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CLINICAL PHARMACOKINETICS

FARMASI KLINIK / APOTEKER B KELOMPOK I (SATU)

1. An 81-years-old woman was admitted to hospital with a 3 week history of increasing jaundice and pale faeces and a 2-month history of darkening urine. The liver

function tests showed markedly raised serum total


bilirubin, ALP. and GGT with slightly elevated AST levels. Her plasma albumin level and prothrombin time were normal. A diagnosis of obstructive jaundice was made. Comment on hepatic drug clearance in this patient !

SOAL

Hambatan

aliran

empedu

yang

disebabkan

oleh

sumbatan mekanik menyebabkan terjadinya kolestasis

yang disebut sebagai ikterus obstruktif

Aktifitas enzim alkalifosfatase akan meningkat dan ini merupakan tanda adanya kolestasis.

Penyakit hati kolestatik ditandai dengan akumulasi substansi hepatotoksik, disfungsi mitokondria dan gangguan pertahanan antioksidan hati.

JAUNDICE OBSTRUKTIF

Feses biasanya menjadi pucat karena kurangnya bilirubin yang mencapai usus halus.

Ketiadaan garam empedu dapat menyebabkan malabsorpsi, mengakibatkan steatorrhea dan defisiensi vitamin larut lemak (A, D, K); defisiensi vitamin K bisa mengurangi level protrombin.

Retensi bilirubin menyebabkan hiperbilirubinemia campuran. Beberapa bilirubin terkonjugasi mencapai urin dan

menggelapkan warnanya.

PATOFISIOLOGI

1. When hepatocytes are damaged Clint decreases hepatic clearance reduces 2. If the drug has a hepatic first-pass effect BA will increases

3. A simultaneous effect of (1) and (2) results in extremely large increases in Css for orally administered drugs

Altered pharmacokinetic parameters

4. LBF decreases depresses hepatic drug clearance even further 5. The liver produces albumin and a-1-acid glycoprotein in the blood. The production of these proteins decline in patient with cirrhosis free fraction of drugs in the blood. 6. Since clearance decreases and Vd usually increases the t almost always increases.

Altered pharmacokinetic parameters

No single laboratory test to assess the liver function (not like CLCr to measure renal function) The most common way to estimate the ability of the liver to metabolize drug is to determine the Child-Pugh score

for a patient.
The Child-Pugh score consists of ve laboratory tests or

clinical symptoms. The ve areas are serum albumin, total


bilirubin, prothrombin time, ascites, and hepatic encephalopathy

Determination of Child-Pugh Scores

Determination of Child-Pugh Scores

Each of the symptom is given a score of 1

(normal) to 3 (severely abnormal), and the scores


for the five areas are summed.

The Child-Pugh score for a patient with normal liver function is 5, whereas for abnormal (hepatic damage) is 15

Determination of Child-Pugh Scores

A Child-Pugh score equal to 89 is grounds for a

moderate decrease (~25%) in initial daily drug


dose for agents that are primarily (60%) hepatically metabolized, A score of 10 or greater indicates that a signicant decrease in initial daily dose (~50%) is required for drugs that are mostly liver metabolized.

Determination of Child-Pugh Scores

For example, the usual dose of a medication that is 95% liver metabolized is 500 mg every 6 hours, and the total daily dose is 2000 mg/d. For a hepatic cirrhosis patient with a Child-Pugh score of 12, an appropriate initial dose would be 50% of the usual dose or 1000 mg/d. The drug could be

prescribed to the patient as 250 mg every 6 hours


or 500 mg every 12 hours.

Determination of Child-Pugh Scores

1. An 81-years-old woman was admitted to hospital with a 3 week history of increasing jaundice and pale faeces and a 2-month history of darkening urine. The liver function

tests showed markedly raised serum total bilirubin, ALP.


and GGT with slightly elevated AST levels. Her plasma albumin level and prothrombin time were normal. A diagnosis of obstructive jaundice was made. Comment on hepatic drug clearance in this patient !

KESIMPULAN

TES

SKOR

Total Bilirubin
Serum Albumin

3
1

Waktu Protrombin
Ascites

1
1

Hepatik Encefalopati
CHILD-PUGH SCORE

1
7

KESIMPULAN

1. E-book Applied Clinical Pharmacokinetics


2nd edition (2008)

PUSTAKA

2. A single dose antibiotic tablet 250 mg is administered to a man (32 years old; creatinine clearance 122 mL/min; 78 kg). According to the references, its Vd isi 21% of body weight and its elimination half-time 2 hours. Normally, 90% of the dose is available in systemic. Urine excretion of the drug that is not unchanged equal with 70% of absorbed dose. a) Count the total clearance of this drug ! b) Determine renal clearance of this drug ! c) What is the most likely mechanism for renal clearance of this drug !

SOAL

Klirens Total (ClT) = 21% 78 = 16,38 = 16380 = 0,693 2 = 0,3465/ =

= 0,3465 1 16380
= 5675,67 1 = , /

KLIRENS TOTAL OBAT (Cl )

= 70% = 0,7 0,3465 = 0,24255/

= = 0,24255 16380 = 3972,969 1

atau
= , /

KLIRENS GINJAL (Cl )

MEKANISME KLIRENS GINJAL

MEKANISME KLIRENS GINJAL

Laju filtrasi glomerulus diukur dengan menggunakan suatu obat yang dieliminasi hanya dengan filtrasi (tidak direabsorpsi atau disekresi). Contoh obatnya adalah inulin dan kreatinin. Oleh karena itu, klirens inulin atau klirens kreatinin sama dengan laju filtrasi glomerulus. Klirens inulin = 125-130 ml/menit

Klirens kreatinin = 122 ml/menit


Klirens obat = 66,22 ml/menit KESIMPULAN:

Karena klirens obat (Clr) lebih kecil daripada klirens inulin/kreatinin


maka mekanisme yang mungkin untuk klirens ginjal adalah obat difiltrasi dan sebagian direabsorpsi.

MEKANISME KLIRENS GINJAL

1. E-book Applied Biopharmaceutics and


Pharmacokinetics 5th edition

PUSTAKA

SEKIAN & TERIMA KASIH


FARMASI KLINIK / APOTEKER B