Acetaminophen administration

Bolesta S, Haher SL (2002) Hepatotoxicity associated with chronic acetaminophen administration in patients without risk factors. Ann Pharmacother 36 331-333. 

A large body of evidence is available examining the acute toxicity of acetaminophen in animal models. Mice and rats have been widely used to study the toxic effects of acetaminophen. Since the rat is relatively resistant, the mouse has been the most widely used species to study both the mechanisms of acetaminophen toxicity and to examine chemicals that potentiate or protect from the toxicity. Hepatotoxic-ity and nephrotoxicity are the two main effects associated with acute overdose of acetaminophen. Of these, death in most species is due to acute hepatic failure. LD50 values range from 350 to 4500mgkg depending on the species and the route of acetaminophen administration, mice (LD50 350-... 

WHson SP, Kamin DL, Feldman JM. Acetaminophen administration interferes with urinary metanephrine (and catecholamine) determinations. Clin Chem 1985 31 1093-4. 

Lin JH, Levy G. Sulfate depletion after acetaminophen administration and replenishment by infusion of sodium sulfate or N-acetylcysteine in rats. Biochem Pharmacol 1981 30 2723-5. 

Gomisin A protects the liver from injury by acetaminophen. One of its possible mechanisms involves the suppression of lipid peroxidation [265], It inhibited not only the elevation of serum aminotransferase activity and hepatic lipoperoxide content, characteristic of acetaminophen administration, but also the appearance of histological changes such as degeneration... 

Shi Y, Evans JE, Rock KL (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425 516-521 Smith GS, Nadig DE, Kokoska ER, Solomon H, Tiniakos DG, Miller TA (1998) Role of neutrophils in hepatotoxicity induced by oral acetaminophen administration in rats. J Surg Res 80 252-258... 

Liu ZX, Han D, Gunawan B, Kaplowitz N (2006) Neutrophil depletion protects against murine acetaminophen hepatotoxicity. Hepatology 43(6) 1220-1230 Lores Amaiz S, Llesuy S, Cutrin JC, Boveris A (1995) Oxidative stress by acute acetaminophen administration in mouse liver. Free Radic Biol Med 19(3) 303-310 Lou H, Kaplowitz N (2007) Glutathione depletion down-regulates tumor necrosis factor alpha-induced NF-kappaB activity via IkappaB kinase-dependent and -independent mechanisms. J Biol Chem 282(40) 29470-29481... 

Hepatotoxicity does not occur at recommended doses of acetaminophen. Administration of 2 g, or twice the recommended dose, of intravenous paracetamol in healthy subjects has been shown to stay far below the threshold of hepatotoxicity. When ingested at high doses, acetaminophen is metabolized to JV-acetyl-p-benzoquinone-imine (NAPQI). NAPQI is rapidly conjugated with glutathione to a nontoxic compound. The depletion of glutathione results in the accumulation of NAPQI that is responsible for liver injury. Acetaminophen has a narrow therapeutic window and even minor overdoses may cause severe hepatic injury. Liver necrosis occurs at 7.5-10 g of acetaminophen. 

Thus, acetylation of aniline affords acetanilide (20), an analgesic widely used in proprietary headache remedies. A similar transformation on p-aminophenol gives the analgesic, acetaminophen (21). It is of interest that the latter is also formed in vivo on administration of 21. An interesting preparation of this drug involves Schmidt rearrangement of the hydrazone (24) from p-liydroxyacetophenone. ... 

When administering acetaminophen, the nurse assesses the overall health and alcohol usage of the patient before administration. fatients who are malnourished or abuse alcohol are at risk of developing hepatotoxicity (damage to the liver) with the use of acetaminophen. 

The effects of metoclopramide are antagonized by concurrent administration of anticholinergics or narcotic analgesics. Metoclopramide may decrease the absorption of digoxin and cimetidine and increase absorption of acetaminophen, tetracyclines, and levodopa Metoclopramide may alter die body s insulin requirements. 

Bromobenzene, similarly to acetaminophen, is considered as model compound in liver necrosis (refs. 9-11, 20, 21). After the administration of these compounds, a considerable decrease in GSH levels, an increase in GTP activity in the serum and, histopathologically, necrosis of hepatocytes are observed. 

Amphotericin B is the mainstay of treatment of patients with severe endemic fungal infections. The conventional deoxycholate formulation of the drug can be associated with substantial infusion-related adverse effects (e.g., chills, fever, nausea, rigors, and in rare cases hypotension, flushing, respiratory difficulty, and arrhythmias). Pre-medication with low doses of hydrocortisone, acetaminophen, nonsteroidal anti-inflammatory agents, and meperidine is common to reduce acute infusion-related reactions. Venous irritation associated with the drug can also lead to thrombophlebitis, hence central venous catheters are the preferred route of administration in patients receiving more than a week of therapy. 

Fever, rigors, chills, malaise headaches, myalgia Nausea, emesis Neutropenia Hepatic enzyme elevation Cutaneous—alopecia, transient, mild rashlike reaction Acetaminophen (APAP). NSAID if APAP is not effective. Meperidine for severe chills and rigors. Bedtime administration. 5-HT3 antagonist, prochlorperazine, metoclopramide, fluids Weekly complete blood count reduce dose by 30-50% Liver function tests (LFTs) weekly withhold treatment until LFTs normalize restart at 30-50% dose reduction reversible on dose reduction or cessation. Interferon is contraindicated in patients with psoriasis because exacerbation of psoriasis has been noted during IFN therapy. 

Other potential adverse effects include impaired absorption of fat-soluble vitamins A, D, E, and K hypernatremia and hyperchloremia GI obstruction and reduced bioavailability of acidic drugs such as warfarin, nicotinic acid, thyroxine, acetaminophen, hydrocortisone, hydrochlorothiazide, loperamide, and possibly iron. Drug interactions may be avoided by alternating administration times with an interval of 6 hours or greater between the BAR and other drugs. 

A particular toxicity associated with the administration of interferon to humans and experimental animals has been depression of the cytochrome P-450 monooxygenase (MFO) metabolizing enzymes. As a consequence of MFO inhibition following treatment with IFN, the sleep-time of mice treated with hexabarbital is increased, as is the toxicity of acetaminophen (Stebbing and Week, 1984). Possible effects on the metabolism of chemotherapeutic agents or other drugs processed by the P-450 MFOs should be anticipated. 

B. K. (1967) Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration. British Journal of Pharmacology and Chemotherapy, 29, 150. 

Administration of chloroform to laboratory animals resulted in the depletion of renal GSH, indicating that GSH reacts with reactive intermediates, thus reducing the kidney damage otherwise caused by the reaction of these intermediates with tissue MMBs (Hook and Smith 1985 Smith and Hook 1983, 1984 Smith et al. 1984). Similarly, chloroform treatment resulted in the depletion of hepatic GSH and alkylation of MMBs (Docks and Krishna 1976). Other studies demonstrated that sulfhydryl compounds such as L-cysteine (Bailie et al. 1984) and reduced GSH (Kluwe and Hook 1981) may provide protection against nephrotoxicity induced by chloroform. The sulfhydryl compound N-acetylcysteine is an effective antidote for poisoning by acetaminophen, which, like chloroform, depletes GSH and produces toxicity by reactive intermediates. 

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