What is the mechanism of action of hydroxyurea?

From the Guidelines

Hydroxyurea works by inhibiting ribonucleotide reductase, increasing fetal hemoglobin production, and reducing inflammation and vascular occlusion, ultimately decreasing sickling of red blood cells and improving outcomes in sickle cell disease. The mechanism of action of hydroxyurea involves the inhibition of ribonucleotide reductase, an enzyme essential for DNA synthesis, which prevents cells from converting ribonucleotides to deoxyribonucleotides, the building blocks needed for DNA replication 1. As a result, hydroxyurea blocks cells in the S-phase of the cell cycle, preventing cell division and slowing the growth of rapidly dividing cells. In sickle cell disease, hydroxyurea also increases the production of fetal hemoglobin (HbF), which reduces the polymerization of sickle hemoglobin and decreases sickling of red blood cells 2.

Some key benefits of hydroxyurea include:

• Decreasing vaso-occlusive complications, including episodes of painful events and acute chest syndrome, hospitalizations, and need for transfusion 1
• Increasing total and fetal hemoglobin 1
• Reducing white blood cell counts and modifying the expression of adhesion molecules on blood cells, which helps decrease inflammation and vascular occlusion 2
• Improving health-related quality of life in people with HbSS or Sb0-thalassemia 1

The medication is typically dosed at 15-35 mg/kg/day orally, with adjustments based on blood counts and clinical response 2. Regular blood monitoring is essential during treatment to avoid excessive myelosuppression, as hydroxyurea can cause bone marrow suppression resulting in decreased production of all blood cell types 1, 2.

From the FDA Drug Label

The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described However, the reports of various studies in tissue culture in rats and humans lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein.

The mechanism of action of hydroxyurea is believed to be through the inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor. This means that hydroxyurea works by blocking the production of DNA, which is necessary for cell growth and division.

• Key points about the mechanism of action of hydroxyurea include:
  • Inhibition of DNA synthesis
  • Acting as a ribonucleotide reductase inhibitor
  • No interference with the synthesis of ribonucleic acid or protein 3

From the Research

Mechanism of Action of Hydroxyurea

• Hydroxyurea is an oral chemotherapeutic drug that ameliorates some of the clinical problems of sickle cell disease (SCD) by raising fetal haemoglobin (HbF) 4.
• It is a myelosuppressive agent that reduces the frequency of painful episodes in SCD patients by increasing the level of HbF and haemoglobin 5.
• Hydroxyurea has been shown to decrease the rate of acute chest syndrome (ACS) episodes and blood transfusions by approximately 50% in adults with SCD 5.
• In chronic myelogenous leukemia (CML), hydroxyurea induces cytogenetic responses with tolerable toxicity, making it an attractive agent for further study as a component of treatment strategies aimed at eradicating the Ph1+ population in CML 6.

Effects of Hydroxyurea on Sickle Cell Disease

• Hydroxyurea probably improves pain alteration and life-threatening illness in SCD patients, but there is no difference in death rates 4.
• It may improve measures of HbF and probably decreases neutrophil counts, but there are no consistent differences in terms of quality of life and adverse events 4.
• Hydroxyurea has been shown to reduce the frequency of pain episodes and other acute complications in adults and children with SCD of HbSS or HbSβºthal genotypes 4.

Side Effects and Safety of Hydroxyurea

• Common side effects of hydroxyurea include neutropenia, bone marrow suppression, elevation of hepatic enzymes, anorexia, nausea, vomiting, and infertility 5.
• Hydroxyurea has been associated with pulmonary toxicity, including hypersensitivity pneumonitis 7.
• The safety of hydroxyurea in pregnancy has been evaluated, and while the quality of evidence is low, it has been recommended that hydroxyurea be discontinued at least 3 months before conception 8. However, a systematic review of the literature found that pregnancy risks associated with hydroxyurea are lower than anticipated, and its use in pregnancy may be justified considering the significant risks associated with untreated conditions such as SCD 8.