PEMBERIAN OBAT

PADA KELAINAN FUNGSI HEPAR

PEMBERIAN OBAT PADA
KELAINAN FUNGSI HEPAR

Dr. AGUNG WIWIEK INDRAYANI

BAGIAN FARMAKOLOGI
FK UNUD
Dr. AGUNG WIWIEK INDRAYANI
BAGIAN FARMAKOLOGI FK UNUD
 HEPAR
 METABOLISME KARBOHIDRAT, ASAM
AMINO & PROTEIN
 PENYIMPANAN & METABOLISME
VITAMIN
 METABOLISME OBAT, BAHAN ASING,
HORMON
 OBAT – OBAT FUNGSI HATI
KERUSAKAN HATI

PENYAKIT HATI RESPONS THD OBAT

METABOLISME
AKUMULASI METABOLIT
KESEIMBANGAN CAIRAN ELEKTROLIT
PROTEIN PLASMA
 EFEK TOKSIK OBAT/BAHAN
KIMIA PADA HEPAR
 CHOLESTATIC JAUNDICE
(ASA, Erythromycin Estolat, Penicillin,
Sulfonamid, Methyl Testosteron, Chlorpropamid,
Chlorpromazine)
 HEPATOCELLULAR REACTION
predictable type
unpredict type
 CARCINOGENESIS

( Nitrosamin, Aflatoxin )
 Predictable Type
Dose related, > treshold dose, dpt diulang pada binatang
coba
 Berhubungan dengan metabolisme bilirubin

- Novobiocin, Derivat testosteron ( substitusi pada

C-17 )

 Berhubungan dengan kerusakan sel hepar

- Carbon tetrachloride, tetracycline,
paracetamol, chloroform, anticancer drugs
 Unpredictable Type
Tdk dose related, hanya pada beberapa orang, tdk
Diulang pada binatang coba
 HEPATITIS –LIKE REACTION
- MAO INHIB, HALOTHANE,CHLOROFOM
 CHOLESTATIC INJURY
- PHENOTHIAZINE ( CPZ), CHOLRPROPAMIDE,
THIOURACIL

 GENERALIZED DRUG ALLERGIES

- PENICILLIN , SULPHONAMIDE, PAS, PHENYTOIN,
IMIPRAMINE
DRUG INDUCED LIVER INJURY
 KLASIFIKASI
* TYPE A (Augmented) terjadi karena dosis
- CENTRIZONAL NECROSIS ( paracetamol ,
carbon tetrachloride )

- HEPATOCELLULER NECROSIS
( salicylate > 2 g/hari )

- FATTY LIVER AND HEPATIC FAILURE

( tetracycline > 2 g/hari oral )

- HEPATITIS ( ALKOHOL >>, AMIODARONE > 600 mg/hari)

* TYPE B ( BIZARRE) – pada dosis terapi
- ACUTE HEPATOCELLULAR NECROSIS
( Halothane, Carbamazepine, Phenytoin, SOD ,
Valproate, Phenobarbitone, MAO, INH,
Indomethacine, Ibuprofen, Isoniazid, Sulphonamide,
Nitrofurantoin, Methyl-Dopa, Hydralazine)

- CHOLESTATIC HEPATITIS
( Chlorpromazine, OAD, Carbimazole, Erythromycin,
Gold )
* TYPE C ( CONTINUED USE)
- CHRONIC ACTIVE HEPATITIS
( Methyldopa, Isoniazid, Dantrolene, Nitrofurantoin )
- HEPATIC FIBROSIS OR CIRRHOSIS
( Alcohol, MTX, Amiodarone )

* TYPE D ( DELAYED EFFECTS)

- BENIGN LIVER TUMOR
( Anabolic steroids, oral contraceptives > 5 years )
- Hepatocelluler carcinoma
 paracetamol
Paracetamol Glucoronide ,
Detoxification Sulphate

Glutathione
Intermediate Conjugate
Metabolite ( Mercaptopurine Acid )

Cell. Damage
Protein
 CIRRHOSIS HEPATIS
 Peningkatan PLASMA HALF LIFE
Amylobarbitone, Chloramphenicol ,
Phenylbotazone, Rifampicin,
Tolbutamide

 Penurunan Cholinesterase Activity

 Deficiency Hepatic Alcohol Dehydrogenase

 Prescribing in liver disease
bila benar-benar diperlukan
 CENTRAL NERVOUS SYSTEM
(Pethidine, lorazepam,
oxazepam,temazepam ,
TCA)
 CARDIOVASCULAE SYSTEM
( beta blocker,
calcium channel blocker dose menurun )
 GI System
antasidfluid retention,
constipation  abs. toxic substance
meningkat
 RESPIRATORY SYSTEM
Theophylline dose menurun
 DOSE ADJUSTMENT FOR PATIENS
WITH HEPAR IMPAIRMENT

1. Adjustment of the initial dose

2. Adjustment of the maintenance dose
3. Special cautions
 Biotransformasi
Obat yang larut dl. air

Obat yang larut dalam lipid

Hati
Saluran cerna
Paru

ekskresi
Ekskresi
Biotransformasi fase I / Asintetik
 Oksidasi (cytochrome P450)

 Reduksi

 Hidrolisis

 Deamination

Biotransformasi fase II / Sintetik konyugasi dengan :

Asam glucuronic
Asam asetat (Acetylation)
Glycin
Asam sulfat
Glutamin
 Induksi Enzym / Enzyme inducer

o Barbiturate : Coumarin
Pil kontrasepsi

o Phenytoin : Dexamethasone
Pil kontrasepsi

o Merokok : Nicotine
(Nicotine ) Pil kontrasepsi

Theophyllin
o Rifampicin : Pil kontrasepsi
 Enzyme Inhibitor / inhibisi enzim

o Chloramphenicol Phenytoin
Tolbutamide

o Cimetidine Chlordiazepoxide
Diazepam
Chlorazepate
Phenytoin
Theophyllin
 PHARMACOKINETIC
1. Drugs metabolising capacity is reduced
2. Liver cells that metabolise drugs are
bypassed
3. Liver disease cause hypoproteinaemia,
allowing more unbound and active drugs to
circulate
 PHARMACODYNAMIC

1. Cellular response to drugs may alter

CNS sensitivity to opioids, sedatives,
antiepilepsy
2. Fluid and electrolyte balance are altered
Sodium retention (induced by NSAID,
corticosteroid)
Ascites and oedema
 Dosage in liver disease

Tergantung BSP retention

 BSP retention < 5% (No Liver Damage)

 BSP retention 5-25% (Mild Liver Damage)

dosis maintenance dikurangi 25-50%

 BSP retention 25-75% (Severe Liver Damage)

dosis maintenance dikurangi 50-80%

 BSP retention >75% (Very Severe Liver Damage)
dosis maintenance dikurangi 80%