Chapter 3. Clinical Pharmacokinetics

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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.
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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.
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C. Bioavailability (F) refers to the fraction of
a drug administered that gains access to the
systemic circulation F
Bioavailability is 100 following an intravenous
injection (F1), 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.
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Bioavilability (F)
Area under curve (AUC)
Time (h)
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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.
The bioavailability ? to 95. Newdrug becomes a
best-selling product
Redesign the pill with a coating ? stable in acid
but dissolves in the more basic pH of the small
intestine.
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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)
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Apparent volume of distribution
Vd
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.
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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 lt 5 L ? the drug is retained
within the vascular compartment. a value Vd of lt
15 L ? the drug is restricted to the
extracellular fluid, while (Vd gt 15 L) ?
distribution throughout the total body water or
concentration in certain tissues.
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4. The loading dose for a drug by IV injection
Vd x C where C is the serum drug concentration
oral loading dose
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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
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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.
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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 mg/ml.At
the end of the second hour, mg of crud
has been removed (1000 ml of 0.9 mg/ml). The
aquarium now has mg of crud remaining,
for a concentration of mg/ml
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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.
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During repeated administrations, it takes 4-5 t
1/2 to attain a steady state drug concentration.
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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.
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For oral administration
Oral maintenance dose
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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.
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Elimination of some drugs follow the zero-order
reactions e.g. alcohol, heparin, phenytoin and
aspirin at high concentration.
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Part II. Fundamentals of Pharmacodynamics and
Toxicodynamics
Chapter 4. Drug receptors
A. Pharmacodynamics is a description of the
properties of drug-receptor interactions.
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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.
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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
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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.
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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
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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.
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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
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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
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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

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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

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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

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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

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• 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

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Receptor function altered by disease
Myasthenia gravis autoantibody to the receptors
in the neuromucsular junction administration of
ACh esterase inhibitors e.g. neostigmine,
physostigmine
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Graves, disease antithyrotropin receptor agonist
effect thyroid hormone ?, hyperthyroidism
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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.
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Law of mass action adsorption of gas -metal
surface, hyperbolic curve,
Langmuir adsorption isotherm
X R ? XR ? E(effect) Kd XR/XR
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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 lt100 occupancy
  leaving spare receptors

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2. Representation of the dose-response curves a.
graded (e.g. blood pressure) b.quantal (all or
none) e.g. death
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Graded representation
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quantal (all or none) representation
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3. Agonists and Antagonists
Agonists - compounds that activate
receptor-mediated processes via reversible
interactions based upon the laws of mass action.
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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 )
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Exception of Clark occupancy model Non-linear
relationship between occupancy and response X
R ? XR
E(effect) Intrinsic activity or efficacy
introduced by Ariens and Stephenson (1956)
inherent qualities of the drug, independent of
concentration, that modulate the effect.
Intrinsic activity or efficacy
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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).
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Antagonists are compounds that diminish or
prevent agonistic effects and are usually
classified as competitive or noncompetitive.
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1. competitive - for same binding site the
efficacy of agonist may be regained if
concentration high, Fig 6-6,
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2. noncompetitive, allosteric inhibition, Fig
6-7, this effect cant be reversed by increasing
concentration of agonist
Without anatgonist
With less or more anatgonist
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Other types of antagonisms Physiological
antagonism - compensatory mechanism to maintain
homeostasis Chemical antagonism -forming
complex Phamacokinetic antagonism - enzyme
induction to increase metabolism or elimination