thudc (adverse drug experience/adverse drug event - ADE) la tai
bien phat sinh trong qua trinh dieu trj nguyen nhan chua dugc xac dinh.
3. Ha dudng huyet khi dung thudc dieu tri dai thao dudng la ADR typ B.
4. Loet dudng tieu hoa khi dung NSAID la ADR typ A.
5. Tao bon khi giam dau bang Morphin la ADR typ B.
6. Di ung thuoc la ADR typ A.
7. Nhung benh nhan cd tien sir dj ling vdi mdt thudc cung cd the gap di ung vdi mot thuoc
khac cd cau true tuong tir.
8. Sir khac biet ve gen va chiing tdc khdng lam khac biet ve tan suat gap ADR.
9. Thay ddi ky thuat bao che dan tdi tang toe do giai phong hoat chat cd the gay ADR typ
A.
10. San pham phan huy ciia thudc cd the gay ra ADR typ B.
* Chgn 1 trd ldi diing nhdt cho cdc cau tie 11 den 15
11. Cac ADR la phan ling
A. Do thuoc gay ra
B . Do sir tien trien nang them ciia benh trong qua trinh dieu tri
132
C. Do xuat hien benh mdi mac ddng thdi trong qua trinh dieu trj
D. Ca 3 y tren
12. Theo djnh nghTa ciia WHO, cac ADR xay ra khi dung thuoc vdi lieu:
A. Lieu dieu trj thong thudng
B. Lieu cao (ngg dgc)
C. Lieu thap
D.Ca3ytren
13. Nguy co gap ADR tang len trong cac trudng hgp
A. Nguoi benh la nguai cao tuoi
B. Ngudi benh la tre so sinh Ifi'T' vi;;: m.i
C. Ngudi benh la phu nu

>p '-.-rii ni-,;fti ;•::••;;••;.••
D. Ngudi benh la nam gidi
E. CaA,B,C
F. CaA,B,D
'•n.A '.Jo',.,*
14. Cac yeu to sau lam tang nguy co gap ADR:
A. Chat lugng san pham kem
B. Dieu trj nhieu thudc
C. Dieu trj keo dai
D. Ca 3 y tren
15. Cac bien phap han che ADR:
A. Han che so thuoc dung:
B. Nam vung thdng tin ve loai thuoc dang dung cho benh nhan
C. Nam vung thdng tin ve cac doi tugng benh nhan co nguy ca cao:
D. Theo ddi sat benh nhan, phat hien sdm cac bieu hien ciia phan ung co hai do thudc va cd
nhung xii' tri kjp thai.
E. Ca 4 y tren
J :jh ^j;1 : .HA;;:.
* Trd ldi cdc cau hdi dudi day dudi dgng trd ldi cau hdi ngan (Tie cau 16 den cau 19):
16. Moxifloxacin la mdt khang sinh mdi de dieu trj lao da khang. 20%) so benh nhan cd khd
ehju d dudng tieu hoa. Day la phan ung typ A hay typ B?
17. ADR la nguyen nhan dan den tinh trang nhap vien d 2-6% tdng sd benh nhan nhap vien.
ADR nao la nguyen nhan thudng gap nhat gay ra tinh trang nhap vien?
18. Nhuoc diem chinh ciia he thong bao cao tu nguyen cac ADR?
19. Tai sir dung (rechallenge) la gi? .."O'hiS. H'...' .
:\\\ . j',^y\
DAP AN CHO CAU HOI LlTONG GIA
* Phdn biet dung sai (cau tie 1 den 10):

1. S 2. D 3. S 4. D 5. S
6. S 7. D 8. S 9. D 10.D
133
*Chgn 1 trd ldi dung nhat (cau tir 11 din 15):
11.A 12.A 13.E 14.D 15.E
* Trd ldi cdc cau hdi dudi dgng trd lai cau hdi ngan (Tie cau 16 den cau 19):
16. Day la phan ung typ A, tan suat cao >1% va lien quan den thudc, khong lien quan den
benh nhan
17. Roi loan chay mau do cac thuoc doi khang vitamin K (phenprocoumon) va/hoac cac
thuoc chong viem non-steroid (NSAIDs) va aspirin hoac clopidogrel.
18. Bao cao chon loc va bao cao thieu.
•
19. Tai sir dung la viec tiep tuc sir dung lai cung mdt thudc, khi benh nhan da dung thuoc
nay trudc do va cd mdt ADR, viec sir dung lai nay dugc thuc hien dudi sir giam sat y
te va de chung minh moi quan he nhan qua ciia mdt ADR cd muc do nhe va trung
binh.
) H At/j ."•}
TAI LIEU THAM KHAO
1. Bd Y Te, (2011), Duac lam sang - Sach diing dao tgo dugc si dgi hgc. Nha xuat ban Y
hgc, Ha Ndi.
2. Bd Y Te, (2011), Thdng tu 23/2011/TT-BYT ban hanh ngay 10 thdng 6 nam 2011
hudng ddn su dung thuoc trong cdc ca say te cd giudng benh - phu luc 5: Mau bao cao
phdn ung cd hgi cua thudc.
3. American Society of Health-System Pharmacists,(1995), "ASHP guidelines on adverse
drug reaction monitoring and reporting",Am J Health-Syst Pharm., 52: p. 417-9.
4. Aronson J. K., et al.,(2003), "Joining the DoTS: new approach to classifying adverse
drug reactions", BMJ, 327(7425): p. 1222-5.
5. Aronson J. K., (2006), Meyler's side effects ofdrugs-The International Encyclopedia of
Adverse Drug Reactions and Interactions. 15th ed., Elsevier Science.
6. Davies L., (1998), Davies' Textbook of Adverse Drug Reactions. 5th ed.: A Hodder
Arnold Publication.
7. Lee A., (2006), Adverse Drug Reactions. 2nd ed.: Pharmaceutical Press.
8. Strengthening Pharmaceutical Systems (Sps), (2009), Supporting Pharmacovigilance in
Developing Countries: The Systems Perspective. Submitted to the U.S. agency for
international Development by the SPS Program. ; Arlington, Va: Management
Sciences for Health.
9. World Health Organization, (2002), Safety of Medicines - A guide to detecting and
reporting adverse drug reactions. WHO, Geneva.
10. World Health Organization, (2006), The safety of medicines in public health
programmes: pharmacovigilance an essential tool. WHO, Geneva.
11. World Health Organization, (2007), Pharmacovigilancefor antiretrovirals in resource-
poor countries, WHO, Geneva.
134
PHU LUC
Phu lye 5
BAO CAP PHAN IJNG CO HAI CUA THUOC
i ADR
THONG TIN VE NGITOI BAO CAO, B$NH NHAN VA DON V\ BAo CAO Ma so bao cao cua don vr
SE DU^C BAO MAT Ma sd bao cao (do Trung tam quoc gia quan ly)
Xin anh/chi hSybio do ki ci khikhdng chic chin vSsin phim di gay raphin Cmg va/hoic khdng co diy du cic thdng tin
2. Ngay sinh: ../ /. 3. Gidi tinh 4. C3n n^ng:

1. Ho va ten:
Ho#ctu6i.\... • Nam • NO- kg
oumm ve phan ung co hai (aor>
6. Phan ting xuat hien sau bao lau (tinh tu lan dung cuoi cung cua
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135
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136
CHIPCNG 6. TIPCVNG TAC THU6C
Nguyen Tuan Dung, E.N. van Roon

MUC TIEU
1. Trinh bay dugc tuang tdc thuoc theo ca che duac dgng hgc qua 4 giai dgan: hap thu, phdn
bo, chuyen hda, thdi trie
2. Trinh bay dugc tuang tdc thudc theo ca che dugc luc hgc
3. Neu dugc cdc yeu to nguy cagay tuang tdc thuoc bdt lgi khi sie dgng thuoc.
4. Trinh baydugc cdc tuang tdcgiieathuoc va thucan-dd uong
5. Trinh bay dugc mdt sdgidiphap lam hgn che tuang tdc thuoc bdt lgi.
MO DAU
Viec phoi hgp thuoc la khong the tranh khoi, nhat la trong dieu kien da benh ly, da
trieu chung. Bo chinh la nguyen nhan lam cho nguy ca tuang tac thuoc bat lgi de dang xay
ra. Ty le tirang tac tang theo cap so nhan vai so lirgng thuoc phoi hgp va tuang tac thuoc la
mot trong nhung nguyen nhan quan trong trong cac phan ung co hai cua thuoc dugc ghi
nhan. Hau qua cua tuang tac thuoc anh huang den chat lugng dieu tri va sue khoe cua
nguai benh, tham chi co the dan den tu vong. Ve mat lam sang, hau het cac tuang tac thuoc
quan trong xay ra co the dua den he qua "su giam hoat tinh" dong nghla vai giam hieu qua
hoac k'su tang hoat tinh qua muc" dan den tac dung bat thuang. Vai cac thuoc co khoang trj
lieu hep nhu lithium, theophyllin va digoxin, hoac duang cong ve lieu va dap ieng cua thuoc
co dang doc dung, nhu thuoc chong dong mau, thuoc ngua thai duang uong va thuoc tri
dong kinh, cac tuang tac thuoc bat lgi thuang de xay ra.
Trong da so truang hgp, nguai thay thuoc chu dong phoi hop thuoc de co hieu qua cao
nhat va giam thieu tac dung phu, hoac van phai ket hgp thuoc khi can nhac giua lgi ich va
nguy ca. Tuy nhien co nhung tuang tac nam ngoai du doan cua nguai thay thuoc nhu yeu to
sinh ly, benh ly, nhung tuang tac chua dugc biet, tuang tac lien quan den yeu to di truyen,...
Mac du da co nhieu no luc de dam bao viec cung cap day du cac thong tin ve muc do
an toan cua loai thuoc mai khi dua thuoc ra thj truang, tiem nang gay ra phan ung bat lgi do
tuang tac thuoc gay ra khong phai luon luon dugc chung minh.
Cac nguon tu lieu ve tuang tac thuoc kha phong phu cung khong the thay the dugc vai
tro cua nguai dugc sT lam sang trong viec co van cho bac sT, huan luyen cho dieu duang- y ta
va huang dan su dung thuoc cho nguai benh. Yeu cau tren doi hoi nguai dugc sT can dugc
trang bi kien thuc ve lTnh vuc truang tac thuoc de gop phan vao viec su dung thuoc hop ly.
1. TlTONG TAC THUOC - THUOC

1.1. Dinh nghia
Mot phan ung dugc coi la tuang tac thuoc khi hieu qua cua mot thu thuoc bi thay doi
khi co su hien dien cua mot thuoc khac, dugc thao, thuc an, thuc uong hay cac tac nhan hoa
hoc trong moi truang (Baxter 2005).
137
Tuang tac hieu theo nghTa rong la tuang tac vai cac yeu to sinh ly, benh ly, thuc
pham, chat noi sinh, moi truang.
1.2. Cac loai tucng tac thuoc
Trong phan nay ca che cua tuang tac thuoc (TTT) dugc chia theo dae tinh dugc ly:
dugc dgng hoc va dugc luc hgc.
1.2.1. Tuang tdc duac ddng hoc
Cung nhu bat ky chat ngoai lai nao, khi dua thuoc vao ca the bang nhieu duang sir dung
khac nhau, nhung qua trinh dong hgc cua thuoc cung dien ra theo cac buac hap thu - phan bo
- chuyen hoa - thai tru. Co su khac biet lan ve mat dugc dgng giua nguai nay vai nguai khac
nen cung kho tien doan truac dugc. Tuang tac loai nay xay ra tai mgt hoac nhieu giai doan
trong qua trinh tuan hoan cua thuoc trong ca the, dan den su thay doi nong do thuoc trong
mau va a nai tac dong; hau qua la lam tang doc tinh hoac giam tac dung cua thuoc.
1.2.1.1. Tuang tdc do su thay ddi miec do hap thu
Cac thuoc su dung bang duong uong dugc hap thu qua mang nhay cua duang tieu
hoa. Cac tuang tac xay ra trong rugt co khuynh huang lam giam nong do cua cac thuoc han
la tang su hap thu. Chu y tuang tac co the lam thay doi toe do hap thu, mac du tong lugng
thuoc hiip thu khong bi anh huang.
Doi vai loai thuoc dung dai ngay nhu thuoc chong dong duang uong thi anh huang
cua toe do hap thu khong quan trgng vi tong lugng hap thu khong thay doi dang ke. Trong
khi do viec tri hoan su hap thu se co y nghTa ve mat lam sang (lam cham tac dong ciia
thuoc) khi thuoc bi anh huang co thai gian ban huy ngin hoac can dat nong do cao nhanh
trong mau, nhu truang hgp cac thuoc giam dau hoac thuoc ngu. Thuang thi nhung tuang
tac nay co the tranh dugc khi su dung each xa khoang 2-3 gia cac thuoc co tuang tac.
• Do su thay ddi pH dich vi
Su hap thu thuoc qua niem mac rugt phu thuoc vao ty le dang khong ion hoa than dau
con tinh trang ion hoa cua thuoc lai phu thuoc vao pH dich vi, pKa cua thuoc va ky thuat
bao che. Cac thuoc la acid yeu nhu acid acetyl salicylic (aspirin) hap thu tot 6 pH thap do
dang khong ion hoa chiem uu the.
Binh thuang djch vj co pH tu 1 den 2. Mot su thay doi pH do thuoc khang acid, thuoc
khang histamin H2, thuoc uc che bam proton... se lam thay doi do hap thu cua thuoc can
co moi truang acid de dugc hap thu, thi du nhu ketoconazol, itraconazol; trong khi
fluconazol va voriconazol it bj anh huang bai sir thay doi pH djch vj.
Trai lai, neu dung nhung chat co ban chat acid (thi du vitamin C) co the lam cho
nhung thuoc kem ben trong moi truang acid de bj pha huy han. Vi du truang hgp sir dung
chung vitamin C vai thuoc khang sinh nhom beta lactam (ampicillin, cephalexin) hoac
macrolid (erythromycin).
Khi bj ngo doc chat sk, cac bieu hien lam sang nhu non, dau bung, viem da day rugt,
soc... neu khong dugc dieu trj dung muc co the dua den acid, hon me va tham chi tu vong.
Mot trong nhung giai phap la su dung deferroxamin de giai doc theo ca che tao phuc chelat.
Tren thuc te, cung co truang hap kho xac dinh dugc muc do tuong tac do sir thay doi pH
vi co nhung ca che tuangtac khac dan xen nhu chelat hoa, thay doi nhu dong rugt...
138
• Do su hap phu, tgo phiec hay chelat hda
Than hoat thuang dugc sir dung trong xu tri ngo doc hoac khi qua lieu, tuy nhien dung
a lieu dieu trj, than hoat lam giam nong do va lam giam hieu luc cua thuoc bj tuang tac.
Antacid cung lan cac loai thuoc dung qua duang tieu hoa, ngoai
ra co the tao chelat hoa vai thuoc dung dong thai, vi du vai tetracyclin.
Cholestyramin, colestipol (mot chat tiia muoi mat dung trong dieu trj roi loan lipid
huyet)... co the tao phuc voi digoxin, warfarin, levothyroxin lam giam hap thu ciia cac
thuoc nay.
Cac kim loai da hoa trj gom cac cation Ca, Al, Bi, Mg,... va cac san pham tir sua co
the tao phuc chelat lam giam hap thu cac thuoc nhom tetracyclin va fluoquinolon.
Bang 6.1. Phuc chelat giua thuoc va ion kim loai
Thudc Ion kim loai
Tetracyclin Al, Ca, Fe
Levodopa Fe
Methyldopa Fe
Fluoquinolon Al, Bi, Fe, Ca, Mg

Natri fluorua Ca
•''- )\l
Lien ket 1,3-diketon vol Mg
Hinh 6.1. Co che tao phuc chelate giua tetracyclin va Mg
Biphosphonat thuang dugc ke dan dong thai vdi Ca trong benh loang xuang. Tuy
nhien viec sir dung dong thai 2 thuoc tren se tao phuc va lam giam sinh kha dung ciia ca 2
loai thuoc tren dong nghTa vdi viec lam giam hieu luc ciia thuoc.
Phong tranh tuong tac thuoc do hap phu va do tao phuc bang each su dung thuoc ket
hgp each xa nhau tir 2 den 4 gid.
• Do su thay ddi nhu dgng dudng tieu hda
Ve mat nguyen tac, nhung thuoc dugc tong nhanh ra khdi da day se cd lgi cho sir hap
thu do thuoc phan ldn thuoc dugc hap thu toi uu d ta trang theo ca che khuech tan thu ddng,
139
ngugc lai nhung thuoc bj tong nhanh ra khdi rudt se lam giam hap thu ciia thudc do giam
thdi gian tiep xiic giua thudc va niem mac rudt.
Thi du: propenthelin lam giam toe do lam rong da day se la giam hap thu ciia
paracetamol trong khi metoclorpramid lam tang su hap thu ciia paracetamol va propranolol,
mefloquin, lithium, cyclosporin, rugu,...
suyen) benztropin (dieu trj Parkinson), imipramin tram cam) ... lam giam sir hap
thu ciia cac thuoc ket hgp nhu trudng hgp ciia levodopa hoac lam thay doi do hap thu ciia
dicoumarol do lam tang thai gian ra.
Bang 6.2. Cac chat lam thay doi toe do lam rong da day va su anh hudng den su hap thu cua
paracetamol
Tdc do lam rong da day Hap thu paracetamol

Diamorphin/Pethidin Giam Giam
Codein +/- Khong anh hudng

Metoclopramid T3ng T3ng
• Do su thay ddi he vi khuan dudng rudt

Doi vdi mdt so thuoc, he vi khuan dudng rudt giu vai trd quan trong trong qua trinh
hap thu thuoc.
Sulfasalazin la tien dugc, khi vao ca the dudi tac ddng ciia vi khuan rudt se chuyen
thanh 5-aminosalicylic (5-ASA) va sulphadiazine. 5-ASA. Neu dung khang sinh, he vi khuan
bj diet nen qua trinh tren khong xay ra va do dd thuoc khong cd tac dung.
Viec su dung khang sinh se lam anh hudng den he vi sinh vat nay va he qua la anh
hudng den tac dung ciia thuoc. Vi du: sir dung khang sinh dai ngay de diet vi khuan H.
pylori cd the se lam tang chi so INR trong qua trinh dieu trj bang chatchong ddng coumarin
vi khang sinh tieu diet ca he vi sinh vat dudng rudt- tac nhan tdng hgp vitamin K.
• Chuyen hda a thanh rudt
Monoamin oxidase cd d thanh rudt, cd the bj uc che bdi cac chat 1MAO se gay tang
huyet ap khi phoi hgp vdi phenyleprin.
• Lam gidm hap thu do thudc
Neomycin gay hoi chirng kem hap thu tuang tu nhu benh Sprue khdng nhiet ddi. Tac
ddng nay lam giam hap thu mot sd thudc nhu digoxin, methotrexat,...
Su hap thu digoxin bj giam do mang nhay rugt bj ton thuang khi dieu trj ung thu
bang phuang phap hda trj (cyclophosphamid, vincristin, procarbazin, prednison...).
Ngoai ra ddi vdi dgng thudc tiem:
Tiem dudi da hon hgp procain trgn lan ciia
procain do adrenalin gay co mach ngoai bien lam cham su hap thu cua procain.
Protamin - kem - insulin (PZI) : lam cham su
dudng huyet ciia insulin.
140
1.2.1.2. Tuang tdc do su thay ddi sirphdn bd
• Cdc tuang tdc do day thudc ra khdi lien ketprotein trong huyet tuang
Sau khi hap thu, thudc nhanh chong dugc phan bd trong ca the qua he tuan hoan
tuang,
mot phan dae biet la vdi albumin d djch ngoai bao hoac d md, thi du
nhu mo ca tim ciia digoxin.
Thudc cd dang acid lien ket vdi albumin va nhung thuoc cd tinh kiem lien ket vdi
acid a-1 glycoprotein.
Bang 6.3. Cac vi tri ket hgp cua thuoc vao protein
Lien kdt protein Thudc
Albumin Warfarin
acid a-1 glycoprotein Amitryptilin

Disopiramid
Protein huyet tuong Lidocain
Propranolol
Lipoproteim Cyclosporin
Transcortin Corticosteroid
Mo te bao Na+K+ / ATPase Digoxin
Thanh phan d dang tu do va dang ket hgp d trang thai can bang dong; chi co dang
thudc d dang tu do mdi co tac dung dugc ly trong khi dang ket hgp d dang dir tru va nha
dan thudc ra dang tu do khi nong do dang tu do bi giam.
Khi ket hop vdi mot thuoc khac cd ai luc manh han vdi protein se day thuoc co ai luc
yeu hon ra khdi lien ket nay va lam tang nong do thuoc d dang tu do trong mau va do do
lam tang tac dung.
Tuang tac loai nay chi xay ra vdi thuoc cd ty le lien ket protein cao (tren 80%).
Bang 6.4. Lien ket protein va the tich phan bo ciia mot so thuoc
Thuoc Lien ket protein The tich phan bd (Vd)

Warfarin 99% 10 lit
Phenytoin 90% 35 lit
Tolbutamid 96% 10 lit
Hau qua ciia tuang tac se nguy hiem neu thuoc bj day la thuoc co khoang trj lieu hep.
Thi du mdt thuoc co lien ket protein la 95%, khi bj chuyen thanh 90% cd nghTa la thuoc d
nong do tir do da tang gap 5 lan. Nhu trudng hgp tuang tac giua NSAID va aspirin vdi
warfarin, methotrexat,...
141
Bang 6.5. Mot so tuong tac do day thuoc ra khoi lien ket protein
Thudc Thudc He qua lam sang

gay tu'cng tac bj tu'cng tac (*)
Valproat Carbamazepin, TSng nong do tu do carbamazepin va
Phenytoin phenytoin —• tSng dgc tinh
Salicylat" Valproat TSng nong do tu do valproat
Salicylat, Methotrexat TSng nong do tu do methotrexat, -»tSng
probenecid doc tinh
Sulphaphenazol Tolbutamid Tang nong do tu do tolbutamid -» t§ng tac

dung ha dudng huyet
Phenylbutazon warfarin TSng nong do tu do warfarin -> nguy co
xuat huyet
(*) bi day ra khoi lien ket protein

• Cdc tuangtdc do thay ddi ty le nude cua dich ngogi bao cua ca the
Nhung thuoc phan bo nhieu trong nude nhu digoxin, theophyllin, khang sinh nhom
aminoglycosid,... rat nhay cam vdi sir mat djch ngoai bao. Thudc lgi tieu la thuoc gay mat
djch ngoai bao manh, dae biet la furosemid se dan den tang nong do cac thudc neu tren.
/. 2.1.3. Tuangtdc do su thay ddi su chuyen hda
Tuang tac nay xay ra doi vdi cac thuoc chuyen hoa qua gan. Cac chat co he so chiet
xuat qua gan nhd (EH < 0,3) rat nhay cam vdi hien tugng cam ling hoac uc che ciia enzym
gan. Mot thuoc lam thay doi hoat tinh ciia enzym gan se lam thay ddi chuyen hda ciia cac
thuoc qua gan, do do se anh hudng den sinh kha dung (bioavailability) ciia cac thuoc sir dung
phoi hgp. Tuy nhien hau qua chi nghiem trgng doi vdi thudc cd khoang trj lieu hep (khi sir
thay doi nhd ve nong do se lam thaydoi tac dung dugc ly hoac ddc tinh).
Thong thudng thuoc dugc chuyen hoa tir mdt chat khdng phan cue thanh mdt chattan
trong nude, mat di hoat tinh va dugc dao thai ra khdi ca the. Sir chuyen hda thuoc cd the
xay ra trong mau, than, da, rudt, nhung phan ldn bdi tac ddng ciia nhung enzyme nam trong
phan tran ciia ludi ndi sinh chat ciia te bao gan (microsom). Sir chuyen hda thuoc thudng
trai qua 2 giai doan : thuoc bj oxy hda, khu hda hoac thuy phan thanh chat phan cue han
(pha I) sau do lien hgp vdi cac chat trd nen mat hgat tinh (pha II).
Sir oxy cac thuoc d pha I, dudi tac ddng ciia enzyme cytochrom P450. Cytochrom
P450 la mdt dai gia dinh cd 100 dang dong hinh dugc dat ten theo quy udc:
CYP D
i
Gen chuyen biet
Phan ho
Ho \nv, i
Cytochrom P450
Hinh 6.2. Danh phap enzym cytochrom P450
142
Cac hg hemoprotein ciia cytochrom P450 dugc chia thanh hg, phan hg va cac gen
chuyen biet (hinh 6.2, 6.3)
Ho
CYP1 CYP2 CYP3 CYP4
I
Phan ho
B C D E
Hinh 6.3. Su phan chia cac enzym cytochrome P450 theo ho va phan hQ
Cac hoat chat dugc phong thich se cd the ehju tac ddng bdi enzym CYP d rugt tao
thanh cac chuyen hoa chat; sau do cac chat nay theo tTnh mach cua vao gan va cd the tiep
tuc chuyen hoa tai day trudc khi vao vong tuan hoan chung.
I
Ruot Te bao ruot Te bao gan
(1) : Hogt chat (nguyen thuy) TTnh mach cua

V6ng tuan
(2) : Chat chuyen hda hoan chung
Hinh 6.4. Su chuyen h6a thuoc qua he thong CYP450 d rugt va CYP450 d gan
Nhieu dang dong hinh ciia cytochrom tham gia vao qua trinh chuyen hda thuoc. Tuy
dieu kien va tuy sir phoi hgp thudc, cac hoat chat cd the se ddng vai trd la chat nen, chat
cam ling hoac chat uc che.
143
Bang 6.6. Mot vai chat nen, chat cam ung va chat uc che thudng gap ciia enzym P450
CYP P450 Chit nen Chat cam ipng Chat (vc che
CYP1A2 Cafein Omeprazol Amiodaron
Clozapin Lansoprazol Cimetidin
Imipramin Phenytoin Fluoroquinolon
Olanzapin Khoi thuoc la Ruvoxamin
Theophyllin
Chong tram cam 3 v6ng
R-warfarin
CYP2C9 Diazepam Barbiturates Amiodaron
Diclofenac Rifampicin Khang nam "azol"
Losartan :> o Isoniazid
Statins SSRIs
.r. im;v-,
S-warfarin
CYP2C19 Cilostazol Carbamazepin Cimetidin
Diazepam Rifampicin Fluoxetin
Lansoprazol Lansoprazol
Omeprazol • Omeprazol
CYP2D6 Amitriptylin Dexamethason Tranylcypromin
Codein Rifampicin Amiodaron
Holaperidol Bupropion
Imipramin Celecoxib
Nortriptylin Duloxetin
Olcnzapin Fluoxetin
Ondansetron
Opioid
Paroxetin
CYP2E1 Enfluran Rugu (man tinh) Disulfiram

Halothan Isoniazid
CYP3A4 Amiodaron Carbamazepin Cimetidin
Terfenadin Phenytoin Clarithromycin
Ciclosporin Barbiturates Erythromycin
Corticosteroids Dexamethason Itraconazol
Thuoc ngua thai (uong) Primidon Ketoconazol
144
Tacrolimus Rifampicin Nude budi
R-warfarin Diltiazem
Chen kenh calci Uc che protease

g ;4<P .
Benzodiazepin Verapamil
• Cam ieng enzym

Cac chat cd tinh cam ling enzym manh gdm khang sinh rifampicin, chong dong kinh
(barbiturat, phenytoin, carbamazepin,...). Mot vai chat co tinh tu cam ling (auto-induction)
nhu barbiturat, carbamazepin.
Ngoai ra, hut thudc la, nghien rugu (man tinh) va dugc thao (Hypericum perforatum -
St John's wort) cung co the co tinh cam ung.
Sir cam ling enzym lam tang tong hgp protein mdi can co thdi gian tu vai ngay den vai
tuan sau khi bat dau sir dung cac thuoc cam ung enzym, tuong tu, thdi gian de ket thuc cam
ling enzym cung keo dai vai ngay den vai tuan. Chat cam ling cd thai gian ban huy ngan nhu
rifampicin co tac dung nhanh han chat co thdi gian ban huy dai nhu phenytoin, can co thai
gian dai han de dat nong do d trang thai can bang. Thong thudng, cac chat cam ling enzym
lam giam tac dung ciia thuoc, tru khi chat chuyen hoa co hoat tinh.
Tinh cam ung ciia enzym khac nhau giua cac ca the va phu thuoc vao tuoi, di truyen,
thuoc su dung ddng thdi hay benh mac kem,...
Tinh cam ling da dugc chiing minh la phu thuoc vao lieu, tuy nhien cd mdt vai thuoc
qua trinh cam ling xay ra vdi bat ky lieu lugng nao.
Can luu y vdi cac thuoc khong can ke toa vi co the anh hudng den cac thuoc khac
dang dieu trj lien quan den cytochrom P450.
Bang 6.7. Vai thi du ve tuong tac tac thuoc do su cam ung enzym
Thudc bj tirong tac Thudc gay cam ting He qua tren lam sang
Thuoc ngua thai Rifampicin, rifabutin, Giam hieu luc thuoc ngua thai, can
modafinil tSng lieu
Cyclosporin Phenytoin, carbamazepin, Giam nong do cyclosporin, c6 nguy
St John's wort co thai ghep
Paracetamol Nghien rugu (man) Dgc tinh tren gan cd the xay ra d lieu
thap paracetamol
Corticosteroid Phenytoin, rifampicin Tcing su chuyen hda va c6 nguy co
giam hieu luc cua corticoid
• Uc che enzym
Khac vdi chat cam ling enzym, chi co vai loai tuang tac; cac chat uc che enzym cd
tan suat tuang tac thuoc pho bien nhat trong cac loai tuong tac thudc.
Qua trinh tuang tac thudc do cac chat uc che ngan can sir chuyen hda ciia cac thuoc
su dung ddng thai va lam tang sir tich luy cac thuoc nay trong ca the.
Tuang tac thuoc do lie che enzym xay ra ngay khi nong do thudc huu hieu co mat d
trong gan va tac ddng se cao nhat khi nong do thuoc dat trang thai can bang. Do vay, thudc co
thai gian ban huy ngan tac ddng se xuat hien ngay sau vai ngay su dung thudc Ore che enzym
va thdi gian xuat hien se cham han ddi vdi cac thuoc co thdi gian ban huy dai.
DLS...TK) 145
Cac tuang tac do uc che phu thudc vao nhieu yeu to nhu lieu (ca thudc gay tuang tac
va thuoc bj tuang tac), dae diem dugc dgng hgc ciia thudc bj tuang tac (thdi gian ban huy),
dae diem ciia benh nhan nhu tinh trang benh,...
Tuang tac do uc che CYP P450 cd anh hudng quan trgng ddi vdi thudc cd khoang trj
lieu hep nhu theophyllin, cyclosporin, thuoc chdng ddng, phenytoin,...
Bang 6.8. Vai thi du ve tuong tac tac thuoc do su uc che enzym
Thudc bi tipong tac Thuoc ifc chi He qua tren lam sang
enzym
Thuoc chong ddng (uong) Ciprofloxacin Tang tac dung chong ddng va cd nguy
Clarithromycin co xuat huyet
Azathioprin Allopurinol TSng tac dung cua azathioprin dong
nghTa vdi su gia tSng doc tinh
Carbamazepin, phenytoin, Cimetidin T3ng tac dung cua thuoc chong dong
Na valproat kinh/rang dgc tinh
Sildenafil Ritonavir Tctng tac dung cda thuoc sidanefil vdi
nguy co tut huyet ap
1.2.1.4. Tuang tdc do su thay ddi qua trinh dao thdi thudc
Thdng thudng thuoc dugc thai tru bang dudng mat hoac dudng tieu. Mau vao than
dugc lgc qua cau than, nai dd cac chat co phan tu lugng nhd se dugc lgc qua mang va di
vao tieu quan than trong khi cac chat cd phan tir lugng ldn han nhu protein, te bao mau
dugc giu lai trong mau. Sau do thuoc dugc di-tiep vao dng than, nai dd cac thudc d dang
nguyen mau va chat chuyen hoa ciia nd dugc bai tiet chii dgng hoac tai hap thu thu ddng.
Tuang tac thuoc co the xay ra do sir thay doi pH nude tieu, he thdng bai tiet chii dong, hoac
luu lugng mau den than.
• Thay ddi pH nude tieu
Tuang tu giai doan hap thu, sir tai hap thu thu ddng ciia thuoc phu thudc vao dang
khdng ion hoa than dau, cd kha nang xuyen qua mang te bao dng than. Nhu vay d pH kiem,
cac acid yeu cd pHa trong khoang tir 3 - 7,5 nhu acid barbituric hoac aspirin se d dang ion
hoa than nude, khdng the di qua ldp lipid kep ciia mang te bao va do dd dugc dao thai qua
nude tieu. Sir thanh thai cac thudc cd tinh acid yeu nay d than se gia tang khi tang do kiem
nude tieu. Ngugc lai, cac thudc la base yeu cd pKa tir 7,5-10 nhu amphetamin se dugc
thanh thai nhieu han khi acid hda nude tieu. Cac acid manh va base manh hau nhu dugc ion
hda hoan toan trong dieu kien sinh ly ciia pH nude tieu va sir thanh thai khdng bj anh hudng
bdi sir thay ddi pH.
Bang 6.9. Thuoc co tinh acid va tinh kiem dao thai qua mang te bao vao ong than
Thuoc ban chit acid Thudc ban chat base
Acyclovir, bumetanid, cephalosporin, furosemid, Amilorid, cimetidin, ethambutol,

indomethacin, penicillin, Phenobarbital, procainamid, ranitidin
probenecid, salicylat, sulfonamid, lgi tieu thiazid
<>('< yum '-mo rr.fh- y:iy\\ Kb
: fsv.-» i
146
(pH 4.9-5.3)
£P . Acid hda nu'CVc tieu
t 6 —i
'CO ^^ RNH3 +H+ -* RNH/

ietar
o
-ro /
4 _
/
E /
ro
1
a>
x:
a.
P 2 "" f
I Khdnc^cajiibulrj —
E / +~ ~ (pH 7.8-8.2)
c
0 -i
l r— ; i i "
4 8 12
Thoi gian (gio).
Beckett & Rowland, Nature 206:1260; 1965

Hinh 6.5. Su anh hudng ciia pH nude tieu trong su dao thai metamphetamin
• Su bdi tiet theo ca che van chuyen tich cue
Hai thuoc cd cung ca che bai tiet qua van chuyen tich cue se canh tranh nhau trong
qua trinh dao thai. Tuang tac nay dugc van dung de gia tang tac dung dugc ly nhu trudng
hop probenecid lam tang nong do trong mau cua penicillin va cac chat anion khac do lam
giam su dao thai qua than qua sir canh tranh bdi protein van chuyen OAT (organic anion
©
transporters).
Thi du nhu methotrexat cd the gia tang ddc tinh va nguy ca de dga tinh mang khi dung
dong thai vdi aspirin va mdt so thuoc NSAID. Ddc tinh se gia tang khi sir dung methotrexat d
lieu cao hoac d benh nhan suy than can phai theo ddi nong do methotrexat ky han.
• Thay ddi lieu lugng mau den than
Luu lugng mau den than dugc kiem soat bang each san xuat prostaglandin gian mach
d than. Neu sir tong hgp prostaglandin bj uc che chang han bdi indomethacin thi sir bai tiet
cua lithium bj giam va he qua la cd sir gia tang nong do lithium trong mau, can phai theo
doi nong do lithium ciia benh nhan trong qua trinh dieu trj. Tuy nhien su tuang tac nay rat it
bj anh hudng bdi mdt chat uc che manh prostaglandin E2 dd la aspirin (Ingrid W. Reimann,
Arch Gen Psvchiatrv. 1983).
• Bai tiet qua mat vd chit trinh gan rudt
Mdt so thuoc dugc bai tiet qua mat dudi dang nguyen ven hoac lien hgp (glucuronic)
trd nen phan cue han. Thuoc d dang lien hgp cd the bj vi khuan dudng rudt be gay lien hgp
glucuronic va trd ve dang ban dau de dugc tai hap thu vao mau. Chu trinh gan-rudt nay keo
dai thai gian luu giu thuoc trong ca the; nhung neu su dung dong thai khang sinh, thudc se
khong theo chu trinh gan rudt ma bj dao thai ra ngoai nhanh han. Dien hinh la thudc ngua
thai ethinyl estradiol tuang tac vdi khang sinh pho rong, lam giam hieu lire ciia thudc ngua
thai. Khac phuc bang each dung bien phap tranh thai khac (bao cao su).
147
• Protein van chuyen thudc
Thudc va cac chat ndi sinh khdng chi di qua mang sinh hgc ciia te bao theo ca che
khuech tan thu dgng ma con di qua mang bdi chat van chuyen.
P-glycoprotein la mdt chat van chuyen kha pho bien, cd mat trong dng lugn gan ciia
than, te bao gan, mang rudt, tuyen tuy, hang rao mau nao,... P-gp tac ddng nhu mdt bam
ngugc, bam thudc tir trong mau ra nude tieu, mat, rudt,.. va lam giam lugng thudc di vao nao.
Thi du khi su dung ddng thai digoxin va verapamil (chat uc che P-gp) se lam tang
nong do digoxin va cd nguy ca tang ddc tinh ciia digoxin.
Tuang tu cac cytochrom P450, cac P-gp cung cd chat nen, chat cam ung va chat lie
che. Trong mot sd trudng hgp thudc co the ehju tac dgng bdi ca 2 ca che qua CYP450 va P-
gp (hinh 6.4).
Bang 6.10. Thuoc chiu tac ddng bdi CYP450 va P-gp
Nhom thudc Hoat chit

Thuoc tri loan nhip Amiodaron, lidocain, quinidin
Khang sinh Erythromycin
Chen kenh calci Diltiazem, nifedipin, verapamil

Hormon/Steroid Cortisol, progesteron, Tamoxifen
Thuoc uc che mien dich Cyclosporin
Sir chuyen hoa ciia digoxin trudc day van gan cho CYP 450, va ngay nay da chiing
minh la do P-gp.
1.2.2. Tuong tac duoc luc hoc
Tuang tac dugc lire hgc xay ra khi tac ddng dugc lire cua mdt thuoc bj thay doi khi co
sir hien dien cua mdt thudc khac d nai tac ddng, cd the qua thu the hoac khdng qua thu the.
1.2.2.1. Tuang tdc gay tdc dung ddi khang
• Tuang tac xay ra khi 2 thudc cd cung dich tac ddng tren mdt receptor:
Thudng dugc van dung trong giai ddc thudc; cd the minh hga bang mdt so thi du nhu sau:
- Naloxon tren thu the opioid de giai ddc cac thudc thudc nhdm opioid (morphin,
heroin,...).
- Flumazenil (imidazobenzodiazepin) canh tranh tren thu the benzodiazepin dugc
dung trong giai ddc cac thudc thudc nhdm benzodiazepin nhu diazepam, clonazepam,...
• Tuong tac do ddi khang ve tac dung duac ly:
- Thudc chdng ddng va vitamin K.
- Levodopa va cac thudc khang dopamin.
r o r
1.2.2.2. Tuang tdc gay tdc dung hiep luc

Mdt sd thudc cd cung tac ddng dugc ly, khi phoi hgp se dua den tac ddng hiep lire.
Mac du day khdng bde Id day du la mdt tuang tac nhung thudng dan den nhung tac dung
phu nguy hai.
iii l» I t 1*1 ,
148
Bang 6.11. Mdt so tuong tac cd tac dung hiep luc
Tu'cng tac thudc - thudc Tac dung dugc ly

NSAID Warfarin, clopidogrel TSng nguy co xuat huyet
UCMC Thuoc lgi tieu tiet kiem K Nguy co t§ng kali huyet
Verapamil Khang p-adrenergic Cham nhip tim
Khang than kinh co Aminoglycosid Chen than kinh co
Rugu Benzodiazepin TSng tac dung an than

Thiodazin Soyalol Nguy co keo dai song QT
Clozapin Co-trimoxazol Suy tuy xuong
Bang 6.12. Tuong tac dugc luc hgc true tiep va gian tiep
Thuoc gay tuong tac Thuoc bi tuong tac He qua lam sang
Tac dgng true tiep
Aminoglycosid, quinidin, Thuoc gian co khu cue Tang tac dung giSn co
quinin
Verapamil Loan nhip
l
Khang p-adrenergic
Naloxon Opioid Giam tac dung giam dau
Vitamin K1 Warfarin Giam tac dung chong ddng
Steroid dong hda Warfarin TSng tac dung chong ddng
Clofibrat Warfarin TSng tac dung chong ddng
Corticosteroid Warfarin TSng tac dung chong ddng
Oestrogen Warfarin TSng tac dung chong ddng
Tetracyclin Warfarin TSng tac dung chong ddng
Tac dgng gian tiep
Thuoc chong loan nhip (I) va Thuoc chong loan nhip (I) TSng nguy co loan nhip
amiodaron va amiodaron
Chong ket tap tieu cau Thuoc chong ddng TSng nguy co xuat huyet
Thuoc gay xuat huyet tieu Thuoc chong ddng T3ng nguy co xuat huyet da day
hda
Thuoc gay tieu fibrin Thuoc chong ddng Mat can blng ndi mdi
Thuoc lam mat K Digoxin TSng tac dung
Thuoc chong loan nhip T3ng loan nhip
Sulfonylurea Giam tac dung
Thuoc lam giam Ca huyet Digoxin TSng tac dung
(vit D, calci,..)
Thudc gay ha Na huyet Thuoc lgi tieu TSng tac dung ha Na huyet nguy
hiem
Thuoc gay u dich Thuoc lgi tieu Giam tac dung

Thuoc gian mach Khang p-adrenergic Cai thien viec kiem soat huyet ap
hoac dau thSt nguc
149
A jA _ _ . _ A A . __a/_a! D.'iLAill.J
1.3. Cac yeu to nguy co" gay tirong tac thuoc bat loi
1.3.1. Yeu to lien quan den thuoc
- Phoi hgp nhieu thu thudc: lao khoa, benh nhiem trung (lao, HIV,...).
- Khoang trj lieu hep: khang sinh nhdm aminoglycosid, digoxin, warfarin,...
- Lieu lugng va lieu trinh dieu trj (ngat quang/lien tuc, ngan han/dung trong thdi gian dai).
- Thai diem dung thudc: anh hudng ciia bua an gay tang hoac giam hap thu thudc.
- Che do dung thudc cung cd the anh hudng den tuang tac thudc tren benh nhan. Thi
du khi tang lieu flueonazol thi kha nang uc che chuyen hda ciia mdt sd thudc cung tang.
Tuy nhien khi dung lieu duy nhat flueonazol it gap phai tuang tac thudc nghiem trgng so
vdi benh nhan dung flueonazol hang ngay.
1.3.2. Yeu to lien quan den ngudi benh
- Tuoi : tre em, ngudi cao tuoi.
- Gidi tinh: nu1
- Suy giam chuc nang gan, than: nai chuyen hda va dao thai thudc chii yeu.
- Benh ly : benh nang, benh cap (mat nude, nhiem trung) hoac benh man tinh (dai
thao dudng, ddng kinh,...), ghep caquan, dang dieu trj bang phau thuat,...
- Benh chuyen hda hoac ndi tiet: nhugc giap, protein huyet giam, beo phi,...
- Di truyen: G6PD.
- Dung nhieu thudc.
Thi du khi dung lieu phap thay the thyroid cho nhung benh nhan dang dieu trj dn djnh
bang warfarin, tac dung ciia warfarin cd the tang len, dan den tac dung chdng ddng mau
tang qua muc. Trai lai, khi ngung dung thyroid cho benh nhan dang dieu trj dn djnh bang
warfarin, can tang dan lieu warfarin de tranh tac dung chdng ddng mau bj giam.
1.3.3. Yeu to khac
:> 0" -
Nhieu bac sT ke toa cho mdt benh nhan: do mac nhieu thu benh.
Nhieu dugc sT cap phat thudc: mua thudc tai cac nha thudc khac nhau.
Nguon truy cap tuang tac thudc: sach vd, phan mem, trang web true tuyen,...
Khdi lugng edng viec: sd lugng benh nhan qua ddng (ung budu, nhi khoa,...).
2. TlTONG TAC THUOC - THlTC PHAM
Thuc an va thuc uong cung cd the lam thay ddi cac thdng sd dugc ddng hgc ciia thudc
cung nhu tahy ddi tac ddng dugc ly va ddc tinh ciia thudc. Ngugc lai, thudc cung anh hudng
den sir hap thu ciia thuc an. Van dung cac nguyen ly ve sir tuang tac thudc-thuc an vao che dd
dieu trj de cd the dat dugc muc tieu hieu qua - an toan cho ngudi benh.
2.1. Anh hudng ciia thuc an
2.1.1. Thuc an lam thay doi dutfc dong hoc cua thuoc
2.1.1.1. Thuc dn lam thay ddi su hap thu thudc
Anh hudng den tdc dd lam rong dg day: neu uong thudc vao liic da day rong thi thdi
gian luu d da day tir 10-30 phut, trong khi uong liic no cd the len den 4 gid. Cac
150
thudc giau chat beo, qua man hay qua chua deu lam cham tdc dd lam rdng da day
nen khdng cd lgi cho cac thudc kem ben d da day.
Anh hudng den su ben vieng cua thudc: cac thudc kem ben trong mdi trudng acid
nhu peni G, L-Dopa, penicillaamin, didanosin, ampicillin, erthromycin,
lincomycin, mercaptopurin,... neu bj luu giu lau d da day se lam giam sinh kha
dung ciia thudc
khi luu lai d da day
hap thu nhu

gia
viec hap thu cac

tan
tang sir
hap thu ciia vitamin,
+ Cac thudc d dang dang
long. Thi du nhu se bj giam sinh kha
dung 50%, trong khi an.
+ Ddi vdi dang vien bao tan trong rudt, viec luu giu lai trong da day lau se pha vd
ldp bao ngoai, lam anh hudng dung
Bang 6.13. Cac thuoc bi giam hap thu do thuc Sn
Thudc Dang bao che Thudc Dang bao chi

Acetazolamid Vien nen Isoniazid Vien nen
Aminophyllin Vien nen Levodopa Vien nen
Ampicillin Vien nang Metacyclin Vien nang

Aspirin Vien nen Oxytetracyclin Vien nang
Cefradin Vien nen Phenobarbital Vien nen
Erythromycin stearat Vien nen Rifampicin Vien nang

Erythromycin base Vien nang Sit sulfat Vien nen
Bang 6.14. Cac thuoc bi giam hap thu do thuc Sn
Thudc Dang bao che Thudc Dang bao che

Acetaminophen Vien nen Digoxin Vien nen
Amoxiclin Vien nang Furosemid Vien nen
Aspirin Vien siii Kali (dang muoi) Vien nen
151
Cefradin Vien nang Sulfadiazin Hon dich
Cephalexin Vien nang Sulfanilamid Hon dich
Bang 6.15. Cac thuoc tSng hap thu do thuc Sn
Thuoc Dang bao chi Thuoc Dang bao chi

Carbamazepin Vien nen Nitrofurantoin Vien nang
Griseofulvin Vien nen Propoxyphen Vien nen
Hydroclorothiazid Vien nen Riboflavin Vien nen
Lithium Vien nen Spironolacton Vien nen
Bang 6.16. Cac thuoc khdng bi thuc Sn anh hudng den su hap thu
Thudc Dang bao chi Thudc Dang bao chi

Augmentin Vien nang Labetalol Vien nen
Chloramphenicol Vien nang Prednisolon Vien nen
Digoxin Vien nang Ranitidin Vien nen
Doxycyclin Vien nang Spiramycin Vien nen
Ery. ethylsuccinat Vien nen Theophyllin Vien nen
2.1.1.2. Thuc dn dnh huang den chuyen hda thudc

Bua an lam thay doi luu lugng mau qua, lam tang lugng thuoc qua gan va cd the gay
bao hda thudc trong vdng tuan hoan dau (first-pass) tang hgat tinh, dae biet doi vdi cac
thudc cd he sd thanh thai d gan ldn nhu thuoc chen beta giao cam, hormon, morphin,...
Thanh phan trong thuc an uc che chuyen hda thuoc, dan den tang nong do va tang tac
ddng ciia thudc . Thi du nhu trudng hgp nude ep budi chum (grapefriut juice) gay tuang tac
vdi cyclosporin, thudc uc che kenh Ca2+ nhdm dihydropyridin lam gia tang nong do cac
thudc nay len den vai tram phan tram.
Ngugc lai, thanh phan thuc an cd the anh hudng den tac ddng ciia thuoc. Thi du nhu
vitamin B6 va levodopa, vitamin B9 va methotrexat,...
Thjt nudng than kieu "barbecue" cd the gay cam ung enzyme CYP1A2, do do lam
tang chuyen hda cac thuoc la ca chat ciia enzym nay, dien hinh la cafein, theophyllin bj
chuyen hda bdi CYP1A2, lam giam hieu lire ciia thuoc.
2.1.1.3. Thuc an dnh hudng den su dao thdi thuoc
Mdt sd thuc an cd the lam thay doi pH nude tieu va do do anh hudng den sir dao thai
thudc. Thi du vitamin C va cac acid huu ca trong thuc an cd the lam tang nguy ca ket tinh
thudc sulfamid trong than.
2.1.2. Thuc an lam thay doi tac dung va doc tinh cua thuoc
2.1.2.1. Do su cdn trdca hgc cua thiec dn ddi vdi thudc
Thuc an ngan can sirtiep xiic ciia thuoc vdi niem mac tieu hda, hau qua:
152
+ Lam giam lugng thudc vao mau dan den giam tac dung ddi vdi cac thudc cd tac
dung toan than, ngugc lai, lam tang tac dung va giam ddc tinh ddi vdi nhung thudc cd tac
dung tai cho trong long rudt.
+ Tranh dugc tac mac da day, rudt. Do dd
lam giam tac dung phu gay budn (aspirin, quinin,
erythromycin, KG,...)
2.1.2.2. Do su tuang tdc
+ Chuyen tir che
mau gay ddc.
+ Dung cac thuc
uc che MAO (MAOI)
ciia enzyme MAO bj lie che nen
hoan chung gay ra cac bieu hien tren tim mach nhu tim dap nhanh mat dd bung, dau dau du
ddi, can tang huyet ap
dung chung vdi isoniazid se gay
chiing
histaminase).
cac thudc chdng
ddng
haricot,...cd the gay kich ling thuc quan - da day; giam hap thu cac chat sat, Na, K
hoac Mg do tao cac chat khdng tan; ket calci oxalate d than, tranh dung cho nhung
ngudi bj sdi than, tang acid uric va viem khdp.
.2. Anh
2.2.1. Dd uong cd cdn
- Rugu kich thich dudng tieu hda lam tang tinh tham qua mang nhu aminoglycosid,
thudc chdng giun san,...
- Rugu anh hudng den sir hap thu thudc: lam giam hap thu mdt so thuoc do co that ha
vj (diazepam, peniV, ...) va lam tang hap thu mdt so thuoc do tang hda tan va tang luu
lugng mau d rudt (glyceryl trinitrat)
- Rugu anh hudng den sir phan bd thudc: d ngudi nghien rugu,albumin huyet giam
nen lam tang sir phan bd thudc vao cac md
- Rugu anh hudng den chuyen hda thudc: nghien rugu man lam tang cam ung enzym
va lam giam tac dung ciia cac thudc tren.
Bang 6.17. Mdt tuong tac thuoc thudng g#p giua thuoc va thuc uong cd con
Thuoc Ca chi tucng tac He qua lam sang
Metronidazol, bactrim, Phan irng "giong disulfiram" Od bung m£t, tim nhanh, do mo
mdt so C3G hdi, dau dau,...
153
Thuoc gi§n TSng tac dung phu Nguy co tut huyet ap, de te nga
mach,nitroglycerin
Sulfonylure, insulin T3ng tac dung phg Ha dudng huyet
Opioid TSng tac dung phu TSng tac dung tren he TKTLT
Warfarin - Giam chuyen hda d benh - T£ng nguy co xuat huyet
nhan mdi nghien rugu
- T3ng chuyen hda d benh
- Giam tac dung chong ddng
nhan nghien rugu man
NSAID, aspirin TSng tac dung phu TSng nguy co loet da day
Paracetamol TSng tao thanh chuyen hda TSng ddc tinh tren gan
chat ddc tinh (NAPQI)
2.2.2. Sua
- Lam giam hap thu cac khang sinh nhdm tetracyclin, quinolon do taophuc chelat khd tan.
- Sua chiia nhieu lipid giiip cac thudc ua lipid de tan.
- Sua cd pH kha cao nen lam giam kich ling da day ciia mdt sd thudc cd ban chat acid.
2.2.3. Trd, cd phe
- Lam giam hap thu mdt sd chat nhu sat (phuc hgp vdi tanin), alendronat, aminazin,
haloperidol,...
- Lam tang dao thai mdt sd chat do tac dung lgi nieu.
- Lam tang tac dung ciia mdt so thudc tac ddng tren than kinh trung uang, thudc giam
dau ha sot.
- Lam tang tac dung phu cua cac thudc uc che MAO, phenylpropanolamin.
theophyllin gay kich thich lam bdn
chon,
3.
3.1.
tac
thuoc, muc khac nhau ddi chut giua cac tai lieu,
nhung nhin chung cd 3 y la nhung con sd
bieu
osn
154
Bang 6.19. Phan chia muc dd tuong tac thuoc theo ORCA (OpeRational ClassificAtion of drug
interactions)
Muc dd Xutri
tucng tac
1 Tranh phoi
2 Tranh phoi
Tranh phoi
3 Han che
- Thay the
- Theo doi nhlm phat hien sdm nguy co tuong tac thuoc
4 Nguy co khdng cao, cd the phoi hgp thuoc
5 Chua cd bang chung ve tuong tac thuoc
3.2. Thoi gian xay ra tuong tac thuoc

Thai gian xay ra tuang tac thudc cung la mdt yeu to quan trgng can phai xem xet thai
gian khdi phat, thdi gian tac ddng tdi da dua tren cac thdng sd dugc ddng hgc va dugc luc,
thai gian xuat hien tac dung phu va khi tac dung phu giam,... Thi du trudng hgp phoi hgp
amiodaron va warfarin.
dung chdng ddng. Do dd, can phai giam lieu warfarin 30-50% va can phai theo
trong vdng 3-4 ngay sau khi bat dau dung
nguy ca xuat huyet khi phdi hgp 2 thuoc tren. Ngoai ra, do amiodaron cd
dai, can tiep tuc theo
3.3. Mot so giai phap
3.3.1. Tuan thu cdc
- Lira chgn thudc va phac
- Khdng phdi hgp cac thudc cd cung tac dung phu hoac ddc tinh len mdt
hoac to chuc.
- Luu y ddi vdi cac thudc cd ddc tinh cao va cd khoang trj lieu hep.
- Luu y den cac thudc gayra nhungtuong tac bat lgi da dugc ghi nhan ro trong y van.
- Luu y den chuc nang gan than d benh nhan.
- Luu y dan thudc cho nhung benh nhan khd theo doi qua trinh sir dung thuoc.
- Luu y den sir tuan thu ciia benh nhan.
3.3.2. Nang cao kien thuc vd cap nhdt thdng tin ve tuang tdc thudc
Chia se thdng tin giua cac thanh vien trong ddi ngu y te.
Canh bao cac tuang tac thudc cho cac doi tugng dae biet.
Su dung edng cu vi tinh de ho trg viec khao sat tuong tac thuoc: phan
mem, e-book,...
Loai bd cac canh bao nhdm
statin, macrolid, anti-Hl,... trai lai, bd
tuong tac nguy hiem.
qua cac
155
KET LUAN
Viec danh gia tuang tac thudc gap mdt so trd ngai do tuang tac thudc cd bieu hien
gidng nhu nhung tac dung phu thudng gap, nhieu khi khd cd the xac djnh do cac yeu to lien
quan den benh nhan hoac viec tu y dung them thudc, khdng khdng tuan thu theo chi djnh ciia
bac sT... Vi nhung ly do tren dugc sT lam sang can theo doi sat viec ke dan va su dung thudc
ciia benh nhan de kjp thai xu tri nham giam tac dung bat lgi do tuang tac thudc gay ra.
TINH HUONG LAM SANG
Tinh huong 1.
Benh nhan nu 70 tuoi, nhap vien do rung nhT khdng kiem soat. Ba ta than phien bj hdi hop,
tim dap nhanh, va thd ngan.
Tien sie benh: rung nhT va da sir dung:
Digoxin 125 mg/ngay va
Warfarin 3 mg/ngay trong 2 nam nay.
Furosemid
Can lam sang:
Creatinine huyet: 120 mmol/L (BT = 60-120 mmol/L)
Kali: 3.4mmol/L (3,5 - 5mmol/L)
Nong do digoxin la 1,6 ng/mL (0,8 - 2 ng/mL).
Thudc sie dung:
Amiodaron 300mg trong dung djch glucose 5% IV trong 2 gid.
Sau dd sir dung lieu tan edng dudng uong 200 mg x 3 lan/ngay trong 1 tuan, 200 mg 2
lan/ngay trong tuan ke tiep va duy tri vdi lieu 200 mg/ngay
Cau hdi:
1- Nhung tuong tac cd the xay ra trong tinh hudng tren?
2- Cach xu tri de han che tuang tac thudc?
Trd ldi:
1/ Nhung tuang tac cd the xay ra
TSng tac dgng cua

warfarin do ipc che sy
chuyen h6a warfari TSng nong d0
digoxin
Warfarin Digoxin
!?VUi
TSng doc tinh amiodarone

t
rang <jqC tinh
cua digoxin
Furosemid
156
2/ Cach xu tri de han che tuong tac thudc Hi. '
Thudc gay Thudc ehju Anh hudng Ccche Xutri

tucng tac tac ddng
Amiodaron warfarin t3ng tac dung uc che chuyen hda -1 lieu xuong cdn 1/3
chong ddng 2/3
thdi
Amiodaron digoxin T£ng nong dd -1 thai tru d cdn 62.5

ngoai th$n
- Canh tranh
a md
-1 hap thu
amiodaron t nguy co gay
loan nhip
uong
Furosemid furosemid sang

digoxin tang tinh nhay - canh tranh vi tri gin K co-amilofruse
(Kali thap) cam ciia co tim tren Na+/K+-ATPase,
(amilorid/furosemid)
digoxin t gin -> tim (5/40) de ngan mat kali
nhanh qua muc va
loan nhip
Tinh huong 2.
Mdt benh nhan nu, 36 tuoi, den kham benh vi di tieu rat bdng, dau bang quang, dai
gat. Nude tieu due, protein nieu ++.
Trong khi chd dai ket qua xet nghiem, bac si ke toa:
Nitroxolin 300mg/ ngay x 15 ngay,
Ket qua xet nghiem cho thay so lugng vi khuan la 105 vi khuan/ml kem bach cau
nieu. Vi khuan dugc phan lap la E.coli.
Den ngay dieu tri thie 3, vdn cdnphdt hien vi khuan trong nude tiiu bac si quyet dinh diing
thudc:
Cotrimoxazol (1600/320mg/ngay)
Mictasol bleu 2 vien x 3 lan/ngay
Ngoai ra, benh nhan cdn tu y dung them thuoc "lam tang sue de khang, chong nhiem
trung".
Vitamin C lOOOmg
Cau hdi:
1- Nhung tuang tac cd the xay ra
157
2/ Cach xu tri de han che tuang tac thudc
Trd ldi:
1/Tuang tac giua vitamin C va sulfamid, vitamin C va mictasol bleu:

Cd 2 tuang tac trai ngugc nhau do mdi trudng acid tao ra bdi vitamin C:
Vitamin C lam tang nguy ca ket tinh sulfamid trong than d mdi trudng acid. Day la
tuong tac thudc bat lgi.
Vitamin C thuc day phan ling chuyen djch theo chieu thuan ciia methenamin thanh
formaldehyd cd tac dung sat khuan tai cho dudng nieu
-N- HX>
If I
NJ. M £5
he xam ethyl en e-
tetramine
2/ Cach xu tri tuang tac thudc:

Nen uong vitamin C each xa thai diem uong thuoc sulfamid va uong ddng thai vdi
mictasol bleu.
CAU HOI LlTONG GIA

1. Chgn phat bieu diing ve tuang ky va tuang tac thuoc:
a) Chi cd tuang ky mdi dua den dieu bat lgi khi phoi hgp thuoc
b) Tuang ky la nhung giao thoa thuoc ve mat vat ly va tuang tac ve mat hda hgc
c) Chi khac nhau ve mat tir ngu ma thdi
d) Tuang ky xay ra ben ngoai ca the va tuang tac xay ra ben trong ca the
e) Tuang tac thuoc luon luon dan den nhung bat lgi trong dieu trj
2. Metoclorpramid lam thay doi sir hap thu ciia cac thuoc khac qua ca che :
a) Lam tang tdc dd lam rdng da day
b) Lam tang nhu ddng rudt
c) Lam bien doi he vi khuan dudng rudt
d) Anh hudng len sir van chuyen tich cue
iL\ i. ,>>*.;i'jiM
e) Ca a va b deu diing
3. Al+++ va Ca++ uc che hap thu ciia thuoc nao sau day?
a) Isoniazid d) Erythromycin ^rfiOOO?
b) eloramphenieol e) Phenoxymethylpenicillin
4. Dd hap thu ciia tetracyclin dung dudng uong bj giam nhieu nhat trong trudng hgp nao:
158
a) Uong thuoc trong bua an d) Uong thudc vdi nude
b) Uong thuoc sau khi an e) Uong thudc edng vdi an phd-mat
c) Uong thudc vdi sua
5. Mdt chat la acid yeu cd pKa = 4,4:
a. Cd the hap thu tot d da day do ndng dd dang ion cao han dang phan tir
b. Cd the hap thu tot d da day do ndng dd dang phan tur cao han dang ion
c. Cd ndng dd dang ion va dang phan tu tuang duang nen cd the chuyen ddi qua lai d
mang te bao.
d. Khdng the hap thu tai da day
e. Cd the hap thu tai da day nhung khdng phai do su thay ddi do ion hda
6. Digoxin cd the tuang tac vdi chat nao sau day do lam thay ddi the tich phan bd:
a) Cholestyramin d) Clarithromycin
b) Aminoglycosid e) Cac cau tren deu sai
c) Quinidin
7. Ndng dd benzodiazepin trong mau tang khi sir dung ddng thai vdi thudc nao sau day:
a. Cimetidin d. Fexofenadin
b. Ranitidin e. Cac cau tren deu diing

c. Famotidin
8. Dang ddng hinh (isoform) ciia cytochrome P450 nao sau day ehiem ty le cao nhat trong
su chuyen hda thudc.
a. CYP1A2 d. CYP2E1
b. CYP 2C e. CYP 3A
c. CYP 2D6
9. Mdt benh nhan dugc hudng dan khdng nen uong rugu trong khi dieu trj bang thudc.
Tuy nhien, benh nhan nay da khdng tuan thu theo ldi chi dan va da uong rugu. Sau khi
uong rugu vai phut, benh nhan bj do mat, dau dau, ndn mua. Benh nhan dang sir dung
thudc nao sau day?
a. Phenobarbital d) Diazepam
b. Tanylcypromin e) Disulfiram
c. Naltrexon
10. Probenecid lam tang hieu qua ciia Cefotaxim, Penicillin theo cache:
a) Canh tranh lgc qua cau than
b) Canh tranh trong sir bai tiet chii ddng d dng than
159
c) Canh tranh tai hap thu thu ddng d dng than
d) Cau (a) va (b) diing
e) Ca 3 cau deu sai
DAP AN
1-d 2-e 3-c 4-c 5-b 6-c 7-a 8-e 9-e 10-b
TAI LIEU THAM KHAO
1- Bd Y Te (2006), Tuang tac thuoc va chii y khi chi djnh, Nha xuat ban y hgc.
2- Hoang Thj Kim Huyen (2006), Dugc lam sang- sach dung dao tao dugc sT dai hgc, Nha
xuat ban y hgc.
3-Anne Lee, Ivan H. Stockley (2001), Drug-Drug Benefits and Risks: International
Textbook of Clinical Pharmacology, John Wiley & Sons.
4- Ashraf Mozayani, Lionel P. Raymon (2004), Hand book of Drug interactions - A clinical
and Forensic Guide - Humana press.
5- Karen Baxter (2008), Stockley's Drug Interactions - Pharmaceutical Press.
6- Laurence A. Trissel (2009), Handbook on injectable drugs - American Society of Health-
System Pharmacists.
7- Lauerence D.R.(1997), Clinical Pharmacology 8th ed. - Churchill Livingstone.
8- Roger Walker, Cate Whittlesea (2007), Clinical Pharmacy and Therapeutics - Churchill
Livingstone / Elsevier.
!i!.->M .mi f.CM'I'S.) >-:•'*'.> *-•:.
rinr'» (a
160
CHlTONG 7. TUONG KY - TlTONG HOP VA DO ON DINH
CUA THUOC
Nguyen Tuan Dung, J.R.B.J. Brouwers

MUC TIEU
1. Phdn biet dugc tuang ky - tuong hgp thudc ve mat vat ly va hda hgc
2. Trinh bay dugc cdc ca che gay tuang ky thudc
3. Trinh bay dugc cdc yeu to dnh hudng den dg dn djnh ciia thudc
4. Ung dung kien thiec da hgc de xet tinh hudng lam sang lien quan den tuang ky
toan; tuy nhien dieu nay khdng phai

diem mdi trong dieu trj la
thudc de dua vao

ung thu, viec phdi hgp thudc la dieu tat yeu. Ngay nay, cac
ke de cho phep dua ddng
gian. Mat trai
Vi nhung ly do tren, ddi ngu dugc phai khdng ngung phat trien ky nang de vua han che
nguy ca den tir su khdng dn djnh va tuang ky thudc, vua phat huy tdi da dugc hieu qua dieu
trj cho benh nhan.
Cau hdi dat ra la khi chiing ta gap phai mdt phac dieu trj ddng thdi da thudc trong
khi thdng tin can thiet lai khdng du hoac tham chi khdng cd, chiing ta se xu tri ra sao? Cac
thdng tin trong chuyen luan nay hy vgng se cung cap thdng tin giiip cho cac dugc sT
sang thuc tot han.
1. DAI ClTONG VE TlTONG KY VA TUONG HOP
1.1. Mot so thuat ngu* thuong dung

Cac thuat ngu "6n djnh - stability" va "tuang hgp - trong san xuat
hoac tham chi khdng cd thdng tin ve

Mdt
Sir khdng tuc (vi du nhu
sir thuy phan va phan ling oxi hda) va giua cac thudc dan den sir hinh
thanh chat mdi (san pham thoai bien) cd the vua gay ddc tinh vua khdng cd hoat tinh trj lieu.
Sir tuang hien tugng vat ly- hda hgc nhu sir
ket tiia phu thudc ndng phan ling acid - base vdi nhung san pham de nhan thay nhu sir
thay doi trang thai vat ly hay tuang ky gay
DLS...T11 161
ra nhung thay ddi nhan thay ro rang nhu sir ket tiia, due, sir thay ddi mau sac hay dd nhdt,
sir siii bgt hay sir hinh thanh nhung ldp chat long khdng ddng tan thi sir tuong ky vat ly hay
chinh xac han la tu "tuang ky kha kien" dugc su dung.
Han sir dung {expiration timet'shelf life): hay gidi han thdi gian hieu dung chi ra khoang
thdi gian it nhat 90% thudc cdn nguyen ven va cd the sir dung cho benh nhan. Sir mat hoat
tinh khi bao quan thudc la do tinh khdng d djnh hay ky cung nhu cac tac nhan khac
de duy tri tinh trang vd trung. Thai dung do nha san xuat qui djnh dugc chap nhan khi
thudc cdn d dang nguyen ven. Tuy nhien trong khi khi thudc dugc hoan nguyen hoac pha
loang thudc khi sir dung thi han
1.2. Dinh nghia
"Cam nghTa ciia
hai thuat ngu
* Tuang hgp: thanh pham thudc tao ra sau khi pha trdn dugc xem la hgp khi
nd dap ling
- Khdng cd cac hien thay ddi
hoac phat hien bang kinh
hien vi.
- On 24 gid dudi dang h6n hgp hoac

trong toan
* dugc mdt trong hai hoac ca hai
tieu chi tren. gian la viec xuat hien ket tiia trong thay dugc (mdt
nhan djnh sai kha ky). Cd nhieu vi du ve sir tuang ky thudc ma
dudi mat nd la sir thay ddi ve mat hda hgc
va dan den mat hoan toan tac
2. PHAN LOAI TlTONG Ky

Tuang ky thudng dugc phan thanh hai loai la "tuang ky vat ly" va "tuang ky hda
hgc", mac du ban chat ciia ca hai deu la nhung thay ddi ve mat hda hgc, nhung vdi tuang ky
vat ly, cac hien tugng thudng thay la sir thay ddi do tan hay tuang tac giua san pham thudc
vdi bao bi, han la nhung thay ddi d cap do phan tir ciia thudc.
2.1. Tuong ky vat ly
2.1.1. Cdc yeu to lien quan den tuang ky
Ndng do:
Mdt chat chi tan trong dung djch nude khi cd ndng do thap han ndng dd bao hda ciia
nd trong dung djch dd. Khi vugt qua ndng dd bao hda, ket tiia se xuat hien.
Sir xuat hien ket tiia khdng nhat thiet x£y ra ngay lap tuc ma cd the xay ra d bat ky
thdi diem nao, khdng the du doan dugc, vi du: Thai diem xuat hien ket tiia khac nhau ciia
cac thudc trimethoprim-sulfamethoxazol, etoposid,
Sir xuat hien ket tua cdn phu thudc nhiet vi du: dung djch mannitol 10% khdng
bao hda d trang thai dn djnh, trong khi ndng dung djch mannitol 20% cd hien tugng ket tiia,
khi ha nhiet dd den dudi 15°C.
162
Dung mdi: ddi vdi nhung thudc khdng tan trong nude thi khi pha che/hoan nguyen, can den
cac dung mdi than nude phu trg nhu ethanol, propylene glycol, polyethylene glycol. Vi du
nhu cac thudc digoxin, phenytoin, trimethoprim, sulfamethoxazol, etoposid, va teniposid.
Diazepam la mdt vi du kinh dien cho trudng hgp tao tiia khi dung dung mdi phu trg.
Diazepam dang tiem dugc bao che d ndng dd 5 mg/ml trong hon hgp dung mdi g6m nude
hda trdn vdi propylen glycol 40%, ethanol 10%, benzyl alcohol 1,5%. Tuy theo ty le pha
loang ma ta quan sat dugc cac hien tugng vat ly khac nhau nhu d ty le pha loang 1:1 den
1:10 thay ket tiia xuat hien, hien hinh thanh tiia cham sau 6 den
dung djch thuoc duy tri trang thai
trong 24 gid. Tuang tu nhu diazepam, cac tuang ky vat ly cung xay ra vdi cac
thudc can dung mdi hd trg nhu trimethoprim-sulfamethoxazol, digoxin, etoposid, teniposid
va taxol.
Bang 7.1. Cac chat phu gia lam t£ng do hda tan cua cac chat
Hoat chit Dung mdi/ta duo'c

Amiodaron (Cordaron) Polysorbat (tween)
Clonazepam (Rivotril) Propylenglycol, acid acetic
Cotrimoxazol (Bactrim) Propylenglycol
Diazepam (Valium) Propylenglycol, EtOH
Esomeprazol (Nexium) NaOH, EDTA
Phenobarbital Propylenglycol
Phenytoin (Phenhydan) Glycofural-75, EDTA
Paracetamol (Perfalgan) Mannitol, phosphat, NaOH
Do cac chat dugc hda tan trong cac dung mdi va ta dugc chuyen biet, neu pha loang
hoac thay ddi pH se cd nguy ca gay tiia.
pH dung dich: ddi vdi cac thudc la acid hoac base yeu thi dd tan phu thudc true tiep
vao pH dung djch. Cung vdi hang sd phan ly, pH quyet djnh ty le ciia thudc d dang phan ly
va do tan ciia dang khdng phan ly.
De pha che mdt thudc la acid yeu, ddi hdi pH dung djch phai du cao de dat dugc dd
tan mong muon. Vi du nhu muoi natri ciia barbiturat, phenyltoin, methotrexat,
mercaptopurin, thioguanidin va bromodeoxyuridin. Neu pH dung djch ciia cac thudc nay
thap han pH tdi uu thi dd tan ciia chiing trong dung djch se vuot qua ngudng va cd the ket
tiia. Mdt vi du dien hinh la trudng hgp tiia barbiturat khi phdi hgp nd vdi cac thudc cd tinh
acid. Ta cung cd ly giai tuang tu vdi cac thudc cd tinh base yeu dugc pha che trong mdi
trudng kiem.
Bang 7.2. Phan ung acid-base khi trdn lan thuoc-thuoc ho£c thuoc-dung mdi
Loai tucng ky pH dung djch

Furosemid Glucose 5%
Thuoc-dung mdi
pH = 9 pH = 4,5-6
Thuoc - Thuoc Furosemid Verapamil HCI
163
pH = 9 pH = 5
Furosemid Dopamin
pH = 9 pH = 3,5
Dgng muoi:
khdng tan nhu khi pha trdn muoi calci
gap trong cac che pham dinh dudng. Tuy
phosphat trong mdt sd che pham
van de phuc tap, vi cd qua nhieu yeu to phu thudc. Sau
phosphat:
Cau true amino acid.

- Ndng do dextrose.
- Nhiet dd dung djch.
pH dung djch.
Thanh phan cac chat phu gia.
Thu tu pha che.
Mac du khdng the du doan nhieu nhung ngudi ta nhan thay viec hinh thanh gia tang
khi tac ddng vao mdt vai yeu to anh hudng nhu: tang ndng calci va phosphat, tang pH
dung djch, giam ndng do amino acid, tang nhiet them calci vao trudc phosphat, toe do
tiem truyen cham hay keo dai, sir dung muoi calci clorid.
Cac anion va cation huu ca phan tir hay cac phuc khdng
tan. Mdt sd vi du tieu bieu cho hien tugng nay nhu la mdt anion
pholysulfonated mucopolysaccharide, vdi cdc khdng amikacin,
gentamicin, netilmicin, tobramycin) la nhung cation phan ldn. Ly giai cho hien tugng
nay la muoi heparin ciia cac thudc cation khd tan trong Do tua trong trudng hgp nay
phu thuoc trong dung djch
cao, nhung cung cd the khdng xay ra neu
2.1.2.
2.1.2.1. Hien tuang
thuoc giam do mdt phan thuoc bj hap phu len be mat
hay hap thu vao cau mang
lgc.
dactinomycin,
hien tugng hap phu len be mat thudng xay ra khi cd
tac
cd diem g4n silanol phan
164
cue, nhung qua trinh xu ly nay khdng ngan dugc viec vdi cac vi tri so nude khdng phan
cue tren be mat. Hap phu cung xay ra tren be mat chat deo
hay pheu lgc. Sir hap phu trd nen nghiem trgng han khi thudc dieu trj vdi lugng nhd hay d
ndng do thap, khi do
trj. Ngugc lai, vdi nhung thudc dieu trj d ndng
nen khdng dang ke so vdi tdng lieu dieu trj. Nguyen do
gan tren be mat dung cu chua da bao hda, dieu nay dat dugc khi ndng
djch cao.
Hap thu (absorption): binh
chiia va dung cu tiem truyen, biet la polyvinyl chloride (PVC), la nguyen nhan dan den
hao hut thudc trong cac che pham thudc tan trong dau. Trong san xuat PVC, de cd dugc cac
dae dang ke chat phu gia lam
tang tinh deo la lam bang
chua
tan trong dau vao loi polymer giua cac nguyen

lieu dugc van dung de san xuat cac dung cu tiem truyen thich hgp cho loai thudc.
Ngugc lai nhung chat deo phthalate cung cd the bj khuech tan ngugc vao trong dung djch,
nhat la khi cd sir hien dien ciia cac chat hoat ddng be mat hay lugng ldn cac ddng dung mdi,
sir khuech tan ngugc se gia tang dang ke.
Bang 7.3. NhCmg thuoc tuong ky vdi bao bi PVC, PE va silicon
Hoat chit PVC PE
Nitroglycerin ++ ± ++
Insulin ++ + ++
Diazepam ++ 0
:= Ui'.-nri Oc JOfv;
Chlopromazin ++ OiVJ +
Trifluoperazin ++ '.. 'A \'\ v<i y +
Retinol acetat ++
2.1.2.2. Tao muoi
Nguyen nhan cua hien tugng nay la do sir cd mat cua cac chat dien di manh nhu natri,
kali, calci chloride lam giam dd tan ciia cac ion huu ca khdng phan ly va hydrate hda yeu.
Mdt dung djch thuoc huu ca trung tinh nhu diazepam hay clorpromazin hydroclorid cd the
xuat hien ket tiia, tuy thudc vao nong dd thudc va muoi, nhiet do va pH dung djch.
2.1.2.3.Tgo phuc
«
Cac tetracyclin la vi du dien hinh cho hien tugng tao phuc chelat khdng tan vdi Al
Ca+2, Fe+2, va Mg+2 d nong dd va pH nhat djnh. Cung nhu amphotericin B va erythromycin
gluceptat tao phuc khd tan vdi chat bao quan khang khuan cd trong nude pha tiem vd trung.
2.1.2.4. Thay ddi mau sac
Day la trudng hgp de nhan thay nhat bang cam quan, ban chat ciia hien tugng nay la
cac tuang tac hda hgc dan den sir thay doi cau true phan tir ciia thuoc. Vi du nhu khi phdi
165
hgp cac amin kich thich he giao cdm, hay anthracyclin, hay amsacrin, hay tetracyclin vdi
cdc thudc cd tinh kiem nhu aminophyllin vd ganciclovir, se cd sir phan huy cau true hda
hgc, tao ra cac san pham thoai giang cd mau.
Oanciclor + Amsacrin -> mau cam
• :i
Ganciclor + Doxorubicin -> mau tim
Sir thay ddi mau sac cdn tuy thudc vao ndng do ciia cac thudc pha trdn :
Ca gluconat 4mg/mL va 1 mg/mL: tuang hgp
Ca gluconat 4mg/mL & Meropenem 50 mg/mL: Tuang ky
2.1.2.5. Tgo khi
ung hda hgc giua muoi carbonat hay bicarbonat

tugng nay khdng chi xay ra khi tiem truyen natri
cephalosporin nhu cephalothin natri, cephradin, cefamandol
carbonat hay bicarbonat trong edng thuc ciia nd. Cung nhu
vd khi carbon dioxid dugc tao thanh va gay
trong dng tiem.
Mac du hien tuong tao mau va sinh khi cung la ket qua ciia
trong sir phan loai nay, tuong ky hda hgc phai cd nhung thay ddi d muc dd phan tu, tao ra cac
cau true mdi khac vdi phan tu thudc ban dau va khdng the quan sat dugc bang mat thudng.
2.2.1. Phan ieng
Day la hien bien, va la nguyen nhan chu yeu lam thudc
mat dn djnh. trong dung djch thudc se be gay nhirng lien ket yeu, lam thay ddi cau
triic phan tu* thudc. Mdt sd nhdm ester tao bdi acid
carboxylic va phosphate, cac amide, lactam, va Ddi vdi ester, khi bj thuy phan lien
ket giua phan tu carbon va oxy se bj be gay.
Trudng hgp ester ciia acid carboxylic, RCOOR' bj thuy phan se cho ra mdt alcohol
(R'OH) va mdt acid carboxylic (RCOOH) hoac mdt base lien hgp (RCOO-).
RCOOR' + H20 = R'OH + RCOOH / RCOO"
San pham thuy phan ciia amid la acid carboxylic va amin.
cac imine nhu

base. Cac nhdm thudc "nhay
phosphat
2.2.2.
dau anh
i luyj vi (\rj\fi qsrii ii; ':•:., in\)y •.••}!> h,<-;i „»,••; -•ro
166
Oxy khdng khi: nhung thuoc nhay cam vdi oxy khdng khi cd the ke ra nhu la cac steroid,
hrp chatba vdng, cac thudc dae nhdn phenol.
pH dung dich: yeu to amine he
giao cam cd nhanphenol de bj oxy hda pH trung tinh hoac pH kiem, nhung cham d pi i < 4.
Sir oxy hda cung cd the dan den sir chuyen mau ciia thudc, vdi mdt lugng nhd
epinephrine bj oxy hda thanh adrenochrome, san pham cd mau, da lam dung dich thuoc tir
khdng mau chuyen sang cd mau dang ke.
OH
HO f\ I
C-CH2NHCH3 -O
OH
I O,
HO H
Hien tugng nay dugc kiem soat bang each loai bd su cd mat ciia oxy trong thanh phan
cung nhu bao bi thuoc, dieu chinh pH phu hgp, them cac chat chdng tao phuc chelate nhu
acid ethylendiamintetraacetic (EDTA), chat chdng oxy hda nhu natri bisulfit, natri
metabisuliit hay acid ascorbic.
Trong tuang ky thudc, phan ung khu (la tang electron, giam hda trj, va them hallogen
hay hydro vao lien ket ddi C=C) it pho bien han nhieu so vdi oxy hda. Vi du ve phan ung
khu trong tuang ky thudc la beta-lactam nhu
phan se tao ra cac aldehyd khu. Mdt vi du khac ve hien tugng nay cd the thay d kim tiem,
cisplatin day nhdm trong kim tiem ra tao ra tiia platin.
2.2.3. Hi$n tuang quang phdn (photolysis/photodegradation)
La cac phan ung phan huy nhu oxy hda hay thuy phan vdi sir xiic tac ciia anh sang. Nang
lugng buc xa tir
ngudng liic dd se cd sir tai sap xep cau triic phan tir va hinh thanh
nhung cau triic mdi. Mdt amphotericin B, furosamid,
dacarbazin, doxorubicin hydroclorid, natri nitroprussid, vd vitamin A.
Nang lugng can cho mdt photon anh sang tham gia phan ung tang theo do dai budc
song, tuc la tia UV vdi budc song ngan song
dai han, do tu den huynh quang.
song cudng dd anh
sang, cudng dd each giua
thi toe dd va muc dd ciia anh sang len
thudc, nhat la vdi nhung thuoc qua nhay cam vdi anh sang nhu natri can phai
tranh sang cho bao bi, tuyp chua bang each bgc giay bac.
Bang 7.4. Mgt so bien phap khac phgc tuong ky giua thuoc vdi anh sang
Thudc Bi$n phap han che

Isoprenalin, nitroprussiat Na Su dung bom tiem dgc
Lipid, vitamin A Bao quan tranh anh sang
Amphotericin B, furosemid, vecuronium - Bao quan tranh anh sang
- Khdng su dgng lai thuoc du (bao quan)
167
2.2.4. Hien tuang racemic vd epimer hda
Hien tugng nay xay ra vdi nhung thudc cd ddng phan quang hgc do trong cau triic cd
nhdm carbon bat ddi xung. Neu mdt ddng phan cd hoat tinh dugc ly trdi han ddng phan cdn
lai thi hien tugng nay se lam giam tac dung dieu trj ciia thudc. Dieu nay xay ra vdi
epinephrin, hoat tinh ciia 15 lan ddng phan dang D. Neu phan
tir thudc chi cd 1 carbon bat ddi xung thi sau khi hda, ta se cd hdn hgp 2 ddng phan
vdi ty le 50:50. Trong trudng hgp cd han 1 carbon bat ddi xung, 1 dang ddng phan se trdi
han ddng phan vdi ty le khac 50:50, qua trinh
nay ggi la epimer hda.
3. CAC YEU TO ANH HlTONG DEN DO ON DINH CUA THUOC

pH va nhiet do la hai yeu to quan trgng nhat anh hudng den do dn djnh ciia thudc,
nghTa la lien quan den tdc do phan huy thudc khi xet den viec dua thudc vao ca the. Ngoai
ra cdn cac yeu to khac cung quan trgng khdng kem la ndng do thudc, anh sang, va do manh
ion ciia dung djch thudc.
'MO iil'jii
3.1. pH dung djch
pH dung djch cd anh hudng nhieu den do tan ciia thudc, tir do anh hudng den dd dn
djnh ciia thudc. Nhieu thudc bj phan huy d pH dung djch qua cao hoac qua thap do phan
ung vdi ion H+ hay OH" trong dung djch. Trong khi do toe do phan ung cham han nhieu d
cac gia trj pH trung binh.
Bang 7.5. pH cua mdt so dich/dung djch
PH Thidu
1 Dich vi (HCI)
3 Dich dp trai chanh
7 Nude tinh khiet
11 Ammoniac dam dSc

14 NaOH
Thang pH ciia mdi thudc dai dien cho dd dn djnh ciia thuoc do tai nhung gia trj pH
khac nhau, va dugc bieu thj bang do thj hoac bang. Dua vao thang pH ciia mdt thuoc ma ta
xac djnh dugc gia trj pH phu hgp de bao che thuoc do, gia trj nay cd the la pH tai do thuoc
dn djnh nhat, hoac pH ma tai do thudc tan tot nhat. Nhieu trudng hgp trong bao che phai
can den dung djch dem de duy tri pH toi uu cho dung djch thuoc.
Bang 7.6. pH ciia mdt so thuoc thdng dgng
Thudc acid Thuoc kiem
jisj :(A [u\\ nq ",
(PH < 7) (PH > 7)
Amiodaron (Cordaron) pH = 4 Aciclovir (Zivirax) pH = 11
Adrenalin pH = 3 Cotrimoxazol (Bactrim) pH = 10
Dobutamin (Dobutrex) pH = 3 Furosemid (Lasix) pH = 9
Midazolam (Dormicum) pH = 3 Ganciclovir (Cymeven) pH = 9
168
Morphin pH = 3 Omeprazol (Antra) pH = 9
Vancomycin (Vancocin) pH = 3 Phenytoin (Epanutin) pH = 12
tir
nhanh
toe Vi ly do do,
hon hgp, can phai danh gia pH ciia
thuoc - thuoc, thuoc - dung cu cd the tranh dugc bang each kiem soat
va ludng nhung thay ddi pH.
i Li O, tno'A X.t
Bang 7.7. pH ciia mdt so dich truyen va tuong ky thuoc
Djch truyen PH Bat lgi Tuang ky

Amphotericin B,
NaCI 0,9% 6- 7 Chua Na+ Amiodaron. Nitroprussiat
Na, Filgrastim
Aciclovir (nong do cao)
G5%,G10% 4-5 TSng dudng huyet Phenytoin,
Furosemid
Phosphat,
Ringer-lactat 6,3 Chua Ca++
Carbonat
3.2. Nhiet do
Khi nhiet do tang len 10°C, toe do phan ling cd the tang len tu 2 den 5 lan. Tuy nhan
cd mdt vai thudc khi nhiet do giam, tdc dd

Bang 7.8. Ty le phan hiiy cac dung mdi va nhiet dd khac nhau
Nhiet do Dextrose 5% Natri cloride 0,9%

-20 13.6 1.2
0 6.2 0.4
5 10.1 1.2
27 21.3 1.8
Theo bang 7.9, do djnh ciia ampicillin thay ddi theo nhiet dd, tdc do phan ra giam
khi nhiet do giam tir 27 °C xuong 5 °C, roi xuong 0 °C. Tuy nhien, khi nhiet dd tiep tuc giam
xuong dudi 0 thi tdc do phan huy ciia ampicillin trong dung djch lai tang len. 0 -20 °C, nude
trong dung djch ddng dae, hinh thanh mang ludi bang va bay cac tiii dam dae trong
cau triic do, dan den sir tu thuy phan, lam tang tdc do phan huy. Ben canh do, thdng tin trong
bang 2 cdn cho thay ro vai trd xiic tac ciia dextrose trong phan ling phan huy.
Moi tuang quan tuyen tinh giua tdc do phan ling va nhiet dd cd the giiip udc doan
thai gian su dung thuoc tai mdt nhiet dd xac djnh. Tuy nhien trong thuc te viec udc doan
nay khdng phai liic
khi nhiet do tang lam bay hai dung mdi, ndng do thudc trd nen dam dae han, lugng hai am
trong thuoc thay doi, nhung dieu nay deu anh hudng den tdc do phan ung. Ben canh do,
169
nhiet dd cao cd the lam mdi trudng khd han, do am va lugng oxy trong bao bi giam, lam
cho nhung du doan ve tdc do, thdi diem phan huy thudc bj sai lech.
Nhiet do cung lam thay ddi ca che phan huy, vi du nhu cac peptide d nhiet do thap se
bj phan ra bdi phan ling thiiy phan va oxy hda, nhung khi d nhiet dd cao chiing lai bj phan
huy do bien tinh. Cac phan ung can enzyme xiic tac cung chi phu thudc nhiet dd cho den
khi enzyme bat dau giam hoat tinh. Tdm lai do anh hudng ciia nhiet do tren su phan huy
thudc kha phuc tap nen du doan tdc do dira vao mdt yeu to nhiet dd
de ket luan thi khdng the chinh xac.
3.3. Nong do cua thuoc
Tang ndng dd thuoc se lam toe do phan ra thudc se tang theo cap luy thua, tu xiic tac va
dem pH cung lam tang toe dd phan ra, trudng hgp nay xay ra vdi ampicillin (bang 7.9).
Bang 7.9. Ty le phan ra ampicillin tai cac nong dd khac nhau d 5°C trong nude pha tiem sau 8 gid
Ndng do (%) Ty le phan huy (%)
1 0,8
5 3,6
10 5,8
15 10,4
20 12,3
25 13,3
Tuy nhien cung cd nhung thudc phan huy cham han d ndng do
tugng tu oxy hda ciia catecholamin hay phan ung thiiy phan ciia nafcillin giam di khi cd
mat aminophylin. Cd the ly giai rang khi nafcilin d ndng dd cao thi ndng dd dem trong dung
djch nafcillin hien nhien cung cao, se bao ve thudc khdi anh hudng ciia pH cao ciia
aminophylin va cung lam cham qua trinh thiiy phan. Tiep xiic vdi anh sang cung anh hudng
ldn den tdc do phan huy thudc thdng qua su quang phan. Trong trudng hgp ciia natri
nitroprussid, anh sang la tac nhan quan trgng va duy nhat anh hudng den dd dn djnh ciia nd.
Nhung thay ddi trong dd manh ion ciia thudc cd the lam tang, giam, hoac khdng anh
hudng den tdc dd phan huy thudc. Mdt thudc mang dien duang dugc xiic tac bdi ion H se
trudng cd ndng do natri chloride cao; ngugc lai, tdc do phan huy
se cham khi cac thudc tich dien duang nay dugc sir xiic tac bdi ion OH". Ddi vdi thudc
trung tinh, do manh ion khdng anh hudng den tdc do phan huy ciia thudc.
3.4. Dang bao che cua thuoc
SfU <> ;u yrsoiix
nhu dich gdm:
:?kv;t
, pnj Pha nude: nude
Pha dau: dau dau nanh
Chat nhu hda: lecithin (long do triing)
Vi du: lipovenos, propofol, Vitalipid, Etomidat, Lipuro,... iiiiii ioril
• !<:.!.; 15'-'IT i) 1 »;7>l

':6* n
170
'! -'A
• © •••••••
© ••© •#•• ©
© • ©©••§•6
© • •© •©•• ©
Dang ben V® • ©'

• • • •
vCrng © •© •
: lf% .1 .... • ,U ijj
* . <.•
f\ '• • ,^tf" V-' '
Phase inversion Coalescence Ostwald ripening
cac thudc cd ndng cao, ddi hdi tiem cham, lien tuc trong nhieu ngay, khi gian
171
ro tren, day tiem truyen chu Y dugc dua vao su dung, cho phep
thuoc thanh phan ngin han, thudng la
Y (Y-site)
khao sat dd on
dam bao cung
DUNG THUOC
173
Tir cac thu nghiem tren, tac gia da di den ket luan la cd sir tuang ky giua propylen
glycol (Voltaren) vdi metabisulphit (Isolyte P).
2/ Theo tac gia tren, vi sir an toan cho benh nhan, khdng the kiem chung lai tac dung nguy
hai ve mat lam sang. Tuy nhien nguy ca gay thuyen tac phdi la dieu cd the xay ra khi kich
thudc ciia cac tieu phan > 6 urn. Ngoai ra, tuang ky tren cung lam giam hieu luc ciia thudc,
do giam do tan ciia diclofenac.
CAU HOI TI/ LlTONG GIA

1. Hai thuoc dugc coi nhu tuang hgp khi hon hgp ciia chiing cd muc do phan huy < 10%,
it nhat 24 gid
a) Khdng cd su tao thanh tieu phan
ft m nb. <;f': ii • • *•••:!"!
b) Khdng tao tiia
c) Khdng van due
d) Chi cd (a) va (b) diing
e) Ca (a), (b) va (c) diing
2. Mannitol bj ket tiia d ndng dd nao khi ha nhiet dd xuong dudi 15 C?
a) Ndng do mannitol 1%
b) Nong do mannitol 3%
c) Ndng do mannitol 5%
' i <•.'. .j • ; •
d) Ndng dd mannitol 10%
•• • i i
e) Ndng do mannitol 20%

3. Ta dugc Polysorbat dugc cho vao che pham de lam tang do hda tan ciia chat nao sau day:
a) Amiodaron
b) Cotrimoxazol
c) Diazepam
d) Esomeprazol
e) Paracetamol
4. Tetracyclin cd the tao phuc chelate vdi cac ion sau day, NGOAI TRU:
a) Na+
£'.:'i 3 H.: '.•:,'./? iii:'!-l f:if:.":ti i''.'/•/' x;t ;?•
b) Ca+2
c) Fe+2 ..•'. :<< :j>.
d) Mgt2
,. ..^y
e) Al+3
174
5. NaCl 0,9% tuang hgp vdi chat nao sau day:
a) Ampho B
b) Amiodaron
c) Nitroprussiat Na
d) Filgrastim
e) Phenytoin
6. Thudc nao sau day cd pH acid
a) Aciclovir (Zivirax)
b) Amiodaron (Cordaron)
c) Cotrimoxazol (Bactrim)
d) Omeprazol (Antra)
e) Phenytoin (Epanutin)
7. O dieu kien nhiet do nao, ty le phan huy ampicillin pha trong glucose 5% trong thai
gian 4 gid la cao nhat:
a) - 20°C (am 20°C)

b) 0°C
c) 5°C
d) Khdng cd su phan huy d cac dieu kien nhiet dd neu tren
e) d cac dieu kien nhiet do neu tren, su phan huy ciia ampicillin la nhu nhau
8. Cac thudc sau day chi dugc bao quan d nhiet dd phdng khdng qua 72 gid, NGOAI
TRU':
a) vaccin ngua bai Met - udn van (Pediarix)

b) Dornase alfa (Pulmozym)
c) Fosphenytoin Na (Cerebyx)
d) Interferon-1 a (Avonex)
e) Vaccin ngua ciim (Fluarix)
9. Khi pha trdn hdn hgp thudc tiem sau day, phan ling xay ra nhanh trong vdng 1 gid,
NGOAI TRU':
a) Calcium glubionate (Calcium Samdoz) - Indo-methacin (Indocid)

b) Amoxicillin/Ac clav (Augmentin) - Midazolam (Dormicum)
c) Furosemid (Lasix) - Amiodaron (Cordaron)
d) Ceftriaxon (Rocephin) - Flueonazol (Diflucan)
e) Phenytoin (Phenydan) - Fentanyl (Sintenyl)
175
10. Thuoc nao de bj huy bdi anh sang can phai dugc bao ve.
a) Amikacin
b) Ceftazidim
c) Cefotaxim
d) Cau (a) va (b) diing
e) Cau (a), (b) va (c) dung
Dap an: 1-a / 2-e / 3-a/ 4-a / 5-e / 6-b / 7-a/ 8-d / 9-c / 10-e
TAI LIEU THAM KHAO
1. Bd Y te (2005), Tai lieu tap huan - Su dung thuoc hgp ly trong dieu trj (Tai lieu dung
cho dao tao lien tuc bac sT, dugc sT benh vien).
2. Hoang Thi Kim Huyen (2010), Cham sdc dugc : sach dao tao dugc sT va hgc vien sau
dai hgc, nha xuat ban y hgc.
3. De Giorgi I, Guignard B, Fonzo-Christe C, Bonnabry P.(2010), Evaluation of tools to
prevent drug incompatibilities in paediatric and neonatal intensive care units - Pharm
World Sci.
4. Lawrence A. Trissel (2008), Handbook on Injectable Drugs / Edition 15 - American

Society of Health-System Pharmacists.
5. Patricia Schull (2010), Nursing Spectrum Drug Handbook Fifth Edition - McGraw-
Hill's. '
6. Victor Cohen; Samantha P. Jellinek; Leftherios Teperikidis et al. (2008), Room -

temperature Storage of Medications Labeled for Refrigeration, American Society of
Health-System Pharmacist.
i m;..'•:; ":->o :< jn'^.f.- :'>
!•! -• {\<'uif-':','.! uWi:>\i '. '••} 0.l..'.if-:')i!i'wii' (Hl.'i.A.CJ •'<;
.>:</:i:\r;n)) •!- •ay.un:,:/^ -j7] ;*j
ilrn^Jft'i^) l.-.CviiiU'I -.(jU>bvn,.!T"\ *iiii-r, fkitii >;:>
176
Albumin
Amphotericin
Asparaginase
Calcitonin
Cisplatin
Yeu
Yeu
Fibrinogen
Glucagon
Hormon
Immunoglobulin
Phu luc 2. Thdi gian bao quan d nhiet dd phdng (20-25°C) doi vdi nhung thuoc da dugc cac
nha san xuat ghi tren nhan la " bao quan d 2-8°C "
(Victor Cohen; Samantha P. Jellinek - American Journal of Health-System Pharmac, 2007)
7"
Hoat chat / dang bao che Biet duc/c
Thdi gian
bao quan Nguon thdng tin
Abciximab 2-mg/mL (tiem) Reopro (Centocor B.V 8 ngay Nha san xuat
[Lilly])
Allergen extract concentrate NAa (Greer) 28 ngay Nha san xuat
Alprostadil (tiem) Prostin VR Pediatric 34 ngay d 20 Nha san xuat

(Silcor) °C
26 ngay d 30
°C
Alteplase Cathflo Activase 4 thang Nha san xuat

(Genentech)
Atracurium (tiem) Tracrium (Catalytica 14 ngay Thdng tin ke don

Pharmaceuticals)
Becaplermin 0,01% Regranex topical gel 6 ngay Nha san xuat

(Ortho-McNeil-Janssen)
Botulinum toxin type-A 100 Botox (Allergan) 5 ngay Nha san xuat
units
Calcitonin (tiem) Miacalcin (Novartis) 14 ngay Nha san xuat
DLS...T12 177
Calcitonin (bom mui) Miacalcin (Novartis) 35 ngay Thdng tin ke don
Calcitonin Fortical (Upsher-Smith) 7 ngay Nha san xuat
Candida albicans skin test Candin (Allermed 7 ngay Nha san xuat
Laboratories)
Cisatracurium (tiem) Nimbex (Abbott) 21 ngay Thdng tin ke don
Conjugated estrogens (tiem) Premarin IV (Wyeth) 7 ngay Nha san xuat
Dacarbazin (tiem) DTIC-Dome (Ben Venue 3 thang Nha san xuat

Laboratories)
Daptomycin (tiem) Cubicin (Cubist 12 thang Nha san xuat

Pharmaceuticals)
Darbepoetin alfa Aranesp (Amgen) 7 ngay Nha san xuat
Digoxin immune fab (ovine) Digibind (GlaxoSmithKline) 30 ngay Thdng tin ke don
Diphtheria - tetanus toxoids - Pediarix (GlaxoSmithKline) 24 gid Nha san xuat

acellular pertussis adsorbed,
hepatitis B (recombinant) &
inactivated poliovirus vaccine
(hon hgp)
Diphtheria and tetanus toxoids Infanrix (GlaxoSmithKline) 72 gid Nha san xuat
& acellular pertussis vaccine
adsorbed
Dornase alfa Pulmozyme (Genentech) 24 gid Thdng tin ke don
Epoetin alfa multidose Procrit (Ortho Biotech) 7 ngay Nha san xuat
Epoetin alfa single dose Procrit (Ortho Biotech) 14 ngay Nha san xuat
Eptifibatide 2 mg/mL Integrilin (Schering) 60 ngay Thdng tin ke don
Erythromycin ethylsuccinate EES (Abbott) 14 ngay Thdng tin ke don

(nhu dich uong)
Etanercept (bdt) Enbrel (Immunex 7 ngay Nha san xuat

Corporation [Amgen and
Wyeth Pharmaceuticals])
Etanercept prefilled (bom Enbrel (Immunex 4 ngay Nha san xuat

tiem) Corporation [Amgen and
Wyeth Pharmaceuticals])
Etoposide (tiem) Vepesid (Gensia/Sicor) 24 thang Thdng tin ke don
Exenatide Byetta (Amylin 6 ngay Nha san xuat
178
Pharmaceuticals [Lilly])
Famotidine Pepcid (Bedford) 3 thang Nha san xuat
Filgrastim vials and Singleject Neupogen (Amgen) 7 ngay Nha san xuat
prefilled (bom tiem)
Fosphenytoin Na (tiem) Cerebyx (Pfizer) 48 gid Thdng tin ke don
Glatiramer acetate (tiem) Copaxone (Teva 7 ngay Thdng tin ke don

Neuroscience)
Hepatitis A vaccin, inactivated Havrix (GlaxoSmithKline) 72 gid Nha san xuat
Hepatitis A vaccin, inactivated Vaqta (Merck) 12 thang 6-37 °C Nha san xuat
Hepatitis B immune globulin Hyperhep B S/D (Bayer) 7 ngay Nha san xuat
(human)
Hepatitis B vaccin Engerix-B 72 gid Nha san xuat

(recombinant) (GlaxoSmithKline)
Immune globulin (human) Gamastan S/D (Bayer) 7 ngay Nha san xuat
Influenza virus vaccin Fluarix (GlaxoSmithKline) 72 gid Nha san xuat
Insulin as part (rDNA origin) Novolog (Novo Nordisk) 28 ngay Thdng tin ke don
injection
Insulin glargine (rDNA origin) Lantus vial or cartridge 28 ngay Thdng tin ke don
vial / cartridge (Sanofi-Aventis)
70% insulin aspart protamine Novolog Mix 70/30 pen fill 14 ngay Thdng tin ke don
(hon dich) & 30% insulin (tiem) cartridge (Novo Nordisk)
(rDNA origin) pen fill cartridge
70% insulin aspart protamin Novolog Mix 70/30 vial 28 ngay Thdng tin ke don
(hon dich) & 30% insulin (Novo Nordisk)
(rDNA origin) vial
Lente human insulin (rDNA Humulin L (Lilly) 28 ngay Thdng tin ke don
origin) zinc suspension
Insulin lispro (rDNA origin) vial Humalog vial (Lilly) 28 ngay Thdng tin ke don
NPH, human insulin isophan Novolin N vial (Novo 30 ngay Thdng tin ke don
(hon dich) (rDNA origin) Nordisk)
Regular human insulin (tiem) Novolin R vial (Novo 30 ngay Thdng tin ke don
Nordisk)
(rDNA origin)
Humulin Ultralente human Humulin U (Lilly) 28 ngay Thdng tin ke don

insulin uDNA oriain^ extended
179
zinc (hon dich)
Hyaluronic acid Healon (AMO Advanced 14 ngay Nha san xuat

Medical Optics)
Interferon beta-1a (I.M). Avonex (Biogen Idee) 30 ngay Thdng tin ke don
Interferon beta-1a (S.C). Rebif (Serono) 30 ngay Thdng tin ke don
Latanoprost 0.005% (nhd mlt) Xalatan (Pharmacia and 6 tuan Thdng tin ke don
Upjohn)
Lopinavir/ritonavir (vien nang) Kaletra capsules (Abbott) 60 ngay Thdng tin ke don
Lopinavir/ritonavir (dung dich) Kaletra solution (Abbott) 60 ngay Thdng tin ke don
Melphalan 2-mg (vien nen) Alkeran (GlaxoSmithKline) 7 ngay Thdng tin ke don
Methylergonovin maleat (tiem) Methergin (Novartis) 14 ngay Nha san xuat
Neomycin sulfat-polymixin B Neosporin G.U. Irrigant 6 thang Nha san xuat

sulfat solution for irrigation Sterile (Monarch
Pharmaceuticals)
Octreotid acetat (hon dich) Sandostatin (Novartis) 14 ngay Thdng tin ke don
(tiem)
Palivizumab (bdt & dung mdi) Synagis (Medlmmune) 14 ngay Nha san xuat
Pancuronium bromide (tiem) Pavulon (Gensia/Sicor) 6 thang Thdng tin ke don
Peg-interferon alfa-2a vial Pegasys vial (Roche) 14 ngay Nha san xuat
Peg-interferon alfa-2a vial Pegasys prefilled syringe 6 ngay Nha san xuat
prefilled syringe (Roche)
Penicillin G benzathin Bicillin LA (Monarch 7 ngay 77 °F Nha san xuat

suspension(tiem) Pharmaceuticals) 1 ngay 104 °F
Penicillin G benzathin and Bicillin CR (Wyeth) 7 ngay 77 °F Nha san xuat

penicillin G procain suspension 1 ngay 104 °F
(tiem)
Pneumococcal 7-valent Prevnar (Wyeth) 7 ngay Nha san xuat

conjugate vaccin (diphtheria
CRM197 protein)
Proparacaine hydrochlorid Alcaine (Alcon Research 30 ngay Nha san xuat

(nhd mlt) Ltd.)
Quinupristin-dalfopristin for Synercid (DSM 7 ngay Nha san xuat

(tiem) Pharmaceuticals)
180
Rabies immune globulin Hyperab S/D (Talecris) 7 ngay Nha san xuat
(human) solvent/detergent
treated
Rabies vaccin Rabavert (Chiron) Giam 6.2% Nha san xuat

sau 12 thang
Ritonovir (vien nang) Norvir (Abbott) 30 ngay Thdng tin ke don
Rh0D immune globulin Hyperrho SD (Bayer) 7 ngay Nha san xuat

(human)
Rocuronium bromid Zemuron (Organon USA) 60 ngay Thdng tin ke don
Saquinavir (vien nang) Fortovase (Roche) 90 ngay Thdng tin ke don
Succinylcholin chloride Anectine 14 ngay Thdng tin ke don

multidose (GlaxoSmithKline)
Tetanus immune globulin Hypertet S/D (Talecris) 7 ngay Nha san xuat
human solvent/detergent
treated
Tipranavir (vien nang) Aptivus capsules 60 ngay (sau Thdng tin ke don
(Boehringer-lngelheim) khi md hop)
Tobramycin inhalation solution Tobi (Chiron) 28 ngay Thdng tin ke don
Trifluridine (nhd m£t) Viroptic (Monarch 14 ngay Nha san xuat

Pharmaceuticals)
Vinorelbin tartrate (tiem) Navelbine (Pierre Fabre 72 gid Thdng tin ke don
Pharmaceuticals)
Vitamin A Aquasol-A parenteral (Aai 4 tuan Nha san xuat

Pharma/Mayne)
181
Phu luc 3. Mdt so c3p tuong ky giua (Thuoc - Thuoc) phan chia theo muc dd tuong ky (Isabella
de Giorgi- Pharm World Sci., 2010)
Muc do
Hoat chit Biet du'gc Hoat chat Biet dugc
tuang ky
1.1 Amox/Clav Augmentin Midazolam Dormicum
Ca glubionate Calcium Sandoz Indomethacin Indocid
Gentamicin Garamycin Propofol Disoprivan
Ceftriaxon Rocephin Fluconazole Diflucan
Insulin Actrapid Digoxin Digoxine
I.2 Clarithromycin Klacid Cefuroxime Zinacef
Metronidazol Metronidazol Augmentin Amox/Clav
Meropenem Meronem Ca glubionate Calcium Sandoz
Gentamicin Garamycin Heparin Heparin
Dopamin Dopamin Aciclovir Zovirax
C.1 Epinephrin Adrenalin Dopamin Dopamin
Dobutamin Dobutrex Mg sulfate Mg sulfate

Midazolam Dormicum Clonidin Catapressan
Amoxicillin Clamoxyl K clorid KCI
Heparin Heparin Alteplase Actilyse
C.2 Phenytoin Phenhydan Flueonazol Diflucan
Labetalol Trandat Cefazolin Kefzol
Furosemid Lasix Amiodaron Cordaron
Hydrocortison Solu Cortef Metronidazol Metronidazol
Fentanyl Sintenyl Phenobarbital Phenobarbital
Chii thich:
1.1. : Tuong ky xay ra ngay tuc khlc hoSc trong vdng 1 gid
1.2. : Tuong ky xay ra trong khoang 1 gid den 4 gid
C.1.: Tuong ky xay ra trong khoang 4 gid den 24 gid
C.2.: Khdng cd tuong ky, ngay ca sau 24 gid
Phu luc 4. Su tuong hgp giua thuoc va dung dich tiem truyen (Thong tin duoc cung cip tu nha
sin xuit) [5]
D5 Cac dung dich
D5 D10 NS R LR
khac
%S S
Acetazolamid C C C C C C C
Acid aminocaproic C C C C c Dextrose/nude cat
Avid ascorbic C C C c Dung dich Na lactat
182
Acyclovir C
Alprostadil C c c
Alteplase Nude cat pha tiem
Amdinocillin c c c c c c c D5% trong dd ringer
Amikacin c c
Ammonium CI c Cd the them KCL
Amphotericin B c
Ampicillin c c
Amrinon lactat c dd nude muoi

0,45%
Antithrombin III c c Nude cat pha tiem
Azlocillin c c c
Atenolol c c dd nude muoi

0,45%
Aztreonam c c c c c dd Normosol-R
Bretylium tosylat c c
Cefamandol c c
Cefazolin c c
Cefotetan c c
Cefoxitin c c c c c dd Aminosol
Ceftazidim c c c c c c
Ceftriazon c c
Cefuroxim c c c c Na lactat
Cephalothin c c c Na lactat
Cephapirin c
Chat uc che a-1 Nude cat pha tiem

proteinase
Ciprofloxacin c c
Cyclosporin c c Chi dung vat chua

bSng thuy tinh
Dobutamin . c c Na lactat
Dopamin c c c c c Cd the Na lactat
Doxycylin c Dudng don 10%
Edetat Na c c
Ganciclovir c c c c
Gentamicin c c dd Normosol-R
i —
183
Heparin Na C c c c
Ifosfamid C c c Nude cat pha tiem

Isoproterenol C C c c Dudng don
5%, 10%
Kanamycin C c
Metaraminol C C c c c dd Normosol-R
Methicilin C c
Metoclopramid C C c c
Mezlocillin C C C c c c c Dudng fructose 5%

Moxalactam C C C c c c c Cd the Na lactat
Netilmicin C C c c c c dd Normosol-R
Nor-epinephrin C C c c
Nitroglycerin C c c
Piperacillin C c c c
Ritodrin C
Ticarcillin C c c
Tobramycin C c
Vidarabin C c c
Chu thich:
C Tuong hgp D10 Dextrose 10%

<Di_*-:
D5 Dextrose 5% NS Dung dich NaCI 0,9%
D5 VzS Dextrose 5% trong nude muoi 0,45% R Dung dich Ringer
D5 S Dextrose 5% trong nude muoi 0,9% LR Dung dich Ringer Lactat
184
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Citti Acyclovir Na
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• o o o o o - o - - o o o o
Amiodarone
o o - - * o - -
:.| ° Amphotericin
o o o o o o o o o o - o Aztrezonam
o • o . o o o Ca chlorid
o • o • o o - - o o o Ca gluconate
o o o o o o o ♦ - - o Cefazolin
o o Cefepim •C
o o o o o o - -
Ceftazidim •c
o
o o o o o • - o o o
o o Clindamycin
o • o o o Cyclosporin
o • o o o o
!".:;; Dexamethaso Q
n
o o - - o
1 Digoxin oa
- o o o o o o o -
mil Diltiazem ^C
CQ
- o • o o • o
Diphenhydra
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o o o o o o » . o o DJ
Dobutamin
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Dopamin =y
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Famotidin
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o o o o o o
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• - o - - » •
Furosemid
o o o o n • • « o o o - o o o -
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o o - o • - o o
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o i • - o • - o • • o
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o - o o o o o o
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o o Melhylprednis ^<
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Metoproloi
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o o o • o o o o • - o o Metronidazol
- o o o • o • o - o o o o
Midazolam =5
- o o o o o o o o o o o
Milrinon
- o o o o o o o o o o o o o o o o Morphin
o o o o o o
Nitroglycerin
o o o o o o o o •
Nitroprussid
o o o o Norepinephri
- o o ' » o o o o - o
o Ondansetron
o o o o o Phenylephrin
- o o o o o o • • o o o o o o o o
Potassium
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. o o o • ' - o o o o
Tobramycin
o - o • o o o o
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Vancomycin
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CHl/ONG 8. DICH TE DlTOC HOC
Nguyen Thanh Binh, L.T. W. de Jong-van den Berg C. de Vries

MUC TIEU
1. Trinh bay duac khdi ni$m, phgm vi vd ddi tugng nghien cuu cua djch te dugc hgc.
2. Phdn tich dugc qua trinh hinhthanh vaphdt trien ciia djch te dugc hgc.
3. Phdn tich dugc phuang thiec tiep cgn de gidi quyetmdi quan h? Nhdn-Qud cua dich te dugc
hgc.
4. Trinh bay dugc cdc md hinh thiet ke nghien cieucua d\ch te dugc hgc.
mOdAu
Trong vai thap ky gan day, y hgc hien dai ndi chung va nganh dugc ndi rieng da dat
dugc nhung thanh tuu vugt bac trong lTnh vuc cham sdc sue khoe. Vdi su phat trien manh
me cua khoa hgc va cong nghe, con ngudi da phat minh ra nhieu loai dugc pham, mang lai
nhung lgi ich to ldn trong viec dieu tri cac benh dich va nhung benh hiem ngheo, cai thien
tot hon viec cham sdc sue khoe cho con ngudi. Tuy nhien, cung vdi su phat trien cua cac
loai dugc pham, nhung nguy co bat lgi do thudc tao ra cung ngay cang nhieu hon. Van de
dat ra la lam the nao de danh gia dugc nhung tac dung bat lgi do la do thudc hay do nguyen
nhan nao khac? De tra ldi cau hdi nay, cac nha khoa hgc da tirng budc van dung each thuc
tiep can cua djch te hgc vao nghien cuu nguy ca phan ung bat lgi cua thudc va hinh thanh
nen mdn khoa hgc Dich te dugc hgc. Cd the ndi rang, mdi quan tam khdi dau cua dich te
dugc hgc chinh la nghien cuu phan ung bat lgi xay ra trong qua trinh su dung thudc, va
chinh bdi vay nd giup cho khung phap ly trong nganh dugc cung ngay cang hoan thien hon
nham han che dugc nhung nguy ca bat lgi do. Cang ve sau, vai trd cua dich te dugc hgc
ngay cang dugc khang dinh. Ngoai viec nghien cuu van de su dung thudc ndi chung va cac
phan ung bat lgi cua thudc ndi rieng, vai trd ciia nd cdn md rdng sang cac lTnh vuc khac nhu
kinh te y te (Health Economics), kinh te dugc (Pharmacoeconomics) de danh gia, lua chgn
thudc, lua chgn cac phac do dieu tri va danh gia chat lugng dich vu y te...
1. KHAI NIEM DICH TE DUOC HOC

Djch te dugc hgc dugc dinh nghTa la "mdt mdn khoa hgc nghien cuu ve viec su dung
thudc va hieu qua dieu tri cua thudc trong edng ddng".
Thuat ngu djch te dugc hgc (Pharmaco - Epidemiology) bao gdm 2 tu ghep la djch te
hgc va dugc hgc. De de dang tim hieu the nao la dich te dugc hgc, dau tien chung ta phai
hieu djch te hgc la gi va mdi quan he qua lai giua djch te hgc va djch te dugc hgc nhu the
nao. Viec so sanh nay rat huu ich cho viec tim hieu ddi tugng, pham vi nghien cuu cua mdn
djch te dugc hgc vdi cac lTnh vuc khac cd lien quan.
Ve djnh nghTa, djch te hgc "la mdt "mdn khoa hgc nghien cuu cac yeu td gay benh va
phan bd cac yeu td dd trong edng ddng". Trong khi do, djch te dugc hgc lai nghien cuu van
de su dung thudc va hieu qua dieu trj trong edng ddng.
187
Xet ve doi tugng va pham vj nghien cuu, djch te hgc quan tam den "benh", cu the la
nghien cuu su phan bo va cac yeu to gay benh trong quan the. Trong khi do djch te dugc
hgc quan tam den "thuoc", va cu the la nghien cuu van de su dung thuoc va hieu qua dieu tri
cua nd trong quan the.
Nhu chung ta da biet, thuoc la con dao 2 ludi, ngoai tac dung dieu trj benh nd cdn
luon tiem an cac tac dung bat lgi doi vdi ngudi benh. Khdi dau, cac nha khoa hgc da sir
dung phuang phap nghien cuu cua djch te hgc de nghien cuu tac dung bat lgi cua thudc
(ADR) va budc dau da hinh thanh nen mdn hgc djch te dugc hgc.
Khi mdi hinh thanh vao thap ky 60-70 cua the ky XX, djch te dugc hgc chi quan tam
den cac phan ung bat lgi cua thuoc. Den thap ky 80-90 the ky XX, djch te dugc hgc da md
rdng pham vi nghien cuu, ngoai nghien cuu cac phan ung bat lgi cua thudc nd cdn dat nen
mdng cho cac nghien cuu kinh te y te, kinh te dugc de lira chgn thudc, lira chgn edng thuc
dieu trj va danh gia hieu qua dieu trj cua thuoc. Ngoai ra, dich te dugc hgc cdn dugc ung
dung de nghien cuu va hoan thien chinh sach dugc cung nhu la chat lugng djch vu dugc.
Nhu vay, cd the ndi rang, khdi dau djch te dugc hgc da su dung nhung phuang phap
ca ban ciia djch te hgc de nghien cuu ve cac phan ung bat lgi ciia thudc, cung nhu sau nay
la van de su dung thudc trong edng ddng
Cd the minh hga moi quan he giua djch te hgc va djch te dugc hgc qua hinh sau:
Hinh 8.1. Pham vi nghien cuu cua djch te hgc va dich te dugc hgc
2. QUATRINH HINH THANH VA PHAT TRIEN CUA DICH TE DlTOC HOC

Cd the ndi rang ljch su ra ddi cua mdn djch te dugc hgc g4n lien vdi cac su kien ve
phan ung bat lgi xay ra trong qua trinh luu thdng va dae biet la khau sir dung thudc.
Nam 1937, han 100 ngudi chet vi suy than do su dung mdt san pham cd ten la
sulfanilamid cua edng ty Massengill, trong mdt thai pian dai thuoc nay dugc phep luu hanh
tren thj trudng va menh danh la mdt trong nhirng thudc chua bach benh.
Dau nam 1950, ngudi ta mdi kham pha ra phan ung bat lgi cua eloramphenieol cd the
gay ra thieu mau bat san do suy tuy, dae biet la ddi vdi tre so sinh.
Mua ddng nam 1961 the gidi da dugc chung kien "tham hga thalidomid". Thalidomid
da dugc dua ra thj trudng nhu la mdt loai thuoc an than lam em dju than kinh, dugc cac phu
nu cd thai rat ua chuong do lam giam cam giac bon chon, lo lang, mat ngu trong thai ky
mang thai. Mdt thai gian sau, tai nhung quoc gia cho phep luu hanh thudc thalidomid,
ngudi ta phat hien ra sir gia tang qua muc ve ty le de non, ty le tre sa sinh quai thai vdi cac
bieu hien thieu chan, tay hay mdt phan chan tay hoac la ban tay mai cheo...
Mac du cac qui djnh phap ly ve viec dang ky thudc ngay cang ddi hdi chat che han,
nhung cuoi nhung nam 1960 - 1970 va dae biet nhung nam 1980 - 1990, djch te dugc hgc
da phat hien ra rat nhieu phan ung bat lgi nguy hiem do viec su dung thudc. Chang han,
cloquinol dugc dua ra thj trudng vao dau nhung nam 1930, mai den nam 1970 ngudi ta mdi
phat hien ra nd la nguyen nhan gay ra hdi chung loan than kinh thj giac ban cap. Sau khi
practolol dugc dua ra thj trudng 5 nam, vao giua nam 1970 ngudi ta da khang djnh nd la thu
pham gay ra hdi chirng viem niem mac mat. Vao dau nhung nam 1980, ticrynafen va
benoxaprofen da dugc luu y do anh hudng den chuc nang gan, tham chi cd the dan den tir
vong. Tiep sau dd la zmepiac, mdt thudc chdng viem khdng steroid khac, lam tang nguy ca
phan ung phan ve. Nhung benh nguy hiem ve te bao mau cd lien quan tdi phenylbutazone.
Indometacin dugc bao che dudi dang giai phdng cham la nguyen nhan gay ra nhung Id
thiing d rudt non. Bendectin, mdt thudc phdi hgp dugc chi djnh dieu trj chung budn ndn,
chdng mat cho phu nir cd thai, da bj cam luu hanh bdi vi cd cac vu kien cao khang djnh nd
da gay ra quai thai mac du la cdn thieu nhung bang chung khoa hgc vung chac khang djnh
van de nay. Suprofen la thu pham gay ra hdi chung dau sudn cap va suy than cap tinh cd hdi
phuc. Isotretinoin gan nhu da bj loai bd khdi thj trudng bdi vi nd gay ra hien tugng de non.
Nam 1979, triazolam dugc dua ra thj trudng, dau nam 1990 ngudi ta phat hien ra tac dung
phu ciia nd la nguyen nhan chinh dan den mdt vai trang thai khdng binh .thudng cua he
thdng than kinh trung uong. Silicon la chat ddn nguc dugc hang trieu ngudi My quan tam vi
muc dich tham my, gan day da bj budc tdi la nguyen nhan gay ra ung thu, benh thap khdp
va nhieu van de lien quan khac. Fluoxetin dugc tung ra thj trudng nhu la mdt thu thudc tam
than mdi quan trgng va dat dugc nhieu thanh edng trong kinh doanh, nhung sau do nd da bj
mat phan ldn thj trudng do gay ra y mudn tu van cua ngudi sir dung. Hien tugng loan nhjp
cd lien quan tdi viec su dung che pham khang histamin la terfenadin va astemizol. Can cao
huyet ap dot ngdt va dot quy cd lien quan den viec sir dung bromocriptin cua phu nu sau khi
de... Chinh sir phat trien khoa hgc da giup cac nha djch te dugc hgc xac djnh dugc thu pham
cua cac sir kien lien quan den cac phan ung bat lgi ndi tren.
Nam 1952 cuon sach giao khoa dau tien ve cac phan ung bat lgi da dugc xuat ban.
Cung vao nam do, lan dau tien ca quan ve nghien cuu ve cac tac dung bat lgi va thu thap
cac benh ve te bao mau do thudc gay ra da dugc thanh lap. Nam 1960, ca quan quan ly
dugc pham - thuc pham My (FDA) bat dau thu thap bao cao ve cac phan ung bat lgi cua
thudc, va tai trg cho cac chuang trinh theo doi thudc mdi tai cac benh vien. Chuang trinh
Giam sat thudc Boston da trien khai theo ddi tai cac benh vien va hinh thanh cac nghien cuu
thuan tap, nham phat hien tac dung bat lgi cua thudc trong qua trinh sir dung d trong benh
vien. Hinh thuc nay sau dd cung dugc trien khai d Vien Shands, Bang Florida cua My.
Viec xac djnh sir cd mat cua thalidomid trong nhau thai, giup cho cac nha nghien cuu
djch te dugc hgc tim ra dugc nguyen nhan cua nhirng sir kien khung khiep nay. Nhirng phu
nu dang trong thai ky mang thai da su dung thalidomid nhu la thudc an than trong thai ky
dau cua thai ky. Sau sir kien nay, nam 1968 tai Anh ngudi ta da thanh lap Hdi ddng An toan
ve Thudc (Committee on Safety of Medicines). Sau do Td chuc Y te the gidi va rat nhieu
cac quoc gia khac da thanh lap ca quan chuyen thu thap va tap hgp cac thdng tin ve cac
phan ung bat lgi cua thudc cung nhu cac hau qua cua nd.
189
Giua nhung nam 1960 da xuat hien nhirng an pham dau tien ve nghien cuu su dung
thuoc. Nhung nghien cuu nay da cung cap nhung thdng tin sinh ddng ve su dung thudc cua
cac thay thuoc, va bat dau bang cac chuyen muc ve dieu tra muc dd ke dan sai, cac yeu td
dan den viec ke dan sai cua bac sT thdng qua thu thap cac dan thuoc hoac nhirng benh nhan
gia djnh (benh nhan giay - paper patient). Vdi sir phat trien do, nam 1960 cd the coi la su
khdi dau cho sir ra ddi lTnh vuc djch te dugc hgc.
Nhung phat hien nhu da neu d tren cung vdi sir hoan thien cua he thdng phap ly da giup
loai bd dugc rat nhieu thuoc kem chat lugng, khdng dam bao an toan ra khdi thj trudng.
Nam 1968, WHO da thanh lap Trung tam giam sat thuoc dat tai Uppsala, Thuy Dien
(UMC) vdi sir tham gia cua mdt Hdi ddng cac chuyen gia quoc te chuyen lam nhiem vu
theo doi, giam sat tac dung bat lgi cua thudc tir cac quoc gia thanh vien cua WHO va phan
hoi cac thdng tin canh bao ve thudc.
Dau nhirng nam 1970, Ca quan nghien cuu djch te ve thuoc da dugc hinh thanh va
phat trien tai My, hien nay dugc ggi la Trung tam djch te Slone. T6 chuc nay dugc phat
trien den tan cac tuyen benh vien ca sd, theo Chuang trinh Phoi hgp Giam sat Thudc
Boston, bang each thu thap nhirng phan ung bat lgi cua thuoc trong qua trinh dieu trj cho
cac benh nhan, va sir dung nhung du lieu do de hinh thanh cac nghien cuu doi chirng tai
benh vien. Tai My nam 1976, Hdi dong Phoi hgp Ke dan Su dung Thuoc dugc thanh lap,
Hgi dong nay bao g6m cac chuyen gia cd nhiem vu danh gia vai trd cua djch te dugc hgc
trong thdi gian nay va dua ra nhung de xuat cho tuang lai. Ca quan chuyen phan tich cac sd
lieu ve y te va He thong Giam sat da dugc thanh lap lan dau tien vao nam 1977, nham su
dung cac so lieu ve ke dan thuoc de hinh thanh cac nghien cuu djch te dugc hgc. Nam 1980,
Co quan Nghien cuu Giam sat An toan Thuoc da dugc thanh lap d Anh chuyen lam nhiem
vu giam sat viec ke dan cua cac thay thuoc. Nhung to chuc nay da gdp phan to ldn cho sir
phat trien lTnh vuc djch te dugc hgc.
Sau cung vao nhirng nam 1980, dae biet la nhung nam 1990 da xuat hien mdt sir
chuyen ddi trong lTnh vuc nghien cuu cua djch te dugc hgc. Ngoai vai trd cua djch te dugc
hgc trong viec nghien cuu sir dung thuoc va cac phan ung bat lgi ciia thuoc, nd cdn md rdng
sang cac ndi dung khac nhu sir dung dugc djch te hpc de nghien cuu cac tac dung cd lgi cua
thuoc; xay dung va ap dung cac chi so trong kinh te y te de lira chgn thuoc, dua ra cac phac
do dieu tri va nghien cuu hieu qua dieu trj cua thuoc; ung dung djch te dugc hgc de nghien
cuu lTnh vuc quan ly va chinh sach dugc cung nhu la nghien cuu chat lugng djch vu dugc.
3. DOI TlTONG NGHIEN ClfU DICH TE DlTOC HOC

Djch te dugc hgc nghien cuu viec sir dung thuoc va hieu qua dieu trj cua thudc trong
edng ddng. Van de sir dung thuoc d day phai dugc hieu theo nghTa rdng (xem Hinh 8.2), cd
nghTa la nd bao gom cac yeu to cd tac ddng, anh hudng den qua trinh su dung thudc.
Nhu d tren da trinh bay, khdi dau djch te dugc hgc nghien cuu ve cac phan ung bat
lgi cua thuoc, va sau dd cac sir kien bat lgi lien quan den van de su dung thudc, dae biet la
giai doan sau khi thuoc dugc phep luu hanh tren thj trudng. Thuc te cho thay, ljch sir ra ddi
cac qui djnh phap ly trong lTnh vuc dugc dugc gin lien vdi sir phat hien ra cac phan ung bat
lgi cua thuoc. Moi mdt sir thay ddi trong khung phap ly cua nganh dugc deu cd lien quan
den cac sir kien bat lgi cua thuoc. Chinh moi quan tam nay cua djch te dugc hgc da lam thay
doi va hoan thien dan khung phap ly trong ITnh vuc quan ly dugc.
190
Nhu vay cd the ndi rang doi tugng, pham vi nghien cuu cua djch te dugc hgc khdng
chi la nhung van de lien quan true tiep den tac dung cua thudc nhu: tac dung bat lgi va hieu
qua dieu trj cua thuoc, ma cdn bao g6m ca cac doi tugng lien quan den van de sir dung
thuoc sT vdi vai trd cung ung/cap phat thudc; ngudi
benh vdi vai trd sir dung thuoc true tiep, va ca mdi trudng phap ly, kinh te - xa hdi, van hoa
trong dd ton tai cac mdi quan he tren.
Hinh 8.2. Pham vi va doi tugng nghien cuu cua dich td dugc hgc
4. PHlTONG PHAP NGHIEN ClfU DICH TE Dl/OC HOC

Trong djch te dugc hgc, van de rat quan trgng la tra ldi dugc cau hdi: ket qua/hau qua
B (cd the la cd lgi hoac khdng cd lgi) xay ra cd xuat phat tir nguyen nhan nao? Tac
nhan/nguyen nhan A se dan dew ket qua/hau qua nhu the nao? Hoac ket qua/hau qua B xay
ra cd phai do nguyen nhan/tac n»<an A hay khdng va ngugc lai? Tra ldi dugc cac cau hdi do
cd nghTa la chung ta da lam ro dugc moi quan he giua yeu td nguyen nhan/tac nhan va ket
qua/hau qua, hay cdn ggi la mdi quan he nhan - qua:
Nguyen nhan/Tac nhan (A) —• Hau qua/Ket qua (B)
Hinh thuc cua moi quan he nay trong tung lTnh vuc la rat da dang va phong phu.
Chang han, mdt benh nhan dugc dieu trj sau mdt thai gian thi khdi benh, vay nguyen nhan
khdi benh la do thuoc nao hay do mdt yeu to nao khac? Mdt ngudi benh trong qua trinh
191
dieu trj xuat hien tac dung khdng mong muon, vay tac dung khdng mong muon do cd phai
gay ra do thuoc hay khdng va thuoc do la thuoc nao trong so thuoc da dugc dieu trj? Hoac
nguyen nhan dan den benh ung thu phoi cd phai la do hut thuoc la hay la yeu to nguy ca
nao khac, ngugc lai hut thuoc la cd dan den bj ung thu phdi hay khdng... Day la nhung mdi
quan he giua yeu to tac nhan/nguyen nhan va ket qua/hau qua can phai lam ro trong nghien
cuu djch te dugc hgc.
Ve mat phuang phap, cd 2 each tiep can de lam ro mdi quan he tren:
(i) Dua vao viec quan sat sir vat hien tugng lien quan den yeu to tac nhan/nguyen
nhan va ket qua/hau qua. Tren thuc te cd 2 each thuc quan sat:
- Quat sat mang tinh chat md ta: nham muc dich chinh la md ta lai thuc trang sir vat
hien tugng. Neu viec md ta tot cd the hinh thanh dugc gia thuyet ve moi quan he nhan qua:
tac nhan A —*• ket qua B, hoac ngugc lai.
- Quan sat mang tinh chat phan tich: nham muc dich chinh la giai thich moi quan he
nhan qua: tac nhan A cd moi lien he vdi ket qua B, hoac ngugc lai.
(ii) Dua vao md hinh thu nghiem: nham muc dich chirng minh moi quan he nhan qua:
tac nhan A dan tdi ket qua B, hoac ngugc lai.
4.1. Dua vao quan sat su* vat hien tuong
Cac nghien cuu dua vao quan sat sir vat hien tugng nghTa la trong qua trinh nghien
cuu, ngudi nghien cuu khdng tac ddng vao doi tugng nghien cuu hay qua trinh dien bien
cua sir vat hien tugng, ma dan gian chi la "dung ngoai" quan sat dien bien cua sir kien va
md ta lai hoac phan tich nhung dae tinh cua sir vat hien tugng de tu dd dua ra mdt gia
thuyet (gia dinh) ve moi quan he nhan qua hoac giai thich moi lien quan giua yeu to dugc
coi la nguyen nhan (tac nhan) va yeu to ket qua (hau qua).
De quan sat dien bien cac sir kien, ma sir kien nay cd the la da xay ra, dang xay ra,
thdng thudng ngudi ta sir dung phuang phap dieu tra chgn mau tir quan the nghien cuu,
trong dd mdt mau nghien cuu dai dien dugc chgn ra de quan sat nhung dae tinh ciia cac ca
the trong mau ma chung ta can quan tam. Dieu nay cd the dugc tien hanh thdng qua cac
cudc phdng van cac doi tugng hay bang each thu thap cac thdng so dae trung cua cac thuc
the hay dan gian bang each thu thap thdng tin tir nhirng nguon sin cd nhu: don thuoc, benh
an, so sach ghi chep, bao cao thong ke...
Cac nghien cuu quan sat, trong do cac thdng tin lien quan den yeu to nguyen nhan va
ket qua dugc thu thap dong thai hoac khdng xac djnh theo trinh tu thdi gian, dugc coi la cac
nghien cuu mang tinh chat md ta, thdng thudng chi nhim muc dich la md ta thuc trang hay
md ta nhu cau... hoac hinh thanh gia thuyet lien quan giua yeu to nguyen nhan/tac nhan va
ket qua/hau qua hay con ggi la xay dung gia thuyet nhan qua.
Cac nghien cuu quan sat, trong do cac thdng tin lien quan den yeu to nguyen nhan va
ket qua dugc thu thap va sap xep theo mdt trinh tu nhat djnh theo thdi gian, dugc coi la
nghien cuu mang tinh chat phan tich. Muc dich cua nghien cuu mang tinh phan tich thudng
la chung minh moi quan he giua yeu to nguyen nhan/tac nhan va ket qua/hau qua hay cd the
rut ra suy luan ve moi quan he nhan qua.
4.2. Dua vao cac nghien cuu thir nghiem
Nghien cuu thu nghiem la loai nghien cuu cd sir tac ddng len doi tugng nghien cuu
theo y muon chu quan cua con ngudi vdi tu each nha nghien cuu, nham danh gia gia
192
loai nghien cuu
nhat de kiem tra cac gia thuyet ve moi quan he nhan qua. Tuy
thir
Nhung nghien cuu mang tinh phan tich nay cd the la

chung) hoac tien cuu hay vua hdi cuu vua tien cuu
trong cac cudc nghien cuu nguyen nhan va hau qua. Thay vao
thuan lgi ro ret nhat trong nghien cuu thu
cd the loai tru gan het nhung yeu td chgn mau lam tang sai sd khdng cd y trong cac
cuu quan sat bang qua trinh chgn mau ngau nhien. Tuy nhien cac sai so khac khdng dugc
phap thu nghiem ddi khi khdng nhan thay dugc bdi
bang chung ve mdi quan he nhan qua neu nghien cuu dd khdng dua tren cac
phap nghien cuu khac cd the
DLS...T13 193
195
Trong djch te dugc hgc, loai thiet ke nghien cuu nay thudng hay dugc su dung de
danh gia phan ung bat lgi cua chgn mdt nhdm ca
the cd dau hieu xay ra phan ung bat lgi cua thuoc cd
phan ung bat lgi cua thuoc (nhdm chung). Sau do
cua ca hai nhdm de quan cua thudc vdi dau hieu phan ung bat lgi
cua thudc.
nhdm cd B va it nhat
mdt nhdm doi chung khdng cd B. Budc tiep theo la khai thac lai qua khu cua ca hai nhdm
de xem sd ca the tiep xuc va khdng tiep
gian nhung
hoan
la mdt nghien cuu dgc nen qua trinh tiep
xuc vdi ng4n
khac nhau, vi vay ngoai cac sai so chung (nhu trong nghien cuu thuan tap) cd the nay sinh
cac loai sai sd khac nhu sai so nhd lai, do vay can phai biet chu y de han che den muc
thap nhat loai sai sd nay.
chgn cac ca the cd hau qua hay ket qua A trong nghien cuu cd doi chirng de
dang han. Tuy nhien, viec lua chgn nhdm doi chung (khdng cd ket qua hay hau qua B) la
khdng he don gian. Day cung la van de can phai chu y cua nghien cuu cd doi chung do cac
sai sd chgn mau trong nhdm ddi chung cd the lam mat gia trj cua ket qua nghien cuu, chinh
vi vay khi phan
tich sd lieu tir cac nghien cuu cd ddi chirng.
Nghien cuu cd ddi chung la mdt nghien cuu dgc cd tinh chat hdi cuu do vay khdng
197
OR = —
be
ich trong viec tim ra tac nhan gay benh ddi

chgn cac
du sd ca
dung de tim
lua chgn nhdm "tinh cd" khdi
de cd nhan
kien
kien dd trong nghien
neu
nghien cuu yeu cau phai cd dieu tra djnh ky thi cd the cd hao hut ve mau do mdt sd ddi
tugng cd the tu chdi khdng tiep tuc hgp tac nua.
Trong rat nhieu trudng hgp, loai nghien cuu nay la ca sd de hinh thanh cac nghien
cuu phan tich khac nham khang djnh chac chan mdi quan he nhan qua.
Tuy nhien de tang tinh gia trj cua nghien cuu cd ddi chung, thiet ke nghien cuu can
phai dam bao rang:
- Nhdm doi chung phai rat khach quan, tot nhat dugc lira chgn tuong tu nhu nhdm
benh khi xet ve yeu td nguy ca.
phai
cd
benh hay
nhdm benh va
le cd lien
neu
hay la
hudng
nghien gian (tien cuu).
198
•
(a)
Tiep xuc vdi
tac nhan A
Khdng cd hau qua/
ket qua B (b)
Mau nghien
cuu
Cd hau qua/ket qua B

Khdng tiep (c)
xuc vdi tac
nhan A Khdng cd hau qua/
ket qua B (d)
Hinh 8.4. Thiet ke nghien cuu thuan tap

Phuang phap tinh toan nay la mdt sir cai tien so vdi each tinh ty le mac thdng thudng
do quan tam den ca sd lugng dugc quan sat va thai gian quan sat cho mdi ca the. Chang han
dugc quan sat trong 3 nam, 5 trong 4
ngudi dugc
quan sat dugc
Cach tinh toan de dua ra mdt ty le
khdng dai dien
quan sat cd the la 400 ngudi ma mdi ngudi trong sd
quan sat
djnh chac chan thdi diem
chinh xac khi benh xay ra va ty le phat trien thanh benh qua thdi gian khdng nhat thiet phai la
khdng phd bien cd lien quan. Nhu giam sat
ve thudc sau khi thudc luu hanh, nham danh gia bat ky do
ciia thudc khi mdi dua ra thj trudng.
Quan the nghien ciiu dugc xac djnh trudc, sir hien dien ciia cac ca the cd nguy ca
dugc xac djnh ro nen cd kha nang tinh toan true tiep nguy ca tuang ddi ciia sir phat trien
mdt tinh trang benh nao do (kha nang phai nhiem) cho nhung ca the cd mdt dae diem cu
the so vdi nhung ca the khdng cd dae diem dd tren ca sd do ludng ty le mac dugc tinh toan
rieng re cho mdi nhdm.
sir
deu khdng bj benh khi bat dau nghien cuu. Dieu
nay cho phep ket luan ve mdi quan he nhan qua (day cung mdi chi la dieu kien can, de khang
hien nen
tinh trang benh nhu gap phai trong
bj loai ra khdi
cd the lien
tinh
benh
201
ca the bj nhiem cac yeu to nguy khdng bj nhiem cac yeu td nguy ca.
Sau khi chgn cac ca the vao nhdm nghien cuu, ngudi ta tim hieu ngay ca the xem
chiing cd bj nhiem cac yeu td nguy
Mdt nghien cuu thuan tap hdi cuu phu thudc vao cac sd lieu hay tai lieu
ghi chep cho phep tai tao lai cac cac ca the vdi yeu td
nguy ca diem, dja
diem khi xay ra kien lien quan den quan the nhung hg cd the tai tao lai nhung sir
thdi
cd mdt sd diem bat lgi
hay
- Van de hao hut mau cd lien quan den viec ghi chep hay luu lai tai lieu khdng day du
cuu va
thdng tin dang tin cay lien quan den yeu
(a)
Tiep xiic vdi
tac nhan A
Khdng cd hau qua/ket
qua B(b)
Mau
nghien cuu
(c)
Khdng tiep
xiic vdi tac
Khdng cd hau qua/ket nhan A
qua B(d) '
Thdi diem hien tai
Hinh 8.5. So do thiet ke nghien cuu thuan t3p hoi cuu

2) Thuan tap tuang lai
Thiet ke nghien ciiu thuan tap tuang lai la viec lua chgn nhdm chii cuu gdm cac ca
the dugc tiep xiic vdi yeu td nguy ca, va nhdm ddi chirng gdm cac ca the khdng dugc tiep
xiic vdi yeu td nguy ca. Sau khi chgn dugc nhdm chii cuu va nhdm ddi chung, tien hanh
giam sat tinh trang tiep xiic va khdng tiep xiic vdi cac yeu td nguy ca ciia cac nhdm nay mdt
each thudng xuyen, ddng thai theo ddi cac ca the xem cd hay khdng tinh trang bj nhiem cac
yeu td nguy ca.
Thiet ke thuan tap tuang lai lai dugc phan ra lam 2 dang nghien ciin thuan tap tuang lai:
i) Thiet ke thuan tap tuang lai cd tiep xuc bat dau tiehien tgi
Nghien ciiu dugc bat dau vdi nhdm chii cuu, toan bd ca the ciia nhdm nay dugc tiep
xiic vdi yeu td nguy ca ngay tir khi bat dau. Nhdm ddi chiing se khdng bj tiep xiic vdi yeu
td nguy ca. Theo ddi cac ca the d ca 2 nhdm cho den khi xuat hien tinh trang bi nhiem cac
yeu td nguy ca.
Thiet ke nghien cuu thuan tap tuang lai bat dau tir hien tai cho ket qua tuang ddi
chinh xac, nhung thai gian nghien cuu dai va ton kem.
ii) Thiet ke thuan tap tuang lai cd tiep xuc bat dau tiequa khu
203
(a)
Tiep xiic vdi
tac nhan A
hi :H '• Khdng cd hau qua/ket
qua B(b)
Mau nghien
cuu

Khdng tiep (c)
xiic vdi tac
nhan A
Khdng cd hau qua/ket
qua B(d)
Thdi diem hien tai
Hinh 8.6. So do thiet ke nghien cuu thuan t£p tuong lai

Ngudi ta chgn nhdm chii cuu gdm nhung ca the ma trudc do da cd tiep xiic vdi yeu td
nguy ca. Nhdm doi chung khdng tiep xiic vdi yeu td nguy ca. Theo ddi cac ca the d ca 2
nhdm cho den khi xuat hien tinh trang bi nhiem cac yeu td nguy ca. Vdi each thiet ke nay,
cho phep ngudi ta chi can theo ddi mdt thai gian ngan nua, de chd dgi xem cac ca the cd
tinh trang bj nhiem cac yeu to nguy ca hay khdng, do vay tiet kiem dugc thai gian va giam
chi phi nghien cuu.
5.2.3. So sanh nghien cieu thuan tap vd nghien cuu cd ddi chung
NGHIEN ClTU CO DOI
CHlTNG
Nghien cuu cd ddi chung va nghien cuu thuan tap dua ra
nhung thdng tin nhu nhau, nhung hudng lua chon du lieu
tir cac phia ddi dien YEU TO HAU QUA (HQ)/
KET QUA (KQ)
C& HQ/KQ KHONG

HQ/KQ
NGHIEN ClTU Yeu td CO TIEP XUC A b

THUAN TAP tac nhan
KHONG TIEP XUC
c d
Hinh 8.7. So sanh su giong nhau va khac nhau giua nghien cuu cd doi chung va nghien cuu
thuan tap
Sir khac nhau ca ban giua nghien cuu thuan tap va nghien cuu cd ddi chung (benh
chung) la ca sd da de cap d tren, do la nhung ddi tugng nao dugc tuyen chgn vao nghien
cuu. Cac doi tugng dugc tuyen chgn vao cac nghien cuu cd ddi chung dua tren ca sd la
204
doi
Ngau nhien —•
1 ' ^ '
NH6M CAN THIEP NH6M06I CHLTNG
11
<V KtT QUA 2

nghien
thudc vao viec chgn mau nghien cuu mang tinh dai dien nhu the nao.
nghiem tren
Tuyen bd
die nghien
khdng Nhirng
doi tugng cdn lai sau khi da tham gia
nghien cuu. Day la nhdm doi phan bd
mdt each ngau nhien dua theo chung.
Mdt khi cac doi tugng da dugc phan thanh thu nghifm va nhdm doi chung, hg se
dugc theo ddi can than trong mdt giai doan cu thi vdi cac dieu kien chat che va ket qua ciia
thu nghiem dugc ghi chep lai. Ket qua dd cd the la mdt sir kien nhj phan, chang han nhu
chua dugc.benh, giam dugc dau... hoac cd the dugc do lugng nhu mdt bien so lien tuc nhu
giam so lan ban khang sinh, giam huyet ap... hay tung phan doan ciia bien so. Tiep dd ngudi
ta dung cac phuang phap thong ke thich hgp de so sanh cac so do ket qua giua cac nhdm.
nhien cho cac nhdm thu nghiem
Van cd the cd nhung khac biet
so nhieu tiem an. Do vay neu
thich hop khi hoan thien viec
thuat
xu ly sd
cuu
dugc
hgc ung dung cac phuang
Hien
nhung
quan
phan tich mdi lien quan giua djch te dugc hgc
DLS...T14
209
3. Phan tich phuang thuc tiep can
hien tugng.
4. Phan tich phuang thuc tiep can
nghiem.
5. Thiet ke nghien cuu md ta: khai niem, cac loai thiet ke nghien cuu md ta va phan tich
uu nhugc diem.
6. Nghien cuu cd ddi
thu thap sd lieu va
7. Nghien cuu thuan tap: thiet ke nghien cuu,
thap sd lieu va
8. So sanh thiet ke nghien cuu cd ddi chung va thiet ke nghien cuu thuan tap.
9. Nghien cuu can thiep: thiet ke nghien cuu, cac loai nghien cuu can thiep va uu nhugc
diem.
TAI LIEU THAM KHAO
1. Nguyen Thanh Binh (2007). Djch te dugc hgc. Nha xuat ban Y hgc.
2. F. Dabis, J. Drucker, A. Moren (1992). Djch te hgc can thiep. Nha xuat ban Y hgc 1992.
Dang Van Khoat djch ra tieng Viet.
3. Remigio D. Mercado (1994). Djch te hgc danh cho cac nha quan ly y te. De an dao tao
03/SIDA/Indevelop - Bd y te.
4. Brenda Waning, Michael Montagne (2001). Pharmacoepidemiology - Principles and
Practice. McGraw - Hill, Medical Publishing Division.
5. Brian L. Strom (2005). Pharmacoepidemiology. Fourth Edition, John Wiley & Songs.
6. Charles H. Hennekens, Julie E. Buring (1994). Epidemiology in Medicine. Little,
Brown and Company Boston/Toronto.
7. WHO (1992). How to investigate drug use communities. WHO, Action Programme on
Essential Drug.
• '- >• > >, .1 < -r-jp • ?L'|.,
"'{wn;:«':'qBf(q
210
CHUCVNG
MUC
1. Trinh bay dugc khdi ni?m, qua trinh phat trien, phgm vi va doi tugng nghien cuu cua kinh
te dugc.
2. Trinh bay dugc cdc logi chi phi trong kinh te dugc vacho vi du.
3. Trinh bay dugc cdc logi thietke nghien cuu ung dgng trongkinh te dugc. .
4. Trinh bay dugc cdcphdn tich kinh te dugc, ung dung va cho vi du:
a. Phdn tich gidm thieuphi ton (CMA);
b. Phdn tich Phi ton - Lgi ich (CBA);
c. Phdn tich Phi ton - Hi$u nghi?m (CEA);
d. Phdn tich Phi ton - Hii>u dung (CUA).
dang ke va
sd y te ndi rieng, ke
ddi mdi -
pham mdi cung vdi gia
ban
lau va ung dung vao thuc tien mdi ngay mdt phat
cu vd cung quan trgng cho cac nha hoach djnh chinh sach y te, cac nha
mdn hgc nay van cdn xa la
nay nham gidi
lTnh
can bang giua cac

thuc dieu trj mdi) vdi hieu qua dieu trj ma nd
xa
thudc hay djch
khde ngudi dan trong
thuan chi nham vao phi ton hay

phuang dien
khde. Kinh te dugc coi trgng gia
211
dien va
ban de danh gia

dien phi ton va chat
sue
tich khac nhau nhu: phan tich
va phi ton - huu dung.
toan
nay, vdi dieu kien cac md hinh phan tich phai thda
phap
tich tdi thieu
lugng
dugc
ndi rieng vdi kinh te hang hda
(My), da gidi thieu nhung khai niem ban dau ve phan tich phi ton - lgi ich, phi ton - hieu
nguon
cac nha quan ly va quan trj ngan sach tai chinh phai
sdc
212
den
chi
gia trj
nua,
%
nam
the len den
thudc
nen
den
dang
cho cac quan ly va nha hoach djnh

nhung
nhung
nghiem
cho thay
edng
Journal
Lancet,
trinh ndi
tap chi
Formulary,
Health
nhung tap
Economics,
Care...
thdng tin
khde (Delivery
cac nghien cuu
—hieu qua (Cost
loai thir
chi phi -
92.250
bai (nam 1999)
vi ling dung cac ket qua cua kinh te dugc gom ba ddi tugng chinh: phuc vu xa
can cu
ciia san
pham nghien cuu
nay la ca
quan dam bao
213
chat lugng cudc sdng ciia tung ca nhan dugc cai thien han thi doi tugng hudng tdi la ca
nhan. Mdi mdt nhdm ddi tugng ma kinh te dugc hudng tdi se cd mdt loat cau hdi khac
nhau, udc tinh phi tdn trong mdi trudng hgp cung se cho nhung cau tra ldi khac nhau.
Qua ljch su phat trien ciia lTnh vuc kinh te dugc va sir md rdng ngay cang ldn ve
pham vi ciia lTnh vuc nay, ddi tugng quan tam ciia cac nghien cuu ve kinh te dugc can dugc
can nhac ky ludng. Diem quan trgng nhat la can phai xac djnh cac nghien cuu phan tich
kinh te dugc nay nham vao quan diem hay doi tugng nao, bdi vi m6i mdt doi tuong se cd
mdt phuang phap thu thap so lieu va danh gia ket qua khac nhau va phu thudc vao tung boi
canh cu the.
Trong ljch su, khi danh gia mdt loai thuoc mdi, nhung nha hoach djnh tai chinh trong
viec lira chgn thudc cho cac ca quan djch vu y te thudng can cu tren cac ket qua thu nghiem
lam sang lien quan den do an toan va hieu qua (hay hieu nghiem) ciia thuoc. Hieu nghiem
ciia thudc thudng danh gia kha nang ciia mdt dugc pham thdng qua mdt danh gia thu
nghiem ldn trong khudn khd thu nghiem trong phdng thi nghiem va dugc thua nhan la cd
ket qua tot. Tuy nhien, sir hieu nghiem ciia thudc khi tham gia vao thj trudng trong boi canh
cd sir tham gia su dung rdng rai ciia nhieu doi tugng: cac ca sd dieu trj, ngudi benh va nhan
vien y te vdi cac dieu kien mdi trudng va hoan canh khac nhau, hoan toan khdng giong nhu
cac thu nghiem trong phdng thi nghiem. Kinh te dugc chii trgng den sir huu hieu va huu
dung that sir ciia thudc tren edng ddng han la hieu nghiem dugc edng bo bdi cac hang dugc
pham thdng qua nhirng edng trinh thu nghiem lam sang tren mdt so benh nhan tinh nguyen
va theo mdt loat tieu chuan da dugc an djnh trudc.
2. CAC LOAI CHI PHI TRONG KINH TE DI/OC
Ngoai nhung ddi tugng hudng tdi khac nhau, chi phi hay phi ton cung chia ra rat
nhieu loai trong kinh te dugc, chi phi dugc djnh nghTa nhu la nhirng phi ton ganh chiu dung
de cung cap san pham va djch vu y te. Phi tdn nhin chung dugc phan loai thanh cac loai chi
phia sau:
2.1. Chi phi co djnh (Fixed Cost) va chi phi bien doi (Variable Cost)
Chi phi cd djnh (Cf) la chi phi ma trong khoang ngan han khdng phu thudc vao so
lugng san pham dugc tao ra, la cac chi phi can cho thiet lap mdt hoat ddng san xuat nao dd.
Vi du, trong hoat ddng kham chua benh ciia benh vien, mot trong cac loai chi phi co djnh la
chi phi tra luong ca ban cho nhan vien y te, chi phi nay khdng phu thudc vao so lugng
ngudi benh den kham chua benh tai day.
Chi phi bien ddi (Cv) la chi phi thay ddi true tiep theo sd lugng san pham. Trong vi
du tren chi phi cho tien thudc dieu trj cho ngudi benh la chi phi bien doi vi nd tang hay
giam theo sd lugng benh nhan.
Chii y rang, trong khoang dai han tat ca cac chi phi cd the bj thay doi va chi phi co
djnh thudng dugc djnh nghTa trong mdi quan he vdi thai gian dugc xem xet, chang han nhu
mdt chu ky tai chinh (thudng la mdt nam).
2.2. Tong chi phi (total cost) va chi phi trung binh (Average Cost)
Tdng chi phi (Ct) la tat ca cac chi phi de san xuat ra mdt muc san pham nhat djnh. Vi
du, chi phi de cung cap djch vu bao ve sue khde ba me va tre em. Tong chi phi dugc tinh
theo edng thuc sau:
Tdng chi phi (Ct) = Chi phi cd djnh + Chi phi bien doi
214
Tdng chi phi (Ct) = Chi phi von + Chi phi thudng xuyen
Tdng chi phi (Ct) = Chi phi true tiep + Chi phi gian tiep
Chi phi trung binh (Ca) hay chi phi dan vj la chi phi cho mdt san pham dau ra. Chi
phi trung binh dugc tinh bang tong chi phi chia cho so lugng san pham dau ra. Vi du chi phi
dieu trj trung binh cho mdt ngudi benh tai benh vien A nam 2010 bang tong chi phi dieu trj
chia cho sd benh nhan tai benh vien A trong nam 2010.
Hinh 9.1. Tong chi phi, chi chi co dinh va chi phi bien doi N (Nam)
2.3. Chi phi bien hay chi phi ngoai bien (Marginal Cost)
Chi phi bien (Cm) la chi phi them khi san xuat them mdt dan vj san pham hang hda
nao dd, ndi each khac do la chi phi phat sinh khi chuyen tir n san pham sang n+1 san pham.
Ndi rdng han, chi phi bien the hien sir thay doi ve moi quan he giua tong chi phi vdi
khdi lugng hoat ddng ciia mdt chuang trinh nao do. Van de dat ra la chi phi bien cd y nghTa
nhu the nao so vdi chi phi trung binh? Xem xet moi quan he giua chi phi bien va chi phi
trung binh, ta thay khi chi phi bien ciia dan vj san pham tiep theo ldn han chi phi trung binh
ciia dan vj san pham da dugc san xuat ra thi viec san xuat dan vj san pham tiep theo se lam
tang chi phi trung binh cho mdi dan vi san pham. Ngugc lai, chi phi bien cho dan vj san
xuat tiep theo nhd han chi phi trung binh ciia dan vj san pham da dugc san xuat ra thi viec
san xuat dan vj san pham tiep theo se lam giam chi phi trung binh cho moi don vj san pham.
Khi chi bien bang chi phi trung binh thi viec san xuat dan vj san pham tiep theo se khdng
lam thay ddi chi phi trung binh ciia dan vj san pham.Trong phan tich chi phi, viec xac djnh
chi phi bien thudng khdng de dang va trong nhung trudng hgp nhu vay ngudi ta phai su
dung chi phi trung binh thay cho chi phi bien.
2.4. Chi phi true tiep (Direct Cost) va chi phi gian tiep (Nondirect Cost)
Chi phi true tiep trong lTnh vuc y te la nhung chi phi phat sinh cho he thong y te, cho
cong ddng va cho gia dinh ngudi benh trong giai quyet true tiep benh tat. Chi phi nay dugc
chia lam 2 loai:
215
- Chi phi true tiep cho dieu trj la nhung chi phi lien he true tiep den viec cham sdc sue
khde nhu choc ho phdng benh, cho dieu trj, cho cham sdc va cho phuc hdi chuc nang...
- Chi phi true tiep khdng cho dieu trj la nhung chi phi true tiep khdng lien quan den
kham chua benh nhung cd lien quan den qua trinh kham va dieu trj benh nhu: chi phi di lai,
dtrg...
Chi phi gian tiep la chi phi thuc te khdng chi tra. Chi phi nay dugc djnh nghTa la mat
kha nang san xuat do mic benh ma ngudi benh, gia dinh hg, xa hdi va dan vj nai hg edng
tac... phai ganh ehju. Hau het cac nghien cuu ve chi phi do mac benh da djnh nghTa chi phi
nay la gia trj ciia mat di kha nang san xuat do nghi viec, do mat kha nang van ddng va do
chet som ma cd lien quan den benh va dieu trj benh.
Chi phi gian tiep nay sinh dudi 2 hinh thuc, chi phi do mac benh va chi phi do tu
vong. Chi phi mac benh bao g6m gia trj ciia mat kha nang san xuat ciia nhung ngudi benh
do bi 6m phai nghi viec hoac bj that nghiep. Chi phi do tu vong dugc tinh la gia trj hien tai
ciia mat kha nang san xuat do chet sdm hoac mat kha nang van ddng vTnh vien do bj benh.
2.5. Chi phi v6n va chi phi thudng xuyen
Thdng thudng chi phi von va chi phi thudng xuyen cd hinh thuc bieu hien gidng
nhau, chi khac nhau ve muc dinh va thai gian.
Chi phi von hay chi phi dau tu la chi phi de mua hanh hda cd gia trj su dung tir mdt
nam trd len. Vi du, chi phi cho xay dung ca ban, dau tu trang thiet bj may mdc...
Chi phi thudng xuyen hay cho phi cho trien khai la nhung chi phi de mua hang hda cd
gia trj sir dung dudi mdt nam. Vi du, chi phi tra luang cho can bd y te, chi cho mua thudc
hay vat tu tieu hao...
2.6. Chi phi khong ro rang
Khi xem xet cac chi phi trong kinh te dugc de dieu trj ciia mdt benh nao do, ngoai
viec xem xet cac chi phi true tiep, gian tiep cac nha kinh te cdn xem xet den mdt loai chi phi
khac do la chi phi khdng ro rang. Thdng thudng do la chi phi do dau ddn, lo sg, giam sut
chat lugng cudc song ciia ngudi benh va gia dinh, mat thdi gian nghi ngai. Tuy vay, trong
thuc te cac chi phi nay thudng it dugc xem xet den trong danh gia kinh te dugc bdi vi nd
mang tinh chii quan va phu thudc rat nhieu vao van hda. Do vay, khd cd the djnh gia cac chi
phi nay sang dan vj tien te.
Chi phi gian tiep va chi phi khdng ro rang can dugc tinh den khi xem xet ganh nang
kinh te ciia mdt benh tren quan diem xa hdi hay quan diem ciia ngudi benh.
Ngoai ra, cac chi phi trong kinh te dugc cdn dugc phan loai thanh mdt sd chi phi khac
nhu: chi phi ca hdi (opportunity cost), va chi phi trong tuang lai udc tinh vdi thdi gian...
3. CAC PHlTONG PHAP NGHIEN ClTU KINH TE DlTOC
Tu lau ngudi ta da sir dung nhirng phuang phap phan tich trong nghien cuu kinh te de
ap dung vao thuc hanh y dugc, nhung phan tich kinh te nay da dugc chii y nhieu va la
phuang tien de giiip cac lTnh vuc lien quan den djch vu sue khde tim each phat trien cac md
hinh trong nganh kinh te dugc.
Nghien cuu kinh te dugc la nhung nghien cuu cd muc dich nhan djnh, do ludng, tinh
toan va so sanh cac phi tdn (ngudn tai nguyen tieu thu) va ket qua (lgi ich, hieu qua, chat
216
lugng cudc song, huu dung, hieu lire, an toan, thong ke ve benh, so tu vong) ciia nhung san
pham bao che/san xuat trong nganh dugc.
3.1. Cac thiet ke nghien cuu kinh te dugc
Tuy theo kieu djnh gia kinh te dugc, nha nghien cuu cd toan quyen lua chgn loai hinh
nghien ciiu va nhung tai lieu tham khao da cd sin trong y, dugc van de lam ca sd phan tich.
Su chgn lua phan tich ket qua cd the la rieng biet cho tung phan tich hay hon hgp ciia phi
ton - lgi ich, phi ton - toi thieu, phi ton - hieu qua, phi tdn - huu dung hay pham chat cudc
song.
Diem quan trgng d day la nhung nghien cuu kinh te dugc thudng dung tdng hgp cac
loai tai lieu tham khao ciia nhieu nguon khac nhau vdi muc dich de tranh nhung nhan dinh,
y kien chii quan cd the cd ciia nhung ket qua thu nghiem lam sang.
Cac ngudn du' lieu so cap sir dung trong kinh te dugc:
- Thu nghiem ngau nhien cd ddi chiing hay thu nghiem cd kiem soat va ngau nhien
hda (Randomized Controlled Trials - RCTs). Day la thiet ke nghien cuu thudng dugc ap
dung de danh gia muc dd an toan va hieu qua ciia san pham thu nghiem. Hien nay, nhung
thuoc muon cd trien vgng dugc chap thuan de dua vao edng thuc dieu tri deu phai dung
nhung thu nghiem loai nay de danh gia hieu qua cua thudc. Md hinh thiet ke ngau nhien cd
doi chiing thudng bao ham cac dir lieu dugc kiem soat ky ludng va day du yeu td thdng ke
de tim ra nhung sir khac biet dang ke trong cac phuang thuc dieu trj. Nhung du lieu thu
thap trong nghien ciiu ngau nhien cd ddi chiing thudng dugc ghi chep lai sau khi tien hanh
thu nghiem hay cdn ggi la du lieu tien ciiu (prospective data), khac vdi each thuc thu thap
dir lieu trong qua khu (retrospective) nghTa la khdng phai khi d trong thu nghiem.
- Nhung nghien cuu quan sat (Observational Studies). Nghien cuu quan sat thudng
thu thap cac du lieu xay ra trong thuc te, vi du nhu lay tu hd so benh an, benh vien, ca quan
quan ly y te... Cac quan sat nay thudng do ludng do hieu nghiem ciia thudc, va thudng phan
anh chat lugng cham sdc ngudi benh. Loai nghien ciiu nay thudng dugc lam trong cac ben
vien vdi muc dich phan tich/danh gia mdt qua trinh quan trj trong ndi bd, vi du nhu chinh
sach dung thudc hay quyet djnh ciia Ban giam ddc de dua mdt thudc vao edng thuc dieu
trj... Vi loai nghien ciiu nay cd tinh chat lam tai chd cho nen khdng de dang de dung ket qua
nay ap dung cho mdt dja diem khac vdi mdt edng ddng hay benh nhan khac.
Cac ngudn dir lieu thu cap sir dung cho kinh te dugc:
- Nhung du lieu hoi ciiu (retrospective databases). Nhung ngudn du lieu nay nay gdm
nhung du lieu lay tir ca quan quan ly y te, tir phdng luu tru' hd sa benh ly (phdng ke hoach
tdng hgp) trong benh vien, benh an, hay phdng mach tu, thudng dugc dung de chi ra dugc
thudc thich hgp dua vao vao cong thuc dieu trj. Lgi diem ciia phuang thuc nay la cac sd lieu
phan anh thuc tien xay ra trong dieu trj va cd the lay dugc tuang ddi de dang. Han che cua
phuong thuc nay la chat lugng ciia cac du lieu thay ddi tuy theo nhung ca quan quan ly hay
nhung dja diem khac nhau. Han nua neu du lieu dugc luu tru qua he thdng ma sd, vi du nhu
DRG hay 1CD cd the khdng ddng nhat.
- Y kien ciia nhung chuyen gia lam sang (Expert Clinical Opinion) cung duac coi la
quan trgng trong nhung trudng hgp nhung bien sd nghien ciiu bj thieu va nhung phan tich
nhay cam phai dugc dung den.
- Lugng gia dung thudc dung (Drug Use Evaluations - DUEs/Drug Use Reviews -
DURs) cung tot khi sir dung de phan tich chi phi va hieu qua ciia thudc tai mdt dja diem cd
217
djnh nhu benh vien hay ca quan quan ly y te nao do. DUEs cd the phan tich ca thdng tin ve
sd lugng va chat lugng. Muc dich ciia phan tich ve sd lugng ciia DUEs la phat trien xu
hudng va thai gian dung thudc d nhirng cap do khac biet trong mdt he thdng cham sdc sue
khde. Muc dich ciia phan tich ve chat lugng ciia DUEs la xem thudc dung cd phu hop hay
khdng. Tdm lai, muc dich ciia nhung thu nghiem loai DUEs la tim hieu va tinh toan nhirng
van de khi thudc dugc dung va neu ket qua ciia nhung tham khao nay cho thay cd sir bat lgi
ciia thudc thi thudc cd the dugc thay ddi trong viec su dung.
- Ngudn an pham, nhu da ndi d phan tren, nhung ngudn tai lieu ve kinh te dugc vdi
nhung ket qua thu nghiem hien cd rat nhieu tren cac loai tap chi nganh va chuyen nganh.
Trudc khi dung nhirng ket qua thu nghiem tu cac tap chi chuyen nganh, nhung edng trinh
nghien ciiu nay can phai dugc danh gia ky ludng qua nhirng cac bieu mau hudng dan de
lam sao hoan tat mdt nghien cuu kinh te dugc.
3.2. Cac phan tich kinh te dugc
Phuong phap luan ve kinh te dugc cd the dugc chia ra lam bdn loai can ban, bao gdm:
Phan tich giam thieu phi tdn (Cost Minimizing Analysis - CMA);
Phan tich Phi tdn - Lgi ich (Cost Benefit Analysis - CBA);
Phan tich Phi tdn Hieu nghiem (Cost Effectiveness Analysis - CEA);
Phan tich Phi tdn Huu dung (Cost Utility Analysis - CUA).
Bang 9.1. Don vi do ludng cac phan tich kinh te dugc
Phuang phap Dan vj do lud'ng Den vi do ludng ket qua

phi ton
Phan tich giam thieu phi ton Tien te Gia dinh tuong duong trong moi
(CMA) nhdm
Phan tich Phi ton - Loi ich Tien te Tien te

(CBA)
Phan tich Phi ton - Hieu Tien te Don vj tu nhien (so nSm song sdt
nghiem (CEA) them, huyet ap mmHg, lugng dudng
trong mau...)
Phan tich Phi ton - Huu dung Tien te So n3m song sdt them d§ dieu chinh
(CUA) chat lugng hay nhung phuong tien
huu dung khac
Trong bdn phan tich tren, hai don vj do ludng dugc dung la phi tdn va ket qua:
- Do ludng phi tdn cua ca bdn loai la tien te.
- Do ludng ket qua khac biet cho mdi phan tich.
3.2.1. Phdn tich gidm thieu phi tdn (CMA)
Phan tich giam thieu phi tdn (CMA) nham muc dich so sanh phi tdn ciia cac loai dugc
pham, phac do dieu trj hay cac djch vu... dugc coi la cho mdt ket qua tri lieu gidng nhau.
Khi hai ket qua (an toan va hieu lire) ciia hai can thiep hay phuang thuc dieu trj hay nhieu
han nua dugc coi la nhu nhau (bang nhau), thi phan tich nay hay dugc sir dung, khi do
chiing ta chi quan tam dau vao va phuang thuc nao cd chi phi dau vao thap han thi dugc coi
la hieu qua han.
218
cac
cd the xay ra, nhung chi khac
generic.
Enzyme
han
chi phi se re han de dua vao
che tac dung cho biet

ling
kinh
djnh
the ap dung
huyen
hgc dudng. Tuy
3.2.2. Phdn tich
viec
te hay
tdn tinh toan xem cd the tiet kiem dugc bao nhieu tien, phan tich Phi ton - Lgi ich cdn tru
phan tich Phi ton - Lgi ich la xac
djnh va minh chung dugc pham nao cho ket qua sau khi dieu trj tot nhat vdi so tien an djnh.
ty so Phi tdn/Lgi ich hay la
Mac du dugc ggi la ty so Phi ton/Lgi ich, each
vi thudng nd cho ta mdt ty so ldn han 1.
vj do ludng ciia phan tich nay la
dan vj tien te (xem Bang
Khi so sanh dau vao va dau ra
chi phi dau vao thap han lgi ich
Hieu nghiem.
dieu trj hay chuang trinh.
219
tuoi bj
nhung
loai khang
khang khang
mac benh
phuang
tdn -
vdi hg.
cho nam
35.000
moi nam.
moi nam
USD cho moi
ty so
da lam
ceftriaxone
(Claforan)
hieu qua
vdi cefotaxime
II
Can thiep cd hieu qua cao hon, chi phi Can thiep cd hieu qua cao hon, chi phi
cung cao hon thap hon
IV III
Can thiep cd hieu qua thap han, chi phi Can thiep cd hieu qua thap hon, chi phi
cung cao hon cung thap han
phan tich tren, phan tich
bat lgi hoac trj lieu that bai deu phai dugc liet ke ra. Loai phan tich nay hay
tung phuang an va so sanh ket qua nay giua cac
tim (myocardial
infarction), ngudi ta ap dung phan tich phan tich Phi ton - Hieu nghiem (CEA) nham muc
221
Nhung thu nghiem lam sang cho thay ngoai thuoc trj tang huyet ap cho benh nhan, neu cho
sir dung kem statin - la thuoc dieu mach
tim rat cd hieu qua nham giam ty le xay ra cac bien co tren. Phan tich Phi nghiem
ciia kinh te dugc neu chiing minh dugc viec phoi hgp vdi thudc dieu trj mau
(statin) de kiem soat sir tang cholestreol hiem
cuu
phan
de dieu trj
thudc
trong
dudng
nhung
lam
tinh
sd
ly
hgp
nhugc
222
ich
nay
dd
sau:
di
sang,
54.000
phu
trinh
phi
chi cdn
quyet
chi
la
nguy
dugc
"dae
223
224
chi phi de keo dai tuoi
cho thay moi QALY cd the trj gia khoang

vao benh nhan suy
song
sd chat lugng song khoang 0,69. Vi the, tinh tren moi QALY trj
Tuy nhien, ngay ca con so nay cung van
dung la phan tich cd ti so phi ton va ket qua trj lieu

luu y den tinh trang benh nhan. Phan tich
phan tich Phi ton - Hieu nghiem vdi dan vj dau ra
- Huu dung dung

nhien (cuu sdng benh nhan, khdi benh, kiem soat dugc ap huyet cao, kiem
soat dugc lugng dudng trong mau) lam don vj do ludng ket qua cho chi phi hay djch vu,
mdt
- CUA dua tren sd do dau ra chung cho mgi nghien cuu (ca trong va ngoai nganh y te)
khach hang cdn CEA chi phan anh ban than gia trj
dung nay cd the dugc ap dung tren toan quoc va
tren chat lugng dieu chinh theo so nam song them cd chat lugng (QALYs) trong phan tich
loai nay: da duac dung©de so sanh mdt sd tri• lieu
• va thudc. A£.
Dan vj QALYs bao gom chat lugng va so lugng cudc ddi. QALYs rat khd ma do
ludng dugc chinh xac. Khac vdi CEA, trong CEA dan vj ket qua tu nhien dugc dung,
nhung khd ma cd the cho ring tinh trang sue khoe ciia mgi ngudi deu giong nhau, thi du
Trong
khoe
khde khac
dan vj QALY ma khdng can dat gia
do
dau ra nay cd
tich Phi tdn - Huu
X
nhan
hiem
khde manh nhu thudng.
tieu
pacing).
dugc dieu
(QALYs)
giai phau se cd lgi ich va huu dung cho benh nhan han.
ung
cancer)
(Taxotere)
phai
cd
cho moi benh
phan
song
nay
lugng
Vay thi khi nao thi sir dung phan tich CUA? Nhirng trudng hgp sau day nen sir dung
- Khi chi cd the thu dugc sd lieu hieu qua dau ra trung gian. Vi du, trong mdt nghien
la huyet ap giam dugc bao nhieu
giam bdt phi tdn, tang them ich lgi, hieu nghiem (hieu qua) va huu dung,
nghTa
cho cudc sdng nganh kinh te dugc dang ngay cang dugc
thua
khdng the thieu dugc trong quan ly y te ndi chung va quan ly su dung thudc ndi rieng. Cach
nhin ban dau chi coi kinh te
nhieu. Ngudi dugc tac lien quan den dugc dang thuc
hanh, vdi ket qua nghien cuu thu nghiem trong nganh
kinh te
thdng viec dieu trj, dieu kien kinh
te, lam
CAU
1.
2.
3. Trinh cac khai niem ve chi phi trong kinh te Cho cac vi du ve chi phi co djnh, chi
tiep, chi phi gian tiep, chi phi
228
229
ldn
trudng Nhirng
khac doi
ve dugc thudc.
Ngoai chgn
thuoc va dieu hgc va
dugc thai an
toan
1. SC
quan
den tinh an toan dan cd
the viem
khdp thdng
tin ma ca nhan vien y te va ngudi dung thuoc de cd dugc nhat la td thdng tin san pham dang
dugc luu tru khi
lgi ich thu dugc ldn sir can
thiet phai la "cd" hay
manh
me sau khi cd
hang ciia
cac ba me dung thuoc khi mdi cd thai. Ve sau, ti le quai thai gay ra do dugc
thong dung
230
thudc
ngan
nhan dan den ung thu
yeu cau cac thudc mdi phai dugc thu nghiem

tien lam sang chat che trudc khi dugc cap phep luu hanh. Tuy nhien cac thu nghiem tien
an toan tuyet doi tren phu nu. Vi
cd thai (PNCT) phai tuan theo cac quy djnh
la "kha nang anh

cac tac dung nay rat
khiem
gay quai thai, chi cd
Diethylstibestrol
Thuoc uc che enzym chuyen dang angiotensin
Etretinat
Thuoc uc che thy the AT-II
Isotretinoin
Vitamin A (>25.000 dvqt/ngay)
cd thai, hau het cac thudc cd the qua rau thai vao mau ciia
lieu cao corticoid
thai. Thai nhi cung
gian tiep nhu khi dung thudc chdng tang huyet
me bj giam qua manh se gay thieu oxy cho thai nhi. Cac tac
doan trudc. Tuy nhien trong nhieu trudng
doan trudc
to nhu:
gian dung thudc ciia
khdi ca
thai khi ngudi
tre so sinh cd the

thai tru
mdt so thuoc cd the bj tich luy dang ke va gay ddc cho tre. Vi
231
thai nhi
nhay cam it hen

ciia thai)
liic sinh
6-8
sinh
9-16
9-12
10-17
liic sinh
232
bd
tdi
nao
Hau het
Da sd cac
vai chat theo con dudng
trong
tan
md lay
hay ngung thd d tre so sinh. Cac
trong md
lugng nhd han 600-800 nen deu cd the qua rau thai.
lai qua rau thai bang
Vi vay, khi dung thudc cho phu nu cd thai,
hau het cac thuoc cd the qua rau thai Ngoai le, chi vai loai thuoc cd cau triic phan tu rat
cd thai, ddc tinh ddi vdi sinh san tuan theo 4 nguyen tac
Thdng khi phe nang va luu thdng mau d phoi tang 30%. Niem mac mui de bj sung
huyet. Luu lugng mau d da tang lam cho hap thu d da va niem mac manh hon. Vi vay can
than trgng khi dung thuoc dudng hd hap, bdi
hap thu thudc cd the tang.
hap
lire
deu; tiem bap d tay, vai, thudc se hap thu
1.5.2.
trd ve the tich binh
la nhung thuoc tan nhieu trong

thay doi
nhung thuoc cd pham vi dieu
lieu dung cho ngudi me sau khi sinh.
234
gay tac hai cho bao thai
235
trong
sinh
cuoi thai ky, can tiem Vitamin K cho ca me va con.
236
tiep vdi ngudi benh va ngudi mua thuoc nen cd the giiip ngan
y nhung diem sau:

sinh de de biet hg cd ke hoach mang thai khdng hoac lieu
cd thai. Neu su dung thuoc cd

kha nang gay quai thai, can tu van de ngudi benh ap dung cac bien phap tranh thai
dung lau dai, tranh cac
237
huyet tuang trong vai thang dau ddi cua tre. Tuy nhien do
than se tang dan va thai tru thudc
diem. Trong thuc te, ti le nay dao ddng

nhieu nen ngudi ta thudng tinh trung binh do trong khoang vai gid lien, thdng
qua chi so dien tich dudi dudng cong ndng do
sua/huyet tuang tuy
thudc vao thdi
Ti le tdng the
giua cac thuoc, nd khdng phu hgp de danh gia so sanh nguy giua cac thudc khi dung cho
ba me dang
Neu ti le thudc
trong huyet tuang. Vi the neu cung se
thap. Ti le sua/huyet tuang thap (nhd han 1) cho biet thudc khdng tich luy trong sua me.
Tuy nhien neu nong cao, thudc cung se dat den
ndng do dang ke trong sua.
2.3.2. Luang thudc cd trong sua vd muc lieu tuang ddi
Lugng thuoc tre phai "dung" trong mdt ngay khi bii sua me ma ngudi me dang dung
thuoc dugc tinh bing tich sd ciia ndng do thudc trong sua me (CM) va the tich sua tre da bii
(Vm). The tich sua tre bii moi ngay dugc qui udc la khoang 0,15 l/kg the trgng. Do vay neu
biet nong do thuoc trong sua, cd the tinh dugc tuang ddi tdng lugng thudc tre bj dung mdi
ngay. Vi du, neu nong do thuoc trong sua me do dugc la 50 u.g/1 thi sau mdi ngay bii me,
tong lugng thuoc tre bj dung la:
50 u.g/1 x 0,15 l/kg = 7,5 ng/kg
Lieu tuang doi dugc dinh nghTa la ti le thudc so vdi lieu ciia me (tinh theo kg the
trgng) ma tre bii me bj dung do bii sua me (tinh theo can nang ciia tre), hay cd the ggi la ti le
phan tram ciia lieu me tinh theo can nang.
Lieu dung tu bu sua me/kg
Lieu tuong ddi (%) = ; x 100%
Lieu dung cua me/kg
Carbimazol 1 27
Valproic acid 0,05 7
Lithium 1 80
cd lieu tuang doi kha nhd

me hiem
dung
Thudc phdng
Sirdung phdi
- Thuoc can quang chua iodin, thuoc long
iodin phd rdng.
Trong nhung
241
Khi su dung thudc d phu nu cho con bii, can tuan thu nhung nguyen tac sau:
242
Tre em (Child) Tu 2 den 11 tuoi
Thieu nien (Adolescent) Tu12 tuoi den 18 tuoi
ldn. Ca 2 yeu td nay deu anh
nen han che tiem bap
243
* Dudng diing tai chd
x -'-dl '
Dudng dua thudc qua da can dae biet dugc luu y vi da tre em mdng nen kha nang
tham thudc manh han so vdi ngudi ldn, cd the gay ra phan ung cd hai. Mdt sd che pham bdi
ngoai cd chua prilocain va lidocain khdng dugc bdi cho tre sinh thieu thang vi prilocain cd
the hap thu dang ke va gay methemoglobin.
Thudc nhd mat hoac nhd mui, khi dung cho tre
ldn va gay ra tac dung cd hai: vi du phenylephrin
huyet ap. Cac loai tinh dau nhu mentol, long nao neu xoa vao mui hoac len da tre nhd cd the
thu dan den ngat do liet hd hap.
the la chi sd the tich phan bd
the bao gdm sir tudi

lien ket protein huyet tuong
the va the tich djch ngoai bao, neu tinh
Do vay de dat dugc ndng do
cac thudc tan nhieu
nhu aminoglycosid d tre so sinh se phai ldn han so vdi tre ldn han.
Bang 10.8. TI le nude va dich ngoai bao trong ca the so vdi the trgng
Lua tuoi Tong luc/ng nud'c (%) Djch ngoai bao (%)
Sa sinh thieu thang 85 50
Sa sinh du thang 75 45
3 thang 75 30
1 ncim 60 25
Ngudi ldn 60 20
,;>;
244
Bang 10.9. So sanh the tich phan bo ciia m0t so thuoc d tre em va ngudi ldn
The tich phan bo (l/kg)

Thudc
Tre sc sinh du thang Ngudi ldn
Phenobarbital 0,6-1,5 0,6-1,5
Diazepam 1,8-2,1 1,6-3,2
Digoxin 6,0-10,2 5,7-7,3
Gentamicin 0,8-0,16 0,3-0,7
Ampicillin 0,5 0,2
morphin,
ldn khi tre tir 3
sinh yeu han
245
246
Tre dudi 3 thang 100 8,1 1,9
Tre tren 3 thang 100 22,5 1,0
Tre tren 5 tuoi 75 88,9 0,9
gap khi dung tri.

- He thdng dieu hod than nhiet:
- Dj ling da:
cdn cd be mat rdng
gay ddc khi bdi len da.
da rat khd phan biet vdi cac dang dj ung khdng phai do thudc. Cac
cephalosporin,
iod, cac khang
d ldp tudi
thudc ddi vdi tre
nitrofurantoin.
thudc dung
cho tre can can nhac tdi tudi, can nang va dien tich be mat vao
kha nang hoan
nhu cau thay ddi lieu dung thudc d tre em
lai ti le the. Cd the su dung toan do de
tinh dien tich be mat tre. Cung cd the su dung
bang ti le lieu so vdi ngudi ldn the (bang
10.14)
Lua
So
2
4
1
248
10 nam 30 60
12 nam 39 75
14 nSm 50 80
16n§m 58 90
- Trgngthai benh: benh cap tinh, benh man tinh, muc dd nang nhe...
- Tudi: tre cang nhd, viec cho udng thuoc cang khd khan...
- Lieuphap dieu triphdi hap dang tien hanh: vi du benh nhan dang phai truyen djch,
bao mau,
(cha, me,
ciia thdng
cho tre
chinh xac
hau qua
250
hgc va
xem la ngudi cao tudi. Xa hdi cang

lam tang ty le
ngudi ta ggi ldp tudi
nay chi dung cho nhung ngudi
2008, ty le ngudi
the cd nhieu thay ddi ve mat sinh ly cung nhu benh ly. Thay ddi
the. Quy luat lao hoa
dung thudc d ddi
yeu den sir
ca the
la benh man tinh, vi

tac thudc- thudc
thudc: ti le gap ADR d lua tudi 60- 70 gap ddi so vdi
ca cudc
ddi la nguyen nhan lam thay doi dap ung vdi thudc lien quan den tudi tac cung nhu lam
4.1. Dae diem dugc dgng hoc cua thuoc d ngudi cao tuoi
4.1.1. Hap thu thudc
* Dudng udng:
Nhung thay ddi do tudi tac xay ra d dng tieu hda va gan ngudi cao tudi nhin chung it
anh hudng den hap thu ciia da phan cac thudc. Mac du tdc dd hap thu ciia mdt sd thudc nhu
digoxin cd the bj giam, nhung muc thi khdng cd khac biet so vdi d
ngudi tre. che van chuyen tich cue
ciia cac thudc
Nhung thay ddi lien quan tdi gan d ngudi cao tudi cd the lam giam chuyen hda qua
gan lan dang ke. Cac thudc da dugc
chung minh la cd giam chuyen hda dau qua gan d ngudi cao tudi bao gdm:
clomethiazol,
* Dudng
Khoi mau cung giam nen hap thu thudc
theo dudng
* Dudng
Da cao tudi khd, thanh phan lipid giam, khd tham cac thudc nen hap thu thudc
qua da giam.
251
4.1.2. Phdn bo thudc
morphin,
thuoc
ca the. Mat
trong
tirdo cd
cd ban
warfarin)
thuoc
dugc
phan bd hay lien ket protein.
4.1.3. Chuyen hda
tai gan.
gan,
den chuyen
qua gan, hoat tinh cac enzym chuyen hoa thudc.
Sir thay doi hinh thai gan ddng vai trd quyet djnh
de nay.
chuyen
4.1.4.
giam ddng qua phoi hgp vdi suy giam nang
- Giam lugng nude trong ca the
- Giam khoi ca Can thay doi lieu nap ciia thuoc
- TSng lugng md trong ca the
- Giam lugng albumin huyet tuang Thay doi lieu ciia cac thuoc lien ket nhieu vdi
- ai- acid glycoprotein it bj anh hudng protein huyet tuang
- Giam kich thudc gan Cd the can giam lieu nhung thuoc cd he so
- Giam ddng mau qua gan. chiet xuat tai gan ldn, mdt so thuoc chuyen
hda qua pha 1 tai gan (oxy hda) va tren benh
- Giam hoat tinh cac enzym chuyen hoa
nhan bi xa gan nSng
thuoc.
Giam chuc n£ng than do:

?V; :'•-.•' i;jl'J >•/.' '•'
- Giam ddng mau tdi than. Toe dd lgc cau th$n giam khoang 1ml/phut
- Giam sue loc cau than. moi nSm. Can giam lieu ciia cac thuoc thai tru
•
qua th§n
- Giam bai tiet qua ong th3n.
- Giam khoi lugng than.
4.2. Thay ddi ve dap ung vdi thuoc d ngudi cao tuoi
Cung vdi tudi tac nhung thay ddi d muc dd phan tir va te bao trong ca the khien cho
dap ung ddi vdi thudc d ngudi cao tudi bj thay ddi. Nhung thay ddi ve dugc luc hgc d ngudi
cao tudi cd the phan thanh hai nhdm:
Thay ddi do giam kha nang can bang ndi mdi dao nghjch
Thay ddi thu phat do sir bien ddi tai cac thu the dae hieu va md dich.
4.2.1. Gidm khd ndng cdn bang ndi mdi dao nghich
• De bj tut huyet ap the diing:
Nhirng thay ddi trong cau triic ciia he thdng mach mau cung vdi tudi tac dugc cho la
nguyen nhan lam giam phan xa tang nhjp tim khi dung len hay tang nhjp tim dap ung vdi gian
mach d ngudi cao tudi. Mdt sd thudc nhu chdng tang huyet ap, thudc dieu trj benh Parkinson
(levodopa, bromocriptin)... de gay tut huyet ap the dung d ngudi cao tudi.
• De bj nga do mat thang bang tu the:
Cung vdi tudi tac, do giam sd lugng thu the dopamin D2 tai the van, tan suat va bien
dd cua cac cu ddng dieu chinh tang len, lam giam kha nang giu thang bang ciia ca the.
Chinh vi the mdt sd nhdm thudc nhu thudc ngii, thuoc an than... lam tang ti le nga d ngudi
cao tudi.
• Giam dieu hda than nhiet:
Tan suat giam kha nang dieu hoa than nhiet gap nhieu han d ngudi cao tudi. Ha nhiet
bat thudng cd the gap khi dung cac thudc cd tac dung gay ngii, thudc lam giam kha nang
nhan biet nhiet do ciia ngudi dung, lam giam hoat ddng ciia ca, lam gian mach. Vi du nhu:
phenothiazin, benzodiazepin, chdng tram cam 3 vdng, opioid.
• Giam chuc nang nhan thuc:
He thdng than kinh trung uang cd sir thay ddi ldn ve cau triic va chat trung gian hoa
hgc d ngudi cao tudi. Sir suy giam tri nhd ma hau qua cudi cung la sir sa sut tri tue la benh
ly thudng gap d tudi gia. Benh ly nay de tram trgng them khi dung mdt sd nhdm thudc nhu
253
nay lam giam hap thu cac thuoc dung ddng thai.
- Gidm
- Mdt kem: khd dgc.
- Run tay:
tung khi gap cac chai thudc khd md.
- Thich
- Loang
loet thuc quan vdi cac thudc kich ung manh.
dgng
4.4.
cac
trj
dugc
trgng. Can tuan thu
254
ngudi cao tuoi thudng kem tuan thu dieu trj. Vi vay, nen ap dung
cac bien phap lam tang tuan thu dieu trj nhu ghi nhat ky dung thudc, ddng gdi rieng biet,
dung thudc cho cac ddi
Vdi phu nu cd thai, thuoc su dung cho me cd the qua rau thai, vao thai nhi va gay hai
phu nu cd
tdi ddc tinh vdi thai
thuoc, thdi diem dung thuoc trong thai ky, kha nang van chuyen thudc qua rau thai
the vao
me. Cac yeu td can dugc xem xet bao gdm: kha
thudc ddi vdi tre bii
lugng thudc cd trong sua va muc lieu tuang
cho con bii.
Ngoai ra, thuoc cung cd the anh hudng tdi kha nang bai tiet me, can can nhac.
255
tre nhd dudi mdt
tuoi cd the ddi vdi thudc. Vi vay, can luu
y de benh
nhan. Cha me hoac ngudi bao mau ddng vai trd quan trgng trong bao tuan thu dieu trj
ciia
tinh
nen thudng phai dung nhieu thuoc tac thudc- thudc
va tac dung khdng mong muon hgc cua
thuoc d ngudi cao tuoi cung cd chgn
thuoc, sdng
ciia
TINH
Ca
an.
Benh nhan cd tien su suy tim xung huyet, rung va suy than, dang dugc dieu trj bang
digoxin 250
Digoxin: 3,5 mcg/L (1 - 2)

Cau hdi: giai thich ly do benh nhan cd nhung trieu chirng nhu tren. Cd can thay ddi gi trong
dieu trj cho benh nhan khdng?
Trd ldi:
Benh nhan nam 7 tudi, 16kg nhap vien do 2 ngay lien bj dau vung hang, sdt cao tren
mu, xet nghiem mau thay CRP =

thay
trong 2
giam.
chgn hang dau cho

a. Dudng udng
SiHUl
257
la:
gdm:
di va
10. Cac yeu to lam giam kha nang tuan thu dieu trj d ngudi cao tuoi cd the la:
a. Su dung thuoc lam giam chat lugng cudc sdng.
258
CHlTONG 11. HOA SINH SANG TRONG THlTC
HANH DlTOC LAM SANG
Nguyen Thi Lap, J.R.B.J. Brouwers

MUC TIEU
1. Phdn tich dugc y nghia ciia cdc xet nghiem hda sinh thudng diing lien quan den mgt sd
b$nh.
2. Van dungcdc kien thiec ve hdasinh lam sang de sang lgc, chan doan va theo doi mdt sd tinh
trgng b$nh.
cd nhung
phan bd cac
lam gia
ddi hdi dugc sT
nguyen li ve sinh benh hgc, chuyen hda cac chat, ddng vai trd thiet yeu trong thuc hanh
phat hien ra nhirng van de sai sdt trong
dung thudc an toan, hgp li, hieu qua va
kinh te trong benh vien. Ngoai nhirng xet nghiem cd dien, thdng dung, mdt sd xet nghiem
y d cac phdng xet nghiem d cac
De dat dugc cac muc dich nay, cac phdng xet nghiem hda sinh lam sang cd 3 chuc
va can bd chuyen trach ve dieu kien thich hgp ddi vdi
thich hgp va kjp thdi.

cac xet nghiem hda sinh va de nghj thu
Ciing vdi tham kham lam sang va cac xet nghiem khac, cac xet nghiem hda sinh lam
thdng qua ket qua xet

nghiem phat hien va xac djnh ham lugng bat thudng cac chat xet nghiem phu hgp vdi chan
xuyen va
259
260
dieu kien bao quan khac nhau,
ra nhung thay ddi sinh hgc do 2 yeu td chinh la yeu td
mang
(stress). Biet thay ddi sinh hgc rat can thiet vi nd giiip danh gia cac ket qua xet
nghiem
nghiem hda sinh can tham gia vao mang ludi ngoai xet nghiem ben canh quy trinh ndi xet
trinh kiem soat lien phdng thi nghiem. Tat ca cac phdng thi nghiem gui mau chuan
tinh cho
tinh cho
ngudi
ket qua xet nghiem am tinh cho ngudi cd benh

Li tudng la tat ca cac ket qua thuc nghiem duang tinh deu duang tinh that va tat ca
cac ket qua thuc nghiem deu am tinh that. Tuy nhien khdng phai khi nao cung nhu vay,
qua
thu
thudng
Dd
nghiem so vdi
lam sang va cac

hgc nham phan tich, bien
theo
yeu
tac ve sinh li, hoa sinh,
nghiem,
cac ket qua xet

thudc
thi can
minh
chat
lugng xet nghiem.
• Su dung tdt ket qua xet nghiem trong chan doan va dieu trj benh.
2. BENH
2.1.
dua ra cac
tieu chuan chan doan benh dai thao ap dung rdng rai d cac
nude.
Bang
Oai
Roi
nap
262
gian sau khi an, chi dugc
coi nhu khdng bj tieu
12 gid trudc khi

hgp chan
(3,9-5,5 mmol/L)
lay
263
mach)
Mau
mach)
nhan
Bang
Glucose
Liic
Sau
- Test
dudng
mg/dL
ngudi
2.2.2.
264
gian dung thudc de phuc
ciia benh
albumin nieu bai xuat theo nude tieu 24 gid rat
nieu tang
bien chiing than. Bien chung
thudng). Giai doan 2: cd microalbumin nieu (albumin nieu: 20-300mg/L hoac 30-300mg/24
Tdm lai, ket hgp vdi gia trj glucose huyet,
MACH
3.1. Roi loan chuyen hda lipid

Rdi loan chuyen hda lipid cd the gay ra nhung van de sue khde rat nghiem trgng vdi
ca the dae biet la cac benh tim mach. Xa vua ddng mach (XVDM) la benh dien bien tham
lang vdi khoang thai gian dai (hang chuc nam) cho den khi xuat hien cac trieu chirng lam
tram trgng ciia benh tim mach nhu can dau thit nhoi tim, tai bien mach
nong
do di chuyen trong mau,

xet
lipid,
cdn cd gia trj
thay doi cac chi

hemoglobin (> 200mg/dl) va bilirubin
mau
265
III (3 VLDL t CT t + TG Due ftgSp +++
CTt T
IV VLDLt TGt Due sua Thudng gSp +++
V CMt TGt Due sua Hiem ++
VLDLt
Giam a HDL j HDL-C | Trong Thudng g§p +++
high
mach
lugng
60-75%
vdi
266
3.2.3. Lipoprotein (LP)
• '."~ •/ •. . .
- HDL-cholesterol:
Viec djnh lugng HDL-cholesterol cung vdi LDL-cholesterol cd y nghTa quan trgng
trong viec chan doan va theo doi dieu trj rdi loan lipoprotein va benh xa vua ddng mach.
HDL bj anh hudng bdi nhieu yeu td nhu hut thudc la, tap luyen the due, tuoi, gidi. Cd moi
quan thuan vdi tan

sd bj benh mach vanh. Vi vay, xet nghiem LDL-cholesterol nay cd gia trj djnh hudng trong
< 130 mg/dl, neu cd
tao mang xa vua d
nong dd HDL-
LDL-cholesterol la giai doan quan trgng trong
267
3.4.4.
nhung ket qua xet

lipoprotein.
dugc coi nhu
apo B va vdi tan
lipid
tim
thudng ciia. Tn-I nhd han 1 ng cm"3, nhung nong do ciia protein nay trong huyet thanh dugc
nang len den 30-50 ng cm"3 trong vdng 24 gid sau nhoi mau ca tim. Protein nay dugc phat
hien bing phuang phap mien djch "sandwich ", trong do khang the dugc gin vdi
phosphatase kiem. Su dung ca chat la phosphate 4- methylumbelliferone, 4-
methylumbelliferone giai phdng dugc do bing huynh quang.
ZT
0)
2?
<
CD*
ZT
jun O
•Q)
i—f
Q» CK-MB
o
Total CK
- LDI
o>- •:yA'V.\-. .
- AST
CQ
Troponin I
Q. Myoglobin
o>
;A:i ii lo;
Hinh 11.1. chat trong nhoi mau ca tim

trong
tim, nhung thai
Mdt
tim trong trudng hgp
(phuong phap mien djch). CK-MB ket hop vdi CK toan phan cd the phat hien benh nhanh,
hieu han myoglobin nhung lai xuat hien trong mau cham han. Tn-I cd the djnh lugng
la 70% trong
tim
271
ciia cac
bilirubin trong da) va xuat hien
bilirubin
'\i\', !•-.
chinh dan den ung thu gan, ben canh dd cdn cac nguyen
nhan khac nhu viem gan do virut B, C, nghien rugu. Ung thu te bao gan (hepatom,
90% do te bao nhu md gan; ung thu dudng mat do te bao bieu md
5-10% cac ung thu gan tien phat. Cung cd the hon hgp
gidng
ldp vi
gan.
Bon enzym thudng xuyen dung trong xet nghiem giiip chan doan phan biet se gidi thieu sau
(ALT)
ciia chiing trong
gan. 6 gan, hai
ALT d bao tuong con AST cd
70% hoat do enzym
ALT la 47 gid trong khi
ALT nhieu han
ve gan. Hau het cac
hay dung mdt so loai thudc, do dd cung lam tang ndng trong huyet thanh.
<.i-r\h\m<\;v:.
272
Enzym nay dugc tim thay trong hau het cac md nhung
nham phat hien sdm

Bang 11.7. Mdt so loai thuoc cd the thay doi gia tri enzym gan
Enzym Thudc lam tang Thudc lam giam

hoat ddng enzym hoat ddng enzym
GGT Carbamazepin, erythromycin, heparin, Clofibrat
phenytoin
ALT Amiodaron, acid salicylic
AST/ALT Carbamazepin, heparin

AST Oxacillin, paracetamol, phenytoin,
ranitidin, rifampicin.trimethoprim,
sulphamethoazaol, acid valproic
trach nhiem thai bd cac chat thai ra

creatinin,
biet khac quyet
chat dien giai, can bang
quan ndi tiet san xuat
ciia
nephron
mdi nephron cd qua trinh lgc mau,
nude lgc dau tien nay ggi la nude tieu ban dau chua cac thanh phan khdng khac gi huyet
tuang, tru protein. Moi nephron san xuat khoang 100mm3 nude tieu ban dau mdi ngay, tuc
273
bang thudc nham tiet kiem cho benh nhan chi tra chi phi chay than hoac ghep.
Bang 11.8. Cac muc dd suy th$n man
Cac muc do GFR(ml/phut/1.73m2) Muc do lam sang
cac
cac
hieu cho than vi chi dao thai qua than va tai hap
lgc va rat cd gia trj trong chan
creatinin
creatinin
so nude tren the gidi quy djnh khi dung mdt so thudc tren benh nhan
Huyet tuang cd chua so lugng rat ldn cac protein trong dd nhieu protein chi cd d
thudc.
dugc tong
va ky thuat
275
san xuat bdi tuyen vu ngay sau khi sinh). IgA la rao can chinh doi vdi mien djch gay benh
xam nhap qua cac mang nhay.
IgM dugc tim thay trong ndi mach ddng vai trd loai bd cac vi sinh vat va khang
IgM
va
benh
sinh san
so
vung
la
so
phan
ggi
vi
day bj sut can, uong nhieu bia va
nghien rugu, hut thuoc la han
8,5 mmol/L, HDL

CK 916U/L.
doan benh gi? Can phai lam xet nghiem gi them de chan doan chinh xac?
yeu to nguy ca ve tim mach: qua can, nghien rugu, hut nhieu thuoc la, huyet
so chi so xet nghiem cd gia trj binh thudng:
278
Xet nghiem cho ket qua:
- Huyet thanh: Protein toan phan: 7.4 g/dL
279
- ALP, GGT tang khoang 3 lan: tic mat, ton thuang te bao gan va dng mat
- Nude
Thdng
Cac enzym nhu
tang 3-10
Hudng chan doan: vang da do hdi
5. Benh
5.1. Trd
1. Hay cho biet ngudn gdc
2. Nhirng yeu to anh
3. Chi
4. Muc dich su dung ket qua
5. Ke ten
Dap an
1. Creatinin
than tir cac acid amin nhu arginin, glycin,
va cac ca
tru nang lugng cao.
2. Thuc
3. Dd thanh lgc cau than (GFR)
4. Chan doan, tien lugng va theo ddi dieu trj cac benh ve than va su dung thudc.
5. Trimethoprim, cimetidin va cephalosporin
' i rn
5.2. Ca lam sang
Be gai 10 tuoi dua den benh vien vdi trieu chiing: nhuc dau, chdng mat, tieu budt sau
moi lan di tieu, sung mi mit sau khi ngii day (trudc dd 1tuan bi viem hgng do).
Ket qua xet nghiem nude tieu: protein (+), hong cau va tru cau (+). Xet nghiem mau :
Ure: 10 mol/L, Creatinin: 240 jimol/L.
Cau hdi:
1. Be gai tren cd the bj benh gi?
2. Can phai lam them xet nghiem nao khac de chan doan va theo ciia
Dap dn:
1. nhiem
tieu cd
cau than lam
hai ket qua xet nghiem ure
280
2. Can lam them cac xet nghiem hda sinh khac nhu tim khang the khang streptococus,
dd thanh lgc CRN-C1, protein...kem cac xet nghiem ve huyet hgc.
6. Protein huyet tuong
6.1. Trd ldi cau hdi ngan
1. Tiiy xuang tong hgp loai protein huyet tuang nao?
r
2. Vai trd chinh ciia albumin huyet tuang?

3. Ky thuat sinh hgc phan tu nao de phan tach protein huyet tuang dung pho bien trong
chan doan lam sang?
4. Ig nao ehiem ty le cao trong so cac Ig huyet tuang cd kha nang qua dugc nhau thai
va dugc sir dung trong xet nghiem lam sang nhu mdt chi so cho biet kha nang dap
ung mien djch ciia ca the khang lai cac benh nhiem trung?
5. Ig nao hay dugc dung trong xet nghiem lam sang nhu mdt chi sd cho biet ca the bj
sir xam nhiem ciia vi khuan, vi rut?
6. Trong xet nghiem lam sang ciia cac protein dap ung giai doan cap, chi so nao hay
dugc su dung nhu mdt chi to (marker) bieu hien sir viem nhiem?
Dap an
1. Immunoglobulin (Ig)
2. Dieu hda ap lire tham thau, van chuyen mdt so chat va thuoc.
3. Ky thuat dien di
4. IgG
5. IgM
6. protein phan ling C (CRP)
6.2. Ca lam sang:
Benh nhan la nam 45 tuoi vao vien vdi trieu chirng met mdi, da xanh nhgt va dau
nhuc xuang lan tda. Xet nghiem mau cho ket qua nhu sau:
- Acid uric: 0.5 mmol/L, canxi: 3.21 mmol/L, protein toan phan 124 g/L, ure: 23
mmol/L, creatinin 380 umol/L.
Cau hdi:
1. Bien giai cac ket qua xet nghiem tren?

2. Benh nhan tren cd the bj benh gi ?
3. Can phai lam them xet nghiem gi de cd dugc chin doan xac djnh?
Dap dn
1. Ure huyet, creatinin tang cao bieu hien ciia suy than. Tang canxi huyet, protein
huyet cho thay bieu hien ciia mau bj cd dae tuc tang san xuat protein khac (y-
globulin).
281
2. Tir cac xet nghiem tren va trieu chung dau xuang lan tda cd the cho thay bieu hien
ciia benh da u tuy xuang da cd bien chung suy than.
3. Can lam them cac xet nghiem cac xet nghiem khac: chup X quang xuang, lam tieu
ban mau, xet nghiem ve huyet hgc, dien di protein mien djch va xet nghiem de tim
protein Bence Jones trong nude tieu.
TAI LIEU THAM KHAO

1. Dao Kim Chi, Bach Vgng Hai (2003), Hda sinh lam sang-Bien giai Cas lam sang.
Trudng DH Duac Hd Ndi xuat ban.
2. Do Dinh Ho (2010), Hda sinh lam sang. NXB Yhgc.
3. Hgc Vien Quan Y (2010), Hda sinh Y hgc. NXB Quan ddi nhdn ddn.
4. Le Due Trinh (2009), Hda sinh lam sang - y nghTa lam sang ciia cac xet nghiem hda
sinh. NXB Yhgc.
5. Allan Gaw, Robert A. Cowan, Denis St. J. O'Reilly, Micheal J. Stewart, James
Shepherd (1999.), An illustrated colour text: Clinical Biochemistry. Churchill
Livingstone. Second edition.
6. Carl. A. Burtis, Edward R. Ashwood, David E. Bruns. (2008), Tietz fundalmentals of
clinical biochemistry. Elsevier Sounder. Sixth edition.
7. Carl. A. Burtis, Edward R. Ashwood, David E. Bruns. (2006), Tietz textbook of clinical
chemistry and molecular diagnostics. Elsevier Sounder. Fourth edition.
8. Kieth Wilson and John Walker (2010), Principles and techniques of biochemistry and
molecular biology. Cambridge University Press. Seventh edition.
;wv.
282
PHU LUC» •
Gia trj tham chieu cua mot sd xet nghiem hoa sinh lam sang thdng dung [7]
Xet nghiem Benh Giai Ban vi He sd Dan vi SI

pham Tuoi thdng dung chuyen
. .
doi
Alanin HT NL U/L 0.017 ukat/L

aminotransferase^ Nam <45 <0.77
T, GPT)
Nu <34 <0.58
Albumin HT g/dL 10 g/L

Tre em 3.8-5.4 38-54
14-18t 3.2-4.5 32-45
NL 3.2-4.6 32-46
NT/24h Mg/ngay 1 mg/ngay
3.9-24.4 3.9-24.4
DNT mg/dL 10 mg/L
17.7-25.1 177-251
Amylase HT NL U/L 0.017 ukat/L

IFCC, 37°C 28-100 0.48-1.70
Apolipoprotein-AI HT NL mg/dL 0.01 g/L

20-69t 105-173 1.05-1.73
Apolipoprotein B HT NL mg/dL 0.01 gA.

20-69t 59-160 0.59-1.60
Ap suat C02 rieng M NL mmHg 0.133 kpa

phan Nam 35-48 4.66-6.38
pC02 Nu 32-45 4.26-5.99
Aspartat HT NL U/L 0.017 ukat/L

aminotransferase Nam <35 <0.60
(AST, GOT)
Nu <31 <0.53
Bilirubin toan phan HT mg/dL 17.1 umol/L

3-5 ngay 4.0-8.0 68-137
NL 0-2.0 0-34
Bilirubin lien hgp NL 0-0.2 0-3.4
Canxi toan phan HT NL mg/dL 0.25 mmol/L

Ht 8.6-10.2 2.15-2.55
(heparin)
Cholesterol HT NL mg/dL 0.0259 mmol/L
(20-60t):
Nam 118-280 3.06-7.25
Nu 121-294 3.14-7.61
283
Nguy ca
benh tim
mach: • t;; •. i '•
An toan
<200 <5.18
T3ng vua
200-239 5.18-6.19
T3ng
>239 >6.19
CI' (chlorur) HT NL mEq/L 1.0 mmol/L
98-107 98-107
Creatin kinase(CK) HT U/L

Nam 15-160 (37°C)
Nu 15-130 (37°C)
Creatin kinase- MB HT ug/L.
(CK-MB) Nam 8.7
Nu 4.8
Protein phan ung C HT NL mg/dL 10 mg/L

C- reactive protein (20-60t) <0.5 <5
(CRP)
Creatinin(ky thuat HT NL mg/dL 88.4 umol/L
enzym) Nam 0.62-1.10 55-96
Nu 0.45-0.75 40-60
Creatinin-CI HT Nam 97-137ml/phiit/1.73m2

(Dd thanh lgc) NO 88-128 ml/phut/1.73m2
Glucose mg/dL 0.0553 mmol/L
HT TE 60-100 3.3-5.6
(khi ddi) NL 74-100 4.1-5.6
DNT TE 60-80 3.3-4.5
NL 40-70 2.2-3.9
Gamma glutamyl HT U/L 0.017 ukat/L

transferase (GGT) Nam <55 <0.94
IFCC, 37°C Nu <38 <0.65
HbA1C M % Hb toan phan

Glycated hemoglobin 4.0-6.0
Hb glycosyl hda
HDL-C HT mg/dL 0.0259 mmol/L
Cholesterol- Nam 30-75 0.78-1.95

lipoprotein ty trgng Nu 33-96 0.86-2.49
cao
LDL-C HT mg/dL 0 0259 mmol/L

Cholesterol- Nam 66-210 1.53-5.44
lipoprotein ty trgng Nu 57-224 1.48-5.81
thap
284
Nguy ca mg/dL 0.0259 mmol/L
benh • tim
mach:
Toi uu
<100 <2.59
Gan/tren toi
100-129 2.59-3.34
uu
TSn vua
130-159 3.37-4.12
TSng
160-189 4.15-4.90
Rat cao
.
< 189 >4.90
Insulin HT NL Û/mL 6.95 pmol/L

2-25 12-150
Lactat dehdrogenase HT NL U/L 0.017 ukat/L

(LD) IFCC, 37°C 180-360 3.1-6.1
Lipase, 37oC HT NL U/L 0.017 ukat/L

<38 <0.65
pH (37°C) M
Ddng mach TE 7.35-7.45 1.0 7.35-7.45
TTnh mach NL 7.32-7.43 7.32-7.43
Phosphat HT mg/dL 0.323 mmol/L

Ht(heparin) TE 4.0-7.0 1.29-2.26
NL 2.5-4.5 0.81-1.45
Phosphatase alkaline HT NL U/L • 0.017 ukat/L

(ALP) Nam 53-128 0.90-2.18
Phosphatase kiem Nu 42-98 0.71-1.67
IFCC, 37oC
K+ HT mEq/L 1.0 Mmol/L
Kali (postassium) TE 4.1-5.3 • 4.1-5.3
NL 3.5-5.1 3.5-5.1
Protein toan phan HT 1-2t g/dL 10 g/L
NL 5.6-7.5 56-75
6.4-8.3 64-83
Na+ (sodium) HT, Ht mEq/L 1.0 mmol/L
TE 139-146 139-146
NL 136-145 136-145
Triglycerid (TG) HT NL mg/dl 0.0113 nmol/L
20-69t
Nam 44-256 0.50-2.90
NO* 37-260 0.42-29.4
Diem cSt
Binh thudng < 150 <1.70
285
Cao 150-199 1.70-2.25
T3no, TG 200-499 2.26-5.64

huyet
Rat cao >499 >5.64
Troponin (Tn) HT ug/L

Nam 0.8
Nu 0.7 tuy thuge ky thu$t XN
Blood urea notrogen HT mg/dL 0.357 mmol/L
(BUN) TE 5-18 1.8-6.4
Nita Ure NL 2-20 2.1-7.1
>60t 8-23 2.9-8.2
Acid uric HT mg/dL 0.059 mmol/L
(ky thuat enzym) TE 2.0-5.0 0.12-0.32
NL
Nam 3.5-7.2 0.21-0.42
Nu 2.6-6.0 0.15-0.35
Chu viet t£t:TE: tre em; NL: Ngudi ldn; HT: huyet thanh; Ht: huyet tuang; M: Mau toan phan;
NT: Nude tieu; DNT: dich n3o tuy. .
Chu y:
So lieu trong bang tren khdng phai la tat ca cac gia tri tham chieu ciia mdt labo hda sinh lam
sang ma chi la cac gia trj tham chieu dugc su dung mang tinh chat tham khao va dinh hudng,
de tra ldi cho cac ca lam sang va vi du trong khudn kho nOi dung ciia chuang nay. Cac gia trj
nay dugc trich dan tu TLTK 7, chuang 56.
VI:.
286
CHUCJNG 12. CHAM SOC DUOC
Hoang Thi Kim Huyen, J.J. de Gier

MUC TIEU
/. Trinh bay dugc cdc ngi dungca bdn trongcham sdc dugc cho b$nh nhdn
2. Trinh bay dugc nhungnhiqm vu ciia dugc si lam sang trong mdhinhchamsdc
3. Trinh bay dugc each thiec thu thdp va xu ly thdngtin khi thu-c hi^n CSD.
MOfDAU
Khai niem ve cham sdc dugc (CSD) dugc de cap tdi lan dau tien bdi Mikael va edng
su tai My vao nam 1975, coi CSD la "sir cham sdc ma mdt benh nhan cu the ddi hdi va
dugc hudng, giiip dam bao viec su dung thudc an toan va hgp ly". Cang ve sau khai niem
nay cang mang tinh nhan van han khi djnh nghTa "CSD la mdt lTnh vuc thuc hanh, trong do
chuyen gia y te nhan trach nhiem dap ung cac nhu cau ve thudc ciia benh nhan va ludn ludn
phai dam bao hoan thanh trach nhiem dd". Gan day nhat, trong cuon "Thuc hanh CSD" xuat
ban lan thu 2 vao nam 2007, nhdm tac gia My Strand L.M., Cipolle R.J. va Morley P.C.
hoan thien djnh nghTa CSD mdt each day dii va khai quat han, theo do: "Cham sdc duac Id
mot linh vuc thuc hanh lay benh nhdn lam trung tdm, trong do chuyen gia y te nhdn trach
nhiem ve cdc nhu cau lien quan den thudc cua benh nhdn vd ludn ludn phdi dam bao hoan
thanh trach nhiem do ".
Nhu vay nhin chung cd the thay mgi dinh nghTa deu thong nhat d mdt diem:
"Cham sdc duac (Pharmaceutical Care) Id su chudn bi cho dieu tri lien quan den
thudc nham muc dich dgt dugc hieu qua tdtnhdt ve chat lugng song ciia benh nhdn ".
De dat muc tieu nay, benh nhan (BN) khdng chi dugc cung cap thuoc vdi chat lugng
tdt, gia ca phu hgp ma cdn dugc hudng quyen lgi dugc nhan cac loai thuoc cd each sir dung
thuan tien, it gay khd chiu va phien toai nhat. Mat khac, thuoc dugc sir dung phai chua khdi
benh nhung cung phai it de lai hau qua nhat sau dieu trj, nghTa la phai han che toi da phan
ung cd hai va cac van de phat sinh khi sir dung thuoc. Cau "Thuoc ddng da tdt..r vdi hien
tai cd the khdng cdn chinh xac nua vi muc tieu liic nay khdng chi khdi benh ma cdn phai
dem lai tam ly thoai mai khi dung thuoc va cudc song tinh than ciia benh nhan cung phai
dugc cai thien. Theo cac quan niem nay, vai trd chinh trong cham sdc dugc ro rang da dat
vao tay ngudi dugc sT.
287
8.Giai quyet cac
van de
7. Xac dinh cac 1. Thu th$p va phan tich

van de (neu cd) thdng tin benh nhan
2. Xac dinh muc tieu

6. Trien khai ke dieu tri
hoach theo ddi
3. Tiep'cSn ke hoach
5. Cung cap thuoc dieu tri
va thao lu$n vdi BN
4. Thiet ISp ke hoach

theo ddi
Hinh 12.1. Vdng trdn ch3m sdc dugc cua Hepler

1. NHlTNG NOI DUNG CO BAN TRONG CSD
Ndi dung CSD khdng chi bit dau tir khau phat thudc ma phai ngay tir khau lira chgn
thuoc cho ke dan (tu van lira chgn thuoc); tiep theo la hudng dan su dung thuoc, theo dpi
hieu qua, do an toan, phat hien nguyen nhan that bai dieu trj lien quan den su dung thudc
neu xay ra (khdng tuan thu dieu tri, tuang tac thudc, lira chgn sai thudc, sai lieu...) va de
xuat bien phap xu tri. Bang12.1 liet ke cac ndi dung can lam trong CSD ciia dugc sT lam
sang (DSLS) vdi benh nhan.
Bang 12.1. Cac ndi dung ca ban trong CSD
TT Ndi dung
1 Xac dinh muc tieu uu tien hang dau trong dieu tri
2 Lua chgn thuoc cd chi so hieu qua/an toan va hieu qua/kinh te cao nhat
3 Xay dung mdt ke hoach dieu tri hd thong va lien tuc ve thuoc cho benh nhan
4 Xac djnh dugc cac van de hi£n tai va lau dai lien quan den sue khde
5 Dam bao su phoi hgp dong bd giua cac bd ph$n dieu trj
6 Xac dinh nhung vide can lam khi ch3m sdc benh nhan ngoai tru
Cac tieu chi tren la danh cho DSLS nhung khdng cd tieu chi nao cho thay DSLS dung
rieng le.
2.1. Xac djnh muc tieu uu tien hang dau trong dieu trj
Viec xac djnh muc tieu uu tien hang dau trong dieu trj nhSm han che tdi da sd thudc
trong moi lan dieu tri, vua tranh dugc tuang tac thuoc, vua dat hieu qua kinh te.
288
Cai.
Benh nhan (BN) nam gidi, 36 tuoi, den benh vien kham vi di ngoai ra mau tuoi;
han nua gan day thay met mdi. BN cho biet may thang gan day, khi di ngoai thinh thoang
lai thay cd mdt it mau ra theo phan, lugng mau ra khdng nhieu va chi phat hien do tham
vao giay ve sinh, benh cung khdng anh hudng nhieu den sinh hoat nen chua bao gid dieu
tri. Benh nhan khdng mac benh nao khac.
Ket qua xet nghiem mau cho thay so lugng hong cau: 3.600.000/mm3, huyet ap va
nhjp tim binh thudng. Qua ket qua kham lam sang va ndi soi, bac sT ket luan benh nhan bi
benh trT.
* Gidi quyet vdn de

Day la trudng hgp xuat huyet tieu hoa man tinh do tri. Do mat mau ra rich nen huyet
ap va nhip tim chua bi anh hudng nhung neu de tiep dien keo dai thi se dan den thieu mau
tram trgng. Do do muc tieu uu tien hang dau trong dieu trj cho benh nhan nay la cam mau;
tiep theo la giai quyet benh tri. Viec ke dan ngay tir dau cac thuoc bo sung sat va vitamin la
chua can thiet vi so lugng hong cau cd giam nhung khdng nhieu va khi cam dugc mau,
benh tri dugc giai quyet thi so lugng hong cau cd the se tu phuc hdi. Day la benh nhan tre
tuoi, dudng tieu hoa hoat ddng tot (khdng bj cac benh tieu hoa khac) thi vdi tudi ciia benh
nhan nhu tren, cac chat dinh dudng hoan toan cd the bu bang thuc pham ma khdng can can
thiep bing thuoc bo mau hoac truyen mau.
2.2. Lua chon thuoc cd chi so hieu qua/an toan (H/A) va hieu qua/kinh te (H/K) cao
nhat
Trd lgi ca lam sang 1: d day benh nhan cd the dugc cam mau bing ndi soi hoac thudc.
Gia su neu sir dung thuoc, cac thuoc dua thing vao dai trang d dang kem bam vao true trang
hoac vien dat true trang dugc uu tien vi tac dung nhanh va it anh hudng den toan than.
De lua chgn dugc thuoc cd chi so H/A cao, can cd kien thuc tot ve benh va thudc. Vi
du vdi trudng hgp can giam dau trong cac benh dau xuang 'khdp, thuoc chong viem khdng
steroid (NSAID) don ddc hoac phoi hop vdi paracetamol cd the giai quyet dugc dau trong
hau het cac trudng hgp. Neu chi sir dung dan ddc NSAID, tinh trang viem se dugc giai
quyet nhung hieu qua giam dau cd the khdng dii. Can luu y lieu toi da cho mdt lan va cho
24 gid vdi cac NSAID; khi da su dung lieu toi da cho phep van khdng dii de giam dau thi
khdng dugc phoi hgp them mdt NSAID khac vi se tang nguy ca gay tac dung khdng mong
muon nhu chay mau va loet da day ta trang. Paracetamol dung dan ddc se khdng cd tac
dung chong viem, han nua hieu qua giam dau cung bi khong che bdi lieu tdi da nhu vdi
NSAID. Trong trudng hgp nay, de tang chi so H/A, nen phoi hgp NSAID vdi paracetamol.
Ca 2 loai thuoc nay hien luu hanh chii yeu d dang thuoc generic, do dd lira chgn chi sd H/K
chii yeu tuy thudc vao dang bao che. Gia ca ciia cac dang bao che cai tien (vien siii, vien
bao tan trong rudt, vien giai phdng keo dai) thudng dit han cac dang bao che kinh dien
(vien nen, vien nang thdng thudng). Can nhic lira chgn tuy thudc tinh trang dau va hoan
canh kinh te ciia benh nhan.
289
2.3. Xay dung mot ke hoach dieu trj he thong va lien tuc ve thuoc cho benh nhan
Ca2.
Ba L., 65 tuoi, tdi benh vien de kham djnh ky. Tien su benh ciia ba L. la tang huyet
ap va dai thao dudng typ 2.
Trong 6 thang qua, ba L. tu theo ddi dudng huyet va nhan thay tang dan, 2 tuan gan
day la 11 den 13 mmol/L.
Thudc dang dung la:
- Perindopril 4 mg 1 vien/ngay
- Metformin 500 mg 1 vien/lan x 3 Ian ngay
- Diamicron MR 30 mg 1 vien/ngay
Dugc biet benh nhan chua dj ung vdi thuoc nao trudc do.
Tai phdng kham, huyet ap do dugc la 135/85 mmHg, nhjp tim 75 lan/phut. Benh
nhan can nang 58kg vdi chieu cao 1,55 m. Ba L. khdng nghien rugu va khdng hut thuoc
la; tap the due va di bd deu dan, moi ngay khoang 1h.
* Gidi quyet vdn de:
Muon dieu trj thanh edng benh dai thao dudng (DTD), khong che muc dudng huyet
trong gidi han la rat quan trgng vi se han che dugc sir xuat hien cac bien chung ciia benh.
Vdi nhirng benh nhan bj benh man tinh nhu ba L., viec xay dung mdt ke hoach dieu trj he
thong va lien tuc ve thuoc cho benh nhan la can thiet. Nhin vao cac thdng tin lien quan den
benh ciia ba L. thi thay ba bj mac hai benh thudng gap d ngudi cao tuoi va viec su dung
thuoc phai lau dai. Han nua, benh cd the tiep tuc dien bien theo tuoi tac, nen ngoai viec
hudng dan dung thuoc, viec hudng dan theo ddi dien bien xau di ciia benh cung la nhiem vu
ciia DSLS.
Nhieng thdng tin cdn cung cap cho ba L. la:

•:Aj V? >!
- Tam quan trgng phai kiem tra dudng huyet (glucose huyet):
Trong thuc te, day la viec khdng dan gian vi cd nhieu yeu to anh hudng nhu che do
an, lieu lugng thuoc, cac stress gap phai (sot cao, nhiem khuan, bj tai nan giao thdng, phai
phau thuat...) hoac tang hoat ddng the lire... Viec phat hien kjp thai muc dudng huyet (qua
cao hoac qua thap) se giiip benh nhan dieu chinh lai che do an, che do luyen tap the lire va
thdng bao kjp thai cho bac sT dieu tri.
De lam tdt viec nay, benh nhan phai hieu:
- Muc glucose huyet do khi ddi bao nhieu la dat yeu cau? bao nhieu la dau hieu xiu
cho thay thudc khdng kiem soat dii?
- Do dudng huyet khi nao thi coi la do liic ddi.
Ve theo doi dieu tri:
Ngoai viec hudng dan benh nhan each do dudng huyet tai nha, nen cho benh nhan
biet cac dau hieu nguy ca khi tien trien ciia benh xau di de lap tuc den gap bac sT. Ngoai ra
cung phai cho biet thai han cho cac lan kham djnh ky va tai sao phai djnh ky kham lai mac
du benh van on djnh (nhu trudng hgp muc huyet ap neu tren).
r»3d bi
290
2.4. Xac djnh
mdt loai bien chiing lien quan den nhieu nguyen nhan, trong
su dung thuoc la: dung qua lieu chi djnh (thudng lien quan den
che
huyet
than, tang kha nang nhiem khuan, nhiem nam...
mach
gay anh hudng nghiem trgng den cudc sdng ngudi benh.
2.5.
day la
doi lieu
thuoc va hudng dan benh nhan dieu trj tai nha. Vdi 2 benh ma ba L gap phai, khd khan ldn
nhat la che
liic
bd
de
do vj
tru
nhung
thudc
nay ben canh benh nhan khdng cd nhan vien y te
tai
van phai kiem tra
291
huyet ap, loet da day, hen, dj ung...
293
Thdng tin
benh
bdi lua
Tuoi khoe
tuoi.
Idp tuoi
tuoi. Vi
benh
hay
Gidi
thai
dudng
Cd thai
Dang nudi con gap dudng, tang huyet ap
b^ng sua me sue khoe va can phai dieu trj.
cam sau khi sinh va can phai dieu tri.
dung cho phu nu cho con bii cd the qua
he than kinh trung uang, gay buon nau

hoac gay ao giac tu dd lam giam tap trung trong edng viec. Dieu nay can
294
- Ty l$ mac benh tai dja phuang tai thdi diem BN nhap vidn
- Dieu tri khdng dung thuoc
- Dieu trj bang thuoc:
Nguyen tic dieu tri
Can nhac muc dich can dat dugc khi dung thuoc:
. Kha nang chua khdi?
. Giam trieu chung?
- Giai quyet dau hieu, trieu chung va cac bat thudng tren chi so xet
nghiem.
Muc dich dieu tri - Cai thidn:
thuoc
*Cholesterol toan phin: nhan bao gdm:
tang huyet ap, hut thuoc ia, tien su gia
< 200mg/dL
nhat
bat
do
luang
LDL-C
dieu trj,
qua trinh
thang den
dudng
bien
lien vet
the dan
nhieu, an
dai thao
296
tri
297
••"•'
Hen phe
dugc them vao de kiem soat lau dai,
quan . Mdc 60 1
su cai thien the hien trong vdng 1-2
FEVi hoac PEF > 80-85% tuan vdi hieu qua toi da trong vdng 4-8
. Muc 6q 2 tuan.
f'MPJi fi-'u'-. FEVt hoac PEF > 80% - Khi benh nang len phai dieu tri ndi tru,
Muc dQ 3 can tdi 3-7 ngay de chuc nang phoi trd
trinh dieu trj

benh nhan can dugc
hudng dan
sat ket qua dieu trj cho BN. Nhirng dieu
*• ^
298
•S Thudc dung khdng cd chi djnh: khdng phu hgp vdi chan doan, khdng cd trong benh
an.
nhdm.
299
Phat sinh benh mdi khi dang dieu tri
Can thiet phai diing thuoc de du phdng nhim lam giam nguy ca
de tang
Neu tao lap dugc mdi quan he tdt thi DSLS se cd the phat hien cac nguyen nhan khdng
dai dieu trj...). Mudn lam
nghT, lo
ngudi dugc tu van,
do ciia
cao nhat.
biet hay gap khd khan khi giai thich ve benh va each dieu trj vi gap phai nhieu
la chi DSLS ndi. Ludn quan sat
ngudi dugc tu van va tiep nhan phan hdi ve cac thdng tin dua ra. Khdng nen chi neu
lien quan den tien trinh dieu trj. Khi
300
Ure 10,6 mmol/L (Binh thudng: 3-8 mmol/L)
Creatinin 67 jamol/L (Binh thudng: < 90 umol/L)
Glucose mau liic ddi 18 mmol/L (Binh thudng: 3 - 6 mmol/L)
A - Nhdn dinh ciia DSLS:
- Khdng kiem soat dugc dudng huyet -> Phai tim nguyen nhan! (tuan thu dieu trj?,
lieu khdng dii do benh nang them theo tudi tac? stress ...).
- Ure tang nhung creatinin lai binh thudng! -> cd the do mat nude do DTD?, do mat
6 la thang ndng, dae biet
phan do thudng
bdsung kali.
dung NSAID; trudc
nhung phai theo
ve benh DTD. Hudng dan BN each kiem tra
302
- Theo ddi
Ca 3.2. Mgt ngudi
Day la tinh
khdng de y va ban
each su dung ngay
S - Thu thdp thdng tin tiengudi duac tu van:
- Mua thudc
- Ngudi bj benh la tre em hay ngudi ldn. Neu la tre em thi tuoi bao nhieu?
- Da mua
0 - Cdc thdng tin ve tinh trgng benh
Day la trudng hgp mua va dieu trj tai nha, vi vay thdng tin
BN chi cd dugc nhd phdng van. De cd dugc thdng tin chinh xac, DSLS can cd kien thuc ve
benh. Vdi cac nude cd nganh dugc lam sang phat trien, DSLS dugc coi la ngudi chan doan
benh dau tien vdi cac benh thdng thudng (cam, ciim, tao bdn, ia chay...).
Bj ia chay lau chua?
- Phan (mau, mui)?
- Moi ngay di ngoai may lan?
Benh nhan tinh tao hay met mdi?
Tinh trang tieu tien?
- Cd sot? ndn?
A - Nhdn dinh cua DSLS:
P - Lap ke hogch CSD cho BN:

cho uong
(so
trang benh
xau di can
KET
tat ca ddi
ngu hoan thanh
cong vdi benh
nhan (BN) la rat can thiet. Nhung mong muon cua BN trong nhu cau ve thudc van de chii
va phdng
can cu vao
danh gia
hop tac chat che

nhiem vu
303
hieu qua tdt nhat
*.»v %
B. II diing E. I, II va III dung

C. Ill diing
6. Xay dung mdt ke hoach dieu trj he thdng va lien tuc ve thudc cho benh nhan:
thudng xet
III. Sir trd ve binh thudng ciia cac chi so xet nghiem can lam sang
ddc tinh
305
Pharmaceutical
NHA XUAT BAN Y HOC
DTjdC LAM SANG

NHUNG NGUYEN LY CU BAN VA SUf DUNG THUOC TRONG DIEU TRI
TAP 1: CAC NGUYEN L? CO BAN TRONG Dl/OC LAM SANG
Chiu trach nhiem xuat ban

«•>
TONG GIAM DOC
CHU HUNG Cl/ONG
Bien tap vien: BS. DANG CAM THUY

SCfa ban in: DANG CAM THUY
Trinh bay bia: NGUYET THU
Kt vi tinh: TRAN THANH TO
In 1.000 cuon, kho 19 x 27 cm tai Cong ty in Y hpc. So dang ky ke hoach xuat ban:
1760 - 2014/CXB/6 - 123/YH. So' xuat ban: 317/QD-YH ngay 17/9/2014. In xong va
nop lull chieu quy III nam 2014.

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TRUONG DAI HOC DUOC HA NQI DAI HQC GRONINGEN, HA LAN

DLPaC LAM SANG

NHtTNG NGUYEN LY CO BAN VA

CAC NGUYEN LY CO BAN TRONG

Chu bien: GS. TS. Hoang Thj Kim Huyen

NHA XUAT BAN Y HQC

•^.j sjr $ •/• • ;<,

f, i H 9 V ' sft ?'3

GS. TS. Hoang Thj Kim Huyen

THAM GIA BIEN SOAN:

Cac tac gia Viet Nam

TS. Nguyen Hoang Anh Truang Da hoc Dugc Ha Ngi

PGS. TS. Nguyen Thanh Binh Trirong Da hgc Dugc Ha Ngi

TS. Nguyen Tuan Dung Truang Da hgc Y Dugc TP Ho Chi Minh

ThS. Nguyen Thuy Duong Truong Da hgc Dugc Ha Noi

TS. Duong Xuan Chir Truong Da hgc Y Dirge Can Tho

ThS. Nguyen Thu Hang Truong Da hoc Du'oc Ha Noi

PGS. TS. Nguyen Dang Hoa Truong Da hgc Dirge Ha Ngi

TS. Vu Dinh Hoa Truong Da hgc Dugc Ha Ngi

ThS. Duong Thj Ly Huong Truong Da hgc Dugc Ha Ngi

ThS. Le Kim Khanh Trirong Da hgc Y Dugc Can Tho

TS. Phan Quynh Lan Trirong Da hoc Duoc Ha Noi

TS. Nguyen Thj Lap Truong Da hgc Dugc Ha Ngi

GS. TS. V6 Xuan Minh Truang Da hgc Dugc Ha Ngi

PGS. TS. Nguyen Hai Nam Truang Da hgc Dugc Ha Noi

TS. Vo Thanh Plurong Nha Truong Da hgc Y Dugc TP Ho Chi Minh

ThS. Do Thj Nguyet Que Truang Da hgc Dugc Ha Ngi

TS. Dao Thi Vui Truang Da hgc Dugc Ha Ngi

TS. Tran Van Tuan Truong Da hgc Y Dugc Thai Nguyen

PGS. TS. Nguyen Manh Tuyen Truong Da hoc Duoc Ha Noi

GS. TS. J.R.B.J. Brouvvers Centre of Pharmacy, University of Groningen, the

GS. TS. M.J.Postma Centre of Pharmacy, University of Groningen, the

GS. TS. C. de Vries University of Bath, United Kingdom

GS. TS.JJ.de Gier Centre of Pharmacy, University of Groningen, the

GS.TS. Kees van Grootheest Centre of Pharmacy, University of Groningen, the

TS. Frank Jansman Deventer Ziekenhuizen, the Netherlands

GS. TS. A.J.M. Loonen Centre of Pharmacy, University of Groningen, the

TS. E.N. van Roon Medisch Centrum Leeuwarden, the Netherlands

K. Taxis Centre of Pharmacy, University of Groningen, the

TS. Herman J. Woerdenbag Centre of Pharmacy, University of Groningen, the

GS. TS. B. Wilffert Centre of Pharmacy, University of Groningen, the

GS. TS. J. Zaagsma Centre of Pharmacy, University of Groningen, the

BAN THI/ KY:

BIEN TAP BAN THAO

PGS. TS. Nguyen Hai Nam

T.M. BAN QUAN LY DlT AN NPT -VNM -240

PGS. TS. Le Viet Hung

!(:, jj1- : .wH "}' ;-»:• 0 -jg-:i( i '• i£

;f •'! •' .!> :-..!f'-fi-i

i.'! ' : ;Ui.',

GS. TS. Hoang Thi Kim Huyen

) A, .U ,,,-V.f u\ .^\./\ >AT 9;\uoY\

Loi noi dau 7

Mot so tu viet tat 11

Chuong 1. Dugc dong hgc lam sang 13

Hoang Thi Kim Huyin, B. Wilffert

Nguyen Hoang Anh, Nguyin Dang Hoa, J.R.B.J. Brouwers

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