Hydrоxyureа (hydrоxycаrbаmide) [Drоxia, Siklos] OverviewGeneric / Trade Names: Hydroxyurea (Hydroxycarbamide) / Droxia, SiklosDrug Class: Antimetabolite; ribonucleotide reductase inhibitor; cytotoxic agentPrototype Example: Hydroxyurea Mechanism of ActionInhibits ribonucleotide reductase → ↓ deoxyribonucleotide synthesis → ↓ DNA synthesisCell-cycle specific (S phase) → impairs DNA replication in rapidly dividing cellsIn sickle cell disease: induces γ-globin gene expression → ↑ HbF (α2γ2) → ↓ HbS polymerization → ↓ sicklingImproves RBC survival and reduces endothelial adhesion PharmacokineticsAbsorption: Oral administrationMetabolism: Hepatic metabolism (partial)Elimination: Renal excretionClinical note: exposure-dependent toxicity (myelosuppression risk increases with accumulation) PharmacodynamicsOnset: Delayed in SCD (weeks to months for HbF increase)Duration: Sustained with continuous useTherapeutic Index: Narrow (dose-limiting bone marrow suppression) IndicationsMyeloproliferative neoplasms (MPNs): polycythemia vera; also used in CML (adjunct/selected cases)Solid tumors (historical/limited use): melanomaSickle cell disease: reduces vaso-occlusive crises, hemolysis, and hospitalization; improves survivalNot used for acute sickle crises due to delayed onset Adverse EffectsCommon: myelosuppression (neutropenia, anemia, thrombocytopenia) — boxed warningSerious: secondary malignancies (including leukemia) — boxed warningMechanism-based: cytotoxic DNA synthesis inhibition → bone marrow toxicityOther: hyperpigmentation, skin rash, nail changes Contraindications Pregnancy; breastfeeding (teratogenic and cytotoxic risk) Interactions Additive myelosuppression with other cytotoxic or marrow-suppressing agents Question: A 28-year-old woman with a history of sickle cell disease presents for routine follow-up. She reports fewer pain crises since starting a new medication several months ago. Laboratory studies show improved hemoglobin levels and increased fetal hemoglobin (HbF). The medication works by increasing HbF production, which reduces hemoglobin S polymerization. Which of the following is the primary mechanism by which this medication decreases vaso-occlusive crises?