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What is pharmacokinetics?
Absorption
Distribution
Metabolism
Excretion
Farmakokinetik
Bioavailabilitas
Rute pemberian
Absorpsi
Distribusi
- Difusi
- Kelarutan lipid
- Ionisasi
- Ikatan depot
Metabolisme
Ekskresi
Farmakodinamik
Aksi Obat
Reseptor
- Hubungan
dosis-respon
- Antagonisme
Efek Obat
-Efek samping
-Indeks terapi
-Perubahan perilaku
Pharmacokinetics
ADME
http://www.thebody.com/content/art875.html
Routes of Administration
Cara/jalur pemberian
(Routes of administration)
Bagaimana dan di mana obat memasuki tubuh akan
menentukan seberapa banyak obat mencapai
tempat aksinya dan, pada gilirannya, menentukan
besarnya efek
Jalur pemberian dapat mempengaruhi absorpsi obat
Yang menentukan adalah :
Luas permukaan absorpsi
Banyaknya membran/barrier yang harus dilewati
Banyaknya obat yang terdegradasi
Jumlah ikatan dengan depot
Injeksi subcutaneous
Sublingual
Injeksi Intramuscular
Intra vena
Inhalasi
ip
Routes of administration
Cp max
Tmax
Onset
Cl
T1/2
Overview
Liberation
Ex:
Ex:Enteric
Entericcoated
coated
aspirin
aspirinslows
slowsabsorption
absorptionin
in
stomach
vs
non-coated
stomach vs non-coated
Absorption
Absorpsi Obat
Mekanisme perpindahan/
transport obat
Difusi pasif:
Perpindahan obat/senyawa dari kompartemen yang
berkonsentrasi tinggi ke konsentrasi rendah
merupakan mekanisme transport sebagian besar
obat
Transport aktif
Perpindahan obat/senyawa dari kompartemen yang
berkonsentrasi rendah ke konsentrasi tinggi
membutuhkan energi dan protein pembawa/carrier
mekanisme transport obat-obat tertentu
Difusi Pasif
Senyawa lipofilik
Senyawa hidrofilik
Transport Aktif
carrier
Difusi pasif:
Tergantung pada:
ukuran dan bentuk molekul obat
kelarutan obat dalam lemak
derajat ionisasi obat
Akibatnya, obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble)
P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium).
Po/w = (Coil/Cwater)equilibrium
Derajat ionisasi
Basa
Levodopa
Diazepam
Klordiazepoksid
Penisilin
Aspirin
Trimetoprim
Makin asam
Morfin
Metotreksat
Norepinefrin
Sulfametoksazol
Dopamin
Klorotiazid
Propranolol
Fenobarbital
Amfetamin
Fenitoin
Klorokuin
Asam askorbat
Makin basa
Aturan:
Contoh:
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi
di lambung atau usus ?
Mengapa ?
Formulation factors
Tablet disintegration
Inert ingredient /
solvent effects
Solubility
Drug pH
Concentration
Patient factors
Absorbing surface
Blood flow
Environmental pH
Disease states
Interactions with food,
other drugs
Small,
uncharged
H2O, urea,
CO2, O2, N2
Swoosh!
Large,
uncharged
Glucose
Sucrose
DENIED!
Small
charged
ions
H+, Na+,
K+, Ca2+,
Cl-, HCO3-
DENIED!
NON-IONIZED
Why?
Why?
Ionized
Ionized form
form
(charged)
(charged)
A-
Ionized
Ionized form
form
(uncharged)
(uncharged)
HA
HA
Basic
Basicdrugs
drugsare
arebest
bestabsorbed
absorbedfrom
from
basic
basicenvironments
environments
So...
To
Toabsorption
absorptionof
ofan
anacidic
acidicdrug
drug
acidify
acidifythe
theenvironment
environment
To
Toabsorption
absorptionof
ofan
anacidic
acidicdrug
drug
alkalanize
alkalanizethe
theenvironment...
environment...
Contoh :
Distribution
Rate of perfusion
Plasma protein (albumin) binding
Accumulation in tissues
Ability to cross membranes
Blood-brain barrier
Placental barrier
Distribution
warfarin
warfarin(Coumadin)
(Coumadin)isishighly
highlyprotein
proteinbound
bound(99%).
(99%).Aspirin
Aspirin
binds
bindsto
tothe
thesame
samesite
siteon
onserum
serumproteins
proteinsas
asdoes
doesCoumadin.
Coumadin.
IfIfaapatient
patienton
onCoumadin
Coumadinalso
alsotakes
takesaspirin,
aspirin,what
whatwill
willhappen?
happen?
Blood-Brain Barrier
The
The blood
blood brain
brain barrier
barrier consists
consists of
of cell
cell tightly
tightly
packed
packed around
around the
the capillaries
capillaries of
of the
the CNS.
CNS.
What
What characteristics
characteristics must
must aa drug
drug possess
possess to
to
easily
easily cross
cross this
this barrier?
barrier?
Elimination
Excretion
Drug Metabolism
(Biotransformation)
Metabolism (Biotransformation)
Two effects
Slows metabolism
Prolongs effects
Metabolisme
(biotransformasi)
First-Pass Metabolism
keringat, dll.)
Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma
kurang bioavailabilitasnya
efek berkurang
Intravenous
Administration
Oral
Administration
Metabolis
m
Liver
Intestines
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)
Oxidasi, reduksi, hydrolysis, alkilasi, dealkilasi
Metabolitnya bisa lebih aktif/tidak dari pada senyawa
asalnya
Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya
metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II)
Konjugasi (glukoronidasi, sulfatasi)
Penggabungan suatu obat dengan suatu molekul lain
Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Metabolisme
Fase I
Obat A
Obat B
Eliminasi
Fase II
Konjugasi
aktif
Konjugasi
inakti
f
Konjugasi
Obat C
Obat D
aktif
inaktif
Lipofilik
Hidrofilik
bioavailabilitas meningkat
Consequences Of Metabolism
Elimination
Partial reabsorption
Hemodialysis
Renal disease
Slows excretion
Prolongs effects
Eliminasi/ekskresi
urin
Probenecid
Probenecid is
is moved
moved into
into the
the urine
urine by
by
the
the same
same transport
transport pump
pump that
that moves
moves
many
many antibiotics.
antibiotics. Why
Why is
is probenecid
probenecid
sometimes
sometimes given
given as
as an
an adjunct
adjunct to
to
antibiotic
antibiotic therapy?
therapy?
It competes with the antibiotic at the pump and slows
its excretion.
AA patient
patient has
has overdosed
overdosed on
on phenobartital.
phenobartital.
Phenobarbital
Phenobarbital is
is an
an acid.
acid. IfIf we
we alkalinalize
alkalinalize the
the
urine
urine by
by giving
giving bicarbonate
bicarbonate what
what will
will happen
happen
to
to the
the phenobarbital
phenobarbital molecules
molecules as
as they
they are
are
filtered
filtered through
through the
the renal
renal tubules?
tubules?
Ionized
H+ + A-
Decreased
Decreasedreabsorption
reabsorption
Increased
Increasedelimination
elimination
ADME - Summary
Plasma Concentration
PK Definitions
Cmax: Maximum
concentration may relate to
some side effects
10000
3000
1000
Cmin: minimum or
trough
concentrations: may
relate with efficacy of
HIV drugs
100
0
10
12
Concentration
Effective
Ineffective
0
24
TIME
12
18
One-Compartment Model
Dose
1
k
Two-Compartment Model
Central compartment (drug entry and
elimination)
Dos
e
0.5/hr
0.2/hr
ka
D
Cp
DB
kel
CHEE 440
B. Amsden