PHARMACOKINETICS OF INTRAVENOUS INFUSION

IKA NURZIJAH

Purwokerto, November 15, 2017

 MULTIPLE DRUGS ADMINISTRATION

Most drugs used in the

treatment of diseases are
taken over a course of at least
several days and sometimes a
lifetime
● Intravenous infusions

● Multiple intravenous doses

● Skin patches
 INFUS INTRAVENA

● Infus intravenous adalah sediaan steril

berupa larutan atau emulsi, bebas pirogen
dan sedapat mungkin dibuat isotonis
terhadap darah, disuntikkan langsung ke
dalam vena dalam volume relatif banyak

● dosis obat tidak masuk sekaligus →

pemberian diatur
 THE PRINCIPLES OF INTRAVENOUS INFUSIONS

● Untuk mempertahankan kadar obat dalam

plasma tetap

● Pada infus tidak terjadi fluktuasi kadar

karena interval pemberiannya yang
frekuen Yaitu pemberian dalam dosis kecil
dengan interval waktu yang sering

● Karakteristik infus : 1 ml sebanding dengan

20 tetes infus
 THE ADVANTAGES OF INTRAVENOUS INFUSION

● Mudah diberikan untuk pasien yang kritis

● Laju infus dapat diatur sesuai kebutuhan

pasien

● Mencegah fluktuasi puncak(maksimum) dan

palung (minimum) kadar obat dalam darah
 THE DRAWBACKS OF INTRAVENOUS INFUSION

● Tidak bisa dilakukan “drug Recall ” sehingga

resiko toksisitas dan sensitivitas tinggi
● Kontaminasi mikroba melalui titik akses ke
sirkulasi
● Iritasi Vaskular
● Inkompatibilitas obat dan interaksi dari berbagai
obat tambahan
MODEL AND EQUATION
EQUATION (1)
 EXERCISE 1

A drug (S = 1, Cl = 2 L/h, and Vd =

50 L) is administered as an
intravenous infusion at a rate of 10
mg/h. Calculate the plasma
concentration 4 h into the infusion
EXERCISE 1
 STEADY STATE PLASMA CONCENTRATION

● EQUATION 1

● EQUATION 2
At steady state, the plasma concentration is constant. Thus, the rate of drug
administration must equal the rate of drug elimination
 EXERCISE 2

A drug (S = 1, Cl = 2 L/h, and Vd =

50 L) is administered as an
intravenous infusion at a rate of 10
mg/h. Calculate the steady state
plasma concentration !
EXERCISE 2
 EXERCISE 3

Suatu obat (S = 0.9, F=0.94, Cl=1.44 L/h, dan Vd=0.65 L/kg)

memiliki range terapi 10-20 mg/L. Obat tersebut
diformulasikan dalam bentuk sediaan infus intravena, yang
mampu menghantarkan obat dengan kecepatan konstan 12
mg/jam. Sediaan didesain untuk pemberian setiap 12 jam
dimana dosis sediaan yang tersedia adalah 250 mg, 300
mg, dan 400 mg. Tentukan pemilihan dosis sediaan obat
yang tepat untuk mencapai konsentrasi tunak 15 mg/L pada
wanita berbobot 60 kg
 EXERCISE 3

The unit dosage forms are designed to administer the dose at a constant rate over a 12-h
period. If a rate of 25.5 mg/h is required, the unit dose must contain 25.5 × 12 = 306 mg.
Thus, the 300-mg unit should be given twice daily
 FACTOR CONTROLLING STEADY STATE PLASMA
CONCENTRATION

● Cpss is directly proportional to the infusion rate (k0). If the infusion rate is
doubled, Cpss will double. For example, if a drug is administered at a rate of 5
mg/h and achieves a steady-state plasma concentration of 2 mg/L, doubling the
infusion rate to 10 mg/h would double the steady-state plasma concentration to 4
mg/L
● Cpss is directly proportional to the drug’s bioavailability (F).
● Cpss is inversely proportional to the drug’s clearance (Cl). For example, consider
a drug normally administered at a rate of 10 mg/h to achieve a desired steady-
state plasma concentration of 2 mg/L. The same rate of administration in an
elderly patient, who has a clearance of half the normal value, would result in a
steady-state plasma concentration twice the desired value—4 mg/L.
● Cpss is independent of the volume of distribution (Vd). The volume of distribution
is absent from the basic formula for the steady-state plasma concentration.
Variability in Vd will not influence the steady-state plasma concentration.
 FACTOR CONTROLLING STEADY STATE PLASMA
CONCENTRATION

● The equation can be used to estimate a rate of drug

administration to achieve a desired steady-state plasma
concentration and to estimate a steady-state plasma
concentration from a given rate of administration.

● The equation demonstrates that it may be necessary to

modify the usual rate of drug administration in patients who
have altered clearance or bioavailability.
 TIME TO STEADY STATE

● The time to get to steady state is determined by a drug’s half-life

● Clinically, it is usual to consider that it takes 3–5 half-lives to achieve steady state
● The half-life is a secondary pharmacokinetic parameter, determined by a drug’s
clearance and volume of distribution. Thus, changes in either of these primary
parameters will alter the time to steady state by virtue of their in uence on the
half-life. For example, increases in the volume of distribution and decreases in
clearance will increase the time it takes to get to steady state
 LOADING DOSE

If a drug has a long half-life and/or if it is necessary to achieve

therapeutic plasma concentrations immediately, a loading dose may
be given to achieve steady state immediately
e.g : Lidocain

The loss of drug from the bolus is exactly matched by the gain
of drug from the infusion
 PROVING THE CONCEPT

If the loading dose is administered simultaneously with the start of the infusion, the net drug in the
body at any time is the sum of that remaining from the bolus loading dose and that gained from the
infusion:
 EXERCISE 4

A drug (Cl = 6L/h,Vd = 150L, and S=1) is to be administered as

an intravenous infusion. A steady-state plasma concentration of
1.2 mg/L is desired. Calculate:

(a) A suitable infusion rate.

(b) The time it would take to achieve steady-state plasma
concentrations.
(c) The value of a loading dose that would immediately achieve
the desired steady-state plasma concentration of 1.2 mg/L.
EXERCISE 4
 TERMINATION OF INFUSION
At some time, the infusion will be stopped or terminated. At this time, there will be no ongoing inputs into
the body, and first-order elimination becomes the only process that affects the plasma concentration.
Thus, after termination, the plasma concentration will decay monoexponentially from its value at the time
of termination:

Where CpT is Cp when the infusion is terminated at time T, and t′ is the time elapsed since
Termination.
Termination After Steady State When the infusion is stopped after steady state has been achieved, the
plasma concentration at termination is Cpss, and after termination

Termination Before Steady State When the infusion is stopped before steady state has been achieved,
the basic equation for an infusion has to be used to calculate the plasma concentration at the time of
termination:

Where T is the time of termination. After termination, Cp will decay monoexponentially from this value:
 EXERCISE 5

A 70-kg patient is receiving an infusion of lidocaine

hydrochloride (S = 0.87) (1 mg/min) to achieve a desired
steady-state plasma concentration of 4 mg/L. His steady-state
plasma concentration is found to be 3 mg/L. Recommend a
new infusion rate using :

a. Proporsional changes in the rate of administration

b. Patient's clearance (if population average volume of
distribution is 0.88 L/kg)
 EXERCISE 5

Solution : using patient's clearance

 REFERENCES

Rosenbaum, S. E. (Ed.). (2016). Basic pharmacokinetics

and pharmacodynamics: An integrated textbook and
computer simulations. John Wiley & Sons.
 EXERCISE 6

● Suatu obat (S = 1) memiliki nilai parameter rata-rata populasi sebagai berikut : Cl

= 10.3 L/jam dan Vd = 75 L. Terapetik range sebesar 0.5 – 1.25 mg/L. Pasien
geriatrik akan ditreatmen menggunakan obat tersebut.
a. Hitung nilai kecepatan infus to mencapai Cpss 1 mg/L
b. Kapan waktu yang tepat untuk menghentikan infus agar dicapai Cpss sesuai
target
c. 48 jam setelah infus dengan kecepatan 10.3 mg/jam, diketahui konsentrasi
plasma obat pada pasien sebesar 1.5 mg/L. Apakah pada jam tersebut obat
telah mencapai steady state? Tetapkan regimen infus yang paling tepat (Ko)
agar Cpss 1 mg/L
● Vancomycin diberikan secara infus dengan kecepatan 500 mg/jam. Infus
dihentikan setelah 1 jam. Diketahui konsentrasi plasma obat yang diambil dua
jam setelah pemberian infus adalah 20 mg/L. Konsentrasi plasma kedua yang
diambil 10 jam setelah pemberian infus adalah 7 mg/L. Hitung nilai t1/2
vancomycin pada pasien tersebut?