The therapeutic paradigm

Drug Body Target Effect

Pharmacokinetics Pharmacodynamics
PHARMACOKINETICS
kinetics behavior of a drug in the human body
"What the body does to the drug"

Pharmacokinetics
Route of
administration

Blood/Plasma
Route of
elimination

Tissues
Absorption
Distribution
what is the concentration of a drug at the biophase?
Metabolism
Excretion
Quantitative temporal analysis of the processes of absorption, distribution,
metabolism and elimination of a chemical in the body
Routes of administration

Paths by which a drug, fluid, poison or other substance is brought into contact with the
body.

Enteral: Drug is placed directly into the gastro-intestinal tract .

Oral (30-90; self administered vs. sometimes inefficient; first pass)
Sublingual (3-5 ; drug stability; avoid first pass vs. small doses; taste)
Rectal (5-30; by-pass liver; not well accepted)

Parenteral: Drug is injected via a hollow needle into the body. Recommended for high
molecular weight drugs.

intravenous (iv) (30-60; precise and accurate vs. risk of embolism; oops effect)
intramuscular (im) (10-20; reservoir vs. pain at injections in certain regions)
subcutaneous (sc) (15-30; slow and constant absorption vs. circulation)

Other

inhalation (2-3; gaseous and volatile agents vs. particles <0.5 m are rejected)
topical (min-hr; no first-pass metabolism)
dermal (local)
transdermal (systemic)
Time evolution of a drug in the bloodstream
Plasma drug concentrations are affected by the rate at which drug is administered, the
volume in which it distributes, and its clearance, which determine their half-life
Absorption

Process by which a drug enters the bloodstream from the administration site without being
chemicaly altered.

Physicochemical properties of the drug
size and shape
solubility at the site of absorption
degree of ionization
relative lipid solubility

Physiological factors
Transport accross cell membranes
Blood circulation at the site of absorption
Plasma protein binding


Have an influence on:
Form of administration
Dosage form
Concentration of the drug

Mechanisms of drug transport across cell membranes
Passive transport. No energy expense. Flux due to a potential gradient
Rate: dependent on potential gradient and lipophilicity of the drug
Direct, like diffusion, osmosis or filtration.
Carrier-mediated facilitated diffusion
Active transport. Require energy, provided by ATP. Flux against potential gradient
Maximum transport and saturation
Subject to inhibition
Structure specific
Cell type specific
Endocytosis. Require energy provided by ATP
Receptor-mediated endocytosis
Phagocytosis
Bulk-phase endocytosis
Diffusion
Rate is dependent on:
Chemical potential
lipophilicity of the drug





Carrier-mediated facilitated diffusion
([AT] is the concentration of [A] to get into the cell membrane. One inside moves by diffusion )
L
A
D
dx
A d
D J
o
] [ ] [
= =
L
[A]
s
[A]
o

T
K A
T A
AT AT T T
AT
T A
K
AT T A
o
o
+
= + =
=
+
] [
] ][ [
] [ ] [ ] [ ] [
] [
] ][ [
L
A
DK J
A
A
K
s
D
s
o
D
] [
] [
] [
= =
K A
A
J
K A
A T
DK
L
A
DK J
o
D
s
D
+
=
+
= =
] [
] [
] [
] [ ] [ ] [
max
Plasma protein binding

Drugs bind to plasma proteins, as a consequence an equilibrium is created between
bound and unbound drug.

Plasma protein+ drug Plasma proteindrug

Unbound fraction can traverse cell membranes or diffuse, producing the therapeutic effect.
It is also is metabolized and/or excreted from the body. (drug halfs life.)

The bound fraction will be released in order to maintain equilibrium, acting as a reservoir
from which the drug is slowly released as the unbound form.

Common blood proteins that drugs bind to are:
Human serum albumin: 67 kDa; 50-70 M
Lipoprotein: 200-2400 kDa; ~ M
Glycoprotein, , : 42 kDa; ~20 M
o,|, globulin: 59 kDa,13,5 kDa; ~ M

Concentrations are affected by the health of individuals
Bound and total concentrations
B
max
: maximal concentration of binding sites
proportional to plasma protein concentration
K
D
: free drug concentration corresponding to half maximal
binding
inversely proportional to drug affinity for the protein
[D]
bound

[D]
free

B
max

K
D

B
max
/2

f = =
free concentration
total concentration
[D]
free

[D]
tot

Free fraction of unbound drug
] [
] [
] [
max
D K
D B
D
D free
free
bound
+

=

Causes for drug depletion
First pass metabolism (iv drugs have 100% bioavailability)
Solubility -hydrophilic implies poor diffusion; Hydrophobic
implies insoluble in aqueous media
Chemical stability -penicillin and acid pH
Drug formulation -salt form, particle size, "excipients" all
affect rate of dissolution

Bioequivalence -relative bioavailability of two drugs
Bioavailability
Is the percentage (fraction) of administered drug that
reaches systemic circulation.

Ratio of oral (or other route) AUC to intravenous AUC
(AUC: area under the plasma concentration versus time
curve)


iv
po
AUC
AUC
f =
Process by which drug leaves circulation and enters in tissues., organs and fluids.
After distribution, plasma levels correlate with the concentration in the rest of the tissues.

Most capillaries are leaky and do not impede diffusion of drugs

Blood-brain barrier formed by high level of tight junctions between cells makes
impermeable to most water-soluble drugs

Distribution of Drugs
Plasma
Drug
Capillarry
endothelium
Extracellular Fluid
Cellular
Membrane
Intracellular
Fluid
Free drug
Free drug
Bound non-
Active sites
Bound to
receptor
Bound non-
Active sites
Total body weight
Water
60%
Intracellular fluid
35%
Plasma 4%
Intersticial fluid
21%
Intersticial
Fluid

Blood flow rates vary widely as function of tissue structure/function and consquently
drugs reach tissues at a rate proportional to their blood flow


Organ/Tissue Resting Blood Flow ml/min/100 g
(ml/min)

Liver 1350 (27%) 95
Muscle 750 (15%) 4
Kidney 1100 (22%) 360
Heart 200 (4%) 70
Skin 300 (6%) 3
Brain 700 (14%) 50
Bronchi 100 (2%) 25
Other 500 (10%)


Distribution of Drugs
Apparent Volume of Distribution


Hypothetical volume into which the drug is dissolved or distributed. Limited physical
interpretation but useful concept to understand water compartments
p
d
c
D
V =
D= Amount of drug in the body

c
p
= concentration in plasma
Total volume of 70 kg man total body
water is 42 L

If a drug has a V
d
~ 1518 L we might
assume that its distribution is limited to
extracellular fluid

If a drug has a V
d
~ 40 L, the drug may be
distributing into all body water

If V
d
>>4050 L, the drug probably is being
concentrated in tissue outside the
extracellular fluid
Clearance

Clearance is the volume of plasma removed of a drug in the vascular compartment cleared of
drug per unit time by the processes of metabolism and excretion (drug loss from the body)


Clearance from different tissues is additive

Parameter is independent of the mechanism of removal (i.e.,
excretion,equilibrium binding in tissue, metabolism, etc.)
Expressed in volumen/time

Example: Cl = 100 ml/min means that the
chemical is completely removed from 100
ml of blood every minute.
Basic Kinetics

Basic rate law for a reaction in which molecule A is converted to molecule B




Zero-order kinetics: n = 0





Rate of the reaction is independent of substrate concentration
Rate constant k has units of concentration per unit time





Concentration versus time plot is linear
[A]
o

t
[A]
n
A k
dt
A d
] [
] [
=
e o e
k A k
dt
A d
= = ] [
] [
t k A A dt k A d
e o e
= = ] [ ] [ ] [
First order kinetics
t k
o
e
e
e A A
A k
dt
A d

=
=
] [ ] [
] [
] [
ln(Concentration) versus time plot is linear




Half-life -time to decrease concentration by one-half
Rate of the reaction is dependent on substrate concentration
Rate constant k has units of reciprocal time
ln[A]
t
ln[A]
o
[A]
t
e
e
o
k
t t k
A
A 2 ln
2 ln
2
1
ln
] [
] [
ln
2
1
2
1
= = = =
|
|
.
|

\
|

Elimination reactions mediated by transport proteins and metabolic enzymes are typically
saturable and can be described in terms of the maximum rate of elimination (V
max
) and
the concentration producing 50% of V
max
(K
m
).




If concentrations are large in relation to Km then the elimination rate will appear to be
independent of concentration and this is called a zero-order reaction.





If concentration is small in relation to Km then the elimination rate will appear to be first-
order i.e. linearly dependent only on concentration.





Concentrations that are neither small nor large in relation to Km will give rise to a mixed-
order reaction. The mixed-order reaction should be considered as the general case for all
drugs eliminated by metabolism.
] [
] [
A K
A v
v
m
m
+
=
m m
m
m
v v A K
A K
A v
v = <<
+
= ] [ ;
] [
] [
] [ ] [ ;
] [
] [
A
K
v
v A K
A K
A v
v
m
m
m
m
m
= >>
+
=
Clearance
d e
V k Cl =
Where k
el
is the elimination constant from blood or tissue
Elimination rates can be thought as a chemical kinetics problem
Cl
V
t
d
) ( 2 ln
2
1
=
An alternative form to calculate the clearence is through the AUC
AUC
D
Cl
Cl
V
V
D
dt e
V
D
dt e c AUC
d
d
t
V
Cl
d
t k
p
d e
= = = =

} }
0 0
Half life
How to administer a drug

How frequently should a drug be administered to maintain plasma concentration in the
therapeutic range and below the toxic range

In order to maintain the therapeutic levels in plasma it is necessary to administer the drug
either continuously or in several administrations.

Continuous administration

Steady-state concentration of drug in blood (Css), is the concentration achieved when the dose
rate of a drug (k
o
) balances the rate of elimination from plasma.


Cl
k f
V k
k f
c e
V k
k f
c
e
k
k f
D D k k f
dt
dD
o
d e
o
ss
t k
d e
o
p
t k
e
o
e o
e
e

= =

) 1 (
) 1 (
c
p
t
c
ss

Need to determine how frequently to give a drug so that we maintain blood concentration in the
therapeutic range and below the toxic range






t

=
Cl
D f
c
ss
f=fractional bioavailability
Cl=clearance
t=Dosage interval in min
Multiple doses administration
Represents the balance between dose rate, rate of absorption from gut and rate of elimination
blood

Reach a state in which drug concentration fluctuates within a narrow window (akin to chemical
kinetics with formation balancing degradation)
C
p
t
C
p.min
C
p.max
t
t
t
t
t
t
t
t
t
t
t
t t t t t t
t t
t t
e
e
e
e
e
e
pn
e
e
e
e
e e e e e
p
e e
e
p
k
k
nk
d
k
k
nk
o
p
k
nk
d
k
nk
o
p
o
pn
k k o
p
k k o
p
k o
p
k o
p
k o
p
o
p
o
p
k o
p
e
e
e
V
D
e
e
e
c c
e
e
V
D
e
e
c c
e e c e e c e c c
e c e c c c
e c c

|
|
.
|

\
|

=
|
|
.
|

\
|

=
|
|
.
|

\
|

=
|
|
.
|

\
|

=
+ = + = =
+ = + =
=
1
1
1
1
1
1
1
1
...
) ( ) 1 (
) 1 (
1
1
2
1 1 2
1 1 1 2
1
2
1
Multiple doses administration
|
|
.
|

\
|

= =
|
.
|

\
|

= =

t
t
t
t
e
e
e
k
k
d
p p
k
d
p
o
p
e
e
V
D
c c
e V
D
c c
1
1
1
min
max
Achieve C
ss
at ~5 half-lives
LD=loading dose
MD=maintenance dose
|
.
|

\
|

=
t
e
k
e
MD LD
1
1

The clearance of cephprololopam is 0.2 liters/min
The volume of distribution of cephprololopam is 20 liters
The therapeutic concentration is 2 g/ml.

1. What is it the half-life of cephprololopam. 69min

2. What is the initial dose of cephprololopam? 40mg

3. How much drug should I give to the patient to maintain a cephprololopam concentration of 2
g/ml? 0.4 mg /min

4. We want to put the patient on an oral form of cephprololopam, which he/she will take every 24
hr. How much should I give him/her, assuming the drug is completely absorbed, and I want his/her
concentrations, on average, to be at the target?

576 mg/day

5. How long will it take the patient to reach steady-state dosing with these repeated oral doses?

5 half-lives = 345 min, i.e., the patient will be at steady state dosing within the time course of the
first dose!