First Order Reaction

Equation C = C0e-kt
Rate constant – units 1/hr
Biologic half-life t1/2 = 0.693/k
Effect of time on rate Rate is concentration-
dependent

Effect of time on rate Rate constant is

concentration
constant independent
 Zero Order Reaction
Equation C = -k0t + C0
Rate constant – units (mg/L)/hr
Biologic half-life t1/2 = 0.5C/k0
Rate is concentration-
Effect of time on rate independent (constant)
Effect of time on rate Rate constant is
constant concentration-dependent
 Straight line plot
• Zero order – concentration vs. time
• First order – log concentration vs. time
o Zero order – regular graphing paper
o First order – straight (SL or graph
during log/ln conc.)
 Zero order – curve SL ; straight CS
 First order – straight SL ; curve CS
 First Order Equation
Variable Meaning

C Drug concentration

C0 CIonnitcieanltdrrautigon

k ceolnimstiannattion rate
t time
 Rate vs. Order
• The rate of a chemical reaction or
pharmacokinetic process is the velocity with
which it occurs
• The order of a reaction is the way in which
the concentration of a drug in a chemical
reaction affects the rate
 Zero order reaction
• Drug conc. changes with respect to time at a
constant rate
dC/dt = -ko

C = -kot + Co

ko = zero-order rate constant

(conc./time)
 First order reaction
• Change in drug conc. with respect to time
equals the product rate constant and the
concentration of drug remaining
dC/dt = -kC
k = first-order rate constant
(reciprocal time)
C = Coe-kt
First order reaction Integration
C = Coe-kt
ln C = -kt + ln Co
log C = -kt/2.3 + log Co
 Zero-order First-order
reaction reaction

Effect of time on Constant with Will change with

rate respect to time respect to time as
concentration
changes

Effect of time on With respect to time Remains constant

rate constant changes as the with respect to time
concentration
changes
 Zero-order First-order
reaction reaction
Drug conc. vs. straight curved
time – plotted on
rectangular
coordinates

Drug conc. vs. curved straight

time plotted on
semilog graph
 Zero-order First-order
reaction reaction
Equation dC/dt = -ko dC/dt = -kC
C = -kot + Co C = Coe-kt

Half-life t ½ = 0.5C/k0 t ½ = 0.693/k

t 1/2 (not constant) (constant)
 Parameters
• Biologic half-life (t ½)
• Elimination rate constant (ke)
• Volume of distribution (Vd)
• Total body clearance (CL)
• Plasma concentration at 0 time (Co)
• Plasma concentration at a given time
interval (Cx)
 Biologic half-life (t1/2)
• Time required for the concentration of a
drug to decrease by one half
• Formula:
t ½ = 0.693/k

• Half-life is a constant and is related to the

first-order rate constant
• Unit: mins., sec., hrs.
 Elimination rate constant (k or kel)
• Drug elimination is a first-order kinetic
process
• Sum of the rate constants for removal of the
drug from the body, including the rate
constants for renal excretion and
metabolism (biotransformation)
 Elimination rate constant (k or kel)
• Not affected by the route of administration
• Affected by physiologic or pathologic
conditions of the patient (e.g. liver failure,
age)
 Elimination rate constant (k or kel)
• Formula:
kel = ke + km
ke = rate constant for renal excretion;

km = rate constant for metabolism

•Unit: reciprocal time (sec-1, mins-1,

hrs.-1)
 Apparent Volume of Distribution
(Vd)
• Hypothetical volume of body fluid in which
the drug is dissolved
• Not a true anatomic or physical volume
• Is needed to estimate the amount of drug in
the body relative to concentration of drug in
the plasma
 Apparent Volume of Distribution
(Vd)
• Formula:
Vd x Cp = Ab

Vd = apparent volume of distribution (L,

mL)
Cp = plasma drug concentration (mg/mL,
ug/mL)
Ab = amount of drug in the body (mg, g)
 Apparent Volume of Distribution
(Vd)
• Reflects the amount of drug in the tissues,
not in the plasma
• Inversely proportional in relation to the
drug plasma concentration

• Unit: volume (mL, L), % body weight

• Vd: 20% body weight (BW: 70 kg) = ??
 Apparent Volume of Distribution
(Vd)
• Influenced by:
1.binding affinity of a drug for blood or
tissue elements
2.blood flow (i.e., delivery of drug to the
tissues)
3. ability to cross biomembranes
4.physicochemical properties (lipophilicity,
extent of ionization, pH, pka) that determine
partitioning to tissues
 Apparent Volume of Distribution
(Vd)
• Influenced by:
5. Body weight of the patient
 Importance of Vd
• Directly proportional to the half-life à
prolongs the half-life à shorter duration of
action
• Used for the computation of the loading
dose of a drug
 Importance of Vd
• Determine or predict the distribution of
drugs (is it predominantly in the plasma or in
the body tissues?)
• Compare the distribution characteristics of
various drugs
 Importance of Vd
• A drug which is more bound to plasma
proteins than tissue proteins will Cp and
Vd
• A drug which has a high affinity for adipose
tissues than plasma proteins will Cp
and Vd
• Vd of a lipophilic drug is large in an obese
patient
Total body clearance (ClT, CL)
• Irreversible removal of drug from the body
by an organ of elimination
• Units are flow à volume per time (mL/min,
L/hr)
• Defined as the volume of blood irreversibly
cleared of drug per unit of time
• Influenced bypathologic conditions and
……of the patient
age
Total body clearance (ClT, CL)
• Product of blood flow to the organ (Q) and
extraction ratio (ER) of that organ

CL organ = Q x ER
• Extraction ratio – fraction of drug that is
irreversibly removed by an organ or tissue
as the plasma-containing drug perfuses that
tissue
Total body clearance (ClT, CL)
• Drug elimination rate divided by the plasma
concentration
ClT = rate of drug elimination
plasma concentration
= dDe/dt
Cp
dDe/dt = rate of drug elimination (mg/min, g/hr)
Cp = drug plasma conc. (mg/mL)
Total body clearance (ClT, CL)
• According to the concept of clearance, the
body contains an apparent volume
distribution in which a drug is dissolved
(Vd) and a constant portion of this is
cleared or removed from the body per unit
time (kel or ke)
ClT = ke x Vd
Total body clearance (ClT, CL)
• Since ke and Vd are constant, CLT is
constant
• Rate of drug elimination based on clearance
is not constant because it changes as
plasma concentration changes
rate of elimination = CLT x Cp
Total body clearance (ClT, CL)
ClT = FDo
AUC

F= absolute bioavailability
Do = amount of drug administered (mg, g)
AUC = area under the curve, rate and extent
of drug absorbed in the systemic circulation
(mg.hr/mL)
 Total body clearance (ClT, CL)
• Sum of all clearances of the
body CLT = CLR + CLNR
CLT = total body clearance
CLR = renal clearance
CLNR = non-renal clearance is often equated to
hepatic clearance (CLH)

• It is always assumed that the drug is

eliminated/cleared by first-order kinetics
Total body clearance (ClT, CL)
• In relation to biologic half-life
ClT = keVd
ClT = 0.693Vd
t1/2
t ½ = 0.693Vd
ClT
Total body clearance (ClT, CL)
• Influenced by:
– Body surface area/ body weight
– Cardiac output
– Drug-drug interactions (renal or hepatic)
– Extraction ratio/ blood flow
– Genetics
– Plasma protein binding - albumin
– Hepatic and renal function
Importance of Total body clearance
(ClT, CL)
• Computation of the maintenance dose
• Determine or predict the duration of action
of a drug à good or bad outcome
 Analyze

ClT = t 1/2 = Vd

Cp = Vd
 Which of the following are constant?
• Elimination rate constant (ke)
• Volume of distribution (Vd)
• Total body clearance (CL)
• Plasma concentration at 0 time (Co)
• Plasma concentration at a given time
interval (Cx)
 Which of the following are real data?
• Elimination rate constant (ke)
• Volume of distribution (Vd)
• Total body clearance (CL)
• Plasma concentration at 0 time (Co)
• Plasma concentration at a given time
interval (Cx)