Tolerance of High-Dose Oral Amiodarone for Cardioversion of Atrial Flutter.

In atrial arrhythmias, amiodarone is usually given either intravenously for acute management, requiring in-hospital monitoring, or orally for chronic control, as doses given 60 times per half-life, requiring weeks to reach full effect. A high-risk, 245-kg male with heart failure exacerbated by atrial flutter was successfully cardioverted using an atypically large, 8000-mg oral amiodarone dose. The only adverse effect was transient sinus arrest, which did not require intervention, only 24 hours of inpatient monitoring. Amiodarone's unique pharmacokinetics, including its long elimination half-life and its extensive distribution into a large volume of adipose tissue, make high-dose oral amiodarone boluses a reasonable strategy for cardioversion of atrial arrhythmias.

En présence d'arythmie auriculaire, l'amiodarone est généralement administrée par voie intraveineuse dans la phase aiguë de la prise en charge, ce qui nécessite une surveillance du patient en milieu hospitalier, ou encore par voie orale dans le cadre d'un traitement au long cours à des doses représentant 60 fois la demi-vie, le plein effet du médicament n'étant obtenu qu'au bout de plusieurs semaines. Un homme de 245 kg à haut risque souffrant d'insuffisance cardiaque aggravée par un flutter auriculaire a subi avec succès une cardioversion médicamenteuse faisant appel à une dose exceptionnellement élevée d'amiodarone ­ 8000 mg ­ administrée par voie orale. Le seul effet indésirable a été une pause sinusale n'ayant pas nécessité d'intervention, seulement 24 heures de surveillance en milieu hospitalier. Vu la pharmacocinétique particulière de l'amiodarone, notamment sa longue demi-vie d'élimination et sa distribution étendue dans un grand volume de tissu adipeux, l'administration perorale de ce médicament en dose de charge constitue une stratégie raisonnable de cardioversion en cas d'arythmie auriculaire.

A liquid chromatography-mass spectrometry method for nicotine and cotinine; utility in screening tobacco exposure in patients taking amiodarone.

A liquid chromatographic mass spectrometric (LC-MS) assay for the quantification of nicotine and cotinine in human specimens was developed. Human serum and urine (100 µL) were subjected to liquid-liquid extraction. For glucuronidated cotinine, serum was alkalinized and hydrolyzed before extraction. The dried samples were reconstituted and run using gradient flow reverse-phase liquid chromatography with MS detection. The ions utilized for quantification of nicotine, cotinine and milrinone (internal standard) were 162.8, 176.9 and 211.9 m/z, respectively. The mean recoveries were over 80% for cotinine and nicotine with excellent linearity between nominal concentrations and peak area ratios, over a wide concentration range. The percentage coefficient of variation and mean error of the inter- and intra-day validations were <15% for nicotine and cotinine. Analysis of serum from cardiac patients receiving amiodarone suggested that a number of patients were either active smokers or exposed to second-hand smoke. Significant concentrations of nicotine and cotinine were measured in the urine of a known smoking volunteer. The method was highly specific, sensitive and applicable as a tool in detecting and monitoring the passive exposure to tobacco smoke using small specimen volumes (0.1 mL).

Influence of peroxisome proliferator-activated receptor-alpha (PPARα) activity on adverse effects associated with amiodarone exposure in mice.

Although amiodarone is the most effective antiarrhythmic agent currently available, concerns regarding adverse effects, including liver, lung and thyroid toxicity, often limit its use. Previously, we reported that amiodarone-induced hepatic steatosis in mice was associated with an upregulation of target genes modulated by peroxisome proliferator-activated receptor-alpha (PPARα). Because amiodarone does not directly stimulate PPARα, target gene induction may reflect a compensatory reaction countering some adverse effects of amiodarone. To test this, we examined co-treatment with the PPARα agonist, fenofibrate, and amiodarone in both PPARα(+/+) and PPARα(-/-) mice. Amiodarone treated PPARα(-/-) mice exhibited significantly greater weight loss and higher serum aspartate aminotransferase (AST) compared to PPARα(+/+) mice. Fenofibrate co-treatment reduced weight loss in amiodarone treated PPARα(-/-) mice, but not PPARα(+/+) mice. Fenofibrate stimulation of PPARα reduced serum amiodarone concentrations in normal mice. Serum amiodarone concentrations were higher in mice without PPARα expression given at 40-80 mg/kg amiodarone doses. These results are consistent with a protective influence of PPARα in reducing amiodarone-induced hepatic toxicity. In addition to PPARα-dependent effects, fenofibrate also demonstrated PPARα-independent actions that suggest a complex interaction modulating both hepatic lipid metabolism and amiodarone disposition. Further studies of the beneficial effect of fenofibrate and the interplay between lipid metabolism and amiodarone pharmacokinetics are required.

Treatment Decisions in Geriatric Cardiac Lymphoma Facilitated by Serial Cardiac Magnetic Resonance Imaging and Positron Emission Tomography.

A tumour encasing the right coronary was identified on computed tomography pulmonary embolism protocol in an 81-year-old man. Concerns regarding tolerability of chemotherapy in an octogenarian were addressed using cardiac magnetic resonance imaging to monitor a trial of modified-chemotherapy for his primary cardiac B-cell lymphoma. Residual activity on positron emission tomography computed tomography mandated consolidation with radiotherapy to achieve a tumor-free return to health. Despite advanced age, successful therapy in this, the oldest case of primary cardiac lymphoma reported, was facilitated by monitoring treatment effectiveness with advanced cardiac imaging and the use of standardized frailty scores in communicating his appropriate level of robustness for tolerating chemotherapy.

Une tumeur enveloppant l'artère coronaire droite a été décelée lors du protocole de tomodensitométrie à la recherche d'une embolie pulmonaire chez un homme de 81 ans. Les préoccupations relatives à la tolérance à la chimiothérapie chez un octogénaire ont été prises en considération lors de l'imagerie cardiaque par résonance magnétique pour surveiller l'essai d'une chimiothérapie modifiée de son lymphome cardiaque primitif à cellules B. L'activité résiduelle à la tomographie par émission de positons associée à la tomodensitométrie a rendu nécessaire la consolidation par radiothérapie pour un retour à la santé sans tumeur. En dépit de son âge avancé, la réussite du traitement de cet homme, le cas signalé le plus ancien de lymphome cardiaque primitif, a été facilitée par la surveillance de l'efficacité du traitement par une technique avancée d'imagerie cardiaque et l'utilisation des scores de fragilité standardisés pour connaître son degré de robustesse approprié pour tolérer la chimiothérapie.

Amiodarone hepatotoxicity.

Potential hepatotoxicity related to amiodarone therapy is often a concern when deciding whether to initiate or continue treatment with this medication. While mostly associated with long-term oral administration of the drug, toxicity has also been reported early during intravenous administration and months after discontinuation of therapy. In the majority of patients, it is discovered incidentally during routine testing of liver biochemistry and rarely do the hepatic effects develop into symptomatic liver injury or failure. Despite the widespread use of amiodarone, prospective clinical studies have been sparse and there has been little consensus among experts in the field regarding optimum monitoring for adverse effects in patients receiving this drug. In order to examine the current state of knowledge surrounding the incidence, pathogenesis and mechanism of liver effects associated with amiodarone, the existing literature was reviewed, with particular emphasis on clinical recommendations for monitoring.

Personalized Anticoagulation: Guided Apixaban Dose Adjustment to Compensate for Pharmacokinetic Abnormalities Related to Short-Bowel Syndrome.

A 45-year-old woman who required lifelong anticoagulation for recurrent thrombosis had her therapeutic choices limited by heparin-induced thrombocytopenia and abnormal pharmacokinetics (greatly reduced absorption) resulting from short gut syndrome from extensive gut resection after mesenteric thrombosis. As an alternative to inconvenient and expensive injections of fondaparinux, personalized dosing of a direct oral anticoagulant was sought using clinical pharmacology techniques. Enteral absorption was ascertained with small test doses of apixaban, and the ability of supraconventional doses to deliver effective concentrations was verified.

The use of amiodarone for in-hospital cardiac arrest at two tertiary care centres.

BACKGROUND: Although amiodarone significantly increases survival to hospital admission when used in resuscitation of out-of-hospital pulseless ventricular tachycardia and fibrillation, there are limited data on its utility for in-hospital arrests. OBJECTIVES: To determine whether the use of amiodarone, as recommended by the year 2000 American Heart Association Advanced Cardiac Life Support guidelines, improved survival following its introduction to the resuscitation algorithm at two tertiary care institutions. METHODS: Charts of 374 cardiac resuscitations were retrospectively studied at the two institutions. Basic survival outcomes and demographic data were recorded for cardiac arrests with ventricular tachyarrhythmias qualifying for administration of antiarrhythmic agents. RESULTS: Qualifying rhythms were present in 95 patients. Clinical uptake of amiodarone was limited. In the 36 patients who received amiodarone, survival of resuscitation was 67% versus 83% (P=0.07) in the 59 patients receiving only other antiarrhythmic agents (chiefly lidocaine [94%]), while survival to discharge was 36.1% and 55.9% (P=0.06) in these two groups, respectively. CONCLUSIONS: Following two years' experience with the introduction of intravenous amiodarone for resuscitation in the institutions, use was less than 50% and no clinically observable survival benefit could be documented. Possible explanations for the difference between this experience and that found in out-of-hospital resuscitation trials include differing patient populations and operator bias during resuscitation. These results should provoke other institutions to question whether amiodarone has improved survival of cardiac arrest under the conditions prevailing in their hospitals. A patient registry or prospective, randomized trial will be required to assess what parameters affect the success of intravenous amiodarone for resuscitation in-hospital.

Use of population modeling to define rational monitoring of amiodarone hepatic effects.

BACKGROUND: Amiodarone causes hepatotoxicity in experimental models, but in humans, the relationships between drug administration, serum concentrations, markers of liver function, and how to monitor for hepatotoxicity have not been well characterized. METHODS: An open-dose, prospective study collected serum amiodarone, desethylamiodarone, ALT, AST, lactate dehydrogenase (LDH), alkaline phosphatase, total bilirubin, and albumin concentrations over a 5-year period from 125 patients. Nonlinear mixed-effects modeling (NONMEM) was used to explore the relationship between markers of hepatotoxicity and concentrations of amiodarone and desethylamiodarone. RESULTS: No patients had clinical symptoms of hepatotoxicity during follow-up. The natural history of changes in hepatic makers showed ALT to have the strongest independent relationship to changes in serum amiodarone (r = 0.32, P <.001). An ALT greater than 3 times the upper limit of normal developed in only 8 patients (7%), with the earliest occurrence at 55 days of therapy. A mixed-effects model relating ALT elevation to serum amiodarone was improved by the addition of an effect compartment having an equilibration half-time of 87 days (r = 0.81, P <.001). The model predicts that 6% of patients will have an ALT greater than 3 times the upper limit of normal if amiodarone concentrations are maintained at less than 2.5 mg/L, and virtually no patients will have such ALT elevations if amiodarone concentrations are maintained at less than 1.5 mg/L. CONCLUSIONS: Concentrations of amiodarone below a threshold of 1.5 mg/L are associated with a minimal risk of hepatotoxicity, whereas concentrations greater than 2.5 mg/L are associated with a greater than 6% risk of hepatotoxicity. There is significant hysteresis between changes in amiodarone concentration and the resulting change in ALT. The model suggests that monitoring ALT at baseline, 1, 3, and 6 months, and then semiannually would be an efficient strategy to detect amiodarone-induced hepatotoxicity.

Teaching application of clinical pharmacology skills using unusual observations from clozapine overdoses.

Massive drug overdoses provide a unique opportunity to observe human pharmacokinetic data not otherwise ethically available. They can also provide practical examples for teaching thoughtful application of the principles of clinical pharmacology. Following a case of clozapine overdose in which onset of toxicity was delayed by 72 hours, a probable explanation was found in an exploration of three cases with unusual concentration-time profiles and revealed unexpected implications for the management of clozapine overdoses. The authors systematically addressed the possible mechanisms proposed in the literature for an unusual plateau in concentrations observed in three clozapine overdoses. The effects that the most commonly suggested explanations (i.e., delayed absorption and saturated or impaired metabolism) would have on both clozapine and norclozapine concentrations were then modeled using the data available from those three cases to provide an objective illustration for comparison. This exercise was then used as a teaching seminar, leading students through the steps required to reach a logical explanation for the observed delayed toxicity and to consider the implications for therapy. Delayed absorption best predicted the sustained serum clozapine and norclozapine concentrations observed in three cases, and modeling suggests that much of the drug remains in the gut, available for absorption for days following an overdose. As a seminar, the exercise provides students with a practical example of the value of systematically ruling out possible explanations by considering what effects various pharmacokinetic alterations would have on observed data. Absorption following massive clozapine overdose appears fundamentally different from that with conventional dosing. This suggests a potential for delayed or prolonged toxicity, extending well beyond the time frame predicted by its half-life, unless aggressive and sustained efforts are applied to remove clozapine from the gut. Data from drug overdoses provide opportunities to explore unusual aspects of pharmacokinetics, better understand future overdoses of the same agent, and present excellent material for teaching. A seminar illustrating the role that thoughtful application of pharmacologic principles had in addressing this case is now used to introduce the clinical aspects of pharmacology to students at our institutions.

Delayed recovery associated with persistent serum concentrations after clozapine overdose.

Experience with managing overdoses of the atypical antipsychotic agent, clozapine, has been limited. A 20-year-old woman, who presented 6 h after ingesting 3500 mg of clozapine, had an unexpectedly prolonged duration of tachycardia and somnolence. Successful recovery followed management with supportive measures for several days in the intensive care unit. However, the duration of symptoms greatly exceeded that predicted by the published 12-h half-life of clozapine and was associated with an unexplained persistence of serum clozapine concentrations. Recovery with normalization of autonomic function occurred only after serum clozapine began to decline again after a 4-day plateau, as revealed by serum monitoring. Similar observations have been reported in two other cases. In overdose, clozapine may not behave as predicted by its published pharmacokinetics. Persistent serum drug concentrations may prolong the period of intensive care, suggesting that aggressive measures to remove clozapine from the gut at the time of overdose may be warranted.