Acetaminophen; Butalbital; Caffeine Adverse Reactions
- abdominal pain
- acneiform rash
- acute generalized exanthematous pustulosis (AGEP)
- agranulocytosis
- anaphylactic shock
- anaphylactoid reactions
- anemia
- angioedema
- anorexia
- anxiety
- confusion
- constipation
- contact dermatitis
- diarrhea
- dizziness
- drowsiness
- edema
- elevated hepatic enzymes
- encephalopathy
- erythema
- exfoliative dermatitis
- fever
- headache
- hemolysis
- hemolytic anemia
- hepatic necrosis
- hypoprothrombinemia
- impotence
- insomnia
- interstitial nephritis
- jaundice
- lethargy
- libido decrease
- maculopapular rash
- methemoglobinemia
- miosis
- mydriasis
- nausea/vomiting
- neutropenia
- nystagmus
- osteopenia
- palpitations
- pancytopenia
- photosensitivity
- polyuria
- pruritus
- ptosis
- purpura
- rash (unspecified)
- renal failure (unspecified)
- renal papillary necrosis
- renal tubular necrosis
- respiratory depression
- sinus tachycardia
- thrombocytopenia
- thrombocytosis
- tolerance
- toxic epidermal necrolysis
- tremor
- urticaria
- withdrawal
Acetaminophen; Butalbital; Caffeine Adverse Reactions
NOTE: This monograph discusses the use of acetaminophen; butalbital; caffeine combination products. Clinicians may wish to consult the individual monographs for more information about the adverse effects of each agent.
Acetaminophen can be hepatotoxic. In most cases, acetaminophen-induced hepatotoxicity occurs as a result of an acute overdose; however, moderately excessive doses, if taken chronically, may also produce hepatotoxicity. 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 of ingestion of toxic doses. Elevated hepatic enzymes and hypoprothrombinemia are also seen with acetaminophen overdose. Both cimetidine and ethanol can affect the severity of acetaminophen-induced hepatotoxicity (see Drug Interactions). The exact incidence of acetaminophen-induced hepatotoxicity seen with acetaminophen; butalbital; caffeine is not known.
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.
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. Other hematologic reactions reported with acetaminophen include agranulocytosis, neutropenia, thrombocytopenia, thrombocytosis, and pancytopenia. 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. Agranulocytosis, thrombocytosis, and pancytopenia have only been documented in the literature after acetaminophen overdose. Blood dyscrasias can occur during therapy with barbiturates. Regular blood tests should be undertaken if barbiturates are to be used for long-term therapy. Symptoms such as unusual tiredness or weakness, unusual bleeding or bruising, and unexplained sore throat or elevated temperature should be investigated promptly.
GI effects, such as nausea/vomiting, diarrhea, and constipation, have been reported during therapy with acetaminophen; butalbital; caffeine combinations but generally are not severe.
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. 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. 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. 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. Dermatologic effects of barbiturates include photosensitivity, acneiform rash, and purpura. Discontinuation of the drug may not be sufficient to reverse cutaneous reactions because of the slow metabolism and excretion of butalbital.
Pharmacologic tolerance to the sedative/hypnotic affects of barbiturates including acetaminophen; butalbital; caffeine combinations may occur in some patients. Tolerance is the need for increasing doses to maintain effects. Typically, tolerance presents as a decrease in the duration of effects and can be managed by increasing the dose or frequency; however, dosage increases in patients receiving acetaminophen combination therapy will be limited by the total daily dose of acetaminophen. When increasing doses of analgesia are required causes may be multi-factorial including tolerance, progression of disease or psychologic distress.
Barbiturates can cause respiratory depression. Respiratory depression is more common in elderly or debilitated patients or when barbiturates are given with other agents which cause CNS depression. CNS-depressant effects, including drowsiness, dizziness, lethargy, headache, vertigo, severe depression, anxiety, and irritability, can develop during therapy with butalbital. Hypnotic doses produce residual sedation, mood distortions, and mental impairment. Patients undertaking activities requiring mental alertness should be warned of possible adverse effects. Geriatric patients may experience more reactions such as excitation, depression, or confusion. Adverse behavioral reactions can be seen in individuals with developmental disabilities. However, in the case of combination products with caffeine, the stimulatory effects of caffeine may counteract some, but possibly not all, of the depressive effects of butalbital.
Overuse of combination analgesics such as acetaminophen; butalbital; caffeine products by headache-prone patients frequently produces drug-induced rebound headache accompanied by dependence on symptomatic medication, tolerance (refractoriness to prophylactic medication), and withdrawal symptoms. In this case, overuse of acetaminophen; butalbital; caffeine products has been defined as taking 3 or more doses per day more often than 3 days per week. 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.
Caffeine is a CNS stimulant. Many adverse reactions to caffeine are an extension of caffeine’s pharmacologic actions. At therapeutic or nontoxic doses, caffeine can cause tremor, sinus tachycardia, and heightened attentiveness. Other adverse reactions include diarrhea, excitement, palpitations, insomnia, headache, and muscle twitches. After excessive doses, caffeine can cause considerable nausea/vomiting and anxiety. Cardiac arrhythmias, seizures, and delirium are possible after deliberate overdoses. A distinct caffeine withdrawal syndrome has been described. Patients who consume or receive caffeine daily for several weeks experience notable physical and psychiatric responses including lethargy, anxiety, dizziness, or headache.
Caffeine is a mild diuretic. Polyuria can occur.
Barbiturates, especially phenobarbital, can induce osteopenia, particularly with long-term use. Unusual weight loss, bone pain or tenderness, or muscle weakness should be investigated.
Ocular adverse reactions with barbiturates occur most commonly after chronic use or toxic doses. Miosis is seen most frequently, but mydriasis predominates during toxic states. Disturbances in ocular movement may be seen with weakness of the extraocular muscles and nystagmus. Ptosis has been reported after chronic use.
Barbiturates have been associated with sexual dysfunction. Primarily these effects have been impotence and libido decrease.
[ Last revised: 8/26/2005 9:55:00 PM ]
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