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PHARMACOLOGY
Pharmacokinetics
What the body does to the drugs
Absorption
Distribution
Biotransformation
Excretion
Pharmacodynamic
What the drug does to the body
Pengobatan rasional
ABSORPTION
Movement of drug from the site of administration into the
blood stream
Administration of drug:
ORAL (ENTERAL) the most important
Sublingual
PARENTERAL
= Intravenous (IV)
= Subcutaneus (SC)
= intra articular
ABSORPTION
How does absorption occur ?
1.
Passive diffusion:
Absorption method for most drugs
Energy independent
Following concentration gradient
2. Active transport
Energy dependent
May opposite concentration gradient
3. Facilitated diffusion
Memerlukan transporter
ABSORPTION
Ada 2 jenis transporter utk obat
Transporter utk efflux atau eksport obat ABC (ATPBinding Cassette) Transporter
P-Glikoprotein (P-gp)
Multidrug Resistance Proteins (MRP)
Perlu energi
Transporter untuk uptake obat
Organic anion transporting polypeptide (OATP)
Organic anion transporter (OAT)
Organic kation transporter (OCT)
energi
1. Difusi Pasif
Rate of diffusion is proportional to :
degree of ionization (depends on the pH of
drug and environment)
lipid solubility of the drug molecule
concentration gradient across the membrane
(the driving force)
Surface area of absorption
1. Difusi Pasif
2. Transport aktif
Perlu energi --> dpt melawan perbedaan kadar/
potensial listrik
Terutama di usus halus
Untuk zat2 mknan: glukosa, asam amino, bbrp
vitamin
Obat2 yg struk. kimia mirip struk. zat makanan:
levodopa, metildopa
Memakai carier
Membrane factors:
A bilayer amphiphatic lipids
Protein serve as receptors, channels, or transporter
Type of transport
passive diffusion, active transport, facilitated diffusion
Waktu disintegrasi
Waktu disolusi
Eksipien
Stabilitas dlm sal.cerna
2. Karakteristik pasien
a) pH sal. Cerna
b) Kecepatan
pengosongan lambung
c) Waktu transit dlm usus
d) Luas permukaan
absorbsi
e) Penyakit sal. cerna
f) Aliran darah usus
Faktor2 yg mempengaruhi
absorbsi obat dlm sal cerna
3. Keberadaan substrat
lain dlm sal. Cerna
4. Sifat farmakokinetik
obat
a) Interaksi dg obat2
lain
b) makanan
2.Rektal
3. Paru-paru
Bentuk gas/ cairan yg mudah menguap
mis. anesthesi umum, btk aerosol
mis.isoprenalin
Absorbsi mel. mucosa sal nafas & epitel paru
Keuntungannya:
- absorbsi cepat --> permukaan absorbsi luas
- terhindar dari eliminasi presistemik
- obat dapat langsung di beri pada bronkus
Intranasal
Per oral --> degradasi ekstensif
Absorbsi jelek
Mata
Efek lokal pada mata
Efek sistemik krn absorbsi melalui kanal nasolakrimalis
Kulit
Keuntungan:
- Terhindar dari metabolisme presistemik
- Menghindari peaks and thoughs in plasma
concentration versus time curve
- Mengurangi variabilitas individu
Bioavailability
Definition: the amount of administered
drug which reaches systemic circulation in
active form
Depends on:
pharmaceutical factors
GI absorption
Presystemic metabolism (first pass metab.)
Bioavailability
Ingested
(100%)
100-A-B
( 100-A-B-C)%
Bioavailability (F)
B % metab.
In intest. wall
A%
Not absorbed
C% metab.
in liver
Absorption: (100-a)%
(b + c) % = presystemic
elimination/metabolism =
first-pass metabolism
Metabolism = Biotrasformation
Main site of drug metabolism : the liver
Other tissues : intestine, kidneys, lung, blood, brain, skin
Aim of metabolism: to convert lipid soluble drugs to water
soluble (more polar) compounds can be excreted via
kidneys or bile
PHASE I: oxidation, reduction, hydrolysis
- drugs become inactive, less / more active, or toxic
- drugs obtain polar groups (-OH, -NH2, -COOH, SH) can
react with endogenous substrates in phase II reactions
Metabolism = Biotrasformation
PHASE II : conjugation
Conjugation with endogenous substrates
(glucuronic acid, sulphate, acetyl, glutathion)
- drugs almost always become inactive
Drug metabolism: Phase I reaction only, phase II
only, or phase I followed by phase II
Example :
Terfenadine, astemizole, cisapride (substrates of CYP3A4)
contraindicated with
ketoconazole, itraconazole, erythromycin, clarithromycin
(potent inhibitors of CYP3A4)
GENETIC POLIMORPHISM
A number of genetic polymorphisms: poor, intermediate,
extensive, or ultrarapid metabolizer
CYP2D6
extensive vs poor metabolizers
CYP2C9
(EM vs PM)
CYP2C19
NAT2 : rapid vs slow acetylators (RA vs SA)
In South-east Asians :
- frequency of PM CYP2D6 : 1 - 2 %
- frequency of PM CYP2C19 : 15 - 25 %
- frequency of SA NAT2
: 5 - 10 %
Metabolisme
Aktivitas enzim dalam metabolisme obat yang
telah diteliti dan ternyata dipengaruhi oleh
adanya perbedaan ras/etnis, antara lain:
N-Asetil Transferase (NAT2)
individu diklasifikasi sebagai slow & rapid
asetilator
Sitokrom P450 subenzym CYP2C (CYP2C19 &
CYP2C9) dan CYP2D6
individu diklasifikasi sebagai poor & ekstensive
metabolizer
POLIMORFISME CYP2D6
Haloperidol me pd ras Cina
me pd ras Kaukasius
POLIMORFISME NAT
INH 60% bangsa eskimo rapid asetilator
60% bangsa eropa slow asetilator
Pharmacokinetic Interactions
ABSORPTION
Antacids are chelated by tetracycline and quinolones,
and the complex is not absorbed.
Cholestyramine adsorbs and inhibits the absorption of
thyroxine, cardiac glycosides, warfarin,
corticosteroids, and probably other drugs.
Anticholinergics slower gastric motility and increase
absorption of other drugs
Vit. C increase the absorption of Fe
ABSORPTION
Antibiotics that alter the gastrointestinal flora
can reduce the rate of bacterial synthesis of
vitamin K enhances the effect of oral
anticoagulants
Digoxin is metabolised by GI microorganisms,
antibiotic therapy may result in an increase of
digoxin concentration
Transporter Interaction
Quinidine, verapamil : substrates & inhibitors of
P-gp
Digoxin : substrate of P-gp
interaction : plasma digoxin concentration
(inhibition of P-gp in the intestine & kidney)
DISTRIBUTION
Many drugs are extensively bound to plasma albumin
(acidic drugs) or a1-acid glycoprotein (basic drugs).
Displacement of one drug from its binding site by
another might be expected to result in a change in drug
effects.
Warfarin + NSAID risk of bleeding
Oral anti diabetics + NSAID risk of hypoglycemia
Bilirubin + salicylate kern icterus in neonates
METABOLISM
Phenobarbital, rifampicin, phenytoin: induces
cyt P-450
increases metabolism of other drugs
warfarin, quinidine, corticosteroids, estrogen
contraceptives, theophylline, mexiletine, and some
b-blockers.
ELIMINATION
Probenecid inhibits biliary elimination of rifampicin
and indomethacin
Probenecid inhibits renal secretion of penicillin
prolongs the effects of penicillin
Pyrazinamid, thiazide: reduces renal excretion of uric
acid exacerbation of gout
Bicarbonate enhances water solubility of salicylate
reduces tubular reabsorption and increases excretion