CLINICAL PHARMACOKINETICSFARMASI KLINIK / APOTEKER B
KELOMPOK I (SATU)
SOAL
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 !
JAUNDICE OBSTRUKTIF
• 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.
PATOFISIOLOGI
• 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.
Altered pharmacokinetic parameters
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
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 t½ almost always increases.
Altered pharmacokinetic parameters
Determination of Child-Pugh Scores
• 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 five laboratory tests or clinical
symptoms. The five 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 8–9 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 significant
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.
KESIMPULAN
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 3
Serum Albumin 1
Waktu Protrombin 1
Ascites 1
Hepatik Encefalopati 1
CHILD-PUGH SCORE 7
PUSTAKA
1. E-book Applied Clinical Pharmacokinetics
2nd edition (2008)
SOAL
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 !
KLIRENS TOTAL OBAT (ClT)
Klirens Total (ClT)
KLIRENS GINJAL (Clr)
atau
MEKANISME KLIRENS GINJAL
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.
PUSTAKA
1. E-book Applied Biopharmaceutics and
Pharmacokinetics 5th edition
SEKIAN & TERIMA KASIHFARMASI KLINIK / APOTEKER B
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