大家看完了，还是会继续用Tylenol。

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A metabolite of acetaminophen, N-acetyl-para-benzoquinoneimine (NAPQI), is hepatotoxic. The amount of NAPQI production and exposure is limited in patients with normal hepatic function that take recommended dosages (see Pharmacokinetics). Excessive acetaminophen exposure saturates the sulfation pathway and can lead to greater NAPQI exposure. Also, induction of the oxidative pathway by ethanol or other drugs may result in a greater fraction of the acetaminophen dose being converted to NAPQI (see Drug Interactions). Lastly, malnutrition and chronic ethanol use can cause depletion of glutathione and sulfate hepatic stores, which can result in greater NAPQI exposure. In most cases, acetaminophen hepatotoxicity occurs as a result of an acute overdose; however, moderately excessive doses, if taken chronically, can also produce hepatotoxicity. Furthermore, idiosyncratic reactions have been noted. Acetaminophen-induced hepatotoxicity is manifested as hepatic necrosis, jaundice, bleeding and encephalopathy. After acute overdose, 2 or 3 days pass before maximum liver damage becomes apparent. Nausea/vomiting, anorexia, and abdominal pain usually occur within 2—3 hours after ingestion of toxic doses. Elevated hepatic enzymes and hypoprothrombinemia are seen. GI bleeding can occur secondary to low prothrombin levels. Administration of intravenous vitamin K is recommended for hypoprothrombinemia due to acetaminophen overdosage. Recovery may occur within 5—10 days. Young children appear to be at less risk of developing hepatotoxicity, possibly because of an age-related difference in the metabolism of the drug. It has also been suggested that recent fasting is associated with hepatotoxicity in patients taking higher than recommended doses.[583] Prompt oral administration of N-acetylcysteine, which serves as a substitute sulfhydryl donor for glutathione, is the recommended treatment for an acute acetaminophen overdose if the ingested acetaminophen dose is at least 140 mg/kg or in other applicable situations, such as ongoing hepatic damage likely due to recent acetaminophen ingestion. Obtain immediate and daily serum transaminase concentrations. Serum acetaminophen concentrations that are obtained at least 4 hours after acetaminophen ingestion help predict toxicity; however, do not delay acetylcysteine administration for serum acetaminophen concentration results.

Acetaminophen can cause acute renal tubular necrosis and chronic analgesic nephropathy, which is characterized by interstitial nephritis and renal papillary necrosis, in patients receiving high doses (e.g., 2.5—10 g/day) chronically or after acute overdose. Acute renal failure (unspecified) may occur in 25—30% of patients secondary to liver dysfunction. Rarely, acute renal failure may occur without severe hepatic toxicity. The risk of renal complications appears to be higher in patients with alcoholism. Chronic acetaminophen use has been implicated as a contributing factor in the decline of renal function in patients with underlying renal disease, including diabetic nephropathy.[541]

Methemoglobinemia can occur after acute overdoses of acetaminophen and can lead to hemolysis thereby causing hemolytic anemia. This can result in cyanosis of the fingernails, skin, and mucosa. Children develop methemoglobinemia more readily than do adults. Slow intravenous administration of methylene blue is recommended for the treatment of methemoglobinemia above 30%.

Acetaminophen sulfate, a metabolite of acetaminophen, may cause immune-mediated thrombocytopenia. Two adults had improvement in their platelet counts from 45—50 x109/L to 165—325 x109/L within 7—10 days of acetaminophen discontinuation. The sera from each patient had antibodies against platelets in the presence of acetaminophen sulfate.[8205] Other hematologic reactions reported with acetaminophen include agranulocytosis, thrombocytosis, and pancytopenia. However, these events have only been documented in the literature after acetaminophen overdose. Symptoms such as unusual tiredness or weakness, unusual bleeding or bruising, and unexplained sore throat or fever should be investigated promptly.

A 17-year-old man with a history of hepatitis, agranulocytosis, desquamative dermatitis, and a febrile eruption after receiving acetaminophen with or without concurrent drugs had febrile exanthema; neutropenia; and increased C reactive protein, creatine phosphokinase (CPK), tumor necrosis factor-[alpha], interleukin-6, and interleukin-10 concentrations within 5 hours of an oral paracetamol 400 mg challenge. The eruption and fever lasted 36 hours. His total CPK concentration was 1747 U/L on day 1, 1268 U/L on day 2, and 252 U/L on day 13 after acetaminophen ingestion. The CPK MM concentration, found primarily in skeletal muscle, was 1236 (U/L) on day 2.[8206] Myocyte injury was also reported in a 15-year-old female. She developed fatal heart failure due to toxic myocarditis after an unspecified intentional overdose of acetaminophen.[8207]

A case of acquired purpura fulminans developed in a 32 year old woman who was instructed to take acetaminophen 1000 mg every 4—6 hours as needed for pain.[4443] The patient noted rapidly spreading purpuric lesions and edema. Her lesions were nonblanchable and enlarging, and she had multiple purplish-black hemorrhagic and necrotic areas. Purpura fulminans is usually associated with disseminated intravascular coagulation and can occur in patients with inherited or acquired deficiencies of the protein C anticoagulant pathway. The patient developed acquired protein C deficiency from alcohol-induced hepatotoxicity. Fibrin thrombi in the dermal blood vessels, a characteristic finding of purpura fulminans, were present. Discontinuation of alcohol and acetaminophen and administration of vitamin K, heparin, and a systemic antibiotic led to almost complete purpuric lesion and hepatotoxicity resolution in 6 days.

Hypersensitivity reactions to acetaminophen may be manifested by urticaria, erythema, generalized pruritus, rash (unspecified), maculopapular rash, and fever. Anaphylactic shock, angioedema, and anaphylactoid reactions have been rarely reported with acetaminophen. Toxic epidermal necrolysis (TEN) occurred in a 7 year old girl after she took 3 doses of acetaminophen 10 mg/kg.[4442] Twelve hours after the last dose, an erythematous rash appeared, which became generalized over the next few hours. The patient developed a fever, low blood pressure and an elevated erythrocyte sedimentation rate and liver function tests. A skin biopsy showed subepidermal blister formation with full-thickness necrolysis of the epidermis and a sparse upper dermal lymphocytic infiltrate. On rechallenge with 10 mg/kg given orally, fever, low blood pressure, and diffuse urticaria and erythema developed 30 minutes after acetaminophen ingestion. In addition to the case of TEN, 4 cases of allergic contact dermatitis (delayed hypersensitivity type) have been reported in the literature.[4444] [4445] Various reactions including generalized pruriginous micropapular eruption, facial edema, generalized pruriginous exanthem, exfoliative dermatitis, and generalized exanthema occurred within several hours after acetaminophen ingestion. Acetaminophen has also been associated with acute generalized exanthematous pustulosis (AGEP). The nonfollicular, pustular, erythematous rash starts suddenly, is associated with fever above 38 degrees C, and is distinct from pustular psoriasis, although biopsy results in each reveal spongiform subcorneal pustules. Drugs are the main cause of AGEP. A period of 2—3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional reexposure may cause a second episode within 2 days. Clinical presentation is diverse with cutaneous lesions beyond erythema and pustules present in half of the cases. For example, bullous lesions, edema, purpura, pruritus, and mucosal erosions are possible. The mean duration of the pustules is 9.7 days followed by an annular desquamation, as long as the causative drug or factor is discontinued. The physiopathological mechanisms of AGEP have not been determined but the pathological criteria of edema, leukocytoclastic vasculitis, eosinophil exocytosis, and keratinocyte focal necrosis are distinctive. Pustule confluence or very small pustules may lead a clinician to make an incorrect diagnosis of TEN, of drug-induced erythroderma, or of staphylococcal scalded skin syndrome.[4446]

Overuse of acetaminophen by headache-prone patients frequently produces drug-induced rebound headache accompanied by dependence on symptomatic medication, tolerance (refractoriness to prophylactic medication), and withdrawal symptoms. When increasing doses of analgesia are required, the cause may be multi-factorial, including tolerance, progression of disease or psychologic distress. Overuse of acetaminophen (i.e., simple analgesic) has been defined as taking 3 or more doses per day more often than 5 days per week.[4043] The frequency of use may be more important than the dose. Features of a rebound headache include morning headache, end-of-dosing interval headache, or headache improvement with discontinuation of overused medication. Stopping the symptomatic medication may result in a period of increased headache and then headache improvement. Analgesic overuse may be responsible for the transformation of episodic migraine or episodic tension headache into daily headache and may perpetuate the syndrome.[4043]