Ribonucleotide Reductase Inhibition

DRUG and COMMON INDICATIONS	MECHANISM OF ACTION	CLINICAL POINTS
Hydroxyurea Control of hyperleukocytosis in the setting of acute leukemias and CML Prevention of thrombosis and hyperleukocytosis in myeloproliferative neoplasms, including polycythemia vera and essential thrombocythemia Sickle cell anemia	Inhibits RNR, which is responsible for converting ribonucleotide diphosphates to deoxyribonucleotides, in particular, it targets the RNR-M2 subunit. In sickle cell disease, hydroxyurea increases hemoglobin F (HbF) via intermittent cytotoxic suppression of erythroid progenitors that affects kinetics of erythropoiesis leading to recruitment of erythroid progenitors with increased HbF levels. Free radical formation, iron chelation, activation of soluble guanylyl cyclase, and direct nitric oxide production are among other mechanisms of action for HbF induction by hydroxyurea	Oral tablet/capsule Doses titrated to changes in peripheral WBC count Well-tolerated Adverse events include myelosuppression (primarily leukopenia), nausea, dermatological disorders with long-term therapy (hyperpigmentation, maculopapular eruption, dry skin, foot ulcer), and mucocutaneous vasculitis with high doses

CML, chronic myeloid leukemia.