Midodrine for the weaning of vasopressor infusions.

WHAT IS KNOWN AND OBJECTIVE: Midodrine, an orally available α1-agonist indicated for the treatment of orthostatic hypotension, has been used at our institution as an adjunctive treatment to provide haemodynamic support to facilitate intravenous (IV) vasopressor weaning. Limited published data exist for this off-label use; thus, the objective of this study was to evaluate outcomes in patients who received midodrine for IV vasopressor weaning compared to control patients. METHODS: This retrospective comparison included adult ICU patients admitted to our institution from January 2007 to March 2012. The primary outcome was the time to IV vasopressor discontinuation after midodrine initiation. Secondary outcomes included a comparison between midodrine and control patients of the time from IV vasopressor discontinuation to ICU discharge, hospital and ICU length of stay (LOS), and the number of ICU readmissions. RESULTS AND DISCUSSION: The analysis included 188 patients (94 midodrine and 94 control). Patients discontinued IV vasopressors a median of 1·2 days (IQR 0·5-2·8) after midodrine initiation. ICU discharge occurred sooner after IV vasopressor discontinuation (0·8 vs. 1·5 days, P = 0·01), and 96% of patients remained off IV vasopressors after midodrine treatment. Hospital LOS was longer in midodrine patients (P < 0·01), but there were no differences in ICU LOS or readmissions. Adverse event rates after midodrine use were consistent with those observed in other studies. WHAT IS NEW AND CONCLUSION: Midodrine may serve as a useful adjunct to wean IV vasopressors in difficult-to-wean patients. Further studies are needed to assess the efficacy and safety of midodrine for this indication.

Drug interactions with cisapride: clinical implications.

Cisapride, a prokinetic agent, has been used for the treatment of a number of gastrointestinal disorders, particularly gastro-oesophageal reflux disease in adults and children. Since 1993, 341 cases of ventricular arrhythmias, including 80 deaths, have been reported to the US Food and Drug Administration. Marketing of the drug has now been discontinued in the US; however, it is still available under a limited-access protocol. Knowledge of the risk factors for cisapride-associated arrhythmias will be essential for its continued use in those patients who meet the eligibility criteria. This review summarises the published literature on the pharmacokinetic and pharmacodynamic interactions of cisapride with concomitantly administered drugs, providing clinicians with practical recommendations for avoiding these potentially fatal events. Pharmacokinetic interactions with cisapride involve inhibition of cytochrome P450 (CYP) 3A4, the primary mode of elimination of cisapride, thereby increasing plasma concentrations of the drug. The macrolide antibacterials clarithromycin, erythromycin and troleandomycin are inhibitors of CYP3A4 and should not be used in conjunction with cisapride. Azithromycin is an alternative. Similarly, azole antifungal agents such as fluconazole, itraconazole and ketoconazole are CYP3A4 inhibitors and their concomitant use with cisapride should be avoided. Of the antidepressants nefazodone and fluvoxamine should be avoided with cisapride. Data with fluoxetine is controversial, we favour the avoidance of its use. Citalopram, paroxetine and sertraline are alternatives. The HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir inhibit CYP3A4. Clinical experience with cisapride is lacking but avoidance with all protease inhibitors is recommended, although saquinavir is thought to have clinically insignificant effects on CYP3A4. Delavirdine is also a CYP3A4 inhibitor and should be avoided with cisapride. We also recommend avoiding coadministration of cisapride with amiodarone, cimetidine (alternatives are famotidine, nizatidine, ranitidine or one of the proton pump inhibitors), diltiazem and verapamil (the dihydropyridine calcium antagonists are alternatives), grapefruit juice, isoniazid, metronidazole, quinine, quinupristin/dalfopristin and zileuton (montelukast is an alternative). Pharmacodynamic interactions with cisapride involve drugs that have the potential to have additive effects on the QT interval. We do not recommend use of cisapride with class Ia and III antiarrhythmic drugs or with adenosine, bepridil, cyclobenzaprine, droperidol, haloperidol, nifedipine (immediate release), phenothiazine antipsychotics, tricyclic and tetracyclic antidepressants or vasopressin. Vigilance is advised if anthracyclines, cotrimoxazole (trimethoprim-sulfamethoxazole), enflurane, halothane, isoflurane, pentamidine or probucol are used with cisapride. In addition, uncorrected electrolyte disturbances induced by diuretics may increase the risk of torsade de pointes. Patients receiving cisapride should be promptly treated for electrolyte disturbances.

Torsade de pointes resulting from the addition of droperidol to an existing cytochrome P450 drug interaction.

OBJECTIVE: To report a case of QT prolongation associated with concomitant cyclobenzaprine and fluoxetine administration followed by torsade de pointes potentiated by droperidol. CASE SUMMARY: A 59-year-old white woman who had been receiving long-term fluoxetine and cyclobenzaprine therapy was admitted for Achilles tendon repair. Baseline QTc was prolonged at 497 msec. Prior to surgery, the patient received droperidol, an agent known to prolong the QT interval. During surgery the patient developed torsade de pointes, which progressed into ventricular fibrillation. On postoperative day 1, after cyclobenzaprine discontinuation, the QTc decreased toward normal (440 msec). DISCUSSION: Cyclobenzaprine shares anticholinergic effects, tachycardia, and dysrhythmic potential with the tricyclic antidepressants (TCAs). Fluoxetine is a known inhibitor of the CYP2D6 isoenzyme (along with CYP3A4 and CYP2C) and has been shown to increase TCA serum concentrations. The combination of cyclobenzaprine and fluoxetine resulted in significant QT prolongation in our patient that progressed to torsade de pointes after preoperative droperidol administration. Resolution of QT abnormalities after cyclobenzaprine discontinuation provided further evidence of a drug-induced etiology. Other possible medical and drug-related causes of torsade de pointes are reviewed and ruled out. CONCLUSIONS: Clinicians should be aware of the dysrhythmic potential of cyclobenzaprine and fluoxetine, monitor for other cytochrome P450 inhibitors, and avoid concomitant drugs known to prolong the QT interval.

Update: clinically significant cytochrome P-450 drug interactions.

Recent technologies have resulted in an explosion of information concerning the cytochrome P-450 isoenzymes and increased awareness of life-threatening interactions with such commonly prescribed drugs as cisapride and some antihistamines. Knowledge of the substrates, inhibitors, and inducers of these enzymes assists in predicting clinically significant drug interactions. In addition to inhibition and induction, microsomal drug metabolism is affected by genetic polymorphisms, age, nutrition, hepatic disease, and endogenous chemicals. Of the more than 30 human isoenzymes identified to date, the major ones responsible for drug metabolism include CYP3A4, CYP2D6, CYP1A2, and the CYP2C subfamily.

Diltiazem-associated thrombocytopenia.

Nine days after starting diltiazem therapy for new-onset atrial fibrillation, a patient's platelet count had diminished to 61 x 10(3)/mm3, and 2 weeks later the nadir was reached at 23 x 10(3)/mm3. No hypersensitivity reaction otherwise was noted, and other hematologic values were unaffected. The patient's platelet counts were not affected by platelet transfusions. Bone marrow examination showed normal to increased numbers of megakaryocytes, suggesting peripheral destruction. After discontinuing diltiazem and administering high-dose immunoglobulin infusions, the platelet count returned to normal. This case suggests an immune-mediated cause for thrombocytopenia after exposure to diltiazem.

Pharmacokinetics of vancomycin in adult cystic fibrosis patients.

Although the depositions of many antibiotics are altered in cystic fibrosis patients, that of vancomycin has not been studied. To assess vancomycin pharmacokinetics, 10 adult cystic fibrosis patients were given a parenteral dose of vancomycin (15 mg/kg) during the first 72 h of hospitalization for acute bronchopulmonary exacerbation. Blood samples were obtained at 0, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 15, and 24 h. The mean (standard deviation) weight, measured creatinine clearance, and Taussig clinical score were 51 (13) kg, 130 (39) ml/min/1.73 m2, and 64 (13), respectively. Multicompartmental pharmacokinetic parameters were best described by a two-compartment model. The mean (standard deviation) volume of distribution, total body clearance, and terminal elimination rate constant were 0.58 (0.15) liter/kg, 91 (19) ml/min/1.73 m2, and 0.123 (0.05) h-1, respectively. These values were consistent with vancomycin pharmacokinetic parameters obtained in previous studies of healthy adult volunteers. Vancomycin dosages predicted by using a two-compartment Bayesian model were approximately 15 mg/kg every 8 to 12 h. There were poor correlations between clinical score or creatinine clearance and any pharmacokinetic parameter (r values of < 0.32). The coefficient of correlation between urine flow rate and total body clearance was 0.7 (P < 0.05). Adult cystic fibrosis patients exhibit a disposition of vancomycin similar to that exhibited by healthy adults, and thus cystic fibrosis does not alter vancomycin pharmacokinetics.