HYDRINE

Indications

• Chronic myeloid leukaemia
• Squamous cell carcinoma of the head and neck
• Sickle cell disease

Dosage

Children: For paediatric patients, refer to the BNF for Children for specific dosing recommendations.

Adults: The usual starting dose for adults is 15 mg/kg/day, which may be adjusted based on response and tolerance, with a maximum dose of 35 mg/kg/day.

Mechanism of action

Hydroxyurea inhibits DNA synthesis by acting as a ribonucleotide reductase inhibitor, which reduces the conversion of ribonucleotides and deoxyribonucleotides. This interference is particularly effective in cells with high proliferation rates. It has been shown to enhance the effects of irradiation on cancer cells by holding them in the G1 phase of the cell cycle, making them more susceptible to radiation damage, and by impairing the repair processes of cells damaged by irradiation.

Pharmacodynamics

The relationship between hydroxyurea concentration, the reduction of crisis rates in sickle cell disease, and the increase in fetal hemoglobin (HbF) levels remains unclear. However, it is known that increased levels of HbF can lead to reduced sickling and potentially decrease the frequency of vaso-occlusive crises.

Pharmacokinetics

Hydroxyurea is well absorbed following oral administration, with peak plasma concentrations typically reached within 1 to 4 hours. It is extensively metabolized in the liver, with a half-life ranging from 3 to 5 hours. Hydroxyurea is excreted primarily through the kidneys, and dosage adjustments may be necessary in patients with renal impairment.

Contra-indications

• Severe bone marrow depression
• Pregnancy
• Known hypersensitivity to hydroxyurea or any of its excipients

Adverse effects

• Myelosuppression
• Anemia
• Leukopenia
• Thrombocytopenia
• Gastrointestinal disturbances (nausea, vomiting, diarrhea)
• Dermatological reactions (rash, hyperpigmentation)
• Pulmonary toxicity

Interactions

• Concurrent use with other myelosuppressive agents may increase risk of bone marrow suppression
• Use with antiretroviral agents may affect efficacy

Precautions

• Monitor blood counts regularly due to risk of myelosuppression
• Use with caution in patients with renal impairment
• Consider potential embryotoxicity and teratogenicity in women of childbearing potential

Pregnancy

Hydroxyurea is contraindicated in pregnancy due to potential teratogenic effects.

Breast-feeding

Caution is advised when administering hydroxyurea to breastfeeding mothers; effects on the infant are unknown.

Storage

Store in a cool, dry place, away from light. Keep out of reach of children.

Formulations

• Capsules
• Tablets
• Oral solution

Mechanism of action

The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in rat and human tissue cultures 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. Hydroxyurea probably acts by decreasing the rate of conversion of ribonucleotides and deoxyribonucleotides. This effect is particularly apparent in cells with a high rate of proliferation. Particularly, hydroxyurea reduces the tyrosyl free radical at the active site of the M2 via a one-electron transfer reaction through the –NH2-OH moiety. Three mechanisms have been postulated for the potentiation of the therapeutic effects of irradiation by hydroxyurea on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea is lethal to normally radioresistant S-stage cells and holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells: it appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; there is no alteration of RNA and protein syntheses. Another proposed mechanism of action of hydroxyurea is the elevation of HbF concentrations in Sickle Cell Disease patients. HbF interferes with the polymerization of HbS (sickle haemoglobin) and thus impedes the sickling of red blood cell. Recently, hydroxyurea has shown to be associated with the generation of nitric oxide, suggesting that nitric oxide stimulates cyclic guanosine monophosphates (cGMP) production, which then activates a protein kinase and increases the production of HbF. Other known pharmacological effects of hydroxycarbamide which may contribute to its beneficial effects in Sickle Cell Disease include decrease of neutrophils, improved deformability of sickled cells, and altered adhesion of red blood cells to the endothelium. The exact mechanism of antineoplastic activity of hydroxyurea has not been fully determined. Some studies indicate that hydroxyurea interferes with the synthesis of DNA without interfering with the synthesis of RNA or protein. Although hydroxyurea may have multiple sites of action, it appears likely that the drug inhibits the incorporation of thymidine into DNA; in addition, it may directly damage DNA. Hydroxyurea can destroy the tyrosyl free radical that is formed as the catalytic center of ribonucleoside diphosphate reductase, the enzyme that catalyzes the reductive conversion of ribonucleotides to deoxyribonucleotides; this conversion is a critical and probably rate-limiting step in the synthesis of DNA. The drug is an S-phase inhibitor and may cause cells to arrest at the G1-S border, decrease the rate of cell progression into the S phase, and/or cause cells to accumulate in the S phase as a result of inhibiting DNA synthesis. Animal studies indicate that the cytotoxic effects of hydroxyurea are limited to those tissues with high rates of cellular proliferation and the effects are evident only in those cells that are actively synthesizing DNA. Hydroxyurea, a drug widely used in therapy of several human diseases, inhibits deoxynucleotide synthesis and, consequently, DNA synthesis by blocking the cellular enzyme ribonucleotide reductase. Hydroxyurea inhibits human immunodeficiency virus type 1 (HIV-1) DNA synthesis in activated peripheral blood lymphocytes by decreasing the amount of intracellular deoxynucleotides, thus suggesting that this drug has an antiviral effect. Hydroxyurea has now been shown to block HIV-1 replication in acutely infected primary human lymphocytes (quiescent and a

Pharmacodynamics

The correlation between hydroxyurea concentrations, reduction of crisis rate, and increase in HbF, is not known.