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Pak Endang - Rational Use of Drugs Part V - How Do I Design and Adjust A - 1
Pak Endang - Rational Use of Drugs Part V - How Do I Design and Adjust A - 1
Pak Endang - Rational Use of Drugs Part V - How Do I Design and Adjust A - 1
ADJUST A DOSAGE
REGIMEN?
WHAT IS THE BEST WAY TO GAIN AN
UNDERSTANDING OF HOW TO
DESIGN AND ADJUST A
DOSAGE REGIMEN?
PHARMACOKINETICS
WHAT IS PHARMACOKINETICS?
PHARMACOKINETICS is the study of the kinetics of
drug absorption and disposition.
ABSORPTION DISPOSITION
ELIMINATION DISTRIBUTION
EXCRETION METABOLISM
WHY BE CONCERNED ABOUT
PHARMACOKINETICS AND
DOSAGE REGIMENS?
Pharmacokinetics and Dosage Regimens Dete
rmine:
•How much drug is in the body at any given time
(Stir)
(Stir)
Calculate Volume
Calculate Volume
(This volume is called VD)
By DEFINITION: VD = A/[D]P
(where A is amount of drug in body and [D]P is concentration of drug in plasma)
CONCEPT OF VOLUME OF DISTRIBUTION OF DRUGS:
DEFINITION OF VD
By DEFINITION: VD = A/[D]P
Rearranging: A = VD x [D]P
VD x [D]P(target)
LD =
B
CONCEPT OF VOLUME OF DISTRIBUTION OF DRUGS:
INTRODUCTION TO VD
LD = (VD x [D]P(target))/B
Small VD vs Large VD
Restriction of Drug to
Limited Areas of Body Free Assess of Drug to
Many Areas of Body
CONCEPT OF VOLUME OF DISTRIBUTION OF DRUGS:
DETERMINANTS OF VD
Tissue Binding
[D]P A
VD =
[D]P
CONCEPT OF VOLUME OF DISTRIBUTION OF DRUGS:
DETERMINANTS OF VD
A
VD =
[D]P
[D]P
CONCEPT OF VOLUME OF DISTRIBUTION OF DRUGS:
DETERMINANTS OF VD
[D]P
A
VD =
[D]P
CONCEPT OF VOLUME OF DISTRIBUTION OF DRUGS:
OBTAINING VD
1. Give bolus
of drug.
Log [D]P
2. Measure plasma
levels over time.
3. Extrapolate to find
plasma level at time 0.
Time (hrs)
(Time)
Initial Restriction of
Drug to
Slow Equilibration of Drug to
Limited Areas of Body
Other Areas of Body
CONCEPT OF VOLUME OF DISTRIBUTION OF DRUGS:
OBTAINING VD
One
VD(initial) Two
Time (hrs)
Two-Compartment Behavior
Time (hrs)
Two-Compartment Behavior
VD(final) is difficult
to obtain for
Body
2-compartment
Slowly Equilibrating Tissues
behavior! Plasma
Time (hrs)
VD(final) = VD() = Amount in body at time t after distribution /[D]Ptime t after distribution
Because of elimination, amount in body at time t after distribution DoseIV
CONCEPT OF VOLUME OF DISTRIBUTION OF DRUGS:
OBTAINING VD
Two-Compartment Behavior
NOTE THAT:
1 2
(KEY EQUATION #1)
VD x [D]P(target) V? x [D]P(target)
LD = LD =
B B
[Lidocaine]P (g/ml)
[D]P(target)
Constant rate infusion without LD
[Lidocaine]P (g/ml)
[D]P(target)
Window suboptimal levels
Suboptimal levels
CONCEPT OF VOLUME OF DISTRIBUTION OF DRUGS:
EXAMPLE OF USING VD TO CALCULATE LD
By Definition:
Rate of Drug Elimination
Cl =
[D]P
Units of Cl:
Amount/Time Volume
=
Amount/Volume Time
CONCEPT OF DRUG CLEARANCE:
DEFINITION OF Cl
Example:
Rate of Drug Elimination = 10 mg/hr
[D]P = 4 mg/L
10 mg/hr
Cl = = 2.5 L/hr
4 mg/L
CONCEPT OF DRUG CLEARANCE:
INTRODUCTION TO Cl
Cl is usually constant over a wide range of [D]P
Cl
[D]P
This is a consequence of the fact that most
drugs are eliminated from body by
1st order kinetics (dA/dt = -k•A).
CONCEPT OF DRUG CLEARANCE:
INTRODUCTION TO Cl
Cl is a major determinant of [D]P at STEADY STATE ([D]PSS)
INPUT
STEADY
STATE
LEVEL
Toxic Threshold
[D]PSS
(Therapeutic Window)
[D]P (mg/L)
Therapeutic Threshold
Multiple Doses
Single Dose
Time (hrs)
[D]PSS = [D]P at steady state
CONCEPT OF DRUG CLEARANCE:
INTRODUCTION TO Cl
(Input = Output)
CONCEPT OF DRUG CLEARANCE:
INTRODUCTION TO Cl
By definition of Cl:
Rate of Drug Elimination
(Eq A) Cl =
[D]P
Rearranging Eq A:
(Eq B)
Rate of Drug Elimination
[D]P =
Cl
CONCEPT OF DRUG CLEARANCE:
INTRODUCTION TO Cl
Substituting Eq D into Eq C:
(Eq E)
SS
R0
[D]P =
Cl
CONCEPT OF DRUG CLEARANCE:
INTRODUCTION TO Cl
Additional definitions:
Substituting Eq F into Eq E:
SS B x MD
[D]P =
DI x Cl
SS B x MD
[D]P =
DI x Cl
CONCEPT OF DRUG CLEARANCE:
INTRODUCTION TO Cl
[D]P (mg/L)
Toxic
[D]PSS
Therapuetic
Time (hrs)
Constant rate infusion o 224 mg bolus 672 mg bolus e
f 672 mg per 24 hr every 8 hr very 24 hr
a) Therapeutic Response
b) Toxicity
Cl is important!!
CONCEPT OF DRUG CLEARANCE:
INTRODUCTION TO Cl
(Eq G)
[D]PSS x Cl
MD/DI =
B
Substituting Eq H into Eq G:
(Key Equation #3)
[D]P(target) x Cl
MD/DI =
B
CONCEPT OF DRUG CLEARANCE:
DETERMINANTS of Cl
Rate of Elimination/[D]P =
Cl Rate of Elimination/[D]P =
Cl = ClR + ClH
DUE TO:
Cl = ClR + ClH
REDUCED BY:
DUE TO:
REDUCED BY:
INCREASED BY:
Cl = Rate of Infusion/[D]PSS
Cl = Dose/AUC
(Don’t worry about derivation!)
CONCEPT OF DRUG CLEARANCE:
OBTAINING Cl
There are many ways to obtain Cl:
[D]P(target) x Cl
MD/DI =
B
DEFINITION
DEFINITION
DEFINITION
Elimination t1/2:
.
Time required for drug elimination processes to decrease
the amount of drug in the body by 50%.
• If calculated DImax is ~24 hrs, give all of daily dose once daily
• If calculated DImax is too short, give daily dose by constant
rate infusion over 24 hrs
• If DImax is some fraction of the day, give daily dose in divide doses
CONCEPT OF DRUG CLEARANCE:
EXAMPLE OF CALCULATING DOSAGE REGIMEN
By definition:
Rearranging Eq I:
(Eq J)
Rate of Drug Elimination (i.e., -dA/dt) = Cl x [D]P
Rearranging Eq K:
(Eq L) -dA/A = (Cl /VD) x dt
Taking definite integral of Eq L over appropriate limits:
1/2Ainitial t1/2
(Eq M)
-dA/A = (Cl /VD) x dt
Ainitial 0
CONCEPT OF ELIMINATION HALF-LIFE:
INTRODUCTION TO t1/2
1/2Ainitial t1/2
(Eq M)
-dA/A = (Cl /VD) x dt
Ainitial 0
t1/2 = 0.693 x VD
Cl
CONCEPT OF ELIMINATION HALF-LIFE:
DETERMINANTS OF t1/2
(KEY EQUATION # 5)
t1/2 = 0.693 x VD
Cl
t1/2 = 0.693 x VD
Cl
Time (hrs)
CONCEPT OF tSS :
INTRODUCTION TO tSS
Note that:
Note that:
BY GENERAL CONSENSUS
tSS = 4 x t1/2
CONCEPT OF tSS :
DETERMINANTS of tSS
Pharmacokinetic
Calculation of tSS for Digoxin:
Parameters for Digoxin:
tSS = 4 x t1/2
t1/2 = 39 hrs
tSS = 4 x 39 hrs = 156 hrs = 6.5 days!!
PK Values
Value of PK Parameter
Population values represent average Individual values represent the values in
values rather than the value YOUR patient, but they have to be
for YOUR patient. determined in YOUR patient.
Population versus Individual Values for PK Parameters
Yes No
Next
Do not give LD. Calculate LD.
slide
Does the drug exhibit 1- or
2- compartment behavior?
1 2
(Key Equation #1)
VD x [D]P(target) V? x [D]P(target)
LD = LD =
B B
[D] P(target) x Cl
= PSS x DI x Cl
MD/DI[D]
B
B
Step #3:
Determine DI.
DImax is determined by interplay between
therapeutic window (TW) and t1/2.
• If calculated DImax is ~24 hrs, give all of daily dose once daily
• If calculated DImax is too short, give daily dose by constant
rate infusion over 24 hrs
• If DImax is some fraction of the day, give daily dose in divide doses
Capacity-Limited Metabolism
(Also called “Zero Order Kinetics”)