Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and bleeding

Few published reports have suggested a substantial interaction between cranberry juice and warfarin, although a definite link could not be established. We encountered a patient taking stable doses of warfarin who developed major bleeding and high INR soon after starting daily cranberry juice. No other identifiable reasons for the high INR were apparent. The patient resumed his usual dose of warfarin after stopping the juice. This case suggests a definite relationship between cranberry juice and warfarin.     

Rhabdomyolysis causing AV blockade due to possible atorvastatin,esomeprazole, and clarithromycin interaction

OBJECTIVE: To report rhabdomyolysis (RML) causing third-degree atrioventricular block secondary to a possible interaction between atorvastatin, esomeprazole, and clarithromycin. CASE SUMMARY: A 51-year-old white woman presented to the emergency department with severe weakness, near syncope, shortness of breath, and chest pain. On admission, her electrocardiogram demonstrated bradycardia (40 beats/min) and third-degree heart block. A creatine kinase (CK) level was >7000 U/L. Her medication history was significant for long-term use of atorvastatin (>1 y), a 6-week history of esomeprazole use, and three 500-mg doses of clarithromycin just prior to admission. Her symptoms of weakness, shortness of breath, and chest pain coincided with starting the esomeprazole. During her hospitalization, the woman required pacemaker placement and her CK continued to rise to >40,000 U/L. Screening for other causes of RML, such as thyrotoxicosis, infection, and immune or hepatic diseases, was negative. She gradually improved over a 26-day hospitalization. DISCUSSION: This is a case of RML resulting in third-degree atrioventricular blockade. An objective causality assessment of the adverse reaction via the Naranjo probability scale revealed a probable association with atorvastatin and a possible association with esomeprazole and clarithromycin. The pharmacokinetic profiles of these agents suggest that a possible contribution to this reaction was P-glycoprotein (PGP) inhibition by esomeprazole altering atorvastatin's normally significant first-pass clearance. CONCLUSIONS: PGP drug interactions with atorvastatin and other hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) may be associated with unreported risks for RML. Further investigation into PGP impact on HMG-CoA appears warranted.     

Digoxin disposition kinetics in dogs before and during azotemia

The purpose of this study was to evaluate the disposition kinetics of digoxin after the administration of a single intravenous dose to the same dogs before and during azotemia. The digoxin plasma concentration-time data were fitted to a multicompartment model using nonlinear regression analysis. During azotemia, the biological half-life of digoxin was prolonged in six of seven dogs, while digoxin renal clearance, body clearance and apparent volume of distribution were significantly decreased. There was a corresponding increase in the apparent volume of the "central" compartment of digoxin. Approximately 45% of a digoxin dose was excreted by the kidney in these animals indicating a substantial nonrenal component to digoxin elimination in the dog. This nonrenal elimination did not change during azotemia, despite a decrease in renal clearance by 61%.     

Inhibition by ranitidine of acetaminophen conjugation and its possible role in ranitidine potentiation of acetaminophen-induced hepatotoxicity

Pretreatment with ranitidine (RA) potentiates the hepatotoxicity of acetaminophen (APAP) in male Fischer 344 rats. The present studies were undertaken to investigate the role of APAP metabolism in this potentiation. Administration of RA (50 mg/kg p.o.) to male Fischer 344 rats 30 min before [3H]APAP (750 mg/kg p.o.) increased the plasma concentrations of acetaminophen at 2 hr (193%) and 4 hr (277%) after APAP. Covalent binding of [3H]APAP-related material to hepatic macromolecules in RA-pretreated animals was similar to APAP alone values up to 12 hr after treatment; however, 24 hr after APAP, binding in the RA-pretreated animals was twice that observed in animals given [3H]APAP alone. Urinary excretion (0-24 hr) of APAP and APAP glucuronide were reduced in ranitidine-pretreated animals to 64 and 66% of control, respectively, indicating that in vivo RA altered APAP conjugation with glucuronic acid. APAP uridine diphosphoglucuronyltransferase activity in rat hepatic microsomes was competitively inhibited by RA (0.1-2 mM). The Ki apparent for RA inhibition of APAP uridine diphosphoglucuronyltransferase was 0.04 mM. In contrast, neither APAP nor 4-nitrophenol sulfotransferase activity in rat hepatic cytosol was inhibited by RA at concentrations up to 5 mM. Together, these results support the suggestion that RA-mediated alterations of APAP conjugation may explain the potentiation of APAP-induced hepatotoxicity by RA in rats.     

Verapamil toxicity resulting from a probable interaction with telithromycin

OBJECTIVE: To report a case of hypotension and bradyarrhythmia caused by verapamil toxicity in a patient prescribed telithromycin. CASE SUMMARY: A 76-year-old white woman receiving verapamil 180 mg/day for hypertension experienced a sudden onset of shortness of breath and weakness and was found to be profoundly hypotensive and bradycardic, with a systolic blood pressure of 50-60 mm Hg and a heart rate of 30 beats/min. She had been taking telithromycin 800 mg/day for 2 days previously for acute sinusitis. The patient was treated with crystalloids, vasopressors, and transvenous pacing. Approximately 72 hours after admission, her blood pressure and heart rate rapidly returned to normal, and she was discharged several days later. DISCUSSION: Telithromycin is a known substrate of the CYP3A4 system, and several pharmacokinetic interactions can occur by displacement of other drugs from this system. Verapamil is metabolized through several cytochrome P450 isoenzyme systems. Although there are no previous reports of an interaction between these drugs, other possible causes for the patient's symptoms were excluded and the diagnosis of a probable interaction between verapamil and telithromycin leading to verapamil toxicity was made. CONCLUSIONS: Telithromycin is a ketolide antibiotic approved for treatment of respiratory tract infections and acute sinusitis. The potential for clinically significant drug interactions should be considered before using this agent, especially in patients taking other drugs that are metabolized through the CYP3A system. Caution should be exercised when considering the use of this antibiotic in patients receiving verapamil.