Tissue Receptor

EFFECT
K+ Na+ Ca2+

-protein A A

-fat

I.V
Liberation Blood
Specific barrier
PROTEIN
FREE DRUG BOUND
H. Achmad Basori Absorption DRUG Renal
Departemen Farmakologi GI tract
FK UNAIR METABOLITE
-Aktif
-Tidak aktif
Enterohepatic
circulation Glomerular filtration
Liver Tubular secretion
-Microsome Passive reabsorption
-Non microsome
BIOTRANSFORMATION

Drug ADME
(absorption, distribution, metabolism & excretion)

1
 Pharmacokinetics &
Pharmacodynamics
Single-compartment model
Primary Pharmacokinetics Parameter
Clearance (Cl)
Half-lives (t ½ )
C Distribution Volumes (Vd)
ka ke
Vd Bioavailability Measures (AUC)
Absorption Body Elimination
Secondary Pharmacokinetic Parameter
Vss, Css av, Css min, Css max, dll

First Order Elimination

Fraksi obat yang dihilangkan dari tubuh per
satuan waktu adalah constan
14
Jumlah obat yang dieliminasi dari tubuh
Plasma concentration

per satuan waktu adalah tergantung

12
pada jumlah obat didalam tubuh
10
Hampir semua obat dieliminasi dari tubuh
8
menurut reaksi tingkat pertama ( first
6 order reaction)
4
Zero order
2
0 jumlah obat yang dieliminasi
0 5 10 15 20 persatuan waktu adalah konstan
TIME (hours)

2
 Kinetika Obat Dalam Tubuh
First-order process: Zero Order Kinetics First Order Kinetics
dC/dT = k•C (constant fraction)
Rate = k Rate = k C
C = Co e-kt
Zero-order process: C = Co - kt
dC/dT = k (constant amount) C vs. t graph  tdk
C vs. t graph linear, menurun
 LINEAR secara
Capacity limited process: exponential.
low C, first-order; high C, zero-order Log C vs. t graph
 linear.

First order Zero Order

rate of elimination depends rate of elimination is constant
on plasma concentration and independent of plasma
concentration

3
 Conc. Vs. time plots

C = Co - kt ln C = ln Co - kt

Log Plasma Concentration

10000
dA/dt ∝A DA/dt = – k•A
First Order Elimination
14 DC/dt = – k•C 1000
Plasma concentration

12 Ct = C0 . e – Kel •t
100
10 lnCt = lnC0 – Kel • t
8 logCt = logC0 – Kel •t
2.3 10
6
4 y = b – a.x 1
2 0 1 2 3 4 5 6
0
Time
0 5 10 15 20
TIME (hours)

4
 lnCt = lnC0 – Kel.t
logCt = logC0 - Kel . t
2.303
lnCt = lnCo – Kel.t
Ln = 2.3 log

Bila Ct = ½ Co,
 Kel.t = 0.693.
t1/2 = 0.693/Kel

t ½ : the time for the plasma concentration to reach

half the original, i.e., the half-life of elimination.
Useful in estimating:
- time to reach steady state concentration.
- time for plasma concentration to fall after dosing is stopped.

HALF LIFE AND PERCENT OF Half life and onset of action using
maintenance dose and no loading dose
DRUG REMOVED
Number of Percent of Drug Percent of Drug Number of Percent of final
Half-lives Remaining Removed Half-times steady state concentration
0 100 0 0 0
1 50 50 1 50
2 25 75 2 75
3 12.5 87.5
4 6.25 93.75
3 87.5
5 3.125 96.875 4 93.75
5 96.875

5
 Single dose – 120

Loading dose Half-time to Css

7 100

6
Plasma Concentration

Therapeutic 80

5 level

% Css
60
4 A
40 B
3
20
2 Repeated doses –
1 Maintenance dose 0
0 12 24 36 48 60 72
0 time (hr)

0 5 10 15 20 25 30 t1/2 elim Ke Css Vd dose

A 12 hr 0.0577/hr 10 mg/L 50 L 28.8 mg/hr
Time B 24 hr 0.0288/hr 10 mg/L 50 L 14.4 mg/hr

VOLUME OF DISTRIBUTION
Extracellular
Vascular Extravascular Intracellular

3L 9L 28 L

4% BW 13% BW 41% BW

Components of Total Body Water

6
 Apparent volume of distribution (Vd) Plasma Extracellular water

amount of drug in body

Vd 
plasma drug concentrat ion
Vd = Dose/C0
VOLUME OF DISTRIBUTION FOR SOME DRUGS

DRUG Vd (L)
cocaine 140
clonazepam 210 Plasma protein Tissue protein
amitriptyline 1050 drug
amiodarone ~5000

- Obat terikat kuat dgn protein
- Vd kecil
Misalnya,. Aspirin  warfarin
Experimental Drug A: 90% bound
10% free  11% free
Free drug concentration  10%
Experimental Drug B: 99% bound
1% free  2% free
Free drug concentration  100%
Clearance
Volume darah yang dibersihkan dari
obat dari organ tertentu per satuan
waktu.
Clearance merupakan konsep yang
lebih fisiologik dari t 1/2 atau kel,
karena berdasarkan blood flow rate
Clearance bervariasi dengan berat
tubuh dan protein binding

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 Blood Flow to organs Organ Clearance
Lung

Adipose Carterial Cvenous

Bone Q Organ of elimination
plasma flow
Brain
Venous Blood

Arterial Blood

Heart
Rate of elimination = Q(Carterial – Cvenous) (mass/time)
Kidney

Muscle “E” = Single pass extraction fraction:

E = Elim. flux/ input flux = (Carterial – Cvenous)/Carterial
Skin

Liver
Spleen
Clearance  Elim. flux/C (vol/time)
Portal
Vein
Gut

IV PO
Clearance = EQ
29

Rate of elimination = Kel x Amount in body

Rate of elimination = CL x Plasma Concentration
Elimination Rate
Therefore, CL =
Concentration
Kel x Amount = CL x Concentration

Kel = CL/Vd •Renal

•Hepatic
0.693/t1/2 = CL/Vd •Lung

t1/2 = 0.693 x Vd/CL

Total Body Clearance = CLliver + CLkidney + CLlungs + CLx

8
 Clearance BLOOD OUT

Rate of elimination = kel D CA CV

 C = D/Vd I
D = C Vd N
CLT = kel Vd
Blood Flow = Q
 Rate of elimination = kel C Vd
Total rate of elimination = CLT C ELIMINATED
Rate of Elimination = QCA – QCV = Q(CA-CV)

•
Liver Clearance (Cl h) = Q(CA-CV)/CA = Q x EF

1. Mass Balance 2. Mass Balance Normalized to Rate of Entry

Q x CA Q x CV 1 1-E

Q(CA - CV) E
Rate of Extraction Extraction Ratio

9
 Recall that CL = QE; hence
3. Mass Balance Normalized to CA
CLH =
Q Q(1 – E) QHE clearance
CLH = hepatic
QH = hepatic blood flow
E = hepatic extraction ratio
QxE QH - from 1.0 to 1.5 L/min
Clearance
E – ranges from 0 to 1

HEPATIC EXTRACTION RATIO OF Hepatic Clearance

REPRESENTATIVE DRUGS Clearance  Elim. flux/C
Eliminasi dari Unbound Cu (free fraction)
Low (<0.3) High (>0.7) (metabolism, transport)  Cu = fuC
Antipyrine Lidocaine (fu biasanya tidak diukur secara rutin)
Diazepam Meperidine Hepatic Clearance = EQ
Phenylbutazone Propoxyphene high E (E>0.7), CL sensitive thd Q, bukan fu
Theophylline Propranolol
(Heart failure, cirrhotic)
Tolbutamide Verapamil
Warfarin low E (E<0.3) Q   transit time  E –
CL sensitive thd fu (CYP induction atau
Intermediate: Quinidine inhibition)

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 Renal clearance Renal Clearance (CLR)
C x Cl r = U x V Net Elim. flux = filtration + secretion – reabsorb.
C = plasma concentration,
Net CLR = (urine exc. rate)/(mid-collection C)
Cl r = renal clearance, (or use 24 hour urine collection and C(t) )
U = urinary concentration,
Renal Filtration flux = GFR fuC
V = urinary volume GFR  CLcreat= 120 ml plasma water/minute
CLR << GFR fu  significant reabsorption
Cl r = U x V/ C CLR >> GFR fu  significant secretion

Total Clearance (CLT or just CL)

CL = CLR + CLH + nonrenal/nonhepatic clearance

Harga CL dari dosis tunggal :

i.v. Dose: CL = Dose/ ∫ C(t)dt0 = Dose/AUC

Oral Dose: CL = FOral Dose/AUC

F = fraksi dose mencapai “central pool”
(plasma + jaringan dlm keseimbangan cepat dgn plasma)

CLoral  CL/F = Oral Dose/AUC

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 Pharmacokinetic equations

Distribution and Elimination

10000 Vd = dose/Co
Plasma Concentration

1000
C0
Elimination only Ke = 0.693/t 1/2
100 T 1/2 = 0.693/Ke
10
Cl = Vd x Ke
1
Distribution equilibrium Loading dose = Css x Vd
0 1 2 3 4 5 6
Maintenance dose = Css x Vd X Ke
Time

Pemberian infus kecepatan tetap (i.v.)

 Pada pemberian dosis ganda  kdr dalam
drh meningkat dengan cepat pada saat
pertama  kdr dlm darah naik dgn cepat 
lambat dan mencapai plateau
( kadar tunak),dimana :
rate of administration = rate of elimination .
steady state dicapai
 Pada steady state:
Dose (Rate of Administration) = clearance x
plasma conc.

12
 Intravenous infusion The time to reach steady
state is ~4 t1/2’s
Pada keadaan steady state (tunak)
rate of infusion = rate of elimination
= Css.Clearance
Concentration due to
repeated doses
Css (plateau)

Cp Concentration due to a single dose

C = Css(1- e-kt)
Time to 90 % of Css = 4 t1/2

time

Fase ini ditentukan oleh Tingginya kadar tunak (plateau)

rate of elimination Ditentukan oleh rate of infusion
Half life hours steady state

Lignocaine 2 8 hours
2X mg min-1
Valproate 6 24 hours

Digoxin 32 6 days Cp X mg min-1

Digitoxin 161 28 days

time

13
 Dosing interval
Css max Css av

MTL Css min

Cp

time

Multiple dosing
Dosing rate =Rate of elimination
Pada Steady State
(pada intermittent doses) amount administered = amount eliminated between doses

CSS max: maximum concentration of

steady state（ Peak C） Cavss

Css min: minimum concentration of steady Cp

state Fase pada kurva ini ditentukan
oleh rate of elimination

Peak Time: It is a time achieving the CSS

max
time

14
 Loading dose(s) Cavss = F . Dose
Clearance. T
Loading dose = Cmax x Volume of distribution

T = dosing interval

Cavss
Cp

time Menurunkan dosis dan menurunkan interval

Cavss tetap, tetapi fluktuasi Cp berkurang
Tetracycline t1/2 = 8 hours
500mg loading dose diikuti oleh 250mg setiap 8 hours

Hubungan antara dosing rate dan

konsentrasi drug pada steady state Continuous repeating administration in
Ass: amount of drug in the body intravenous injection
Css: concentration in steady state Administration dose: D
R: dosing rate Dosing interval: τ
Dosing interval: τ In steady state:
Pada steady state: dosing rate=rate of elimination
dosing rate = rate of elimination R=Ass·k
R = A ss x k Ass=Css·Vd
A ss=C ss xVd R=D/τ = Css·Vd·k = Css·Vd·0.693/t1/2
R = D/τ = Css x Vd x k = Css x Vd x 0.693/t ½ Css=1.44·t1/2D/(Vd·τ )
C ss=1.44 x t1/2 x D/(Vd xτ ) Ass=1.44·t1/2D/τ
A ss=1.44 x t1/2D/τ

15
 Css=1.44·t1/2D/(Vd·τ ) Css=1.44·t1/2D/(Vd·τ )
Merubah interval dosis 0.5t1/2, Merubah dosis 2D, D, 0.5D; t1/2 tidak
t1/2,2t1/2, ;Dosis tetap, Css tetap, berubah, Css berubah , Tss tidak
Tss berubah berubah

Loading dose
Diberikan pertama kali untuk mencapai Css
dengan cepat

Loading dose = Jumlah obat didalam tubuh

yang mencapai Css setelah diberikan
loading dose

Loading dose : dosis awal yang menaikkan

kadar obat dalam darah untuk mencapai
konsentrasi sasaran

Umumnya diberikan sebesar 2 x dosis

maintenance dan interval = t ½

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 Therapeutic Drug Monitoring For which specific drugs is drug concentration monitoring helpful?

The important drugs are:

• aminoglycoside antibiotics (plasma or serum)
• ciclosporin (whole blood)
• digoxin and digitoxin (plasma or serum)
• lithium (serum)
Drug plasma concentration monitoring is helpful for drugs • phenytoin (plasma or serum)
• theophylline (plasma or serum)
•that have a low therapeutic index • paracetamol and salicylate (overdose) (plasma or serum).

•that are not metabolized to active metabolites

•whose concentration is not predictable from the dose Other drugs are sometimes measured:
• anticonvulsants other than phenytoin (eg carbamazepine, valproate)
•whose concentration relates well to either the therapeutic effect • tricyclic antidepressants (especially nortriptyline)
or the toxic effect, and preferably both • anti-arrhythmic drugs (eg amiodarone).

•that are often taken in overdose

The uses of monitoring are

• to assess adherence to therapy

• to individualize therapy

• to diagnose toxicity

• to guide withdrawal of therapy

• to determine whether a patient is already taking a drug before starting therapy

(eg theophylline in an unconscious patient with asthma)

• in research (eg to monitor for drug interactions in post-marketing surveillance

using population pharmacokinetics).

17