Case Presentation:

A 32–year–old Asian woman with a variant of multiple sclerosis (MS) was admitted with pyelonephritis and sepsis. She was started on ciprofloxacin (Cipro) 400 mg IV Q12 hours and continued on her home medications including tizanidine (Zanaflex) 4 mg PO QD. The morning after her admission, cipro and tizanidine were co–administered followed an hour later by profound hypotension, bradycardia (Fig. 1) and hypoxemia. A “rapid response” was called and the patient was transferred to the ICU.

Discussion:

Tizanidine is a centrally acting skeletal muscle relaxant and one of few FDA approved anti–spastic medications. Unfortunately, it has a narrow therapeutic index and great interpersonal variation. Oral bioavailability is low due to its first pass metabolism principally by the Cytochrome P450 (CYP) 1A2 enzyme. Cipro, a common fluoroquinolone to treat pyelonephritis, is a potent and selective inhibitor of the CYP system thereby capable of potentiating the toxicity of tizanidine. Our literature search found limited clinical data on the interaction between these two drugs. The only published case series indicated that three out of eight MS patients in Japan receiving PO cipro while chronically on tizanidine immediately developed drowsiness, hypotension and bradycardia. Interestingly, our patient’s symptoms were triggered only once cipro and tizanidine were co–administered (Fig. 1). Pharmacokinetic studies showed that the toxicities of tizanidine were dose–dependent and occur around its maximum plasma concentration, approximately 1.5 hours after administration. In a small randomized, double–blind crossover study by Granfors, 10 healthy subjects on cipro 500 mg for 3 days were then given 4 mg of tizanidine 1 hour after the final dose of cipro. The total area of plasma concentration over time (AUC) and maximum plasma drug concentration of tizanidine were up 10 fold and 7 fold respectively compared to the control group. Half–life was not affected and all side effects resolved within 9 hours with heart rate rebounding before blood pressure.

Conclusions:

Upon transfer to the ICU, cipro and tizanidine were replaced by broad spectrum antibiotics. Norepinephrine was initiated and weaned off 10 hours later. Other causes for simultaneous hypotension and bradycardia (e.g., opiate overdose, adrenal insufficiency and seizure) were ruled out. Urine culture grew pan–sensitive E. coli and she was soon after discharged to complete 12 days of Bactrim. This case report highlights the danger of co–administering ciprofloxacin and tizanidine within a close time frame due to the inhibition of the CYP1A2 by cipro. This side effect is relatively short lived due to tizanidine’s short half–life. Co–administration of ciprofloxacin and tizanidine should be avoided.

Figure 1Heart rate (HR) and mean arterial pressure (MAP) since the admission to the ER. Her vitals from last office visit prior to this hospitalization was marked at far left for baseline comparison.