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Question : Paracetamol overdose can be fatal. Discuss the scientific basis of paracetamol overdose and its treatment, with reference to the following:
The main metabolites of paracetamol, including the pathways that lead to paracetamol overdose toxicity.
The clinical measurement of whether an overdose has occurred and the administration of an antidote is therefore needed.
How the antidote prevents hepatotoxicity.
Include chemical structures and reaction pathways in your answer.
Answer :
The main metabolites of paracetamol, including the pathways that leads to the paracetamol overdose toxicity can be seen as mentioned below:
During the paracetamol overdose, the pathways for the sulfate and glucuronide become saturated due to which large amount of paracetamol is pushed towards the cytochrome P450 system. This results in production of the toxic form of NAPQI. Due to this, the depletion of hepatocellular supplies of glutathione takes place. The toxic form of NAPQI so produced reacts with the cellular membrane molecules which leads to damage of hepatocytes and causes acute hepatic necrosis. And in case of higher extent of overdose it leads to hepatotoxicity.
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b.) A dose of 150mg/kg is considered to be an overdose and can cause risk of hepatotoxicity whereas the lower doses from 75-150mg are usually associated with the case of hepatic necrosis.
One of the method of prevention from the paracetamol absorption in case of overdose is immediate administration of activated charcoal and especially in cases of ingestions higher than 150mg/kg within an hour.
(c.) The antidote or acetylcysteine used in the paracetamol overdose helps to replenish the hepatic glutathione by acting as a surrogate to glutathione and then combines with the metabolites of paracetamol and thus prevents the hepatic or liver damage. In this process it increases the amount available for detoxification of NAPQI. In simple words, the administration of acetylcysteine is done for preventing from hepatotoxicity by binding with the breakdown products of paracetamol and blocks the pathways so that these breakdown products do not bind to the liver cells.
2. A. Reagents required
• Paracetamol and its metabolites, which included paracetamol-glucuronide, paracetamol-N-sulfate, catechol 3-hydroxyaminophen, 3-methoxy paracetamol, 3-cysteinyl paracetamol, and paracetamol-3-mercapturic acid, were first synthesized and then dissolved in methanol.
• The concentrations of paracetamol and its metabolites that were prepared for the calibration curves was 0.2–500 µg/mL.
B. Conditions for HPLC
• Column: a reversed phase column along with µBondapak C18 with 300 × 4.6 mm i.d. and particle diameter of 10 µm was used.
• Mobile phase: methanol or 0.1 M potassium dihydrogenphosphate that contained 0.75 % acetic acid in ratio of 7:93 (volume/volume).
• Detection wavelength: 248 nm or an electrochemical detector
• Flow rate: 1.5 mL/min;
• Column temperature: room temperature.
C. Procedure
i. 4 mL of 2 M acetate buffer solution of pH 5.0 along with 1-mL volume of urine were first placed in a centrifuge tube along with a stopper in duplicate.
ii. Two tubes were taken to which 50-µL aliquot of β-glucuronidase-sulfatase and 50 µL of 2 M acetate buff er (PH 5.0) was added separately in both the tubes.
iii. The tubes were then incubated at 37 °C overnight along with some shaking.
iv. Once the incubation was done, both the tubes were cooled using ice in order to stop the enzymatic reaction.
v. The tubes were subjected to the centrifugation after which the supernatant solution was transferred to a clean test tube.
vi. A 10-µL of aliquot from the supernatant liquid was then injected into HPLC.
vii. A varying concentrations of the standard solutions were then processed for constructing of the calibration curves.
The electrochemical detector so used depicted higher sensibility as compared to the UV detector set at 280 nm. It was found out that approximately 95 % of paracetamol was excreted in form of urine in its glucuronide-conjugate form. Hence it is possible to convert the conjugate into free paracetamol along with β-glucuronidase-sulfatase that was to be measured without an authentic standard of paracetamol-glucuronide.
D. Advantages
1. The method is simple as the biological samples can be injected without any prior treatment.
2. The Electro chemical detector allows a detailed study of the pharmacokinetics of the drug.
3. The analysis time is quite short; paracetmol can be seen to be eluted in less than 5 min in the mobile phase without using any organic modifier.
E. Disadvantage:
1. Lower resolution compared to UPLC/MS results where detection of more components can be done.
2. Low sensitivity due to which discovery of the low-level metabolites cannot take place.
3. Expensive method when compared to colorimetric method which produces rapid results than HPLC.
Journal Article Used:
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1. Bose, D., Durgbanshi, A., Martinavarro-Dominguez, A., Capella-Peiro, M., Carda-Broch, S., Esteve-Romero, J., & Gil-Agusti, M. (2005). Rapid Determination of Acetaminophen in Physiological Fluids by Liquid Chromatography Using SDS Mobile Phase and ED Detection. Journal Of Chromatographic Science, 43(6), 313-318. http://dx.doi.org/10.1093/chromsci/43.6.313
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2. Wilson, J., Slattery, J., Forte, A., & Nelson, S. (1982). Analysis of acetaminophen metabolites in urine by high-performance liquid chromatography with UV and amperometric detection. Journal Of Chromatography B: Biomedical Sciences And Applications, 227(2), 453-462. http://dx.doi.org/10.1016/s0378-4347(00)80398-9
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Place Your Order3.1. 11050= 181.4x + 8870. Concentration of replicate 1= x= 12.071 ppm
2. 10000= 181.4x+ 8870. Concentration of replicate 2= x= 6.22 ppm
3. 12000=181.4x+ 8870. Concentration of replicate 3=x=17.25 ppm
4. 11000=181.4x+ 8870. Concentration of replicate 4=x= 11.74 ppm
5. 13000=181.4x+ 8870. Concentration of replicate 5=x= 22.76 ppm
6. 9500=181.4x+ 8870. Concentration of replicate 6=x=3.24 ppm
Concentration of the metabolite = 73.281/ 6 = 12.2165 ppm.
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