Pharmacology???

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Part 2Pharmacokinetics???????
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Kinetics Models Parameters
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• 2. Transport of Drug in the Body

C. carriers (transporters) (into or out of cells)
D. endocytosis exocytosis
A. aqueous channels in the intercellular junctions
B. lipid cell membranes
Mechanisms of drug permeation across cell membrane
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• 2.1 Transmembrane Transport of Drugs
• (1) Non-carrier Transport
• Simple diffusion(????/????)
• Filtration(??)

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• (2) Carrier-mediated Transport
• a. Active transport
• Characteristics of active transport
• Involving specific carrier (transporter)
• Energy-dependent
• Saturability
• Competition at same carrier
• Moving against concentration gradient
  (up-hill)

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• b. Facilitated diffusion(????)
• (transporter-mediated diffusion)
• Involving specific carriers (transporter)
• Energy-independent
• Saturability
• Competition with other drugs
• Concentration gradient (down-hill)
• (3) Endocytosis/exocytosis(??/??)

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• Another classification
• Passive transport
• Simple diffusion(????/????)
• Filtration(??)
• Facilitated diffusion(????)
• Active transport
• Active transport (????)
• Pinocytosis/exocytosis(??/??)

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• A. Simple diffusion

Most drugs are weak acids or bases. Their
diffusion passing through cell membrane depends
the lipid-soluble state (un-ionized form)
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• Determinants of simple diffusion
• For most drugs of small molecules (usually
  are weak acids or weak bases)
• Lipid-soluble or un-ionized forms
• pKa of the drug and pH of the body fluid
• The pKa is the pH at which the concentrations
  of the ionized and un-ionized forms are equal.

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• Henderson-Hasselbalch equation
• Weak acid drugs
• pH - pKa log ( A- / HA )
• pKa - pH log ( HA / A- )
• Weak base drugs
• pKa - pH log ( BH / B )
• pH - pKa log ( B / BH )

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un-ionized form
lipid-soluble
Simple diffusion
pKa
pH
Weak acids

And / or
And / or
And / or
Weak bases
And / or
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B. Carrier (transporter)-mediated transport
Three types of functional membrane proteins.
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Models of transmembrane transport across the
lipid bilayer
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• 2.2 Free and Bound Forms
• Plasma protein binding
• Tissue / organ affinity

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• 3. Fate of the drug in the body
• Absorption
• Distribution
• Metabolism
• (Biotransformation)
• Excretion
• - ADME

ADME
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• 3.1 Absorption
• Absorption is the transfer of a drug from its
  site of administration to the blood stream.
• Gastrointestinal tract
• Parenteral injection - i.m., s.c.
• Inhalation
• Transdermal

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• (1) Gastrointestinal tract
• Route
• Oral
• Sublingual
• Rectal
• Absorption sites
• Oral
• Gastric
• Intestinal
• Rectal

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• Factors influencing absorption
• blood flow to the absorption site
• total surface area available for absorption
• contact time at the absorption surface
• physic-chemical properties of the drug
• first-pass elimination

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• (2) Parenteral injection
• intramuscular injection ( i.m. )
• subcutaneous injection ( s.c. )
• Determinants
• Local blood flow Solubility of the drug
• (3) Others
• Inhalation Intranasal
• Transdermal Topical

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• 3.2 Distribution
• Drug distribution is the process by which a drug
  reversibly leaves the blood stream and enters the
  interstitium (extracellular fluid) and / or the
  cells of the tissues.
• Blood flow-dependent phase of distribution
• Selective distribution
• Tissue-plasma balance importance of
  measuring plasma concentration

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• (1) Binding of drug to plasma proteins
• Bound drug
• can not distribute / inactive temporally
• reversible (storage form) / percentage of binding
• plasma protein capacity
• competitive displacement

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(2) Physic-chemical properties of the drug
(3) Blood flow and re-distribution (4)
Affinity to organs or tissues (5) Barriers
Blood-brain barrier (BBB) Placental
barrier Blood-eye barrier
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Blood-brain barrier (BBB) Able to pass
through Unable to pass through
Small molecules Large molecules
Lipid-soluble
Water-soluble Transporter-mediation
Amount of drug passing through BBB
Increases when inflammation or larger doses used
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Placental barrier More permeable
Drugs for pregnant women A, B relatively
safe C - caution D, X - toxic
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• 3.3 Metabolism (biotransformation)
• Drug metabolism is the process transforming
  lipophilic drug into more hydrophilic
  metabolites, which is essential for the
  elimination of these compounds from the body and
  termination of their biological activity.
• (1) Metabolism sites
• Liver for most of the drugs
• Other organs/tissues intestine, kidney,
  lung, plasma, etc.

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• (2) Phases of metabolism
• Phase I Oxidation, reduction, hydrolysis
• most drugs are inactivated
• few (prodrugs) is activated
• Phase II Conjugation
• inactivated
• Metabolites more water-soluble easier to
  excrete

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(No Transcript)
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• (3) Enzymes in drug metabolism
• Enzymes in Phase I
• cytochrome-P450, such as CYP2A6, CYP3A4
• many other enzymes
• Enzymes in Phase II
• acetylase
• glucuronosyltransferase
• etc.

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• Induction of hepatic enzymes by drugs
• example
• phenytoin-steroids, nifedipine
• Inhibition of hepatic enzymes by drugs
• example
• verapamil-diazepam

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• 3.4 Excretion
• Removal of a drug from the body via a number of
  routes.
• Elimination of drugs from the body
• Action on excretory organs

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• 3.4 Excretion
• (1) Excretion routes
• Kidney -renal excretion
• Bile (hepato-enteral circulation)
• Lung
• GI tract
• Milk
• Secretion glands

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• 3.5 Elimination and Accumulation
• Elimination(??)
• Metabolism
• Excretion
• Distribution (stored in fat, hair, etc)
• Accumulation(??)
• Dosing rate gt elimination rate

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Kinetic Processes
Kinetics Models Parameters

• 1. Drug concentration-time curve (C-T curve)
• 2. Kinetic rate processes
• 3. Pharmacokinetic models
• 4. Pharmacokinetic parameters and their
  implications

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Kinetic Processes

• 1. Drug concentration-time curve (C-T curve)
• Maximal (peak) concentration Cmax or Cp
• Time to maximal concentration (Peak time )
• Tmax or Tp
• Area under the curve AUC
• Multiple dosing (steady state)
• Css max, Css min, Css

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? ? ? ?
C
Cmax Cp
i.v.
i.m.
s.c.
Oral
? ? ?
t
Tmax, Tp
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?Cmax
C
AUC
? Tmax
t
Tmax, Cmax and AUC
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C-T curve after multiple dosing (same dose and
interval)
????????????????????????????,????????,????????????
???,???????????,?Css??
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• 2. Kinetic rate processes
• dC / dt -KCn

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• 2.1 Zero order kinetics
• n 0
• dC / dt -K
• Ct C0-K t
• C0-Ct K t
• when Ct1/2 C0, t t1/2
• then, 0.5 C0 K t1/2
• t1/20.5 C0 / K

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• Zero order kinetics
• A. same amounts of drug are
• eliminated per unit time
• B. t1/2 is not a constant
• C. C-T curve is linear
• D. no Css theoretically

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Kinetic properties of C-T curves after single
bolus injection of drug
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• 2.2 First order kinetics
• n 1
• dC / dt -KC
• Ct C0e-Kt
• lnCt lnC0-Kt
• KtlnC0-lnCtln(C0 / Ct)
• when Ct1/2C0,tt1/2, then
• t1/2ln2/K0.693/K

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• First order kinetics
• A. eliminated at same rate per unit time
• B. t1/2 is a constant
• C. logC-T curve is linear
• D. steady state (Css) after 4-5 t1/2

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Kinetic properties of C-T curves after single
bolus injection of drug
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• 2.3 Non-linear kinetics
• Higher concentration (or larger dose)
• zero order kinetics
• Lower concentration (or smaller dose)
• first order kinetics
• Because of limits in elimination capacity
• Examples aspirin, phenytoin, ethanol
• Confirmation different t1/2 when given different
  doses

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• Michaelis-Menten kinetics
• dC / dt Vmax ? C / (Km C)
• if Km gtgt C
• dC / dt Vmax ? C / Km
• Vmax / Km Ke - First
  order
• if C gtgt Km
• dC / dt Vmax ? C / C
• dC / dt -Vmax - Zero order

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Kinetic properties of C-T curves after single
bolus injection of drug
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Kinetic properties of C-T curves after single
dose of aspirin
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• 3. Pharmacokinetic models

• One-compartment model

iv
logC
t
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• 3.2 Two-compartment model

1
2
2, 3
First, enter the central compartment
Then, distributed to peripheral compartment, and
eliminated
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Distribution
Elimination
?
?
t1/2 ? t1/2 ?
logC
iv
?
?
t
logC-T curve
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4. Pharmacokinetic parameters and their
implications 4.1 Bioavailability ( F )
Bioavailability is the fraction of administered
drug (oral) that reaches the systemic circulation
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Absolute bioavailability(???????) F
AUC(po, sc, im) / AUC (iv) Relative
bioavailability (???????) F AUC(tested) /
AUC(standard) Implication Evaluation for
absorption and drug quality control Influence
Absorption rate First-pass elimination
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AUC (iv)
C
AUC (po)
t
Absolute bioavailability F AUC(po) / AUC (iv)
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4.2 Apparent volume of distribution (Vd)
The volume of distribution (Vd) relates the
amount of drug in the body (D) to the
concentration of drug (C) in the blood or
plasma. i.v. Vd D / C
p.o. Vd FD / C
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4.3 Half-life (t1/2) / elimination constant
(Ke) The half-life (t1/2) is the time takes
for the plasma concentration or the amount of
drug in the body reduced by 50. t1/2
0.693 / Ke Vd / Cl (First-order
kinetics, for most cases) Ke A constant
fraction of drug in the body is eliminated per
unit of time (first-order kinetics).
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Implications of t1/2 Elimination rate
Estimating the times of fully elimination and
reaching steady state Classifying short- and
long-acting drugs Adjusting dosage regimens
for patients with hepatic or renal failures
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4.4 Clearance (CL) The drug in a constant
volume of body fluid usually plasma is
eliminated per unit of time. (First-order
kinetics) CLs Ke ? Vd FD/AUC There are
also hepatic CLH and renal clearances CLR.
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First order kinetics One compartment
model Intravenous administration
lnCt lnC0- Ke t slope - Ke t1/2 0.693 /
Ke Vd D / C0 CL Vd Ke
lnC0
lnCt
slope - Ke
t (min)
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Part 3 Factors Influencing Drug Effects
?????????
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Drug
Patient
Dosage regimen drugs, doses, intervals, duration
efficacy/adverse effects drug concentrations
Adjustment
Doctor
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A. Drug Factors

• 1. Physic-chemical properties of drugs
• 2. Dose forms
• 3. Administration
• 4. Multiple-drug therapy
• 5. Long-term drug therapy

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• 1. Physic-chemical properties of drugs
• Stability
• Molecular size
• Lipid- and water-soluble

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• 2. Dose forms
• slow release formulation
• controlled release formulation
• transdermal patch
• inhalation

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• 3. Administration
• Doses
• Routes oral
• intramuscular injection
• subcutaneous injection
• intravenous injection or
  infusion
• Administration time
• Dosing intervals
• Dosing duration

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• 4. Multiple-drug therapy (drug combination)
• Drug-drug interactions
• pharmacy
• pharmacokinetics
• pharmacodynamics
• Drug effects in combination
• synergism potentiation / addition
• antagonism

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Efficacy ?,? Toxicity ?,?
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B. Patient Factors

• 1. Physiological Factors
• 1.1 Age
• Children
• Sensitivity to drugs
• Pharmacokinetic properties
• Elderly
• Sensitivity to drugs
• Pharmacokinetic properties

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Age-related factors influencing pharmacokinetic
processes
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• 1.2 Sex
• Women
• Pregnancy
• - malformation and dysfunction of the fetuses
• Lactation
• - milk effects on infants

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• 2. Psychological Factors
• Placebo effects
• Placebo effects commonly are manifested as
  alteration of mood, other subjective effects, and
  objective effects that are under autonomic or
  voluntary control.

???(placebo)???????????(???????),?????????????????
,????????????????
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Pharmacological effects
Non-specific drug effects
Absolute placebo effects
Placebo effects
Overall responses
Non-specific medication effects
No treatment
Natural recovery
Components underlying drug effects
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• 3. Pathological Factors
• Heart diseases
• Hepatic diseases
• Renal diseases
• Gastrointestinal diseases
• Malnutrition
• Imbalances of acid-base or electrolytes

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• 4. Genetic Factors
• Pharmacogenetics
• abnormality of drug responses
• example tolerance of warfarin
• abnormality of pharmacokinetic properties
• example fast or slow acetylation

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• 5. Individual variation (????)
• (1) Sensitivity to drugs
• Hypersensitivity
• Hyposensitivity (tolerance)
• (2) Abnormal responses to drugs
• Idiosyncracy (genetic abnormality)
• Allergy (immunological abnormality)

One goal in the post-genomic medicine
Individualized Medicine
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• 6. Changed responses after long-term drug use
  (???????????????)
• (1) Tolerance and tachyphylaxis (human body)
• (2) Resistance to chemotherapy (pathogens)
• (3) Drug dependence - an adaptive state
  that develops in response to repeated drug
  administration.

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ADME?????? AGI??/???? D??????,??????,BBB M
??? E???????/????
?????????? C-T??Cmax,Tmax,AUC,Css ??????,??
??????,??/??? ??????????F,??????Vd,??
?t1/2,??????Ke,???Cl
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