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FARMAKOLOGI

Ernawati Sinaga

Farmakokinetik

&

Farmakodinamik

Farmakologi

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Farmakokinetika

1. Absorpsi

2. Distribusi

3. Biotransformasi/ Metabolisme obat

4. Eliminasi

Biotransformasi

•Konversi metabolik molekul obat atau xenobiotik menjadi bentuk lain

• Metabolit yang terbentuk, dapat lebih tinggi atau lebih rendah aktivitas biologisnya, dapat lebih toksik atau kurang toksik

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Biotransformasi Obat

1. Esensi: mengubah molekul obat sehingga mudah diekskresikan

2. Lokasi biotransformasi terutama di hati. Namun juga berlangsung di aringan lain: usus, ginjal, paru, kulit

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The first drug metabolite that was isolated was hippuric acid (a metabolite of

benzoic acid) in 1827

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Metabolisme Obatterdiri dari dua fase:

•Fase I (reaksi fungsionalisasi)

•Fase II (reaksi konjugasi)

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Fase I (Reaksi

Fungsionalisasi)• Mengubah molekul obat menjadi

metabolit yang lebih polar dengan menambahkan atau “unmasking” gugus-gugus fungsional (-OH, -SH, -NH2, -COOH, dsb.)

• Enzim-enzim yang terlibat terutama enzim-enzim mikrosomal yang terdapat di endoplasmik retikulum (ER) sel-sel hepar CYP 450 (sitokrom P450)

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Fase I

(Reaksi Fungsionalisasi)

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Tipikal Reaksi Fase I

•Oksidasi

•Reduksi

•Hidroksilasi/Hidrolisis

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Epoksidasi

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Metabolisme Propoxyphene Fase I Reduksi

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Hidroksilasi Aromatik

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Metabolisme Fasa II Reaksi Konjugasi

– Glukuronat – Glukosa

– Sulfat

– Asetat

– Metil

– Glutation

– Dan lain-lain

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SOME PHASE II REACTIONS

Type of Conjugation

Endogenous Reactant

Transferase (Location)

Types of Substrates Examples

Glucuronidation UDP glucuronic acidUDP glucuronosyl

transferase (microsomal)

phenols, alcohols, carboxylic

acids, hydroxylamines, sulfonamides

morphine, acetaminophen,

diazepam, digitoxin, digoxin, meprobamate,

propranolol

Acetylation Acetyl-CoAN-Acetyl transferase

(cytosol)Amines

sulfonamides, isoniazid, clonazepam, dapsone,

mescaline

Glutathione conjugation

glutathioneGSH-S-transferase

(cytosolic, microsomes)

epoxides, nitro groups,

hydroxylamines

ethycrinic acid, bromobenzene

Sulfate conjugationPhosphoadenosyl

phosphosulfateSulfotransferase

(cytosol)

phenols, alcohols, aromatic amines

estrone, 3-hydroxy coumarin,

acetaminophen, methyldopa

MethylationS-Adenosyl-

methioninetransmethylases

(cytosol)

catecholamines, phenols, amines,

histamine

dopamine, epinephrine, histamine, thiouracil,

pyridine

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Metabolisme Propoxyphene

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Metabolisme Obat

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Metabolisme Parasetamol

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Faktor-faktor yang mempengaruhi Metabolisme

Obat1. Usia anak-anak, lansia 2. Gender 3. Variasi genetik antar spesies4. Variasi genetik intra spesies

(antar individu)5. Kondisi fisiologis, patologis

a. Penyakit b. Kehamilan

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Faktor-faktor yang mempengaruhi Metabolisme

Obat

6. Induksi dan inhibisi enzima) Makanan/Dietb) Interaksi obat c) Faktor lingkungan

7. Jalan masuk (Route of Administration)

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Induksi atau Inhibisi Enzim

Interaksi Obat

(dengan obat lain, makanan, suplemen, atau zat lain)

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Beberapa Isoform CYP450 yang penting

• CYP3A4: 50%• CYP1A2• CYP2C9 • CYP2C19• CYP2D6• CYP2E1

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Inhibitor CYP3A4

Antiarrhithmics Amiodarone

Antibiotics/ Antibacterials

Clarithromycin, erythromycin, metronidazole, norfloxacin, troleandomycin

Antidepressants

Fluoxetine,* fluvoxamine, mirtazapine,* nefazodone HCl, paroxetine,* sertraline*

Antifungal Fluconazole, ketoconazole, itraconazole

Others Other Grapefruit juice, quinine

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Induktor CYP3A4

• Rifampicin• Carbamazepine• Dexamethason• Prednisone• Methylprednisolone• Lovastatin• Phenobarbital• Phenytoin• Spironolactone• St. John’s Wort

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Enzyme Induction

No inductionNo induction

PhenobarbitalPhenobarbital inductioninduction

BenzopyreneBenzopyreneinductioninduction

Time (hrs)Time (hrs)11

1010

100100

Pla

sma

Lev

elZ

oxa

zola

min

e (

g/m

l)

(Classic barbiturate(Classic barbiturate effect)effect)

(Generated from(Generated fromgrilling meat)grilling meat)

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Polimorfisme Genetik

• Beberapa orang tertentu memetabolisme obat-obat tertentu lebih/kurang efisien daripada kebanyakan orang pada umumnya karena tubuhnya memproduksi lebih banyak/ sedikit enzim-enzim pemetabolisme tertentu

• Oleh sebab itu, farmakokinetika obat tersebut dapat saja berbeda pada orang-orang tertentu tersebut.

Eliminasi/Ekskresi

•Pengeluaran zat dari dalam tubuh melalui berbagai jalur ekskresi

Jalur ekskresi

• Ginjal urin

• Saluran pencernaan faeces

• Saluran pernafasan

• Kelenjar keringat

• saliva

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Ekskresi melalui Ginjal

• Filtrasi di glomerulus

• Sekresi aktif di tubuli proksimal

• Reabsorpsi pasif di tubuli proksimal dan distal

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Enterohepatic Recycling

• Beberapa macam obat mengalami eliminasi melalui empedu dalam bentuk yang tidak berubah atau dalam bentuk terkonjugasi.

• Obat yang dieliminasi melalui empedu dapat terabsorpsi kembali melalui saluran pencernaan.

• Masuknya molekul obat kembali ke dalam sirkulasi setelah di”eliminasi” melalui empedu menyebabkan terjadinya “daur ulang” obat, yang menyebabkan makin lamanya waktu yang diperlukan untuk eliminasi obat secara tetap (irreversibel) dari dalam tubuh.

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Molecular weight and polarity are the primary determinants of biliary

excretion:• Agents that are excreted in the bile are generally large

polar molecules. This would include many drugs conjugated with glucuronic acid.

• Some drugs have been specifically designed so as to increase the fraction of the drug that is eliminated in the bile. This provides some options when needed to treat patients with significant renal dysfunction.

• Selecting a drug eliminated primarily by biliary excretion obviates the need to make dosage adjustments due to the patients reduced renal function.

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Pharmacokinetic Parameters: Elimination

1. Clearance: Rate of drug elimination : Plasma drug concentration

2. Renal clearance: Rate of renal excretion of drug : Plasma drug concentration

3. Metabolic clearance: Rate of drug metabolism / Plasma drug concentration

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Pharmacokinetic Parameters: Elimination

5. Rate of elimination: Renal excretion + Extrarenal (usually metabolic) elimination

6. Elimination rate constant: Rate of drug elimination ÷ Amount of drug in body

7. Half life: The time required to reduce the amount of drug in the body or concentration of drug in blood by 50%.

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Klirens / Clearance (Cl)

• ….. volume plasma yang dibersihkan dari obat per satuan waktu.

• Laju eliminasi (oleh seluruh tubuh): kadar obat dalam plasma

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Konstanta Eliminasi (kel)

…. adalah fraksi obat di dalam tubuh yang dieliminasi per unit waktu tertentu

This is represented by the slope of the line of the log plasma concentration versus time.

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Hubungan Vd, Cl, dan kel

• Cl = kel x Vd

• Kecepatan eliminasi = Klirens x konsentrasi obat di dalam darah

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Waktu paruh eliminasi (t1/2)

the time taken for plasma concentration to reduce by 50%.

After 4 half lives, elimination is 94% complete.

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Elimination rate constant (Kel)

• With first-order elimination, the rate of elimination is directly proportional to the serum drug concentration (SDC).

• There is a linear relationship between rate of elimination and SDC. Although the amount of drug eliminated in a first-order process changes with concentration, the fraction of a drug eliminated remains constant.

• The elimination rate constant (Kel) represents the fraction of drug eliminated per unit of time

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Half-life (t ½)

• Another important parameter that relates to the rate of drug elimination is half-life (t ½).

• The half-life is the time necessary for the concentration of drug in the plasma to decrease by half.

• Both t ½ and Kel attempt to express the same idea, how quickly a drug is removed, and therefore, how often a dose has to be administered. An important relationship between t ½ and Kel can be shown by mathematical manipulation:

T ½ = 0.693 / Kel

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Analogi:

• You have a 10ml container of orange squash. You put this into a litre of water. The Vd of the orange squash is 1000ml. If, each minute, you empty 10ml of the orange liquid into the 10ml container, discard this, and replace it with 10ml of water, the clearance is 10 ml per minute. The kel is Cl/Vd = 10/1000 = 0.01. T ½ = 0.693 / Kel 0.693/0,01 = 69.3

• If the volume of the container is increased to 2000ml, then the clearance remains the same, but the Vd, and consequently the t1/2, increases.

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Practice problem-1

• Gambarlah grafik yang menunjukkan hubungan antara berat molekul obat dengan kecenderungan (persentase) ekskresinya melalui empedu.

• Graph the relationship between molecular weight and % of drug excreted in the bile.

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Answer for p-1

• There are two important elements to note in this relationship. First, there is some minimum molecular weight (MW) that must be exceeded before drug appears in the bile. The exact molecular weight cut-off varies among species. Second, note that as MW increases, there is an increase in the % eliminated in the bile.

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Practice problem-2

• Drugs that undergo enterohepatic recirculation sometimes demonstrate an interesting phenomenon seen in the plasma concentration versus time curve. After oral administration, concentration will rise to achieve a peak (as expected), then begin to decline (which is expected after the absorption phase is complete). However, during then decline phase, there are episodic periods of increases in the drug concentration (without the administration of additional doses of drug) that provides a declining curve interspersed with multiple ‘blips’ of brief increases in concentration. This phenomenon is most readily seen with drugs that have a long half-life. Provide an explanation of this phenomenon in the context of biliary excretion.

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Soal latihan-2

• Obat-obat yang mengalami resirkulasi eneterohepatik seringkali menunjukkan fenomena menarik yang ditunjukkan dalam gambaran kurva konsentrasi plasma vs waktu. Setelah konsumsi per oral, konsentrasi plasma akan meningkat sampai mencapai puncak, kemudian akan menurun (sebagaimana yang diharapkan terjadi setelah absorpsi sempurna). Akan tetapi, selama fase menurun tersebut, terjadi beberapa periode episodik dimana konsentrasi obat dalam plasma meningkat (tanpa penambahan dosis) kemudian menurun kembali. Fenomena ini terutama jelas terlihat pada obat-obat yang memiliki waktu paruh panjang. Berikan penjelasan mengenai fenomena ini, hubungkan dengan ekskresi obat melalui empedu (biliary excretion).

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Penentuan Ketersediaan Hayati

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Answer for p2

• When drug is secreted into the bile, it is not immediately emptied into the intestines. Rather, it is delivered to the gall bladder where it is stored until periodic emptying occurs associated with food ingestion. This creates a ‘reservoir’ of drug that is periodically emptied into the small intestine, thereby allowing periodic drug enterohepatic recycling. This can result in a rise in drug concentration, causing periodic increases in an otherwise declining concentration versus time curve.

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Practice problem-3

• Drug X has a half life of 4 hours and is administered as an intravenous bolus dose to produce a concentration of 100 g/ml.

• How long after administration of the dose of Drug X will the concentration drop to 25 g/ml?

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Answer for p-3

• 8 hours. • Since the half-life of the drug is 4 hr,

the concentration will decline from 100 mcg/ml to 50 mcg/ml in 4 hr. In another 4 hr it will decline from 50 mcg/ml to 25 mcg/ml.

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Practice problem-4

• Teofilin (obat asma) diberikan kepada pasien dalam bentuk infus (iv) dengan kecepatan 25 mg/jam. Setelah 3 hari diberikan infus secara terus menerus, tercapai konsentrasi konstan (steady-state) sebesar 10 mg/L. Hitunglah berapa nilai klirens (Cl) teofilin pada pasien ini.

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Answer to p4

• Dosing rate = 25 mg/hr

• Css = 10 mg/L

• CL = Dosing rate/Css

• CL = (25 mg/hr)/(10 mg/L)

• CL = 2.5 L/hr

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Panduan Belajar:

1. Jelaskan, apa yang dimaksud dengan farmakologi, farmakokinetika dan farmakodinamika. Jelaskan definisi dan batasan ruang lingkupnya, serta jelaskan pula apa hubungan ketiga istilah tersebut.

2. Sebutkan 4 komponen dalam farmakokinetika, dan jelaskan masing-masing komponen tersebut.

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Soal Latihan

• Apa yang dimaksud dengan potensi obat? Apa bedanya dengan efikasi ? Jelaskan

• Jelaskan bagaimana resirkulasi enterohepatik (enterohepatic recycling) dapat mempengaruhi aktivitas obat.

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Panduan Belajar:3. Sebutkan faktor-faktor yang

mempengaruhi absorpsi obat, jelaskan

4. Apa yang dimaksud dengan ketersediaan hayati obat (drug bioavailability). Jelaskan mengapa ketersediaan hayati obat berperan besar dalam efektivitas terapi obat

5. Sebutkan beberapa jalur masuk (site of administration) obat. Jelaskan mengapa perbedaan jalur masuk obat dapat mempengaruhi ketersediaan hayati obat.

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Panduan Belajar:

6. Jelaskan 4 pola distribusi obat di dalam tubuh.

7. Sebutkan beberapa faktor yang dapat mempengaruhi distribusi obat, dan jelaskan masing-masingnya.

8. Jelaskan bagaimana protein plasma dapat mempengaruhi distribusi obat.

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Panduan Belajar:

9. Apa yang dimaksud dengan Volume distribusi (Vd), jelaskan.

10.Mengapa keadaan patologis pasien, misalnya dalam keadaan dehidrasi atau gagal ginjal, dapat mempengaruhi Volume distribusi

11.Bagaimana pengaruh sifat lipofilisitas/ hidrofilisitas obat terhadap nilai Vd? Jelaskan

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Istilah yang perlu difahami-1:

• Farmakologi• Farmakinetika• Farmakodinamika• Absorpsi• Distribusi• Metabolisme/Biotransformasi obat• Eliminasi dan Ekskresi obat• Bioekivalensi• Bioavailability (Ketersediaan hayati)

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Istilah yang perlu difahami-2:

• Potensi Obat• Efikasi Obat• First pass effect• Pro drug• Volume Distribusi (Vd)• Klirens (Cl = Clearance)• T1/2 elimination

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Panduan Belajar:

1. Explain how substances travel across plasma membranes.

2. Explain the metabolism of drugs and its applications to pharmacotherapy.

3. Discuss how drugs are distributed throughout the body.

4. Describe how plasma proteins affect drug distribution.

5. Identify major processes by which drugs are excreted.

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Panduan Belajar:

6. Jelaskan bagaimana resirkulasi enterohepatik (enterohepatic recycling) dapat mempengaruhi aktivitas obat.

7. Explain the applications of a drug’s plasma half-life (t1/2) to pharmacotherapy.

8. Explain how a drug reaches and maintains its therapeutic range in the plasma.

9. Differentiate between loading and maintenance doses.