Renal Excretion of Paracetamol | Experiment

Renal Excretion of Paracetamol | Experiment Paracetamol, known as acetaminophen in the USA, is one of the most commonly used analgesic and antipyretic drugs available over-the-counter. Its common name derives from the full chemical name: para-acetyl-amino-phenol, with the chemical formula C8H9NO2Â  and a molecular weight of 151.17. Paracetamol does not have any significant anti-inflammatory action and therefore cannot be accurately described as a non-steroidal anti-inflammatory drug (NSAID), as was once thought. Its mechanism of action is still poorly understood but some studies have suggested that it inhibits a variant of the cyclo-oxygenase enzyme COX-1, which has been designated COX-3 (Swierkosz et al., 2002). Paracetamol acts mainly in the central nervous system and endothelial cells, rather than in platelets and immune cells. Boutaud and colleagues (2002) hypothesised that this may be explained by the high levels of peroxides found in the latter cell types, which inhibit the action of paracetamol. There has been some debate on the subject, with other researchers proposing an inhibitory action against COX-2 (Graham Scott, 2005). Further research is required to fully elucidate the mechanism of action at the molecular level. Following oral administration and absorption from the gastrointestinal tract, paracetamol enters the blood and is distributed throughout the body. It is metabolised by enzymes in the hepatocytes of the liver and the majority is converted to inactive metabolites by conjugation with sulphate or glucuronide. This is then filtered out of the blood by the kidneys and into the urine, via active renal tubular secretion. A small portion of paracetamol remains unaltered and passes into the urine via glomerular filtration and passive absorption (Morris Levy, 1984). There is also a small proportion of the paracetamol that is metabolised by the cytochrome P450 system, which results in the formation of cysteine or glutathione conjugates and mercapturic acid conjugates. These products of oxidative metabolism are also excreted renally (Andrews et al. 1976). Paracetamol has a low therapeutic index, so the therapeutic dose is very close to the toxic dose. Toxicity can occur following a single large dose (>10g) or with chronic lower doses (4-5g/d) and is usually seen as hepatotoxicity, which can result in death within several days (Wikipedia). Toxicity occurs when the enzymes responsible for catalysing sulphate and glucuronide conjugation become saturated, forcing metabolism to be increasingly dependent upon the cytochrome P450 system. This results in formation of a toxic metabolite, N-acetyl-p-benzo-quinone imine (NAPQI), which is normally mopped up by binding to the sulphydryl group of glutathione to form inactive conjugates and mercapturic acid. Toxicity occurs when the glutathione supply becomes exhausted and NAPQI binds indiscriminately to molecules within the cell, such as membranes, to cause cell damage and death, seen as acute hepatic necrosis. Major pathway for normal metabolism Minor pathway via cytochrome P450 system produces toxic metabolite (NAPQI), shown in red. Normally this is detoxified by binding to glutathione. Toxicity occurs when pathways 1 and 2 are overloaded and NAPQI binds to molecules of the cell, causing damage. Modified from Rang et al. 1995. The aim of this experiment is to investigate the renal excretion of paracetamol, by measuring the levels of paracetamol metabolites in human urine over 6 hours following an oral dose of 500mg. The total excretion will be assessed using the spectrophotometric method. From this data the elimination rate constant (KE) and the half-life (T1/2) will be calculated. Qualitative analysis of the various metabolites will be conducted using appropriate chemical identification techniques. METHOD A standard stock solution of paracetamol was prepared at 1mg/cm3 and dilutions were made to give a range of known concentrations. 1 cm3 of the paracetamol solution was added to 1 cm3 blank urine and 4 cm3 4M HCl, and mixed thoroughly. A blank duplicate was also prepared, using water instead of urine. After an hour in a boiling water bath the tubes were cooled and water added, up to 10 cm3. 1 cm3 of this hydrolysed urine solution was added to 10 cm3of colour forming solution, mixed and allowed to stand for 40 minutes. The absorbance of each solution was measured, using the spectrophotometer, zeroing the instrument using the drug free urine sample in between solutions. This produced the readings for the calibration curve. The collected timed urine samples were then processed in the same way, adding 1 cm3 water instead of paracetamol solution. RESULTS AND DISCUSSION Known concentrations of paracetamol underwent spectrophotometry to measure the absorbance at 620nm. These results were used to produce a calibration curve (figure 3). The timed urine samples were then analysed following the same protocol and the absorbance at 620nm was used, in conjunction with the calibration curve to ascertain the concentration of paracetamol in the urine. Unfortunately, half of the samples produced absorbances outside the range of the calibration curve. Because this curve is non-linear, extrapolation and dilution cannot be used to accurately deduce the concentration of paracetamol in the urine. For the purposes of this report the concentration for these samples has been declared as ‘greater than 800ug/cm3’. This is not very satisfactory and further experiments must be done to extend the range of the calibration curve to the maximum absorbancy of the timed samples. The values of KE and T1/2 have been calculated to demonstrate the procedure, but are ina ccurate and will need revising once accurate concentrations have been established form the calibration curve. Table 1: Timed urine sample Mean absorbance 620nm Conc. ug/cm3 Vol. Urine (ml) Total drug (ug of paracetamol) Excretion rate mg/h 0 0 0 0 0 0 1 hour 0.256 192 245 47040 47 2 hours 1.918 >800 50 40000 40 3 hours 1.769 >800 38 30400 30.4 4 hours 1.028 >800 55 44000 44 5 hours 0.349 246 135 33210 33.2 6 hours 0.255 192 160 30720 30.7 Table 1 contains the absorbance results of the timed urine samples and the deduced concentration of paracetamol in the urine, as well as the hourly excretion rate. The total amount of paracetamol excreted over the 6 hour period was 225.3mg, which is 45% of the orally administered dose. Due to problems discussed above, this is an underestimate of the true percentage of dose excreted renally, which has been found to be 55-70% by other studies (Steventon et al., 1996). When log of the excretion rate (equivalent to total drug excreted per hour) is plotted against time, a linear plot should be achieved, from which KE can be estimated. This is shown in Figure 4, but is likely to need revising. The slope of this straight line equates to : KE /2.303, which gives a value for KE of 0.094. Using the formula: T1/2 =0.692/ KE , the value of T1/2 = 7.36 hours. This states that it takes the body 7.36 hours to excrete half of the drug administered. This is longer than the 1-4 hours usually quoted for paracetamol (Rang et al. 1995), and is not surprising given the underestimation of the paracetamol urine concentration. With proper calibration, this would be expected to decrease to nearer the previously found results. There were no results for the qualitative studies for metabolite composition, but it would be expected that sulphate and glucuronide conjugates would constitute the majority of the sample, with a smaller quantity of unchanged paracetamol, cysteine/glutathione and mercapturic acid metabolites. These results only represent one individual on one day and replications of this experiment are crucial. Nutritional status, recent alcohol consumption, ethnic background, concurrent drug usage and illness must all be taken into account as factors that may affect paracetamol metabolism and excretion (Riordan Williams, 2002, Patel Tang, 1992). Further analysis of paracetamol excretion Hepatotoxicity and drug interactions Table 2 shows how concurrent use of phenobarbital, an anti-epileptic drug, can increase the severity of liver damage caused by paracetamol administration and its subsequent metabolism. Table 2: Effect of Phenobarbital on paracetamol induced hepatotoxicity Treatment Dose of Paracetamol (mg/kg) Severity of liver necrosis None3751-2+ Phenobarbital3752-4+_________ This occurs due to metabolism of phenobarbital by enzymes of the P450 cytochrome system, which results in upregulation of their production. As explained in the introduction (see fig. 2), P450 enzymes also metabolise paracetamol, to form the toxic metabolite NAPQI. This is normally a minor pathway but as the amount of P450 enzymes available increases, the activity of this pathway also increases. This results in a larger than normal amount of NAPQI, which is mopped up and inactivated by glutathione. Glutathione supplies will eventually run out, which occurs sooner if the person is malnourished. When this happens the toxic metabolite binds to cell components, causing necrosis. To prevent this occurring, such as in cases of overdose, N-acetylcysteine can be given (Routledge et al., 1998), which is required for glutathione synthesis and helps to boost it. This allows a greater amount of the toxic metabolite to be mopped up and reduces cell damage. Paracetamol metabolism following hepatotoxicity Table 3: Plasma paracetamol concentrations (ug/cm3) PatientsPlasma paracetamol4 hrs after12hrs after Half life (h)ingestioningestion _______________________________________________________________ no liver damage (18)2.9 +/= 0.3163 +/=20 29.5 +/=6 liver damage (23) 7.2+/= 0.7296 +/= 26 124 +/=22___ Table 3 shows that, in a study, the ability of patients with liver damage to eliminate paracetamol from the blood is much decreased, compared to healthy people. This is seen by the prolonged half-life and the high levels of paracetamol in the plasma. The plasma level does come down by 12 hrs, which indicates that there is enough functional liver reserve to metabolise some of the drug, but the level is still very high. To ascertain whether it is just conjugation that is affected, or whether all the pathways are affected equally it would be necessary to quantify the levels of different metabolites in the blood and urine. As conjugation is responsible for the majority of metabolism, damage to all systems will still show up as affecting conjugation the most. In theory reduced clearance of a substance is useful for monitoring the severity of liver damage, but in the case of paracetamol it would be unwise as it could potentiate the hepatotoxic effects and worsen the liver condition. It is also unnecessary as there are already a number of reliable blood tests for liver function and damage. REFERENCES Andrews, R. S., Bond, C. C., Burnett, J., Saunders, A. Watson, K. 1976 Isolation and identification of paracetamol metabolites. J Int Med Res 4, 34-9. Boutaud, O., Aronoff, D. M., Richardson, J. H., Marnett, L. J. Oates, J. A. 2002 Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases. Proc Natl Acad Sci U S A 99, 7130-5. Graham, G. G. Scott, K. F. 2005 Mechanism of action of paracetamol. Am J Ther 12, 46-55. Morris, M. E. Levy, G. 1984 Renal clearance and serum protein binding of acetaminophen and its major conjugates in humans. J Pharm Sci 73, 1038-41. Patel, M., Tang, B. K. Kalow, W. 1992 Variability of acetaminophen metabolism in Caucasians and Orientals. Pharmacogenetics 2, 38-45. Rang, H. P., Dale, M.M., Ritter, J.M. 1995 Pharmacology: Churchill Livingstone. Riordan, S. M. Williams, R. 2002 Alcohol exposure and paracetamol-induced hepatotoxicity. Addict Biol 7, 191-206. Routledge, P., Vale, J. A., Bateman, D. N., Johnston, G. D., Jones, A., Judd, A., Thomas, S., Volans, G., Prescott, L. F. Proudfoot, A. 1998 Paracetamol (acetaminophen) poisoning. No need to change current guidelines to accident departments. Bmj 317, 1609-10. Steventon, G. B., Mitchell, S. C. Waring, R. H. 1996 Human metabolism of paracetamol (acetaminophen) at different dose levels. Drug Metabol Drug Interact 13, 111-7. Swierkosz, T. A., Jordan, L., McBride, M., McGough, K., Devlin, J. Botting, R. M. 2002 Actions of paracetamol on cyclooxygenases in tissue and cell homogenates of mouse and rabbit. Med Sci Monit 8, BR496-503. Wikipedia. http://en.wikipedia.org/wiki/Paracetamol.

Personal Narrative- Ridicule of a Child :: Personal Narrative Essays

Personal Narrative- Ridicule of a Child â€Å"Why do you ask?... Well, she’s weird.... For instance, she wears black outfits that cling to her body with red spandex.... No I’m serious. Her hair is half black and half blonde, too.... The other day she was walking down the hall with a red feathered boa wrapped around her neck.. .. Yeah, I see her every day sifting by herself in a corner all the time. . . . I guess you can’t blame her. What did happen to her when she was little?† â€Å"Oooonnnncccceeee I was at hhhhoooommmmeeee, and I ssssaaaawwww...† We despised the way her heart-shaped lips gawked open as she slurred her words. Mary Beth sounded like a lost, bleating lamb. She was the most entertaining character to imitate when my friends and I were at slumber parties. We all perfected the rhythmic pattern of her speech. And then there was her appearance. Mary Beth’s gangly body towered over the other fourth graders, and her lemon-blonde hair rested on her shoulders in knotted clumps. Strands of hair constantly fell in front of her face, and she would constantly sculpt them behind her ear. Every day she came dressed for school in brilliant colored leggings partially covered by a relaxed sweatshirt unevenly rolled at the sleeves. Her plump belly took shape under her shirts, creasing slightly, like a curtain conforming to its width. Her feet plowed into her white Keds and snuggled inside fluorescent socks scrunched at the ankle. Mary Beth’s Keds curved toward each other as she stepped, and it was evident she was pigeon-toed. (This was another characteristic we loved to imitate.) I saw her ferociously sprint during gym and on our Field Day. It was dreadful. Her leg stampeded into each other in an effort to run straight. Her arms flung back and forth anxiously like an ape’s, and I could see her tongue sticking out of her crooked mouth in determination. She was hopeless. Autumn was approaching, and so was Mary Beth’s birthday party. Incredibly, all the girls invited, including me, showed up. We even brought presents, the ones our moms had carefully picked out in consideration. We were too reluctant and far too busy with our own lives to shop for a person we mocked. The arrival of girls seemed unrealistic until I discovered why they had come. It was a party, who wouldn’t show up?

Effects of Social Problems Symptoms Essay

The symptoms of social problems among teenagers in this day will give you an impression of the enormous impact and in the individual, society and the State. Teens on this day is the main asset and it is essential in the development of the country at the time to come. Effect of long term and short term will surely apply if teenagers and society on this day does not know how to menanganani problems that exacerbated the tapered, this makes the formation of identity and the glory of the morals of our society’s eyes fragile self.Morals is mirrored themselves for personal and individual. If the individual has a bad character, then that personal individual will also be bad. Teens who have bad attitudes, and may give the impression to oneself, family, community, and country. One employee who was born this mortal circle like a white cloth sesuci no kotoranya, it is it is up on the individual it how he wants to mencorakkan his life. Individuals who mencorakkan himself with a good character will be seen noble and high, as opposed to the individual who mencorakkan himself with negative things will be perceived by the public and angle dicemuh round. For someone who had the title of Muslims are predominantly teens, good morals should be decorated with the things of faith and devotion to God. Instead, the muslim teenager kebanyankkan on today is not in accordance with the teachings of islam, by contrast, Nations and religions humiliating the country. Cannot be disclaimed warranties are also symptoms of social impression this gives a deep impression on a person’s teens. Families play a role that is very important because of the happiness and harmony of the institution of kekeluargaanlah something that society was formed. The collapse of the family institution will cause a loss of happiness and harmony experienced something of the community. The morals of an individual good and noble juveniles comes from a family institution that harmony and happy. Therefore, the collapse of morals in the family institution will give a great impression upon the happiness and harmony of the family institution. something As a result of his careless harmonian in family a family no doubt will be the enactment of penceraian. This will make the future children will be left unattended and not well maintained, beyond missing site dependent and bermanja. The effect the enactment of social problems such as drugs, addictive lepak cultures, prostitution, gambling, same-sex relationships and other issues. Falls and ups something the State, religion and the nation at present is to see morals and moral thing for society. The disclaimed warranties not the morals of adolescents in today’s highly membimbangkan society. If this is not dammed by the party – the party that, chiefly by the Empire, then it is not surprising, someday will come our society will crumble and collapse the morals of adolescents – Malay teen will chiefly rosak and perish. However there is the sharpest impression that will be seen on teen attitudes, and presumably today is not dammed quickly. People in this country will be porak-peranda, were divided and not United-ECE. As a result the bad feelings and prejudices will exist within the community. The nature of each curiga-mencurigai will be enthroned in the hearts of the people. This impression when menberi goes pergaduhan in the community. The incoherent issues will exist if pergaduhan this involves between two clans. As for the crime levels in the community will also increase to which this is due to the levels of moral collapse among teenagers has increased. The main implications against the State if the symptoms are not social ditengani soon will lead the country will lose the leadership generation upholstery in the future. This will make the country’s development will be terbantut kerancakan and State socioeconomic data into humid country because his social and moral collapse of the symptoms is high among the public. This makes the case for the crime levels in the country will also increase in line with increased social symptoms he while enhancing the perbelajaan of kos to reduce rates for the crime. Beyond the evils outside evils will seep into the country if the young generation today don’t know keep their morals. And, the main impression is that teens today are predominantly of Islamic morals teenagers crushed and then view rosak Gentiles against religion that we anuti on this day surely gone Askew and bad.

The Relationship Between Food, And Culture - 1433 Words

In every culture, habits involving food such as, choosing, cooking, and eating, play a significant role. Eating is understood and communicated in various symbolic ways because it is never a purely biological activity. The consumption of food is always infused with meaning. People with adequate food resources use food not only as a means for survival but a means for communication. Food is symbolic throughout the world in modern human history. The Boston Tea Party was about taxes, not tea. The turkey on Thanksgivings symbolizes the celebration between the Pilgrims and Native Americans. The Great Depression is symbolized with pictures of bread lines and people selling apples. This paper will discuss the multifaceted relationships among food, and culture. I will be looking at the relationships people have with food, and explore how this relationship reveals information about them. Their food choices of individuals and groups, can reveal their ideals, likes and dislikes. 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