Kidney paracetamol

The half-life will be independent of the dose, provided that the elimination is first order and therefore should remain constant. Changes in the half-life, therefore, may indicate alteration of elimination processes due to toxic effects because the half-life of a compound reflects the ability of the animal to metabolize and excrete that compound. When this ability is impaired, for example, by saturation of enzymic or active transport processes, or if the liver or kidneys are damaged, the half-life may be prolonged. For example, after overdoses of paracetamol, the plasma half-life increases severalfold as the liver damage reduces the metabolic capacity, and in some cases, kidney damage may reduce excretion (see chap. 7). 

This is known as Michaelis-Menten or saturation kinetics. The processes that involve specific interactions between chemicals and proteins such as plasma protein binding, active excretion from the kidney or liver via transporters, and metabolism catalyzed by enzymes can be saturated. This is because there are a specific number of binding sites that can be fully occupied at higher doses. In some cases, cofactors are required, and their concentration may be limiting (see chap. 7 for salicylate, paracetamol toxicity). These all lead to an increase in the free concentration of the chemical. Some drugs, such as phenytoin, exhibit saturation of metabolism and therefore nonlinear kinetics at therapeutic doses. Alcohol metabolism is also saturated at even normal levels of intake. Under these circumstances, the rate of... 

Thus in some cases, enzyme expression is directly influenced in a particular organ by testosterone or estrogens. For example, in the mouse kidney, testosterone directly regulates the expression of cytochrome P-450 isozymes, and this leads to the particular sensitivity of the female kidney to the nephrotoxicity of paracetamol. 

Metabolic activation. Although the kidney does not contain as much cytochromes P-450 as the liver, there is sufficient activity to be responsible for metabolic activation, and other oxidative enzymes such as those of the prostaglandin synthetase system are also present. Such metabolic activation may underlie the renal toxicity of chloroform and paracetamol (see chap. 7). Other enzymes such as C-S lyase and GSH transferase may also be involved in the activation of compounds such as hexachlorobutadiene (see chap. 7). In some cases, hepatic metabolism may be involved followed by transport to the kidney and subsequent toxicity. 

It should also be mentioned that prostaglandin synthetase can activate paracetamol (Fig. 7.20) to reactive metabolites. Although probably not the primary route of activation in the liver, it has been suggested that this could be important in the kidney (which can also be damaged in paracetamol overdose). 

Chemicals which can damage (a) the liver include carbon tetrachloride, paracetamol, bromobenzene, isoniazid, vinyl chloride, ethionine, galactosamine, halothane, dimethyl-nitrosamine (b) the kidney include hexachlorobutadiene, cadmium and mercuric salts, chloroform, ethylene glycol, aminoglycosides, phenacetin (c) the lung include paraquat, ipomeanol, asbestos, monocrotaline, sulfur dioxide, ozone, naphthalene (d) the nervous system include MPTP, hexane, organophosphoms compounds, 6-hydroxydopamine, isoniazid (e) the testes include cadmium, cyclophosphamide, phthalates, ethanemethane sulfonate, 1,3-dinitrobenzene (f) the heart include allylamine, adriamycin, cobalt, hydralazine, carbon disulfide (g) the blood include nitrobenzene, aniline, phenyl-hydrazine, dapsone. 

Overdoses of paracetamol can be very dangerous, as the drug has a narrow therapeutic index and may cause hepatic and renal necrosis. Nausea, vomiting, lethargy, and sweating are the early overdose symptoms. Paracetamol must be given with caution in alcoholics and patients with liver and kidney damage. 

Aspirin, paracetamol, and hydrocortisone are used to control febrile reactions of amphotericin. Patients with a history of adverse effects with amphotericin should be prophylactically treated with antipyretics and hydrocortisone. Antiemetics and pethidine also are used for the treatment of adverse effects of amphotericin. With sodium supplements and hydration therapy, damage to the kidney can be reduced. If conventional amphotericin is not well tolerated by the patient, colloidal carriers can be used as alternative options. Administration of amphotericin with a nephrotoxic drug, such as cyclosporin, may further increase toxicity. Diuretics and anticancer drugs should be avoided with amphotericin. 

The metabolism of paracetamol (Figure 6.6) is an example of potential toxication. Paracetamol is metabolised primarily in the liver, via phase II metabolism, where its major metabolites include inactive sulphate and glucuronide conjugates, which are excreted by the kidneys. 

As up to 10% of about 42 000 dialysis patients have suffered from renal insufficiency due to analgesic nephropathy (in the postphenacetin era), German nephrologists have demanded that medications that contain fixed combinations of analgesics (paracetamol, aspirin, or propyphenazone plus caffeine) be withdrawn from the market, following the example of their US colleagues in the National Kidney Foundation (27). 

The principal sites for sulfation reactions are the liver and kidneys, although an important site, especially after oral administration of drugs, is the small intestine. Sulfation in the gut can seriously affect the bioavailability of some drugs such as paracetamol (see Figure 5.3) and is the main reason why adrenaline (epinephrine) is not effective when given orally... 

C. Lorz, P. Justo, A.B. Sanz, J. Egido, A. Ortiz, Role of Bcl-xL in paracetamol-induced tubular epithelial cell death, Kidney Int. 2005, 67, 592-601. 

It is an analgesic and an antipyretic with similar effectiveness as aspirin. It has a greater potential for toxieity (hemolytic anemia and methemoglobinemia) than paracetamol. Irreversible kidney damage with prolonged ingestion of phenacetin has been established whieh ultimately resulted in complete withdrawal of this drug in many countries. 

Adefovir is excreted by the kidneys, by a combination of glomerular filtration and active secretion via the rend transporter, human Organic Anion Transporter 1 (hOATl). The potential for pharmacokinetic interactions with co-trimoxazole, ibuprofen, lamivudine, paracetamol and tenofovir (other drugs that also undergo, or may affect tubular secretion) has been investigated. ... 

Extracorporeal shunts have been proposed for the treatment of several clinical conditions. The most likely applications for enzymatic treatment are the removal of urea during kidney failure, ronoval of toxins (e.g., paracetamol) during liver failure, or the reduction of key metabolites from the circulation to treat cancer. 

An analgesic drug which is metabolized to its pharmacologically active metabolite, paracetamol. However, it is now infrequently used because of its toxic effects on the kidney. 

A 27-year-old woman took paracetamol daily throughout pregnancy. She also took Benedictin and Vitron C, but the composition of these preparations was not mentioned. Severe anaemia in the 4th month necessitated blood transfusion. During the 5th month hydramnios developed and 8 amniocenteses were performed with the removal of 16 litres of fluid. The infant was bom at 34 weeks and died at 8 weeks of age at autopsy the non-functioning kidneys showed dilated distal tubules containing granular eosinophilic casts with scattered calcium oxalate and apatite crystals in the cortex (252 =). It is not clear why these changes should be attributed to maternal consumption of paracetamol. 

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