perjalanan obat dan nasib obat dalam tubuh

8/18/2019 Perjalanan Obat Dan Nasib Obat Dalam Tubuh

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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 ??


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•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


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•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


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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


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•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


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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


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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


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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


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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.


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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


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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


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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.


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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.


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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


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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.


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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.


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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.


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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.

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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

perjalanan obat dan nasib obat dalam tubuh

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