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Calculation

This document discusses pharmacokinetic concepts including: - Pharmacokinetics involves quantitatively studying drug absorption, distribution, metabolism, and excretion over time. - Differential and integral calculus are used to model drug movement and response in the body over time. - Pharmacokinetic data and graphs help visualize the relationship between drug concentration and time in the body. - Parameters like clearance, volume of distribution, half-life, and rate constants can be calculated from plasma concentration-time data and used to adjust drug dosing.

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hablet1
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434 views

Calculation

This document discusses pharmacokinetic concepts including: - Pharmacokinetics involves quantitatively studying drug absorption, distribution, metabolism, and excretion over time. - Differential and integral calculus are used to model drug movement and response in the body over time. - Pharmacokinetic data and graphs help visualize the relationship between drug concentration and time in the body. - Parameters like clearance, volume of distribution, half-life, and rate constants can be calculated from plasma concentration-time data and used to adjust drug dosing.

Uploaded by

hablet1
Copyright
© Attribution Non-Commercial (BY-NC)
Available Formats
Download as PPT, PDF, TXT or read online on Scribd
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Pharmacokinetics –

Basics Calculus

Habibur rahman
PSG College of pharmacy, coimbatore-641004
Pharmacokinetics
• The quantitative study and characterization
of the time course of drug absorption,
distribution, metabolism, and excretion.
• Pharmacokinetic data are mathematical
representations (simplifications) of complex
physiological processes.
• Pharmacokinetic data establish the time
course of the drug in the body and are
most useful when related to drug effects
(pharmacodynamics)
Calculus
• Calculus – analyzing drug movement quantitatively
– Differential equations are used to relate the concentration of
drugs in various body organs over time
– Integrated equations are frequently used to model the
cumulative therapeutic or toxic responses of drugs in the body
• Differential calculus
– Involves finding the rate at which a variable quantity is
changing
• Example – rate of drug diffusing away from the surface of
solid (Noyes Whitney's equation (dissolution rate = dx/dt =
DA/L (c1-c2)
Calculus
• In pharmacokinetics – amount of drug in body is a
variable quantity (dependent variable) & Time is
independent variable
– Thus, amount of drug to vary with respect to time
• Integral calculus
– Reverse of differentiation and is considered as the
summation of = f(x) . Dx
– A definite integral of a mathematical function is
the sum of the individual areas under the graph of
that function
• Graphs
– Visualizing the relationship between variables
• Independent variable (time) are placed on
the horizontal line
• Dependent variable are placed on the
vertical line in the plane

• Types of graphs in pharmacokinetics


– Cartesian or rectangular coordinate graph paper
– Semi-log graph paper
Curve Fitting
– Relationship between variables x & y

– Dose of drug Vs pharmacological effect

– Relationship not confined to isolated points but in a continuous function


of x & y

– Hypothesis is made concerning the relationship between variables

– Empirical equation must satisfactorily fit the experimental or observed


data

– Physiological variables are not always linearly related

– However, the data may be arranged or transformed to express the


relationship between the variables as a straight line
• Y = mx + b; m = slope; b = y intercept
Determination of slope
Slope of straight line on a rectangular coordinate graph
– Any two points ∆y / ∆x slope (m) = y2 – y1 / x2-x1
Slope of straight line on a semi log graph
– Y values are plotter on a log scale without performing actual log
concentration
– X values plotted on a linear scale
K = 2.3 . Slope
Regression line – straight line characterize the relationship between two
variables
Least square method
• Law of parsimony in curve fitting
– Keep it simple
Units in pharmacokinetics
• Any equation to be valid, the units or
dimensions must be equal on both
sides
CLT = k VD mL / hr = 1/hr .
mL
Units in Pharmacokinetics
Parameters Symbol Unit Example
Rate dD/dt Mass/time Mg/hr
Zero order rate K0 Conc/time µg/ml hr
constant
First order rate K 1/time 1/hr or hr-1
constant
drug dose D0 Mass Mg
Concentration C Mass/volume µg/ml
Plasma drug Cp Drug/volume µg/ml
concentration
Volume V Volume mL or L
Area Under Curve AUC Conc. Time µg hr/mL
Fraction of drug F No units 0-1
absorbed
Clearance Cl Volume/time mL/hr
Half – life T1/2 Time hr
Measurement and use of significant figures
• Every measurement is performed within a certain degree of
accuracy which is limited by the instrument used for
measurements
• Mass of drug can be measured as 1 mg but not the weight
of the freight

Significant figures

If balance measures mass of drug in mg digits representing


less than mg is inaccurate

Statistics

Degree of errors – determinate (constant)


- indeterminate (accidental, instrumental)
Rates and Orders of reaction
• Zero order reaction
– dA / dt = -k0 k0 zero order rate constant
Integrate
A = -k0t + A0 ; A = A0 e-kt
A0 is the amount of drug at t=0
Zero order - Half Life
A
t ½ = 0.5
A0
A0 / K0
Intercept

- Not constant
Slope = -k
0

- little practical value


Time
Order of reaction
First order reaction
dA / dt = -kA k First order rate constant
Integrate
ln A = -kt + ln A0 ; log A = - kt / 2.3 + log A0;
C = C0 e –kt

Straight line is obtained when the log concentration


versus time is plotted in the graph
Drug conc

First order - Half Life

Log conc
Slope = -K / 2.3
t ½ = 0.693 / Ke

Time Time
Revision of pharmacokinetic terms

Plasma
Concn
(Cp) zero
1st

time
1st order elimination
rate of elimination depends on plasma concentration
C = C0e-kt (k= rate constant of elimination)

Half life (t1/2 ) Half life (t1/2 )


time for plasma concentration to fall by 50%

Zero order elimination (pseudo zero order)


rate of elimination is constant and independent of
plasma concentration
One Compartment Open
Model
• IV Bolus
• Offers the simplest way to describe
the process of drug distribution and
elimination in the body
• The App. Vd is a parameter of this
model because it governs the plasma
concentration of the drug after a
given dose
Elimination rate constant
• First order process
K = Km + ke
k = elimination rate constant
Km = metabolism 100 DB 0
Ke = Excretion
dDB / dt = -kDB Slope = -k/2.3DB0
Integrate log DB = -kt / 2.3 + log DB0

D
B = drug in body at time t
Time
D 0
B =drug in body at time t = 0

D = DB0 e-kt
Volume of distribution
• Vd = dose / Cp0 =D 0
B / Cp0

• Vd from dose, elimination rate constant and AUC


dDB / dt = -kDB0 DB = VD Cp
dDB / dt = -kVD Cp
Rearrange
dDB = -kVD Cp dt
As both k and VD are constant ; integrate
∞
∫o dDB = - kVD ∞∫o Cp dt
Continue…….
Volume of distribution
The integral ∞∫o Cp dt represents the AUC0∞

D0= k vDAUC0∞

VD = D0 / k [AUC]∞0
Model Independent method

Trapezoidal rule
Clearance (CL) & VD
Substitute k with CL/V
The clearance concept may also be applied a
biologic system in physiologic modeling
without the need of a theoretical compartment

Cp = Cp0e-kt

Cp
= D0/ Vd e –(cl/vd)t
Calculation of K from urinary
excretion data
• Excretion of the drug is assumed to be
first order
• The term Ke is the renal excretion rate
constant rate constant & Du is the
amount of drug excreted in the urine
dDu / dt = keDB
substitute DB0 e-kt=D B

dDu/dt = Ke DB0 e-kt log on both sides


Calculation of K from urinary
excretion data
Log dDu/dt = - kt / 2.3 + log Ke DB0

K-ke = Knr nr = non renal

Knr ~ Km 100 Ke DB0


Log dDu / dt
Slope = -k/2.3

Time
Continued………
Dose Adjustment

clinical example with kanamycin,


showing theoretical curve after
multiple dose and a better curve after
dose adjustment. Kanamycin is a
useful drug but it can cause some
serious side effects. By controlling the
blood concentration of this drug it is
possible to use it effectively. In the
case of patients with impaired renal,
or kidney, function it is possible to
determine the kidney function ahead
of time and adjust the kanamycin
dosing schedule accordingly.
First-order kinetics
To illustrate first order kinetics we might consider what would
happen if we were to give a drug by iv bolus injection, collect
blood samples at various times and measure the plasma
concentrations of the drug. We might see a steady decrease
in concentration as the drug is eliminated

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