DC NG HC CC NG

A THUC

B mn Dc lm sng, i hc Dc H Ni.

Dc ong hoc cc ng thuoc theo

mo hnh mot ngn bc mot
Mc lc
1. Dc ng hc mt ngn ng tim tnh mch bolus, thi tr theo ng hc bc 1 ............................... 4
1.1. Mc tiu: ................................................................................................................................................. 4
1.2. M t m hnh: ....................................................................................................................................... 4
1.3. Din bin nng trong ngn trung tm: .............................................................................................. 4
1.4. M t trn th nng thuc thi gian ta c: ................................................................................ 5
1.5. Cc thng s dc ng hc c trng: ................................................................................................. 5
1.5.1. Th tch phn b: ............................................................................................................................. 5
1.5.2. Din tch di ng cong .............................................................................................................. 7
1.5.3. thanh thi Cl (clearance)............................................................................................................. 7
1.5.4. Thi gian bn thi t1/2....................................................................................................................... 8
2. Dc ng hc mt ngn dng ng ngoi tnh mch, hp thu v thi tr theo ng hc bc 1. ........... 8
2.1. Mc tiu: ................................................................................................................................................. 8
2.2. M t m hnh: ....................................................................................................................................... 8
2.3. Din bin thay i lng thuc .............................................................................................................. 9
2.4. M t trn th nng thuc thi gian ........................................................................................ 10
2.5. Cc thng s dc ng hc c lin quan n m hnh ...................................................................... 10
2.5.1. Hng s tc thi tr (ke) v hng s tc hp thu (ka) ......................................................... 10
2.5.2. Sinh kh dng ................................................................................................................................. 15
2.5.3. Din tch di ng cong: ........................................................................................................... 16
2.5.4. Thi gian t nng cc i (tmax) ............................................................................................ 17
2.5.5. Nng cc i (Cmax) ................................................................................................................. 18
2.5.6. Thi gian lag ................................................................................................................................... 18
2.5.7. Th tch phn b ............................................................................................................................ 18
3. Dc ng hc mt ngn ng truyn tnh mch lin tc, thi tr theo ng hc bc 1: ...................... 20
3.1. Mc tiu: ............................................................................................................................................... 20
3.2. M t m hnh: ..................................................................................................................................... 20
3.3. Din bin thay i lng thuc trong ngn trung tm:........................................................................ 21
3.4. M t trn th nng thuc thi gian ........................................................................................ 22
3.5. Mt s thng s dc ng hc: .......................................................................................................... 23

B mn Dc lm sng, i hc Dc H Ni.

3.5.1. Nng thuc trng thi cn bng (Css, C steady-state)........................................................... 23

3.5.2. Tc truyn nng trng thi cn bng t c ngng iu tr ................................ 23
3.5.3. Liu np (loading dose) .................................................................................................................. 23
4. Dc ng hc ng tim tnh mch a liu............................................................................................ 24
4.1. Mc tiu ................................................................................................................................................ 24
4.2. Xy dng phng trnh nng thi gian ........................................................................................... 24
4.3. Mt s thng s dc ng hc c trng .......................................................................................... 25
4.3.1. Nng thuc trng thi cn bng (Cpss)................................................................................... 25
4.3.2. H s tch ly .................................................................................................................................. 25
4.3.3. Nng nh (peak concentration) ............................................................................................... 26
4.3.4. Nng y (trough concentration) ............................................................................................. 26
4.3.5. H s dao ng (fluctuation) ......................................................................................................... 26
4.3.6. Nng trung bnh trng thi cn bng..................................................................................... 27

B mn Dc lm sng, i hc Dc H Ni.

1. Dc ng hc mt ngn ng tim tnh mch bolus, thi tr theo

ng hc bc 1
1.1. Mc tiu:
1. M t m hnh dc ng hc mt ngn bc mt ng tim tnh mch
2. Nu phng trnh nng thuc theo thi gian v m t th ng vi phng trnh ny.
3. Trnh by cc thng s dc ng hc lin quan n m hnh mt ngn bc 1 ng tim tnh mch: th
tch phn b, thi gian bn thi, thanh thi, din tch di ng cong.
Lng thuc: A
Nng : Cp
Th tch: Vd

Tim bolus

ke
Gan, thn

1.2. M t m hnh:
Tim bolus l tim ton b lng vo tnh mch trong khong thi gian ngn (thng ko di khong mt
vi pht, so vi qu trnh thi tr thuc khi c th (thng t vi gi n vi ngy th thi gian tim coi
nh bng 0)
A l lng thuc trong ngn trung tm, Cp l nng thuc trong ngn trung tm (p y l ch plasma
tc l huyt tng). A v Cp l hai hm s ca thi gian t. y l m hnh dc ng hc mt ngn nn
nng trong ngn trung tm cng chnh l nng thuc trong huyt tng. Vd l th tch phn b ca
thuc v khng ph thuc vo thi gian t. Ta c Cp=A/Vd
Hng s tc thi tr l ke. Th nguyn ca ke l thi gian-1. Do n v ca ke c th l 1/gi, 1/pht
v.v

1.3. Din bin nng trong ngn trung tm:

Ti thi im t=0: Mt lng thuc A0 c tim thng vo ngn trung tm.
Sau , thuc s c dn dn thi tr khi c th nh qu trn thi tr vi hng s tc thi tr ke (e l
elimination hay l thi tr). V thuc thi tr theo ng hc bc 1 nn lng thuc c ra khi ngn l
ke.A (du m cho thy thuc i ra khi ngn). Bn cnh s thay i lng thuc ti ngn trung tm
c c trng bi dA/dt. Hai lng ny bng nhau, do :

Gii phng trnh vi phn trn nh sau:

(vi Const l mt hng s)

Khi t=0 th Const=ln(A)t=0 = lnA0 do :

(pt 1.1)

B mn Dc lm sng, i hc Dc H Ni.

Vi A0 l lng thuc trong c th ti thi im ban u sau tim. Chia hai v ca (1) cho Vd (Volume of
distribution) tc l th tch phn b, ta c:
(pt 1.2)
Vi Cp l nng thuc (trong ngn trung tm) ti thi im t bt k v D l liu tim tnh mch (bng A0)

1.4. M t trn th nng thuc thi gian ta c:

Ngay sau khi tim tnh mch ti thi im t=0, thuc phn b u trong ngn trung tm v t nng
bng D/Vd. Sau , thuc thi tr dn khi ngn theo ng hc bc 1 vi hng s tc thi tr ke. th
biu din nng thuc theo thi gian l:

10
9

C0

Nng

7
6
5
4
3
2
1
0
0

10

15
Thi gian

20

25

30

Hnh 1.1. th nng thi gian

1.5. Cc thng s dc ng hc c trng:

Cc thng s c trng dc ng hc tuyn tnh bc 1 l th tch phn b Vd, thi gian bn thi t1/2 , hng
s tc thi tr ke v thanh thi Cl (clearance) u l nhng thng s khng ph thuc vo liu.
1.5.1. Th tch phn b:
Theo gi nh th c th l mt ngn ng nht vi nng thuc bng nng thuc trong mu (l do l
ngi ta thng o nng thuc trong mu nghin cu v dc ng hc). Tuy nhin, trn thc t,
thuc khng phn b ng nht gia mu v cc c qua khc. Khi ngi ta c khi nim th tch phn
b. Th tch phn b c xc nh bng nng ti thi im ban u C0 v liu dng ca thuc D.
(pt 1.3)

B mn Dc lm sng, i hc Dc H Ni.

Ty theo kh nng thuc phn b vo m, gn vo cc c quan nhiu hay t m ta c th tch phn b ln

hay nh. Thng thng, cc thuc c c tnh thn nc kh thm vo cc c quan do nng thuc
trong mu thng cao v do th tch phn b thng nh. Ngc li, cc thuc c c tnh thn lipid
thng d thm qua cc mng sinh hc ng thi phn b nhiu vo cc c quan lm cho nng thuc
trong mu nh v do c th tch phn b ln. Th tch phn b c th dao ng t 7L (th tch mu tun
hon) n vi trm, thm ch vi nghn L. Th tch phn b c th c tnh theo n v khi lng c th.

Hnh 1.2. Th tch phn b ca mt s thuc

Mt lu l cc thuc c th tch phn b ln thng c nng thuc trong mu nh, do vic nh
lng nng thuc nghin cu dc ng hc c th gp kh khn do gii hn nh lng di ca
phng php phn tch c th khng o c cc nng ny.

B mn Dc lm sng, i hc Dc H Ni.

Nu thuc tun theo dc ng hc tuyn tnh mt ngn th th tch phn b ca thuc trn mi c th
l mt hng s khng ph thuc vo liu dng hay ng dng. Mt s yu t bnh l c th nh hng
n t l phn b thuc gia mu v c quan v do s nh hng n th tch phn b. Cc yu t sinh
l nh tr em, ngi cao tui, ph n c thai v.v cng nh hng ti th tch phn b.
1.5.2. Din tch di ng cong
Din tch di ng cong nng thi gian (AUC) l din tch phn pha bn di ng cong nng
thi gian. AUC phn nh tng lng thuc m c th phi nhim theo thi gian. AUC c th c tnh theo
nhiu cch khc nhau:
+ Phng php tch phn theo phng trnh nng thi gian

(pt 1.5)

+ Phng php hnh thang (trapezoidal rule)

(pt 1.6)

Hnh 1.3. Xc nh AUC bng phng php hnh thang

1.5.3. thanh thi Cl (clearance)
thanh thi phn nh th tch mu c lc sch thuc trong mt n v thi gian. Trong trng hp
thuc c thi tr nguyn vn, thanh thi c th c tnh theo cc cch sau:

Tch phn v phi vi t t 0 n

ta c
(pt 1.7)

B mn Dc lm sng, i hc Dc H Ni.

D l liu dng (trong trng hp tim tnh mch). Trong trng hp dng ngoi ng tnh mch v thi
tr qua thn ngi ta c th xc nh lng A0 bng cch o tng lng thuc c thi tr qua nc tiu.
T 1.5 v 1.7 ta cng c th tnh thanh thi bng cng thc
Cl = ke.Vd (pt 1.8)
1.5.4. Thi gian bn thi t1/2
L thi gian lng thuc (hoc nng thuc) trong mu c thi tr cn mt na. Trong m hnh
dc ng hc bc 1, mt ngn, thi gian bn thi l mt hng s v bng:
(pt 1.4. t chng minh)
Nh vy thi gian bn thi ph thuc vo hng s tc thuc c thi tr khi tun hon chung (ngn
trung tm). Theo pt 1.8 ta c hng s tc thuc thi tr khi c th l ke=Cl/Vd. Nh vythi gian bn
thi ph thuc vo hai thng s dc ng hc c bn l thanh thi v th tch phn b. Vi thuc c
th tch phn b cng ln th kh nng thi tr ca thuc cng chm (t1/2 di) do thuc c phn b nhiu
vo cc c quan. Tng t, vi thuc c thanh thi cng ln th thi gian bn thi cng ngn do tc
thi tr thuc tng.

2. Dc ng hc mt ngn dng ng ngoi tnh mch, hp thu v thi

tr theo ng hc bc 1.
2.1. Mc tiu:
1. M t m hnh dc ng hc mt ngn bc mt ng dng ngoi tnh mch
2. Nu phng trnh nng thuc theo thi gian v m t th ng vi phng trnh ny.
3. Trnh by cc thng s dc ng hc lin quan n m hnh mt ngn bc 1 ng dng ngoi tnh
mch: Sinh kh dng (F), hng s tc hp thu (ka), thi gian lag (tlag), th tch phn b, din tch di
ng cong (AUC), thi gian t nng cc i (tmax), nng cc i (Cmax).

ka
Aa

Lng thuc: A
Nng : Cp
Th tch: Vd

ke
Gan, thn

2.2. M t m hnh:
ng ngoi tnh mch c th l ng ung, ng tim bp, ng tim di da, ng tim trong da,
ng t trc trng, ng qua da hp thu qua ming dn Cc ng dng ny c c im l i hi
phi c qu trnh hp thu thuc vo mu. Qu trnh hp thu vo mu trong m hnh ny c gi nh tun
theo ng hc bc 1 vi hng s tc hp thu l ka (th nguyn l thi gian-1).

B mn Dc lm sng, i hc Dc H Ni.

Theo m hnh ta thy c mt lng thuc Aa cn hp thu vo trong h tun hon chung t v tr hp thu
(rut, trc trng, bp c) vi hng s tc hp thu ka. V y l m hnh mt ngn nn nng thuc
trong h tun hon chung cng bng nng thuc trong ngn trung tm. Thuc trong ngn trung tm s
c thi tr vi hng s tc thi tr ke.

2.3. Din bin thay i lng thuc

Bin thin lng thuc ti v tr hp thu:

(pt 2.1)

(Aa = lng thuc ti v tr hp thu, vi a l absorption ngha l hp thu, du - phn nh thuc i ra khi
v tr hp thu)
Bin thin lng thuc ti ngn trung tm:

(pt 2.2) (bng lng thuc hp thu tr

lng thuc c thi tr).

Bin thin lng thuc ti v tr thi tr (lng thuc c thi tr khi ngn trung tm):

(pt

2.3)
tm hiu din bin lng thuc trong ngn trung tm theo thi gian, cn gii phng trnh vi phn (2):
T phng trnh (pt 2.1), tng t nh phng trnh nu phn tim bolus, ta c:

Lng thuc ti v tr hp thu ti thi im t=0 l lng thuc c th c hp thu (lng thuc khng
c hp thu khng tnh vo Aa0) vo h tun hon chung. Lng thuc ny bng F.D vi F l sinh kh dng
v D l liu dng.
Thay vo phng trnh (pt 2.2), ta c:

Nhn hai v vi

(pt 2.4) (Vi Const l mt hng s)

Khi t=0 th A = 0, do :

; Thay vo (pt 2.4) ta c:

(pt 2.5)

Chia c hai v cho Vd ta c

(pt 2.6)

B mn Dc lm sng, i hc Dc H Ni.

2.4. M t trn th nng thuc thi gian

Cmax

4.5
4
3.5

2.5
2

pha hp thu

Nng

1.5
1
0.5

pha thi tr

0
0

tmax

10

15

20

Thi gian

Hnh 2.1. th m t ng cong nng thi gian ca dc ng hc mt ngn ng ngoi tnh mch
Pha hp thu: tc hp thu vo ngn >> tc thi tr khi ngn (hay ka.Aa>> ke.A)
Ti thi im t=tmax v A= Amax (hay C=Cmax): tc thuc hp thu = tc thuc thi tr (hay ka.Aa=ke.A)
Pha thi tr: tc thuc thi tr >> tc thuc hp thu (hay ka.Aa<<ke.A)

2.5. Cc thng s dc ng hc c lin quan n m hnh

2.5.1. Hng s tc thi tr (ke) v hng s tc hp thu (ka)
Hin nay, trong nghin cu dc ng hc, ngi ta vn cha th o s bin thin nng thuc trong
mu theo thi gian (nh trong cc phng trnh ton hc ca m hnh gii trn). V vy, ngi ta
thng ly mu ti mt s thi im v o nng thuc tng ng. Sau , ngi ta a ra cc m hnh
dc ng hc gi nh ri khp ng cong nng thi gian vi s liu thc nghim. Bn cnh vic c
nhiu m hnh dc ng hc gi nh, nhiu phng php khp ng cong cng c a ra. C th
trong m hnh dc ng hc mt ngn ng ung ngi ta c th p dng phng php sau:
+ Xc nh hng s tc thi tr:
Ta c:
Thng thng, ka>>ke (tc hp thu thuc thng nhanh hn tc thi tr). Do , khi thi gian cng
tng v on cui ca pha thi tr th
dn v 0. Do vi thi gian cui ca pha thi tr ta c:

B mn Dc lm sng, i hc Dc H Ni.

Do khi thuc dng ng ung hng s tc ke thng c c lng bng nhng s liu on
cui ca pha thi tr. S liu nng thng c logarit ha c th s dng hi quy tuyn tnh nhm
xc nh ke (hi quy tuyn tnh l m hnh hi quy n gin nht nhng cng ph bin nht).
(

)
4

100
ln (Nng ) (mg/L)

Nng (mg/L)

Giao trc tung=

10

dc = -ke/2.303

Giao trc tung= ln(

0.1
0.01

2
1

dc = -ke

0
-1
-2
-3
-4

10

20
Thi gian

30

40

10

20
Thi gian

30

40

Hnh 2.2. Xc nh hng s tc thi tr ke

+ Xc nh hng s tc hp thu:
Thng thng, ngi ta thng p dng phng php phn d (method of residuals; ngoi ra cn c
mt s tn khc l curve stripping hay feathering). Ta c:
(pt 2.7)
Do giao im ca ng hi quy pha thi tr vi trc tung xc nh c, ke xc nh c, Cp l s
liu thc nghim bit. Khi ng vi mi gi tr t, v phi ca phng trnh trn cng c th tnh c.
v phi ca phng trnh l hiu ca ng ngoi suy pha thi tr (mu ) vi ng nng thi gian
nn gi l phn d (residual). Cc gi tr phn d thu c s xc lp ng cong hng s tc hp thu
(residual line). T tnh c hng s tc hp thu.

B mn Dc lm sng, i hc Dc H Ni.

18
16

Giao trc tung=

14

Nng (mg/L)

12
10
8

C=

6
4

C=

2
0
0

10

20

30

40

Thi gian
Trn h ta bn logarithm:

Giao trc tung=

Nng (mg/L)

10

dc = -ke/2.303

dc =
-ka/2.303

0.1

C=

C=
0.01
0

10

20

Thi gian
Hnh 2.3. Xc nh hng s tc hp thu ka
+ Khp ng cong m hnh vi s liu thc nghim:

B mn Dc lm sng, i hc Dc H Ni.

30

40

12
10

Cp

8
6
4
2
0
0

10

15

20

25

30

Thi gian

3
2.5
2

Ln (Cp)

1.5
1
0.5
0
-0.5
-1
-1.5
0

10

15

20

25

30

Thi gian
3

Ln(Cp)

2.5
2
1.5
y = -0.1065x + 2.4778

1
0.5
0
-0.5
-1
-1.5
0

10

15
Thi gian

B mn Dc lm sng, i hc Dc H Ni.

20

25

30

3
2.5
2

Ln(Cp)

1.5
y = -0.1065x + 2.4778

1
y = -2.0342x + 3.0171

0.5
0
-0.5
-1
-1.5
0

10

15

20

25

30

Thi gian

12

Cp

10
8
6
4
2
0
0

10

15

20

25

20

25

Thi gian
M hnh tnh c

S liu thc t

Cp

10

0.1
0

10

15
Thi gian

S liu thc t

M hnh tnh c

B mn Dc lm sng, i hc Dc H Ni.

Hnh 2.4. Phng php thu cn khp ng cong vi d liu dc ng hc thc nghim
Phng php thu phn d gip c lng kh chnh xc cc thng s dc ng hc theo m hnh mt
ngn bc 1 vi iu kin ka> 5 ln ke. Nu chnh lch hai hng s tc hp thu v hng s tc thi
tr di 5 ln, phng php s km chnh xc hn.
2.5.2. Sinh kh dng

Hnh 2.5. M t cc yu t c th nh hng n sinh kh dng ca thuc

Sinh kh dng phn nh lng thuc vo c vng tun hon chung so vi lng thuc c dng. Theo
hnh 2.5 th sinh kh dng ng ung ph thuc vo lng thuc c hp thu ti rut v lng thuc
c chuyn ha ti thnh rut cng nh vng tun hon u qua gan. T l lng thuc vo c vng
tun hon chung so vi liu dng l sinh kh dng v k hiu l F. Lu l F khng ph thuc vo cc thng
s dc ng hc khc nh ke, ka, Vd hay Cl. N l mt thng s dc ng hc c bn (bn cnh Vd v
Cl).
Kh c th xc nh bao nhiu % thuc vo c tun hon chung (F) mt cch trc tip. Do ngi ta
phi xc nh gin tip sinh kh dng (tuyt i) thng qua t l AUC ng ngoi tnh mch vi ng tnh
mch. AUC ng tnh mch t l vi 100% liu dng trong khi AUC ng ngoi tnh mch t l vi t l
lng thuc vo c tun hon chung.

B mn Dc lm sng, i hc Dc H Ni.

2.5.3. Din tch di ng cong:

(

)
)

(pt 2.8)
(Vi dc ng hc tuyn tnh bc 1, 1 ngn, ng ung, din tch di ng cong khng ph thuc vo
tc hp thu ca thuc).
Theo pt 2.8 AUC khng ph thuc vo ka, tc l khng ph thuc vo tc hp thu ca thuc. iu ny
th hin trong hnh di dy

45.0
Nng trong ngn trung tm

40.0
35.0
30.0
25.0
20.0
15.0
10.0
5.0
0.0
0

10

15

20

Thi gian
Cp1

Cp2

Cp3

Cp4

Hnh 2.6 nh hng ca ka n ng cong nng thi gian

Cp1
Cp2
Cp3
Cp4

ka
ke
Vd
Liu
AUC
Cl
t1/2
tmax
Cmax
0.10 0.24
11
458
173
2.6
2.9
6.25
9.3
0.50 0.24
11
458
173
2.6
2.9
2.82
21.1
1.00 0.24
11
458
173
2.6
2.9
1.88
26.5
0.24

11

458

173

2.6

2.9

0.00

41.6

Cc ng cong Cp1 n Cp4 c cng sinh kh dng l 1. Khi thay i ka, cc thng s tmax, Cmax l khc
nhau nhng AUC l bng nhau.

B mn Dc lm sng, i hc Dc H Ni.

Tuy nhin, AUC li ph thuc vo mc hp thu, tc l sinh kh dng. Nu sinh kh dng bng 1, din tch
di ng cong ca ng ung s bng ng tim. Ngoi ra AUC cn ph thuc vo liu dng v
thanh thi
100.0

Nng trong ngn trung tm

90.0
Cp1

80.0
70.0

Cp2

60.0
Cp3

50.0
40.0

Cp4

30.0
20.0
10.0
0.0
0

10
Thi gian

.
F

ka

Cp1 (IV)
Cp2 (ung)
Cp3 (ung)

1
1
0.6

ke
Vd
Liu
AUC
Cl
t1/2
tmax
Cmax
0.24
11 1000
379
2.6
2.9
0.00
90.9
1.00 0.24
11 1000
379
2.6
2.9
1.88
57.9
1.00 0.24
11 1000
227
2.6
2.9
1.88
34.8

Cp4 (ung)

0.3

1.00

0.24

11

1000

114

2.6

2.9

1.88

17.4

Hnh 2.7. nh hng ca ng dng v sinh kh dng ln ng cong nng thi gian
2.5.4. Thi gian t nng cc i (tmax)
Tmax l kh nim c trng cho dc ng hc ng ngoi tnh mch n liu. Tmax l thi gian nng
thuc trong mu t cc i sau khi dng mt liu thuc ng ngoi tnh mch.
Tnh tmax:
Ta c ti thi im tmax:

, do
(

).
(

B mn Dc lm sng, i hc Dc H Ni.

Nh vy, vi gi nh dc ng hc mt ngn hp thu v thi tr bc 1 th tmax ph thuc vo ka v ke

(do ph thuc Vd v Cl v ke ph thuc vo Vd v Cl). Cc thng s nh sinh kh dng hay liu dng
khng lm thay i thng s ny.
2.5.5. Nng cc i (Cmax)
Nng cc i l nng thuc ti thi im tmax. Thay tmax vo phng trnh nng -thi gian (pt
2.6) ta s c nng cc i Cmax.
2.5.6. Thi gian lag
V mt l thuyt, ng ngoi suy pha thi tr
phng php phn d

v ng hp thu thu c t
phi nm trn trc tung. Tuy nhin, trn s liu tnh ton t

thc t th thng giao im ny khng nm trn trc tung. Khi , thi gian ng vi giao im ny gi l
thi gian lag. Nu thi gian lag ny nh, ta c th b qua v n lin quan n sai s gia gi nh m hnh
(hp thu v thi tr theo ng hc bc mt, mt ngn) v s liu thc nghim thu c. Tuy nhin, nhiu
lc thi gian lag ny kh ln m nguyn nhn c th lin quan n nhng vn giai on hp thu. V d
thuc khng ha tan, km ha tan, li dng bo ch, b lu lu d dy (nu ung thuc cng ba n th
rt d c pha lag ny) hoc thuc c thit k gii phng theo chng trnh v.v Trong trng hp ,
cn tnh n thi gian lag ny khi tnh ton cc thng s dc ng hc.

100
100

10

Nng (mg/L)

Nng (mg/L)

10

0.1

0.1

0.01

0.01
0

20

40

Thi gian (h)

20

40

Thi gian (h)

Hnh 2.5. Thi gian lag

2.5.7. Th tch phn b
Theo phng trnh m hnh nng (trong ngn trung tm)- thi gian cng nh tnh ton t s liu thc
nghim nh trnh by, ta c th xc nh c gi tr
th xc nh c gi tr ca biu thc

. V ke v ka c xc nh, nn ta c

. Vn l liu dng ta bit trc nhng sinh kh dng (t l

lng thuc vo c vng tun hon) th khng bit trc c nu khng tin hnh nghin cu so snh
vi dng tim tnh mch. Do , t s liu dc ng hc ng ung, ta ch c th xc nh c Vd/F.

B mn Dc lm sng, i hc Dc H Ni.

B mn Dc lm sng, i hc Dc H Ni.

3. Dc ng hc mt ngn ng truyn tnh mch lin tc, thi tr theo

ng hc bc 1:
3.1. Mc tiu:
1. M t c m hnh dc ng hc mt ngn ng truyn tnh mch lin tc thi tr bc 1
2. Trnh by phng trnh nng thuc theo thi gian v m t th ng vi phng trnh ny.
3. Trnh by nng thuc trng thi cn bng (Css) v tc truyn t Css mong mun
4. Trnh by phng php tnh liu np t Css mong mun.

3.2. M t m hnh:

Lng thuc: A
Nng : Cp
Th tch: Vd

ke
Gan, thn

Thuc c a vo ngn trung tm theo ng hc bc 0. Tc l thuc c a vo ngn trung tm vi

tc khng i. Ni cch khc trong mi n v thi gian, c mt lng thuc Q khng i c a vo
ngn trung tm. Lng thuc ny lin quan n tc truyn, trong m hnh ny gi nh tc truyn l
khng i.
A l lng thuc trong ngn trung tm, Cp l nng thuc trong ngn trung tm (p y l ch plasma
tc l huyt tng). A v Cp l hai hm s ca thi gian t. y l m hnh dc ng hc mt ngn nn
nng trong ngn trung tm cng chnh l nng thuc trong huyt tng. Vd l th tch phn b ca
thuc v khng ph thuc vo thi gian t. Ta c Cp=A/Vd
Thuc c thi tr vi hng s tc thi tr l ke. Th nguyn ca ke l thi gian-1. Do n v ca ke
c th l 1/gi, 1/pht
Mt s thit b y t dng tim truyn tnh mch lin tc.

B mn Dc lm sng, i hc Dc H Ni.

3.3. Din bin thay i lng thuc trong ngn trung tm:
Ti thi im t=0, nng Cp = 0.
Sau , thuc c a vo ngn vi tc Q. Lng thuc trong ngn s tng dn ln. Song song, thuc
c thi tr khi ngn vi tc l ke.A. Do tc thay i lng thuc trong ngn = tc thuc
vo tc thuc ra. Tc l:
(pt 3.1)
Gii phng trnh vi phn trn nh sau:

Lu , vi phn ca hm s hp: d(uv) = vdu+udv. Trong trng hp ny u l A v v l eket, do :

(
(

(
)

(Vi C l mt hng s)

B mn Dc lm sng, i hc Dc H Ni.

Ti thi im t=0, lng thuc A trong c th =0, do

Thay vo h nghim phng trnh vi phn ta c:

) (pt 3.2)

Chia c hai v ca (pt 3.2) cho Vd ta c:

(

) (pt 3.3)

3.4. M t trn th nng thuc thi gian

Truyn tnh mch lin tc ng vai tr quan trng trong s dng thuc trong iu tr c bit bnh vin.
u im ca truyn tnh mch lin tc so vi cc dng dng khc l c th to c nng thuc n nh
trong mu v do d t nng trong phm vi iu tr (Xem hnh)
8
7

Ngng ti thiu gy c
6

Nng

Phm vi
iu tr

4
3

Ngng ti thiu c tc dng

2
1
0
0

6
Thi gian

10

12

Hnh 3.1. th biu din ng cong nng thi gian ca ng truyn tnh mch lin tc v phm vi
iu tr

B mn Dc lm sng, i hc Dc H Ni.

3.5. Mt s thng s dc ng hc:

3.5.1. Nng thuc trng thi cn bng (Css, C steady-state)
Khi nim Css thng c p dng cho trng hp truyn tnh mch lin tc v trng hp dng a liu
(nhiu liu) cc dng dng khc (s gii thiu sau).
Trong truyn tnh mch lin tc, trng thi cn bng l trng thi m tc truyn bng tc thi
tr, tc l khi ke.A=Q. Theo phng trnh *2+ ta c:
(
) Q vi mi t>0. Du bng xy
ra khi t= . C ngha l trng thi cn bng v mt l thuyt ch t c khi thi gian v cng. Khi
nng trng thi cn bng l:

(chnh l ng tim cn ca hm s nng - thi gian)

Quy tc 5.t1/2:
t t s nng t c so vi nng trng thi cn bng l thuyt l fss, ta c
(

Trong N l t s gia t v t1/2

Ti t=5.t1/2 ta c N=5. Khi

Tc l nng thuc t c ~ 97% nng trng thi cn bng l thuyt. V mt thc hnh, lc ta
c th coi thuc t trng thi cn bng.
3.5.2. Tc truyn nng trng thi cn bng t c ngng iu tr
Gi s ch nng trng thi cn bng cn t m bo iu tr l Cpss-ch:
(pt 3.4)
Tc l tc truyn cn thit s ph thuc vo t1/2 v Vd. Cc thng s ny c th tra cu t cc ti liu
chuyn kho.
3.5.3. Liu np (loading dose)
Nh trn trnh by, sau 4.32 ln t1/2 th nng thuc mi t trng thi cn bng v mt thc hnh.
Vi nhng thuc c t1/2 di th thi gian ny kh lu (v d t1/2 = 3 gi => cn khong 13 gi) v khng
ph hp trong iu kin bnh nhn cn t nng iu tr sm. Trong trng hp , ngi ta c th s
dng liu np bng cch tim bolus tnh mch vi liu D nhm nhanh chng t nng cn thit sau
truyn tnh mch lin tc duy tr nng iu tr.
Nng thuc do liu np l:
(

Nng thuc do truyn tnh mch lin tc l:

)
(

Nng thuc trong mu (ngn trung tm) s l:

Nng ny cn t ti

, tc l

B mn Dc lm sng, i hc Dc H Ni.

Rt gn phng trnh ta c

(pt 3.5)

Nh vy, liu np s ph thuc vo th tch phn b v ch nng m mnh mong mun

14

Nng trong mu = liu np + truyn lin tc

12

Nng

10

Truyn tnh mch

lin tc

8
6
4

Liu
np

2
0
0

10
Thi gian

15

20

Hnh 3.2. th phn nh vai tr ca liu np trong truyn tnh mch lin tc
Trong thc t, bnh nhn c gim thi tr thuc (vd. Bnh nhn suy thn v thuc thi tr qua thn
dng cn hot tnh) th t1/2 s b ko di, t nng trng thi cn bng nh mong mun, nht thit
phi iu chnh li tc truyn (Xem phng trnh pt 3.4). Tuy nhin khng cn phi iu chnh li liu
np (Xem pt 3.5) trong trng hp ny. L do l v liu np ch ph thuc vo nng ch cn t ti v
th tch phn b. V mt l thuyt th tch phn b khng ph thuc vo qu trnh thi tr.

4. Dc ng hc ng tim tnh mch a liu

4.1. Mc tiu
1. Trnh by phng trnh nng thuc theo thi gian v m t th ng vi phng trnh ny.
2. Trnh by c cch tnh v ngha ca mt s thng s dc ng hc c trng: H s tch ly (R),
nng nh (Cpeak), nng y (Ctrough), h s dao ng (), v nng trung bnh trng thi cn bng
( )

4.2. Xy dng phng trnh nng thi gian

Gi s thuc c tim tnh mch a liu vi khong cch a liu l T. Cn xc nh nng thuc sau n
ln a liu.
Lng thuc ca liu thuc u l:
Lng thuc ca liu thuc 2 l:
Lng thuc ca liu thuc n l:
Lng thuc trong c th ti thi im t bng tng lng thuc ca n liu ti thi im t:

B mn Dc lm sng, i hc Dc H Ni.

Lu : Nu ta cn kho st bin thin nng thuc trong khong thi gian t 0 n ca liu th n. Khi
chuyn gc ta n (n-1). v ta c tn=t-(n-1). (tc l tn l thi gian sau khi tim liu th n, tn=0 khi
bt u truyn liu mi, >tn>o).

T s Dost =
Khi :
Chia hai v cho Vd ta c:
Vi Cp1 l nng thuc ti thi im tn ca liu u tin.

4.3. Mt s thng s dc ng hc c trng

4.3.1. Nng thuc trng thi cn bng (Cpss)
T s Dost phn nh t s nng thuc ca liu dng th n so vi nng thuc ca liu th nht ti cng
thi im (tnh t khi bt u mi liu thuc). Khi n tng th t s Dost cng tng dn n nng thuc ni
chung s tng dn. Do , t s Dost phn nh qu trnh tch ly ca thuc khi dng a liu. Tuy nhin, lu
l khi n-> th t s Dostss dn ti

l hng s. Khi , thuc t c trng thi cn bng (steady

state). Nng thuc trng thi cn bng (ti thi im tn) c biu din bi cng thc:
(Lu vi >tn>o)
+ Quy tc 5 .t1/2:
T s fss gia nng thuc liu dng th n so vi nng thuc trng thi cn bng ti cng thi
im s l Dost/ Dostss=
. Tng t nh phn ng truyn tnh mch lin
tc, sau khon 5 ln t1/2 (tc l n. = 5. 1/2) th nng thuc t trng thi cn bng trn thc hnh
(khong 97 % nng trng thi cn bng l thuyt).
4.3.2. H s tch ly
L t l gia nng thuc trng thi cn bng so vi nng thuc liu u tin (ti cng thi im).
Ta c s tch ly

B mn Dc lm sng, i hc Dc H Ni.

H s tch ly phn nh mc thuc c tch ly trong c th khi dng a liu. H s ny cng ln chng
t so vi nng thuc liu u, nng thuc trng thi cn bng s cng ln. H s ny ph thuc
vo ke (hay t1/2=0.693/ke) v khong cch a thuc. Thuc c thi gian bn thi cng di (do bn cht
ca thuc hoc do chc nng thi tr gim) th R cng ln v thuc cng c nguy c tch ly trong c th.
iu ny cho thy rng vi cc thuc c thi gian bn thi cng di th cng phi thn trng khi dng a
liu. Ngc li, ni rng khong cch a thuc s lm gim h s tch ly. H s tch ly khng ph thuc
vo liu.
4.3.3. Nng nh (peak concentration)
Nng nh l khi nim c trng cho dc ng hc a liu. y l nng cao nht trong mi khong
a thuc. Trng hp dng tim tnh mch a liu, nng nh l nng ngay sau mi ln tim. Nng
ny t c khi tn=0 V khi , nng peak ti liu dng th n l:

Tc l sau mi liu dng, nng nh s bng Dost ln nng nh ca liu u tin Cpeak1.
Ti trng thi cn bng, Dost->Dost v nng Cpeakss s l
4.3.4. Nng y (trough concentration)
Nng y l khi nim c trng cho dc ng hc a liu. y l nng thp nht trong mi khong
a thuc. Trng hp dng tim tnh mch a liu, nng nh l nng cui khong a thuc, ng
vi nng ti thi gian t= . Trong thc hnh lm sng, thng nng trough c o ngay trc khi
ngi ta dng liu mi.

Ngoi ra, nng y ca liu u l

, nn

Vi Ctrough0 l nng y ca liu u tin (ng vi n=1) Tc l sau mi liu dng, nng y s bng
Dost ln nng y ca liu u tin.
Ti trng thi cn bng Ctroughss s l
4.3.5. H s dao ng (fluctuation)
H s dao ng l mt thng s c trng cho dc ng hc a liu. H s dao ng c tnh l

H s dao ng phn nh mc dao ng ca thuc trong mu khi dng thuc a liu. Vi cc thuc c
hng s tc thi tr cng nh (thi gian bn thi di) th h s dao ng cng ln v ngc li. Tuy nhin
thng s ke l hng s nn lm gim h s dao ng trong mt s trng hp ta c th rt ngn khong
cch a thuc.

B mn Dc lm sng, i hc Dc H Ni.

4.3.6. Nng trung bnh trng thi cn bng

Ta bit rng din tch di ng cong l tch gia nng v thi gian. Do ta c th coi nng trung

bnh ti liu dng n l

Trong thc t, ngi ta quan tm nhiu n nng trung bnh ti trng thi cn bng. Khi t trng thi
cn bng cn bng, ta c n-> , khi

(1 Din tch di ng cong ng vi 1 khong

liu trng thi cn bng l:

Nh vy din tch di ng cong trong mt khong liu ti thi im cn bng l

. Lu y cng

chnh l din tch di ng cong khi tim tnh mch n liu. iu ny c th hin trong hnh di
y:

Hnh 4.1. Nng thuc theo thi gian ca dc ng hc a liu ng tim tnh mch.
Do nng trung bnh ti trng thi cn bng l
Nh vy nng ti trng thi cn bng ph thuc vo liu dng, th tch phn b, hng s tc thi tr
ke (hay l t1/2 ca thuc) v khong cch a thuc. Do Vd v ke l hai hng s (theo dc ng hc mt
ngn bc 1) nn t mt mc no (trong ngng iu tr) th ta c th thay i liu dng D hoc
khong cch a thuc (phng php hiu chnh liu):
- Khi gi nguyn khong cch a thuc , liu dng D cng cao th cng tng (v tng c tnh cht
tuyn tnh). Lu , nu khng tng mt cch tuyn tnh th thuc tun theo dc ng hc khng tuyn
tnh v trng hp khng nm trong phm vi ca bi ging ny.

B mn Dc lm sng, i hc Dc H Ni.

Hnh 4.2 Dc ng hc tuyn tnh v dc ng hc khng tuyn tnh.

- Khi gi nguyn liu D, khong cch a thuc T cng ln th cng nh.

B mn Dc lm sng, i hc Dc H Ni.