Acetaminophen hepatic effects

D. Pharmacokinetics and Clinical Use Acetaminophen is effective for the same indications as intermediate-dose aspirin. Acetaminophen is therefore useful as an aspirin substitute, especially in children with viral infections and in individuals with any type of aspirin intolerance. Acetaminophen is well absorbed orally and metabolized in the liver. Its half-life, which is 2-3 hours in persons with normal hepatic function, is unaffected by renal disease. 

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. 

When taken in therapeutic doses (approximately 4 g 60mg/kg body weight) paracetamol (N-acetyl-para-ami nophenol, acetaminophen) is a safe and effective analgesic, but overdosage, possibly with the intent of self-harm, is a major cause of drug-induced hepatic toxicity. The cellular damage which may not be evident for up to... 

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. 

Because 1,4-dichlorobenzene is a liver toxin, it probably can interact with other chemicals that are liver toxicants. These toxicants are many, and include ethanol, halogenated hydrocarbons (chloroform, carbon tetrachloride, etc ), benzene, and other haloalkanes and haloalkenes. In addition, 1,4-dichlorobenzene toxicity may also be exacerbated by concurrent exposure with acetaminophen, heavy metals (copper, iron, arsenic), aflatoxins, pyrrolizidine alkaloids (from some types of plants), high levels of vitamin A, and hepatitis viruses. Such interactions could either be additive or S5mergistic effects. 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

Rimantadine (Flumadine) [Antiviral] Uses Prophylaxis Rx of influenza A viral Infxns but not for HlNl swine flu Action Antiviral Dose Adults Feds >9 y. 100 mg PO bid Feds 2-9 y. 5 mg/kg/d PO, 150 mg/d max daily w/ severe renal/hepatic impair elderly initiate w/in 48 h of Sx onset Caution [C, -] w/ cimetidine avoid w/ PRG, breast-feeding Contra Component amantadine allergy Disp Tabs SE Orthostatic X BP, edema, dizziness, GI upset, X Sz threshold Interactions T Effects W/ cimetidine i effects W/ acetaminophen, ASA EMS Concurrent EtOH usage may result in light-headedness, confusion, syncope, and hypotension OD May cause N/V, tremors, Szs, anticholinergic Sxs, ventricular arrhythmias give IV fluids... 

HA, mild pain Action Nonnarco tic analgesic w/ barbiturate Dose 1—2 tabs or caps PO q4-6h PRN i in renal/hepatic impair 4 g/24 h APAP max Caution [C, D, +] Alcoholic liver Dz Contra G6PD deficiency Disp Caps, Liq, tabs SE Drowsiness, dizziness, hangover effect Interactions T Effects OF benzodiazepines, opiate analgesics, sedatives/hypnotics, EtOH, methylphenidate hydrochloride i effects OF MAOIs, TCAs, corticosteroids, theophylline, OCPs, BBs, doxycycline EMS See Acetaminophen may impair coordination, monitor for depression concurrent EtOH use T CNS depression butalbital is habit forming... 

Zang et al [140] reported the liver protective effects of the saponins isolated from A. membranaceus and A. sieversianus against chemical injury induced by CCU, D-galactosamine and acetaminophen in mice. In all cases there were positive activities and the saponins inhibited the rise in SGPT levels, decreased the malondialdehyde (MDA) content and increased the glutathione reduced (GSH) concentration in mouse liver. The same compounds were also evaluated in cultured rat hepatocytes, and the results indicated that the activity may be due to to the antioxidative activity of the saponins, since the content of liver protein in treated mice was more than the control. Moreover, in all treated mice, the level of hepatic microsomal cytochrome P-450 was increased. The liver metabolism and immunoregulating action produced by saponins may be also involved in their hepato-protective effects. Similar results were obtained by Zhang et al [141] when they studied the activity in vitro and... 

Although quercetin may stimulate UGT, it inhibits human hepatic sulfation of resveratrol, acetaminophen, dopamine, (-)-salbutamol, minoxidil, and paracetamol in vitro.69,98-101 This inhibition may be chemopreventive, as activation of some promutagens occurs via SULT reactions.68 However, SULT inhibition may also lead to the accumulation of some xenobiotics and possible toxicity. The magnitude of inhibition by quercetin of SULT appears dependent on the isoform because SULT1A3 is less affected than other isoforms, suggesting a tissue-dependent effect of quercetin.69... 

However, the effect of piperine on SULT and flavonoid status across the life cycle remains to be investigated. Induction of phase II metabolism appears to decrease the bioavailability and accelerate the excretion of flavonoids. For example, Siess et al.115 and Walle et al.116 reported flavones induced rat hepatic UGT activity in HepG2 and Caco-2 cells. This induction of UGT enhanced quercetin glucuronidation in Caco-2 cells. In addition to inducing UGT activity, the flavone chrysin inhibits hepatic SULT-mediated sulfation of acetaminophen and minoxidol." The impact of chrysin on the capacity of COMT action toward flavonoids has not been examined. Further, the effect of age on phase II modulation by piperine and chrysin has not been reported. Thus, information on the relationship between age and intake of flavonoids and other phytochemicals that also affect phase II metabolism is required. 

Nearly all NSAIDs have the potential to induce hepatic injury, although this effect has not been documented in the horse. In other species, hepatic injury associated with most NSAIDs is an idiosyncratic reaction with a low incidence of occurrence. The hepatotoxicity of carprofen in dogs, for example, was not observed until the NSAID was in widespread use in the USA (MacPhail et al 1998). The heptatoxicity of a few compounds, such as aspirin and acetaminophen (paracetamol), however, is a dose-dependent side-effect that is well described (Fry Seeff 1995). 

Much of the evidence, however, is based on prolonged plasma half-lives of drugs that are metabolized totally or mainly by hepatic micrasomal enzymes (e.g antipyrine, phenobarbital, acetaminophen). In evaluating the effect of age on drug metabolism, one must differentiate between normal" loss of enzymatic activity with aging and the effect of a disea.sed iiver from hepatitis, cirrhosis, etc., plus decreased renal function, becau.se much of the water-soluble conjugation products are excreted in the liver. 

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-... 

The packaging of the kava products was unavailable for identification purposes. Liver biopsy revealed active fulminant hepatitis with extensive necrosis and tests for viral hepatitis were negative. She underwent a successful liver transplantation and was able to return to normal activity upon recovery (34). Unfortunately, no information was provided indicating that acetaminophen toxicity had been ruled out, and the observed toxic effect could also have been associated with a large, undiagnosed acetaminophen ingestion. 

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