Transcript Pharmacology

Pharmacology
Introduction to Pharmacology
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.
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
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 B>A
A and B: to have same TI, difference slope
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.
D+R
K1
DR
……E
K2
Note: D: drug; R: receptor; DR: drug receptor
complex; E: effect; K: rate constant.
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 > EA + EB
3. Potentiation occurs if a drug lacking an
effect of its own increases the effect of a
second, active drug:
EAB > 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-4.5biphosphate(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, G=G-protein; E=enzyme
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 –β (TGFβ), 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.
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 - α 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 α,β andγ )
When the system in inactive, GDP is bond
to the α 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 α subunit, and the α–GTP
subunit is then thought to dissociate from
the β,γ 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 α submit association / dissociation
cycle. The GTP-liganded subunit activates
some processes exclusively, and release of
β γ subunit, upon activation of Gα allows
for regulation by β γ subunit of shared or
distinct effectors.
The regulatory cycles involved in G proteinmediated 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, relocalization, 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: antiarrhythmic 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+-K+ATPase of stomach to
treat stomach ulcer
F: Influence of nucleic acid metabolism:
nucleic acid metabolism of bacteria is
influenced by antibiotics to abolished the
life of bacteria.
F. Receptors.
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.
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.
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 (<200D), lipid
solubility of drug, unionized form are easy
to across the membrane.
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.
The pKa of drug is define as the pH at which 50% of
the molecules in solution are in the ionized form
Handerson – Hasselbalch equation
For an acid
For a bases
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.
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.
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.
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.
The mechanisms and disposition of drugs by
the body.
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
The major portion of drug absorption is in
small intestine, which has considerably
greater absorptive surface, to wriggle
slowly, particularly, pH = 7.4 (neutral)
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
(2): Injection: Intravenous injection and
intravenous infusion are administration
which directly enter circulation and rapidly
act in the body
(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.
(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
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.
Drug distribution
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 α1 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.
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%.
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.
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.
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
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.
Some drugs may be modified to avoid the
centre nervous system reaction. Such as
Atropine methyl-atropine. Haloperidol
N-n-butyl haloperidol iodide
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.
Drug Biotransformation
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.
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.
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
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.
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.
Cytochrome P-450 transformation (oxidation)
Cytochrome P-450 transformation (reduction)
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.
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). Nonionized 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.
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.
Renal disease will affect the excretion of
certain drugs which may prolong the effect
of these drugs. Such as cardiac glycosides
administration.
Modify the urine of pH to treat toxicity.
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.
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.
The change course of drug concentration
with time (time- concentration relationship)
The relationship is described by time-Concentration curve
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 overeffect concentration is effective period. The concentration in
blood by one-half is called elimination half life.
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.
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.
F = A / D *100%
D: Dose of drug A: dose of entering circulation
Absolute F=AUC ( oral) / AUC ( iv) *100%
Relative F=AUC (test) / AUC (standard) *100%
Standard drug compared with test drug to get the rate
of absorption.
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.
Bioavailability of three form preparations
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 = -k*Cn
C: plasma concentration(dose/volume) ; A:
dose of plasma volume; k: rate constant
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:
n=1 dc / dt = ke*C1 Ct=C0e-ket
lnCt = ln C0 – ket
to convert from nature log to base 10 log units
Log Ct = log C0 – ke / 2.303*t
t = log C0 / Ct * 2.303/ke
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
At=A0e-0.693*n=A0(1/2)n When n=5, At = 3% .
after 5 half life of a drug, the drug are almost
eliminated
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.
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
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
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.
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)
Vd = A / C 0
Calculation of Vd
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
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.
dC/dt = -KC0= -K, Ct = C0-Kt, when slope = -K,
Ct / C0=1/2, t = t1/2
t1/2C0=C0- k t1/2,
t1/2=0.5* 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.
In clinic, the treatment need in a therapeutic
level of drug. For a drug displaying firstorder 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
Css = RE / CL= RA / CL = Dm / τ/ CL
= Dm / τ / Ke*VD
Dm = maintenance doses, τ = 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.
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.
Time-concentration curve of intravenous infusion
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.
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
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
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
the log plasma concentration is plotted against the time after IV dose
with the one-compartment model
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.
C = Ae –αt + Be –βt
An early, rapid, α-phase , which represent the
redistribution of the drug to the peripheral
compartment and a modest component of
elimination. An later, slow, β –phase, which is
combination of elimination and return of drug
form to peripheral compartment to the central
compartment in which the drug distribution
rapidly.
Time-concentration curve of two compartment
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