perjalanan obat dan nasib obat dalam tubuh
Post on 07-Jul-2018
248 Views
Preview:
TRANSCRIPT
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
1/19
07/09/2009
1
oleh
Eka Deddy Irawan,S.Si.,M.Sc.,Apt.Bagian Farmasetika Fakultas Farmasi Universitas Jember
•Shargel – Applied Biopharmaceutics and, . . , ,
•Ritchel – Handbook of Basic Pharmacokinetic,4th Ed.
•Niazi – Textbook of Biopharmaceutic s andClinical Pharmacokinetic, Ch 3,4
•Gibaldi – Bio harmaceutics and ClinicalPharmacokinetics Ch, 3, 4, 5, 6
Mengingat kembali Macam Bentuk Sediaan +
Mekanisme Pelepasan Obat – Sediaan –Faktor-2
Macam Rute Pemakaian
Proses Absorpsi – Rute Pemakaian – Faktor-2
–
Usaha untuk Meningkatkan Pelepasan –Absorpsi Obat
Keuntungan – Kerugian Rute Tertentu
Obat dengan sifat fisika kimia tertentu – bentuksediaan/rute emakaian manakah an ter ilih?
Faktor/hal-hal apakah yang harus diperhatikan ?
Mengapa diadakan berbagai bentuk sediaan/ rute
pemakaian?
Pada pemakaian peroral – berapa % obatdiabsorpsi
di lambung/usus ?
Pada multi drug therapy- kapan obat digunakan?
- satu waktu ??
- berturutan ??
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
2/19
07/09/2009
2
•Kapan / mengapa suatu obat digunakan
•Bentuk sediaan manakah yang terpilih untukpasien dengan kondisi tertentu?
•Rute pemakaian manakah yang terpilih untukpasien dengan kondisi tertentu
Sifat Fisika-Kimia Bahan Obat. Pka – H------ Pers. HH. Ukuran Partikel – Noyes –Whitney. Koefisien Partisi. Poliformisme. Solvat-Hidrat. Garam – Ester
Bentuk Sediaan. Larutan . Suppositiria. Suspensi . Kapsul/Tablet. Emulsi . “Controlled Release”. Salap/krem
Sediaan Padat. Pengisi-laktosa, CaHPO4
. Disintegran – starch, sellulosa
. Lubrikan – Mg stearat, talk
. Bahan Granulasi- sukrosa, polivinil pirolidon. Penyalut – HPMC, CAP
. Fabrikasi
PelepasanAbsorpsi
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
3/19
07/09/2009
3
•Sediaan Cair . a an pensuspens pengemu s
. Pemanis
. Pelarut
. Surfaktan
. PengawetPelepasanAbsorpsi•Rute Pemakaian ---- Aspek Fisiologik
-Luas tempat absorpsi
-
-First pass effect (FPE)
-Ada tidaknya ikatan protein thd obat
INTRAVASKULAR- -- Intrathecal - Intracardial•EKSTRAVASKULAR - Peroral - Bukal , Sublingual - Rektal - Inhalasi - Intramuskular, Subkutan, Intraperitoneal
Enteral OralParenteral Non OralTopikal, Transdermal
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
4/19
07/09/2009
4
OBATLullman, Color AtlasPharmacologyTUJUAN RUTEOBAT :
.2.SISTEMIK
Lullman, Color Atllas Pharmacology, 2002
IDEALNYA DELIVERI OBAT
.
2.Reprodusibel
3.Mudah untuk diakhiri4.Tidak ada / kecil ESO
•Sediaan ditelan dan diabsorpsi dalam saluran cerna
•Keuntungan :
- Pemakaian mudah, sendiri
- Ekonomis
- Aman- Tidak sakit
•Kerugian :
- ua , mun a
-Tidak stabil dalam GIT
- Absorpsi Errartic
- Interaksi dengan makanan
- First Pass Metabolism
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
5/19
07/09/2009
5
•Sebagian besar obat diabsorpsi – difusi pasif
• er a sepan ang sa uran cerna
•Usus Halus >>>
Luas permukaan >>>(MIKROVILI)
Perfusi darah >>>
Mempertahankan gradien konsentrasi obatantara lumen usus - darah
•Pengosongan isi lambung usus halus
dalam lambungFeldman 1984 GET Soft drink 30’ Scrambled egg (digestible) 154’
Radio a ue undi estible 3-4jam•Partikel besar (tablet, kapsul) 3-6
jam- ada makanan
•PENGOSONGAN LAMBUNG
• –
•PERFUSI DARAH KE GIT
•INTERAKSI OBAT, MAKANAN•METABOLISME – FIRST PASS METABOLISM
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
6/19
07/09/2009
6
Laju absorpsi
Beberapa obat tidak stabil dalam suasana asam
Penundaan absorpsi terjadi peruraian
contoh : Penisilin
Faktor pengosongan lambung
- makanan : karbohidrat, rotein, lemak- obat : antikholinergik
analgesik narkotik
- Emosi
- dll (lihat Shargel, Ritchel)
Gerakan peristaltik normal
- mencampur s usus
- partikel obat kontak – mukosa usus
ABSORPSI
•Waktu tinggal (residence time) –harus cukup
•Small Intestine Transit Time (SITT) 3 – 4 jam
•Puasa lambung + usus 4 – 8 jam•Keadaan makan – SITT 6 – 12 jam
•Faktor ??
•Aliran darah penting untuk membawa obat
•Pembuluh kapiler mesenterika
•Aliran limfatik•“Splanchnis Circulation” 28% cardiac output
Meningkat setelah makan
Mengubah --- pH, motilitas, GET, kelarutan
- absorpsi obat ↑↑ : Griseofulvin
- absorpsi obat ↓↓ : penisilin, tetrasiklin
•Merangsang aliran empedu
- ↑↑ kelarutan lemak, obat larut lemak
• ,
- ↑↑ kelarutan -- ↑↑ absorpsi
•Keadaan puasa : absorpsi lebih baik
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
7/19
07/09/2009
7
Penyakit dapat mengubah:
- p am ung – usus
- Pengosongan lambung
- Motilitas saluran cerna
- Aliran darah intestin
- Permeabilitas dinding usus
- Sekresi enzim pencernaan
- Sekresi empedu
- Flora normal saluran cerna
ABSORPSI OBAT
First PassMetabolism - FPE
Hepatic Portal Pain
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
8/19
07/09/2009
8
MULUT – VENA JUGULARIS INTERNA
USUS
REKTAL - VENA H. SUPERIOR
- VENA H. MIDDLE
- VENA H. INFERIOR
oleh
Eka Deddy Irawan,S.Si.,M.Sc.,Apt. ag an armaset a a u tas armas n vers tas em er
To understand and describe the processes by
body
To understand the effect of protein binding
on drug distribution and methods by whichprotein binding is measured
Drug distribution means the reversible
another within the body
Once a drug has entered the vascular system
it becomes distributed throughout thevarious tissues and body fluids in a patternthat reflects the physiochemical nature of the drug and the ease with which itpenetrates different membranes
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
9/19
07/09/2009
9
1) The drug may remain largely within the,
as dextran and drugs which are stronglybound to plasma protein
2) Some are uniformly distributed,
molecular weight water soluble compounds(ethanol) and a few sulfonamides
3) A few drugs are concentrated specifically
be the site of action, ex: Iodine (in thethyroid gland), chloroquine (in the liver even
at conc 1000 times those present in plasma),tetracycline (irreversibly bound to bone anddeveloping teeth) and highly lipid solublecompoun s s r u e n o a ssue
4) Most drugs exhibit a non-uniform
by the ability to pass through membranesand their lipid/water solubility). The highest
concentrations are often present in thekidney, liver, and intestine.
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
10/19
07/09/2009
10
Drug Liters/Kg Liter/70 Kg
Chloroquine 94 - 250 94 - 250
Nortriptyline 211 500
Digoxin 7 500
Lidocaine 1.7 120
Theophylline 0.5 35
The volume of plasma is approximately 3-4L in an adult therefore a value of V in therange of 3-5 L would be compatible withpattern 1.
Pattern 2 would be expected to produce a Vvalue of 30 to 50 L, corresponding to totalbody water.
Dru s exhibitin attern 3 would exhibit verlarge values of V. Chloroquine has a V valueof approximately 17,000 L.
Drugs following pattern 4 may have a Vvalue within a wide range of values.
Fluid
substances
Volume (liter) Test
Extracellular
Fluid
13-16 Inulin, Na23, Br -,
I-
Plasma 3-4 Evans blue, I131
albumin,
dextrans
-
Intracellular
fluids
25-28
Total body water 40-46 Antipyrine, D2O,
ethanol
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
11/19
07/09/2009
11
Rate of distribution - Membrane
permeability
Blood perfusion
Extent of Distribution
-
Lipid Solubility
pH - pKa
Plasma protein
binding
Intracellular binding
A. Membrane permeability The capillaries are typically lined with
en o e um w ose ce s over ap, oug o alesser degree than epithelial cells. Also, thejunctions between cells are discontinuous.Capillary walls are quite permeable. Lipidsoluble drugs pass through very rapidly. Watersoluble compounds penetrate more slowly at arate more dependent on their size. Lowmolecular weight drugs pass through by simplediffusion. For compounds with molecular
ame er a ove rans er s s ow. For drugs which can be ionized the drug's pKa
and the pH of the blood will have a large effecton the transfer rate across the capillarymembrane.
i) Permeability is greatly increased in the renalcapillaries by pores in the membrane of theendothelial cells, and in specialized hepaticcapillaries, known as sinusoids which maylack a complete lining. This results in more
extension distribution of many drugs out of the capillary bed.ii) On the other hand brain capillaries seem to
have impermeable walls restricting thetransfer of molecules from blood to braintissue. Lipid soluble compounds can bereadily transferred but the transfer of polarsubstances is severely restricted. This is thebasis of the "blood- brain" barrier.
B. Blood perfusion rate
different organs varies widely
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
12/19
07/09/2009
12
Organ Perfusion Rate
(ml/min/ml of
tissue
% of cardiac
output
Bone 0.02 5
Brain 0.5 14
Fat 0.03 4
Heart 0.6 4
Kidneys 4.0 22
Liver 0.8 27
Muscle 0.025 15
Skin 0.024 6
Total blood flow is greatest to brain, kidneys,,
to brain, kidney, liver, and heart. It would beexpected that total drug concentrationwould rise most rapidly in these organs.Certain organs such as the adrenals(1.2/0.2%) and thyroid (2.4/1%) also have
arge per us on ra es.
Exam ple : thiopental gets into the brain faster than muscle, whereas,
penicillin gets into muscle more quickly than it gets into brain.
i) Thiopental is only partly ionized and passes into the brain ormuscle easily. Perfusion limits the transport. Since brain has ahigher perfusion rate the thiopental can transfer in and out morequickly.
ii) Penicillin is quite polar and is thus slowly permeable.Permeability limited transfer is faster in muscle as musclecapillaries are less restrictive. Thus transfer of penicillin is fasterin muscle than brain.
n ra n, per us on or mem rane permea ty m ts rugtransport or distribution. Thiopental diffuses readily, thusperfusion limits its distribution. Since perfusion is higher to thebrain than to muscle, transport to the brain is faster. Penicillinless readily diffuses thus it is diffusion which limits penicillindistribution. Muscle diffusion is easier thus distribution intomuscle is faster for penicillin than distribution into brain.
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
13/19
07/09/2009
13
A. Plasma protein binding
drug to stay in the central blood compartment.Therefore drugs which bind strongly to plasmaprotein tend to have lower volumes ofdistribution.
Of these plasma proteins, albumin, whichcomprises 50 % of the total proteins binds the
.bind to albumin, while basic drugs often bind toalpha1-acid glycoproteins and lipoproteins. Manyendogenous substances, steroids, vitamins, andmetal ions are bound to globulins.
Drugs Binding Sites for Acidic
Agents
Bilirubin, Bile acids, Fatty
Acids,Vitamin C, Salicylates,
Sulfonamides,Barbiturates,
Phenylbutazone,Penicillins,
Tetracyclines, Probenecid
Albumins
Binding Sites for Basic
Agents
Adenisine, Quinacrine,
Quinine,Streptomycin,
Chloramphenicol,Digitoxin, Ouabain,
Coumarin
Globulins, alpha1,
alpha2, beta1, beta2,
gamma
electrostatic interactions between groupson the rotein molecules with dru s i.e.
- the –NH3+ of lysine and N- terminal
amino acids,
- the –NH2+
- of histidine,- the - S- of cysteine- the - COO- of aspartic and glutamic
. van der Waal's forces (dipole-dipole; dipole-
induced dipole; induced dipole-induceddipole)
hydrogen bonding.
Agents which denature protein may cause.
Often there may be competition betweendrugs, in which agents that are bound very
tightly, such as coumarin anticoagulants, areable to displace less tightly boundcompounds from their binding sites.
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
14/19
07/09/2009
14
Drug Percent Unbound (100 * fu)
Caffeine 90
Digoxin 77
Gentamicin 50
Theophylline 85
Phenytoin 13
Diazepam 4
Warfarin 0.8
Phenylbutazone 5
Dicumarol 3
Slight changes in the binding of highly bounddrugs can result in significant changes in clinical
.the free drug in plasma which equilibrates withthe site of pharmacological or toxic response, aslight change in the extent of binding, such as 99to 98 % bound, which can result in an almost 100% change in free concentration, can cause verysignificant alteration in response.
For a large number of drugs, including warfarinand phenytoin, drug response will be dependent
on ree rug concen ra on. era on o reeconcentration by drug interaction or diseasestate can alter the intensity of action of thesedrugs. Examples include phenylbutazone andsalicylates displacing tolbutamide to give anincreased effect, hypoglycemia.
oleh
Eka Deddy Irawan,S.Si.,M.Sc.,Apt.Bagian Farmasetika Fakultas Farmasi Universitas Jember
The (BCS) has been developed to provide
prediction of in vivo pharmacokinetics oforal immediate release (IR) drug products
by classifying drug compounds based ontheir solubility related to dose andintestinal ermeabilit in combinationwith the dissolution properties of thedosage form
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
15/19
07/09/2009
15
The importance of drug dissolution in the
the gut wall barrier in the oral absorptionprocess has been well known since the 1960s,but the research carried out to constitutethe BCS has provided new quantitative dataof great importance for modern drug
eve opmen espec a y w n e area odrug permeability
According to the BCS, drug substances areclassified as follows:
Class I - High Permeability, High SolubilityClass II - High Permeability, Low SolubilityClass III - Low Permeability, High SolubilityClass IV - Low Permeability, Low Solubility
The BCS is a scientific framework for
aqueous solubility and intestinalpermeability. When combined with the
dissolution of the drug product, the BCStakes into account three major factors thatgovern the rate and extent of druga sorp on rom so ora osage orms:dissolution, solubility, and intestinalpermeability.
A drug substance is considered HIGHLY SOLUBLEwhen the highest dose strength is soluble in <250 ml water over a pH range of 1 to 7.5.
A drug substance is considered HIGHLYPERMEABLE when the extent of absorption in
humans is determined to be > 90% of anadministered dose, based on mass-balance or incomparison to an intravenous reference dose.
DISSOLVING when > 85% of the labeled amount ofdrug substance dissolves within 30 minutes usingUSP apparatus I or II in a volume of < 900 mlbuffer solutions.
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
16/19
07/09/2009
16
It can save both time and money—if theimmediate -release orall administered drumeets specific criteria, the FDA will grant awaiver for expensive and time-consumingbio-equivalence studies.
The aim of the BCS is to provide a regulatorytool for the replacement of certain BE studiesby conducting accurate in vitro dissolution
tests.
This step will certainly reduce timelines in thedru develo ment rocess both directl and,indirectly, and reduce unnecessary drugexposure in healthy volunteers, which isnormally the study population in BE studies.
It has also been reported that the applicationof a BCS strategy in drug development willlead to significant direct and indirect savings
for pharmaceutical companies
BCS has been developed primarily for,
several other applications in both the pre-clinical and clinical drug development
processes and has gained wide recognitionwithin the research-based industry
Combined with the dissolution, the BCS takes
governing bioavailability viz. dissolution,solubility and permeability.
This classification is associated with drugdissolution and absorption model, whichidentifies the key parameters controllingdrug absorption as a set of dimensionlessnumbers viz.
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
17/19
07/09/2009
17
Absorption number (An), defined as the ratio of
time.
Dissolution number (Dn), defined as the ratio ofmean residence time to mean dissolution time.
Dose number (D0), defined as the mass (Dose)divided by the product of (uptake volume (250
. 0 .
Class I drugs exhibit a high absorption.
rate limiting step is drug dissolution.
If dissolution is very rapid, then gastricemptying rate becomes the rate determiningstep.
e.g. Metoprolol, Diltiazem, Verapamil,
Propranolol.
Class II drugs have a high absorption number buta low dissolution number. In vivo dru dissolutionis then a rate limiting step for absorption exceptat a very high dose number. The absorption forclass II drugs is usually slower than class I andoccurs over a longer period of time.
In vitro- In vivo correlation (IVIVC) is usuallyexce ted for class I and class II dru s.
e.g. Phenytoin, Danazol, Ketoconazole,Mefenamic acid, Nifedinpine.
For Class III drugs, permeability is ratelimitin ste for dru absor tion. These dru sexhibit a high variation in the rate andextent of drug absorption.
Since the dissolution is rapid, the variation isattributable to alteration of physiology andmembrane permeability rather than thedosage form factors.
e.g. Cimetidine, Acyclovir, Neomycin B,Captopril.
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
18/19
07/09/2009
18
Class IV drugs exhibit a lot of problems.
Fortunately, extreme examples of class IVcompounds are the exception rather thanthe rule and are rarely developed andreach the market. Nevertheless a numberof class IV dru s do exist. e. . Taxol.
Once the solubility and permeability
becomes an easy task for the researchscientist to decide upon which drug delivery
technology to follow or develop.
The major challenge in development of drugdeliver s stem for class I dru s is to achieve atarget release profile associated with aparticular pharmcokinetic and/orpharmacodynamic profile.
Formulation approaches include both control ofrelease rate and certain physicochemicalro erties of dru s like H-solubilit rofile of
drug.
07/09/2009
-
8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh
19/19
07/09/2009
19
The systems that are developed for class II,
lyophilization, addition of surfactants,formulation as emulsions and microemulsionssystems, use of complexing agents likecyclodextrins.
Class III drugs require the technologies that
absolute or regional permeability. Peptidesand proteins constitute the part of class IIIand the technologies handling such materialsare on rise now days.
Class IV drugs present a major challenge for
route of choice for administering such drugsis parenteral with the formulation containing
solubility enhancers
top related