Refractory coronary artery spasm associated with tacrolimus
After the diagnosis of medically intractable CAS was established, benidipine, diltiazem, and nicorandil were titrated to a dose that prevents ischemic attacks. Control of CAS was gradually achieved by decreasing the circulating level of tacrolimus; finally, the patient was free from ischemic attack. However, he developed toxic megacolon because of unresponsiveness to the conventional UC therapy and underwent subtotal colectomy and ileostomy. His postoperative course was unremarkable, and he was discharged after complete relief from symptoms.
Tacrolimus is a widely used immunosuppressive agent, but several cardiovascular adverse events have been reported 1. The mechanisms underlying vasoconstriction induced by tacrolimus are considered to be multifactorial. Tacrolimus binds to FK-binding protein (FKBP), and these complexes associate with calcineurin, preventing the downstream phosphatase activity of the Ca-dependent enzyme. As a consequence, they induce the expression of proinflammatory genes. FKBP binds to ryanodine receptors and tacrolimus increases intracellular calcium concentration. Tacrolimus-induced endothelial dysfunction also occurs because of decreased expression of endothelial nitric oxide synthase 2.
In the present patient, despite careful monitoring of tacrolimus concentrations, blood levels of tacrolimus exceeded 30 ng/ml. This could probably be attributed to its pharmacological interaction with nifedipine because tacrolimus and nifedipine are primarily metabolized by cytochrome P450 3A4 and 3A5 enzymes 3. The clinical handling of tacrolimus is challenging because of its narrow therapeutic window and multiple pharmacokinetic drug interactions. Therefore, reduction of its dose or careful monitoring of blood tacrolimus levels is essential to prevent cardiovascular adverse events. More importantly, administration of tacrolimus should be avoided in patients diagnosed with CAS.