Transcript pharmacokinetics

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Pharmacology
Pharmacology
1. General Principles of Pharmacology (Yuan)
2. Peripheral Nervous Pharmacology (Cao)
3. Central Nervous Pharmacology (Liu)
4. Cardiovascular Pharmacology (Zang)
5. Splanchnic and Blood Pharmacology (Ma)
6. Endocrine Pharmacology (Zhao)
7. Chemotherapeutic Pharmacology (Lin)
(7 sections )
PART 1
GENERAL PRINCIPLES OF
PHARMACOLOGY
Dr. Yuan Bing-Xiang
Department of Pharmacology,
Medical School,
Xi’an Jiaotong University,
Tel: 82657724,
Email: [email protected]
GENERAL PRINCIPLES
Pharmacology
CHAPTER 1
Introduction of Pharmacology
Ⅰ CONCEPTION
1. Pharmacology can be defined as the science or
course studying the interaction between drugs and
bodies (living systems) including human being,
animals and pathogens including pathogenic
microorganisms (bacteria, virus, fungus…) , parasites
and tumor cells…
GENERAL PRINCIPLES
Pharmacology
Drugs are the chemicals beneficially
altering biochemical and physiological
states of body, applied to prevent, treat or
diagnose diseases.
Peripheral Nervous Pharmacology
Central Nervous Pharmacology
Systems Cardiovascular Pharmacology
Drugs of bodies Splanchnic Pharmacology
Act on
Blood Pharmacology
Bodies
Endocrine Pharmacology
Pathogens- Chemotherapeutic Pharmacology
Antibacterial drugs; Antifungal drugs;
Antivirus drugs; Antiparasitics
Anticancer drugs
GENERAL PRINCIPLES
Pharmacology
2. Three aspects of pharmacology
drug
Pharmacodynamics, PD
Pharmacokinetics, PK
Impact factors
body
Pharmacology
GENERAL PRINCIPLES
1) Pharmacodynamics (drug acts on body)
Drugs
actions
Primary acting
on the target
effects
Secondary Inducing effects
in the organ or system
effects * therapeutic effects
* adverse reaction
* dose-effect curves
E
└→PD parameters (KD, EMAX…)
action（mechanism of effect） * Specific actions:
drug-receptors; drug-ion channels; drug-enzymes;
* Unspecific actions: drugs influence physical and
chemical condition around cells (pH, osmosis …)
D
Pharmacology
GENERAL PRINCIPLES
2) Pharmacokinetics (body acts on drug)
Undergoing of
drug in body
C-T curves
absorption
transportation
 distribution
 excretion
 biotransformation

drug blood Concentration-Time curves
└→PD parameters from C-T curves:
t1/2, Ka, Ke, F, Vd…
C
T
Pharmacology
GENERAL PRINCIPLES
3) Impact factors
Drug
Body
Drug
drug
physico-chemical
property
dosage form
batch number
Medication
dose and route
time and interval
course of treat
association
PK
PD
physiolopathopsychogenoliving habit
……
body
PHARMACOLOGIC PRINCIPLES
CHAPTER 2
pharmacokinetics
（ body Acts on drug ）
Undergoing of drugs
pharmacokinetics
(sites of action)
binding
free
(accumulation)
free
binding
distribution
drugs
(plasma)
(renal)
absorption
distribution
Free drugs
excretion
po sc im
binding drugs metabolites
distribution
transport
transformation
Metabolism
(liver)
out of body
permeation across membranes
pharmacokinetics
Ⅰ.Drug permeation across membranes
1. Membrane
The membranes with pore
are composed of lipids and
proteins in a ratio of 70:1.
The liquid-form double-deck
of membranes is formed
a
b
c
from lipid molecules; The
d
special proteins inserted into
the double-deck are
receptors, enzymes, ion
channels, carriers……
e
O＜ ＞O
lipids
O＜
＞O
O＜ ＞O
O＜
＞O
pore
O＜ ＞O
O＜ ＞O
O＜ ＞O
carrier
O＜ ＞O
O＜
＞O
carrier
ATP
O＜ ＞O
O＜ ＞O
O＜ ＞O
ion
channels
O＜
＞O
O＜ ＞O
O＜ ＞O
O＜ ＞O
Lipid
diffusion
Filtration
Facilitated
transport
Active
transport
Ion
transport
p
a
s
s
i
v
e
permeation across membranes
pharmacokinetics
2. Passive transport across membranes
(down hill)
A drug molecule moves from
a side of membrane relatively
high concentration to another
side of low concentration
without requiring energy, until
an equilibrium has been
achieved on both sides of the
membrane.
high
…..
…..
…..
…..
…..
low
..
…..
…..
…..
…..
…..
…..
…..
…..
…..
…..
…..
…..
…
…..
…..
…
equilibrium
Lipid diffusion; Filtration; Facilitated transport
permeation across membranes
pharmacokinetics
1) Lipid diffusion ( Simple diffusion)
The most important mechanism of drug transport
Drug movement across membranes is driven
by a concentration gradient after solution in the
lipids of membranes.
pH (pKa) ┐
Nonionized form
pKa is pH when Ionized rate is 50%
k1
k2
Ionized form
more lipid soluble
easy permeation
less lipid soluble
hard permeation
←less polar molecules
polar molecules→
ion trapping
Lipid diffusion
HA (weak acids)
HA
k1
k2
H+＋A-
k1
[H+][A-]
Ka＝──＝─────
k2
[HA]
[A]
pKa＝pH－log ───
[HA]
[A-]
pH－pKa＝log ───
[HA]
[A-]
───＝10pH－pKa
[HA]
pharmacokinetics
B (weak bases)
B＋H+
k1
BH+
k2
k1
[H+][B]
Ka＝──＝ ────
k2
[BH+]
[B]
pKa＝pH－log ───
[BH+]
[B]
pH－pKa＝log ───
[BH+]
[B]
───＝10pH－pKa
[BH+]
Lipid diffusion
[A-]
───＝10pH-pKa
pharmacokinetics
[B]
───＝10pH-pKa
[HA]
[BH+]
weak acids
weak bases
★ pH↑↓→[A-]↑↓→
★ pH↑↓→[BH+]↓↑→
Degree of ionization↑↓ degree of ionization↓↑
→lipid solution↓↑
→lipid solution↑↓
→permeation↓↑
→permeation↑↓
Neither weak acids or weak bases are dissolved in same
acid-base solution, the lipid solution↑, permeation↑;
They are dissolved in opposite solution, the lipid solution↓,
permeation↓.
Lipid diffusion
pharmacokinetics
For example, Bicarbonate (NaHCO3)
is very effective for treatment of acute
toxication from weak acid drugs (like
barbiturates).
why？
Lipid diffusion
pharmacokinetics
① Alkalization of gastric juice →ionization↑
→ permeation↓ →absorption ↓
pH ↑ > pH blood
[A-]↑ > [A-]
drug
drug
gastric juice
Gastrolavage of NaHCO3
② Alkalization of blood plasma →
permeation↓→across blood-brain barrier↓
pH↑> pH Cerebrospinal fluid
[A-]↑> [A-]
drug
drug
blood
Intravenous drop of NaHCO3
Lipid diffusion
pharmacokinetics
③ Alkalization of humor (extra-cellular fluid)
→ionization↑ →permeation↓
cell
drug
drug
pH < pH↑
[A-] < [A-] ↑
④ Alkalization of urine→ionization↑
→permeation↓→ drug tubular reabsorption↓→
excretion↑
blood
urine pH ↑
drug [A-]↑
filtration
pharmacokinetics
) Filtration (Aqueous diffusion):
2
Small molecules (<100-200 dalton) pass
through aqueous pores without requiring
energy driven by concentration gradient.
* Water-soluble drugs with low molecular weight
(Inc. some polar molecules) can diffuse through the
aqueous pores of membrane.
* A almost free drugs can be filtrated across large
pores of capillaries from or to plasma. (like drug
distribution, glomerular filtration and absorption
following im or sc injection)
facilitated transport
3) Facilitated transport
(Carrier-mediated transport)
The movement of a drug
across the membrane could be
facilitated by its special carrier
and concentration gradient. In
the carrier-mediated transport,
the drug is released to another
side of the membrane, and the
carrier then returns to original
side and state.
pharmacokinetics
facilitated transport
pharmacokinetics
The properties of facilitated
transport are as follows:
a. saturable process;
b. special binding to the carrier
c. cannot move against a concentration
gradient without energy.
Active transport
pharmacokinetics
2. Active transport (up hill)
A drug molecule moves from a side
of membrane relatively low to one of
high concentration with requiring
energy and special carrier.
a. saturable process
b. special binding to the carrier
c. transport against concentration gradient
with consuming energy.
Active transport
pharmacokinetics
For example: penicillin and probenecid
Blood→tubule
Blood→tubule
penicillin
probenecid
Glomerular
filtration
(passive)
H2O absorption
Tubule high
osmosis
competitively inhibit
tubular
Secretion
(active)
Excretion of
penicillin
After glomerular filtration, penicillin undergoes tubular
secretion (an active transport), having a very short halflife (t1/2=20~30 min); probenecid having the same active
mechanism can competitively inhibit the tubular secretion
of penicillin. The t1/2 & effects of penicillin are prolonged.
Absorption
pharmacokinetics
Ⅱ.Absorption
The transport of drugs
from administration
locale to bloodstream.
Absorption
pharmacokinetics
1. The routes of absorption
1) im or sc
Absorption of drugs in solution through
filtration from subcutaneous or intramuscular
injection sites to blood is limited mainly by
blood perfusion rate.
im > sc (adrenalin), why?
a. blood perfusion rate (im > sc)
b. adrenalin ┌α↑→vesseel↑(subcutaniea) → perfusion↓
└β↑→vesseel↓(skeleton muscle) →perfusion ↑
Absorption
2) po (per oral)
pharmacokinetics
What about weak acids?
Drugs are absorbed in gastrointestinal tract
through lipid diffusion. The absorption takes
place mainly in the upper small intestine.
With oral administration of drugs, extensive
gastrointestinal and hepatic metabolism may
occur before the drugs are absorbed into
systemic circulation and reach its site of action.
This process is defined as the first-pass
elimination.
gastric mucosa
small intestine mucosa
Absorption
pharmacokinetics
3) Sublingual or rectal administration
Absorption properties of the administration
a. incomplete and irregular absorption;
b. without or less First-pass elimination.
For example
Nitroglycerin given sublingually bypasses
liver and enters the superior vena cava and,
in turn, perfuses the coronary circulation,
therefore is immediately effective to relive
patients with angina pectoris.
Absorption
pharmacokinetics
2. Bioavailability (F)
F would be the extent and rate of drug
absorption following extravascular administration
(like orally).
F could be the absolute rate of a drug, used for
indicating the absorption amount (AUC) compared
with that of intravenous administration, or relative
rate of a pharmaceutical product, used for
indicating the absorption amount (AUC) compared
with that of standard preparation in the same
administration (same route and dose).
Absorption
pharmacokinetics
A (drug amounts in body)
F
(absolute) ＝───────────── ×100%
D (administered dose)
AUC (area under extravascular curve)
F
＝────────────────── ×100%
(absolute) AUC (area under intravenous curve)
AUC (test pharmaceutics)
F
(relative) ＝──────────────×100%
AUC (standard preparation)
C
C
iv
standard
im
test
po
T
T
Distribution
pharmacokinetics
pharmacokinetics
Ⅲ.Distribution
The transport of drugs from
bloodstream to various organs
and tissues, or to different
physical compartments of
body.
Distribution
pharmacokinetics
1. Compartments
According to perfusion rate of drugs
to various organs and tissues, body can
abstractly be divided into one, two or
more parts (one compartment model,
two compartments model, three…).
Distribution
1) One compartment model
Drugs within the model are assumed to be
distributed just to the organs or tissues with high
blood flow and rapid uniform (brain, heart, liver,
kidneys, lungs, active muscle, …). The C-T curve
have one phase: elimination. The distribution is
too rapid to be found in the C-T curve..
drug
Ka
Ke
。
。
T
Distribution
dC
  KC
dt
drug
Ke
C
Co
C  C0 e
1/2
1/4
Ke
。
。
logC
t1/2
logC0
t1/2
 Kt
T
K
logC  logC 0 
t
2.303
T
Distribution
pharmacokinetics
2) Two compartments model
Drugs are not only distributed to the organs or
tissues with rich blood perfusion (central
compartment), but also to that with low blood flow
(peripheral compartment: fat, skin, bone, resting
muscle). The C-T curve have two phases:
a. The distribution rate is known as the alpha
half-life, t1/2α.
b. The elimination rate is known as the beta
half-life, t1/2β.
Distribution
pharmacokinetics
central
peripheral
K1
Ka
Ke
K2
C
α
distribution
α
β
β
T 。
。
Ct＝CAe-kαt＋CBe-kβt
elimination
Distribution
pharmacokinetics
2. Apparent volume of distribution (Vd)
Vd is that drug in a plasma concentration should
be solved in apparent volume of body fluid
including the general circulation and the tissues.
Vd is used for measuring distribution range,
relating the amount in the body (A) to the
concentration of drug (C ) in blood.
total amount of drug in body, A(mg)
Vd(L)＝──────────────────── ＝──
concentration of drug in plasma, C(mg/L)
F.D
C
Distribution
pharmacokinetics
3. Factors influencing distribution
1) Barrier: blood-brain barrier, placental barrier)
a. less ionized drug & small particle→permeable
b. inflammation→permeable
2) active transport→tissues concentration↑
active transport
iodium
thyroid
3) regional blood flow
subcutaneous < intramuscular
Distribution
pharmacokinetics
4) Binding rate to plasma： binding ratio to
plasma protein at the therapeutic dosage.
moving balance
free drug＋plasma
binding drug
(active form)
(inactive storage form)
small particle of drug
large particle of drug
→rapid filtration
→ no filtration
→rapid distribution → → no distribution →
┌ action
┌no action
└elimination
└no elimination
(metabolism & excretion)
Characters of binding to plasma
a. saturability
Dose↑→binding rate ↓→free drug ↑
Malnutrition
liver function↓
Renal function↓
Plasmaalbumin↓
b. Unspecific competition
competive
combination
binding
binding
rate↓
binding
rate↓
free
drug↑
free
drug↑
warfarin
A 98% (2%) ┅ ┅ ┅ ┅ ┅→96% (4%) →effect (toxicity)↑↑→bleeding
2%↓
B 92% (8%) ┅ ┅ ┅ ┅ ┅→90% (10%) →effect (toxicity) ↑
phenylbutazone
Biotransformation
pharmacokinetics
Ⅳ.Biotransformation
mainly in the liver
hepatic microsomal mixed function oxidase system
1. two phases
Phase 1
oxidation
reduction
hydrolysis
Phase 2
conjugation
with glycuronic acid
Prodrugs
drug activity↓
toxicity↓
binding rate↓
more polar
activation
Inactivation
excretion↑
Biotransformation
pharmacokinetics
2. Factors affecting drug metabolism
1) drugs
activity of enzyme↑
enzyme inducer
Chlorpromazine
phenobarbital
→tolerance (dosage↑)
enzyme inhibiter
phenylbutazone
chloromycetin
activity of enzyme↓
→hypersensitivity (dosage↓)
Biotransformation
pharmacokinetics
2) Pharmacogenetics
hereditary variation in handling of drugs
For example:
* Deficiency in the activity of acetylase results
peripheral neuritis from isoniazid;
* Absence of glucose 6-phosphate dehydrogenase
(G6PD) results hemolytic anemia from:
sulfonamides
vitamin K (antihemorrhagic)
primaquine (antimalarial agent)
phenacetin (antipyretic analgesic)
broad beans.
Biotransformation
pharmacokinetics
Glucose
Oxidizing agent
ATP
G-6-P
G6PD↓
6-PG Acid
ADP
NADP
NADPH↓
GSSG
H2O2 ↑↑
GSH↓
H2O↓
Hemolytic anemia
sulfonamides
vitamin K
Absence of G6PD + primaquine
anminopyrine
broad beans
Biotransformation
pharmacokinetics
3) Physiological and pathological condition
Age
完善flaw
elder
liver function
renal function
newborn
deficiency of
drug elimination
toxicity
of drugs
Less dosage
For example:
newborn
chloromycetin
gray syndrome
elder
numerous drugs
toxicity↑
Circulatory failure
Biotransformation
pharmacokinetics
Illness
hepatic
disease
Renal
dysfunction
enzyme
production↓
Plasma
production↓
drug
metabolism↓
Plasma binding↓
→free drug↑
Plasma
loss↑
hypersensitivity
Should dosage↓
pharmacokinetics
Ⅴ.Excretion of drugs
Drugs
and
their
metabolites
in
circulation are excreted by kidneys,
bile, milk, sweat and lungs.
excretion
pharmacokinetics
1. Renal excretion tubular secretion
tubular reabsorption
Plasma (Drug & metabolites)
Bicarbonate?
glomerular filtration
Penicillin?
Probenecid?
tubular water reabsorption
hyperosmotic in renal tubules
lipid-solubility
tubular reabsorption
Drug excretion ↓
active diffusion
tubular secretion
Drug excretion ↑
excretion
pharmacokinetics
2. Excretion in bile
Plasma
(drug)
liver
active transport
bile
Hepato-enteric
circulation
portal vein
intestine
prolongation of half-life
 high concentration in bile
PO

Beneficial for antiinflammatory
of cholecystitis
Excretion
Exclusion
excretion
pharmacokinetics
3. Excretion in milk
weak alkaline drugs
(morphine, atropine)
effects↑
If the mather is the addict,
whai would be resulted?
nursing
mother
concentrations
in breast milk↑
reactions in infant
lactiferous
Ducts milk
(low pH)
reabsorption 
dissolved in the milk↑
fat-soluble drugs
(sodium pentothal)
Kinetics
pharmacokinetics
Ⅴ.Kinetics and rate process
Kinetics
model
2 compartment
1 compartment
drug
K12
drug
K
K
Differental
equation
dC
  KC
dt
K 21
dC C
  KCC  K 12 C C  K 21C P
dt
dC P
  K 21C P  K 12 C C
dt
Kinetics
pharmacokinetics
1 compartment
Exponent
equation
C  C0 e
2 compartments
C  Ae
 Kt
  t
α
C
C
 Be
  t
β
T
T
Linear
equation
logC
logC
Semi-logarithmic
equation
K
logC  logC 0 
t
2.303
T
A
α
β
B
T

log(C - Be )  logA t
2.303

logC  logB 
t
2.303
-  .t
Elimination
pharmacokinetics
1. Elimination of drugs
Drugs and their metabolites are eliminated
from the body by excretion and metabolism with
decrease of drug blood concentration.
1st-order
0-order
0
1
2
100
50
25
1000 900 800
3
4
5
……
9
10
11
12
……
100
50
25
12.5
12.5 6.25 3.125
700
600
500
Elimination
pharmacokinetics
1) First-order kinetic
All most drugs
Blood concentration of drug is reduced in
equal rate or in constant half-life (t1/2). The
eliminated rate is direct ratio with blood
concentration of a drug.
C
dC
  KC 1
dt
one compartment
t1/2
T
dC
  KC
dt
2) Zero-order kinetic
Blood concentration of drug is reduced in
equal amount or eliminated in continuant shorten
half-life (t1/2).
C
dC
 K 0 C 0
dt
dC
 K 0
dt
T
3) non-linear kinetics
Low dose→ 1st order
Overdose→ zero order
salicylic acid, phenytoin, alcohol
aspirin
Low
dose
1st order
kinetics
Large
dose
Urine pH↓→reabsorption↑
zero order T1/2=15-30 h
kinetics
C
C
first
T1/2=2-3 h
zero
T
T
Elimination
pharmacokinetics
4) Half-life of drug (t1/2)
The half-life (t1/2) is the time required to decrease the
drug plasma concentration by one-half (50%) during
elimination.
It is considered that drugs are almost (97%)
eliminated after 5 t1/2.
T1/2 is relates to drug character (lipid-solubility, size
of particle, molecular structure, drug interaction) and
body condition (function of kidneys and liver…), but
generally not relates to drug blood concentration and
the routes of administration (therapeutic dose).
Elimination
pharmacokinetics
C
C
iv
po
T1/2
constant
of a drug
T
T1/2
Relation to
drug character
t1/2
Individual
variation
No relation to
Relation to
body condition
T1/2
T
lipid-solubility,
size of particle,
molecular structure
drug interaction
Kidneys
Liver
……
concentration of drug (therapeutic dose)
way of administration
Steady state
pharmacokinetics
2. Steady state concentration (Css)
When given at a regular interval, a drug plasma
concentration approximately could reach a plateau
after 5 t1/2.
1) Level of Css relates to:
* dose ↑→Css↑
* interval shorten → wave of Css ↓
intravenous drip → smooth concentration curves.
（the most effective and safe administration)
Steady state
pharmacokinetics
2) Time to reach Css relates to:
* When a drug is given at a regular interval, its Css
could reached after 5 t1/2;
* loading dose →reaching Css rapidly
When the regular interval is t1/2 and loading dose is
double ， Css can be reached immediately in
intravenous injection.
Steady state
C
2D-D
pharmacokinetics
C
D
ivd
93.8%
97%
87.5%
75%
50%
T
1st-order
T
0-order
Steady state
pharmacokinetics
Steady state concentration
T1/2
0
first -order
1
2
100
50
200
100
100
75
200
150
100
87.5
200
175
100
100
93.5
96.9… 100
200
200
187.5 193.8… 200
C. dose 200
amount
zero -order
100
100
100
100
100
100
100
100
100
100
dose
amount
100
50
100
100
100
150
100
200
100…
250…
A. dose
amount
B. dose
amount
100
200
100
3
4
5…
n