Development of Acute Gout Secondary to Pyrazinamide in a Patient without a Prior History of Gout

Possible theophylline-amiodarone interaction TO THE EDITOR: Amiodarone is an antiarrhythmic drug that has been reported to interact with several drugs.• We present a case of a possible interaction between amiodarone and theophylline. An 86-year-old man (47 kg, nonsmoker) with a previous history of chronic obstructive pulmonary disease and atrial fibrillation was seen by the Home Care Unit of our hospital because of worsening dyspnea and development of nausea. He was receiving furosemide 40 mg/d, digoxin 0.25 mg/d five days per week, domperidone 10 mL tid, and sustained-release theophylline 300 mg bid chronically. His physical examination showed signs of biventricular failure, with an arrhythmic pulse rate of UO beats/min and respirations 28 breaths/min. A routine blood analysis revealed a creatinine of 111.4 JJ.moiiL (range 44.2-114.9), aspartate aminotransferase (AST) 25.6 X 104 kataiiL (range 16-64), alanine aminotransferase (ALT) 13.3 X lQ-8 kataliL (range 16. 7-66.8), alkaline phosphatase (AP) 592.8 X 10-1 kata!IL (range 164-459), total bilirubin 23.9 JJ.moiiL (range 3.4-20.5), and albumin 3.37 giL (range 3.5-5.0). His theophylline and digoxin serum concentrations (fluorescence polarization immunoanalysis, TDx, Abbott) obtained 12 and 24 hours after the last dose, in the middle of the week, were 93.24 JJ.moiiL (therapeutic range 55-110) and 3.07 nmoiiL (therapeutic range 0.6-2.8), respectively. Because of suspicion of digoxin toxicity, digoxin was discontinued. Two days later his nausea had improved, but he was still tachycardic (120 beats/min). Digoxin was reintroduced at half the initial dose, and amiodarone (600 mg/24 h) was also started. The rest of his medication was left unchanged. Nine days later, the patient's condition was stable without clinical data of worsening heart failure. However, his heart rate had slightly worsened (130 beats/min), he was nervous, and had hand tremors. Theophylline and digoxin concentrations measured at that time were 194.2 JJ.mol/L and 2.2 nmoi/L, respectively, leading to a suspicion of theophylline intoxication. This drug was withdrawn. His serum biochemistry that day was creatinine 97.2 JJ.moiiL, AST 32 x lQ-B kataiiL, ALT 13.3 X 10-1 katai/L, AP 571.1 X 104 kataiiL, bilirubin 18.8 JJ.moi/L, and albumin 3.5 g/L. Forty-eight hours later his pulse rate decreased to 90 beats/min and the signs and symptoms of xanthine intoxication had disappeared, and theophylline was reintroduced at a dose of 150 mg bid. Further evaluation was not possible because the patient suffered a cardiorespiratory arrest and died four days later. Theophylline is cleared in the liver and the process is hepatic blood flow-independent, relying on the intrinsic metabolic capacity of hepatocytes. As a consequence, different drugs can reduce theophylline's clearance through an inhibition of hepatic microsomal enzymatic activity.1 Amiodarone has been reported to behave in this way. 3,4 Mter the introduction of amiodarone, the theophylline serum concentration increased from 93.2 to 194.2 JJ.mol!L. A number of factors that could explain this were excluded. An acute hepatic dysfunction was ruled out by the normal or slightly altered hepatic function tests before and after the introduction of amiodarone. An important hemodynamic alteration would not be expected to modify the clearance of theophylline through an enzymatic dysfunction, as the metabolism of the drug is independent of hepatic blood flow and, thus, of hemodynamic status. The liver function tests again exclude this situation. Also, there was no clinical worsening of the patient's cardiac function after the introduction of amiodarone. Further, there was no evidence of changes in the patient's volume of distribution of xanthine intake. The drug was always given to the patient by the same sibling, so the possibility of irregular administration seems remote. The only other possible cause is an amiodarone-theophylline interaction; both the temporal relationship (similar to interactions with other drugs) and amiodarone 's capacity of inhibiting hepatic metabolism of other drugst.4 strengthen this impression. More reports are needed to confirm this interaction; in the meantime we suggest caution when using these drugs together, and monitoring theophylline serum concentrations in order to prevent the development of a(Jverse reactions.