Pharmacology Introduction to Pharmacology

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Pharmacology Introduction to Pharmacology

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Title: Pharmacology Introduction to Pharmacology

1
PharmacologyIntroduction to Pharmacology
2

Drugs should be used to prevent, to cure
and to diagnose diseases.
Pharmacology is the study of the actions,
uses, mechanisms, and adverse effects of drugs.
Pharmacodynamics, Pharmacokinetics
Toxicology

Pharmacodynamics is the study of the
biochemical and physiological effects of drugs
and their mechanism of action

1. General classification of Drugs effects

A. Excitation is an increase or enhancement
of mental activity by a drug. For example,
stimulation of mental activity by caffeine.
Inhibition is a decrease of the function produced
by a drug. For example, barbiturates induced
sedative-hypnotic effect.

B. Direct Action refers to the action produced
directly by a drug at the site of contact with
drug. A direct action at one part can at times
elicit effects on remote organs or tissues, which
are designated as indirect action.

For example, norepinephrine constricts the
blood vessels directly, increases blood pressure,
It is the direct action. It reflexively
decreases heart rate. That is the indirect
action.

C. Selectivity A drug is usually described
by its most prominent effect or by the action
thought to be the basis of that effect. Cardiac
glycosides mainly stimulate myocardium diazepam
inhibits central nervous system streptomycin
suppresses tubercle bacilli.

D. Therapeutic effect is the effect affecting
the physiological and biochemical functions of
the organisms and pathogenic processes. It is
used to prevent and treat diseases.

Etiological treatment means that the drug may
eliminate the primary pathogenic factor and cure
disease. Such as, antibiotics eliminate
pathogenic organisms within body.

Symptomatic treatment means that the drug may
improve the symptoms of disease, such as, use
aspirin to treat high fever. In some critical
condition, shock, convulsion, congestive heart
failure, high fever, severe pain, symptomatic
treatment is more urgent than etiological
treatment.

E. adverse effect
Any response to drug that is noxious and
unintended and that occurs at doses used in man
for prevention, diagnosis and therapy of a
disease, or for the modification of physiological
function.

Side effects of drugs are the effects which we
do not want to have , but are nondeleterious,
such as dry mouth with atropine which treat the
spasm of intestine .

Toxic effects mean noxious effects induced by
over dosage of drugs or accumulation of large
amount of drugs.

They include acute toxicity which may damage
the functions of circulatory system, respiratory
system and nervous system, and chronic toxicity
which may damage hepatic, renal, bone marrow and
endocrine function.

Carcinogenesis, teratogenesis and mutagenesis
belong to chronic toxicity. Toxic effect are
necessary prelude to avoidance of them or, if
they occur, to rational and successful management
of them.

Allergy is an adverse reaction that result
from previous sensitization to a particular
chemical or to one that is structurally similar.
Such reactions are mediated by the immune system.
The terms hypersensitivity and drug allergy are
often used to describe the allergic state.

After effect The effect still exists , after
withdrawal of the drug, the drug concentration
is below the threshold, such as, the patient
feels hangover next morning, after taking
barbiturates.

Secondary reaction After long term of using
broad spectrum antibiotics, due to the change of
intestinal normal flora, the sensitive bacteria
are abolished, then it appears the overgrowth of
non-sensitivity bacteria such as staphylococcus
and fungi, staphylococcus enteritis or candida
infection (candidiasis) appears, This called
secondary reaction.

20
Dose-Effect Relationship

Graded Dose- Response curve
As the dose administered to a single subject
or isolated tissue is increased, the
pharmacologic effect will also increase. At a
certain dose, the effect will reach a maximum
level.

Graded dose-response curve
23

Efficacy The maximum effect of drug, Emax is
a measure of drug efficacy. Efficacy is also
called intrinsic activity.

Potency A comparative measure, refers to the
different doses of two drugs that are needed to
produced the same degree of effect. These two
drugs have similar chemical structure and
mechanisms of action. The lower the dose of drug
effect, the higher the potency of drug.

Graded dose-response curve for three
drugs
Efficacy and potency

B. Quantal Dose Response Curve
1. A quantal response is an all or none
response to a drug and relates to the frequency
with which a specified dose of a drug produces a
specified response in a population.

2. The quantal dose-response curve is a
cumulative graph of the frequency distribution
curve . The dose of drug required to produce a
specified magnitude of effect in a large number
of individual patients or experimental animals
are plotted the cumulative frequency distribution
of responses versus the log dose.

The specific quantal effect may be chosen on
the basis of the clinic relevance (e.g. relief of
headache or it may be in experimental animal).
When these responses are summated, the resulting
cumulative frequency distribution constitutes a
quantal- dose-effect curve of the proportion or
percentage of individuals who exhibit the effect
plotted as a function of log dose.

Quantal dose effect plots

Quantal dose effect curve may also be used
to generate information regarding the margin of
safety to be expected from a particular drug used
to produced a specified effect

ED50 The dose at which 50 of the
individuals exhibit the specified quantal effect.
LD50 The dose at which 50 of the animals
exhibit death.

Therapeutic index (TI) LD50 / ED50

Dose-response curve of effect and toxicity of
A,B equal ED50 and LD50, toxicity BgtA

34
A and B to have same TI, difference slope
35

III. Receptor Theory and Drug Receptor
Interaction

Receptor. Macromolecular structure to which a
drug binds in such a way as to initiate or modify
a biological function.

37

K1

DR DR E

K2
Note D drug R receptor DR drug receptor
complex E effect K rate constant.
38

A. Receptor Theory

1. Receptor occupation theory

When the receptors are occupied, the
pharmacological effects will occur. The effects
of drug are directly proportional to the numbers
of receptors occupied. Stephenson revised the
opinion it is not necessary to occupy all the
receptors, when the maximal effect occurs.

Affinity It is the tendency of a drug to form
a combination with the receptors
Affinity 1/KD KD dissociation constant

Intrinsic activity Its inherent ability to
produce an effect

Dissociation constant, KD is a characteristic
of the drug and of the receptor, it has the
dimensions of concentration and is numerically
equal to the concentration of drug required to
occupy 50 of the sites of equilibrium (50 of
the maximal effect. Minus log KD is pD2 -log
KD), which is called affinity index. The higher
the affinity of the drug for the receptor, the
lower will be KD, at the same time, the higher
pD2, the stronger will be the effect of the drug.

A
B
A a, b, c (equal pD2 ,
difference Emax)
B a, b, c (equal Emax
, difference pD2)
Intrinsic activity and affinity of a
drug

2. Rate Theory The response of a drug is the
function of the rate of dissociation of drug
receptor complex.

3. Two model theory Receptors have to
different conformation, activated conformation
(R ) and resting conformation (R ). They may
change to the other one. Activated form may
combine with agonists, then may show its effect
resting conformation may combine with antagonist,
which has no effect.

Ligand chemical substances which can combine
with receptors are called ligands, ligands
include drug, hormones and neurotransmitters.

Spare receptors For a highly active agonist
with a high efficacy, the maximal response will
be produced by a concentration that dose not
occupy all receptors. The receptors remain
unoccupied are termed spare receptors.

B. Agonists and Antagonists

1. An agonist has high affinity to receptors
and high intrinsic activity. An agonist is a
drug that produces a pharmacological effect when
it combine with receptors

An antagonist binds to the receptors to
inhibit the action of an agonist, but initiate no
effect themselves. Sometimes, the inhibition can
be overcome by increasing the concentration of
the agonist, ultimately achieving the same
maximal effect. Examples of pure antagonists are
atropine and curare, which inhibit the effects of
acetylcholine.

Partial agonists They have agonistic
activity but also have antagonistic activity

Pharmacological Antagonism occurs when an
antagonist prevent an agonist from acting upon
its receptors to produce an effect

1. Competitive antagonism Competitive
antagonists compete with agonists in a reversible
fashion for the same receptor site. When the
antagonist is present, the log dose-response
curve is shifted to the right. In the presence
of a fixed concentration of agonist, increasing
concentration of a competitive antagonist
progressively inhibit the agonist response high
antagonist concentrations prevent response
completely.

Non competitive antagonism The
noncompetitive antagonist binds irreversibly to
the receptor site or to another site that
inhibits the response to the agonist. For
example, drugs such as Verapamil and Nifedipine
prevent the influx of calcium ions through the
cell membrane and thus block non-specifically the
contraction of smooth muscle produced by other
drugs.

Graded dose-response curve illustrating the
effect of competitive antagonists

Graded dose-response curve illustrating the
effect of non-competitive antagonists

Two state model of receptor

D. Enhancement of drug effect

1. Additive drug effects occur if two drug
with the same effect, when given together,
produce an effect that is equal in magnitude to
the sum of the effects when the drugs are given
individually
EAB EA EB

2. Synergism occurs if two drugs with the same
effect, when given together, produce an effect
that is greater in magnitude than the sum of the
effects when the drugs are given individually.
EAB gt EA EB

3. Potentiation occurs if a drug lacking an
effect of its own increases the effect of a
second, active drug
EAB gt EA EB

IV. Cellular Response of Receptor- Effector
Linkage.

Drugs or ligands combine with receptors induce
a series of cellular responses and hence
physiological or biochemical effects. These are
four types of cellular responses.

A. Direct Regulation of Membrane Permeability
to Ions

After drug combine with receptors, the
receptors are activated. This has effects on ion
channel of membrane, changing ion flow across the
transmembrane, generating membrane potential or
changing intracellular ion concentration, that
may induce physiological effect. Such as when
cholinergic receptors are activated at
neuromuscular junction, Na influx will be
increased.

B. Regulation via Intracellular Second
Messages

After the receptors are activated, the second
message C-AMP / C-GMP increases or decreases,
phosphatidyl-inositol-4.5-biphosphate(PIP2)
decomposes to the second messagers inositol
triphosphate (IP3) and diacylglycerol (DG).

Effect of second message

C. Direct Modulation of Protein
phosphorylation, such as insulin receptor

D Regulation of DNA Transcription

Regulation of protein synthesis it induces
biochemical and physiological effect, such as
steroid hormones.

Type of receptor effector linkage
CR-receptor, GG-protein Eenzyme

V. Receptor Families and Their Transducer and
Effector Molecules.

Receptor has ligand binding domain and
effctor domain.

A. Receptors as Enzymes

This class of receptor molecules mediates the
first step in signaling by insulin, epidermal
growth factor (EGF), platelet- derived growth
factor (PDGF), atrial natriuretic factor (ANF),
transforming growth factor ß (TGFß), and many
other topic hormones. These receptors are
polypeptides consisting of an extracellular
hormone binding domain and a cytoplasmic enzyme
domain, which may be a protein tyrosine kinase,
a serine kinase, or a guanylyl cyclase.

Catalytic activities
Tyrosine kinase growth factor receptors,
neurotrophic factor receptors
Insulin, epidermal growth factor (EGF)
receptors, platelet- derived growth factor (PDGF)
receptors

B Multisubunit ligand-gated Ion Channels
Nicotinic Ach receptor
Glutamate receptor, GABAA receptor
Glycine receptor, 5-HT3 receptor

C. G-protein Coupled Receptor Systems

G- protein coupled receptors comprise many
of the receptors, 5-HT receptors, opiate
receptors, receptors for many peptides, purine
receptors and many others, including the
chemoreceptors involved in olfaction.

82
This system divided to three parts

1. G protein coupled binding site.
They consist a single polypeptide chain of
400-500 residues. They all possess seven
transmembrane - a helics. Both the
extracellular amino terminus and the
intracellular carboxyl terminus vary greatly in
length and sequence. Agonists combine with the
receptors.

2. G protein
G protein is the short term of guanine
nucleotide binding protein (also called
GTP-binding protein). The G proteins are bond to
the inner face of plasma membrane. They are
heterotrimeric molecules (subunits are designated
a,ß and? )

When the system in inactive, GDP is bond to
the a subunit. An agonist receptor complex
facilitates GTP binding to the subunit in part
by promoting the dissociation of bond GDP.
Binding of GTP activates the a subunit, and the
aGTP subunit is then thought to dissociate from
the ß,? subunit and interact with a membrane
bound effector.

There are two types of G-protein, one is
excitatory G-protein (Gs) which stimulates
adenylyl cyclase (AC) to increase cAMP. Another
is inhibitory G-protein (Gi) which inhibits AC
and decrease cAMP

GDP-binding protein activation of effectors
is regulated simultaneously by a GTPase cycle and
a submit association / dissociation cycle. The
GTP-liganded subunit activates some processes
exclusively, and release of ß ? subunit, upon
activation of Ga allows for regulation by ß ?
subunit of shared or distinct effectors.

The regulatory cycles involved in G
protein-mediated signal transduction.

3. Effectors.

D Nucleus Receptors
Regulation of transcription Receptor for
steroid hormones, thyroid hormone, retinoid are
soluble DNA-binding proteins that regulate the
transcription of specific genes.

VI. Relationship Between Regulatory
Mechanisms of Receptors and the Pharmacological
Action

Receptors are themselves subject to regulatory
control, superstimulation or subnormal response
may occur if the receptor activity or receptor
numbers have been modified by up-or down
regulation. Such regulatory mechanisms are
usually evident with chronic use of a agonist or
an antagonist.

Receptor down regulation (desensitization)
may follow continued stimulation of cells with
agonists. Several mechanisms are possible (1)
phosphorylation of the receptors, destruction of
the receptors, re-localization, sequestiation
(isolation of receptor) (2) decreased synthesis
and number of receptors. For example, chronic
use of isoprenaline for asthmatic patient the
bronchial relaxation effect will be decreased.

Receptor up-regulation (supersensitivity) may
follow continued use of antagonists (or
denervation), usually synthesis of additional
receptors. Up-regulation is connected with
increase of sensitization for chronic use of in
antagonist or having symptoms induced by withdraw
of drugs, such as after chronic use of
propranolol for hypertensive patient, suddenly
stop to use it, it will induce rebound (increase
of blood pressure)

VII. Mechanism of Action

A. Change the Physical and Chemical
Properties of the cellular Environment
Antacid neutralizes gastric acid, IV mannitol
induces diuretic effect (osmotic diuretic)

B. Interfere or Incorporate into Metabolic
Process Sulfarages inhibit dihydrofolic
synthetase, and interfere the synthesis of
dihydrofolic acid, nucleic acid and protein.
Cholinesterase inhibitors increase the effect of
Ach.

C. Influence of Biologic Membrane
anti-arrhythmic drugs influence Na, Ca2, K
transport. Polymycin B, E can damage bacterial
cytoplasmic membrane.

D. Influence Physiological Transmitters and
hormones Ephedrine enhances the release of NA
from the adrenergic nerve endings. Tolbutamide
enhances the release of insulin and decreases the
blood sugar concentration.

E Influence of enzyme omeprazole inhibit
the Na-KATPase of stomach to treat stomach
ulcer

100

F Influence of nucleic acid metabolism
nucleic acid metabolism of bacteria is influenced
by antibiotics to abolished the life of bacteria.

101

F. Receptors.

102

Pharmacokinetics That considers drug
disposition and the way the body affects the drug
with time i.e. the factors that determine its
absorption, distribution, metabolism and
excretion. So, we know how rapidly and in what
concentration and for how long the drug will
appear at the target organ.

103

Drug transportation In order to reach its
site of action (receptor site), a drug have to
traverse a succession of membranes
1. Passive diffusion passive diffusion take
place when a drug molecule moves from a region of
relatively high to one of low concentration
without requiring energy, carrier, saturation and
competitive inhibition. Simple diffusion is
major state of passive diffusion for drug
transportation.

104

The rate of diffusion depend on the state,
area and a concentration gradient of membrane.
Nature of drug is key point to across the cell
membrane. The drug which are small molecules
(lt200D), lipid solubility of drug, unionized form
are easy to across the membrane.

105

Most drugs are either weak acid or bases.
Therefore, the pH of environment in which they
dissolve, as well as the pKa of the drugs will be
important in determining the fraction in
unionized form that is in solution and able to
diffuse across cell membrane.

106
The pKa of drug is define as the pH at which 50
of the molecules in solution are in the ionized
form Handerson Hasselbalch
equationFor an acid For a
bases

107

Drugs exist in non-ionized and ionized forms.
The non-ionized form of drugs are more lipid
soluble and able to penetrate the cellular
membrane, but ionized form of drugs are very
difficult to penetrate the membrane. That is
called ion trapping.

108

Weak acids (e.g. barbiturates) are more
readily absorbed from the stomach than from other
regions. Weak base drugs are more absorbed from
the intestines than from stomach.

109

2. Active transport is a carrier mediated
process. This process require energy and proceed
against a concentration gradient. Such as
methyldopa. The carriers of drug are selective
and saturable in transport process. Like
Probenecid blocks the active tubular secretion
of Penicillin and hence prolong its action.

110

With facilitated diffusion, the transport
process is selective and saturable, but the drug
is not transferred against a concentration
gradient. Such as absorption of glucose.

111

The mechanisms and disposition of drugs by the
body.

112

Absorption (1). Administration of
gastrointestinal tract most drugs are
administered orally. The tablet and capsule need
to be disintegration and dissolution, then that
may be absorbed

113

The major portion of drug absorption is in
small intestine, which has considerably greater
absorptive surface, to wriggle slowly,
particularly, pH 7.4 (neutral)

114

Drugs that are administered orally and enter
the portal circulation of liver and can be
biotransformed by this organ prior to reaching
the system circulation. This is called first pass
elimination. Some drugs are reduced by first
pass elimination. so the sublingual and rectum
administration are recommended to avoid the first
pass elimination

115

(2) Injection Intravenous injection and
intravenous infusion are administration which
directly enter circulation and rapidly act in the
body

116

(3) Other parenteral method. Such as
intramuscular injection and subcutaneous
injection are important method. The drugs via
these methods are absorbed better, which are
related to the temperature of site. massaging of
the site where a drug has been administered
increases the rate of absorption.
Vasoconstrictive substance may prolong the
absorption of drug.

117

(4) Special method such as intra-artery,
local anesthetics were also used in order to
avoid the side effect of body. Administration of
respiration tract Aerosol vaporize the drug
solution into small particle (5µm), so it may be
absorbed through the capillaries which adhere to
the pneumoaheolus face, but the face area is
larger and the blood volume of lung is rich.
Such as aerosol of isoprenaline is used to treat
asthma

118

Transdermal administration the lipophilic
drugs may pass through the skin, so it is
absorbed slowly, such as, toxicosis of pesticide,
and Transderm-nitro (nitroglycerin) and
Nifedipine are used to prevent the angina from
attack.

119

Drug distribution

120

The drug has the plasma protein binding after
the drug enters the circulation. Nonbinding
drugs are called free drugs. More acidic drugs
are bound to albumin, more basic drugs are bound
to a1 acid glucoprotein. Less drugs are bound to
globulin. The state of binding similar to
receptor binding of drug . The percent protein
binding is very important, because the part does
not exert any pharmacological effects, but has a
store form in plasma.

121

Plasma protein binding is a reversible
process, that is influenced by DP, D, and KD of
plasma. The binding site of protein are not
unlimited and subject to saturation. The percent
protein binding of drugs varies dramatically.
Drugs may alter the protein binding of other
agents. Such as, only a slight displacement of a
highly bound drug like bishydroxycoumarin can
oral anticoagulant by phenvlbutazone, can cause
serious haemorrhage. Because only 1 of
anticoagulant is free, and additional
displacement of 1 increase its effect by 100.

122

The rate of distribution of drug from blood to
tissue depend on the blood volume of organs. The
more blood volume the organ has, the faster the
amount of drug diffused. Then there is a
redistribution in some organs. e.g. Thiopental
is lipophilic drug, and it diffuses into brain
more quickly, then, redistribute to the fat and
other tissues.

123

The concentration of drug at target organ
should be measured through the concentration of
plasma. So the effect of the drug may be
estimated at target organ.

124

The pKa and pH are other key points.
Generally, weak base drugs penetrate the cellular
membrane facilely when the toxicity of weak acid
drug take place, the basic substance should be
used to alkalify the blood in order to transfer
the acid drugs out of the cells

125

Blood-Brain Barrier Drug can enter the
brain from circulation by pass through the
blood-brain barrier. This boundary consist of
several membranes, including those of capillary
wall, the glial cells closely surrounding the
capillary, and neuron. Such a structure limit
the entry of many drugs into the brain.

126

Some drugs may be modified to avoid the centre
nervous system reaction. Such as Atropine
methyl-atropine. Haloperidol N-n-butyl
haloperidol iodide

127

The placental barrier is membrane separating
fetal blood from maternal blood in intervillous
space. It resembles the capillary, and almost
all drugs may penetrate the placental barrier.
During pregnancy, the drugs which affect fetal
developing should be contraindicated.

128

Drug Biotransformation

129

Drug is a xenobiotic. Before being excreted
from body, most drugs are metabolized. A small
number of drug exist in their fully ionized form.
More lipid-soluble drugs are metabolized by the
liver. The goal of metabolism is to produce
metabolites that are polar, or charged, and can
be eliminated by the body.

130

Using two general sets of reaction, called
phase I and phase II. Phase I metabolic reaction
include oxidation, reduction and hydrolysis.
Phase II reaction involve conjugation. During
phase I , most drugs are inactivated
pharmacologically, a few drugs become more active
and toxic in nature. Phase II result in the drug
being more hydrophilic and thus more easily
excreted from the body.

131

The hepatic cytochrome P450 is the most
important enzyme (hepatic drug enzyme). It
consist of more than 70 enzymes. A drug
substrate binds to cytochrome P450, then the
complex acquired two hydrogen ions, a molecular
oxygen from NADPH and cytochrome b5 and the drug
undergoes hydroxylation by O, the another O bind
the two H to H2O.
RH NADPH O2 2 H ROH NADP H2O
The enzyme system is called mixed function
oxidases or monooxygenase

132

Enzyme activation and inhibition. Some drugs
are able to increase the activity of certain
isoenzyme forms of cytochrome P450 and thus
increase their own metabolism, as well as that of
other drugs. So that it may enhance the
tolerance of drugs for the body. Such as
phenobarbital. In contrast, some drugs inhibit
cytochrome P450 activity and therefore increase
their own activity as well as that of other
drugs, like cimetidine.

133

In cytochrome P450 system, CYP3 and CYP2c play
a significant role, that related to the
metabolism of many drugs. 30-50 of drugs are
metabolised by CYPA4 which is the member of CYP3.

134

Cytochrome P-450 transformation (oxidation)

135

Cytochrome P-450 transformation
(reduction)

136

Phase II reactions are conjugation reaction
To combine a glucuronic acid, sulfuric acid,
or glycine with the drug to make it more polar,
the high polar drugs can then be excreted by
kidney.

137

Excretion of Drugs
Drugs are excreted from the body in variety
of ways. Excretion can occur by kidneys into
urine. That is most important routes for the drug
excretion. Some drugs in the blood pass into the
glomerulor filtrate. Drugs can excreted in free
forms (water-soluble substances). Non-ionized
lipid- soluble drugs may be reabsorbed by tubule.
Some drug may transported into the lumen of the
tubule by either of two transport mechanism. One
transport mechanism deal with acidic molecules,
the other with basic molecules.

138

Competition between drugs that share the same
transport mechanism may occur, in which case the
excretion of these drugs will be reduced.
Probenecid is a drug that was designed to compete
with penicillin for excretion and therefore
increase the duration of action of penicillin.
Toxicity with acid drug can be treated by
alkalifying which makes the urine more alkaline,
this ionizes substance and renders it less prone
to re-absorption. In contrast, basic drugs is
same reason for their toxicity.

139

Renal disease will affect the excretion of
certain drugs which may prolong the effect of
these drugs. Such as cardiac glycosides
administration.

140

Modify the urine of pH to treat toxicity.

141

Drugs are also excreted from the body by the
bile, faeces and by the lungs into exhaled air.
Drugs may leave the body through breast milk and
sweat.

142

The excretion of the drugs from bile posses
three transport channels, i.e. acid, base and
neutrality channels. Some drugs conjugated are
excreted into bile and subsequently released into
the intestines where they are hydrolysted back to
parent compound and reabsorbed ( hepatoenteral
circulation). This effect of circulation
prolongs the action of drugs, but in
hepatocholangiostomy, the stay time of drugs in
plasma which is excreted by bile may be shorten.

143

The change course of drug concentration with
time (time- concentration relationship)

144

The relationship is described by
time-Concentration curve

145
The ascending limb of curve is considered to be a
general reflection of the rate of drug
absorption. The peak concentration (Cmax) express
same speed between absorbing and eliminating
course. The time to reach the peak concentration
of the drug is Tpeak. The descending limb of the
concentration- time curve is a general indication
of the rate elimination of the drug from the
body. The time of over-effect concentration is
effective period. The concentration in blood by
one-half is called elimination half life.

146

The area under the concentration-time curve
AUC
It described the relative dose of drug that
enter the circulation. AUC is an indication of
bioavailability.

147

Bioavailability is the amount and speed of
drug that is absorbed after administration by
route X compare with the amount and speed of drug
that is absorbed after intravenous (IV)
administration. X is any route of drug
administration other than IV.

148

F A / D 100
D Dose of drug A dose of entering circulation
Absolute FAUC ( oral) / AUC ( iv) 100
Relative FAUC (test) / AUC (standard) 100
Standard drug compared with test drug to get the
rate of absorption.

149

The bioavailability of different drugs is
assessed by an evaluation of parameters
The peak concentration The time to reach the
peak concentration The area under the
concentration-time curve
The extent to which the bioavailability of one
preparation form differs from that of another
must be evaluated.

150

Bioavailability of three form preparations

151

Drug elimination kinetics is the eliminating
course of plasma or blood concentration of drug
with its distribution, metabolism and excretion.
It is expressed by mathematics equation
dc / dt -kCn
C plasma concentration(dose/volume) A dose
of plasma volume k rate constant

152

First-order kinetics drug disappear from
plasma by process that are concentration
dependent. The higher of drug concentration is,
the more the drug elimination in unit time is.
The elimination is in percentage course
n1 dc / dt keC1 CtC0e-ket
lnCt ln C0 ket
to convert from nature log to base 10 log
units
Log Ct log C0 ke / 2.303t
t log C0 / Ct 2.303/ke

153

When Ct 1/2C0
t ½ log2 2.303/ke 0.301 2.303/ke
0.693/ke the half life is 0.693/ke. The half
life is the period of the required for the
concentration of drug to decrease by one half .
The half life is constant and related to ke
for drugs in first order kinetics, and not
related with plasma concentration ( C).
Ke the fraction change in drug
concentration per unit of time
Ke 0.5 h -1, t1/2 1.39h

154

AtA0e-0.693nA0(1/2)n When n5, At 3 .
after 5 half life of a drug, the drug are
almost eliminated

155

When a drug is given at dosing interval that
is equal to its elimination half life, the steady
state will be achieved in 5 half life.

156

C L(plasma clearance) is defined as the sum of
clearance of all the organs (liver, kidney and so
on). It is the volume of fluid cleared of a drug
per unit time. CL of drug is different from the
elimination rate which is rate of removal of drug
in weight per unit time, but they are related as
shown in the equation CL ke VD

157

VD (apparent volume of distribution) is
defined as the volume of fluid into which a drug
appears to distribute with concentration equal to
that of plasma, or the volume of fluid necessary
to dissolve the drug and yield the same
concentration as that found in plasma
VD dose administration / initial apparent
plasma concentration

158

The volume of distribution is hypothetical
apparent volume, but not a real volume. It gives
a rough accounting of where a drug goes in the
body, if you have a feel for the various body
fluid compartments and their size. In addition,
it can be used to calculate the dose of drug
needed to achieve a desired plasma concentration.

159

Such as, some drugs have a volume of
distribution that exceeds body weight, in which
case tissue binding is occurring
(bone, fat, nucleic acid and so on)

160
Calculation of Vd
Vd A / C0
161

CL ke VD 0.693 / t1/2 VD
CL A / AUC
When patient suffer from the damage of kidney
or liver, the CL is decreased for drugs. The
dose should be adjusted

162

Zero order kinetics drugs that saturate
routs of elimination disappear from plasma in
non-concentration-dependent manner. Many drugs
will show zero-order kinetics at high dose of
toxic concentration.

163

dC/dt -KC0 -K, Ct C0-Kt, when slope
-K, Ct / C01/2, t t1/2
t1/2C0C0- k t1/2, t1/20.5 C0 /k
So, for drugs with zero-order kinetics, a
constant amount of drug is lost per unit time.
The half life is not constant for zero-order
reaction, but depend on the concentration. Drugs
is eliminated at same speed, such as at alcohol
toxicity state.

164

In clinic, the treatment need in a
therapeutic level of drug. For a drug displaying
first-order kinetics, at first, the plasma level
will be low and infusion rate will be greater
than elimination rate, so, the drug will
accumulate until the amount administered per unit
time is equal to the amount eliminated per unit
time

165

Css RE / CL RA / CL Dm / t/ CL
Dm / t / KeVD
Dm maintenance doses, t interval time
The time needed to reach steady state depends
on the t1/2 , Ke, VD and CL , but not the speed
of administration. The speed of administration
determines the level of Css.

166

Intravenous infusion of drug get the steady
state of plasma smoothly. With repeated dosing
the concentration fluctuates between Cmax and
Cmin. The longer the interval time is , the
bigger the fluctuation is.

167

Time-concentration curve of intravenous infusion
168

If the Cmax is desired higher or lower, the
rate of administration is adjusted, but after the
5 half lives, the new Css is achieved.

169

Sometime, the patient can not wait for the
therapeutic effect to occur. In this condition,
a loading dose is used. Load dose is a single
large dose of a drug that is used to raise the
plasma concentration to a therapeutic level more
quickly than usually occur through repeated
smaller dose

170

Ass Dm Ass e-ket, D1 Ass Dm /
(1-e-ket)
Ass loading dose
At beginning, the 1.44 times of infusion
dose which is dosage of first half life time,
should be intravenous injected , and it may reach
the Css at once.
When interval time is t1/2, the double dose
should be given at first time
Except t1/2 is much longer or shorter, zero
order kinetics, half dose at half life interval
and double dose at first time are necessary to
get a desired effect and less side effects

171

Compartment model
One compartment model The body is a single
compartment . With this single compartment, a
drug is absorbed, immediately distribute (e.g. by
intravenous injection). This situation expresses
itself graphically as a straight line when the
log plasma concentration is plotted against the
time after IV dose

172
the log plasma concentration is plotted against
the time after IV dose
with the one-compartment model
173

Two compartment model
The distribution of drug between the
peripheral compartment. (Such as , muscle , skin
and fat depots) and central compartment (such as
brain, heart, liver and kidney). Because of the
rich blood volume of central compartment organs,
the drug firstly enter the central compartment,
then enter the peripheral compartment.

174

C Ae at Be ßt
An early, rapid, a-phase , which represent
the redistribution of the drug to the peripheral
compartment and a modest component of
elimination. An later, slow, ß phase, which is
combination of elimination and return of drug
form to peripheral compartment to the central
compartment in which the drug distribution
rapidly.