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Chapter 3. Clinical Pharmacokinetics
Clinical pharmacokinetics, which involves the mathematical
description of the process of drug absorption, distribution,
metabolism, and elimination, is useful to predict the serum drug
concentration under various conditions.
A. Absorption of a drug is usually fast, as compared to the elimination; thus, it is
often ignored in kinetic calculations.
B. Elimination usually follows the principles of first order kinetics, which means
that a constant fraction of the drug is eliminated per unit of time.
C. Bioavailability (F) refers to the fraction of a drug administered that gains
access to the systemic circulation:
F=
concentration of drug in the systemic circulation after oral administration
concentration of drug in the systemic circulation after IV administration
Bioavailability is 100% following an intravenous injection (F=1), but drugs are
usually given orally and the proportion of the dose reaching the systemic
circulation varies with different drugs and also from patient to patient.
AUC oral
Bioavilability (F) =
AUC IV
Time (h)
Area under curve (AUC)
Example: Testing a compound (Newdrug) in clinical trials.
Newdrug is administered orally; plasma levels is determined;
only 75% of the oral dose reaches the circulation.  the
bioavailability of Newdrug is 0.75 or 75%.
Discover  some of the drug is inactivated by the acid in the
stomach.
Redesign the pill with a
coating  stable in acid but
dissolves in the more basic
pH of the small intestine.
The bioavailability  to 95%.
Newdrug becomes a bestselling product
The half-life of a drug (t 1/2 )  the time required for the serum drug
concentration to be reduced by 50%
Elimination rate constant (Ke ) = 0.69/ t 1/2
Ke is the fraction of drug present at any time that would be
eliminated in unit time (e.g. Ke = 0.02 min-1 means that 2% of the
drug present is eliminated in 1 min)
Apparent volume of distribution
Vd =
dose
C0
=
total drug dose (mg)
plasma concentration at equilibrium (mg/ml)
The Vd can be very large, even larger than the total body
volume, if a drug is highly bound to tissues. This makes
the serum drug concentration very low and the Vd very
large.
Volumes of body fluid compartments for a 70 kg man: total body (42
L), intracellular (28 L) + extracellular (14 L = plasma 4 L +
interstital 10 L).
[a value Vd of < 5 L  the drug is retained within the vascular
compartment. a value Vd of < 15 L  the drug is restricted to the
extracellular fluid, while (Vd > 15 L)  distribution throughout the
total body water or concentration in certain tissues.
4. The loading dose for a drug by IV injection = Vd x C
where C is the serum drug concentration
oral loading dose =
Vd x C
F
5. Clearance
the rate at which a drug is cleared from the body.
(Definition) the volume of plasma from which all drug is
removed in a given time.
(Cl) = Vd x Ke = Vd x 0.69/ t 1/2
a. Clearance is measured as a volume per unit of time (or
ml/min)
b. Rate of drug elimination (mg/min) = Cl x C
a l0-liter aquarium; contains 10,000 mg of crud.
concentration = 1 mg/ml. Clearance is 1 l/h. the
aquarium filter and pump clear I liter of water in
an hour.
a l0-liter aquarium; contains 10,000 mg of crud.
concentration = 1 mg/ml. Clearance is 1 l/h. the aquarium filter and pump
clear I liter of water in an hour.
At the end or the first hour, 1000 mg of crud has been removed
from the aquarium (1000 ml of 1 mg/ml). The aquarium thus has
9000 mg of crud remaining, for a concentration of
the end of the second hour,
mg/ml.At
mg of crud has been removed
(1000 ml of 0.9 mg/ml). The aquarium now has
crud remaining, for a concentration of
mg/ml
mg of
c. For drug treatment, a steady –state plasma
concentration (Css) is required within a known
therapeutic range.
A steady state will be achieved when the rate of drug
entering the systemic circulation (dosage rate) equals the
rate of elimination.
Thus, the dosing rate = Rate of drug elimination
(mg/min) = Cl x Css. This equation could be applied to
an IV infusion.
During repeated administrations, it takes 4-5 t 1/2 to
attain a steady state drug concentration.
There is also a concentration at steady sate for repeated doses.
Some textbooks call this an average concentration (Css, av).
Repeated dosing is associated with peak and trough plasma
concentrations.]
For oral administration
Oral maintenance dose =
Cl x C x T
F
The above equations do not apply to drugs that have zero
order elimination kinetics
They saturate the routes of elimination and will disappear
from plasma in a non-concentration dependent manner.
Thus, (1) a constant amount of drug is cleared per unit time; (2)
the half-life is not constant, but depends on the drug
concentration.
e.g. clearance rate of ethanol is 10 ml/h, if one consumes 60 ml,
3 h is needed to clear half of it; however, if 80 ml is consumed,
then 4 h is required.
Elimination of some drugs follow the zero-order reactions e.g.
alcohol, heparin, phenytoin and aspirin at high concentration.
Part II. Fundamentals of Pharmacodynamics and Toxicodynamics
Chapter 4. Drug receptors
A. Pharmacodynamics is a description of the properties of drugreceptor interactions.
Receptor concept
P. Ehrlich,
immunochemistry [toxin-antitoxin], chemotherapy [treatment of infectious
disease with drugs derived from dyes]
Drug can have a therapeutic effect only if it “ has the right sort
of affinity… combining group of the protoplasmic molecule to
which the introduced group is anchored will hereafter be termed
receptor.”
B. Nature of receptors
1. Protein; lipoprotein or glycoprotein
2. Usually located in cell membrane
3. Molecular mass in the range of 45-200 kd
and can be composed of subunits.
4. Frequently glycosylated
5. Kd of drug binding to receptor (1-100 nM);
binding reversible and stereoselective.
6. Specificity of binding not absolute, leading to
drug binding to several receptor types (a continuum)
7. Receptors saturable because of finite number.
8. Specific binding to receptors results in signal
transduction to intracellular site.
9. May require more than one drug molecule to bind to
receptor to generate signal.
10. Magnitude of signal depends on number of receptors
occupies or on receptor occupancy rate; signal is
amplified by intracellular mechanisms
11. By acting on receptor; drugs can enhance, diminish, or
block generation or transmission of signal
12. Drugs are receptor modulators and do not confer new
properties on cells or tissues
13. Receptors must have properties of recognition and
transduction.
14. Receptors can be up-regulated or down-regulated.
C. Drugs bind to specific receptors with:
(1) ionic bonds –electrostatic, r2
(2) hydrogen bonds, r4
(3) Van der Waals forces, r7
(4) covalent bonds
D. Receptor classes:
1. Ligand-gated ion-channel receptors
2. Voltage-dependent ion channel receptors
3. G-protein-coupled second messenger receptors
4. Receptors with tyrosine kinase activity
Ligand-gated ion-channel receptors
• Nicotinic acetylcholine (Ach) receptor
– skeletal muscle end plate of the neuromuscular junction,
autonomic ganglia and CNS
– Ach binding causes electric signal via Na + and K +
influx
• GABA receptor
– A type inhibitory Cl- influx, e.g. benzodiazepane
Voltage-dependent ion channel receptors
• membrane bound, excitable nerve, cardiac and skeletal
muscle
• membrane deplorization conformational change, channel
open, Na+ and Ca++ ion influx
• blockade of the receptors, the mechanism of local
anesthetics and some anti-hypertensive agents
G-protein-coupled second messenger receptors
• cAMP, IP3 (inositol triphosphate), DAG (diacyl glycerol)
cascade
– binding of the receptor
– activation of membrane bound G protein
– activation of membrane bound enzyme
– activation of intracellular kinases
• GTP(GDP) binding protein, a, b, g subunit activate
or inhibit adenylcyclase and phospholipase C
Receptors with tyrosine kinase activity
• Growth factors receptors e.g. insulin, EGF, PDGF
– extracellular domain and intracellular
• domain, autophosphorylation
– exclusive on OH- group tyrosine residues
E. Receptor dynamism
- Desensitization
(1) uncoupling of receptor
(2) internationalization and sequestration
(3) down-regulation enzymatic degradation
- Sensitization
thyroid hormone, myocardial b receptor , heart
rate elevated
Receptor function altered by disease
Myasthenia gravis
autoantibody to the receptors in the neuromucsular junction
administration of ACh esterase inhibitors e.g. neostigmine,
physostigmine
Graves, disease
antithyrotropin receptor
agonist effect
thyroid hormone , hyperthyroidism
Chapter 5. Dose-Response Relationship
Simple occupancy theory by A.J. Clark
1. the drug-receptor interaction follows the laws of mass
action.
a. drug molecules bind to receptors at a rate that is
dependent on the drug concentration
b. the number of drug-receptor interactions determines
the magnitude of the drug effect.
Law of mass action
adsorption of gas -metal
surface, hyperbolic curve,
Langmuir adsorption isotherm
[X] + [R]  [XR]  E(effect)
Kd = [X][R]/[XR]
Assumptions in simple occupancy theory of A.J. Clark :
(1) magnitude of pharmacological effect (E) directly
proportional to XR
(2) Emax when all receptors are bound with X
Discrepancy to the simple occupancy theory by A.J. Clark
• “Some experimental data indicates that maximal effect
can be achieved with <100% occupancy; leaving ‘spare
receptors’ ”
2. Representation of the dose-response curves
a. graded (e.g. blood pressure)
b.quantal (all or none) [e.g. death]
Graded representation
quantal (all or none) representation
3. Agonists and Antagonists
Agonists - compounds that activate receptor-mediated processes
via reversible interactions based upon the laws of mass action.
Fig 6-4 shows a series of
agonists with various affinity
to the same receptor
ED50 tells the relative potency
e.g. A is 20-30 times more
potent than D.
But, all four drugs have same efficacy.
Efficacy is the maximal response a drug can produce. Potency
is a measure of the dose (for a drug ) to produce a response (e.g. ED50 )
Exception of Clark occupancy model: Non-linear
relationship between occupancy and response
[X] + [R]  [XR]
E(effect)
Intrinsic activity or efficacy
Intrinsic activity or efficacy introduced by Ariens and
Stephenson (1956): inherent qualities of the drug,
independent of concentration, that modulate the effect.
Fig 6-5: same affinity (i.e. same ED50), efficacy differs, A is 2.5
times more efficacious than C (partial agonist) dual effect
(antagonist also).
Antagonists are compounds that diminish or prevent agonistic effects
and are usually classified as competitive or noncompetitive.
1. competitive - for same binding site; the efficacy of agonist
may be regained if concentration high, Fig 6-6,
2. noncompetitive, allosteric inhibition, Fig 6-7, this effect can’t
be reversed by increasing concentration of agonist
Without anatgonist
With less or more anatgonist
Other types of antagonisms:
Physiological antagonism - compensatory mechanism
to maintain homeostasis
Chemical antagonism -forming complex
Phamacokinetic antagonism - enzyme induction to
increase metabolism or elimination