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TUGAS TOKSIKOLOGI LINGKUNGAN

TOKSIKOLOGI
PARASETAMOL
Oleh:
DINA YUSPITA SARI
NIM: H2061151002

TOKSIKOLOGI

PENGGOLONGAN:
Efek toksis akut
Efek toksik kronis

Hubungan ilmu dasar dan terapan dengan cabang
toksikologi (dimodifikasi dari LOOMIS 1979)

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TOKSIKOLOGI OBAT Pengujian obat yang potensial terhadap toksisitas dan toleransi terhadapnya pada fase praklinik .

5g to 1g every 4 to 6 hours with a maximum daily dose of 4g  Rectal doses for persons over 12 years of age are 0. with a maximum of four doses in a 24-hour period . oral and rectal doses depend on age and body weight.  In children.PARACETAMOL Paracetamol (N-acetyl-paminophenol) AINS dosis :  The conventional adult oral dose is 0.5g to 1g administered up to four times daily.

FARMAKOKINETIK PCT O HN O OCH3 N CYPs O OCH3 HN OCH3 + OH OH O acetaminophen quinone OH acetaminophen-3-ol .

BAB .

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TOKSISITAS PCT BAB .

MCH. MCHC and MCV suggesting interference with the hematological profile at the different doses. Hb total leucocyte count (TLC).  Thrombocytopenia in the course of acetaminophen overdose may be related to the risk of acetaminophen hepatoxicity .EFEK PCT TERHADAP PARAMETER BIOKIMIA Efect on Hematology Values  Doses ranging between 100 mg/kgBB to 500 mg/kgBB. acetaminophen induced damage to the liver promotes varying degrees of hematological parameters suggesting liver damage following changes in of Packed cell volume.

Hence.Efect on Coagulation System  Studies have shown that the coagulation system is activated at 2 hours after the administration of acetaminophen in mice. [44] investigated the impact of gender differences on blood coagulation parameters such as prothrombin time. activated partial thromboplastin time (aPTT).  Lemini et al. thrombin time and fibrinogen concentration (FIB) in mice in vivo. it has been suggested that thrombin is involved in acetaminophen induced liver damage . administration of heparin inhibited the activation of the coagulation system preventing acetaminophen liver damage at 6 hours of the study. This was determined by the increased concentration of thrombin anti thrombin complexes (TAT) and corresponded to the increase in ALT enzyme activity suggesting hepatic damage. . However.

glucose. and Malonyl dialdehyde (MDA) . in an earlier study a dose of 400 mg/kg body weight was shown to significantly elevate the levels of ALT starting 2 hours to 6 hours following acetaminophen administration . ALP. AST.  Other studies have also shown that induced damage to the liver is associated with changes in liver enzyme activities in animals study models. Findings showed insignificant changes in blood urea nitrogen. bilirubin and creatinine levels with reference to their controls. 400 mg/kg and 500 mg/kg of acetaminophen showed significant elevation in activity of ALT values suggesting damage to the liver.Efect on Liver System  A study on the effect of low doses of acetaminophen (16-66 mg/kg) was performed by Payasi et al. ALT. superoxide dismutase (SOD).  Another study using 300 mg/kg. However. Other enzymes assessed include glutathione (GSH).

.Acetaminophen and Liver Necrosis  Acetaminophen overdoses can cause liver injury and even failure in both animals and humans. The apoptotic cell death increased significantly for about 6. 400 mg/kg and 500 mg/kg. it was shown that apoptotic cell death was present at 2 hours after acetaminophen administration.  the number of apoptotic cells declined as the dose increased at the 3 doses of 300 mg/kg.3 cells out of 10 at about 6 hrs after administration.  Similar study findings with a dose of 3 g/kg body weight of acetaminophen showed that acetaminophen induced necrosis in the hepatoxicity groups in rats.  Another study also showed significant necrosis in hepatocytes cells administered with 400 mg/kg of acetaminophen at 6 hours after acetaminophen administration. In a study using 300 mg/kg of acetaminophen for induction of hepatoxicity. Cell death may occur as a result of apoptosis and necrosis.

kolesterol HDL dan rasio LDL/HDL 5 tikus (pct 18 mg. 4xsehari) 2 hari Kadar SGOT. kadar kolesterol LDL. 4xsehari) 4 hari .PENGARUH PARASETAMOL DOSIS ANALGESIK TERHADAP KADAR SERUM GLUTAMAT OKSALOASETAT TRANSAMINASE TIKUS WISTAR JANTAN Metode Animal and experimental design: Tikus jantan galur Wistar. usia 2-3 bulan (200-250 g) Aklimisasi selama 7 hari 5 tikus (kelompok kontrol) 5 tikus (pct 18 mg.

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parasetamol akan membunuh sel-sel hati dan menyebabkan kerusakan hati. Tingginya kadar enzim ini berhubungan langsung dengan jumlah kerusakan sel. Apabila GSH berkurang. SGOT terdistribusi pada sitoplasma dan mitokondria. sel-sel hati cenderung rentan mengalami kerusakan.  Rusaknya sel hati akan memicu enzim SGOT dikeluarkan ke sirkulasi. GSH merupakan faktor penting dalam pertahanan terhadap anti oksidan. sedangkan cedera hati berat akan menyebabkan pelepasan SGOT dari sitoplasma dan mitokondria. SGOT berasal dari fraksi sitoplasma di hepatosit. Mekanisme metabolit yang mengikat makromolekul-makromolekul selular.benzoquinonimin dalam sel hati menjadi sangat rendah. Cedera sel hati ringan akan melepaskan SGOT dari sitoplasma. Pada keadaan normal. Mitokondria merupakan target metabolit reaktif dari parasetamol  Hasil penelitian menunjukkan bahwa kadar GSH yang mengkonjugasi senyawa N-asetil-para. Berkurangnya GSH juga memungkinkan senyawa N-asetilpara-benzoquinonimin berikatan secara kovalen pada makromolekul sel sehingga terjadi disfungsi berbagai sistem enzim. . SGOT bermanfaat untuk mendiagnosa penyakit pada hati.

. sehingga dapat menjadi salah satu indikator kerusakan hati. Sehingga dapat dikatakan bahwa penggunaan parasetamol dosis analgesik untuk menangani nyeri akut pasca operasi dapat meningkatkan SGOT pada pasien.KESIMPULAN Pemberian parasetamol dosis analgesik setelah 2 dan 4 hari dapat meningkatkan kadar SGOT secara berbeda bermakna.

lighting 14 h light and 10 h dark with adequate ventilation 10 rats (control) 10 rats (pct 1 g/kgBB) 3 weeks 10 rats (ginger 1% w/w) 4 weeks 10 rats (pct 1 g/kgBB & ginger 1% w/w) 3 weeks . bean.Ginger (Zingiber officinale) potentiate paracetamol induced chronic hepatotoxicity in Rats Metode Animal and experimental design: 40 adult male albino rats (200±20 g) diet corn. Rh: 50%. bread. milk Allowed food & water ad libitum Acclimatization for 2 weeks Maintain (t: 18±1ºC.

5’ Serum Plasma Kept at -20ºC Estimation of serum activity of ALT. HDL-c. ALP. LDL-c and VLDL-c). AST.Preparation of blood Samples: Blood samples Withdrawn from the retro-orbital vein of each rat. collected into clean tubes Coagulated & centrifuged at 3000 rpm. total protein. GGT and LDH. albumin and globulin fraction levels and lipid profile (total cholesterol. . triglycerides.

glutathione-S-transferase (GST) and glutathione reductase (GR) activities and level of malondialdehyde (MDA) .Preparation of Liver Sample: Liver Weighed 500 mg/each liver Homogenized (25% w/v homogenate) Aliquote 1 Aliquote 2 Deproteinized with ice-cooled 12% trichloroacetic acid Centrifuged at 1000x Centrifuged at 1000x Supernatant Supernatant Estimation of reduced glutathione (GSH) content Estimation of glutathione peroxidase (GPx).

and GGT.Biochemical blood analysis : Serum levels of AST.8 on a cellulose acetate plate using both the electrophoretic and electroendosmotic forces the plate was placed in a solution of sulfosalicylic acid and Ponceau S stain to stain the protein bands Relative percents and absolute values for each band densitometer using 525 nm filter and the narrow slit with computer ) . ERMA-INC-Japan) and commercial diagnostic kits. triglyceride and HDL-c levels determined using automated enzyme analyzers (Biochemical analyzer AE 600N. Cholesterol. ALP. Separated protein (according to their respective electrical charges at pH 8. LDH. ALT.

GSH level in liver homogenate were estimated by spectrophotometer according to the method of Sedlak and Lindsay (1968). 1997). 1967). Glutathione reductase (GR) and glutathione-Stransferase (GST) activities were measured .OXIDATIVE STRESS AND ANTIOXIDANTS: Tissue lipid peroxides (LP) level was determined as thiobarbituric acid-reactive substances. Liver glutathione peroxidase (GPx) activity was determined using reduced glutathione and cummene hydroperxide as substrate by the modified method of (Paglia and Valentine.. measured as malondialdhyde (MDA) (Ohkawa et al.

Result and Discussion .

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Further experimental studies are necessary to explain such interaction. Unfortunately. ginger potentiates the toxic effects of paracetamol on liver indicating an interaction between them. induction of oxidative stress and depletion of antioxidant. .Paracetamol most notably caused hepatic toxicity as indicated by increased serum liver enzymatic activities. decreased albumin and increased globulin fractions.

Hematological and Histological Modulations in Acetaminophen Induced Hepatoxicity and the Potential of \ Urtica Dioica in the Regeneration of the Liver.. 2015.S. J.Daftar Pustaka Forte. No. Journal Drug Metabolism Toxicol. 6. Academic Journal-Journal of Medicinal Plant Research. Juma.A et al... A Review of the Biochemical. halaman 14. Thechronic ill. Lebda. 2002.K. et al. Ginger (Zingiber officinale) potentiate paracetamol induced chronic hepatotoxicity in Rats. M. 2013. Volume 7 (42). . K. halaman 1-7. Paracetamol: Safety versus Toxicity. Volume 6.